Obituary

William C. Koller, MD, PhD

19452005

William C. Koller died unexpectedly on October 3, 2005, in Chapel Hill, North Carolina,
while this volume, which he was co-editing, was in preparation. Bill was born in Milwau-
kee on July 12, 1945, where he graduated with a BS degree from Marquette University
in1968. He went on to Northwestern University in Chicago, where he received a Masters
degree in pharmacology in 1971, a PhD in pharmacology in 1974, and an MD in 1976.
After completing his internship and residency at Rush Presbyterian St. Lukes Medical
Center in Chicago, he held positions at the Rush Medical College, University of Illinois,
Chicago VA, Hines VA, and Loyola University. In 1987, he was appointed Professor
and Chairman of Neurology at the University of Kansas Medical Center, where he
remained until 1999, when he moved to the University of Miami and became the National
Research Director for the National Parkinson Foundation. He subsequently moved on to direct the Movement Dis-
orders clinical program at the Mount Sinai Medical Center in New York, and then to the University of North Car-
olina, where he laid the foundation for yet another superb clinical and academic program.
Bill was a world-renowned neurologist who specialized in Parkinsons disease, essential tremor and related
disorders. He published more than 270 peer-reviewed manuscripts, over 160 review papers and numerous books.
His research interests included the epidemiology and experimental therapeutics of parkinsonism and essential
tremor, and his work contributed enormously to the current treatment of these disorders. His collaborations were
worldwide and many current experts in movement disorders worked with him at one time or another. He was
a Fellow of the American Academy of Neurology, Treasurer of the Movement Disorder Society (19992000),
Executive Board Member of the Parkinson Study Group (19961999), President of WE MOVE (20012002),
a founding member of the Tremor Research Group and founder of the International Tremor Foundation.
Dr. Koller will be especially remembered for his humor, warmth and the youthful vigor and enthusiasm that he
brought to his work. He was the consummate physician, befriending many of his patients who were encouraged to
call him on his cell phone at any time. Whether lecturing in South America, fishing on the boat he shared with
several colleagues, traveling with one of his sons to an international meeting or seeing patients in the clinic, Bills
smile and the sparkle in his eye endeared him to all who knew him. The movement disorders community has lost
a valued colleague, mentor and friend. He is survived by his wife and three sons.

Kelly Lyons
Matthew B. Stern

Photo courtesy of Professor Lindsey and

the European Parkinsons Disease Association.
 Foreword

The Handbook of Clinical Neurology was started by Pierre Vinken and George Bruyn in the 1960s and continued
under their stewardship until the second series concluded in 2002. This is the fifth volume in the new (third) ser-
ies, for which we have assumed editorial responsibility. The series covers advances in clinical neurology and the
neurosciences and includes a number of new topics. In order to provide insight to physiological and pathogenic
mechanisms and a basis for new therapeutic strategies for neurological disorders, we have specifically ensured
that the neurobiological aspects of the nervous system in health and disease are covered. During the last quar-
ter-century, dramatic advances in the clinical and basic neurosciences have occurred, and those findings related
to the subject matter of individual volumes are emphasized in them. The series will be available electronically
on Elseviers Science Direct site, as well as in print form. It is our hope that this will make it more accessible
to readers and also facilitate searches for specific information.
The present volume deals with Parkinsons disease and related disorders. This group of disorders constitutes
one of the most common of neurodegenerative disorders and is assuming even greater importance with the aging
of the population in developed countries. The volume has been edited by Professor William Koller (USA) and
Professor Eldad Melamed (Israel). It is with particular sadness that we must record the sudden and untimely death
of Professor Koller while the volume was coming to fruition. An experienced clinician, neuroscientist, author and
editor, he was a friend of many of the contributors to this volume, as well as of the series editors, and we shall
greatly miss him. It is our hope that he would have been proud of this volume, which he did so much to craft.
As series editors, we reviewed all of the chapters in the volume and made suggestions for improvement, but we
were delighted that the volume editors had produced such a scholarly and comprehensive account of the parkin-
sonian disorders, which should appeal to clinicians and neuroscientists alike. When the Handbook series was
initiated in the 1960s, understanding of these disorders was poor, any genetic basis of them was speculative, sev-
eral of the syndromes described here had not even been recognized, the prognosis was bleak and the therapeutic
options were almost unchanged since the late Victorian era. Advances in understanding of the biochemical back-
ground of parkinsonism during the 1960s and early 1970s led to dramatic pharmacological advances in the man-
agement of Parkinsons disease and profoundly altered the approach to other degenerative disorders of the nervous
system. The pace of advances in the field has continued, and the exciting new insights being gained have man-
dated a need for a thorough but critical appraisal of recent developments so that future investigative approaches
and therapeutic strategies are based on a solid foundation, the limits of our knowledge are clearly defined and
an account is provided for practitioners of the clinical features and management of the various neurological dis-
orders that present with parkinsonism.
It has been a source of great satisfaction to us that two such eminent colleagues as the late William Koller and
Professor Eldad Melamed agreed to serve as volume editors and have produced such an important compendium,
and we thank them and the contributing authors for all their efforts. We also thank the editorial staff of the pub-
lisher, Elsevier B.V., and especially Ms Lynn Watt and Mr Michael Parkinson in Edinburgh for overseeing all
stages in the preparation of this volume.

Michael J. Aminoff
Francois Boller
Dick F. Swaab
 Preface

James Parkinson described Parkinsons disease in his memorable Essay on the Shaking Palsy in 1817. Since then,
and particularly in recent years, there has been tremendous progress in our understanding of this complex and fas-
cinating neurological disorder. Briefly, we have learned that it is not only manifest by motor symptoms but also
that there is a whole range of non-motor features, including autonomic, psychiatric, cognitive and sensory impair-
ments. We now know how to distinguish better clinically between Parkinsons disease and the various parkinso-
nian syndromes. Likewise, it is now well established that in this disorder not only the substantia nigra but many
other central as well as peripheral neuronal cell populations are involved. Novel diagnostic imaging technologies
have become available. The nature of the Lewy body, the intracytoplasmic inclusion body that is a characteristic
element of Parkinsons disease pathology, is being unraveled.
There are new insights in the etiology and pathogenesis of this illness. Experimental models are now available
to understand better modes of neuronal cell death and help develop new therapeutic approaches. There has been
dramatic progress in discovering the genetic causes of dominant and recessive forms of hereditary Parkinsons dis-
ease with the identification of mutations in several genes. There is new knowledge in the intricate circuitry of the
basal ganglia and the physiology of the connections in the healthy state and in Parkinsons disease. There is more
understanding of the role of dopamine and other neurotransmitters in the control and regulation of movement by
the brain.
All of the above led to the development of many novel pharmacological treatments to improve the motor as
well as non-motor phenomena. There is better understanding of the mechanisms responsible for the complications
caused by long-term levodopa administration. Futuristic approaches using deep brain stimulation with electrodes
implanted in anatomically strategic central nervous system sites are now in common use to improve basic symp-
toms and the side-effects of levodopa therapy. Potentially effective neuroprotective strategies are in development
to modify and slow disease progression. Likewise, cell replacement therapy with stem cells offers great promise.
The best of experts in the field joined in this book and contributed chapters that make up an exciting coverage
of all the exhilarating developments in the many aspects of Parkinsons disease. This volume will certainly expand
the current knowledge of its readers and it is also hoped that it will stimulate further research that will eventually
lead to finding both the cause and the cure of this common and disabling neurological disorder.

William C. Koller
Eldad Melamed

Dr. William Koller died suddenly, unexpectedly and prematurely on October 3, 2005, before this volume went to
press. His loss is painful to all his friends and colleagues. His leadership, wisdom and expertise were the main
driving force behind the creation of this very special book. It is the belief of all involved that Dr. Koller would
have been pleased and proud of this volume in its final form. We hope it will be a tribute to his memory.
 List of contributors

L. Alvarez R. Bhidayasiri
Movement Disorders Unit, Centro Internacional The Parkinsons and Movement Disorder Institute,
de Restauracion Neurologica (CIREN), La Habana, Fountain Valley, CA, USA
Cuba
R. E. Breeze
M. Baker Department of Neurosurgery, University of Colorado
European Parkinsons Disease Association (EPDA), School of Medicine, Denver, CO, USA
Sevenoaks, Kent, UK
C. Brefel-Courbon
Y. Balash Department of Clinical Pharmacology, Clinical
Movement Disorders Unit, Department of Investigation Centre and Department of
Neurology, Tel-Aviv Sourasky Medical Center, Neurosciences, University Hospital, Toulouse, France
Tel-Aviv, Israel
D. J. Brooks
E. R. Bauminger MRC Clinical Sciences Centre and Division of
Racah Institute of Physics, Hebrew University, Neuroscience and Mental Health, Imperial College
Jerusalem, Israel London, Hammersmith Hospital, London, UK

M. F. Beal R. E. Burke
Department of Neurology and Neuroscience, Weill Departments of Neurology and Pathology, Columbia
Medical College of Cornell University, New York, University, New York, NY, USA
NY, USA
D. J. Burn
P. J. Bedard Institute of Ageing and Health, University of
Centre de Recherche en Neurosciences, CHUL, Newcastle upon Tyne, Newcastle upon Tyne, UK
Faculte de Medicine, Universite Laval, Quebec,
Canada M. G. Cersosimo
Program of Parkinsons Disease and Other Movement
A. Berardelli Disorders, Hospital de Clnicas, University of Buenos
Department of Neurological Sciences and Aires, Buenos Aires, Argentina
Neuromed Institute, Universita La Sapienza,
Rome, Italy A. Chade
The Parkinsons Institute, Sunnyvale, CA, USA
R. Betarbet
Department of Neurology, Emory University, Atlanta, K. R. Chaudhuri
GA, USA Regional Movement Disorders Unit, Kings College
Hospital, London, UK
K. P. Bhatia
Sobell Department of Motor Neuroscience Y. Chen
and Movement Disorders, Institute of Neurology, Morris K. Udall Parkinsons Disease Research Center
University College London, of Excellence, University of Kentucky College of
London, UK Medicine, Lexington, KY, USA
xii LIST OF CONTRIBUTORS
K. L. Chou
Department of Clinical Neurosciences, Brown
University Medical School and NeuroHealth
Parkinsons Disease and Movement Disorders Center,
Warwick, RI, USA
C. Colosimo
Dipartimento di Scienze Neurologiche, Universita La
Sapienza, Rome, Italy
Y. Compta
Neurology Service, Hospital Clinic, University of
Barcelona, Barcelona, Spain
E. Cubo
Unit of Neuroepidemiology, National Centre for
Epidemiology, Carlos III Institute of Health, Madrid,
Spain
B. Dass
Department of Neurological Sciences, Rush University
Medical Center, Chicago, IL, USA
M. R. DeLong
Department of Neurology, Emory University, Atlanta,
GA, USA
G. Deuschl
Department of Neurology, Christian-Albrechts-
University, Kiel, Germany
V. Dhawan
Regional Movement Disorders Unit, Kings College
Hospital, London, UK
Therese Di Paolo
Centre de Recherche en Endocrinologie Moleculaire
et Oncologique, CHUL, Faculte de Pharmacie,
Universite Laval, Quebec, Canada
R. Djaldetti
Department of Neurology, Rabin Medical Center,
Petah Tiqva and Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv, Israel
M. Emre
Department of Neurology, Behavioral Neurology and
Movement Disorders Unit, Istanbul Faculty of
Medicine, Istanbul University, Istanbul, Turkey
G. Fabbrini
Dipartimento di Scienze Neurologiche, Universita La
Sapienza, Rome, Italy
C. Fox
National Center for Voice and Speech, Denver, CO, USA
S. H. Fox
Toronto Western Hospital, Movement Disorders
Clinic, Division of Neurology, University of Toronto,
Toronto, Ontario, Canada
J. Frank
Department of Neurology, Mount Sinai Medical
Center, New York, NY, USA
C. R. Freed
University of Colorado School of Medicine, Denver,
CO, USA
A. Friedman
Department of Neurology, Medical University,
Warsaw, Poland
J. H. Friedman
Department of Clinical Neurosciences, Brown
University Medical School and NeuroHealth
Parkinsons Disease and Movement Disorders Center,
Warwick, RI, USA
V. S. C. Fung
Department of Neurology, Westmead Hospital,
Sydney, NSW, Australia
J. Galazka-Friedman
Faculty of Physics, Warsaw University of Technology,
Warsaw, Poland
C. Gallagher
Department of Neurobiology, University of
Wisconsin School of Medicine and Public Health,
Madison, WI, USA
D. M. Gash
Morris K. Udall Parkinsons Disease Research Center
of Excellence, University of Kentucky College of
Medicine, Lexington, KY, USA
G. Gerhardt
Morris K. Udall Parkinsons Disease Research Center
of Excellence, University of Kentucky College of
Medicine, Lexington, KY, USA
O. S. Gershanik
Department of Neurology, Centro Neurologico-Hospital
Frances, Laboratory of Experimental Parkinsonism,
ININFA-CONICET, Buenos Aires, Argentina
 LIST OF CONTRIBUTORS xiii
C. G. Goetz J. S. Hui
Department of Neurological Sciences, Rush University Department of Clinical Neurology, University of
Medical Center, Chicago, IL, USA Southern California, Los Angeles, CA, USA

J. G. Goldman
Department of Neurological Sciences, Rush University
Medical Center, Chicago, IL, USA
D. S. Goldstein
Clinical Neurocardiology Section, National Institute of
Neurological Disorders and Stroke, National Institutes
of Health, Bethesda, MD, USA
J.-M. Gracies
Department of Neurology, Mount Sinai Medical
Center, New York, NY, USA
J. Jankovic
Parkinsons Disease Center and Movement Disorders
Clinic, Department of Neurology, Baylor College of
Medicine, Houston, TX, USA
P. Jenner
Neurodegenerative Disease Research Center, School
of Health and Biomedical Sciences, Kings College,
London, UK
M. Kasten
The Parkinsons Institute, Sunnyvale, CA, USA

J. T. Greenamyre H. Kaufmann
Department of Neurology, Emory University, Atlanta, Department of Neurology, Mount Sinai School of
GA, USA Medicine, New York, NY, USA

J. Guridi W. C. Kollery
Department of Neurology and Neurosurgery, Department of Neurology, University of North
University Clinic and Medical School and Carolina, NC, USA
Neuroscience Division, University of Navarra and
CIMA, Pamplona, Spain A. D. Korczyn
Sieratzki Chair of Neurology, Tel-Aviv University
T. D. Halbig Medical School, Ramat-Aviv, Israel
Department of Neurology, Mount Sinai School of
Medicine, New York, NY, USA J. H. Kordower
Department of Neurological Sciences, Rush University
N. Hattori Medical Center, Chicago,
Department of Neurology, Juntendo University School IL, USA
of Medicine, Tokyo, Japan
V. Koukouni
Sobell Department of Motor Neuroscience and
M. A. Hely
Movement Disorders, Institute of Neurology,
Department of Neurology, Westmead Hospital,
University College London, London, UK
Sydney, NSW, Australia
A. E. Lang
C. Henchcliffe
Toronto Western Hospital, Movement Disorders
Department of Neurology and Neuroscience, Weill
Clinic, Division of Neurology, University of Toronto,
Medical College of Cornell University, New York,
Toronto, Ontario, Canada
NY, USA
M. Leehey
B. Hogl Department of Neurology, University of Colorado
Department of Neurology, Medical University of School of Medicine, Denver, CO, USA
Innsbruck, Innsbruck, Austria
A. J. Lees
X. Huang Reta Lila Weston Institute of Neurological Studies,
Departments of Neurology and Medicinal Chemistry, University College London, London, UK
University of North Carolina School of Medicine,
Chapel Hill, NC, USA
y
Deceased.
xiv LIST OF CONTRIBUTORS
F. A. Lenz Y. Mizuno
Department of Neurosurgery, Johns Hopkins Hospital, Department of Neurology, Juntendo University School
Baltimore, MD, USA of Medicine, Tokyo, Japan

N. Lev H. Mochizuki
Laboratory of Neuroscience and Department of Department of Neurology, Juntendo University School
Neurology, Rabin Medical Center, Petah-Tikva, of Medicine, Tokyo, Japan
Tel Aviv University, Tel Aviv, Israel
J. C. Moller
M. F. Lew Department of Neurology, Philipps-Universitat
Department of Neurology, University of Southern Marburg, Marburg, Germany
California, Los Angeles, CA, USA
J.-L. Montastruc
M. Lugassy Department of Clinical Pharmacology, Clinical
Department of Neurology, Mount Sinai Medical Investigation Center, University Hospital, Toulouse,
Center, New York, NY, USA France

R. B. Mailman
Departments of Psychiatry, Pharmacology, Neurology
and Medicinal Chemistry, University of North
Carolina School of Medicine, Chapel Hill, NC, USA
C. Marin
Laboratori de Neurologia Experimental, Fundacio
Clnic-Hospital Clnic, Institut dInvestigacions
Biomediques August Pi i Sunyer (IDIBAPS), Hospital
Clinic, Barcelona, Spain
P. Martnez-Martn Neuroscience Division, University of Navarra and
Unit of Neuroepidemiology, National Centre for
Epidemiology, Carlos III Institute of Health, Madrid,
Spain
I. McKeith
Institute for Ageing and Health, Newcastle University,
Newcastle upon Tyne, UK
K. St. P. McNaught
Department of Neurology, Mount Sinai School of
Medicine, New York, NY, USA
E. Melamed
Department of Neurology, Rabin Medical Center,
Petah Tiqva and Sackler Faculty of Medicine, Tel
Aviv University, Tel Aviv, Israel
M. Merello
Movement Disorders Section, Raul Carrea Institute for
Neurological Research, FLENI, Buenos Aires, Argentina
F. E. Micheli
Program of Parkinsons Disease and Other Movement
Disorders, Hospital de Clnicas, University of Buenos
Aires, Buenos Aires, Argentina
E. B. Montgomery Jr
National Primate Research Center, University of
Wisconsin-Madison, Madison, WI, USA
J. G. L. Morris
Department of Neurology, Westmead Hospital,
Sydney, NSW, Australia
J. A. Obeso
Department of Neurology and Neurosurgery,
University Clinic and Medical School and
CIMA, Pamplona, Spain
W. H. Oertel
Department of Neurology, Philipps-Universitat Marburg,
Marburg, Germany
D. Offen
Laboratory of Neuroscience and Department of
Neurology, Rabin Medical Center, Petah-Tikva, Tel
Aviv, University, Tel Aviv, Israel
F. Ory-Magne
Department of Neurosciences, University Hospital,
Toulouse, France
B. Owler
Department of Neurosurgery, Westmead Hospital,
Sydney, NSW, Australia
D. P. Perl
Mount Sinai School of Medicine, New York, NY, USA
R. F. Pfeiffer
Department of Neurology, University of Tennessee
Health Science Center, Memphis, TN, USA
 LIST OF CONTRIBUTORS
S. Przedborski
Departments of Neurology, Pathology and Cell
Biology, Columbia University, New York, NY, USA
J. M. Rabey
Department of Neurology, Assaf Harofeh Medical
Center, Zerifin, Israel
A. Rajput
Division of Neurology, Department of Medicine,
University of Saskatchewan, Saskatoon, SK, Canada
A. H. Rajput
Division of Neurology, Department of Medicine,
University of Saskatchewan, Saskatoon, SK, Canada
L. O. Ramig
Department of Speech, Language and Hearing
Sciences, University of Colorado-Boulder Department
of Speech, and National Center for Voice and Speech,
Denver, CO, USA
J. Rao
Department of Neurology, Louisiana State University
Health Sciences Center, New Orleans, LA, USA
O. Rascol
Department of Clinical Pharmacology, Clinical
Investigation Centre and Department of
Neurosciences, University Hospital, Toulouse, France
J. Rasmussen
Merstham Clinic, Redhill, Surrey, UK
W. Regragui
Department of Neurosciences, University Hospital,
Toulouse, France
P. F. Riederer
Clinical Neurochemistry, Department of
Psychiatry and Psychotherapy, National Parkinson
Foundation (USA) Center of Excellence Research
Laboratories, University of Wurzburg, Wurzburg,
Germany
M. C. Rodrguez-Oroz
Department of Neurology and Neurosurgery,
University Clinic and Medical School and
Neuroscience Division, University of Navarra and
CIMA, Pamplona, Spain
C. Rouillard
Centre de Recherche en Neurosciences, CHUL,
Faculte de Medicine, Universite Laval, Quebec,
Canada
xv
P. Samadi
Centre de Recherche en Endocrinologie Moleculaire et
Oncologie, CHUL, Faculte de Pharmacie, Universite
Laval, Quebec, Canada
S. Sapir
Department of Communication Sciences and Disorder,
Faculty of Social Welfare and Health Studies,
University of Haifa, Haifa, Israel
A. H. V. Schapira
University Department of Clinical Neurosciences,
Royal Free and University College Medical School,
University College London, London, UK
J. Shahed
Parkinsons Disease Center and Movement Disorders
Clinic, Baylor College of Medicine, Department of
Neurology, Houston, TX, USA
T. Slaoui
Department of Neurosciences, University Hospital,
Toulouse, France
M. B. Stern
Department of Neurology, University of Pennsylvania
School of Medicine, Philadelphia, PA, USA
F. Stocchi
Department of Neurology, IRCCS San Raffaele
Pisana, Rome, Italy
N. P. Stover
Department of Neurology, University of Alabama at
Birmingham, Birmingham, AL, USA
C. M. Tanner
The Parkinsons Institute, Sunnyvale, CA, USA
E. Tolosa
Neurology Service, Hospital Clinic, University of
Barcelona, Barcelona, Spain
C. Trenkwalder
Paracelsus Elena-Klinik, Center of Parkinsonism and
Movement Disorders, Kassel, and University of
Gottingen, Gottingen, Germany
D. D. Truong
The Parkinsons and Movement Disorder Institute,
Fountain Valley, CA, USA
W. Tse
Department of Neurology, Mount Sinai Medical
Center, New York, NY, USA
xvi LIST OF CONTRIBUTORS
J. Volkmann
Department of Neurology, Christian-Albrechts-
University, Kiel, Germany
H. C. Walker
Department of Neurology, University of Alabama at
Birmingham, Birmingham, AL, USA
R. H. Walker
Movement Disorders Clinic, Department of
Neurology, James J. Peters Veterans Affairs Medical
Center, Bronx, and Department of Neurology, Mount
Sinai School of Medicine, New York, NY, USA
R. L. Watts
Department of Neurology, University of Alabama at
Birmingham, Birmingham, AL, USA
D. Weintraub
Departments of Psychiatry and Neurology, University
of Pennsylvania School of Medicine, Philadelphia, PA,
USA
T. Wichmann
Department of Neurology and Yerkes National
Primate Center, Emory University,
Atlanta, GA, USA
M. B. H. Youdim
Department of Pharmacology, Technion-Bruce
Rappaport Faculty of Medicine, Eve Topf and NPF
Neurodegenerative Diseases Centers, Rappaport
Family Research Institute, Haifa, Israel
W. M. Zawada
Division of Clinical Pharmacology, Department of
Medicine, University of Colorado School of Medicine,
Denver, CO, USA
W. Zhou
Division of Clinical Pharmacology, Department of
Medicine, University of Colorado School of Medicine,
Denver, CO, USA
 Contents of Part II

Obituary vi
Foreword vii
Preface ix
List of contributors xi

SECTION 5 Treatment of Parkinsons disease

30. Physical therapy in Parkinsons disease 3

Jean-Michel Gracies, Winona Tse, Mara Lugassy and Judith Frank (New York, NY, USA)

31. Neuroprotection in Parkinsons disease: clinical trials 17

Fabrizio Stocchi (Rome, Italy)

32. Levodopa 31
Thomas D. H
albig and William C. Koller (New York, NY and Chapel Hill, NC, USA)

33. Dopamine agonists 73

Olivier Rascol, Tarik Slaoui, Wafa Regragui, Fabiene Ory-Magne,
Christine Brefel-Courbon and Jean-Louis Montastruc (Toulouse, France)

34. Monoamine oxidase A and B inhibitors in Parkinsons disease 93

Moussa B. H. Youdim and Peter F. Riederer (Haifa, Israel and W
urzburg, Germany)

35. Anticholinergic medications 121

Yaroslau Compta and Eduardo Tolosa (Barcelona, Spain)

36. Antiglutamatergic drugs in the treatment of Parkinsons disease 127

Mara Graciela Cers

osimo and Federico Eduardo Micheli (Buenos Aires, Argentina)

37. Investigational drugs 137

Carlo Colosimo and Giovanni Fabbrini (Rome, Italy)

38. The importance of patient groups and collaboration 151

Mary Baker and Jill Rasmussen (Sevenoaks and Redhill, UK)

SECTION 6 Complications of therapy

39. Motor and non-motor fluctuations 159

Susan H. Fox and Anthony E. Lang (Toronto, ON, Canada)
xviii CONTENTS
40. Levodopa-induced dyskinesias in Parkinsons disease 185
Jose A. Obeso, Marcelo Merello, Maria C. Rodrguez-Oroz, Concepci

o Marin, Jorge Guridi and
Lazaro Alvarez (Pamplona and Barcelona, Spain, Buenos Aires, Argentina and La Habana, Cuba)

41. Treatment-induced mental changes in Parkinsons disease 219

Kelvin L. Chou and Joseph H. Friedman (Warwick, RI, USA)

SECTION 7 Surgical treatment

42. Ablative surgery for the treatment of Parkinsons disease 243

Frederick A. Lenz (Baltimore, MD, USA)

43. Deep brain stimulation 261

J. Volkmann and G. Deuschl (Kiel, Germany)

44. Transplantation 279

Curt R. Freed, W. Michael Zawada, Maureen Leehey,
Wenbo Zhou and Robert E. Breeze (Denver, CO, USA)

45. Gene therapy approaches for the treatment of Parkinsons disease 291
Biplob Dass and Jeffrey H. Kordower (Chicago, IL, USA)

SECTION 8 Other parkinsonian syndromes

46. Multiple system atrophy 307

Ronald F. Pfeiffer (Memphis, TN, USA)

47. Progressive supranuclear palsy 327

David J. Burn and Andrew J. Lees (Newcastle upon Tyne and London, UK)

48. Corticobasal degeneration 351

Natividad P. Stover, Harrison C. Walker and Ray L. Watts (Birmingham, AL, USA)

49. Infectious basis to the pathogenesis of Parkinsons disease 373

V. Dhawan and K. Ray Chaudhuri (London, UK)

50. Toxic causes of parkinsonism 385

Nirit Lev, Eldad Melamed and Daniel Offen (Petah-Tikva and Tel-Aviv, Israel)

51. Drug-induced parkinsonism 399

Federico Eduardo Micheli and Mara Graciela Cers

osimo (Buenos Aires, Argentina)

52. Vascular parkinsonism 417

Yacov Balash and Amos D. Korczyn (Tel-Aviv and Ramat-Aviv, Israel)

53. Old age and Parkinsons disease 427

Alex Rajput and Ali H. Rajput (Saskatoon, SK, Canada)

54. Other degenerative processes 445

J. Carsten Moller and Wolfgang H. Oertel (Marburg, Germany)

55. Hydrocephalus and structural lesions 459

John G. L. Morris, Brian Owler, Mariese A. Hely and
Victor S. C. Fung (Sydney, NSW, Australia)
 CONTENTS xix
56. Calcification of the basal ganglia 479
Jennifer S. Hui and Mark F. Lew (Los Angeles, CA, USA)

57. Trauma and Parkinsons disease 487

Oscar S. Gershanik (Buenos Aires, Argentina)

58. Psychogenic parkinsonism 501

Vasiliki Koukouni and Kailash P. Bhatia (London, UK)

59. Parkinsonism and dystonia 507

Ruth H. Walker (Bornx and New York, NY, USA)

60. Dementia with Lewy bodies 531

Ian McKeith (Newcastle upon Tyne, UK)

61. Myoclonus and parkinsonism 549

Daniel D. Truong and Roongroj Bhidayasiri (Fountain Valley and Los Angeles, CA,
USA and Bangkok, Thailand)

Subject index 561

Color plate section 571
 Section 5

Treatment of Parkinsons disease

Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 30

Physical therapy in Parkinsons disease

JEAN-MICHEL GRACIES*, WINONA TSE, MARA LUGASSY AND JUDITH FRANK

Department of Neurology, Mount Sinai Medical Center, New York, NY, USA

The movement disturbances characteristic of Parkinsons
disease (PD), such as hypometria, akinesia, rigidity and
disturbed postural control, can significantly impact func-
tion and quality of life. Typical disabilities resulting from
these motor impairments range from dressing or rising
from a chair to maintaining balance and initiating gait
(Morris et al., 1995, Morris and Iansek, 1996). Since
the emergence of levodopa in the late 1960s, pharmaco-
logic therapy has been the primary strategy to manage
these symptoms and has been considered the gold-stan-
dard therapy. However, medication regimens are unable
to control the disease satisfactorily in the long term, as
dyskinesias, fluctuations of the medication efficacy and
cognitive difficulties invariably occur after a number of
years (Olanow, 2004). Over the past decades, there has
been increasing awareness as to the potential role of phy-
sical exercise and investigations have been carried out to
evaluate techniques that may alleviate functional disabil-
ities in patients with PD. Despite this rising interest, sur-
veys show that only 329% of PD patients regularly
consult with a paramedical therapist, such as a physical,
occupational or speech therapist (Deane et al., 2002).
A large variety of physical therapy methods have
been evaluated in PD. The approach to therapy in an
individual patient, however, may be governed at the
most basic level by the stage of the disease. In indivi-
duals with mild to moderate disease, who are ambula-
tory and have retained a certain degree of physical
independence, therapy may focus on the teaching of
exercises directly designed to delay or prevent the
aggravation of the motor impairment in PD, with the
goal of maintaining or even increasing functional
capacities. At the other end of the spectrum, in an indi-
vidual with compromised ambulation and significant
disability due to advanced PD, the therapeutic focus
may shift from the teaching of exercises to the
teaching of compensation strategies allowing preser-
vation of as much functional independence as possible.
These strategies include adaptation of the home envir-
onment, both to lessen the effects of motor impairment
and to optimize safety.
30.1. Physical exercises in mild to moderate
stages of Parkinsons disease
Most studies investigating physical exercises have been
carried out in subjects with mild to moderate PD, i.e. up
to Hoehn and Yahr stages 3 (Dietz et al., 1990, Kuroda
et al., 1992, Comella et al., 1994; Bond and Morris,
2000, Marchese et al., 2000, Hirsch et al., 2003).
30.1.1. Metabolic and neuroprotective effects
of physical exercise in Parkinsons disease
Exercise intensity may affect dopaminergic metabolism
in PD. In unmedicated PD patients, 1 hour of strenuous
walking reduces the dopamine transporter availability in
the medial striatum (caudate) and in the mesocortical
dopaminergic system as measured using positron emis-
sion tomography (PET) scans, which has been considered
highly suggestive of increased endogenous dopamine
release (Ouchi et al., 2001). In addition, exogenous levo-
dopa seems to be better absorbed during moderate-inten-
sity endurance exercise, as measured using maximal
levodopa concentrations in plasma (Reuter et al., 2000;
Poulton and Muir, 2005).
The beneficial effect of exercise on the dopamine
metabolism in PD patients has recently been supported
by a number of compelling studies in animal models.
Rats exposed to either 1-methyl-4-phenyl-1,2,3,6-tetrahy-
dropyridine (MPTP) or 6-hydroxydopamine (6-OHDA)
to induce behavioral and neurochemical loss analogous

*Correspondence to: Jean-Michel Gracies, Department of Neurology, Mount Sinai Medical Center, One Gustave L Levy Place,
Annenberg 2/Box 1052, New York, NY 10029-6574, USA. E-mail: jean-michel.gracies@mssm.edu, Tel: 1-(212)-241-8569,
Fax: 1-(212)-987-7363.
4 J. M. GRACIES ET AL.
to PD lesions that are then exercised show significant
sparing of striatal dopamine compared to lesioned ani-
mals that remain sedentary (Fisher et al., 2004; Poulton
and Muir, 2005). Further, one study showed that exercise
after MPTP exposure increases dopamine D2 transcript
expression and downregulates the striatal dopamine
transporter (Fisher et al., 2004). However, behavioral
effects of training were inconsistent in these studies
(Tillerson et al., 2003; Mabandla et al., 2004; Poulton
and Muir, 2005). Rodents with unilateral depletion of
striatal dopamine display a marked preferential use of
the ipsilateral forelimb. After casting of the unaf-
fected forelimb in unilaterally 6-OHDA-lesioned rats,
the forced use of the affected forelimb spares its func-
tion as well as the dopamine remaining in the lesioned
striatum (Faherty et al., 2005). There was a negative
correlation in this study between the time from lesion
to immobilization, i.e. to forced use and the degree of
behavioral and neurochemical sparing. This may sug-
gest the importance of initiating an exercise regimen
early in the course of PD.
Furthermore, two recent studies have shown that
exposing animals to an environment prompting exer-
cise and activity prior to MPTP lesion, or to unilateral
forced limb use prior to contralateral lesioning with
6-OHDA, may prevent the emergence of the beha-
vioral and neurochemical deficits that normally fol-
low the administration of 6-OHDA (Cohen et al.,
2003; Faherty et al., 2005). In one of these studies,
animals receiving a unilateral cast had an increase in
glial cell-line derived neurotrophic factor (GDNF) pro-
tein in the striatum corresponding to the contralateral
overused limb. The prevention of parkinsonian deficits
by prior exercise was suggested partly to involve
GDNF changes in the striatum (Cohen et al., 2003).
30.1.2. Training techniques
Several types of exercise techniques have been evalu-
ated with regard to their impact on motor deficits in
mild to moderate PD. Few studies have been con-
trolled and much of the evidence is anecdotal or relies
on open trials. The strongest line of evidence to date
supports the benefit of lower-limb resistance training
in PD patients, particularly for balance and gait.
30.1.2.1. Resistance training
Major goals of physical therapy in PD should be the
reduction of rigidity, the improvement of postural
control and the prevention of falls as most PD patients
experience balance disturbances and increased risk
of falls in the course of their illness (Koller et al.,
1989; Pelissier and Perennou, 2000; Ochala et al.,
2005). It has been shown that musculotendinous stiff-
ness decreases following strength training in healthy
elderly individuals (Ochala et al., 2005). In a recent
open-label study, 40 Hoehn and Yahr III PD patients
and 20 healthy age-matched controls underwent a
30-day program comprising a variety of physical
therapies including regular physical activity, aerobic
strengthening, muscle positioning and lengthening
exercises (Stankovic, 2004). Physical therapy resulted
in significant improvement in tandem stance, one-leg
stance, step test and external perturbation all tests
of balance in the PD group.
Important risk factors for falls in PD are the muscle
atrophy and the decrease in physical conditioning
that may result from activity reduction (Scandalis
et al., 2001). There is a proven relationship between
decreased lower-limb muscle strength and impaired
balance in PD, as muscle weakness in the lower extre-
mities may limit the ability to mount appropriate pos-
tural adjustments when balance is challenged (Toole
et al., 1996). A controlled study addressed the effects
of lower-limb resistance training in PD, in which
patients were randomized to two groups. The first
group underwent 30-minute sessions three times a
week for 10 weeks of standard balance rehabilitation
exercises, including practicing standing on foam and
weight-shifting exercises. The second group under-
went the same balance training and, in addition,
received tri-weekly high-intensity resistance training
sessions focusing on plantar flexion, as well as knee
extension and flexion. Subjects who received balance
training only increased their lower-extremity strength
(composite score from knee extensor, flexor and plan-
tar flexor strength) by 9%, whereas subjects who
underwent additional resistance training increased
their strength by 52%. Balance training only increased
the subjects ability to maintain balance. This effect
was significantly greater and lasted longer in the group
undergoing additional lower-limb resistance training
(Hirsch et al., 2003).
Improvement in lower-limb muscle strength in PD
may also improve gait. In an open protocol, 14 PD
patients and 6 normal controls underwent an 8-week
course of resistance training, twice a week, with
exercises including leg press, calf raise, leg curl,
leg extension and abdominal crunches. Lower-limb
strength and gait were assessed in the practically
defined levodopa off state (i.e. off medication for
at least 12 hours) before and after the training period,
showing gains in strength in the PD patients that were
similar to those of the control subjects and improve-
ment on quantitative measures of gait such as stride
length, gait velocity and postural angles (Scandalis
et al., 2001).
 PHYSICAL THERAPY IN PARKINSONS DISEASE
30.1.2.2. Attentional strategies and sensory cueing
It is a common clinical observation that increased
attention or effort may allow improvements of remark-
able magnitude in motor tasks performed by PD
patients (Muller et al., 1997). This observation has
contributed to the development of cueing, an increas-
ingly prevalent concept in the field of physical therapy
in PD, in which external visual or auditory cues are
used to enhance attention and thus performance. It
has been hypothesized that the basal ganglia, which
normally discharge in bursts during the preparation
of well-learned motor sequences, provide phasic cues
to the supplementary motor area, activating and deac-
tivating the cortical subunits corresponding to a given
motor sequence (Morris and Iansek, 1996). In PD
however, the internal cues provided by the basal gang-
lia are no longer appropriately supplied. Thus, restora-
tion of phasic activation of the premotor cortex might
be facilitated by external means.
30.1.2.2.1. Auditory cueing
Use of auditory cueing has gained popularity over the
past decade (Rubinstein et al., 2002). In the upper
limb, auditory cues for button-pressing tasks have
shown that added external auditory information dra-
matically reduces initiation and execution time and
improves motor sequencing (Georgiou et al., 1993;
Kritikos et al., 1995). Another study showed that a sin-
gle external auditory cue to start a movement was
associated with a more forceful, more efficient and
more stable movement than if the movement was
accomplished only when the patients were ready
(internal cue) (Ma et al., 2004).
Musical beats, metronomes and rhythmic clapping
have been used as cueing techniques to improve gait
in PD patients (Thaut et al., 1996; McIntosh et al.,
1997). The use of metronome stimulation has been
shown to reduce acutely the number of steps and the
time to complete a walking course, compared to uncued
walking in PD patients (Enzensberger et al., 1997).
A study of a 3-week home-based gait-training program
revealed that PD patients trained with rhythmic auditory
stimulation in the form of metronome pulsed patterns
embedded into the beat structure of music improved
gait velocity, stride length and step cadence compared
to subjects receiving gait training without rhythmic
auditory stimulation or no gait training at all (Thaut
et al., 1996). Additional research further indicated that
these gait improvements occur regardless of whether
the patient is on or off medication at the time of training
(McIntosh et al., 1997). The effects of auditory cueing
by metronome on gait may depend on the frequency
used for the metronome beat, which may have to be
5
slightly faster than the baseline walking cadence to be
efficacious. PD patients using such rhythmic cues set
at rates of 107.5 and 115% of their baseline walking
cadence are able to increase the cadence and mean
velocity of their gait correspondingly (Howe et al.,
2003; Suteerawattananon et al., 2004). In contrast, Cubo
and colleagues (2004) found that the use of the metro-
nome set at the baseline walking cadence slowed ambu-
lation and increased the total walking time without
having any significant effect on freezing. However,
the latter results were obtained in the on state, which
does not allow any conclusions as to the effects of such
treatment in the off state, when patients typically
experience the most slowness and freezing. Another
specific situation in which sensory cueing may not
be associated with functional improvements is that in
which patients initiate walking at their maximal speed.
Sensory cueing then interferes with movement speed
and performance, which suggests competition between
the external and internal signals of movement command
in situations in which strong internal signals may be
adequate to achieve optimal movement performance
(Dibble et al., 2004). In the clinical setting, auditory
cueing is most often used in the form of rhythmic audi-
tory stimulation during gait, in which patients pace their
walking to either a metronome beat or a rhythmic beat
embedded in music.
30.1.2.2.2. Combination of auditory cueing with
attentional strategies
Auditory cueing may also be involved in attentional
strategies such as the use of verbal instruction sets.
In one controlled study in PD, gait was analyzed dur-
ing trials of natural walking interspersed with rando-
mized conditions in which subjects were verbally
instructed to increase arm swing, or step size or walk-
ing speed. In addition to being able to improve any of
these variables in response to specific instructions,
hearing only one of these instructions was associated
with an improvement in the other gait variables as well
(Behrman et al., 1998). Conversely, giving an addi-
tional concurrent task (cognitive or an upper-limb
motor task) to a walking patient worsens gait in PD
as it may distract attention directed towards gait. This
is the situation of dual task, which is a classical cause
of movement deterioration in PD (Brown et al., 1993)
and more specifically of gait deterioration (Bond and
Morris, 2000; Hausdorff et al., 2003). Experimental
situations combining such dual tasks (reducing atten-
tion) with verbal instructions to focus on walking
(increasing attention) or on auditory cues tended to
reverse the deterioration and restore better walking
(Canning, 2005; Rochester et al., 2005).
6 J. M. GRACIES ET AL.
30.1.2.2.3. Visual cueing
Since classic experiments by Martin (Martin and
Hurwitz, 1962), a number of studies have shown that
stride length can be improved by visual cueing, in the
form of horizontal lines marked on the floor, over which
the patient is encouraged to step. In a series of experi-
ments, Morris et al. (1996) demonstrated that PD patients
using such horizontal floor markers as visual cues were
able to normalize their stride length, velocity and
cadence, an effect that persisted for 2 hours after the
intervention. It was noted that although transverse lines
of a color contrasting with the floor and separated by
an appropriate width are effective for this purpose, zig-
zag lines or lines parallel to the walking direction are
not. These visual cues might function by supplying a
now deficient well-learned motor program with external
visual information on the appropriate stride length
(Rubinstein et al., 2002). Similar improvement in stride
length and gait velocity is possible using light devices
attached to the chest to provide a visual stimulus on the
floor over which the patient must step (Lewis et al.,
2000). However, such light devices increase attentional
demand and perceived effort of walking, which suggests
that static cues are more effective in improving gait
while minimizing effort. Finally, there are suggestions
that benefit from cueing techniques might be optimal in
earlier stages of the disease (Lewis et al., 2000).
30.1.2.2.4. Combination of visual cueing with
attentional strategies
Gait improvement also occurs when, instead of using
horizontal markers on the floor, an attentional strategy
is used with instructions to visualize the length of stride
that subjects should take while walking (Morris et al.,
1996). Whether gait is assisted by direct visual cueing
or by such attentional visualization strategy, the benefit
is reversed when patients are given additional tasks to
do while walking, distracting attention from the gait
(Morris et al., 1996). Thus, direct visual cues and visuali-
zation exercises may both function by focusing attention
on the gait, such that walking ceases to be a primarily
automatic task delegated to the deficient basal ganglia
(Morris et al., 1996).
30.1.2.2.5. Combination of visual and auditory cues
Suteerawattananon et al. (2004) have studied the effect
of combining visual and auditory cues to determine the
effect of such a combination on gait pattern in PD. In
this study the auditory cue consisted of a metronome
beat 25% faster than the subjects fastest gait cadence.
Brightly colored parallel lines placed along a walkway
at intervals equal to 40% of the subjects height served
as the visual cue. The auditory cueing significantly
improved cadence whereas the visual cue improved
stride length. However, the simultaneous use of visual
and auditory cues did not improve gait significantly
more than each cue alone.
30.1.2.3. Active appendicular and axial
mobilization, stretch
Axial mobility may affect function in PD. There is a
significant association between reduced axial rotation
and functional reach (maximal reach without taking a
step forward) independent of disease state (Schenkman
et al., 2000). A controlled study confirmed that physical
intervention targeted on improving spinal flexibility
improves functional reach in PD (Schenkman et al.,
1998). An open study suggested that active mobilization
exercises of the trunk and lower limbs improved trans-
fers (from supine to sitting and sitting to supine), supine
rolling and rising from a chair (Viliani et al., 1999).
It has been hypothesized that muscle stiffness alone
may be a factor of functional impairment in PD, particu-
larly in the lower limb with respect to shortened stride
length and altered gait pattern (Lewis et al., 2000).
Aggressive stretch programs might decrease muscle
stiffness. However, stretch alone as a therapy techni-
que has not been systematically evaluated as a method
to improve motor function in PD. In one controlled
study an improvement in rigidity was observed as
compared to baseline after a therapy program invol-
ving passive stretch as well as other motor tasks and
balance training. This effect had disappeared by 2
months after study completion, which suggests that
standard therapy programs should probably be contin-
ued in the long term, or at least repeated frequently
(Pacchetti et al., 2000).
30.1.2.4. Treadmill training
Treadmill training has been increasingly used in the
rehabilitation of patients with spinal cord injury, hemi-
paresis and other gait disorders (Hesse et al., 2003).
However, treadmill training may be expensive for some
patients and the specific literature on treadmill training
in PD must be analyzed with particular caution. Some
studies have recently suggested that treadmill training
might increase walking speed and stride length in PD
(Miyai et al., 2000, 2002; Pohl et al., 2003). However,
although these studies compared treadmill with non-
treadmill training, they were not controlled for the walk-
ing speed used in the training. In particular the non-tread-
mill training did not involve specific requirements of gait
velocity, step cadence or stride length. Under these cir-
cumstances, the positive effects seen after treadmill use
may have been the effects of higher energy demands,
or a higher walking speed used on the treadmill training
 PHYSICAL THERAPY IN PARKINSONS DISEASE
(Miyai et al., 2000, 2002; Pohl et al., 2003). In a study
which did control for walking speed by having subjects
walk first on the ground and then on a treadmill set at
the same speed, both PD patients and age-matched con-
trols showed shorter stride lengths and higher stride fre-
quency in the treadmill condition (Zijlstra et al.,
1998). These effects were more pronounced in the
PD patients. This is consistent with previous findings
that, in healthy subjects, walking on a treadmill results
in smaller steps than when walking on the ground at
the same speed (Murray et al., 1985). This is particu-
larly relevant to the PD patient population, in which
decreased stride length and impaired stride length regu-
lation are fundamental characteristics (Morris et al.,
1996). Thus, the typical shortening of stride length in
PD may in fact be accentuated when walking on a
treadmill (Zijlstra et al., 1998).
30.1.3. Long-term effects of physical therapy
The exact duration of the effects of programs of physi-
cal exercise in PD remains unknown. Most studies on
physical therapy in PD have been open and had fol-
low-up periods of less than 8 weeks, making the long-
term persistence of beneficial effects difficult to deter-
mine (Deane et al., 2001). However, in one recent
open-label trial 20 PD patients followed a comprehen-
sive rehabilitation program three times a week for
20 weeks. Following the program, there was a signifi-
cant improvement in Unified Parkinsons Disease
Rating Scale (UPDRS) activities of daily living and
motor sections scores, self-assessment Parkinsons Dis-
ease Disability scale, 10-meter walk test and Zung scale
for depression, which was still seen at the 3-month fol-
low-up, suggesting that a sustained motor improvement
can be achieved with a long-term rehabilitation program
in PD (Pellecchia et al., 2004). A few previous open
studies have similarly suggested motor improvements
lasting 6 weeks to 6 months after physical therapy
was discontinued (Comella et al., 1994; Reuter et al.,
1999; Pellecchia et al., 2004). This might underscore
the importance of physical therapy not as one event lim-
ited in time, but as a continuous or repetitive effort, so
that its benefits might be maintained and perhaps
strengthened over time.
Other long-term benefits from exercise in PD have
been suggested, involving in particular an increased
sense of well-being and an improved quality of life
(Reuter et al., 1999). One observational study reported
that mortality was higher by a hazard ratio of 1.8
amongst PD patients who did not exercise regularly com-
pared with patients who did. However, the odds ratios
were not adjusted for major health factors, such as cardi-
ovascular disease, lung disease, smoking or obesity.
7
In addition to having greater effects on motor function
than physical therapy without cueing (Thaut et al., 1996;
McIntosh et al., 1997), the use of cueing may extend
the duration of the effects of therapy (Rubinstein
et al., 2002). In a recent single-blind, prospective study,
20 PD patients were randomized to two physical ther-
apy groups (Marchese et al., 2000). The first group
underwent a 6-week program of posture control exer-
cises, passive and active stretch and walking exercises,
whereas the second group combined the same regimen
with a variety of visual, auditory and proprioceptive
cueing techniques. Although both groups showed
improvement on activities of daily living and motor
ability (UPDRS) at the end of the program, the group
without sensory cue training had returned to baseline
at a 6-week follow-up, whereas the group trained with
cueing techniques was still improved at that visit.
Although it remains uncertain whether all the involved
types of sensory cueing or only specific types were
associated with this benefit, the learning of new motor
strategies associated with cueing may have caused the
lasting improvement (Marchese et al., 2000).
30.1.4. Emotional arousal, group therapy and use of
motivational processes
Attempts at increasing cortical excitability in PD have
involved, in addition to external sensory inputs, the
use of emotional arousal. A recent open-label study sug-
gested improved precision of arm movements as a con-
sequence of exposure to stimulating music (Bernatzky
et al., 2004). Pacchetti and colleagues (2000) compared
standard physical therapy (passive stretching exercises,
motor tasks, gait and balance training) with music
therapy, involving choral singing, voice exercises and
rhythmic and free body expression, both administered
in weekly group sessions in a randomized, prospective
controlled study. The improvement of bradykinesia,
emotional well-being, activities of daily living and
quality of life scores was greater in the music therapy
group, whereas rigidity was the only measure that was
more improved in the standard physical therapy group.
These effects dissipated at a 2-month follow-up. The
improvement in bradykinesia associated with music
therapy may have resulted from external rhythmic cues
or from the affective arousal induced by the music,
influencing motivational processes (Pacchetti et al.,
2000).
It has been theorized that physical therapy in group
sessions might enhance socialization and motivation,
but group therapy has not been systematically compared
with individual therapy and group therapy studies have
not been controlled. In their study, Pacchetti and
8 J. M. GRACIES ET AL.
colleagues (2000) evaluated training in a group setting,
both in the physical therapy and music therapy arms.
The authors did not observe any increase in emotional
function or quality of life in the physical therapy
group. In open label studies of group physical therapy
in PD, subjects have reported subjective impressions
of benefit in motor symptoms and quality of life, but
there was no improvement in quantitative measures
of motor function (Pedersen et al., 1990; Lokk, 2000;
Deane et al., 2002).
30.2. Recommendations for physical exercise in
mild to moderate Parkinsons disease
30.2.1. Schedule
Although most protocols of the literature have involved
supervised exercise sessions one to three times per
week (Deane et al., 2002), we recommend that the exer-
cise schedule be intensified and expanded from orga-
nized physical therapy sessions into a daily event,
with a time window (11.5 hours) consistently devoted
to this activity every day. Controlled studies have
STRETCHES & EXERCISES UPPER BODY
Stretch shoulder with hand behind wall (e.g. in a doorway)
5 mins. Each side.
Stretch shoulder with elbow leaning against wall as high as
possible.
5 mins. Each side
Fig. 30.1. Stretches and exercises for the upper body.
indeed demonstrated that PD patients can improve per-
formance on complex motor tasks with intense repeated
practice an effect that persists days after the practice
trials have ended (Soliveri et al., 1992; Behrman
et al., 2000). Similar principles of rapid repetition can
be applied to daily physical exercise.
It has been suggested that such exercises should be
performed during the levodopa on state, in order to
optimize their execution (Koller et al., 1989). However,
this is not supported by evidence and the opposite strat-
egy may also be suggested, i.e. the performance of phy-
sical exercises during the early morning off phase for
example, which might improve dopamine availability
and possibly delay the need for the first daily pill
(Reuter et al., 2000; Ouchi et al., 2001). Finally, for
exercises to be effectively replicated at home, it is prob-
ably optimal to teach them as early as possible in the
course of the disease.
30.2.2. Suggested exercises
We recommend alternating between two types of exer-
cises in a practice session (Figs. 30.1 and 30.2). Active
Lift the weight (bag) forward up & down
Repeat with each arm until fatigued
Lift the weight (bag) to the side, up & down
Repeat with each arm until fatigued
 PHYSICAL THERAPY IN PARKINSONS DISEASE
exercises should consist of vigorous series of light-
resistance rapid alternating movements focused on
strengthening muscles that open the body (extensors,
abductors, external rotators, supinators and shoulder
flexors). Passive exercises should involve limb and
trunk posturing focused on lengthening muscles that
close the body (flexors, adductors, internal rotators,
pronators). Following a series of active exercises with
passive posturing for a few minutes also allows cardi-
orespiratory rest.
In the upper body, the active resistance exercises
may involve light weight-lifting, particularly focusing
on active shoulder abductions and shoulder flexions,
as these movements are associated with spinal extensor
recruitment (Moseley et al., 2002), which should contri-
bute to strengthening these muscles (Fig. 30.1). The
spinal extensors are typically hypoactive in PD and
strengthening them should improve trunk posture.
These exercises should be vigorous so as to provoke a
clear sense of fatigue at the end of the series (Rooney
et al., 1994). In this population we recommend choos-
ing weights so as to avoid using maximal or near max-
imal intensity training (Khouw and Herbert, 1998) in
order to limit the risk of muscle and tendon strain in
STRETCHES & EXERCISES LOWER BODY
Stretch by bending forward
5 mins. on each side
Stand from sitting position without using hands.
Repeat as many times as possible until fatigued.
Fig. 30.2. Stretches and exercises for the lower body.
9
elderly patients. Therefore, the weight recommended
should cause fatigue optimally after 1020 repeats as
opposed to fewer than 10 repeats. On the contrary,
stretching postures should focus on stretching the mus-
cle groups that tend to close the body: horizontal
and vertical adductors, internal rotators at the shoulder,
flexors and pronators at the elbow, flexors at the wrist
and fingers. Ideally, each active exercise should be pur-
sued for about a minute whereas each posture of passive
stretch should be maintained for about 5 minutes on
each side.
In the lower body, stretching postures (passive
exercises) should again focus on muscles such as
the hamstrings and hip adductors that tend to adopt a
shortened position in PD because of hypoactivity in
their antagonists. The active exercises should primarily
focus on sit-to-stand (training trunk and lower-limb
extensors) and walking practice (Fig. 30.2).
30.2.2.1. Sit-to-stand
Patients should repeat a series of sit-to-stand exercises
every day, if possible with arms crossed, ideally as many
times as possible in a continuous series so as to achieve
Walk the same distance in as few steps as possible.
Stand with support and stretch legs for 5 mins.
10 J. M. GRACIES ET AL.
a sense of fatigue in the primary muscles involved (hip,
knee and spinal extensors). This should lead to strengthen-
ing of these muscles, which should improve sit-to-stand
ability and walking balance.
30.2.2.2. Walking
Patients should not focus on the speed achieved while
walking but on their stride length. Ideally the patient
selects a specific distance that should be covered every
day and counts the steps taken to walk that distance.
Each day, the patient should try to walk the same dis-
tance using as few steps as possible (Fig. 30.2). When
stride length improvement over that distance is maxi-
mized (i.e. the number of steps taken cannot be further
decreased), the same process should be repeated on a
longer distance. In terms of walking in conditions
other than a flat ground, treadmill walking has not
been compared to walking in a swimming pool in
controlled studies. However, we would hypothesize
that walking against the viscous resistance of water
should maximize hip flexion and ankle push-off train-
ing and thus better improve stride length than treadmill
walking, which might lead to opposite results
(see above).
30.3. Compensation strategies in advanced
stages of Parkinsons disease
30.3.1. Role of discipline
As PD progresses and motor function deteriorates,
patients become significantly less mobile and therefore
less able to perform daily self-initiated exercises such
as active movements against resistance and walking.
Although the goal of physical therapy remains to
optimize functional independence, the method gradu-
ally shifts towards teaching strategies to patients
and care-givers to compensate for worsening motor
impairments. Omitting some of these strategies may
jeopardize activities such as walking or swallowing,
with potentially serious consequences. The emphasis
on a strict patient discipline and on the importance of
its enforcement by the care-giver thus becomes even
more important than in the early stages, as the patient
must now consistently apply the compensation strate-
gies learned in therapy.
One fundamental compensatory strategy in advanced
PD involves increasing the amount of attention and
effort the patient directs toward any given motor
activity. Tasks such as walking, talking, writing and
standing up are no longer automatic and should
no longer be taken for granted. The individual with
advanced PD must learn to want to perform each of
these activities and actively concentrate on them,
possibly even to rehearse them mentally as a new task
each time, as opposed to just doing them. This corre-
sponds to a major change in the approach to daily
activities. Such change can be facilitated through
a clear understanding by the therapist and/or the
care-giver of: (1) the fundamental difference between
automatic and consciously controlled movements;
and (2) the need to switch to conscious movement
control for virtually all daily motor activities, particu-
larly those that we tend to view as the most natural,
such as talking, writing, standing up and walking.
We provide examples of these changes in daily strate-
gies below.
However, teaching and maintaining such discipline
can become a highly challenging proposition in advanced
PD, depending on the presence of depression and par-
ticularly mental deterioration (impairment in executive
functions) and on the degree of patient motivation to
improve quality of life (Gracies and Olanow, 2003).
Depression is a common feature of PD, particularly
in advanced stages (Gracies and Olanow, 2003;
McDonald et al., 2003) and is characterized by hope-
lessness and pessimism, as well as decreased motiva-
tion and drive (Brown et al., 1988). This may
undermine the motivation to practice or to change
daily living strategies. Apathy and abulia (lack of
drive and initiative) can also be prominent symptoms
in PD, independent of depression, and occur with
greater frequency than in patients of similar disability
level from other causes (Pluck and Brown, 2002).
Most importantly, the gradual emergence of demen-
tia, in particular frontal dysexecutive features (perse-
verations, impulsivity), may hamper the ability to
pursue a strict but slower routine of conscious rehear-
sal when performing daily activities that used to be
automatic. In these cases, the care-giver often
becomes the primary focus of the teaching and the
person effectively responsible for implementing the
discipline of the compensation strategies.
30.3.2. Strategies for freezing episodes
In advanced PD, episodes of freezing, characterized by
an interruption of motor activity especially when
encountering obstacles or constricted spaces, can con-
stitute a significant problem, occurring in up to one-
third of patients (Giladi et al., 1992). Management
may consist primarily of behavioral strategies. As
mentioned in the previous section, one can teach the
patient how to substitute external auditory, visual, or
proprioceptive cues to replace the deficient internal
motor cues normally provided by the basal ganglia
(Morris et al., 1995). Specific attentional strategies
may also be useful (see below).
 PHYSICAL THERAPY IN PARKINSONS DISEASE
30.3.2.1. Sensory cues for freezing
Several techniques have been used to alleviate freezing
episodes through external visual input. Visual markers
can be placed in the home in areas where freezing epi-
sodes are common such as doorways and narrow hall-
ways. These may include horizontal markers on the
floor over which the individual is instructed to step, or
a dot on the wall on which the patient is instructed to
focus in the event of freezing. If the patient is accompa-
nied, the other person may place a foot in front of the
patient, which the patient then steps over (Morris
et al., 1995). Inverted walking sticks, with the handle
used as a horizontal visual cue at the level of the foot,
have also been investigated as a potential means of
improving freezing (Kompoliti et al., 2000). Results
have been inconsistent, with some subjects showing
worsening of freezing while using such a walking stick
and others showing improvement (Dietz et al., 1990;
Kompoliti et al., 2000). Additionally, caution must be
used with inverted sticks in PD patients, as these sticks
may cause tripping and increase the risk of fall. Acous-
tic cues can also be used to decrease freezing. PD
patients may carry a metronome, which can be switched
on during a freezing episode emitting an auditory
beat. Such external cues may be sufficient to initiate
movement.
30.3.2.2. Attentional strategies for freezing
A number of adjustments of motor behavior have been
suggested to alleviate freezing episodes when they occur.
These include:
 Focusing on swaying from side to side, transfer-
ring body weight from one leg to the other (Morris
et al., 1995)
 Singing, whistling, loudly saying go or left,
right, left, right, clapping or saying a rhyme and
stepping off at the last word are behavioral strate-
gies that have the additional advantage of generat-
ing acoustic cues (Morris et al., 1995)
 Cue cards posted on the walls of freezing-prone
areas, with instructions such as go or large step
(Morris et al., 1995)
 The one-step-only technique strategy of distrac-
tion from the functional or social meaning of the
action to be accomplished. Success with a method
using a deep-breathing relaxation technique has
been noted in a patient who had failed several
other techniques to reduce freezing episodes
(Macht and Ellgring, 1999). It is often noted that
during an episode of freezing, the more the patient
worries about the functional end-goal of walking
(freeing the elevator entry for other people to
come out, moving out of a crowded store through
11
a narrow exit, entering the doctors office), the
more difficult the task becomes, particularly as
others look on. The emotional stress associated
with the social function of walking in these situa-
tions makes the freezing episode worse. At the
Mount Sinai Movement Disorders Clinic we
attempt to have the patient disconnect for a short
while from the social and functional implications
of walking forward again, and instead to focus
analytically on the walking technique. Walking is
normally a smooth succession of steps. The patient
is asked to focus only on achieving one elemen-
tary unit of walking, i.e. one step only. One single
step should have minimal social role (since one
step is usually not sufficient to enter or exit a
crowded place) and thus minimal emotional
charge. In practice, the first stage is to stop trying
to walk. The patient may then take a deep breath
to mark a pause in the effort and achieve better
relaxation and spread the feet. Then the patient
should concentrate on taking one big step only
and specifically on the power of the hip, knee
and foot flexor movements required to achieve this
one step. Clinical experience shows that when a
strong first step is achieved the second and third
steps naturally follow.
 Movement planning and attention switching back
from automatic movements to consciously con-
trolled movements. To enhance movement in
advanced PD, patients can be taught or repeatedly
reminded to rehearse mentally each movement
before it is executed and to pay close attention to
the movement while it is being performed. For
example, in crowded environments where the risk
of freezing episodes or tripping increases, the
patient should think ahead and plan the most direct
route through the obstacles. Turning around is
another difficult task in advanced PD, which may
be the most common circumstance causing falls
in the home setting. Before turning, the patient
should rehearse the individual leg movements that
are required to turn the body around effectively.
Also, it is recommended to accomplish the turn
over a wide arc instead of swiveling (Morris et al.,
1995).
30.3.3. Strategies to minimize postural instability
In general, advanced PD patients have difficulty main-
taining balance secondary to slow righting reactions
(recruitment of the appropriate axial muscles) in response
to a challenge to equilibrium. Therefore, patients should
try to apply the above principle of conscious control of
12 J. M. GRACIES ET AL.
previously automatic tasks to postural balance. Patients
may be taught actively to focus their attention on balance
whenever they perform an activity involving standing,
similar to what healthy subjects must do when they stand
on a small boat in a turbulent sea. The purpose is to be
in a state of alertness and readiness to respond to threats
of balance and thus promptly implement the necessary
actions to restore equilibrium (Morris and Iansek,
1996). A recent open-label study suggested that 14-day
repetitive training of compensatory steps might enhance
protective postural responses and shorten the period of
double support during gait in PD. In addition, significant
increases in cadence, step length and gait velocity were
observed after such training. These effects were stable
for 2 months without additional training (Jobges et al.,
2004).
30.3.4. Motor subunits
It is beneficial for the PD patient to treat long move-
ment sequences not as a whole, but to break them
down as a series of component parts or subunits. With
this strategy, each subunit is considered and performed
as if it were itself a whole movement. This strategy
is partly used in the one-step-only technique to allevi-
ate freezing. Focusing on each subunit of a motor
sequence may be particularly effective for multijoint
actions such as reaching and grasping, thus facilitating
activities such as feeding and dressing, or whole-body
activities such as standing up from a bed or a chair
(Morris and Iansek, 1996). For example, to stand up
from a bed, the patient should first mentally rehearse
the entire movement and then break the motor
sequence down into a series of subunits, including
bending the knees, turning the head, reaching both
arms in the desired direction, turning the body, swing-
ing the legs over the bed and then finally sitting up
(Morris et al., 1995).
A similar strategy can be used for rising from a
chair. The patient is encouraged to rehearse the
sequence mentally, then to wriggle forward to the front
of the seat, make sure the feet are placed back under-
neath the chair, lean forward, push on the legs and
straighten up the back to stand up. In an open study,
PD patients trained with these techniques as part of a
6-week physical therapy home regimen showed signif-
icant improvement in their ability to transfer in and out
of chairs and beds (Nieuwboer et al., 2001).
30.3.5. Avoidance of dual-task performance
It has been hypothesized that PD patients may mini-
mize their balance or walking difficulties by using
conscious cortically mediated control to overcome
defective automatic basal ganglia activation (Morris
et al., 2000). When conscious attention is diverted
from the task of maintaining equilibrium, the balan-
cing deficits may be accentuated. The set-shifting dif-
ficulties commonly seen in advanced PD prevent
efficient and rapid switches in concentration between
two motor tasks that must be achieved simultaneously
(Gracies and Olanow, 2003).
Not surprisingly, studies have shown that it is ben-
eficial in PD to avoid performing two tasks simulta-
neously. In a study comparing PD patients to age-
matched healthy controls, subjects performed two
walking trials, one freely and one while carrying a tray
with four glasses on it. Whereas the gait performance
changed only minimally across conditions in controls,
the PD patients showed decreased walking speed and
stride length while carrying the tray with glasses
(Bond and Morris, 2000). In another study, single set
instructions to increase walking speed, arm swing or
stride length (all contributors to efficient walking)
resulted in improvement not only of the specific vari-
able upon which the patient had focused, but in the
other gait variables as well. However, when subjects
were instructed to count aloud while walking (an
activity that is not a direct component of the walking
movement), these gait improvements did not occur
(Behrman et al., 1998). In this particular paradigm,
the acoustic cue provided by the loud counting that
could have been expected to help walking may have
been counteracted by the distraction from the walking
movements caused by the additional cognitive task.
A more recent study confirms that dual-task perfor-
mance worsens gait in PD with an equal impairment
whether the secondary task is motor or cognitive in
nature (OShea et al., 2002).
Dual-task performance appears to affect standing
balance as well, particularly in PD patients with a pre-
vious history of falls (Morris et al., 2000; Marchese
et al., 2003). In a study comparing PD patients and
age-matched controls there were no differences in pos-
tural stability between groups when subjects simply
stood on a platform, but PD patients showed signifi-
cantly greater postural instability compared to controls
when given additional tasks, either cognitive or motor
(Marchese et al., 2003).
Therefore PD patients should be instructed to avoid
carrying out dual tasks and focus on one task at a time.
For example, while walking, patients should be encour-
aged to avoid carrying objects (the use of backpacks
may be recommended), talking or thinking about other
matters and instead, focus attention towards each
individual step and on increasing the stride length
(Morris et al., 1995). To prevent loss of balance and falls,
PD patients should avoid standing while performing
 PHYSICAL THERAPY IN PARKINSONS DISEASE
complex motor or cognitive tasks such as showering,
dressing or conversing (Morris, 2000).
30.3.6. Modification of the home environment
In advanced PD, attention should be paid to the home
environment, with the goal of maintaining indepen-
dence and ensuring safety from falls. The ability to
transfer self from bed to chair, chair to toilet and to
stand up is of primary importance in remaining inde-
pendent. To assist with difficulties in transferring from
a lying or sitting to a standing position, higher chairs,
toilet seats and beds can be beneficial as they reduce
the energy requirements to raise the center of gravity.
In addition, because narrow constricted spaces and
obstacles can induce freezing episodes and place indi-
viduals at risk for tripping and falling, care should be
taken to create clear, wide spaces with a minimum of
low-lying obstacles (such as carpets and stools) in
the home setting. Finally, to assist with difficulties
with turning in bed, sheets made of satin in the upper
part (to allow the body to slide) and of cotton in the
lower part (to allow the heels to grip on it and initiate
the turning movement) may be used.
30.3.7. Ambulation assistive devices
Although walkers are meant to improve walking sta-
bility and prevent falls in general and particularly in
orthopedic conditions, the impact of chronic walker
use in PD needs to be critically examined. The argu-
ments for or against a walker should be weighed on a
case-by-case basis, as the use of walkers may worsen
gait and increase the risk of tripping or falling
(Morris et al., 1995; Kompoliti et al., 2000). A recent
study evaluated the acute effects of standard walkers
and wheeled walkers as compared to unassisted walk-
ing in PD (Cubo et al., 2003). Both wheeled and stan-
dard walkers significantly slowed gait compared to
unassisted walking, and the standard walker also
increased freezing. In addition to potentially exacer-
bating posture and balance difficulties, walkers may
also become deleterious in individuals whose steps
have become faster and shorter: when the frame
advances too far in front of the feet, the person may
bend over too far and possibly fall (Morris et al.,
1995).
However, the main issue with walkers may not be
their acute effects on freezing, gait-slowing or the
possibility of forward falls, but the possibility of
long-standing posture and balance impairment caused
by chronic use of these devices. By chronically
providing passive forward support, walkers may
decondition the forward-righting reactions required
13
during inadvertent backward sways (i.e. appropriately
timed rectus femoris and tibialis anterior contractions)
and aggravate or even generate a clinical syndrome of
retropulsion. This risk has not been measured in a pro-
spective study, but anecdotal evidence has been suffi-
ciently prevalent in our center and others (Morris
et al., 1995), that leads us to limit the chronic use of
walkers in PD to a minimum in our clinics.
The use of a cane without objectively verifying
a positive effect on gait parameters and without provid-
ing specific training to the patient is also questionable.
Patients with PD often handle canes improperly, carry-
ing them around instead of using them as a support.
This is particularly problematic in this condition, as
the use of a cane becomes a form of dual task perfor-
mance, involving the simultaneous activities of walking
and carrying an object. As described above, performing
additional tasks while walking can result in gait dete-
rioration. However, it should be recognized that patients
may sometimes feel more comfortable using a cane for
walking outdoors or in public places, not for the sup-
posed increase in stability that the cane may provide,
but as a social signal helping to be recognized by others
as someone walking slowly or with a handicap.
Whether a cane or a walker is considered, the
indication should be determined objectively and
accurately: psychological reassurance, social signal,
objective improvement in stability, reduction in
energy consumption during gait. Whichever indica-
tions are assumed, patients should be tested with
and without the assistive device at the clinic to obtain
a rigorous assessment of the acute impact of the device
on freezing episodes, walking speed and stride length.
Finally, regardless of the acute effects observed at the
clinic, the potential effects of chronic use of these
devices should also be considered, particularly with
the use of walkers. An assistive device must not neces-
sarily be used indefinitely. One may consider the
temporary use of an assistive device in acute periods
such as after deep brain stimulation surgery, during a
period of intensive medication adjustments with risks
of walking instability due to excess levodopa and dys-
kinesias, or after an orthopedic injury such as a hip
fracture.
30.4. Conclusions
Interest in physical therapy for patients with PD has
grown over recent years. It should intensify further
with the recent evidence of neuroprotective effects of
physical exercises in animal models of PD. Although
a number of studies have explored specific treatment
options, they are complicated by heterogeneous treat-
ment methods, different outcome measures and varying
14 J. M. GRACIES ET AL.
timeframes of analysis (Deane et al., 2002). Many studies
have also been limited by inadequate randomization
methods and lack of convincing sham treatments. The
latter two are a particular problem in physical therapy
research, since neither the therapist nor the patient can
be blinded to the arm of the trial (Deane et al., 2002).
In the future, larger, randomized, sham-controlled studies
with staged follow-up will be necessary to determine for
each program the benefits, the duration and the appropri-
ate frequency of training.
However, the limitations of the current literature
should not lead neurologists to underestimate the fun-
damental role of daily physical exercise in PD. To
optimize motor function, we provide personal recom-
mendations consisting of strict programs of daily
home exercises in the mild to moderate stages of
the disease and the teaching to the patient and then
to the care-giver of compensation strategies in the
late stages.
Acknowledgments
We are grateful to Jerri Chen and Jonathan Alis for
their excellent work in illustrating some of the exer-
cises recommended in this chapter. We also thank
Sheree Loftus Fader, MSN, APRN, BC, CRRN for her
expert comments.
References
Behrman AL, Teitelbaum P, Cauraugh JH (1998). Verbal
instructional sets to normalise the temporal and spatial gait
variables in Parkinsons disease. J Neurol Neurosurg Psy-
chiatry 65: 580582.
Behrman AL, Cauraugh JH, Light KE (2000). Practice as an
intervention to improve speeded motor performance and
motor learning in Parkinsons disease. J Neurol Sci 174:
127136.
Bernatzky G, Bernatzky P, Hesse HP et al. (2004). Stimulat-
ing music increases motor coordination in patients
afflicted with Morbus Parkinson. Neurosci Lett 361:
48.
Bond JM, Morris M (2000). Goal-directed secondary motor
tasks: their effects on gait in subjects with Parkinson dis-
ease. Arch Phys Med Rehabil 81: 110116.
Brown RG, MacCarthy B, Gotham AM et al. (1988). Depres-
sion and disability in Parkinsons disease: a follow-up of
132 cases. Psychol Med 18: 4955.
Brown RG, Jahanshahi M, Marsden CD (1993). The execu-
tion of bimanual movements in patients with Parkinsons,
Huntingtons and cerebellar disease. J Neurol Neurosurg
Psychiatry 56: 295297.
Canning CG (2005). The effect of directing attention during
walking under dual-task conditions in Parkinsons disease.
Parkinsonism Relat Disord 11: 9599.
Cohen AD, Tillerson JL, Smith AD et al. (2003). Neuropro-
tective effects of prior limb use in 6-hydroxydopamine-
treated rats: possible role of GDNF. J Neurochem 85:
299305.
Comella CL, Stebbins GT, Brown-Toms N et al. (1994). Phy-
sical therapy and Parkinsons disease: a controlled clinical
trial. Neurology 44: 376378.
Cubo E, Moore CG, Leurgans S et al. (2003). Wheeled and
standard walkers in Parkinsons disease patients with gait
freezing. Parkinsonism Relat Disord 10: 914.
Cubo E, Leurgans S, Goetz CG (2004). Short-term and prac-
tice effects of metronome pacing in Parkinsons disease
patients with gait freezing while in the on state: rando-
mized single blind evaluation. Parkinsonism Relat Disord
10: 507510.
Deane KH, Jones D, Ellis-Hill C et al. (2001). A comparison
of physiotherapy techniques for patients with Parkinsons
disease. Cochrane Database Syst Rev CD002815.
Deane KH, Ellis-Hill C, Jones D et al. (2002). Systematic
review of paramedical therapies for Parkinsons disease.
Mov Disord 17: 984991.
Dibble LE, Nicholson DE, Shultz B et al. (2004). Sensory
cueing effects on maximal speed gait initiation in persons
with Parkinsons disease and healthy elders. Gait Posture
19: 215225.
Dietz MA, Goetz CG, Stebbins GT (1990). Evaluation of a
modified inverted walking stick as a treatment for parkin-
sonian freezing episodes. Mov Disord 5: 243247.
Enzensberger W, Oberlander U, Stecker K (1997). [Metro-
nome therapy in patients with Parkinson disease.] Nerve-
narzt 68: 972977.
Faherty CJ, Raviie Shepherd K, Herasimtschuk A et al.
(2005). Environmental enrichment in adulthood eliminates
neuronal death in experimental Parkinsonism. Brain Res
Mol Brain Res 134: 170179.
Fisher BE, Petzinger GM, Nixon K et al. (2004). Exercise-
induced behavioral recovery and neuroplasticity in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned
mouse basal ganglia. J Neurosci Res 77: 378390.
Georgiou N, Iansek R, Bradshaw JL et al. (1993). An evalua-
tion of the role of internal cues in the pathogenesis of par-
kinsonian hypokinesia. Brain 116 (Pt 6): 15751587.
Giladi N, McMahon D, Przedborski S et al. (1992). Motor
blocks in Parkinsons disease. Neurology 42: 333339.
Gracies JM, Olanow C (2003). Dementia in Parkinsons dis-
ease. In: DS Charney, EJ Nestler (Eds.), The Neurobiology
of Mental Illness, 2nd edn. Oxford University Press, Lon-
don, pp. 896916.
Hausdorff JM, Balash J, Giladi N (2003). Effects of cognitive
challenge on gait variability in patients with Parkinsons
disease. J Geriatr Psychiatry Neurol 16: 5358.
Hesse S, Werner C, Seibel H et al. (2003). Treadmill training
with partial body-weight support after total hip arthro-
plasty: a randomized controlled trial. Arch Phys Med
Rehabil 84: 17671773.
Hirsch MA, Toole T, Maitland CG et al. (2003). The effects
of balance training and high-intensity resistance training
 PHYSICAL THERAPY IN PARKINSONS DISEASE 15
on persons with idiopathic Parkinsons disease. Arch Phys
Miyai I, Fujimoto Y, Ueda Y et al. (2000). Treadmill train-
Med Rehabil 84: 11091117.
ing with body weight support: its effect on Parkinsons
Howe TE, Lovgreen B, Cody FW et al. (2003). Auditory cues
disease. Arch Phys Med Rehabil 81: 849852.
can modify the gait of persons with early-stage Parkinsons
Miyai I, Fujimoto Y, Yamamoto H et al. (2002). Long-term
disease: a method for enhancing parkinsonian walking
effect of body weight-supported treadmill training in
performance? Clin Rehabil 17: 363367.
Parkinsons disease: a randomized controlled trial. Arch
Jobges M, Heuschkel G, Pretzel C et al. (2004). Repetitive
Phys Med Rehabil 83: 13701373.
training of compensatory steps: a therapeutic approach
Morris M, Iansek R (1996). Characteristics of motor distur-
for postural instability in Parkinsons disease. J Neurol
bance in Parkinsons disease and strategies for movement
Neurosurg Psychiatry 75: 16821687.
rehabilitation. Hum Mov Sci 15: 649669.
Khouw W, Herbert R (1998). Optimisation of isometric
Morris M, Iansek R, Kirkwood B (1995). Moving Ahead
strength training intensity. Aust J Physiother 44 (1): 4346.
with Parkinsons: A Guide to Improving Mobility in Peo-
Koller WC, Glatt S, Vetere-Overfield B et al. (1989). Falls
ple with Parkinsons Kingston Centre, Australia.
and Parkinsons disease. Clin Neuropharmacol 12: 98105.
Morris M, Iansek R, Smithson F et al. (2000). Postural
Kompoliti K, Goetz CG, Leurgans S et al. (2000). On
instability in Parkinsons disease: a comparison with and
freezing in Parkinsons disease: resistance to visual cue
without a concurrent task. Gait Posture 12: 205216.
walking devices. Mov Disord 15: 309312.
Morris ME (2000). Movement disorders in people with
Kritikos A, Leahy C, Bradshaw JL et al. (1995). Contingent
Parkinson disease: a model for physical therapy. Phys
and non-contingent auditory cueing in Parkinsons dis-
Ther 80: 578597.
ease. Neuropsychologia 33: 11931203.
Morris ME, Iansek R, Matyas TA et al. (1996). Stride length
Kuroda K, Tatara K, Takatorige T et al. (1992). Effect of
regulation in Parkinsons disease. Normalization strategies
physical exercise on mortality in patients with Parkinsons
and underlying mechanisms. Brain 119 (Pt 2): 551568.
disease. Acta Neurol Scand 86: 5559.
Moseley GL, Hodges PW, Gandevia SC (2002). Deep and
Lewis GN, Byblow WD, Walt SE (2000). Stride length reg-
superficial fibers of the lumbar multifidus muscle are dif-
ulation in Parkinsons disease: the use of extrinsic, visual
ferentially active during voluntary arm movements. Spine
cues. Brain 123 (Pt 10): 20772090.
27 (2): E29E36.
Lokk J (2000). The effects of mountain exercise in
Muller V, Mohr B, Rosin R et al. (1997). Short-term effects
Parkinsonian personsa preliminary study. Arch Gerontol
of behavioral treatment on movement initiation and pos-
Geriatr 31: 1925.
tural control in Parkinsons disease: a controlled clinical
Ma HI, Trombly CA, Tickle-Degnen L et al. (2004). Effect
study. Mov Disord 12: 306314.
of one single auditory cue on movement kinematics in
Murray MP, Spurr GB, Sepic SB et al. (1985). Treadmill vs.
patients with Parkinsons disease. Am J Phys Med Rehabil
floor walking: kinematics, electromyogram, and heart rate.
83: 530536.
J Appl Physiol 59: 8791.
Mabandla M, Kellaway L, St Clair Gibson A et al. (2004).
Nieuwboer A, De Weerdt W, Dom R et al. (2001). The effect
Voluntary running provides neuroprotection in rats after
of a home physiotherapy program for persons with
6-hydroxydopamine injection into the medial forebrain
Parkinsons disease. J Rehabil Med 33: 266272.
bundle. Metab Brain Dis 19: 4350.
Ochala J, Lambertz D, Van Hoecke J et al. (2005). Effect of
Macht M, Ellgring H (1999). Behavioral analysis of the
strength training on musculotendinous stiffness in elderly
freezing phenomenon in Parkinsons disease: a case study.
individuals. Eur J Appl Physiol 94: 126133.
J Behav Ther Exp Psychiatry 30: 241247.
Olanow CW (2004). The scientific basis for the current treat-
Marchese R, Diverio M, Zucchi F et al. (2000). The role of
ment of Parkinsons disease. Annu Rev Med 55: 4160.
sensory cues in the rehabilitation of parkinsonian patients:
OShea S, Morris ME, Iansek R (2002). Dual task interference
a comparison of two physical therapy protocols. Mov Dis-
during gait in people with Parkinson disease: effects of motor
ord 15: 879883.
versus cognitive secondary tasks. Phys Ther 82: 888897.
Marchese R, Bove M, Abbruzzese G (2003). Effect of cog-
Ouchi Y, Kanno T, Okada H et al. (2001). Changes in dopa-
nitive and motor tasks on postural stability in Parkin-
mine availability in the nigrostriatal and mesocortical
sons disease: a posturographic study. Mov Disord 18:
dopaminergic systems by gait in Parkinsons disease.
652658.
Brain 124: 784792.
Martin JP, Hurwitz LJ (1962). Locomotion and the basal
Pacchetti C, Mancini F, Aglieri R et al. (2000). Active music ther-
ganglia. Brain 85: 261276.
apy in Parkinsons disease: an integrative method for motor
McDonald WM, Richard IH, DeLong MR (2003). Preva-
and emotional rehabilitation. Psychosom Med 62: 386393.
lence, etiology, and treatment of depression in Parkinsons
Pedersen SW, Oberg B, Insulander A et al. (1990). Group
disease. Biol Psychiatry 54: 363375.
training in parkinsonism: quantitative measurements of
McIntosh GC, Brown SH, Rice RR et al. (1997). Rhythmic
treatment. Scand J Rehabil Med 22: 207211.
auditory-motor facilitation of gait patterns in patients with
Pelissier J, Perennou D (2000). [Exercises program and reha-
Parkinsons disease. J Neurol Neurosurg Psychiatry 62:
bilitation of motor disorders in Parkinsons disease]. Rev
2226.
Neurol (Paris) 156 (Suppl 2 Pt 2): 190200.
16 J. M. GRACIES ET AL.
people with Parkinsons disease: a randomized, controlled
Pellecchia MT, Grasso A, Biancardi LG et al. (2004). Physi-
trial. J Am Geriatr Soc 46: 12071216.
cal therapy in Parkinsons disease: an open long-term
Schenkman M, Morey M, Kuchibhatla M (2000). Spinal flex-
rehabilitation trial. J Neurol 251: 595598.
ibility and balance control among community-dwelling
Pluck GC, Brown RG (2002). Apathy in Parkinsons disease.
adults with and without Parkinsons disease. J Gerontol A
J Neurol Neurosurg Psychiatry 73: 636642.
Biol Sci Med Sci 55: M441M445.
Pohl M, Rockstroh G, Ruckriem S et al. (2003). Immediate
Soliveri P, Brown RG, Jahanshahi M et al. (1992). Effect of
effects of speed-dependent treadmill training on gait para-
practice on performance of a skilled motor task in patients
meters in early Parkinsons disease. Arch Phys Med Reha-
with Parkinsons disease. J Neurol Neurosurg Psychiatry
bil 84: 17601766.
55: 454460.
Poulton NP, Muir GD (2005). Treadmill training ameliorates
Stankovic I (2004). The effect of physical therapy on balance
dopamine loss but not behavioral deficits in hemi-parkin-
of patients with Parkinsons disease. Int J Rehabil Res 27:
sonian rats. Exp Neurol 193: 181197.
5357.
Reuter I, Engelhardt M, Stecker K et al. (1999). Therapeutic
Suteerawattananon M, Morris GS, Etnyre BR et al. (2004).
value of exercise training in Parkinsons disease. Med Sci
Effects of visual and auditory cues on gait in individuals
Sports Exerc 31: 15441549.
with Parkinsons disease. J Neurol Sci 219: 6369.
Reuter I, Harder S, Engelhardt M et al. (2000). The effect of
Thaut MH, McIntosh GC, Rice RR et al. (1996). Rhythmic
exercise on pharmacokinetics and pharmacodynamics of
auditory stimulation in gait training for Parkinsons dis-
levodopa. Mov Disord 15: 862868.
ease patients. Mov Disord 11: 193200.
Rochester L, Hetherington V, Jones D et al. (2005). The effect
Tillerson JL, Caudle WM, Reveron ME et al. (2003). Exer-
of external rhythmic cues (auditory and visual) on walking
cise induces behavioral recovery and attenuates neuro-
during a functional task in homes of people with Parkinsons
chemical deficits in rodent models of Parkinsons
disease. Arch Phys Med Rehabil 86: 9991006.
disease. Neuroscience 119: 899911.
Rooney KJ, Herbert RD, Balnave RJ (1994). Fatigue contri-
Toole T, Park S, Hirsch MA et al. (1996). The multicom-
butes to the strength training stimulus. Med Sci Sports
ponent nature of equilibrium in persons with parkinson-
Exerc 26 (9): 11601164.
ism: a regression approach. J Neural Transm 103:
Rubinstein TC, Giladi N, Hausdorff JM (2002). The power of
56180.
cueing to circumvent dopamine deficits: a review of physical
Viliani T, Pasquetti P, Magnolfi S et al. (1999). Effects
therapy treatment of gait disturbances in Parkinsons disease.
of physical training on straightening-up processes in
Mov Disord 17: 11481160.
patients with Parkinsons disease. Disabil Rehabil 21:
Scandalis TA, Bosak A, Berliner JC et al. (2001). Resistance
6873.
training and gait function in patients with Parkinsons dis-
Zijlstra W, Rutgers AW, Van Weerden TW (1998). Volun-
ease. Am J Phys Med Rehabil 80: 3843: quiz 446.
tary and involuntary adaptation of gait in Parkinsons
Schenkman M, Cutson TM, Kuchibhatla M et al. (1998).
disease. Gait Posture 7: 5363.
Exercise to improve spinal flexibility and function for
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 31

Neuroprotection in Parkinsons disease: clinical trials

FABRIZIO STOCCHI*

Department of Neurology, IRCCS San Raffaele Pisana, Roma, Italy

31.1. Introduction PD, as suggested by the association of parkinsonian

Parkinsons disease (PD) is an age-related neurodegen-
erative disorder characterized clinically by resting
tremor, rigidity, bradykinesia and a gait disorder.
Pathologically, there is degeneration of nigrostriatal
neurons in the substantia nigra pars compacta (SNpc)
and the presence of intracytoplasmic inclusions known
as Lewy bodies. Biochemically, degeneration of
nigrostriatal neurons is associated with a decline in
striatal dopamine and this finding is the basis for the
symptomatic treatment of the disorder with the dopa-
mine precursor levodopa. However, in the majority
of patients, levodopa treatment is complicated by
motor fluctuations, dyskinesia and the development
of features that do not respond to the drug (e.g. freez-
ing, dementia, autonomic disturbances and postural
instability). Further, levodopa does not stop disease
progression. Consequently, despite the major benefits
associated with levodopa therapy, the majority of
patients with advanced disease suffer unacceptable
levels of functional disability that cannot be controlled
with existing therapies.
Because of these limitations, there has been a con-
certed effort aimed at designing a neuroprotective
therapy for PD (Marsden and Olanow, 1998). Such a
treatment can be defined as a treatment or intervention
that slows or stops disease progression by protecting,
rescuing or restoring the nerve cells that degenerate
in PD. Toward this end, an understanding of the etiolo-
gic and pathogenetic factors responsible for cell death
is of critical importance. Both autosomal-dominant
and -recessive gene mutations have been reported to
cause PD (see Ch. 9), but these account for only a
small number of cases. There is also evidence that
environmental factors contribute to the etiology of
syndromes with exposure to neurotoxins such as 1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
or hydrocarbons (Langston et al., 1983; Pezzoli et al.,
1996). Further, epidemiological studies indicate that
rural living, well-water consumption and exposure to
pesticides increase the risk of developing PD, whereas
there is a decreased risk of PD associated with smok-
ing and coffee consumption (Koller et al., 1990). None
of these factors, however, explain the large majority of
cases who appear to have a sporadic form of the dis-
ease. Indeed, twin studies suggest that genetic factors
probably play a dominant role in young-onset cases
where environmental factors are likely to be the more
important in most older sporadic cases (Tanner et al.,
1999). It is likely that sporadic PD is related to a com-
plex interaction between a variety of genetic and
environmental factors that may be different in differ-
ent individuals. This implies that there are many dif-
ferent causes of PD and makes it unlikely that a
single neuroprotective treatment aimed at interfering
with a single etiologic factor will be effective in the
majority of PD patients.
Other opportunities for neuroprotection in PD
derive from studies on the pathogenesis and mechan-
ism of cell death. Current information suggests that
neurodegeneration in PD is associated with a cascade
of events including oxidant stress, mitochondrial
abnormalities, excitotoxicity and inflammation (Jenner
and Olanow, 1998). Based on this evidence, a number
of theoretical neuroprotective strategies can be
designed. What is not clear, however, is whether these
processes are primary or secondary, which if any is the
driving force that initiates neurodegeneration and what
role each plays in the neurodegenerative process that
occurs in an individual patient. In addition, recent

*Correspondence to: Dr Fabrizio Stocchi, Department of Neurology, IRCCS San Raffaele, Via della Pisana 285, 00165 Rome,
Italy. E-mail: fabrizio.stocchi@fastwebnet.it, Tel: 39-33-690-9255, Fax: 39-06-678-9158.
18 F. STOCCHI
studies suggest that protein aggregation due to failure
of the ubiquitin-proteasome system to clear unwanted
proteins may be a common theme in PD neurodegen-
eration, but how to prevent or deal with this problem
is presently not known (McNaught et al., 2001; see
Ch. 28). Further, considerable evidence supports the
notion that cell death in PD, regardless of etiology,
occurs by way of signal-mediated apoptosis (Hirsch
et al., 1999). The importance of defining a common
factor that contributes to neurodegeneration in PD is
that it provides an opportunity to develop a single neu-
roprotective therapy that might interfere with the neu-
rodegenerative process that ensues as a result of many
different etiologies and therefore may be of value to a
large population of PD patients. This chapter addresses
a clinical relevant question regarding the management
of PD: are there any therapies that can slow down the
progression of PD?
31.2. Trials with antioxidants and monoamine
oxidase-B inhibitors
Considerable evidence supports the notion that oxida-
tive stress plays a role in the pathogenesis of cell death
in PD (see Ch. 24). Postmortem studies in the substan-
tia nigra of PD patients demonstrate increased levels
of iron (which promotes oxidative stress) and
decreased levels of glutathione (the major brain anti-
oxidant) (Jenner and Olanow, 1998). Further, there is
evidence of oxidative damage to carbohydrates, lipids,
proteins and DNA in the SNpc of PD patients. Addi-
tionally, the oxidative metabolism of levodopa and/or
dopamine can generate reactive oxygen species that
can induce or aggravate underlying oxidative stress.
These considerations formed the basis for initiating
clinical trials aimed at obtaining a neuroprotective
effect in PD with antioxidant agents. The initial drugs
chosen for study were a-tocopherol (vitamin E) and
deprenyl (selegiline, eldepryl). a-Tocopherol was
selected because it is the most potent lipid-soluble anti-
oxidant in plasma and plasma levels can be increased
by dietary augmentation (Ingold et al., 1987). Deprenyl
was selected because in doses of 10 mg/day it is a rela-
tively selective inhibitor of monoamine oxidase type B
(MAO-B) that avoids the risk of a sympathomimetic cri-
sis (the cheese effect) associated with non-selective
MAO inhibition (Elsworth et al., 1978). Interest in depre-
nyl as a possible neuroprotective agent in PD was fos-
tered by the observation that MPTP can induce
parkinsonism in humans (Langston, 1983) and that
MPTP-induced parkinsonism in monkeys can be pre-
vented by deprenyl (Cohen et al., 1985). In this model,
deprenyl inhibits the MAO-B oxidation of MPTP to the
pyridinium ion 1-methyl-4-phenylpyridinium ion
(MPP) which is responsible for MPTP toxicity (Chiba
et al., 1984). It was reasoned that if PD were related to
an MPTP-like protoxin, MAO-B inhibition with deprenyl
might similarly prevent the oxidation of other toxins that
contribute to neuronal degeneration. In addition, it was
also postulated that deprenyl could block the MAO-B-
dependent oxidative metabolism of dopamine and
thereby limit free radical damage to SNpc neurons
(Cohen and Spina, 1989).
A prospective, randomized, double-blind, pla-
cebo-controlled study involving 800 patients known
as the DATATOP study (Deprenyl And Tocopherol
Antioxidant Therapy Of PD) was performed to
evaluate deprenyl 10 mg/day and tocopherol 2000
IU (Parkinson Study Group, 1989a, b, 1993).
Untreated PD patients were randomly assigned in a
2
2 factorial design to treatment with deprenyl
(10 mg/day), tocopherol (2000 IU), the combination
of both, or placebo. Patients were followed with no
other treatment until they deteriorated to a point that
blinded investigators felt that symptomatic therapy
in the form of levodopa needed to be introduced
(the primary endpoint). In this study, no effect on
the primary endpoint was detected with a-tocopherol
treatment. In contrast, treatment with selegiline sig-
nificantly delayed the emergence of disability neces-
sitating treatment with levodopa (P < 0.0001).
After 12 months, levodopa treatment was required
in 26% of selegiline recipients compared with 47%
of those who received placebo. Onset of disability
necessitating levodopa therapy occurred after a
mean of 26 months in the 375 selegiline recipients
compared to 15 months in 377 placebo recipients
(with or without tocopherol). Similar results were
observed with selegiline in a smaller study involving
54 patients that served as a pilot for the DATATOP
study (Tetrud and Langston, 1989). Although these
results were impressive and suggested that deprenyl
might have a neuroprotective effect, a careful post-
hoc analysis demonstrated that selegiline was asso-
ciated with both wash-in and wash-out effects indi-
cative of a symptomatic effect in addition to any
putative neuroprotective effect. Thus, although there
was no doubt that selegiline delayed the emergence
of disability in otherwise untreated PD patients, it
was unclear as to the responsible mechanism
(Olanow and Calne, 1991). Namely, was the delay
in requiring levodopa in selegiline-treated patients
due to the drug having a neuroprotective effect on
remaining dopamine neurons or was it due to the
symptomatic effect of the drug masking ongoing
neurodegeneration?
This confound remains unresolved, although sub-
sequent clinical trials provide some support for the
 NEUROPROTECTION IN PARKINSONS DISEASE: CLINICAL TRIALS
possibility that the drug may have neuroprotective
effects in addition to its established symptomatic
effects. The SELEDO (selegiline-levodopa) study
evaluated 120 early-stage PD patients who received
treatment with either levodopa monotherapy or levo-
dopa plus selegiline (Przuntek et al., 1999). The pri-
mary endpoint was the need for a 50% increase in
baseline levodopa dosage. Selegiline-treated patients
were less likely to require this additional increase in
levodopa, suggesting the possibility that the disease
was progressing at a slower rate. Further, the levo-
dopa plus selegiline group had a lower incidence of
motor fluctuations despite comparable clinical con-
trol, again suggesting that selegiline influences the
natural course of levodopa-treated PD.
The SINDEPAR (Sinemet-Deprenyl-Parlodel) was
a prospective double-blind study that attempted to
define the putative neuroprotective effects of selegiline
in a trial that controlled for the drugs symptomatic
effects (Olanow et al., 1995). Patients with untreated
PD (n 100) were randomized to receive treatment
with selegiline versus placebo in addition to treatment
with either Sinemet or bromocriptine. Thus, patients
were randomized to one of four treatment groups;
Sinemet plus selegiline, Sinemet plus placebo, bromo-
criptine plus selegiline, or bromocriptine plus placebo.
The primary endpoint of the study was the change in
Unified Parkinsons Disease Rating Scale (UPDRS)
motor score between original untreated baseline
and final visit performed 2 months after washout of
selegiline and 7 days after washout of either the
bromocriptine or the Sinemet. This study showed that
deterioration in UPDRS score over the course of the
study was significantly less in patients randomized to
receive selegiline than in those receiving placebo
regardless of whether they received symptomatic
treatment with levodopa/carbidopa (Sinemet) or
bromocriptine (P < 0.0001). To insure adequate drug
washout, a subgroup of 23 patients underwent a
14-day washout of their Sinemet or bromocriptine.
Even with this small sample size, deprenyl-treated
patients had significantly less deterioration from origi-
nal baseline than did placebo controls. The authors
interpreted these findings as being consistent with the
hypothesis that selegiline has a neuroprotective effect
that could not be accounted for by the symptomatic
effect of the drug in view of the fact that patients were
washed out of selegiline for a relatively long period of
time while receiving powerful symptomatic agents in
addition to the study drugs. However, even in this
circumstance some doubt remains as it is not possible
to state with any certainty that washout was sufficient
to rid patients of a long-duration symptomatic effect
associated with either selegiline or the symptomatic
19
agents employed. Indeed, Hauser et al. (2000) suggest
that even 2 weeks of withdrawal from levodopa or
bromocriptine may not be sufficient to eliminate the
symptomatic effects associated with their use.
Although the debate continues as to whether or not
the drug has protective effects, it is clear that selegiline
treatment does not stop disease progression (Elizan
et al., 1989) and several reports suggest that after
many years of treatment patients receiving deprenyl
are no less impaired than patients who have not
received the drug (Parkinson Disease Research Group
in the United Kingdom, 1993; Brannan and Yahr,
1995; Parkinson Study Group, 1996a, b). A long-term
follow-up of the DATATOP patients similarly noted no
major difference between those originally on selegiline
or placebo, but it is perhaps noteworthy that selegi-
line-treated patients had a reduced frequency of freez-
ing and off episodes which are thought to be related
to degeneration of non-dopaminergic systems (Shoulson
et al., 2002). The problem has been further confused by
the report of an open-label long-term study suggesting
that selegiline increases the risk of early death in levo-
dopa-treated PD patients (Lees et al., 1995). There
were, however, statistical concerns about how this study
was performed and analyzed (Olanow et al., 1996a) and
similar findings were not observed in an assessment of
mortality in the DATATOP cohort (Parkinson Study
Group, 1998) or in a large meta-analysis that included
all prospective long-term double-blind controlled trials
comparing selegiline to placebo (Olanow et al., 1998b).
Based on the results of the DATATOP study, trials
of other MAO-B inhibitors were initiated as putative
neuroprotective agents. Lazabemide is a relatively
short-acting, reversible and selective MAO-B inhibitor
that is not metabolized to amphetamines or active
compounds (Cesura et al., 1989). The ability of lazabe-
mide to influence the progression of disability in
untreated PD was assessed in a randomized, multicen-
ter, placebo-controlled, double-blind clinical trial (Par-
kinson Study Group, 1996c). A group of 321 untreated
PD patients were assigned to one of five treatment
groups (placebo or lazabemide at a dose of 25, 50,
100 or 200 mg/day) and followed for up to 1 year.
The risk of reaching the primary endpoint (the onset
of disability sufficient to require levodopa therapy)
was reduced by 51% for the patients who received
lazabemide compared with placebo-treated subjects
(P<0.001). This effect was consistent among all
dosages and the magnitude and pattern of benefits seen
with lazabemide were similar to those observed with
selegiline treatment in the DATATOP clinical trial.
However, as with selegiline, lazabemide also has
symptomatic effects and there were similar concerns
as to whether or not benefits seen with this drug
20
Randomize
N = 404*
intent-to-treat
(n = 134)
Rasagiline
1 mg/d 9 terminated
(n = 132)
Rasagiline
2 mg/d 8 terminated
(n = 138)
Delayed
start Placebo
5 terminated
6 mo
Double-blind,
placebo-controlled
Fig. 31.1. TEMPO trial study design.
were due to neuroprotective or symptomatic effects
(Le Witt et al., 1993). This uncertainty caused the
sponsor to discontinue further trials in PD with this
agent (Youdim and Weinstock, 2001).
31.2.1. Rasagiline
Rasagiline is an irreversible and selective MAO-B
inhibitor which does not generate amphetamine meta-
bolites. The drug proved to be effective in the sympto-
matic treatment of early and advanced parkinsonian
patients. However, there are some indications that the
drug may have disease modification effects. A total of
380 patients from the TEMPO trial (Tvp-1012 (rasagi-
line) in early monotherapy for Parkinsons disease out-
patients a randomized, double-blind study versus
placebo including 404 patients with early PD placebo-
controlled phase) entered a 6-month phase of active
treatment, where patients previously receiving placebo
were switched to rasagiline 2 mg/day (Fig. 31.1). The
aim of this phase of the study was a comparison between
those patients who received 12 months treatment with
rasagiline and those patients, previously on placebo,
who had a delayed start and received only 6 months
treatment with rasagiline. This delayed-start technique
is one of several study designs that have been employed
to evaluate the disease-modifying potential of antipar-
kinsonian agents. The theory behind this particular
design is that by the end of the full 12 months of study,
the symptomatic effects of treatment will be balanced in
all groups, leaving any observed differences attributed
to disease-modifying effects.
Results showed that patients receiving 2 mg/day
rasagiline for a 12-month period had a significant
F. STOCCHI
N = 380/382 completers N = 306/360 completers
started next phase elected to continue
(n = 124)
Open-label
4 terminated Rasagiline 1 mg/d
(n = 124)
6 terminated
(n = 132)
Rasagiline 2 mg/d
10 terminated
Up to 6.5 y from
6 mo TEMPO start
Double-blind, Ongoing extension
rasagiline early vs delayed
benefit over patients who had their treatment delayed
by 6 months, as measured by UPDRS-Total score
(2.29 unit difference, P 0.01) and UPDRS-ADL
(activities of daily living) score (0.96 unit difference,
P < 0.01). Once again, this was supported by a super-
ior responder rate in the 12-month treatment group
(P < 0.05). Comparisons of other subscales (UPDRS-
Motor and -Mental) were not significant. Patients
who received 1 mg/day rasagiline for 12 months also
showed significant benefits over the 2 mg/day delayed-
treatment group in UPDRS-Total score (1.82 unit
difference; P 0.05).
One potential disadvantage of this method of mea-
suring disease modification is that symptomatic effects
may be enhanced if treatment is started earlier in the dis-
ease course. However, taken as a preliminary indication,
this delayed-start study provides promising indications
of disease modification that certainly warrant further
investigation. To this end, a new controlled study of
rasagiline, with disease modification as a primary
endpoint, is ongoing ADAGIO-study (Attenuation of
disease progression with azilect given once-daily).
31.2.2. Antiexcitotoxic agents
There is substantial evidence suggesting that excess glu-
tamatergic stimulation with consequent excitotoxicity
contributes to the neurodegenerative process in PD, rais-
ing the possibility that antiexcitotoxic drugs might be
neuroprotective (Lipton and Rosenberg, 1994).
Physiologic and metabolic studies demonstrate that
neuronal activity in the subthalamic nucleus (STN)
is increased in parkinsonian animals and humans
(Obeso et al., 2000). As the STN uses the excitatory
 NEUROPROTECTION IN PARKINSONS DISEASE: CLINICAL TRIALS
neurotransmitter glutamate as a neurotransmitter and
projects to the internal segment of globus pallidus, the
pedunculopontine nucleus and the SNpc, it is reasonable
to consider that these targets might be subject
to excitotoxic damage (Rodriguez et al., 1998). N-
methyl-D-aspartate (NMDA) receptor antagonists have
been reported to protect dopamine neurons from gluta-
mate-mediated toxicity in tissue culture and in rodent
and primate models of PD (Turski et al., 1991; Greena-
myre et al., 1994; Doble, 1999). Further, there is a retro-
spective report suggesting that early use of the NMDA
receptor antagonist amantadine might slow the rate of
PD progression (Uitti et al., 1996). A double-blind pla-
cebo-controlled dosing study was performed testing the
safety and tolerability of remacemide hydrochloride, a
low-affinity NMDA channel blocker (Parkinson Study
Group, 2000a). Total daily doses of 150, 300 and 600
mg were not as well tolerated as placebo, but were not
associated with serious side-effects and, importantly,
symptomatic effects were not detected, although only
small numbers of patients were studied. However, the
drug failed to provide evidence of a neuroprotective
benefit in patients with Huntingtons disease even when
combined with coenzyme Q10 and formal tests of neuro-
protection in PD have not been carried out (Huntingtons
Disease Study Group, 2000).
Riluzole is another antiglutamate agent that acts
by inhibiting sodium channels and thereby prevents
the release of glutamate in overactive glutamatergic
neurons. The drug is approved for use in the treat-
ment of amyotrophic lateral sclerosis (Bensimon
et al., 1994; Lacomblez et al., 1996) and preclinical
studies have demonstrated the capacity of riluzole to
protect dopamine neurons in rodent and primate mod-
els of PD (Araki et al., 2001; Obinu et al., 2002). A
small open-label pilot study in PD patients demon-
strated that riluzole is well tolerated at doses of 100
mg/day and does not provide symptomatic benefits
(Jankovic and Hunter, 2002). Morover, despite the
short duration of the trial and the small sample size
(20 patients), there was a trend toward benefit for
patients in the riluzole group with riluzole patients
remaining unchanged over the course of the study
whereas those randomized to placebo seemed to
deteriorate. A randomized, double-blind, placebo-
controlled trial evaluated riluzole 50 mg b.i.d. com-
pared to placebo with a primary outcome of change
in UPDRS. No significant difference was found
(Jankovic and Hunter, 2002).
31.2.3. Bioenergetics
A body of information suggests that mitochondrial
dysfunction plays a role in the pathogenesis of PD
21
(see Ch. 22). Decreased levels of complex I activity
and reduced staining are observed in the substantia
nigra of PD patients and the selective complex I inhi-
bitor MPTP induces a levodopa-responsive PD syn-
drome in both animal models and human patients.
More recently chronic administration of rotenone, a
widely available pesticide which selectively inhibits
complex I, has been shown to be capable of inducing
a parkinsonian syndrome with selective degeneration
of nigral dopaminergic neurons, a reduction in striatal
dopamine and intracellular inclusions resembling
Lewy bodies (Betarbet et al., 2000). The precise
mechanism whereby inhibition of complex I activity
leads to a parkinsonian syndrome is not known and
reduced adenosine triphosphate formation, free radical
generation and reduction in mitochondrial membrane
potential have all been implicated. These findings do,
however, raise the possibility that bioenergetic agents
such as creatine, coenzyme Q10, ginkgo biloba, nicoti-
namide, riboflavin, acetyl-carnitine or lipoic acid
might be neuroprotective in PD. Indeed, creatine and
coenzyme Q have been shown to protect dopamine
neurons in MPTP-treated rodents (Beal et al., 1998;
Matthews et al., 1999).
The Parkinson Study Group recently completed a
phase II clinical study of coenzyme Q10 in de novo
PD patients. The study was double-blind and the
patients were randomized to treatment with placebo,
300, 600 or 1200 mg of coenzyme Q10 for 16 months
or until disability required levodopa. The primary out-
come measure was the change from baseline in the
UPDRS. In addition, levels of complex I activity
of the mitochondrial electron transport chain and
coenzyme Q10 levels were obtained. The study demon-
strated a dose-dependent reduction in disease progres-
sion as assessed by the UPDRS which correlated with
increases in plasma coenzyme Q10 levels. Although
the results were not statistically significant, a positive
trend was observed. The study was designed to deter-
mine safety and tolerability and only a relatively small
number of patients were included; therefore a larger
phase III study is required. Nonetheless, this study
supports the notion that bioenergetic agents such as
coenzyme Q10 might offer promise as neuroprotective
agents for PD and studies of other such agents are
likely to be performed in the near future.
31.2.4. Antiapoptotic agents
Although the issue of neuroprotection with deprenyl
and other MAO-B inhibitors remains unresolved at the
clinical level, in the laboratory the situation has become
much clearer. An increasing body of evidence has now
accumulated supporting the capacity of deprenyl to
22 F. STOCCHI
provide neuroprotection for dopaminergic and other
motoneurons in a variety of in vitro and in vivo studies
(Mytilineou and Cohen, 1985; Tatton and Greenwood,
1991; Ansari et al., 1993; Roy and Bedard, 1993; Wu
et al., 1993, and reviewed in Olanow et al., 1998c).
Further, it has now become clear that MAO-B inhibi-
tion is not a prerequisite for these benefits (Mytilineou
and Cohen, 1985; Mytilineou et al., 1997a). Indeed,
there is evidence indicating that the neuroprotective
effects seen with deprenyl are due to its metabolite,
desmethyl deprenyl (Mytilineou et al., 1997b, 1998).
These benefits are attributed to the propargyl com-
ponent of the deprenyl molecule and indeed some
other drugs that are propargylamines show a similar
effect on glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) and similar neuroprotective effects
(Boulton, 1999; Waldmeir et al., 2000; Youdim and
Weinstock, 2001). Data now indicate that neuroprotec-
tion associated with deprenyl is due to an antiapoptotic
effect related to drug-induced transcriptional events
with the synthesis of new proteins (Tatton et al., 1994,
2002). Specifically, deprenyl has been shown to induce
altered expression of a number of genes involved in
apoptosis, including SOD1 and SOD2, glutathione
peroxidase, c-JUN, GAPDH, BCL-2 and BAX. These
findings suggest that the antiapoptotic properties of
deprenyl relate to their potential to protect the mito-
chondrial membrane potential and to exert antioxidant
effects. More recent findings indicate that GAPDH
may be central to these effects. GAPDH is an intermedi-
ate in glycogen metabolism and plays an important role
in protein translation and synthesis. However, under
certain adverse conditions, GAPDH in its tetrameric
form translocates to the nucleus where it interferes with
BCL-2 upregulation and promotes apoptosis. Desmethyl
deprenyl binds to GAPDH and maintains it as a dimmer,
in which form it does not translocate to the nucleus and
allows the normal antiapoptotic neuroprotective pro-
grams to be initiated (Carlile et al., 2000). Other propar-
gylamines can also provide neuroprotective effects in
model systems of parkinsonism (Tatton et al., 2000;
Waldmeir et al., 2000; Youdim and Weinstock, 2001).
Two currently undergoing testing for putative neuro-
protective effects in PD are rasagiline (see above) and
CGP3466 or TCH346. TCH346 is a more potent neuro-
protectant than deprenyl in laboratory models and does
not inhibit MAO-B, which may eliminate a sympto-
matic confound and make detection of a neuroprotective
effect easier to detect. In MPTP monkeys, TCH346 pre-
vented neuronal degeneration and led to functional
improvement (Waldmeir et al., 2000). Prospective dou-
ble-blind trials comparing TCH346 with placebo were
stopped after an interim analysis for lack of efficacy
(Olanow, 2006).
There are several different signaling pathways that
can lead to apoptosis depending on the model and
toxin that are tested, providing different opportunities
for introducing antiapoptotic strategies (Reed, 2002),
but none has yet been adequately tested in clinical
trials or established to be neuroprotective in PD.
31.3. Restorative therapies
Whereas most studies have focused on attempts to
alter the natural course of PD through manipulation
of factors thought to be involved in the pathogenesis
of cell death, other approaches have attempted to
restore dopaminergic neuronal function. This has been
attempted with transplantation strategies designed to
provide new cells to replace those that have under-
gone neurodegeneration or trophic factors that might
restore or enhance function in remaining dopamine
neurons.
Transplanted fetal nigral cells implanted into the
denervated striatum have been demonstrated to sur-
vive, manufacture dopamine and provide behavioral
effects in rodent and primate models of PD (reviewed
by Olanow et al., 1996b). Open-label studies in
advanced PD patients have reported clinical benefits,
increased fluorodopa uptake on positron emission
tomography (PET) and robust survival of implanted
dopamine neurons with organotypic reinnervation of
the striatum (reviewed by Olanow et al., 1996b). How-
ever, these benefits have not yet been reproduced in
double-blind, placebo-controlled trials. Freed et al.
(2001) randomized 40 advanced PD patients to receive
transplantation with embryonic ventromesencephalic
cells or sham surgery. The study failed to meet its
primary endpoint (a quality-of-life measure). Improve-
ment was observed in UPDRS motor scores, particu-
larly in patients younger than 60 years, but benefits
were not of the magnitude reported in open-label
studies. Further, some of the patients developed severe
off-medication dyskinesia which persisted for days
after withdrawal of levodopa. A similar type of dyski-
nesia has now been reported by the Swedish group
(Hagell et al., 2002). The mechanism responsible for
this unanticipated side-effect is not known, but it is
noteworthy that this type of dyskinesia has not been
detected in patients with advanced PD who have not
undergone transplantation (Cubo et al., 2001). This
study illustrates the importance of placebo-controlled
trials (Freeman et al., 1999) and the need to address
clinically relevant issues in the laboratory before
beginning trials in PD patients in order to minimize
the risk of running into unanticipated side-effects. In
this regard it should be noted that transplantation has
not yet been tested in levodopa-treated parkinsonian
 NEUROPROTECTION IN PARKINSONS DISEASE: CLINICAL TRIALS
monkeys to see if they have been primed to develop
off-medication dyskinesia. A second double-blind pla-
cebo-controlled trial of fetal nigral transplantation has
just been completed in which different concentrations
of donor tissue were tested, immunosuppression was
employed and patients were followed for 2 years
(Freeman et al., 1999), but final results are not yet
published.
The use of human embryonic neural tissue creates
logistical and societal problems such as acquiring
enough tissue for grafting in a predictable and large-
scale manner and ethical problems inherent in the use
of aborted human fetal tissue. For these reason alterna-
tive sources of fetal dopaminergic neurons have been
sought. One such approach involves the use of porcine
fetal nigral cells. Implanted porcine fetal nigral cells
have been shown to survive and to provide some beha-
vioral effects. However, open-label trials showed no
benefit for patients with Huntingtons disease and only
minimal benefit in PD patients with no increase in
striatal fluorodopa uptake on PET and only minimal
survival at postmortem (Deacon et al., 1997; Fink
et al., 2000; Schumacher et al., 2000). A double-
blind, placebo-controlled study has been performed
in patients with advanced PD and demonstrated no
benefit in comparison to patients receiving a placebo
procedure (unpublished information). In this study
the magnitude of the placebo effect was extensive
and sustained, emphasizing again the importance of
placebo-controlled trials in evaluating new interven-
tions (Freeman et al., 1999). A small open-label trial
reported some clinical benefits following transplanta-
tion of retinal pigmented epithelial cells (Watts,
2002) and a prospective double-blind placebo-con-
trolled trial has been initiated.
Although these studies are not encouraging, it is
possible that better results can be obtained with differ-
ent transplant variables such as increased numbers of
cells, continued use of immunosuppression, combined
use of antiapoptotic factors and different transplant tar-
gets (Barker, 2002). It is also possible that better
results can be obtained with stem cells (see Ch. 44).
Stem cells are capable of self-renewal and expand
after implantation. Neural stem cells are found in the
developing brain (embryonic neural stem cells), but
also in certain sites within the adult brain (Armstrong
and Svendsen, 2000; Gage, 2000). Embryonic neural
stem cells can be isolated and grown in culture and
made to differentiate into all of the major cell types
of the central nervous system, including dopaminergic
neurons (Kawasaki et al., 2002). Indeed, initial studies
demonstrate that embryonic stem cells can sponta-
neously differentiate into neurons, with a small percen-
tage being dopaminergic neurons. Further, following
23
transplantation, they can survive and induce behavioral
effects in the dopamine-lesioned rodents (Bjorklund
et al., 2002). However, these experiments are not without
their own problems and, in one study, 5 of 19 transplanted
animals developed tumors (Kim et al., 2002). Stem cells
have not yet been implanted into PD patients and,
although they offer considerable promise, many clinical
issues remain to be resolved at the preclinical level before
clinical trials in PD patients can be considered.
A second restorative approach involves the use of
trophic factors. Numerous studies have demonstrated
the capacity of a variety of trophic factors to protect
dopamine neurons in tissue culture and to restore
nigrostriatal function in dopamine-lesioned animals
(Collier and Sortwell, 1999). Among these, glial-
derived neurotrophic factor (GDNF) appears to be
the most effective in laboratory models (see Ch. 45).
GDNF treatment has been shown to protect cultured
dopamine neurons from a variety of toxins (Lin
et al., 1993) and to restore function to the nigrostriatal
system of the MPTP-lesioned monkey even when
treatment is delayed for up to several weeks (reviewed
by Hebert et al., 1999). One of the major limitations of
trophic factors relates to delivery of the protein to the
target site. An open-label trial of intraventricular
GDNF did not provide meaningful benefit to advanced
PD patients, probably because the protein was not able
to gain entry from the cerebrospinal fluid into the brain
(Kordower et al., 1999). Side-effects of GDNF deliv-
ered in this way were troublesome and included consi-
titutional complaints, pain and Lhermittes sign,
probably reflecting meningeal irritation. Another
open-label study was subsequently performed in
advanced PD patients in which GDNF was directly
injected into the striatum (Barker, 2006). These
researchers claimed to observe antiparkinsonian bene-
fits and direct infusion of GDNF was better tolerated
than with the intraventricular approach, although 4 of
5 patients still experienced Lhermittes sign. A pro-
spective double-blind placebo-controlled trial testing
continuous infusion of GDNF into the striatum of
parkinsonian patients, recently conducted, failed to
demonstrate efficacy versus placebo (Lang, 2006). An
alternate approach utilizes gene therapy to deliver
GDNF. Using a modified lentivirus vector to deliver
GDNF to the striatum and nigra of MPTP-lesioned mon-
keys, dramatic histologic and behavioral improvement
was observed (Kordower et al., 2000). Further, the pro-
tein was well tolerated. Long-term safety studies in non-
human primates are currently underway and a clinical
trial of lentivirus GDNF in PD patients is ongoing.
Numerous other preclinical studies have been per-
formed testing different vectors (e.g. adeno-associated
virus), different proteins (e.g. AADC or GAD) and
24 F. STOCCHI
different targets (e.g. SNpc or STN) and it is anticipated
that favorable behavioral results and safety profiles will
lead to clinical trials in PD in the not too distant future.
Based on the unanticipated off-medication dyskinesia
observed in some patients following transplantation, it
remains necessary to demonstrate that GDNF does not
induce dyskinesias and debate continues with regard to
whether or not to use a regulatable gene therapy system.
Nevertheless, based on laboratory studies available to
date and the preliminary results with direct infusion in
PD patients, GDNF therapy appears to be very promising
for PD patients.
Immunophilins are partial ligands for the ciclos-
porin-binding site that, independent of their immuno-
suppressant properties, provide trophic-like effects
for dopamine neurons in tissue culture and animal
models (Steiner et al., 1997). Two immunophilin
agents have been tested in PD patients, but the results
have been disappointing and no evidence of a neuro-
protective or restorative effect has been observed
(Gold and Nutt, 2002).
31.4. Dopamine agonists
There has been considerable interest for more than a
decade in the potential of dopamine agonists to provide
neuroprotective effects and to alter the natural course
of the levodopa-treated PD patient (Olanow, 1992;
Stocchi, 2000). In the laboratory, dopamine agonists
have been shown to protect dopamine neurons from a
variety of toxins in both in vitro and in vivo models
(Olanow et al., 1998; see Ch. 22). Various theories have
emerged to account for these effects, including levo-
dopa-sparing, stimulation of dopamine autoreceptors,
direct free radical scavenging, inhibition of STN-
mediated excitotoxicity and activation of dopamine
receptors with signal-mediated antiapoptotic effects.
Two prospective randomized clinical trials have
recently been performed in early PD patients to test
the putative neuroprotective effects of dopamine ago-
nists. In one study (the Comparison of the agonist pra-
mipexole with levodopa on motor complications of
Parkinsons disease, CALM-PD, study), patients with
untreated PD were randomized to initiate therapy with
either the dopamine agonist pramipexole or levodopa
(Marek et al., 2002). In the second (the Requip as an
early therapy versus levodopa PET, REAL-PET, study),
patients were randomized to initiate therapy with the
agonist ropinirole or levodopa (Whone et al., 2002).
Open-label levodopa could be added to the blinded ther-
apy if deemed necessary for patients in both studies. In an
attempt to circumvent the problems of detecting a neuro-
protective effect with symptomatic agents, both trials uti-
lized a neuroimaging surrogate marker of nigrostriatal
function as a primary endpoint. The REAL-PET study
used striatal fluorodopa uptake on PET whereas the
CALM-PD study used striatal beta-carbomethoxy-3
beta-(4-iodophenyl)tropane (b-CIT) uptake on single-
photon emission computed tomography (SPECT). The
results of two trials have recently been released.
In the CALM PD-SPECT study, an estimate of the
rate of dopamine neuronal degeneration was assessed
by measuring the rate of decline in b-CIT, a marker
of the dopamine transporter. This study was performed
in a subsection of patients participating in the CALM-
PD trial (Olanow et al., 1998). A total of 82 patients
with early PD requiring dopaminergic therapy to treat
emerging disability were enrolled in the study. Patients
were randomly assigned to receive pramipexole in a
dose of 0.5 mg t.i.d. (n 42), or carbidopa/levodopa
25/100 mg t.i.d. (n 40). The primary outcome vari-
able was the percentage change from baseline in stria-
tal b-CIT uptake after 46 months. The mean ( SD)
percentage loss in striatal b-CIT uptake between base-
line and 46 months was significantly reduced in the
pramipexole group compared with the levodopa group
(16.0  13.3% versus 25.5  14.1%; P < 0.05). The
authors concluded that patients initially treated with
pramipexole demonstrated a reduced rate of PD pro-
gression, as determined by rate of decline in striatal
b-CIT uptake if treatment was initiated with the dopa-
mine agonist. As there was no placebo control group, no
comment could be made as to whether the agonist group
deteriorated at a slower rate or the levodopa group at a
faster rate. Interestingly, there was no clinical correlate
of this finding, with patients randomized to initial treat-
ment with levodopa doing as well as or better than ago-
nist-treated patients on the UPDRS scale.
The REAL-PET study was designed to compare the
rate of PD progression using striatal fluorodopa uptake
on PET as a marker of nigrostriatal function. A total
of 186 patients with early untreated PD were rando-
mized in a 1:1 ratio to initiate treatment with either
the dopamine agonist ropinirole or levodopa. The pri-
mary outcome variable was the percentage reduction
in putamenal 18F-dopa influx constant (Ki) over the
2-year study in patients with both clinical and PET evi-
dence of PD. Data were collected from six PET centers
and centrally transformed at the Hammersmith Hospital
(London, UK) so as to standardize brain position and
shape and the placement of the regions of interest
(ROIs) for calculation of putamen Ki. Parametric
images were also interrogated with statistical para-
metric mapping (SPM) to localize regions of significant
within-group and between-group differences in rates of
loss of dopaminergic function. Secondary endpoints
included the incidence of dyskinesias and clinical effi-
cacy evaluations. The central ROI analysis of putamen
 NEUROPROTECTION IN PARKINSONS DISEASE: CLINICAL TRIALS
Ki showed that, over the course of the 2-year study,
there was a significantly slower rate of deterioration in
the ropinirole group as compared to the levodopa group
(13% versus 20%; P < 0.05). Using the SPM analy-
tic technique, a significantly slower rate of progression
for agonist-treated patients was detected in both puta-
men and nigra (P < 0.05 for both). The authors con-
cluded that the progression of PD, as reflected by loss
of putamenal 18F-dopa uptake, was slower in PD
patients when treatment was initiated with the dopa-
mine agonist ropinirole as compared to levodopa. Inter-
estingly, this study also found no clinical correlate for
the imaging finding, with UPDRS scores being compar-
able or superior in the levodopa group.
Both studies clearly demonstrate a reduced rate of loss
of nigrostriatal function, as determined by imaging surro-
gate markers in patients treated with dopamine agonists
compared to levodopa. As previously (Parkinson Study
Group, 2000b; Rascol et al., 2000), patients initiated on
agonists also had a significantly reduced risk of develop-
ing motor complications than did those started on levo-
dopa. Interestingly, neither study demonstrated a
clinical correlate to go along with the improvement
detected in the imaging studies. In both studies clinical
efficacy, as measured by the UPDRS rating scale, favored
patients in the levodopa group. This, too, is similar to
what was described in other trials comparing initial ther-
apy with dopamine agonists versus levodopa (Parkinson
Study Group, 2000b; Rascol et al., 2000). Although the
clinical significance of this difference can be debated,
as patients in the agonist groups could receive levodopa
supplement whenever either the patient or physician
deemed it was necessary, it is evident that there is no clear
clinical indication of slower disease progression in the
agonist groups.
These represent the first studies in PD to demon-
strate positive results utilizing imaging techniques to
seek evidence of neuroprotection. There remain sev-
eral issues. Firstly, if benefits seen on imaging reflect
a change in the rate of disease progression, is this a
function of a neuroprotective effect of the agonist or
accelerated disease progression due to levodopa?
Further studies with a placebo control will be required
to address this issue. Secondly, are there pharmacolo-
gic effects that interfere with the comparison of levo-
dopa versus a dopamine agonist that give the false
impression that agonists have a slower rate of reduc-
tion in imaging markers of nigrostriatal function than
does levodopa? Here too, further studies should clarify
this issue. Preliminary studies have not shown a speci-
fic levodopa or dopamine agonist effect on fluorodopa
uptake on PET or -CIT uptake on SPECT. Finally, if
the imaging studies do reflect a neuroprotective effect
of agonists, why is there no clinical correlate? Is the
25
benefit so slight at this early time point that it is
masked by the symptomatic effects of the drugs and
is longer follow-up required?
These results are most exciting and, independent of
whether or not dopamine agonists prove to be neuro-
protective in the long run, neuroimaging offers the
potential of establishing a surrogate marker of nigros-
triatal function that will enable the assessment of the
many putative neuroprotective drugs that are currently
or will eventually become available. Toward this end,
it is important to perform careful studies to establish
that these imaging surrogates do in fact represent accu-
rate markers of the number of dopamine terminals and/
or neurons and to determine the influence on these
markers of time, drug therapy and disease progression.
A delayed start design trial with pramipexole in early
PD patients is ongoing.
31.5. Levodopa
A double-blind controlled randomized trial levodopa
(150, 300, 600 mg/day) versus placebo including 361
patients was recently conducted. The primary outcome
was masked assignment of change in UPDRS from
baseline after 40 weeks of treatment and a 2-week wash-
out. In addition SPECT -CIT was performed at base-
line and week 40 in a subgroup of 116 patients.
Patients randomized to all levodopa doses had signifi-
cantly better UPDRS scores than patients on placebo,
with the greatest improvement seen on the highest dose,
showing a clear doseresponse relationship. After the
washout period none of the three treated groups matched
the disease severity scored in the placebo group. These
data suggested that patients on levodopa had a sustained
functional improvement and this was more evident in
the higher-dose group. However, it is possible that the
washout period was not sufficient to exclude a persistent
symptomatic effect (long-duration response). Patients
on the highest dose of levodopa developed more dyski-
nesias and motor complications. This may be due to
the dose of levodopa but also to the way levodopa was
administered (t.i.d.). There was no significant difference
in -CIT uptake across the groups. However a greater
reduction in -CIT uptake was observed in patients
taking the higher levodopa dose.
31.6. Conclusion
In establishing that an intervention has a neuroprotective
effect, it is necessary to choose outcome measures of dis-
ease progression that are satisfactory to both clinicians
and regulatory authorities. To date, no drug has been
established to be neuroprotective in PD (Morrish, 2002)
and regulatory agencies have not yet confirmed that any
26 F. STOCCHI
of the outcome measures that have been used are
acceptable for purposes of drug approval and labeling.
Several clinical trials aimed at detecting a neuropro-
tective effect have shown positive results, but interpre-
tation has been confounded by the symptomatic effects
of the drugs being tested. As a consequence, positive
results cannot be interpreted as representing neuropro-
tection. More recently, clinical trials have attempted to
detect neuroprotection by utilizing neuroimaging
surrogate markers of nigrostriatal function. However,
even though results have been positive, it is not estab-
lished that these imaging surrogate markers do in fact
accurately represent the number of dopamine neurons or
terminals and no clinical correlate has been observed in
these studies. In the final analysis, it will probably be
necessary to provide evidence of improvement in both
imaging and clinical markers of disease progression
before it can be declared that an intervention is neuropro-
tective and has a disease-modifying effect.
References
Ansari KS, Yu PU, Kruck TPA et al. (1993). Rescue of axo-
tomized immature rat facial motoneurons by L-deprenyl:
stereospecificity and independence from monoamine oxi-
dase inhibition. J Neurosci 13: 40424053.
Araki T, Kumagai T, Tanaka K et al. (2001). Neuroprotective
effect of riluzole in MPTP-treated mice. Brain Res 918:
176181.
Armstrong RJE, Svendsen CN (2000). Neural stem cells:
from the cell biology to cell replacement. Cell Transplant
9: 132145.
Barker RA (2002). Repairing the brain in Parkinsons dis-
ease: where next? Mov Disord 17: 233241.
Barker RA (2006). Continuing trials of GDNF in Parkinsons
disease. Lancet Neurol 5 (4): 285286.
Beal MF, Matthews RT, Tieleman A et al. (1998). Coenzyme
Q10 attenuates the 1-methyl-4-phenyl-1,2,3,6-tetrahydro-
pyridine (MPTP) induced loss of striatal dopamine and
dopaminergic axons in aged mice. Brain Res 783 (1):
109114.
Bensimon G, Lacomblez L, Meininger V (1994). A con-
trolled trial of riluzole in amyotrophic lateral sclerosis.
ALS/Riluzole Study Group. N Engl J Med 330: 585591.
Betarbet R, Sherer TB, MacKenzie G et al. (2000). Chronic
systemic pesticide exposure reproduces features of
Parkinsons disease. Nat Neurosci 3: 13011306.
Bjorklund LM, Sanchez-Pernaute R, Chung S et al. (2002).
Embryonic stem cells develop into functional dopaminer-
gic neurons after transplantation in a Parkinson rat model.
Proc Natl Acad Sci USA 99: 23442349.
Boulton AA (1999). Symptomatic and neuroprotective
properties of the aliphatic propargylamines. Mech Ageing
Dev 111: 201209.
Brannan T, Yahr MD (1995). Comparative study of selegi-
line plus L-dopa-carbidopa versus L-dopa-carbidopa alone
in the treatment of Parkinsons disease. Ann Neurol 37:
9598.
Carlile GW, Chalmers-Redman RME, Tatton NA et al.
(2000). Reduced apoptosis after nerve growth factor and
serum withdrawal: conversion of tetrameric glyceralde-
hydes-3-phosphate dehydrogenase to a dimmer. J Pharma-
col Exp Ther 57: 212.
Cesura AM, Galva MD, Imhof R et al. (1989). [3H]Ro
19-6327: a reversible ligand and affinity labelling
probe for monoamine oxidase-B. Eur J Pharmacol 162:
457465.
Chiba K, Trevor A, Castagnoli N Jr (1984). Metabolism of
the neurotoxic tertiary amine, MPTP, by brain monoamine
oxidase. Biochem Biophys Res Commun 120: 457478.
Cohen G, Spina MB (1989). L-deprenyl supresses the oxi-
dant stress associated with increased dopamine turnover.
Ann Neurol 26: 689690.
Cohen G, Pasik P, Cohen B et al. (1985). Pargyline and
deprenyl prevent the neurotoxicity of 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP) in monkeys. Eur
J Pharmacol 106: 209210.
Collier T, Sortwell CE (1999). Therapeutic potential of nerve
growth factors in Parkinsons disease. Drugs Aging 14:
261287.
Cubo E, Gracies JM, Benabou R et al. (2001). Early morning
off-medication dyskinesias, dystonia, and choreic sub-
types. Arch Neurol 58: 13791382.
Deacon T, Schumacher J, Dinsmore J et al. (1997). Histologi-
cal evidence of fetal pig neural cell survival after trans-
plantation into a patient with Parkinsons disease. Nat
Med 3: 350353.
Doble A (1999). The role of excitotoxicity in neurodegenera-
tive disease: implications for therapy. Pharmacol Ther 81:
163221.
Elizan TS, Yahr MD, Moros DA et al. (1989). Selegiline use
to prevent progression of Parkinsons disease. Experience
in 22 de novo patients. Arch Neurol 46: 12751279.
Elsworth JD, Glover V, Reynolds GP et al. (1978). Deprenyl
administration in man: a selective monoamine oxidase B
inhibitor without the cheese effect. Psychopharmacol-
ogy 57: 3338.
Fink JS, Schumacher JM, Ellias SL et al. (2000). Porcine
xenografts in Parkinsons disease and Huntingtons dis-
ease patients: preliminary results. Cell Transplant 9:
273278.
Freed CR, Greene PE, Breeze RE et al. (2001). Embryonic
dopaminergic tissue transplants in advanced Parkinsons
disease. N Engl J Med 344: 710719.
Freeman TB, Vawter DE, Leaverton PE et al. (1999). The use
of a surgical placebo-control in evaluating cellular-based
therapy for Parkinsons disease. N Eng J Med 341: 988992.
Gage FH (2000). Mammalian neural stem cells. Science 287:
14331438.
Gold BG, Nutt JG (2002). Neuroimmunophilin ligands in the
treatment of Parkinsons disease. Curr Opin Pharmacol 2:
8286.
Greenamyre JT, Eller RV, Zhang Z et al. (1994). Antiparkin-
sonian effects of remacemide hydrochloride, a glutamate
 NEUROPROTECTION IN PARKINSONS DISEASE: CLINICAL TRIALS
antagonist, in rodent and primate models of Parkinsons
disease. Ann Neurol 35: 635661.
Hagell P, Piccini P, Bjorklund A et al. (2002). Dyskinesias
following neural transplantation in Parkinsons disease.
Nat Neurosci 5: 627628.
Hauser RA, Koller WC, Amin J et al. (2000). Time course of
loss of clinical benefit following withdrawal of levodopa/
carbidopa and bromocriptine in early Parkinsons disease.
Mov Disord 15: 485489.
Hebert MA, Hoffer BJ, Zhang Z et al. (1999). Functional
effects of GDNF in normal and parkinsonian rats and
monkeys. In: M Tuszynski, JH Kordower (Eds.), CNS
Regeneration: Basic Science and Clinical Advances. Aca-
demic Press, San Diego, pp. 419436.
Hirsch EC, Hunot S, Faucheux B et al. (1999). Dopaminergic
neurons degenerate by apoptosis in Parkinsons disease.
Mov Disord 14: 383385.
Huntingtons Disease Study Group (2000). A randomized,
placebo-controlled trial of coenzyme Q10 and remacemide
in Huntingtons disease. Neurology 57: 397404.
Ingold KU, Webb AC, Witter D et al. (1987). Vitamin E
remains the major lipid-soluble, chain-breaking antioxi-
dant in human plasma even in individuals suffering severe
vitamin E deficiency. Arch Biochem Biophys 259:
224225.
Jankovic J, Hunter C. (2002). A double-blind, placebo-
controlled and longitudinal study of riluzole in early
Parkinsons disease. Parkinsonism Relat Disord 8:
271276.
Jenner P, Olanow CW (1998). Understanding cell death in
Parkinsons disease. Ann Neurol 44 (3): 7284.
Kawasaki H, Suemori H, Mizuseki K et al. (2002). Genera-
tion of dopaminergic neurons and pigmented epithelia
from primate ES cells by stromal cell-derived inducing
activity. Proc Natl Acad Sci USA 99: 15801585.
Kim JH, Auerbach JM, Rodriguez-Gomez JA et al. (2002).
Dopamine neurons derived from embryonic stem cells
function in an animal model of Parkinsons disease.
Nature 418: 5056.
Koller W, Vetere-Overfield B, Gray C et al. (1990). Environ-
mental risk factors in Parkinsons disease. Neurology 40:
12181221.
Kordower JH, Palfi S, Chen E et al. (1999). Clinicopathologi-
cal findings following intraventricular glial-derived neuro-
trophic factor treatment in a patient with Parkinsons
Disease. Ann Neurol 46: 419424.
Kordower JH, Emborg ME, Bloch J et al. (2000). Neuro-
degeneration prevented by lentiviral vector delivery of
GDNF in primate models of Parkinsons disease. Science
290: 767773.
Lacomblez L, Bensimon G, Leigh PN et al. (1996). Dose
ranging study of riluzole in amyotrophic lateral sclerosis.
Lancet 347: 14251431.
Lang AE, Gill S, Patel NK et al. (2006). Randomized con-
trolled trial of intraputamenal glial cell line-derived neuro-
trophic factor infusion in Parkinson disease. Ann Neurol
59 (3): 459466.
27
Langston JW, Ballard PA, Tetrud JW et al. (1983). Chronic
parkinsonism in humans due to a product of meperidine
analog synthesis. Science 219: 979980.
Lees AJ (1995). on behalf of the Parkinsons disease
Research Group of the United Kingdom. Comparison of
therapeutic effects and mortality data of levodopa and
levodopa combimed with selegeline in patients with
early, mild Parkinsons disease. BMJ 311 (7020):
16021607.
Le Witt PA, Segel SA, Mistura KL et al. (1993). Sympto-
matic anti-parkinsonian effects of monoamine oxidase-B
inhibition: comparison of selegiline and lazabemide. Clin
Neuropharmacol 16: 332337.
Lin LF, Doherty DH, Lile JD et al. (1993). GDNF: a Glial
cell line-derived neurotrophic factor for midbrain dopami-
nergic neurons. Science 260: 11301132.
Lipton SA, Rosenberg PA (1994). Excitatory amino acids as
a final common pathway for neurologic disorders. N Engl
J Med 330: 613622.
Marek K, Seibyl J, Shoulson I et al. (2002). Dopamine trans-
porter brain imaging to assess the effects of pramipexole
vs levodopa on Parkinson disease progression. JAMA
287: 16531661.
Marsden CD, Olanow CW (1998). Neuroprotection in Par-
kinsons disease: the causes of Parkinsons disease are
being unravelled and rational neuroprotective therapy is
close to reality. Ann Neurol 44 (3): 189196.
Matthews RT, Ferrante RJ, Klivenyi P et al. (1999). Creatine
and cyclocreatine attenuate MPTP neurotoxicity. Exp
Neurol 157 (1): 142149.
McNaught KS, Olanow CW, Halliwell B et al. (2001). Fail-
ure of the ubiquitin-proteasome system in Parkinsons dis-
ease. Nat Rev/Neurosci 2 (8): 589594.
Morrish P (2002). Is it time to abandon functional imaging in
the study of neuroprotection? Mov Disord 17: 229232.
Mytilineou C, Cohen G (1985). Deprenyl protects dopamine
neurons from the neurotoxic effect of 1-methyl-4-phenyl-
pyridinium ion. J Neurochem 45: 19511953.
Mytilineou C, Radcliffe P, Leonardi EK et al. (1997a). L-
deprenyl protects mesencephalic dopamine neurons from
glutamate receptor-mediated toxicity. J Neurochem 68:
3339.
Mytilineou C, Radcliffe PM, Olanow CW (1997b). L-(-)-
Desmethylselegiline, a metabolite of L-(-)-selegiline, pro-
tects mesencephalic dopamine neurons from excitotoxicity
in vitro. J Neurochem 68: 434436.
Mytilineou C, Leonardi EK, Radcliffe P et al. (1998). Depre-
nyl and desmethylselegiline protect mesencephalic
neurons from toxicity induced by glutathione depletion.
J Pharmacol Exp Ther 284: 700706.
Obeso JA, Rodriguez-Oroz MC, Rodriguez M et al. (2000).
Pathophysiology of the basal ganglia in Parkinsons
disease. TINS 81: S8S19.
Obinu MC, Reibaud M, Blanchard V et al. (2002). Neuropro-
tective effect of riluzole in a primate model of Parkinsons
disease: behavioral and histological evidence. Mov Disord
17: 1319.
28 F. STOCCHI
Olanow CW (1992). A rationale for dopamine agonists as
primary therapy for Parkinsons disease. Can J Neurol
Sci 19: 108112.
Olanow CW, Calne D (1991). Does selegiline monotherapy
in Parkinsons disease act by symptomatic or protective
mechanisms? Neurology 42: 1326.
Olanow CW, Hauser RA, Gauger L et al. (1995). The effect
of deprenyl and levodopa on the progression of signs
and symptoms in Parkinsons disease. Ann Neurol 38:
771777.
Olanow CW, Fahn S, Langston JW et al. (1996a). Selegiline
and mortality: a point of view. Ann Neurol 40: 841845.
Olanow CW, Freeman TB, Kordower JH (1996b). Fetal
nigral transplantation as a therapy for Parkinsons disease.
TINS 19: 102109.
Olanow CW, Jenner P, Brooks D (1998a). Dopamine ago-
nists and neuroprotection in Parkinsons Disease. Ann
Neurol 44 (3): 167174.
Olanow CW, Myllyla VV, Sotaniemi KA et al. (1998b).
Effect of selegiline on mortality in patients with
Parkinsons disease: a meta-analysis. Neurology 51:
825830.
Olanow CW, Mytilineou C, Tatton WH (1998c). Status of
selegiline as a neuroprotective agent in Parkinsons Dis-
ease. Mov Disord 13 (S): 5558.
Olanow CW, Schapira AH, Le Witt PA et al. (2006).
TCH346 as a neuroprotective drug in Parkinsons disease:
a double-blind, randomised, controlled trial. Lancet Neurol
5 (12): 10131020.
Parkinson Disease Research Group in the United Kingdom
(1993). Comparisons of therapeutic effects of levodopa,
levodopa and selegiline, and bromocriptine in patients
with early, mild Parkinsons disease: three year interim
report. BMJ 307: 469472.
Parkinson Study Group (1989a). DATATOP: a multicenter
controlled clinical trial in early Parkinsons disease. Arch
Neurol 46: 10521060.
Parkinson Study Group (1989b). Effect of deprenyl on the
progression of disability in early Parkinsons disease.
N Engl J Med 321 (20): 13641371.
Parkinson Study Group (1993). Effects of tocopherol and
deprenyl on the progression of disability in early Parkin-
sons disease. N Engl J Med 328 (3): 176183.
Parkinson Study Group (1996a). The impact of extended
deprenyl and tocopherol treatment in Parkinsons disease
patients requiring levodopa. Ann Neurol 39: 2936.
Parkinson Study Group (1996b). The impact of extended
deprenyl and tocopherol treatment in Parkinsons disease
patients not requiring levodopa. Ann Neurol 39: 3745.
Parkinson Study Group (1996c). Effect of lazabemide on the
progression of disability in early Parkinsons disease. Ann
Neurol 40: 99107.
Parkinson Study Group (1998). Mortality in DATATOP: a
multicenter trial in early Parkinsons disease. Ann Neurol
43: 318325.
Parkinson Study Group (2000a). A multicenter randomized
controlled trial of remacemide hydrochloride as monother-
apy for PD. Neurology 54: 15831588.
Parkinson Study Group (2000b). Pramipexole vs levodopa as
initial treatment for Parkinson disease: a randomized con-
trolled trial. JAMA 284: 231238.
Pezzoli G, Strada O, Silani V et al. (1996). Clinical and
pathological features in hydrocarbon-induced parkinson-
ism. Ann Neurol 40: 922925.
Przuntek H, Conrad B, Dichgans J et al. (1999). SELEDO: a
5-year long-term trial on the effect of selegiline in early
Parkinsonian patients treated with levodopa. Eur J Neurol
6: 141150.
Rascol O, Brooks DJ, Korczyn AD et al. (2000). A five-year
study of the incidence of dyskinesia in patients with early
Parkinsons disease who were treated with ropinirole or levo-
dopa. 056 Study Group. N Engl J Med 342: 14841491.
Reed JC (2002). Apoptosis based therapies. Nat Rev Drug
Discov 1 (2): 111121.
Rodriguez MC, Obeso JA, Olanow CW (1998). Subthalamic
nucleus-mediated excitotoxicity in Parkinsons Disease: a
target for neuroprotection. Ann Neurol 44 (3): 175188.
Roy E, Bedard PJ (1993). L-deprenyl increases survival of
rat foetal nigral neurones in culture. Neuroreport 4:
11831186.
Schumacher JM, Ellias SA, Palmer EP et al. (2000). Trans-
plantation of embryonic porcine mesencephalic tissue in
patients with Parkinsons disease. Neurology 54:
10421050.
Shoulson I, Oakes D, Fahn S et al. (2002), and the Parkinson
Study Group (2002). The impact of sustained deprenyl
(selegiline) in levodopa-treated Parkinsons disease: a ran-
domized placebo-controlled extension. Ann Neurol 51:
604612.
Steiner JP, Hamilton GS, Ross DT et al. (1997). Neurotrophic
immunophilin ligands stimulate structural and functional
recovery in neurodegenerative animal models. Proc Natl
Acad Sci USA 94: 20192024.
Stocchi F (2000). Dopamine agonists in Parkinsons disease:
what is their role in early treatment? In: KJ Palmer (Ed.),
Drug Treatment Issues in Parkinsons Disease. Adis Inter-
national, Hong Kong, pp. 2740.
Tanner CM, Ottman R, Goldman SM et al. (1999). Parkinson
disease in twins: an etiologic study. JAMA 281: 341346.
Tatton WG, Greenwood CE (1991). Rescue of dying neu-
rons: a new action for deprenyl in MPTP parkinsonism.
J Neurosci Res 30: 666677.
Tatton WG, Ju WYL, Holland DP et al. (1994). ()-Deprenyl
reduces PC12 cell apoptosis by inducing new protein
synthesis. J Neurochem 63: 15721575.
Tatton WG, Chalmers-Redman RME, Ju WJH et al. (2002).
Propargylamines induce antiapoptotic new protein synth-
esis in serum- and nerve growth factor (NGF)-withdrawn,
NGF-differentiated PC-12 cells. J Pharmacol Exp Ther
301: 753764.
Tetrud JW, Langston JW (1989). The effect of deprenyl
(selegiline) on the natural history of Parkinsons disease.
Science 245: 519522.
Turski L, Bressler K, Rottig KJ et al. (1991). Protection of
substantia nigra from MPP neurotoxicity by NMDA
antagonists. Nature 349: 414418.
 NEUROPROTECTION IN PARKINSONS DISEASE: CLINICAL TRIALS
Uitti RJ, Rajput AH, Ahlskog JE et al. (1996). Amantadine
treatment is an independent predictor of improved survival
in Parkinsons disease. Neurology 46: 15511556.
Waldmeir PC, Boulton AA, Cools AR et al. (2000). Neuro-
rescuing effects of the GAPDH ligand CGP 3466B.
J Neural Transm 60: 197214.
Watts R. (2002). Neurology abst.
Whone AL, Remy P, Davis MR et al. (2002). Neurology
abst.
29
Wu RM, Chieuh CC, Pert A et al. (1993). Apparent antioxi-
dant effect of I-deprenyl on hydroxyl radical formation
and nigral injury elicited by MPP in vivo. Eur J Pharma-
col 243: 241247.
Youdim MB, Weinstock M (2001). Molecular basis of neu-
roprotective activities of rasagiline and the anti-Alzheimer
drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl
methyl carbamate]. Cell Mol Neurobiol 21: 555573.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 32

Levodopa

THOMAS D. HALBIG1* AND WILLIAM C. KOLLER2

1
Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA
2
Department of Neurology, University of North Carolina, NC, USA

32.1. History Hornykiewicz, 1960). Based on these findings, only 1 year

The English physician James Parkinson from London
first described Parkinsons disease (PD) in 1817. Since
then several different drugs have been employed to treat
PD symptomatically. The first therapeutic agents that
were proven to be clinically effective were anticholiner-
gics. Charcot and Ordendstein in the early 1860s at the
Salpetriere in Paris treated patients with belladonna
compounds. However, therapeutic efficacy of treatments
with potato plant extracts such as belladonna and atro-
pine was disappointing. This changed with the introduc-
tion of synthetic anticholinergics in the 1940s, which
had fewer side-effects and provided better symptomatic
control, in particular of tremor and rigidity.
It was only in the mid-1960s that replacement therapy
with levodopa was introduced and marked the turning
point, eventually leading to a revolution in symptomatic
therapy of PD (for review, see Tolosa et al., 1998;
Hornykiewicz, 2002). Levodopa treatment became the
so-far only true success story in the symptomatic treatment
of a neurodegenerative disorder and PD in particular. The
key for the establishment of dopaminergic replacement
therapy was the hypothesis that dopamine deficiency is
the pathophysiological basis of PD. The work of Arvid
Carlson in Lund in Sweden paved the ground for the estab-
lishment of this assumption. In the late 1950s Carlson
observed that reserpine-treated rabbits present a clinical
picture with parkinsonian features and that these symp-
toms could be reversed by injection of the norepinephrine
precursor DL-dopa. Carlson furthermore provided experi-
mental evidence for the presence of dopamine in the stria-
tum. In 1960, Ehringer and Hornykiewicz in Vienna
finally demonstrated neuropathological evidence for
striatal dopamine deficits of PD patients (Ehringer and
later, Birkmayer and Hornykiewicz administered levo-
dopa in an open trial intravenously in 20 patients and
reported marked improvements of all motor symptoms
(Birkmayer and Hornykiewicz, 1961). However, several
other trials provided conflicting results on the efficacy of
levodopa and a double-blind study published in 1966
reported a negative result (Fehling, 1966). The clinical
breakthrough in levodopa treatment of PD is grounded
on the seminal work of the American Cotzias (Cotzias
et al., 1967). In a placebo-controlled trial, he escalated
doses of externally administered levodopa up to 16 g and
observed marked effects on all cardinal symptoms of PD.
Based on several other confirmatory controlled trials, the
US Food and Drug Administration (FDA) finally
approved levodopa for use in PD in 1970. Since then
it has become the gold standard in the symptomatic
treatment of PD.
32.2. Dopamine pharmacology
32.2.1. Synthesis and storage
Dopamine (3,4-dihydroxyphenylethylamine) is a mono-
amine belonging to the family of catecholamines. In
mammalians, it is synthesized in nerve terminals via
intermediate products in several steps (Webster, 2001).
L-Tyrosine is considered the initial substrate for the
synthesis of levodopa (Fig. 32.1). It is synthesized from
phenylalanine. L-Tyrosine is hydroxylated by tyrosine
hydroxylase (TH) at position 3 of the phenyl ring to
L-3,4-dihydroxyphenylalanine (levodopa). Tyrosine is
present in all catecholamine-containing neurons and
requires tetrahydrobiopterin and oxygen as cofactors.
Tyrosine hydroxylase is a rate-limiting enzyme in
the synthesis of dopamine and higher concentrations

*Correspondence to: Thomas D. Halbig, MD, Centre dInvestigation Clinique et Federation des Maladies du Systeme Nerveux,
Centre Hospitalier Universitaire Pitie-Salpetriere, 47-83 Boulevard de lHopital, 75651 Paris cedex 13, France. E-mail: thomas.
halbig@psl.aphp.fr & halbig.psl@gmail.com, Tel: +33-1-42-16-19-50, Fax: +33-1-42-16-19-58.
32 T. D. HALBIG AND W. C. KOLLER
NH2 specific vesicular transport system and stored in
presynaptic vesicles.
CH2 CH COOH
Calcium-dependent mechanisms mediate the release
of dopamine into the synaptic cleft (von Bohlen und
Halbach and Dermietzel, 2002). More specifically,
Phenylalanine
action potentials induce calcium influx via voltage-
dependent channels, eliciting fusion of the storage vesi-
Phenylalanine hydroxylase cles with the presynaptic membrane and release of
dopamine into the synaptic cleft. After diffusing in the
NH2
synaptic cleft, the dopamine molecule binds at postsy-
naptic receptors, triggering a complex cascade of post-
CH2 CH COOH synaptic intracellular events and eventually leading to
either activation or inhibition of the postsynaptic neu-
HO ron. Nigrostriatal dopaminergic neurons implicated
Tyrosine in motor functions are characterized by continuous
firing (DeLong et al., 1983) with intermittent-burst firing
Tyrosine hydroxylase (Grace, 1991; Schultz, 1986). However, striatal intra-
synaptic dopamine levels are relatively constant and
NH2 ensure continuous dopaminergic receptor stimulation
HO CH2 CH COOH (DeLong et al., 1983; Moore et al., 1998).
The duration of action of dopamine at the postsynap-
tic receptors is a function of several factors, including
HO the amount of dopamine in the synaptic cleft, activation
DOPA
of presynaptic autoreceptors and active removal from
the synaptic cleft. The latter is in part determined
DOPA decarboxylase
by presynaptic reuptake of dopamine by dopamine
transporters (DAT). DAT is a glycoprotein of 619
amino acids (70 kDa). This rapid presynaptic reuptake
HO CH2CH2NH2
system recaptures about 80% of the released dopamine
(Giros and Caron, 1993). Intraneurally, the dopamine
HO that is reuptaken is transported through a specific vesi-
Dopamine
cular transport system and again stored in vesicles until
Fig. 32.1. Synthesis of dopamine from its precursors. Repro- upcoming release into the synaptic cleft. Another
duced from von Bohlen und Halbach and Dermietzel (2002)
important factor determining the amount of dopamine
with permission from Wiley-VCH Verlag Gmbh & Co. KG
in the synaptic cleft is the activation of dopaminergic
and the authors.
autoreceptors located at the presynaptic membrane.
These autoreceptors monitor the intrasynaptical dopa-
of tyrosine do not increase the amount of hydroxylated mine concentration and their activation inhibits the
levodopa. Levodopa is rapidly decarboxylated to 3,4- synthesis and release of dopamine, whereas their block-
dihydroxyphenethylamine (dopamine) by the cytosolic age enhances dopaminergic synthesis and release (von
aromatic amino acid decarboxylase (AADC) which splits Bohlen und Halbach and Dermietzel, 2002).
the carbon acid group of the amino acid. AADC is not
rate-limiting and higher concentrations of levodopa 32.2.2. Metabolization
increase the production of dopamine.
Although the highest concentrations of AADC are Dopamine is metabolized via two pathways to homova-
found in striatal nigrostriatal dopaminergic nerve nillic acid (HVA) (Webster, 2001). Both pathways
terminals (Lloyd et al., 1975; Melamed et al., involve the action of monoamine oxidase (MAO) and
1980; Trugman et al., 1991), there are other, alterna- catechol-O-methyltransferase (COMT). MAO is located
tive sites of levodopa decarboxylation. For example, in, or attached to, the intraneural mitochondria. There
there is also striatal decarboxylase activity in the are two MAO subtypes, A and B. MAO-A is found
terminals of serotonergic and noradrenergic neurons primarily in the gastrointestinal tract and has stronger affi-
and in capillary endothelial or glial cells (Trugman nity to serotonin (5-HT) and norepinephrine. MAO-B, in
et al., 1991). After dopamine is synthesized in dopa- contrast, has a higher affinity for dopamine. In the brain
minergic nerve terminals, it is transported through a 80% of MAO is formed by MAO-B (Squires, 1972).
 LEVODOPA
COMT is a cytoplasmic enzyme present throughout
the body (Guldberg and Marsden, 1975; Schultz et al.,
1989; Schultz and Nissinen, 1989; Mannisto et al.,
1992). Intracerebrally, there is no significant COMT
activity in presynaptic dopaminergic terminals, but
some activity is present postsynaptically and substan-
tial activity is located in glial cells (Guldberg and
Marsden, 1975; Mannisto and Kaakkola, 1999).
On the first pathway, MAO intraneurally oxidatively
deaminates dopamine to 3,4-dihydroxyphenylacetalde-
hyde, which in turn is dehydrogenated by aldehyde
dehydrogenase to dihydroxyphenylacetic acid (DOPAC)
(Fig. 32.2). DOPAC is methylated by COMT to HVA.
On the second pathway, COMT O-methylates dopa-
mine to 3-methoxytyramine (3-MT). 3-MT in turn is
deaminated by MAO to 3-methoxy-4-hydroxyphenyla-
cetaldehyde, which is dehydrogenated by aldehyde
dehydrogenase to HVA (Webster, 2001).
32.3. Pharmacology of orally administered
levodopa
Dopamine does not penetrate the bloodbrain barrier
and therefore cannot be used for symptomatic dopami-
nergic replacement therapy. However, levodopa does
cross the bloodbrain barrier. Orally administered
HO
HO
Dopamine
MAO
HO CH2CHO
HO
3,4-Dihydroxyphenylacetaldehyde
Aldehyde-
dehydrogenase
HO CH2COOH
HO
3,4-Dihydroxyphenylacetic acid
COMT
(DOPAC)
CH3O
HO
HVA
Fig. 32.2. Degradation of dopamine. Reproduced from von Bohlen und Halbach and Dermietzel (2002) with permission from
Wiley-VCH Verlag GmbH & Co. KG and the authors.
33
levodopa is actively resorbed at the level of the small
bowel. Resorption is mediated by an active transport
system, the energy-dependent large neutral amino acid
(LNAA) transport system (Nutt, 1992). Several factors
limit the amount of resorbed levodopa. Firstly, the
speed of gastric emptying can be decreased by auto-
nomic dysfunctions which have been found to be fre-
quent in PD (Edwards et al., 1992; Hardoff et al.,
2001; Pfeiffer, 2003). Transfer of orally administered
levodopa can also be delayed by concurrent food
intake (Djaldetti et al., 1996), with dietary LNAAs
such as lysine or phenylalanine in protein-rich food
competing with levodopa for transport across the gut
wall via the LNAA transport system.
Once absorbed, levodopa is metabolized peri-
pherally by AADC and COMT to dopamine and
3-O-methyldopa (3-OMD), reducing the bioavailabil-
ity of externally administered levodopa. Peripheral
levodopa half-life is thought to be 6090 minutes
(Sasahara et al., 1980; Nutt and Fellman, 1984; Hardie
et al., 1986; Fabbrini et al., 1988).
Levodopa crosses the bloodbrain barrier, again via
an LNAA transport system. Since simultaneous intra-
venous administration of levodopa and intake of pro-
tein-rich meals lead to diminished clinical efficacy, it
has to be assumed that levodopa transport via the
CH2CH2NH2
COMT
HO CH2CH2NH2
CH3O
3-Methoxytyramine (3-MT)
MAO
HO CH2CHO
CH3O
3-Methoxy-4-hydroxyphenylacetaldehyde
Aldehyde-
dehydrogenase
CH2COOH
34 T. D. HALBIG AND W. C. KOLLER
bloodbrain barrier again competes with dietary
LNAAs (Nutt et al., 1985). Due to peripheral absorp-
tion concurrence, peripheral degradation and competi-
tion with LNAA at the bloodbrain barrier, only 1%
of orally administered levodopa reaches the central
nervous system (CNS) (Mannisto et al., 1990).
After transfer via the bloodbrain barrier, levodopa
is decarboxylated by AADC to dopamine. The exact
site of decarboxylation of exogenous levodopa to
dopamine in the brain is unknown (Lloyd et al.,
1975; Melamed et al., 1980; Trugman et al., 1991).
Although probably most striatal AADC is located in
nigrostriatal dopaminergic nerve terminals, decarboxy-
lase activity in the terminals of serotonergic and nora-
drenergic neurons and in capillary endothelial cells
(Trugman et al., 1991) is likely involved in the decar-
boxylation of exogenous levodopa. This is important,
since nigrostriatal dopaminergic AADC activity dimi-
nishes in the course of the progressive dopaminergic
nigrostriatal cell degeneration.
Based on research using animal models, it has
to be assumed that the exogenous dopamine com-
plements remaining endogenous dopamine and is
taken up by nigrostriatal nerve terminals, increasing
striatal dopamine levels (Hornykiewicz, 1974; Horne
et al., 1984). Both the endogenous and exogenous
dopamine are presumably stored in storage vesicles
and subsequently released into the synaptic cleft in
order to mediate its effects via stimulation of post-
synaptic dopaminergic receptors as well as presy-
naptic autoreceptors. Further metabolization underlies
the same mechanisms as described for endogenous
dopamine.
32.4. Dopa-decarboxylase inhibition
Although initial attempts to treat PD using oral levo-
dopa permitted the reduction of symptoms to some
extent, the overall outcome was frustrating. In their
seminal paper published in the New England Journal
of Medicine, Cotzias and colleagues (1967) reported
symptom reduction by oral administration of levodopa
but also marked side-effects. Since only 1% of ad-
ministered levodopa eventually reached the CNS, initi-
ally used doses had to be very high. Due to peripheral
O OH
HO
HO
OH
H3C
NH2 HO
HO
Levodopa Carbidopa
Fig. 32.3. Chemical structures of levodopa, carbidopa and benserazide.
decarboxylation of levodopa to dopamine, patients
experienced intolerable side-effects, such as nausea
or hypotension, resulting from stimulation of periph-
eral dopamine receptors (see section 32.6). Thus,
major problems related to levodopa administration in
initial trials were insufficient efficacy related to
marked side-effects. In consequence, levodopa-only
therapy was not a practical therapeutical option to be
used in most patients.
This changed dramatically when evidence for the
pharmacological and clinical effects of peripheral inhi-
bition of decarboxylase was obtained. For example,
Bartholini et al. (1967) demonstrated that the inhibi-
tion of peripheral decarboxylase enhanced the concen-
tration of cerebral catecholamines. More importantly,
different peripherally acting decarboxylase inhibitors
when coadministered with levodopa were shown to
allow administration of levodopa doses which were
about four times lower than the levodopa-only admin-
istration. Compatible with this, combined administra-
tion of levodopa and AADC led to diminished
dopaminergic side-effects and more efficient and fas-
ter symptom control (Birkmayer, 1969; Cotzias et al.,
1969; Calne et al., 1971; Yahr et al., 1971; Sweet
et al., 1972; Howse and Matthews, 1973; Papavasiliou
et al., 1973; Cedarbaum et al., 1986). In 1975, com-
binations of the AADCs a-methyldopa hydrazine
(carbidopa) and RO44602 (benserazide) plus levo-
dopa were commercialized as Sinemet and Madopar
and since then have been used for symptomatic
dopaminergic replacement therapy (Fig. 32.3).
The pharmacokinetics of carbidopa and beneserazide
differ. Benserazide in conjunction with levodopa leads
to earlier and higher peak dopa levels which decline ear-
lier compared to carbidopa. However, pharmacological
differences between both AADCs in general are not
reflected clinically (Greenacre et al., 1976; Rinne and
Molsa, 1979; Lieberman et al., 1984; Troconiz et al.,
1998). To ensure therapeutic levodopa efficacy without
peripheral side-effects, complete peripheral inhibition
of dopa-decarboxylase is desirable. Although it is gener-
ally agreed that a daily dose of at least 75 mg is needed
to achieve clinically satisfactory inhibition of decar-
boxylase activity, higher doses of up to 290 mg/day
of carbidopa have been shown to increase levodopa
NH2
COOH
HO NH OH
NH NH
NH2 O
HO
Benserazide
 LEVODOPA
bioavailability and decrease time to peak plasma con-
centration (Cedarbaum et al., 1986). It is conceivable
that further increase in carbidopa doses may lead to
penetration of carbidopa through the bloodbrain bar-
rier and consecutive inhibition of levodopa conversion
to dopamine. Yet, there are no data at that point to
support this conclusion.
The administration of AADCs doubles the bioavail-
ability of orally administered levodopa and halves its
plasma clearance (Nutt et al., 1985). Administration of
standard oral levodopa preparations, including AADC,
in general leads to Cmax after 1545 minutes (Nutt and
Fellman, 1984). Plasma half-life is mainly determined
by distribution in tissues and hepatic first-pass effects
and varies between 1 and 1.5 hours (Nutt and Fellman,
1984; Hardie et al., 1986; Fabbrini et al., 1988).
32.5. Clinical effects of levodopa on
Parkinsons disease symptoms
After initial trials (Birkmayer and Hornykiewicz,
1961; Barbeau et al., 1962) with encouraging yet
controversial results, the first study reporting rather
consistent beneficial effects of levodopa on PD motor
symptoms was published in 1967 (Cotzias et al.,
1967). In this ground-breaking report of an open-label
study, Cotzias and colleagues were able to show the
efficacy of levodopa in 16 PD patients with a mean
disease duration of 7.8 years (range 132 years).
Patients received levodopa (DL-dopa) at a dose of
316 g (without AADC) or placebo. The clinical
assessment included handwriting, number of steps
required to walk 10 meters, grasping objects, drawing,
sit-to-stand maneuver, rigidity, tremor, festination,
dysarthria and muscle strength. Eight patients showed
either complete or marked sustained improvements of
symptoms, including tremor, rigidity, festination and
hypomimia, and 2 patients showed mild improvements.
Cotzias et al. already noted that rigidity decreased
or disappeared at low doses whereas improvements in
tremor were observed on higher doses. However, it took
5 more years until again Cotzias demonstrated that
coadministration of a peripheral dopa-decarboxylase
inhibitor reduced the side-effects of levodopa therapy
significantly by allowing the use of markedly lower
doses of levodopa (Papavasiliou et al., 1972). Since
then, levodopa therapy (in the following, levodopa
denominates levodopa AADC) was extensively used
and soon became established as the gold standard of
symptomatic antiparkinsonian therapy.
Interestingly, even though worldwide clinical use
supported the view that levodopa is a highly effective
agent in the treatment of motor symptoms in PD,
it took about 30 years until the first prospective
35
randomized double-blind placebo-controlled trial test-
ing the efficacy of levodopa was initiated in 1999
(Parkinson Study Group, 2004a). The Early Versus
Late L-Dopa (ELLDOPA) study tested the effects of
levodopa on disease progression in de novo PD
patients with a mean age of 64 years and a disease
duration of 2 years. Baseline modified HoehnYahr
scores (Hoehn and Yahr, 1967; Fahn et al., 1987) were
less than 3, total Unified Parkinsons Disease Rating
Scale (UPDRS) score (Fahn et al., 1987) was about
27 and UPDRS III (motor score) was about 19. Sub-
jects were randomly assigned to receive placebo or
levodopa/carbidopa at a dose of 50/12.5 mg three
times daily, 100/25 mg three times daily or 200/50 mg
three times daily, respectively. Doses were increased
to the full amount over a period of 9 weeks in a blinded
fashion. For clinical evaluation, the UPDRS was used
at the screening, baseline and interim visits (at the
end of weeks 3, 9, 24 and 40) and during each of the 2
weeks of a subsequent washout phase. During the
four interim visits, the evaluations were performed
before the administration of the first dose of the study
drug. Of a total of 361 subjects enrolled in the study, 317
(88%) took the study medication for 40 weeks. The
patients in the placebo group had mild improvement
at the week 3 visit, but after that their symptoms
worsened steadily throughout the study period, including
the 2-week washout phase (Fig. 32.4). In contrast, in
patients treated with levodopa, a strong doseresponse
benefit that persisted through week 40 was detected.
12
10
Change in Total Score (units)
8
Placebo
6
4
2 150 mg
0
300 mg
2
4 600 mg
6
8
2 6 10 14 18 22 26 30 34 38 42 46
Baseline Week Withdrawal
of study drug
Fig. 32.4. Early Versus Late L-Dopa (ELLDOPA) study
Unified Parkinsons Disease Rating Scale (UPDRS) changes.
Changes in total scores on the UPDRS from baseline through
evaluation at week 42. The points on the curves indicate mean
changes from baseline in the total scores at each visit. Nega-
tive scores on the curves indicate improvement from baseline.
The bars indicate the standard error. From Parkinson Study
Group (2004a), reproduced with permission. # 2004 Massa-
chusetts Medical Society. All rights reserved.
36 T. D. HALBIG AND W. C. KOLLER
Improvements in the levodopa-treated patients reached a
peak at week 24 in patients receiving the highest dose of
600 mg. At week 24, improvements were found to be
dose-dependent with a decrease of 6 points in the 600
mg group, 4 points (300 mg), no change (150 mg) and
worsening by 4 points in the placebo group. The scores
on the UPDRS in the three levodopa groups worsened
during the 2-week washout period, but these groups did
not deteriorate to the level observed in the placebo group
and the group receiving the highest dose of levodopa had
the best result.
Compatible with these results are findings from stu-
dies assessing the effects of other antiparkinsonian
agents such as dopamine agonists (Rinne et al., 1998b;
Parkinson Study Group, 2000, 2004b; Rascol et al.,
2000) or levodopa slow-release preparations in de novo
patients (Dupont et al., 1996; Block et al., 1997; Koller
et al., 1999) against levodopa as comparator. These
trials assessed de novo patients with a disease duration
of approximately 2 years and patients were followed
for up to 5 years. In the agonist vs levodopa trials,
patients of both treatment conditions usually could
receive additional levodopa when study medication
did not allow sufficient symptom control. Results
obtained in levodopa-only-treated patients consistently
showed improvements of motor functions of up to
30% as assessed by the UPDRS at the end of the study
periods (Table 32.1). Compared to dopamine agonist-
treated patients, studies show significantly greater
improvement in patients treated with levodopa only and
support the notion that levodopa is the most effective
agent in the symptomatic treatment of PD.
32.6. Tolerability and acute non-motor
side-effects
Apart from the nigrostriatal dopaminergic system
which is the target of dopaminergic replacement
therapy in PD, there are several other different central
and peripheral dopaminergic systems (Webster, 2001).
External administration of dopaminergic agents may
therefore exert peripheral, central and combined per-
ipheral and central effects and side-effects. As for the
motor effects, controlled data on side-effects are
mainly obtained from the ELLDOPA study and trials
comparing the effects of different dopaminergic agents
with levodopa as comparator. The most frequent non-
motor side-effects include nausea, sedation, hypoten-
sion and neuropsychiatric symptoms (Table 32.2).
32.6.1. Nausea
The most frequent side-effect in levodopa-treated
patients is nausea, occurring in up to 30% of patients
during treatment initiation (Rinne et al., 1998b;
Parkinson Study Group, 2000, 2004a). Nausea devel-
oped in a dose-dependent way and in the ELLDOPA
study occurred on daily doses as low as 150 mg in
16%, on 300 mg in 26% and on 600 mg in 31% of
patients (Parkinson Study Group, 2004a). Nausea and
vomiting are considered peripheral side-effects of levo-
dopa treatment. They are mediated via dopaminergic sti-
mulation of the area postrema which is located at the
bottom of the fourth ventricle outside the bloodbrain
barrier and involved in the regulation of nausea and
emesis.
In most patients, nausea resolves within days or
weeks of continued levodopa treatment without any
additional action being taken. When nausea persists,
temporary dose reduction and slower levodopa reti-
tration may be tried. Furthermore, several agents
are available to prevent or reduce gastrointestinal
side-effects. For example, peripherally acting dopa-
mine receptor blockers may be employed in order
to avoid dopaminergic receptor stimulation of the
area postrema. Domperidone is a peripherally acting
dopamine-2 (D2) receptor antagonist that does not
penetrate the bloodbrain barrier and has a half-life
of more than 10 hours. Its time to maximum peak
level is about 3060 minutes (Huang et al., 1986).
Domperidone has no significant effect on dopamine
pharmacokinetics (Bradbrook et al., 1986). It is
administered in a dose of 1020 mg per dose of
levodopa. Domperidone has been shown to be as
efficient as carbidopa (see below) in preventing nau-
sea and vomiting as side-effects of levodopa
(Langdon et al., 1986; Barone, 1999). Domperidone
is approved in Europe (Motilium) and Canada but is
unavailable in the USA.
Another option is the add-on of trimethobenzamide
hydrochloride. Although its mechanism of action is
not entirely understood, it may also involve the
chemoreceptor trigger zone of the area postrema.
There are no controlled studies on the effects of
trimethobenzamide hydrochloride in PD; however,
the administration of 200 mg three times daily has
been recommended for the treatment or prevention
of dopaminergically induced nausea and vomiting
(Olanow et al., 2001). Trimethobenzamide is mar-
keted in the USA as Tigan and not available in most
European countries.
Furthermore, additional carbidopa may be added
to the levodopa regimen (Markham et al., 1974).
Carbidopa alone is available as Lodosyn in the USA.
Other agents which may be employed are the 5-HT
receptor antagonist (5-HT3) ondansetron (Wilde and
Markham, 1996) or the antiemetic diphenidol (Duvoisin,
1972).
Table 32.1
Symptomatic motor effects of long-term levodopa (LD) treatment (25 years) reported in phase III studies assessing the effects of dopamine agonists (1, 3, 4, 5) or
controlled release LD (2) against LD as comparator in drug-naive Parkinsons disease (PD) patients

Change in Change in
n at Age H&Y PD duration UPDRS lll UPDRS ll Study duration Levodopa UPDRS lll UPDRS ll
Reference Agents baseline (years) stage months baseline baseline months mg/day at end at end

1 LD 204 62.6 13 24 29.1 NR 48 500
9
2.7*

(cabergoline) (208) (60.5) (22.8) (27.5) (
6) (
2.4*)
2 LD 306 Range 13 Overall 27.6 15.1 8.7 60 426
0.4 0.1

LEVODOPA
(controlled (312) 3075 (15.4) (9.4) (
1.2) (
1.0)
release LD)
3 LD 150 60.9 13 21.6 22 8.3 23.5 509
7.3
2.2
(pramipexole) (151) (61.5) (18) (22.3) (9.1) (
3.4) (
1.1)
4 LD 150 60.9 13 21.6 22 8.3 48 702
3.4 0.5
(pramipexole) (151) (61.5) (18) (22.3) (9.1) (1.3) (1.7)
5 LD 89 63.0 13 30 21.7 8 60 753
4.8 0
(ropinirole) (179) (63.0) (29) (21.5) (8) (
0.8) (1.6)

1, Rinne et al. (1998b); 2, Koller et al. (1999); 3, Parkinson Study Group (2000); 4, Parkinson Study Group (2004b); 5, Rascol et al. (2000).
H&Y, Hoehn and Yahr; UPDRS, Unified Parkinsons Disease Rating Scale; *, % value; NR, not reported.

37
 38
Table 32.2
Side-effects of levodopa within up to 5 years of treatment in controlled studies assessing the effects of LD against dopamine agonists (1, 3, 4), controlled release LD (2)
and placebo (5) as comparator

Withdrawal
Study Hallucinations Orthostatic rate for

T. D. HALBIG AND W. C. KOLLER

Refer- duration Mean LD Nausea/ Sleep (14)/abnormal hypoten- adverse
ences Agents n (months) dose (mg) vomiting* Somnolence* disturbances* dreaming (5)* sion* events*

1 LD (cabergoline) 204 48 500 32 NR 28 NR 24 13

(208) (37) (27) (32) (16)
4 LD 306 60 426 28 6 2 5 2 9
(LD controlled (312) (26) (6) (4) (4) (3) (7)
release)
2 LD (pramipexole) 150 23.5 509 36.7 17.3 22.0 3.3 10 8.0
(151) (36.4) (32.4) (25.8) (9.3) (6.0) (10.6)
3 LD 89 60 753 49.4 19.1 23.6 5.6 12.4 33
(ropinirole) (179) (48.6) (27.4) (25.1) (17.3) (11.7) (27)
5 LD 92 10 150 16.3 0 8.7 3.3 2
(placebo) (90) (13.3) (2.2) (10.0) (0) (3)
5 LD 88 10 300 26.1 5.7 4.5 0 2
(placebo)
5 LD 91 10 600 31.9 5.5 5.5 5.5 1
(placebo)

1, Rinne et al. (1998b); 2, Koller et al. (1999); 3, Parkinson Study Group (2000); 4, Rascol et al. (2000); 5, Parkinson Study Group (2004a).
* indicates % of patients; NR, not reported.
 LEVODOPA
32.6.2. Hypotension
Since the introduction of levodopa as symptomatic PD
therapy, orthostatic hypotension has been reported as a
side-effect (Calne, 1970; Calne et al., 1970). However,
the data on the specific acute and long-term effects of
levodopa on hypotension are controversial and vary
depending on methodological differences. Orthostatic
hypotension occurs in 030% of PD patients without
major comorbidity during the first 35 years of treat-
ment in the early stages of the disease (Rinne et al.,
1998b; Parkinson Study Group, 2000, 2004a). Interest-
ingly, the ELLDOPA trial did not report any incidence
of orthostatic hypotension. Compatible with this
result, several other studies did not find acute effects
of levodopa administration (Sachs et al., 1985; Meco
et al., 1991; Senard et al., 1995). On the other hand,
higher doses of stable levodopa or dopamine agonist
regimes or long-term treatment with levodopa may
be related to orthostatic hypotension (Camerlingo
et al., 1990; Senard et al., 1997). The conflicting data
may be explained by the fact that, at least in some
PD patients, disease-associated pre-existing cardiovas-
cular dysfunction (Brevetti et al., 1990; Hakamaki
et al., 1998), disease duration and levodopa doses are
confounded. Compatible with this, a recent study pro-
vided evidence that levodopa aggravated pre-existent
impairment of the autonomic control of blood pressure
and heart rate in de novo patients (Bouhaddi et al.,
2004).
The mechanisms of orthostatic hypotension induced
by levodopa administration are complex and incom-
pletely understood. Lewy body degeneration has been
shown to be present in the sympathetic and parasym-
pathetic autonomic nervous system on various levels
(Wakabayashi et al., 1993; Kaufmann et al., 2004).
Peripherally, the sympathetic ganglions and parasym-
pathetic cardiac, myenteric and submucosal plexi have
been shown to be involved. Centrally, structures such
as the locus ceruleus, the hypothalamus and the dorsal
vagal nucleus are affected (Wakabayashi and Takaha-
shi, 1997). Compatible with these findings, evidence
suggests that orthostatic hypotension in PD reflects
neurocirculatory failure from generalized sympathetic
denervation (Goldstein et al., 2002; Li et al., 2002).
Based on these abnormalities, orthostatic hypotension
induction by dopaminergic agents might be subserved
peripherally by activation of postsynaptic D1-receptors
mediating vasodilatation and by activation of sym-
pathetic presynaptic D2-receptors (Langer, 1980;
Goldberg and Rajfer, 1985). The latter mechanism
induces reduced vasoconstrictor responses via inhibi-
tion of norepinephrine release (Bouhaddi et al., 2004).
However, peripheral inhibition of decarboxylation of
39
levodopa to dopamine by AADC does not entirely sup-
press the development of levodopa-induced hypoten-
sion. It thus is likely that central mechanisms are also
involved (see Ch. 14).
Symptomatic orthostatic hypotension may be trea-
ted by non-pharmacologic measures such as increased
salt and fluid intake, compressive stockings and sleep-
ing with head-up tilt of bed. Pharmacologic treatment
includes fludrocortisone acetate 0.050.2 mg/day (Hoehn,
1975; Hakamaki et al., 1998), indometacin 50 mg three
times daily (Abate et al., 1979), or midodrine hydro-
chloride, an alpha-adrenergic agonist at a dose of up
to 10 mg three times a day (Jankovic et al., 1993;
Low et al., 1997). Finally, domperidone may be tried.
Yet, although there is a pathophysiologically based
rationale for the employment of domperidone, clini-
cal evidence for its beneficial effects on orthostatic
hypotension is controversial (Merello et al., 1992;
Lang, 2001). Indeed, a recent study, though demon-
strating an increase of blood pressure in apomor-
phine-treated PD patients, failed to show effects on
blood pressure drops in the supine position (Sigurdar-
dottir et al., 2001).
32.6.3. Neuropsychiatric side-effects
32.6.3.1. Hallucinations
Levodopa treatment in PD may cause a number of
neuropsychiatric side-effects. These include hallucina-
tions, paranoid psychosis and, more rarely, impulsive
and compulsive behavior. Based on the reported
controlled studies (Table 32.2), the incidence of hallu-
cinations is rather low: 35% during the first 35 years
of treatment. However, patients in these trials were a
selected population early in the disease. In later stages
of the disease with higher daily levodopa doses and
in patients with additional risk factors (see below),
levodopa-induced hallucinations and other neuropsy-
chiatric side-effects develop in 3050% of patients
(Sanchez-Ramos et al., 1996; Fenelon et al., 2000; de
Maindreville et al., 2005). Hallucinations are sensory
perceptions without external stimulation of the rele-
vant sensory organ (APA, 2000). They are distin-
guished from illusions in which objectively present
stimuli are perceived and then misinterpreted. Dopa-
minergically induced hallucinations are most often
visual; however, they may also present in other sen-
sory modalities (Holroyd et al., 2001). One study
detected auditory hallucinations in 8% of patients
who mostly also experienced visual hallucinations
(Inzelberg et al., 1998). Olfactory or tactile hallucina-
tions have also been reported to be present; however,
data are sparse and prevalence rates have to be
assumed to be rather low.
40 T. D. HALBIG AND W. C. KOLLER
The development of hallucinations is frequently
preceded by vivid dreaming which may further
develop into illusions (Pappert et al., 1999; Fenelon
et al., 2000). Vivid dreaming may lead to sleep frag-
mentation and daytime sleepiness. Illusions are initi-
ally often present during evenings and at night and
predominantly in twilight and darkness. Sometimes
patients report hallucinations of presence the physi-
cal feeling of the presence of persons or objects near
them, usually behind or beside them. Visual pheno-
mena have been described as being simple or complex.
Simple elementary hallucinations may be color
patches, lightnings or geometrical forms. Most fre-
quently patients visualize figural appearances of per-
sons or animals and less frequently unanimated
objects (Barnes and David, 2001). Figural appearances
usually appear normal; however, they may also be
present as distorted or demonic faces or grimaces.
Hallucinations in PD vary on several other characteris-
tics. They may be stationary or moving and may
develop at any time of the day but preferentially and
with longer episodes in the morning and evening
(Barnes and David, 2001). Their duration varies
between seconds and hours. The degree of incapacita-
tion due to hallucinations varies considerably between
patients. In many patients, hallucinations are benign
and patients have insight into the nature of their visual
experiences. In these patients, hallucinations may
occur sporadically and are often non-threatening.
Hallucinations may even be experienced as entertain-
ing and be integrated in artwork production. Although
exact data are lacking, patients suffering from benign
and infrequent hallucinations may present with a stable
clinical manifestation over years. However, in many
patients hallucinatory episodes are experienced as
frightening. Furthermore, frequently patients demon-
strate lack of insight into the nature of their visual
experiences. In many patients, hallucinations increase
in frequency of occurrence and severity and may even-
tually develop into full-blown psychosis (Sharf et al.,
1978). The presence of hallucinations is an important
disease complication and is the most frequent reason
for institutionalization of PD patients (Goetz and
Stebbins, 1993; Aarsland and Karlsen, 1999; Holroyd
et al., 2001).
The pathophysiological basis for levodopa-induced
hallucinations in PD is complex and likely involves
widespread disease-associated neuropathological
changes, including Lewy body degeneration and dopa-
minergic, cholinergic, noradrenergic and serotonergic
denervation in association with the effects of levodopa
supplementation. More specifically, in PD, it is not
only nigrostriatal dopaminergic neurons that degener-
ate. There is also degeneration of mesolimbic and
mesocortical dopaminergic pathways (Agid et al.,
1987). Dopaminergic denervation and chronic levo-
dopa treatment may lead to supersensitization of dopa-
minergic limbic D3- and D4-receptors. Based on
diminished presynaptic buffering capacity, the thera-
peutic non-physiological administration of levodopa
may lead to overstimulation of postsynaptic receptors
and induction of hallucinations (Moskovitz et al.,
1978). Compatible with the role of levodopa for the
induction of hallucinations in PD, dopamine receptor-
blocking agents have been found to alleviate psychotic
symptoms in PD patients (Friedman, 1991; Rabey
et al., 1995; Fernandez et al., 1999; French Clozapine
Parkinson Study Group, 1999; Parkinson Study Group,
1999). Even though treatment with levodopa and other
dopaminergic agents is a contributing factor for the
development of hallucinations in PD, not all patients
treated with dopaminergic agents develop hallucina-
tions. A recent study identified endogen factors
rather than the amount of levodopa doses as relevant
in the genesis of PD hallucinations (Merims et al.,
2004). Compatible with this, there is evidence that
the overall dose of dopaminergic drugs does not
significantly differ between patients with and without
hallucinations (Sanchez-Ramos et al., 1996; Klein
et al., 1997; Aarsland and Karlsen, 1999; Merims
et al., 2004). Furthermore, in one study, high doses
of intravenously administered levodopa did not induce
hallucinations in predisposed patients (Goetz et al.,
1998). Several cofactors have been discussed that
may increase the risk for hallucinations. These include
age, cognitive impairment, depression, sleep disorders,
PD severity, predominance of axial symptoms, ocular
disorders and genetic factors such as the apolipoprotein
E e 4 allele (Sanchez-Ramos et al., 1996; Inzelberg
et al., 1998; Aarsland and Karlsen, 1999; de la Fuente-
Fernandez et al., 1999; Arnulf et al., 2000; Fenelon
et al., 2000; de Maindreville et al., 2005). Furthermore,
treatment with other drugs used in PD therapy, including
dopamine agonists, dopamine-enhancing agents such as
MAO-B and COMT inhibitors, anticholinergic medica-
tions and amantadine have been shown to contribute
(de Smet et al., 1982; Perry et al., 1990; Steckler
and Sahgal, 1995). Furthermore, there is evidence
for an involvement of other than dopaminergic trans-
mitter systems in the pathogenesis of hallucinations
in levodopa-treated PD patients. It has been sugges-
ted that chronic levodopa treatment in conjunction
with serotonergic (5-HT) dysregulation contributes
to the induction of hallucinations. Neurodegeneration
in PD involves brainstem 5-HT neurons associated
with diminished central 5-HT levels. Chronic levodopa
administration may further lower 5-HT levels via
reuptake by 5-HT nerve terminals and conversion to
 LEVODOPA
dopamine (Markianos et al., 1982; Tohgi et al.,
1993). Compatible with this, the administration of
the 5-HT precursor L-tryptophan may reduce the fre-
quency and severity of hallucination in PD (Rabey
et al., 1977). On the other hand, serotonergic dener-
vation and chronic administration of levodopa have
been thought to lead to hypersensitivity of postsynap-
tic 5-HT receptors (Nausieda et al., 1983). Indeed,
blockage of serotonergic receptors using methyser-
gide or the 5-HT3 antagonist ondansetron appears to
alleviate psychotic symptoms in PD patients (Nau-
sieda et al., 1983; Zoldan et al., 1995).
Treatment of psychosis in PD can be difficult.
Although data on empirical validity are lacking, cur-
rently established treatment algorithms usually recom-
mend the identification of those agents in the
individual treatment schema carrying the biggest
potential for the induction of hallucinations. In gen-
eral, it is thought that agents that are major risk
factors for PD psychosis are those with the weakest
antiparkinsonian efficacy. If possible, agents should
be eliminated in the following order: anticholiner-
gics, amantadine, MAO-B inhibitors, dopamine ago-
nists and finally levodopa (Olanow et al., 2001).
Nevertheless, overall reduction of PD medication and
in particular of dopaminergic agents is often done at
the expense of deterioration of motor functions. In
order to prevent worsening of motor functions, the
alternative to decreasing dopaminergic medication is
the introduction of antipsychotic agents (Merims
et al., 2004).
In order to avoid extrapyramidal side-effects and
worsening of PD symptoms, for the treatment of
drug-induced psychosis, only atypical neuroleptics
should be used. A variety of atypical neuroleptics are
available. Atypical neuroleptics have lower D2 occu-
pancy than typical neuroleptics and block 5-HT2A
receptors. The latter mechanism may be responsible
for their antipsychotic effects (Meltzer, 1999). The
current gold standard for the treatment of psychosis
in PD is clozapine. Clozapine has relatively low D2
but strong affinity to 5HT2A receptors, as well as affi-
nity to histamine H1, muscarinergic and cholinergic
receptors. Clozapine has a strong antipsychotic effect
and does not induce motor side-effects (Friedman
and Lannon, 1989a; Kahn et al., 1991; French Cloza-
pine Parkinson Study Group, 1999; Parkinson Study
Group, 1999). Clozapine is slowly titrated, starting
with 12.5 mg at bedtime and may be increased to
75100 mg/day, which usually allows psychotic symp-
toms to be controlled. If necessary, daily doses may be
administered spread out throughout the day. Due to its
sedating effects, clozapine helps to control psychotic
symptoms, agitation and sleep disturbance when given
41
before bedtime. The administration of clozapine, how-
ever, is limited for pragmatic reasons due to its poten-
tial to induce neutropenia. Patients treated with
clozapine require frequent monitoring of white blood
counts, particularly during treatment initiation (Dewey
and OSuilleabhain, 2000; Brandstadter and Oertel,
2002; Morgante et al., 2004). Monitoring of white
blood cell count and absolute neutrophil count should
be based on stage of therapy with monitoring weekly
for 6 months, every 2 weeks for 6 months and every
4 weeks ad infinitum (Novartis Pharmaceuticals
Corporation, 2005).
Alternatively, quetiapine, another atypical neuro-
leptic can be used. Quetiapine also blocks dopaminer-
gic and serotonergic receptors and has affinity to
histamine H1 with only small affinity to muscarinergic
and cholinergic receptors (Dewey and OSuilleabhain,
2000; Ondo et al., 2005). In a randomized, open-label,
blinded-rater, parallel-group trial, quetiapine and
clozapine demonstrated equal efficacy and side-effect
profile in 45 patients with PD with drug-induced
psychosis (Morgante et al., 2004). However, a recent,
smaller placebo-controlled study failed to demonstrate
significant improvement on psychosis rating scales
(Ondo et al., 2005). The starting dose for quetiapine
is 2550 mg at bedtime and the dose may be increased
about every third day up to 125 mg/day.
Another atypical antipsychotic medication with low
affinity for D2-receptors is olanzapine. However,
double-blind, placebo-controlled evaluations of effi-
cacy and safety profile revealed no significant
improvement of hallucinations but worsening of motor
function (Breier et al., 2002; Ondo et al., 2002).
Recently, a new class of neuroleptics with function-
ally selective action mechanisms was introduced. For
example, aripriprazole has partial D2 dopamine ago-
nistic and antagonistic characteristics as well as partial
agonism at 5-HT1A and partial antagonism at 5-HT2A
receptors (Naber and Lambert, 2004). Its pharmacolo-
gical characteristics suggest a low-profile risk of extra-
pyramidal side-effects. However, since preliminary
case studies reported significant motor side-effects,
aripriprazole cannot currently be recommended as
first-line treatment for drug-induced psychosis in PD
(Fernandez et al., 2004; Schonfeldt-Lecuona and
Connemann, 2004).
32.6.3.2. Impulse control deficits
Recently, it has been appreciated that impulse control
deficits may develop in PD associated with dopaminergic
therapy (Vogel and Schiffter, 1983; Uitti et al., 1989;
Fernandez and Friedman, 1999; Molina et al., 2000;
van Deelen et al., 2002; Driver-Dunckley et al., 2003;
Kurlan, 2004). Impulsivity is the failure to resist an
42 T. D. HALBIG AND W. C. KOLLER
impulse, drive or temptation that is harmful to oneself
or others (Hollander and Evers, 2001). The Diagnos-
tic and Statistical Manual of Mental Disorders
(DSM-IV: APA, 2000) classifies conditions such
as intermittent explosive disorder (failure to resist
aggressive impulses), kleptomania (failure to resist
urges to steal items) or pathological gambling (failure
to resist the impulse to gamble despite severe perso-
nal, family or vocational consequences) as impulse
control disorders. Although classified separately,
hypersexuality and punding (see below) are other
examples of deficits of impulse control.
Pathological gambling and hypersexuality have
recently been reported to be present in PD (Molina
et al., 2000; Seedat et al., 2000; Gschwandtner et al.,
2001; Driver-Dunckley et al., 2003; Montastruc
et al., 2003; Avanzi et al., 2004; Dodd et al., 2005).
For example, Molina et al. presented a series of 12
PD patients (out of a cohort of 250: 4.9%) with patho-
logical gambling. Symptoms in 9 patients developed
after initiation of levodopa therapy. Other reports note
the first occurrence of pathological gambling in asso-
ciation with a dose increase of dopaminergic drugs
(Gschwandtner et al., 2001). One retrospective data-
base study identified 9 out of 1884 patients with patho-
logical gambling (Driver-Dunckley et al., 2003). The
study reports an overall incidence of 0.05% and a
slightly higher incidence of 1.5% in patients treated
with levodopa and a dopamine agonist.
Hypersexuality (paraphilia-related disorder) has
repeatedly been reported in smaller case series and case
studies of PD patients in association with the adminis-
tration of dopaminergic drugs (Quinn et al., 1983;
Vogel and Schiffter, 1983; Uitti et al., 1989; van Deelen
et al., 2002; Berger et al., 2003). Compulsive behavior
has also been described in PD. Compulsive behavior
is characterized by stereotypical motor behavior accom-
panied by an intense fascination with a particular
object. For example, repetitive handling and examining
of mechanical objects (punding) have been observed in
single cases of PD and could be related to the overall
dose of dopaminergic medication (Fernandez and
Friedman, 1999; Evans et al., 2004).
These observations have raised concern that dopa-
minergic agents, including levodopa, may be asso-
ciated with the induction of impulse control deficits.
Although the mentioned impulse control deficits differ
regarding their phenomenological presentation and
neurobiological basis, they have commonalities. For
example, compulsive and impulsive control deficits
are characterized by the decreased ability of the indivi-
dual to inhibit motor responses to affective states
which might critically depend on dopaminergic neuro-
modulation. More specifically, animal research and
clinical studies have shown that the monoamines
5-HT and dopamine affect sexual behavior (Melis
and Argiolas, 1995; Kafka, 2003). Furthermore, the
mesolimbic-mesocortical dopaminergic system pre-
sumably has an important role in several aspects of
reward mechanisms and behavioral impulse control
which have been shown to be dysfunctional in patholo-
gical gambling (Fiorillo et al., 2003). The occurrence
of impulse control deficits in PD during dopaminergic
treatment might therefore be interpreted as behavioral
abnormalities induced by overstimulation of dopamine
receptors in denervated mesolimbic structures. Geneti-
cally determined traits might explain why these pro-
blems are induced in only some PD patients (Menza
et al., 1993; Noble, 2000).
However, for methodological restrictions, the
above-cited studies are inconclusive. Furthermore,
data on the prevalence of impulse control deficits in
the general population are not well established and
vary depending on the methods of assessment (Shaffer
and Hall, 1996). In summary, due to methodological
restrictions and limited data, the implications of these
findings are still open. Yet, patients rarely volunteer
to report behavioral abnormalities and their assessment
is not part of the clinical routine in most movement
disorders centers. The prevalence of impulse control
deficits induced by dopaminergic agents, including
levodopa, therefore may be considerable.
32.6.4. Melanoma
Levodopa treatment has been thought to be related to
the development of malignant melanoma. Based on
several case reports on the co-occurrence of PD and
malignant melanoma, the diagnosis of malignant mel-
anoma or the presence of suspicious, undiagnosed skin
lesions has been determined as a contraindication for
the use of levodopa (Physicians Desk Reference,
2003).
The putative causal connection between levodopa
treatment and malignant melanoma was based on the
fact that levodopa is an important substrate for the
formation of melanin. Within the melanocyte, tyrosine
is converted to dopa and then to dopaquinone via
the bifunctional enzyme tyrosinase. Dopaquinone
is further oxidized to form the pigment melanin
(Kincannon and Boutzale, 1999). It was hypothesized
that exogenous levodopa may increase the production
of melanin and promote malignant transformation of
the melanocytes. However, there is no experimental
evidence for this assumption. In contrast, in experi-
mental tumor systems with human and murine mela-
noma cells, levodopa and dopamine had antitumor
activity (Wick, 1979, 1980, 1987, 1989).
 LEVODOPA
Since the first report of malignant melanoma in PD
in 1972 (Skibba et al., 1972), a total of 54 cases have
been reported in the literature (Weiner et al., 1993;
Fiala et al., 2003). Interpretation of these rare cases
with respect to a causal link of levodopa administra-
tion and tumor induction is difficult for a variety of
reasons. Firstly, both PD and malignant melanoma
are highly prevalent conditions, in particular in the
elderly population (Thompson et al., 2005). Based on
the small reported numbers and deficient documenta-
tion of cases, it is therefore not possible to determine
whether co-occurrence of levodopa and malignant
melanoma is coincidental or not (Fiala et al., 2003).
Secondly, pathogenesis of malignant melanoma and
the time gap between exposure to carcinogens and
tumor manifestation are thought to take years to dec-
ades. Given the variety of risk factors for melanoma,
including genetic predisposition with tyrosine kinase
gene mutation, family history, sun exposure, skin
phenotype and history of skin lesion (Thompson
et al., 2005), it is difficult to determine statistical
probabilities for the role of exogenous levodopa.
In conclusion and despite continued warning, based
on experimental and epidemiological data, there is at
present no evidence for a causal relation between
levodopa therapy and malignant melanoma.
32.6.5. Hyperhomocysteinemia
Recently, elevated plasma homocysteine levels have
been described in PD patients treated with levodopa
(Allain et al., 1995; Kuhn et al., 1998; Muller et al.,
1999, 2001; Lamberty and Klitgaard, 2000; Yasui
et al., 2000, 2003; Miller, 2002; Miller et al., 2003;
Nakaso et al., 2003; Rogers et al., 2003; Genedani
et al., 2004; OSuilleabhain et al., 2004a). These findings
raised the question of whether levodopa treatment is a
risk factor for hyperhomocysteinemia (Postuma and
Lang, 2004). Hyperhomocysteinemia in turn is a risk
factor for vascular disease (Perry et al., 1995; Bostom
et al., 1999a, b), possibly for dementia (Seshadri et al.,
2002; Luchsinger et al., 2004; Wright et al., 2004) and
is potentially neurotoxic (Duan et al., 2002). It is thus
possible that the risk for these conditions is increased
in PD patients receiving levodopa.
The mechanisms for increased plasma homocysteine
are most likely associated with peripheral metabolization
of levodopa and more specifically the O-methylation
of levodopa by COMT (see section 32.3) (Postuma and
Lang, 2004). O-methylation of levodopa by COMT
requires S-adenosylmethionine (SAM) as methyl donor.
Demethylation of SAM forms S-adenosylhomocysteine
which is converted to homocysteine. Since levodopa
administration leads to increased metabolic levodopa
43
turnover and the conjunction with an AADC shifts per-
ipheral levodopa metabolization to the COMT pathway,
levodopa therapy may lead to increased plasma homo-
cysteine levels (Morris, 2003).
Yet, the clinical importance of elevated plasma
homocysteine levels in levodopa-treated PD patients is
far from understood. First of all, data on atherosclerosis
and PD are controversial. Several studies found an
increased risk in PD patients for death from stroke and
coronary artery disease (Gorell et al., 1994; Ben-
Shlomo and Marmot, 1995) and an increased risk for
intima media thickness of the carotid artery in patients
undergoing levodopa treatment (Nakaso et al., 2003).
These findings were not confirmed by other studies
(Struck et al., 1990; Korten et al., 2001; Mastaglia
et al., 2002; Jellinger, 2003). A reason for these conflic-
tual findings may be that several other vascular risk fac-
tors appear to be less prevalent in PD patients. For
example, blood pressure is lower in PD patients
(Brevetti et al., 1990; Hakamaki et al., 1998) and smok-
ing is less frequent in PD patients (Hernan et al., 2001).
It is therefore conceivable that homocysteine-associated
increased risk for stroke and coronary heart disease is
outweighed by other diminished vascular risk factors
(Postuma and Lang, 2004).
It is well established that PD is a risk factor for the
development of dementia (Emre, 2003). Elevated
plasma homocysteine levels in some, but not all, studies
have been found to increase the risk for Alzheimers
dementia (Seshadri et al., 2002; Luchsinger et al.,
2004), possibly independently of vascular factors
(Dufouil et al., 2003; den Heijer et al., 2003). One
may thus hypothesize that hypercysteinemia in PD
may contribute to the development of dementia in PD.
Indeed, a recent preliminary study reported that patients
with PD and hyperhomocysteinemia are more likely to
be depressed and to perform worse on psychometric
tasks compared with normohomocysteinemic patients
(OSuilleabhain et al., 2004b). However, further
research is needed to see whether hyperhomocys-
teinemia is a risk factor for neuropsychiatric burden in
patients with PD.
Experimental and animal research suggested that
hyperhomocysteinemia may exert neurotoxic effects on
the substantia nigra. More specifically, hyperhomocystei-
nemia is associated with excitotoxicity via N-methyl-D-
aspartate (NMDA) activation (Lipton et al., 1997) and
free radical formation (Cook et al., 2002; Lawrence de
Koning et al., 2003) and also may have proinflammatory
effects (Lawrence de Koning et al., 2003). Interestingly,
a study using a mouse model of PD demonstrated that
when homocysteine is infused directly into either the
substantia nigra or striatum, homocysteine exacerbates
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-
44
induced dopamine depletion, neuronal degeneration and
motor dysfunction (Duan et al., 2002). Furthermore, the
same authors report that homocysteine exacerbates oxi-
dative stress, mitochondrial dysfunction and apoptosis
in human dopaminergic cells exposed to the pesticide
rotenone or the pro-oxidant ferrous iron (Fe2). How-
ever, there are no clinical data on possible neurotoxic
effects relevant for the development of PD or
hastening of PD progression.
Taken together, there is considerable, converging
evidence for the potential of levodopa long-term
treatment to increase homocysteine plasma levels.
The latter has been shown to be a risk factor for vas-
cular disease and possibly cognitive decline in
humans and to be neurotoxic in experimental models
of PD. Yet, presently, there is no evidence for the
clinical relevance of these findings, which certainly
merits further investigation. Although it appears
rational to screen PD patients presenting with or
being at risk for vascular disease and dementia for
hyperhomocysteinemia and to supplement vitamin B
or COMT inhibitors which have been shown to
decrease homocysteine plasma levels (Nissinen
et al., 2005; Lamberti et al., 2005), further data are
needed before a general guideline regarding screen-
ing and prevention should be given.
32.7. Long-term motor effects: motor
fluctuations and dyskinesias
32.7.1. Clinical presentation
Early during treatment, the response to levodopa is
sustained and extends by far the pharmacological
half-life of 1.5 hours. This long-duration response
Early PD
Dyskinesia
Threshold
Clinical Effect
Response
Threshold
Levodopa 2 4 6
Time (h)
Smooth, extended duration
of target clinical response
Low incidence of dyskinesias
Fig. 32.5. Motor complications in early, moderate and advanced Parkinsons disease (PD). Pharmacologic response to a levo-
dopa dose (arrow) depending on the stage of disease progression. In the early stage, the response is slow in onset, and has a
small magnitude and a very long duration. In the intermediate stage, the severity of motor dysfunction in the off state has
increased and the response is of greater magnitude and shorter duration. Dyskinesias may be elicited at this stage. In the late
stage, the motor response is abrupt and has a very large magnitude but the duration of response is short and the threshold for
dyskinesia is reduced. Reproduced from Obeso and Olanow (1997), published by Wells Medical, Kent.
T. D. HALBIG AND W. C. KOLLER
(LDR) is reflected as gradual improvement of motor
functions after repeated administration and prolonged
wearing-off after cessation of therapy (Muenter and
Tyce, 1971). Benefits from this LDR may even be
maintained if doses are skipped (Fig. 32.5, early PD).
Apart from the LDR, there is a short-duration response
which reflects the plasma dopamine concentration
and may be present even early in the disease; however,
it may be masked by the LDR (Nutt et al., 1995). Evi-
dence suggests that the LDR progressively diminishes
within the course of disease progression. Efficacy of
levodopa in terms of duration of symptom control
decreases and eventually becomes a function of the
levodopa plasma concentration with progressively
shortened (Fig. 32.5, moderate PD), and eventually
even unpredictable, levodopa responses. Moreover,
involuntary movements (dyskinesias) may occur
associated with levodopa administration (Fig. 32.5,
advanced PD). Interestingly, Cotzias et al. (1967), in
their seminal early report on the symptomatic effects
of levodopa in PD, already described involuntary
(athetoid) movements of tongue and extremities
in those patients who had an excellent response to
levodopa.
Motor complications can seriously interfere with
activities of daily living and impair quality of life
and their treatment is a challenge (Chapuis et al.,
2004). From a clinical point of view, hypokinetic
symptoms can be distinguished from hyperkinetic
manifestations (Table 32.3).
The first motor complication that developes in
most patients is the wearing-off phenomenon, i.e.
patients experience a re-emergence of symptoms
before intake of the next dose. The wearing off may
present clinically in the morning as early-morning
Moderate PD Advanced PD
Dyskinesia
Threshold
Clinical Effect
Clinical Effect
Dyskinesia
Response Threshold
Threshold Response
Threshold
Levodopa 2 4 6 Levodopa 2 4 6
Time (h) Time (h)
Diminished duration of target clinical
response Short duration of target
clinical response
Increased incidence of dyskinesias
"On" time is associated
with dyskinesias
 LEVODOPA 45
Table 32.3 of symptoms before the beneficial effects kick in
(beginning-of-dose worsening) (Merello and Lees,
Motor complications
1992). Finally, motor functions at the end of the dose
Motor fluctuations interval may deteriorate below the dose interval base-
End-of-dose worsening or wearing off line level for a prolonged time, before the following
 Re-emergence of symptoms at the end of a dose interval dose becomes effective (rebound) (Gancher et al.,
at daytime 1988; Nutt et al., 1988). Related to the onoff motor
 Nocturnal symptoms manifestations, patients may suffer from neuropsy-
 Early-morning symptoms chiatric symptoms which are present in particular dur-
Beginning-of-dose worsening
ing off phases. These may include depression, anxiety
Dose failures
and panic attacks which may be associated with
Unpredictable worsening (on/off)
Freezing marked autonomic symptoms (Menza et al., 1990;
Rebound worsening Siemers et al., 1993). During on periods patients
Hyperkinetic responses may experience hypomania or, less frequently, mania
Peak-dose dyskinesias (Giovannoni et al., 2000).
Square-wave dyskenias Apart from these fluctuations of levodopa response
Diphasic dyskinesias in terms of temporary restoration of motor functions,
Off-period dystonia/early-morning dystonia long-term levodopa treatment may be associated with
involuntary movements which most often present as
dyskinesias (Nutt, 1990) (Table 32.3). Dyskinesias
are usually initially present during on phases. Later
akinesia, throughout the day (wearing-off) or at night on they may occur at virtually any time of the dose
(Fahn, 1974; Marsden et al., 1982; Nutt, 1987). In interval. Dyskinesias are typically choreiform; they
more advanced stages, drug responses may become may, however, also resemble dystonia or athetotic
more and more unpredictable and patients experience movements or akathisia or present as myoclonic jerks
symptomatic periods of varying duration at any time or ballism (Nutt, 1990; Comella and Goetz, 1994;
during the dose interval (onoff). Related to this, Marconi et al., 1994). Dyskinesias can be distin-
delayed onset of dose effects as well as complete guished regarding their temporal relation with the
doseresponse failures occur. Furthermore, patients intake of a levodopa dose (Fig. 32.6). Most frequently,
may experience a levodopa intake-related worsening they present as peak-dose dyskinesias. Peak-dose

Dyskinesia Dyskinesia

"off" "off"

Levodopa Levodopa Levodopa Levodopa Levodopa Levodopa

Diphasic dyskinesia Diphasic dyskinesia

"on" dyskinesia "on" dyskinesia
A B "off" dystonia
Fig. 32.6. Motor complications: dyskinesias. (A) Schematic representation of dyskinesias in patients with Parkinsons disease.
Each levodopa dose (arrow) induces a predictable motor improvement lasting for about 34 hours. Peak-of-dose dyskinesias
(open squares) occur at the time of maximal improvement but may also occupy the entire on period. Diphasic dyskinesias
(black squares) may occur at the beginning and/or the end of the cycle. (B) An example of a patient with an on response
in which the patient fails to respond to a given dose of levodopa, often associated with off-period dystonia (hatched rectan-
gles). Failure to respond to a dose of levodopa tends to occur in the afternoon or evening after repeated doses. Reproduced from
Obeso et al. (2000), with permission from the American Academy of Neurology.
46 T. D. HALBIG AND W. C. KOLLER
dyskinesias tend to occur at the time of peak plasma
concentration, usually in the middle between two levo-
dopa doses when patients are without typical parkinso-
nian features. Dyskinesias may persist during the
entire on period (square-wave dyskinesias). In con-
trast, diphasic dyskinesias occur at the beginning or
the end of a levodopa dose interval, i.e. when levodopa
plasma concentrations begin to rise and fall, but not
during peak concentrations (Fig. 32.6). Diphasic dys-
kinesias more often affect the lower limbs and in par-
ticular asymmetrically the side of the body that is
more affected by PD. Movements are often stereotypi-
cal and may present with dystonic components. In con-
trast to peak-dose dyskinesias, the presence of diphasic
dyskinesias may overlap with parkinsonian features.
Diphasic dyskinesias are thought to be associated with
rising or falling, yet insufficient levodopa concentra-
tions. Finally, severe off states with marked immobi-
lity may be followed by abrupt onset periods of
violent dyskinesias (yo-yoing). In contrast, off-period
dystonia develops when levodopa levels are low at the
end of a dose interval or when levodopa doses fail to
kick in (Fig. 32.6).
32.7.2. Time of onset of motor complications
Various studies examined the time of onset of motor
complications. Data, however, vary depending on the
methods and patient characteristics. Ideally, in order
to examine the effects of long-term levodopa treatment
for the development of motor complications, prospec-
tive long-term studies should compare drug-naive and
levodopa-treated de novo patients over long time inter-
vals. Yet, the only study meeting this criterium is the
ELLDOPA study (see section 32.5). Results of the
ELLDOPA study indicate that motor complications
may develop after less than 1 year of levodopa therapy
(Parkinson Study Group, 2004a). Within a treatment
period of 40 weeks, dyskinesias were significantly
more frequent in patients treated with a daily dose of
600 mg levodopa (15/91) as compared to patients on
placebo (3/90) or patients receiving 150 mg (3/92) or
300 mg (2/88) per day. Likewise, there was a strong
trend for those patients on 600 mg to present with
more frequent wearing-off phenomenon compared to
all other treatment groups. Other studies allowing con-
clusions regarding onset of motor complications in
levodopa-treated patients compared the effects of levo-
dopa with other antiparkinsonian agents or are based
on chart reviews (Table 32.4). It is generally agreed
that, after 5 years of treatment, about 50% of patients
and after 10 years 80100% of patients have devel-
oped motor complications (Marsden and Parkes,
1977; Burguera et al., 1999; Grandas et al., 1999;
Schrag and Quinn, 2000; Ahlskog and Muenter,
2001; Garcia Ruiz et al., 2004).
32.7.3. Determining factors for motor complications
There is substantial evidence that the disease duration
is a major factor contributing to the development of
motor complications. According to a meta-analysis
(Ahlskog and Muenter, 2001), clinical studies on
patients with PD onset well before levodopa avail-
ability (pre-levodopa era) report high frequencies of
dyskinesias early after treatment initiation, with
approximately half of patients experiencing dyskine-
sias after 56 months. This complies with the early
observations of Cotzias et al. (1967). In contrast, in
more recent series, frequencies were minimal until
12 years and then amounted up to only 25% through
the first 2.53.5 years. At 46 years of follow-up,
modern-era series still had lower median dyskinesia
frequencies (3639%). Several other clinic-based and
community studies confirmed that longer disease dura-
tions and hence more advanced neurodegenerative
changes may play a critical role in the development
of levodopa-induced dyskinesias (Lesser et al., 1979;
Parkinson Study Group, 1996a; Schrag and Quinn,
2000; Kostic et al., 2002).
Furthermore, clinical and experimental evidence
suggests that time of onset and severity of dyskinesias
are associated with the total exposure to levodopa
(Agid et al., 1985; Smith et al., 2002). Another factor
determining onset and frequency of motor complica-
tions is the age of PD onset. Several studies demon-
strated that motor complications and in particular
dyskinesias tend to develop earlier in patients with
young onset of symptoms and are less likely to occur
in patients with onset of symptoms after the age 70
(Golbe, 1991; Kostic et al., 1991; Stern et al., 1991;
Schrag and Quinn, 2000). Another controversial factor,
however, is gender. Few studies provided evidence for
higher frequency of dyskinesias in women (Parkinson
Study Group, 1996a; Lyons et al., 1998).
32.7.4. Mechanisms
The mechanisms that contribute to the development of
motor complications are controversial. Since there is
no change in the peripheral pharmacokinetics of levo-
dopa and dopamine during the course of disease pro-
gression, the underlying mechanisms have to be
assumed to be central. A variety of factors have been
discussed. For the maintenance of motor functioning,
postsynaptic striatal receptors have to be continuously
activated (DeLong et al., 1983). Early in the disease,
remaining endogenous dopamine supplemented by
 LEVODOPA 47
Table 32.4
Prevalence of levodopa-induced motor complications

Prevalence of
Study complications Length of study Method of evaluation

Rajput et al. (1984) 10% fluctuations 5 years Physician evaluation

25% dyskinesias
Poewe et al. (1986) 52% wearing off 6 years Webster Scale
54% dyskinesias Modified Columbia Scale
Hely et al. (1994) 41% wearing off 5 years Modified Columbia Scale
55% dyskinesias Dyskinesia Scale
Physician evaluation
Montastruc et al. (1994) 40% wearing off 5 years Columbia Scale
56% dyskinesias UPDRS
Dupont et al. (1996) 59% fluctuations 5 years UPDRS, part 4
41% dyskinesias
Parkinson Study Group (1996b) 50% wearing off 2 years Physician evaluation
30% dyskinesias UPDRS, part 4
Koller et al. (1999) 20% wearing off 5 years Patient diary
20% dyskinesias Physician-recorded questionnaire/diary
Rascol et al. (2000) 45% dyskinesias 5 years UPDRS, dyskinesia scale
Parkinson Study Group (2000) 38% wearing off 2 years Physician determination
31% dyskinesias
Whone et al. (2003) 27% dyskinesias 2 years Physician evaluation
UPDRS, dyskinesia scale
Parkinson Study Group (2004b) 63% wearing off 4 years Physician evaluation
54% dyskinesias UPDRS, dyskinesia scale
Parkinson Study Group (2004a) 21% wearing off 10 months Physician evaluation
7% dyskinesias UPDRS, dyskinesia scale

UPDRS, Unified Parkinsons Disease Rating Scale.

Adapted from Olanow et al. (2001) and supplemented.

exogenous levodopa is sufficient for continuous dopami-
nergic stimulation (CDS). During progressive degenera-
tion and loss of nigrostriatal neurons, the postsynaptically
available dopamine depends more and more on externally
administered dopamine.
One reason for this is the progressive decrease in
the production of endogenous dopamine. Further-
more, presynaptical reuptake and storage of intrasy-
naptical dopamine progressively diminish. Due to
this loss of presynaptic buffering, fluctuations in
the levodopa plasma levels are reflected as fluctua-
tions in postsynaptic receptor activations which
translate in turn into motor fluctuations. This
hypothesis is supported by the notion that motor
fluctuations develop much faster with severe nigros-
triatal degeneration, as demonstrated by the shor-
tened delay between treatment initiation and
emergence of motor fluctuations in PD patients with
severe disease (Ahlskog and Muenter, 2001) or in
monkeys treated with MPTP, where the cell loss
amounts to 9095% (Clarke et al., 1987). Compati-
ble with this, compared to patients without motor
fluctuations, patients experiencing wearing off show
more pronounced reduction in striatal levodopa
uptake (Leenders et al., 1986).
However, motor fluctuations probably also reflect
changes of postsynaptic receptor responses to dopami-
nergic stimulation. The duration of motor improvements
due to administration of levodopa or the dopamine ago-
nist apomorphine decreases with disease progression,
which cannot be explained by a reduced presynaptic
dopamine storage (Fabbrini et al., 1988; Bravi et al.,
1994; Verhagen Metman et al., 1997).
Apart from the degree of dopaminergic denervation,
the manner in which missing dopamine is replaced by
dopaminergic agents also appears to contribute to the
establishment of motor complications. Dopaminergic
agents used for the symptomatic treatment of PD differ
48 T. D. HALBIG AND W. C. KOLLER
regarding their pharmacological half-life. Dopamine strate that the incidence of dyskinesias is higher in
metabolized from levodopa has a half-life of about patients treated with levodopa only than in patients trea-
1.5 hours, whereas dopamine agonists have half-lives ted with a dopamine agonist and hence a dopaminergic
of up to 65 hours (see Ch. 33). Due to its short half-life, agent with a longer half-life.
repeated oral administration of levodopa leads to Different postsynaptic changes related to the nigros-
rapidly changing plasma levels with pulsatile stimula- triatal degenerative process and associated with exter-
tion of postsynaptic receptors. In contrast, continuous nal administration of levodopa that may account for
levodopa infusions or administration of long-acting motor fluctuations and the establishment of dyskinesias
dopamine agonists is associated with stable CDS. have been identified in experimental models. These
Converging evidence from animal models (Bedard include gene changes with upregulation of preproenke-
et al., 1986; Pearce et al., 1998; Maratos et al., 2001) phalin mRNA and downregulation of dynorphin and
as well as from clinical trials (Rascol et al., 2000; substance P as well as changes of Fos genes and prody-
Parkinson Study Group, 2004b) suggests that the short norphin) (Gerfen et al., 1990; Jolkkonen et al., 1995;
half-life of dopaminergic agents importantly contributes Duty and Brotchie, 1997; Calon et al., 2000; Zeng
to the development of motor complications and in et al., 2000; Westin et al., 2001) and GABA-A receptor
particular dyskinesias. upregulation of the globus pallidus internus (Calon
For example, levodopa and short-acting dopamine et al., 1995). Although the exact mechanisms to date
agonists are much more likely to induce dyskinesias are unknown, it is thought, that these gene changes are
in MPTP-treated monkeys than dopamine agonists associated with abnormal firing patterns of the major
with a long half-life (Bedard et al., 1986; Pearce basal ganglia output nuclei and in particular the globus
et al., 1998). Furthermore, there is evidence that the pallidus internus, as assessed during dyskinetic states
potential of the same dopamine agonist to induce (Papa et al., 1999; Lozano et al., 2000).
dyskinesias depends on whether it has been adminis-
tered pulsatile or in a continuous fashion via infusion 32.8. Toxicity
(Blanchet et al., 1995).
Compatible with this are results from several clinical Though levodopa is considered the gold standard for
trials comparing the incidence of dyskinesias in patients the sympomatic treatment of PD symptoms, its long-
treated with levodopa and dopamine agonists term effects on disease progression are unknown.
(Table 32.5). Patients in the dopamine agonist treatment Different levels of research, including in vitro studies,
arm in these studies usually received supplementary in vivo animal experiments and clinical and neuroima-
levodopa if symptoms remained inadequately con- ging data obtained in humans, raised the possibilities
trolled. Results of these studies consistently demon- of both neurotoxic and neuroprotective effects of
levodopa.
Table 32.5 There is conclusive evidence that oxidative stress is
present in the substantia nigra pars compacta (SNpc)
Prevalence of dyskinesias in patients treated with either in PD (increased Fe2: Dexter et al., 1987, 1989; Sofic
levodopa or dopamine agonists levodopa
et al., 1991; decreased glutathione: Perry et al., 1982;
Riederer et al., 1989; decreased mitochondrial complex
Length of Prevalence of
study dyskinesias 1 activity: Parker et al., 1989; Schapira et al., 1990;
Study (years) Agent (%) Tretter et al., 2004). Furthermore, oxidative stress has
been shown to impair DNA (Schapira et al., 1990),
Rascol et al. 5 Ropinirole 20 proteins (Parker et al., 1989; Tretter et al., 2004) and
(2000) Levodopa 45 lipids (Emerit et al., 2004). On the other hand, in vitro
Parkinson 2 Pramipexole 10 evidence suggests that under certain conditions both
Study Group Levodopa 30
dopamine and levodopa may exert toxic effects on
(2000)
cultured dopaminergic neurons (Mena et al., 1992;
Whone et al. 2 Ropinirole 3.4
(2003) Levodopa 27 Mytilineou et al., 1993) via auto-oxidation, leading to
Parkinson 4 Pramipexole 24.5 the formation of highly reactive oxygen species
Study Group Levodopa 54 (Graham et al., 1978). Compatible with this, high doses
(2004b) of dopamine and levodopa have been shown to decrease
Rinne et al. 4 Cabergoline 6* TH-positive staining neurons in various dopaminergic
(1998b) Levodopa 14* cell cultures (Michel and Hefti, 1990; Steece-Collier
et al., 1990; Mytilineou et al., 1993), probably via apop-
*Peak-dose dyskinesias. totic mechanisms (Ziv et al., 1997; Corona-Morales
 LEVODOPA
et al., 2000). Based on these findings, it is reasonable to
assume that the increased oxidative stress already pre-
sent in PD is potentiated by chronic administration of
dopaminergic agents.
However, for a variety of methodological reasons, the
in vitro findings supporting the neurotoxic potential of
dopaminergic agents do not simply translate into in vivo
effects. For example, the toxic concentration of levodopa
used in most studies was much higher than concentrations
usually achieved by therapeutic levodopa supplementation.
Furthermore, most in vitro studies lack neuroprotective fea-
tures such as antioxidant ascorbic acid or glial cells which
are present in in vivo animal models as well as in humans.
Indeed, it has been demonstrated that culture systems that
were accommodated for these factors were protected
against levodopa toxicity (Kalir and Mytilineou, 1991;
Mena et al., 1993, 1997a; Pardo et al., 1993). Interestingly,
low-dose levodopa administration may exert neurotrophic
effects in in vivo models using other pro-oxidant agents.
For example, in cultures using glia-conditioned media,
levodopa was shown to enhance neurite outgrowth and to
increase cell survival (Mytilineou et al., 1993; Mena et al.,
1997a, b). Furthermore, levodopa may protect mesence-
phalic cultures against oxidative stress, probably via upre-
gulation of glutathione (Han et al., 1996). Taken together,
in vitro data are at present inconclusive.
In vivo animal studies also tried to assess the putative
cell toxic effects of levodopa supplementation
in experimental models of PD. One study evaluated the
effect of 6-month oral levodopa treatment on several
dopaminergic markers in rats with moderate or severe
6-hydroxydopamine (6-OHDA)-induced lesions of
mesencephalic dopamine neurons and sham-lesioned
animals (Murer et al., 1998). Counts of TH-immunoreac-
tive neurons in the substantia nigra and ventral tegmental
area showed no significant difference between levodopa-
treated and vehicle-treated rats. In addition, for rats of the
sham-lesioned and severely lesioned groups, immunora-
diolabeling for TH, DAT and vesicular monoamine trans-
porter (VMAT2) at the striatal level was not significantly
different between rats treated with levodopa or vehicle.
Unexpectedly, quantification of immunoautoradiograms
showed a partial recovery of all three dopaminergic mar-
kers (TH, DAT and VMAT2) in the denervated territories
of the striatum of moderately lesioned rats receiving levo-
dopa. Compatible with these neuroprotective effects,
another study, also using a PD rat model with 6-OHDA-
induced dopaminergic lesions and chronic levodopa
treatment for about 6 months (Datla et al., 2001), also
revealed an increased number of dopaminergic neurons.
Recently, two prospective randomized clinical trials
have compared the effects of levodopa versus the
non-ergot derivative D2-binding dopamine agonists
pramipexole and ropinirole on disease progression
49
(Parkinson Study Group, 2002a; Whone et al., 2003).
As a surrogate marker for disease progression, neuroi-
maging measures indicative of the functional integrity
of the nigrostriatal system were used. For example, in
an imaging substudy of the CALM-PD trial (Compar-
ison of the Agonist pramipexole vs. Levodopa on
Motor complications in Parkinsons Disease), 82 de
novo PD patients were randomized to receive either
300 mg levodopa or 1.5 mg pramipexole per day
(Parkinson Study Group, 2002a). Open-label levodopa
could be added, if clinical symptoms could not be suf-
ficiently controlled by the study drug. The main out-
come variable was the change of iodine-123-labeled
2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane
(b-CIT) uptake on single-photon emission computed
tomography (SPECT) from baseline to month 46 after
trial initiation. Results of the study showed that the 41
patients treated initially with pramipexole had a signifi-
cantly slower mean decline in striatal b-CIT uptake
(16.0%) than the 42 subjects treated initially with levo-
dopa (25.5%). Interestingly, mean total and motor
UPDRS scores obtained in the defined off state in both
the levodopa- and the pramipexole-treated groups did
not differ significantly between baseline and assess-
ments at 34 or 46 months.
Another prospective, randomized trial, the REAL-
PET study (Requip as Early Therapy versus L-dopa
Positron Emission Tomography) (Whone et al., 2003),
assessed the neuroprotective potential of ropinirole
using the rate of loss of dopamine-terminal function in
162 de novo patients over 24 months, as assessed by
fluoro-dopa-PET as primary outcome measure. Patients
were randomized to receive either ropinirole or levo-
dopa. Over the first 4 weeks of the study, doses were
escalated to daily regimens of 3 mg ropinirole, or
300 mg levodopa per day. Titration was flexible, based
on clinical response and tolerability, to a maximum
24 mg of ropinirole or 1000 mg of levodopa per day. If
symptoms were inadequately controlled, titration to
the maximum tolerated dose of the assigned medication
was encouraged. The primary outcome measure was
reduction in putamen 18F-dopa uptake (Ki) between
baseline and 2-year PET. Analysis of the putamen as
the central region of interest revealed that there was a
significantly slower rate of deterioration in the ropinir-
ole group than in the levodopa group (13% versus
20%). Interestingly, UPDRS measures indicated that
motor function during treatment at 2 years was superior
with levodopa compared with ropinirole.
Both the CALM-PD and REAL-PET studies
demonstrated a more rapid decline on imaging biomar-
kers of nigrostriatal functioning in patients treated with
levodopa. Since there was no placebo group in both
studies, it is not clear whether the different rate of
50 T. D. HALBIG AND W. C. KOLLER
decline reflects toxic effects of levodopa or rather neu-
roprotective effects of the dopamine agonists. Further-
more, although the same results were seen in both
studies despite the use of different agonists, different
tracers and different imaging techniques, it is possible
that levodopa and dopamine agonists have different
pharmacological effects and regulate components of
the nigrostriatal system in opposite directions
(Ahlskog et al., 1999). In this case, the different
SPECT and PET findings would simply reflect these
pharmacological differences rather than indicate dif-
ferent rates of disease progression. It is also not clear
why the apparently more rapid decline on PET and
SPECT in the levodopa groups did not reflect clini-
cally. Indeed, UPDRS motor scores in patients treated
with levodopa were equal or superior to scores
obtained in patients treated with agonists.
The ELLDOPA (see section 32.5) study was the first
study ever comparing the effects of levodopa with pla-
cebo. The aim of the ELLDOPA study was to deter-
mine the effect of levodopa on the rate of progression
of PD (Parkinson Study Group, 2004a). The ELLDOPA
study evaluated clinical and imaging functions in 361
patients randomized to receive a daily carbidopa-levo-
dopa dose of 37.5 and 150 mg, 75 and 300 mg, or
150 and 600 mg, respectively, or a matching placebo
for a period of 40 weeks. Patients then underwent with-
drawal of treatment for 2 weeks. The primary outcome
was a change in scores on the UPDRS between baseline
and 42 weeks. Neuroimaging studies of 142 subjects
were performed at baseline and at week 40 to assess
striatal dopamine transporter density by measuring b-
CIT uptake. The clinical component of the study
demonstrates that the severity of symptoms increased
more in the placebo group than in all the groups receiv-
ing levodopa. The mean difference between the total
score on the UPDRS at baseline and at 42 weeks was
7.8 units in the placebo group, 1.9 units in patients
receiving levodopa at a dose of 150 or 300 mg daily
and 1.4 in those receiving 600 mg daily. This result
is consistent with a protective, not a toxic, effect. How-
ever, the possibility of a confounding, long-lasting,
symptomatic effect that persists for months after wash-
out cannot be entirely excluded. In contrast, the imaging
component of the study demonstrated that, in a sub-
group of 116 patients, the mean decline in the b-CIT
uptake was significantly greater with levodopa than
placebo (6% among those receiving levodopa at
150 mg daily, 4% in those receiving it at 300 mg daily
and 7.2% among those receiving it at 600 mg daily, as
compared with 1.4% among those receiving placebo).
Again, as in the CALM-PD and REAL-PET studies,
the imaging findings suggest either a toxic effect of
levodopa or a pharmacologic modification of the
DAT. Thus, the results of the ELLDOPA study with
diverging clinical and controversial imaging findings
are not conclusive.
In summary, even though there is some controversial
evidence from laboratory and human imaging studies
suggesting a toxic effect of levodopa, in the final ana-
lysis it remains unclear whether levodopa is toxic.
In contrast, there is no clinical evidence supporting the
notion of levodopa toxicity and some data even support
the possibility of neuroprotective effects of levodopa.
32.9. Strategies to improve levodopa therapy
32.9.1. Oral formulations aiming at faster onset of
symptomatic effects
Several different approaches have been developed to face
the shortcomings and failures of levodopa therapy. Even
in earlier stages of PD, the time to effect of a single dose
of levodopa may be delayed for various reasons. The
most important factor is usually related to the speed of
gastric emptying, which varies and may be prolonged
in PD (Edwards et al., 1992; Byrne et al., 1994; Kaneoke
et al., 1995; Quigley, 1996; Pfeiffer, 1998, 2003; Hardoff
et al., 2001; Goetze et al., 2005). Furthermore, food may
delay gastrointestinal transit time and LNAA from
protein-rich food may lead to interference and delay of
transmucosal and transendothelial levodopa transport
(Djaldetti et al., 1996) (see section 32.3). In later stages
of the disease, swallowing may also be a problem, further
delaying the time until a levodopa dose kicks in. To
shorten the time to therapeutic effect, conservative mea-
sures such as avoiding food and in particular protein-rich
diets 45 minutes before and 90 minutes after intake of a
levodopa dose may be helpful. Furthermore, special for-
mulations of levodopa and new forms of administration
of levodopa have been developed.
In order to speed up levodopa transfer to the jeju-
num, the major site of resorption, several studies com-
pared the effect of liquefied levodopa with standard
oral administration (Kurth et al., 1993; Metman et al.,
1994; Pappert et al., 1996; Kurth, 1997). In a double-
blind, cross-over study (Pappert et al., 1996), either
liquid levodopa or standard levodopa was administered
to 23 PD patients. Liquid levodopa was produced using
10 tablets of levodopa/carbidopa (LD/CD: 100/25 mg)
and 1 g of ascorbate dissolved in 1 liter of tap water.
Patients were evaluated hourly between 9 a.m. and
4 p.m. for plasma levodopa levels. Furthermore, the
UPDRS, a dyskinesia rating scale and onoff ratings
were employed. Patients receiving liquid LD/CD
ingested significantly higher doses and had significantly
improved motor function and total on time, without an
increase in dyskinesia severity. Levodopa levels and
 LEVODOPA
variability were equivalent with the two formulations.
However, overall dosing frequencies in this study were
much higher for the liquid preparation (17.22 versus
6.96) and the overall ingested levodopa dose was higher
(1321 versus 890 mg). In an open trial comparing a
levodopa/carbidopa/ascorbic acid solution (LCAS) and
standard levodopa, 4 patients with PD with severe
motor fluctuations presented with reduced bradykinesia,
decreased dysfunctional dyskinesias and increased func-
tional on time when treated with LCAS (Kurth et al.,
1993). According to the authors, oral LCAS allowed
better titration of levodopa dosage and offered a more
predictable response than LD/CD tablets. Compatible
with this, in a small double-blind, placebo-controlled,
cross-over study in 5 PD patients, orally administered
liquid LD/CD led to slightly earlier peak plasma
levodopa levels (Metman et al., 1994).
A dispersible formulation of levodopa (LD)/benser-
azide (Madopar LT) is an alternative to the prepara-
tions of liquefied levodopa, as described above.
Madopar LT can be dissolved in water or taken like
a regular tablet and is available in Europe (Contin
et al., 1999). It is characterized by earlier release, rapid
absorption and shorter time to peak plasma levodopa
concentration (Tmax) with no difference in remaining
pharmacokinetic and clinical characteristics (Haglund
and Hoogkamer, 1995). Several open-label trials have
shown its usefulness in the treatment of early-morning
akinesia (Steiger et al., 1992) and in patients with
swallowing difficulties (Bayer et al., 1988). In sum-
mary, even though controlled clinical data are sparse,
based on the shorter Tmax, dispersible and liquid for-
mulations may be worthwhile to shorten the delay to
effect and may be offered to patients as first dose
in the morning, as rescue medication or to shorten
diphasic dyskinesias.
A dual-release preparation has been developed and is
currently marketed in Switzerland. In a double-blind
single-dose study 200 mg levodopa (plus 50 mg benser-
azide) was administered either as dual-release prepara-
tion consisting of a three-layer tablet combining
immediate and slow-release properties or a conven-
tional slow-release formulation (see section 32.9.3)
(Descombes et al., 2001). The cross-over study enrolled
16 fluctuating patients with PD. Compared to the slow-
release formulation, the time to on was shown to be
shorter with the dual-release formulation (43  31 and
81  39 minutes, respectively), whereas the mean
time to relapse to off was similar for both for-
mulations. UPDRS improvement and dyskinesias
scores were similar for either preparation. There were
no differences in tolerability. The dual-release formula-
tion had significantly shorter Tmax and greater maxi-
mum concentration (Cmax) and area under the plasma
51
concentration time curve (AUC: 0.5 hours). Apparent
elimination half-life was similar for both formulations.
Other recent strategies to shorten Tmax used chemi-
cally modified levodopa preparations (Stocchi et al.,
1994, 1996; Djaldetti et al., 2002, 2003). For example,
levodopa ethylester (etilevodopa, LDEE) is a highly
soluble prodrug of levodopa passing unchanged
through the stomach to the duodenum, where it is
rapidly hydrolyzed by local esterases and absorbed as
levodopa. In a recent open-label, randomized, four-
way cross-over study, different oral preparations of
LDEE/carbidopa and LD/CD were compared in 29
PD patients with motor fluctuations (Djaldetti et al.,
2002, 2003). Results showed significantly shorter
plasma levodopa Tmax, higher AUC and Cmax for
LDEE/carbidopa. Compatible with these results, the
same authors were able to demonstrate the clinical
superiority of LDEE in 62 patients with delayed-on
and no-on subtypes of response fluctuation in a con-
trolled double-blind study (Djaldetti et al., 2002).
Results showed that mean latency to turning on was
reduced by 21% (morning dose) and 17% (postlunch
dose) and percentage of no-on episodes after the post-
lunch dose was decreased by 21% in the LDEE/CD
group but increased by 36% in the LD/CD group.
Levodopa methyl ester is another highly water-soluble
levodopa derivative that can be administered orally
and intravenously and has been shown to decrease
latency to on in smaller studies (Juncos et al., 1987;
Stocchi et al., 1994, 1996).
Recently, an orally disintegrating LD/CD tablet
containing phenylalanine has been introduced in the
USA (Parcopa) (Nausieda et al., 2005). It rapidly dis-
integrates on the tongue without chewing and does
not require water to aid dissolution. It is available in
the USA in dosages corresponding to the usual
dosages of standard levodopa preparations. According
to an open-label study, the clinical efficacy of orally
disintegrating LD/CD tablets is equivalent to standard
preparations (Nausieda et al., 2005). This new formu-
lation may be an alternative to standard levodopa for
patients who have difficulties swallowing conventional
tablets or when water is unavailable or inappropriate.
Finally, nasal and transdermal formulations have
been evaluated in rats in in vivo and in vitro studies;
however, clinical evidence in humans is lacking (Sudo
et al., 1998; Kao et al., 2000; Iwase et al., 2000).
32.9.2. Infusions and other non-oral ways of
levodopa administration
In order to control better motor fluctuations related to
the short levodopa half-life, several strategies are
available to provide more continous dopaminergic
52 T. D. HALBIG AND W. C. KOLLER
stimulation. For example, constant intravenous infu-
sion of levodopa replacing standard oral levodopa or
in addition to standard levodopa has been shown to
result in stable plasma dopa concentrations and dra-
matic improvement of motor fluctuations in patients
with predictable wearing off, unpredictable onoff
fluctuations and prolonged offs (Shoulson et al.,
1975; Quinn et al., 1982).
Furthermore, liquid solutions may be used in order
to bypass the oral route. Bypassing the oral route may
be necessary in patients with swallowing difficulties
or in order to smoothen the variable and sometimes
erratic time till levodopa kicks in which is often caused
by delayed gastric emptying. Liquid solutions have
been used in patients with percutaneous endoscopic gas-
trotomy, with a portable duodenal or jejunal pump or
via nasoduodenal catheter (Cedarbaum et al., 1990a;
Metman et al., 1994; Syed et al., 1998). For enteral
application, a stable gel suspension of LD/CD (20/5
mg/ml) has been developed (Duodopa) (Nilsson et al.,
1998, 2001; Nyholm et al., 2003). Continuous intraduo-
denal infusion has been shown to be associated with
stable plasma levodopa concentrations compared to
controlled-release (CR) preparations (see section
32.9.3). Compatible with this, on time increased and
off time and dyskinesias decreased (Nyholm et al.,
2003, 2005). Long-term evaluations for more than
9 years demonstrated that continuous intraduodenal
levodopa infusion may be efficient in patients with
advanced disease and severe onoff fluctuations
(Nilsson et al., 2001). Patients are usually given a bolus
as the first morning dose and then continuous infusion
during the day. In addition to decreased motor fluctua-
tions, infusion therapy permits the reduction of the daily
overall dose of levodopa.
In contrast, rectally administered levodopa was
shown to be of no value in patients who are unable
to take oral medication. In a series of 12 PD patients
postsurgery there was no rise in levodopa plasma
levels and no clinical benefit when levodopa was
administered rectally (Eisler et al., 1981).
32.9.3. Levodopa slow-release preparations
In order to address the fluctuating motor response after
long-term treatment with levodopa and in particular
the wearing-off phenomenon, controlled/slow-release
levodopa preparations have been developed. Their
specific aim is to extend the short half-life of levodopa
to prolong its clinical effects. CR preparations com-
prise levodopa/AADC embedded in a slowly eroding
matrix (Erni and Held, 1987; LeWitt et al., 1989;
Yeh et al., 1989). CR preparations are available in
combination with carbidopa or benserazide and mar-
keted as Sinemet CR and Madopar CR (or HBS, or
Depot). Madopar CR, when in contact with gastric fluid
and after dissolution of the gelatin shell of the capsule,
forms a mucous body that continuously releases its
contents via a hydrated layer by diffusion over a pro-
longed period of time (Erni and Held, 1987). Sinemet
CR is embedded in an erodible polymeric matrix and
dissolves during passage along the duodenal-jejunal
mucosa (LeWitt et al., 1989; Yeh et al., 1989).
Due to their gradual release, CR preparations are
characterized by delayed Tmax by about 4590 minutes
and by prolonged plasma half-life of up to 2 hours.
Furthermore, due to variable gastrointestinal transit, less
efficient absorption in the distal bowel or greater first-
pass systemic metabolism, bioavailability is decreased
by about 30% compared to standard levodopa (Yeh
et al., 1989). Finally, Cmax is reduced (Grahnen et al.,
1992; for Madopar see also Crevoisier et al., 1987; Da
Prada et al., 1987; Jensen et al., 1987; Malcolm et al.,
1987; Nordera et al., 1987; Poewe et al., 1987; Quinn
et al., 1987; for Sinemet see also Cedarbaum et al.,
1987; Yeh et al., 1989; Wilding et al., 1991).
32.9.3.1. Effects on motor fluctuations
The effects of CR preparations on motor fluctuations
are mixed. Overall, there are fewer data available on
the effects of CR LD/benserazide than for LD/CD pre-
parations. A double-blind, cross-over study in 14
patients with PD and motor fluctuations examined
the effects of Madopar HBS or placebo twice a day
in addition to the optimal standard Madopar treatment
(De Michele et al., 1989). Clinical response as evalu-
ated by the Kings College Hospital Parkinsons Dis-
ease Rating Scale and the Mobility in Bed Scale
improved significantly, whereas evaluation by self-
scoring diaries did not show significant changes.
Another open-label study on 22 patients reported longer
on periods, less severe off periods and decrease in
early-morning akinesia (Chouza et al., 1990).
Compatible with the results obtained for LD/ben-
serazide, several double-blind (Hutton et al., 1989;
Mark and Sage, 1989a; Lieberman et al., 1990; Wol-
ters et al., 1992; Wolters and Tesselaar, 1996) and
open studies (Goetz et al., 1988; Deleu et al., 1989;
Rondot et al., 1989; Rodnitzky et al., 1989; Pahwa
et al., 1993) demonstrated significant off-time reduc-
tion and improvement of functional clinical abilities for
LD/CD CR preparations. In particular, the combined
administration of controlled- and immediate-release for-
mulations allowed significant improvement regarding
disability from dyskinesias and number of on hours
without dyskinesias (Sage and Mark, 1988; Friedman
and Lannon, 1989b; Mark and Sage, 1989b; Wolters
et al., 1992).
 LEVODOPA
Other possible advantages of CR preparations are
less frequent dose failures (Pahwa et al., 1993) and
diminished early-morning dystonia and nocturnal awa-
kenings (Goetz et al., 1989; Pahwa et al., 1993).
However, other studies failed to provide evidence
for the superior efficacy of slow-release Madopar in
improving nocturnal and early-morning disabilities.
For example, in a double-blind cross-over study, 103
patients with nocturnal and/or early-morning disabilities
received a bedtime dose of either Madopar CR or
standard Madopar in addition to their usual daytime
levodopa regimen. Both Madopar CR and standard
Madopar improved nocturnal and early-morning dis-
ability equally (UK Madopar CR Study Group, 1989).
Likewise, for LD/CD CR, studies in patients with motor
fluctuations were not able to detect significant differ-
ences between standard formulation and CR regarding
number of off hours (Ahlskog et al., 1988) or effects
on wearing off (Feldman et al., 1989).
The long-term efficacy of CR preparations is also
controversial. Although some studies found efficacy
for several months only (Pezzoli et al., 1988; Klee-
dorfer and Poewe, 1992), other investigators report
satisfactory symptom control for more than 2 years
with Madopar CR (Siegfried, 1987), in particular for
mild to moderate fluctuations or in addition to regular
levodopa (Pacchetti et al., 1990).
Another controversial issue is the effect of CR pre-
parations on dyskinesias. Although some authors
report increase in peak-dose or diphasic dyskinesias
for LD/benserazide (Pezzoli et al., 1988; De Michele
et al., 1989; Kleedorfer and Poewe, 1992) and LD/
CD (Jankovic et al., 1989; Cedarbaum et al., 1990b;
Hutton and Morris, 1991), others report decrease in
dyskinesias (Chouza et al., 1990).
In summary, evidence for the efficacy of CR pre-
parations to control motor fluctuations is only derived
from studies with standard levodopa as comparator
and not including comparisons with placebo. In general,
studies report a reduction in dose frequency (Hutton
et al., 1989; Lieberman et al., 1990). However, most,
but not all, studies (Dupont et al., 1996) report an
increase of overall doses of levodopa by 30%, which
is consistent with the pharmacokinetic profile of
CR preparations. Furthermore, efficacy in reducing
off time, dose failures, nocturnal and early-morning
akinesia and rigidity may be transient. A problem
related to prolonged on- and offset of clinical effects
may be the development or worsening of diphasic dys-
kinesias. Furthermore, associated with erratic levodopa
resorption, levodopa plasma levels may build up unpre-
dictably, with variably high peak dose levels, which
may translate into peak-dose dyskinesias. In conclusion,
the administration of the CR levodopa formulation of
53
levodopa (plus carbidopa or benserazide) can be transi-
ently useful in moderately advanced stages of PD with
motor fluctuations characterized mainly by the wear-
ing-off phenomenon and nocturnal and early-morning
motor symptoms. In contrast, in later stages CR pre-
parations may contribute to dopaminergic side-effects
such as dyskinesias.
32.9.3.2. Effects in de novo patients and prevention
of motor complications
According to the concept of CDS, non-physiologic,
pulsatile receptor stimulation contributes to the devel-
opment of motor fluctuations and dyskinesias. Based
on this consideration, the administration of levodopa
CR preparations has been suggested as pre-emptive
strategy to prevent or delay the development of motor
complications. Two controlled prospective multicenter
trials assessed the potential of CR preparations to
reduce the incidence of motor complications compared
with immediate-release LD/CD (Block et al., 1997;
Koller et al., 1999) or LD/benserazide (Dupont et al.,
1996). The primary endpoints of these studies were
the incidence of motor fluctuations and dyskinesias
after 5 years of treatment. Though both treatment
groups responded well to therapy and CR-treated
patients were found to score better in terms of measures
of activities of daily living (Dupont et al., 1996; Block
et al., 1997), there was no significant difference regard-
ing the primary endpoints between both treatment
groups: About 20% of patients presented with motor
complications after 5 years of continuous treatment.
Thus, compared to standard levodopa, CR levodopa
has not proven to be efficacious in preventing or delaying
the development of motor complications.
32.10. Dopamine-enhancing agents
32.10.1. Monoamine oxidase-B inhibitors
To increase central dopaminergic availability and
to extend levodopa half-life, different agents that
block the breakdown of levodopa and dopamine
have been introduced into clinical practice. One thera-
peutic principle to block the biotransformation of
dopamine is the selective inhibition of MAO-B (see
section 32.2.2 this chapter and Ch. 34). MAO-B inhi-
bitors block the deamination of residual endogenous
dopamine as well as dopamine synthesized from
externally administered levodopa. However, several
other mechanisms, including reuptake inhibition and
action on presynaptic autoreceptors, are involved in
the enhancement of dopaminergic neurotransmission
by MAO-B inhibitors (Riederer et al., 1978). Selegi-
line and rasagiline are both irreversible inhibitors of
54 T. D. HALBIG AND W. C. KOLLER
MAO-B with mild antiparkinsonian effects when used
as monotherapy or in conjunction with levodopa in
early PD (Parkinson Study Group, 1989, 2002b;
Pahwa et al., 1993; Lees, 1995; Block et al., 1997;
Iwase et al., 2000) as well as in fluctuating patients
(Rabey et al., 2000; Parkinson Study Group, 2005;
Rascol et al., 2005). Furthermore, there is evidence
that the use of MAO-B inhibitors may delay the need
for dopaminergic therapy (Parkinson Study Group,
1989). Whether this results from mild symptomatic
effects of MAO-B inhibition or rather from neuropro-
tective, PD progression-delaying effects, as suggested
by recent studies (Olanow et al., 1995; Parkinson
Study Group, 2004c), is debated. For a more indepth
evaluation of MAO-B inhibitors in the treatment of
PD, see Chapter 34.
32.10.2. Catechol-O-methyltransferase inhibitors
Another therapeutic principle that aims at the enhance-
ment of externally administered levodopa is the inhibi-
tion of COMT. Levodopa is mainly metabolized by
AADC and COMT and, when administered orally,
only about 1% reaches the CNS to supplement missing
dopamine in PD (see section 32.3). The previous intro-
duction of AADC inhibitors blocked one of the main
metabolic pathways, allowing a dramatic levodopa
dose reduction of up to 75%. By further blocking the
remaining major peripheral metabolic pathway
(COMT), central levodopa bioavailability could be
significantly further increased. Two different COMT
inhibitors, tolcapone and entacapone, have been
approved in the 1990s as adjunctive therapy to levo-
dopa. Both agents have been shown to result in more
CDS with potentiated and prolonged clinical effects
of each single dose of levodopa.
32.10.2.1. Catechol-O-methyltransferase inhibition:
pharmacokinetics and dynamics
Both COMT inhibitors are rapidly absorbed and their
Cmax is reached within less than 2 hours (Keranen
et al., 1994; Dingemanse et al., 1995b; Jorga, 1998a).
Oral bioavailability is about 60% for tolcapone (Jorga
et al., 1998b) and between 30% and 46% for entaca-
pone (Keranen et al., 1994; Heikkinen et al., 2001).
Cmax and AUC are higher for tolcapone (Keranen
et al., 1994; Dingemanse et al., 1995b). Entacapone
and tolcapone are highly protein-bound (98% and
99.9%, respectively). At therapeutic oral doses (see
Table 32.6) both COMT inhibitors have an elimination
half-life between 1.6 and 3.4 hours (Keranen et al.,
1994; Dingemanse et al., 1995b; Jorga et al., 1998b;
Heikkinen et al., 2001). Tmax upon oral administration
of 100 or 200 mg is 0.6 or 0.7 hours for entacapone
(Keranen et al., 1994; Heikkinen et al., 2001) and 1.7
and 1.8 hours for tolcapone (Dingemanse et al.,
1995b; Jorga et al., 1998b).
Both agents are highly metabolized and only 0.5% of
an oral dose is excreted with the urine. Degradation is
primarily via hepatic glucuronidation. Tolcapone is
primarily eliminated via the biliary route and about
40% of orally administered doses is excreted in the feces
(Wikberg et al., 1993b; Jorga et al., 1999; Heikkinen
et al., 2001; Valeant Pharmaceuticals International,
2006). Entacapone is almost entirely glucuronized in the
liver and eliminated by the kidneys and via the biliary
route, undergoing enterohepatic circulation (Wikberg
et al., 1993a; Jorga et al., 1998b; Heikkinen et al., 2001).
Pharmacokinetics of both COMT inhibitors is not
significantly affected by co-administration of levodopa
and AADC inhibitors (Dingemanse et al., 1995b; Smith
et al., 1997). There is no difference in pharmacokinetics
between healthy young and old subjects and PD patients
and no accumulation in plasma takes place during
chronic administration of both COMT inhibitors (Din-
gemanse et al., 1995b; Jorga et al., 1997). Elimination
half-life for entacapone is shorter than for tolcapone
(0.40.7 hours (Keranen et al., 1994; Heikkinen et al.,
2001) and 23 hours (Jorga, 1998a), respectively).
Entacapone is not lipophilic and does not cross the
bloodbrain barrier. It thus exerts its effects on COMT
only peripherally (Nutt, 1998; Troconiz et al., 1998). In
contrast, tolcapone is able to penetrate the bloodbrain
barrier, as shown in rodents and monkeys (Zurcher
et al., 1990), as well as by 18F-dopa PET imaging in
PD patients (Ceravolo et al., 2002). Nevertheless, the
main clinical effects of both drugs are thought to be
mediated by peripheral actions (Nutt, 2000).
Entacapone and tolcapone inhibit COMT in a dose-
dependent fashion (Jorga, 1998b). Compatible with their
pharmakokinetic differences, COMT inhibition differs
between entacapone and tolcapone. As reflected by inhi-
bition of COMT activity in red blood cells, a measure of
peripheral COMT inhibition, 200 mg entacapone inhibits
COMT by 60% at peak plasma concentration and by 10%
4 hours after administration. In contrast, 200 mg tolca-
pone inhibits COMT by 80% at peak plasma concentra-
tion and by 70% 4 hours after intake (Jorga, 1998b).
The effects of both entacapone and tolcapone on COMT
are fully reversible, as studied in in vitro models (Lotta
et al., 1995; Borges et al., 1997). COMT is recovered
within 8 hours (entacapone) and 16 hours (tolcapone),
respectively (Keranen et al., 1994; Dingemanse et al.,
1995b). COMT-inhibitory effects do not decrease after
repeated administration (Dingemanse et al., 1996;
Ruottinen and Rinne, 1996a; Jorga et al., 1997) and are
maintained independently of PD progression (Ruottinen
and Rinne, 1996a).
 LEVODOPA
32.10.2.2. Effects of catechol-O-methyltransferase
inhibitors on levodopa pharmacokinetics
Both COMT inhibitors increase the AUC without
increasing Cmax for levodopa, as shown in healthy
volunteers when administered as single doses of 100
or 200 mg (Keranen et al., 1993; Dingemanse et al.,
1995a; Sedek et al., 1997) and PD patients (Myllyla
et al., 1993; Roberts et al., 1993; Nutt et al., 1994;
Tohgi et al., 1995; Ruottinen and Rinne, 1996b). Data
obtained in healthy volunteers after administration of
200 mg entacapone or tolcapone revealed increases of
AUC by 40% or 80%, suggesting better clinical efficacy
for tolcapone (Keranen et al., 1993; Jorga et al., 1997;
Sedek et al., 1997). Single doses of entacapone and
tolcapone prolong levodopa half-life in PD patients by
2080% (Myllyla et al., 1993; Roberts et al., 1993; Nutt
et al., 1994; Tohgi et al., 1995; Ruottinen and Rinne,
1996b; Sedek et al., 1997).
Moreover, repeated administration of COMT in-
hibitors leads to smoothening of levodopa plasma
concentration (Rouru et al., 1999). After repeated admin-
istration, the AUC of levodopa is increased (by 2550%)
and levodopa trough levels increase (Keranen et al.,
1993; Nutt et al., 1994; Dingemanse et al., 1995b; Jorga
et al., 1997). Increases of AUC appear to be mildly smal-
ler and elimination half-life shorter after administration
of 200 mg entacapone compared to 200 mg tolcapone
(Kaakkola, 2000). Long-term treatment of 8 weeks by
600 mg/day of tolcapone and 1200 mg/day of entacapone
correspondingly increased the AUC by 33% and 43%,
respectively (Nutt et al., 1994; Yamamoto et al., 1997;
Kaakkola, 2000). Even though Cmax is not increased after
single-dose administration, repeated doses will increase
Cmax (Nutt et al., 1994), which may be explained by the
fact that levodopa plasma concentrations at the end of
each dose interval are higher with COMT inhibition
(Nutt, 2000).
When entacapone is administered with standard levo-
dopa or CR levodopa, the AUC increased for both formu-
lations (Ahtila et al., 1995; Piccini et al., 2000). Again,
when co-administered with CR levodopa, the efficacy of
a single dose of 200 mg tolcapone was higher, with an
increase of AUC by 70% compared to a 20% increase after
200 mg entacapone (Ahtila et al., 1995; Jorga et al.,
1998a).
Increased central dopamine availability by COMT inhi-
bition is reflected in studies using fluoro-dopa (FD)-PET.
Both entacapone and tolcapone plus fluorodopa in con-
junction with an AADC inhibitor increased striatal fluoro-
dopa uptake significantly (Sawle et al., 1994; Routtinen
et al. 1995; Ceravolo et al., 2002). This is compatible with
an enhancement of striatal dopamine, as shown by
microdialysis in rats (for entacapone, see Kaakkola and
55
Wurtman, 1993; Tornwall et al., 1994; for tolcapone, see
Acquas et al., 1992; Napolitano et al., 1995).
32.10.2.3. Clinical effects of catechol-O-
methyltransferase inhibition
32.10.2.3.1. Effects in patients with motor fluctuations
Several prospective, double-blind placebo-controlled
clinical trials assessed the effects of the COMT inhibitors
tolcapone and entacapone as add-on to levodopa on
motor fluctuations (entacapone: Parkinson Study Group,
1997; Rinne et al., 1998a; Myllyla et al., 2001; Poewe
et al., 2002a; Brooks et al., 2003; tolcapone: Baas
et al., 1997; Kurth et al., 1997; Myllyla et al., 1997;
Rajput et al., 1997; Adler et al., 1998). Primary efficacy
measures were daily on and off time. Table 32.6
reports the outcome for treatment with either 100 or
200 mg tolcapone or 200 mg entacapone. On time in
all studies was significantly increased by 515%. Com-
patible with this, off time was reduced between 10
and 22%. Improvements were found to be more pro-
found in patients treated with tolcapone. All studies
report that levodopa doses could be decreased by
1229%, again with higher dose reduction in tolcapone-
treated patients. These differences are compatible with
the pharmacological properties of both agents. However,
based on the differences in observational periods, with
longer study durations for entacapone, it cannot be
excluded that higher efficacy measures for tolcapone at
least partially result from a higher impact of placebo
effects early during the trial and loss of efficacy in the
entacapone-treated patients who were observed longer
(Nutt, 2000).
32.10.2.3.2. Catechol-O-methyltransferase inhibition
to prevent dyskinesias
Apart from its role as levodopa adjunct in the treatment of
motor fluctuations, COMT inhibitors have been impli-
cated in the delay of the development of dyskinesias.
Long-term treatment with levodopa has been shown
to be associated with motor complications, including
wearing off and dyskinesias. Although the pathophy-
siological basis of these complications is incompletely
understood, current pathophysiological and clinical
evidence suggests that the half-life of dopaminergic
agents substantially contributes to the development of
dyskineseas (see section 32.7.4). The administration of
levodopa with its short pharmacological half-life of about
1.5 hours and pulsatile receptor stimulation is therefore
thought to be a major risk factor for the early develop-
ment of dyskinesias (Smith et al., 2003). Based on these
considerations it has been postulated that more conti-
nous dopaminergic stimulation by an extension of the
56 T. D. HALBIG AND W. C. KOLLER
Table 32.6
Effects of catechol-O-methyltransferase (COMT) inhibitors on on and off time in fluctuating patients

Number of
patients on Study
COMT duration Change in Change in Change in daily
Study inhibitor (months) on time* off time* levodopa dose

Entacapone
(200 mg with each LD dose)
Parkinson Study Group (1997) 103 6 1.0 h NR 100 mg
Rinne et al. (1998) 85 6 1.4 h 1.3 h 87 mg
Brooks et al. (2003) 115 6 1.3 h 1.1 h 33 mg
Poewe et al. (2002) 172 6 1.7 h 1.6 h 54 mg
Tolcapone
Adler et al. (1998) 69/74 1.5 2.1 h/2.3 h 2h/2.5h 186 mg/252 mg
(100 mg/200 mg)
Rajput et al. (1997) 69/67 3 NR 2.3h/3.2h 166 mg/207 mg
(100 mg/200 mg)
Baas et al. (1997) 60/59 3 2.6 h/2.6 h 3.0h/2.4h 108 mg/122 mg
(100 mg/200 mg)
Kurth et al. (1997) 41/40 1.5 0.9 h/0.3 h 1.7h/1.3h 139 mg/200 mg
(50 mg/200 mg)

*Change in time as a percent of waking day.

NR, not reported.

levodopa half-life by co-administration of COMT inhi-
bition may delay or prevent the development of dyski-
nesias. Indeed, experimental evidence obtained in
MPTP-treated monkeys revealed that the co-adminstra-
tion of levodopa and entacapone resulted in significantly
less severe dyskinesias compared to levodopa-only treat-
ment (Smith et al., 2005). Interestingly, and in support of
the hypothesis that pulsatile stimulation contributes to the
establishment of dyskinesias, this effect was only present
when the levodopa/entacapone were administered four
times daily. When levodopa/entacapone were adminis-
tered only twice daily, there was no difference in dyskine-
sia rate compared to levodopa-only treatment. In another
study by the same group, the combination of entacapone
with levodopa resulted in even more rapid appearance of
dyskinesias (Smith et al., 2003) when administered twice
daily. Currently, clinical trials in patients with early PD
test the notion that more frequent dosing and the co-
administration of entacapone may delay the development
of dyskinesias.
32.10.2.4. Side-effects of catechol-
O-methyltransferase inhibitors
The side-effect profile of entacapone and tolcapone is
in general favorable. Safety data reported here are
derived from the mentioned controlled phase III enta-
capone and tolcapone studies (Table 32.7). Compatible
with their levodopa-enhancing effects, side-effects of
both entacapone and tolcapone are primarily associated
with dopaminergic overstimulation and may present as
dyskinesia, nausea, vomiting and hallucinations. More-
over, non-dopaminergic side-effects such as diarrhea,
abdominal pain, constipation, urine discoloration and
fatigue have been reported for both agents and liver
toxicity for tolcapone only.
32.10.2.4.1. Dopaminergic side-effects
Dopaminergic side-effects usually develop early during
treatment. The most common dopaminergic side-
effects are dyskinesias, which most often present in
the form of peak-dose dyskinesias. Treatment with both
COMT inhibitors presented with significantly higher
incidence of dyskinesia compared to patients on pla-
cebo. Differences in percentage of patients reporting
dyskinesias as adverse event varied between 7% and
47% depending on the study. Predictors for the devel-
opment of dyskinesias are pre-existing dyskinesias
and higher doses of levodopa (Poewe et al., 2002a;
Reinikainen et al., 2002). Dyskinesias can usually be
managed successfully by reducing the amount of levo-
dopa per dose, by increasing the dose intervals or both
(Poewe et al., 2002a; Brooks et al., 2003).
Nausea has been reported to be the second most
important dopaminergic side-effect. It also emerges
during the first days of treatment. Nausea developed
in about 1323% of patients treated with entacapone
 LEVODOPA
Table 32.7
Incidence of the more frequent side-effects in controlled clinical trials assessing the effects of tolcapone1 or entacapone2
against placebo
Tolcapone Tolcapone
Agent (100 mg t.i.d.) (200 mg t.i.d.)
n 296 298
Side-effects
Dyskinesia 42 51
Nausea 30 35
Diarrhea 16 18
Dizziness 13 6 10
Hallucination 8 10
Vomiting 8 10
Constipation 6 8
Fatigue 7 3
Abdominal pain 5 6
Urine discoloration 2 7
Numbers indicate percentage of patients.
1
Valeant Pharmaceuticals International (2006).
2
Novartis Pharmaceuticals Corporation (2000).
Adapted from Kaakkola (2000) and modified and updated.
(Parkinson Study Group, 1997; Rinne et al., 1998a;
Brooks, 2004) and in about 30% of patients treated with
tolcapone (Baas et al., 1997; Kurth et al., 1997; Rajput
et al., 1997; Waters et al., 1997; Brooks, 2004). Again,
adjustment of the overall levodopa dose usually allows
control of this side-effect (Brooks, 2004).
Interestingly, the incidence of neuropsychiatric side-
effects after introduction of COMT inhibitors is rather
low. However, in an open-label extension study (Larsen
et al., 2003), 19 out of 132 patients (14.4%) of patients trea-
ted with entacapone developed hallucinations. There is
evidence that single patients, in particular elderly patients,
may be more vulnerable to confusion and hallucinations
when treated with entacapone (Henry and Wilson, 1998).
32.10.2.4.2. Non-dopaminergic effects
In contrast to dopaminergic side-effects, non-dopami-
nergic adverse events were reported to occur throughout
the entire study period. The most important non-dopa-
minergic side-effect is diarrhea. Diarrhea usually did
not occur during the first days of treatment. Diarrhea
in clinical trials was more frequent in patients receiving
tolcapone (1618%) than in patients treated with enta-
capone (820%). In tolcapone-treated patients, severe
explosive diarrhea led to treatment discontinuation in
810% of patients (Baas et al., 1997; Kurth et al.,
1997; Rajput et al., 1997), whereas only 14% receiving
entacapone discontinued treatment for diarrhea (Rinne
et al., 1998a; Poewe et al., 2002a; Brooks et al., 2003).
The underlying pathophysiological mechanism leading
to diarrhea is unknown. Even though it appears as if
57
Placebo Entacapone Placebo
298 603 400
20 25 15
18 14 8
8 10 4
8 6
5 4 4
4 4 1
5 6 4
6 6 4
3 8 4
1 10 0
diarrhea is a class effect of the COMT inhibitors, it is
not clear why frequency and severity are clearly more
pronounced for tolcapone. However, an association
with levodopa/AADC inhibitor treatment seems unli-
kely, since diarrhea is also induced when tolcapone is
administered without levodopa (Hauser et al., 1998).
Another frequent side-effect emerging in 737% of
patients is discoloration of urine to dark yellow or red-
dish brown, which is harmless but worrisome to
patients who were not previously informed about it.
A rare but more serious side-effect associated with
tolcapone treatment is liver toxicity (Brooks, 2004). Tol-
capone-treated patients in phase III trials developed
clinically relevant increases of liver enzymes and 3%
of patients had to discontinue the study (Brooks, 2004).
After tolcapone was approved by regulative authorities,
4 out of 60 000 patients receiving tolcapone developed
severe liver dysfunction, which was fatal in 3 patients
(Assal et al., 1998; Olanow, 2000). One of these 3
patients died despite adequate liver function laboratory
monitoring. In consequence tolcapone was withdrawn
from the European and Canadian markets. In the US,
the use of tolcapone was restricted to patients who
experience motor fluctuations refractory to other treat-
ments and who show no clinical evidence of liver disease
or two serum glutamic-pyruvic transaminase (SGPT/
ALT) or serum glutamic-oxaloacetic transaminase
(SGOT/AST) values greater than the upper limit of nor-
mal. Furthermore, in patients treated with tolcapone,
serum SGPT/ALT and SGOT/AST levels should be
determined at baseline and periodically (i.e. every 24
58 T. D. HALBIG AND W. C. KOLLER
weeks) for the first 6 months of therapy. After the first 6
months, periodic monitoring is recommended at inter-
vals deemed clinically relevant. Tolcapone should be
discontinued if SGPT/ALT or SGOT/AST levels exceed
two times the upper limit of normal or if clinical signs
and symptoms suggest the onset of hepatic dysfunction.
Finally, patients who fail to show substantial clinical
benefit within 3 weeks of initiation of treatment should
be withdrawn from tolcapone (Valeant Pharmaceuticals
International, 2006).
All five mentioned phase III entacapone trials reported
occasionally elevations of liver enzymes (Gordin et al.,
2003). However, a clear association with entacapone treat-
ment could not be established. Furthermore, these studies
did not report instances of serious liver dysfunction. One
report, however, describes 3 patients who received entaco-
pone and developed symptopmatic liver dysfunction
which improved after withdrawal (Fisher et al., 2002).
Interpretation of these cases is complicated by several fac-
tors, including poor documentation and lack of rechal-
lenge with tolcapone, multimorbidity of patients and
polypharmacy. Thus, the diagnosis of entacapone-induced
liver dysfunction is probable, although not proven
(Brooks, 2004). Apart from these cases, no further evi-
dence for liver toxicity has been presented and indeed
more than 300 000 patient-years of entacapone exposure
were not reported to be associated with liver dysfunction.
Presently, the liver toxicity seen in COMT inhibitor-
treated patients may therefore not be interpreted as a
COMT inhibitor class effect, but rather a problem asso-
ciated with tolcapone. Compatible with this view, there
are important pharmacological differences between both
agents. Tolcapone has a much higher lipid solubility,
which may enhance penetration in mitochondrial inner
membrane (Nissinen et al., 1997). Furthermore, in contrast
to entacapone, tolcapone may uncouple oxidative phos-
phorylation. On the other hand, entacopone is nearly
entirely glucuronized (Wikberg et al., 1993a; Lautala
et al., 2000), whereas talcapone is glucuronized but also
methylated and oxidized (Jorga et al., 1998c). Both factors
may be important for the putative toxicity of tolcapone.
In summary, due to its safety profile, entacapone is
clearly the first-line COMT inhibitor. However, due to
its superior efficacy in the control of motor complica-
tions, tolcapone may be considered for selected patients
in whom entacapone or other therapeutic measures do
not allow sufficient symptom control, provided the
required safety monitoring is ensured (Factor et al.,
2001; Onofrj et al., 2001).
32.11. Conclusion and practical implications
for the use of levodopa
Levodopa revolutionized the symptomatic treatment of
one of the most prevalent progressive degenerative
diseases. However, since its approval by the FDA in
1970, several other pharmacological compounds
mimicking the effects of dopamine or enhancing levo-
dopa availability have been introduced. Compared to
newer agents and, in particular, dopamine agonists,
levodopa is still the most efficacious drug, as revealed
by consistently better symptom control measured by
the UPDRS (Rascol et al., 2000; Parkinson Study
Group, 2004b). Compatible with this, even though
dopamine agonists allow symptoms to be satisfactorily
controlled during the first years of disease, eventually
nearly all dopamine agonist-treated patients need levo-
dopa supplementation. The particular role of levodopa
is further substantiated by its favorable side-effect
profile (Table 32.2 and see Ch. 33).
Apart from its symptomatic clinical effects and side-
effects, the impact of levodopa therapy on the
disease process has been the subject of considerable
controversy and neuroprotective effects as well as
toxic effects have been examined widely. However, to
date, there is no convincing evidence for toxic effects
of levodopa in humans. Recent data even show some
controversial evidence for mild neuroprotective effects
of levodopa therapy (Parkinson Study Group, 2004a).
However, after more than 30 years of experience
with levodopa, the limitations and shortcomings of
levodopa therapy also became evident. A wealth of
data indicated that long-term levodopa treatment con-
tributes to the early development of motor complica-
tions and in particular dyskinesias (see section 32.7.4
and Tables 32.4 and 32.5). Today it is estimated that,
after 5 years of levodopa treatment, between 20 and
50% of patients have developed motor complications,
including dyskinesias and onoff fluctuations, whereas
the incidence of motor complications in dopamine ago-
nist-treated patients is significantly lower (510%).
These observations led to a reassessment of the role of
levodopa in symptomatic PD therapy and in particular
the debate of when and how to initiate dopaminergic
therapy.
Based on the potential of levodopa to induce long-
term motor complications and the lack of evidence for
neuroprotection, there is presently no rationale for
treating patients with early PD without functional
deficits relevant to activities of daily living and quality
of life with levodopa. Instead, based on preliminary
clinical evidence for their mild neuroprotective poten-
tial, MAO-B inhibitors (Ch. 34) or coenzyme Q10
(Ch. 31) may be tried. In patients with minor symptoms
and a need for treatment, less potent non-dopaminergic
agents such as MAO-B inhibitors or amantadine
(Ch. 36) can be tried.
In patients with more pronounced symptoms needing
symptomatic improvement, dopaminergic agents have
to be employed. Based on the potential of levodopa to
 LEVODOPA
induce motor complications early, current treatment
algorithms often recommend that the use of levodopa
be spared until necessary to control motor symptoms
satisfactorily (Olanow et al., 2001). Instead, dopamine
agonists are recommended as initial treatment. How-
ever, the question of which is the best strategy to initiate
treatment is controversial. There is general agreement
that motor complications compromise patients func-
tionality and well-being. Nevertheless, in the several
controlled studies which compare dopamine agonists
and levodopa and which demonstrate superiority of
dopamine agonists in terms of delay of motor complica-
tions, no difference was found on quality of life and
activity of daily living measures (Rinne et al., 1998b;
Rascol et al., 2000; Parkinson Study Group, 2004b).
Moreover, the use of dopamine agonists may be limited
due to their side-effect profile, in particular in vulner-
able patients where levodopa, as the generally best tol-
erated dopaminergic drug, should be considered.
Furthermore, dopamine agonists also have the potential
to induce motor complications, although precise data on
the temporal profile and exact incidence are as yet
unknown (Jenner, 2003). Further, there is some evi-
dence that establishment of motor complications is
reversible (Jenner, 2002). No controlled study ever
assessed whether patients who were initially treated
with a dopamine agonist and who received levodopa
later on are doing better in terms of motor functions,
activities of daily living and quality of life than patients
who were initially treated with levodopa and developed
motor complications early in the disease and then
received a dopamine agonist as add-on in order to con-
trol the motor complications via more CDS. Based on
these considerations, the more favorable side-effect
profile and its higher efficacy, levodopa administration
may be also considered a rational choice for individual
patients, even in earlier stages of disease progression.
This holds in particular for older de novo patients with
less risk for the development of motor complications
than patients with early onset of PD.
In conclusion, although it is now more than 30 years
after the introduction of levodopa, pharmacological PD
therapy in the beginning of the 21st century involves in
most patients who have access to the full armamentar-
ium of PD therapy a complex, growing array of agents
that is usually continuously modified in the course
of disease progression. For most patients levodopa
sooner or later is indispensable for satisfactory symp-
tom control.
Finally, apart from new modes of administration,
recent conceptual developments may again lead to
changes in current therapeutic thinking. For example,
based on the concept of CDS, clinical trials currently
evaluate whether the combined administration of
59
levodopa and a COMT inhibitor may be able to pre-
vent or delay the development of motor complications.
Thus, the development of levodopa therapy in PD as
one of the few true success stories in the treatment of
a neurodegenerative has by no means come to an end.
References
Aarsland D, Karlsen K (1999). Neuropsychiatric aspects of
Parkinsons disease. Curr Psychiatry Rep 1: 6168.
Abate G, Polimeni RM, Cuccurullo F et al. (1979). Effects of
indomethacin on postural hypotension in Parkinsonism. Br
Med J 2: 14661468.
Acquas E, Carboni E, de Ree RH et al. (1992). Extracellular
concentrations of dopamine and metabolites in the rat
caudate after oral administration of a novel catechol-O-
methyltransferase inhibitor Ro 407592. J Neurochem
59: 326330.
Adler CH, Singer C, OBrien C et al. (1998). Randomized,
placebo-controlled study of tolcapone in patients with
fluctuating Parkinson disease treated with levodopa-
carbidopa. Tolcapone Fluctuator Study Group III. Arch
Neurol 55: 10891095.
Agid Y, Bonnet AM, Ruberg M et al. (1985). Pathophysiol-
ogy of L-dopa-induced abnormal involuntary movements.
Psychopharmacology Suppl 2: 145159.
Agid Y, Javoy-Agid F, Ruberg M (1987). Biochemistry of
neurotransmitters in Parkinsons disease. In: CD Marsden,
S Fahn (Eds.), Movement Disorders 2. Butterworths,
London, pp. 166230.
Ahlskog JE, Muenter MD (2001). Frequency of levodopa-
related dyskinesias and motor fluctuations as estimated
from the cumulative literature. Mov Disord 16: 448458.
Ahlskog JE, Muenter MD, McManis PG et al. (1988). Con-
trolled-release Sinemet (CR-4): a double-blind crossover
study in patients with fluctuating Parkinsons disease.
Mayo Clin Proc 63: 876886.
Ahlskog JE, Uitti RJ, OConnor MK et al. (1999). The effect
of dopamine agonist therapy on dopamine transporter ima-
ging in Parkinsons disease. Mov Disord 14: 940946.
Ahtila S, Kaakkola S, Gordin A et al. (1995). Effect of enta-
capone, a COMT inhibitor, on the pharmacokinetics
and metabolism of levodopa after administration of
controlled-release levodopa-carbidopa in volunteers. Clin
Neuropharmacol 18: 4657.
Allain P, Le Bouil A, Cordillet E et al. (1995). Sulfate and
cysteine levels in the plasma of patients with Parkinsons
disease. Neurotoxicology 16: 527529.
APA (2000). Diagnostic and Statistical Manual of Mental
Disorders, DSM-IV-TR Fourth Edn. American Psychiatric
Association, Washington DC.
Arnulf I, Bonnet AM, Damier P et al. (2000). Hallucinations,
REM sleep, and Parkinsons disease: a medical hypothesis.
Neurology 55: 281288.
Assal F, Spahr L, Hadengue A et al. (1998). Tolcapone and
fulminant hepatitis. Lancet 352: 958.
Avanzi M, Uber E, Bonfa F (2004). Pathological gambling in
two patients on dopamine replacement therapy for Parkin-
sons disease. Neurol Sci 25: 98101.
60 T. D. HALBIG AND W. C. KOLLER
Baas H, Beiske AG, Ghika J et al. (1997). Catechol-O-
methyltransferase inhibition with tolcapone reduces the
wearing off phenomenon and levodopa requirements in
fluctuating parkinsonian patients. J Neurol Neurosurg
Psychiatry 63: 421428.
Barbeau A, Sourkes T, Murphy G (1962). Les Catechola-
mines dans la Maladie de Parkinson Georg, Geneva.
Barnes J, David AS (2001). Visual hallucinations in Parkin-
sons disease: a review and phenomenological survey.
J Neurol Neurosurg Psychiatry 70: 727733.
Barone JA (1999). Domperidone: a peripherally acting dopa-
mine2-receptor antagonist. Ann Pharmacother 33: 429440.
Bartholini G, Burkard WP, Pletscher A (1967). Increase of
cerebral catecholamines caused by 3,4-dihydroxyphenyla-
lanine after inhibition of peripheral decarboxylase. Nature
215: 852853.
Bayer AJ, Day JJ, Finucane P et al. (1988). Bioavailability
and acceptability of a dispersible formulation of levodopa-
benserazide in parkinsonian patients with and without
dysphagia. J Clin Pharm Ther 13: 191194.
Bedard PJ, Di Paolo T, Falardeau P et al. (1986). Chronic
treatment with L-DOPA, but not bromocriptine induces
dyskinesia in MPTP-parkinsonian monkeys. Correlation
with [3H]spiperone binding. Brain Res 379: 294299.
Ben-Shlomo Y, Marmot MG (1995). Survival and cause of
death in a cohort of patients with parkinsonism: possible clues
to aetiology? J Neurol Neurosurg Psychiatry 58: 293299.
Berger C, Mehrhoff FW, Beier KM et al. (2003). [Sexual
delinquency and Parkinsons disease.] Nervenarzt 74:
370375.
Birkmayer W (1969). The importance of monoamine meta-
bolism for the pathology of the extrapyramidal system.
J Neurovisc Relat 31 (Suppl 9): 297.
Birkmayer W, Hornykiewicz O (1961). [The L-3,4-dioxy-
phenylalanine (DOPA)-effect in Parkinson-akinesia.]
Wien Klin Wochenschr 73: 787788.
Blanchet PJ, Calon F, Martel JC et al. (1995). Continuous
administration decreases and pulsatile administration
increases behavioral sensitivity to a novel dopamine
D2 agonist (U-91356A) in MPTP-exposed monkeys.
J Pharmacol Exp Ther 272: 854859.
Block G, Liss C, Reines S et al. (1997). Comparison of
immediate-release and controlled release carbidopa/levo-
dopa in Parkinsons disease. A multicenter 5-year study.
The CR First Study Group. Eur Neurol 37: 2327.
Borges N, Vieira-Coelho MA, Parada A et al. (1997). Studies
on the tight-binding nature of tolcapone inhibition
of soluble and membrane-bound rat brain catechol-
O-methyltransferase. J Pharmacol Exp Ther 282: 812817.
Bostom AG, Rosenberg IH, Silbershatz H et al. (1999a).
Nonfasting plasma total homocysteine levels and stroke
incidence in elderly persons: the Framingham Study.
Ann Intern Med 131: 352355.
Bostom AG, Silbershatz H, Rosenberg IH et al. (1999b).
Nonfasting plasma total homocysteine levels and
all-cause and cardiovascular disease mortality in elderly
Framingham men and women. Arch Intern Med 159:
10771080.
Bouhaddi M, Vuillier F, Fortrat JO et al. (2004). Impaired
cardiovascular autonomic control in newly and long-
term-treated patients with Parkinsons disease: involve-
ment of L-dopa therapy. Auton Neurosci 116: 3038.
Bradbrook ID, Gillies HC, Morrison PJ et al. (1986). The
effects of domperidone on the absorption of levodopa in
normal subjects. Eur J Clin Pharmacol 29: 721723.
Brandstadter D, Oertel WH (2002). Treatment of drug-
induced psychosis with quetiapine and clozapine in Par-
kinsons disease. Neurology 58: 160161.
Bravi D, Mouradian MM, Roberts JW et al. (1994). Wearing-
off fluctuations in Parkinsons disease: contribution of
postsynaptic mechanisms. Ann Neurol 36: 2731.
Breier A, Sutton VK, Feldman PD et al. (2002). Olanzapine in
the treatment of dopamimetic-induced psychosis in patients
with Parkinsons disease. Biol Psychiatry 52: 438445.
Brevetti G, Bonaduce D, Breglio R et al. (1990). Parkinsons
disease and hypotension: 24-hour blood pressure recording
in ambulant patients. Clin Cardiol 13: 474478.
Brooks DJ (2004). Safety and tolerability of COMT inhibi-
tors. Neurology 62: S39S46.
Brooks DJ, Sagar H (2003). UK-Irish Entacapone Study
Group. Entacapone is beneficial in both fluctuating and
non-fluctuating patients with Parkinsons disease: a rando-
mised, placebo controlled, double blind, six month study.
J Neurol Neurosurg Psychiatry 74: 10711079.
Burguera JA, Grandas F, Horga de la Parte JF et al. (1999).
[Entacapone: is it useful as complimentary treatment with
levodopa?] Rev Neurol 28: 817834.
Byrne KG, Pfeiffer R, Quigley EM (1994). Gastrointestinal
dysfunction in Parkinsons disease. A report of clinical
experience at a single center. J Clin Gastroenterol 19:
1116.
Calne DB (1970). L-Dopa in the treatment of parkinsonism.
Clin Pharmacol Ther 11: 789801.
Calne DB, Brennan J, Spiers AS et al. (1970). Hypotension
caused by L-dopa. Br Med J 1: 474475.
Calne DB, Reid JL, Vakil SD et al. (1971). Idiopathic Parkin-
sonism treated with an extracerebral decarboxylase inhibitor
in combination with levodopa. Br Med J 3: 729732.
Calon F, Goulet M, Blanchet PJ et al. (1995). Levodopa or
D2 agonist induced dyskinesia in MPTP monkeys: corre-
lation with changes in dopamine and GABAA receptors
in the striatopallidal complex. Brain Res 680: 4352.
Calon F, Grondin R, Morissette M et al. (2000). Molecular
basis of levodopa-induced dyskinesias. Ann Neurol 47:
S70S78.
Camerlingo M, Ferraro B, Gazzaniga GC et al. (1990). Car-
diovascular reflexes in Parkinsons disease: long-term
effects of levodopa treatment on de novo patients. Acta
Neurol Scand 81: 346348.
Cedarbaum JM, Kutt H, Dhar AK et al. (1986). Effect of
supplemental carbidopa on bioavailability of L-dopa. Clin
Neuropharmacol 9: 153159.
Cedarbaum JM, Breck L, Kutt H et al. (1987). Controlled-
release levodopa/carbidopa. II. Sinemet CR4 treatment of
response fluctuations in Parkinsons disease. Neurology
37: 16071612.
 LEVODOPA
Cedarbaum JM, Silvestri M, Kutt H (1990a). Sustained ent-
eral administration of levodopa increases and interrupted
infusion decreases levodopa dose requirements. Neurology
40: 995997.
Cedarbaum JM, Silvestri M, Clark M et al. (1990b). Results
of long-term treatment with controlled-release levodopa/
carbidopa (Sinemet CR). J Neural Transm Park Dis
Dement Sect 2: 205213.
Ceravolo R, Piccini P, Bailey DL et al. (2002). 18F-dopa PET
evidence that tolcapone acts as a central COMT inhibitor
in Parkinsons disease. Synapse 43: 201207.
Chapuis S, Ouchchane L, Metz O et al. (2004). Impact of the
motor complications of Parkinsons disease on the quality
of life. Mov Disord 20: 224230.
Chouza C, Aljanati R, Caamano JL et al. (1990). Long-term
treatment with Madopar HBS in parkinsonians with
fluctuations. Adv Neurol 53: 519526.
Clarke CE, Sambrook MA, Mitchell IJ et al. (1987). Levodo-
pa-induced dyskinesia and response fluctuations in
primates rendered parkinsonian with 1-methyl-4-phenyl-
1,2,3,6- tetrahydropyridine (MPTP). J Neurol Sci 78:
273280.
Comella CL, Goetz CG (1994). Akathisia in Parkinsons
disease. Mov Disord 9: 545549.
Contin M, Riva R, Martinelli P et al. (1999). Concentration-
effect relationship of levodopa-benserazide dispersible
formulation versus standard form in the treatment of
complicated motor response fluctuations in Parkinsons
disease. Clin Neuropharmacol 22: 351355.
Cook JW, Taylor LM, Orloff SL et al. (2002). Homocysteine
and arterial disease. Experimental mechanisms. Vascul
Pharmacol 38: 293300.
Corona-Morales AA, Castell A, Zhang L (2000). L-DOPA-
induced neurotoxic and apoptotic changes on cultured
chromaffin cells. Neuroreport 11: 503506.
Cotzias GC, Van Woert MH, Schiffer LM (1967). Aromatic
amino acids and modification of parkinsonism. N Engl
J Med 276: 374379.
Cotzias GC, Papavasiliou PS, Gellene R (1969). Modification
of Parkinsonismchronic treatment with L-dopa. N Engl
J Med 280: 337345.
Crevoisier C, Hoevels B, Zurcher G et al. (1987). Bioavail-
ability of L-dopa after Madopar HBS administration in
healthy volunteers. Eur Neurol 27 (Suppl 1): 3646.
Da Prada M, Kettler R, Zurcher G et al. (1987). Inhibition of
decarboxylase and levels of dopa and 3-O-methyldopa: a
comparative study of benserazide versus carbidopa in
rodents and of Madopar standard versus Madopar HBS
in volunteers. Eur Neurol 27 (Suppl 1): 920.
Datla KP, Blunt SB, Dexter DT (2001). Chronic L-DOPA
administration is not toxic to the remaining dopaminergic
nigrostriatal neurons, but instead may promote their func-
tional recovery, in rats with partial 6-OHDA or FeCl(3)
nigrostriatal lesions. Mov Disord 16: 424434.
de la Fuente-Fernandez R, Nunez MA, Lopez E (1999). The
apolipoprotein E epsilon 4 allele increases the risk of
drug-induced hallucinations in Parkinsons disease. Clin
Neuropharmacol 22: 226230.
61
de Maindreville AD, Fenelon G, Mahieux F (2005). Halluci-
nations in Parkinsons disease: a follow-up study. Mov
Disord 20: 212217.
De Michele G, Mengano A, Filla A et al. (1989). A double-
blind, cross-over trial with madopar HBS in patients with
Parkinsons disease. Acta Neurol (Napoli) 11: 408414.
de Smet Y, Ruberg M, Serdaru M et al. (1982). Confusion,
dementia and anticholinergics in Parkinsons disease. J
Neurol Neurosurg Psychiatry 45: 11611164.
Deleu D, Jacques M, Michotte Y et al. (1989). Clinical and
pharmacokinetic evaluation of controlled-release levodopa/
carbidopa (CR-4) in parkinsonian patients with severe
motor fluctuations: a six month follow-up study. Clin
Neurol Neurosurg 91: 303309.
DeLong MR, Crutcher MD, Georgopoulos AP (1983). Rela-
tions between movement and single cell discharge in the
substantia nigra of the behaving monkey. J Neurosci 3:
15991606.
den Heijer T, Vermeer SE, Clarke R et al. (2003). Homocys-
teine and brain atrophy on MRI of non-demented elderly.
Brain 126: 170175.
Descombes S, Bonnet AM, Gasser UE et al. (2001). Dual-
release formulation, a novel principle in L-dopa treatment
of Parkinsons disease. Neurology 56: 12391242.
Dewey RB Jr, OSuilleabhain PE (2000). Treatment of drug-
induced psychosis with quetiapine and clozapine in
Parkinsons disease. Neurology 55: 17531754.
Dexter DT, Wells FR, Agid F et al. (1987). Increased nigral
iron content in postmortem parkinsonian brain. Lancet 2:
12191220.
Dexter DT, Wells FR, Lees AJ et al. (1989). Increased nigral
iron content and alterations in other metal ions occurring
in brain in Parkinsons disease. J Neurochem 52:
18301836.
Dingemanse J, Jorga K, Zurcher G et al. (1995a). Pharmacoki-
netic-pharmacodynamic interaction between the COMT
inhibitor tolcapone and single-dose levodopa. Br J Clin
Pharmacol 40: 253262.
Dingemanse J, Jorga KM, Schmitt M et al. (1995b). Integrated
pharmacokinetics and pharmacodynamics of the novel
catechol-O-methyltransferase inhibitor tolcapone during
first administration to humans. Clin Pharmacol Ther 57:
508517.
Dingemanse J, Jorga K, Zurcher G et al. (1996). Multiple-dose
clinical pharmacology of the catechol-O-methyl-transferase
inhibitor tolcapone in elderly subjects. Eur J Clin Pharmacol
50: 4755.
Djaldetti R, Baron J, Ziv I et al. (1996). Gastric emptying in
Parkinsons disease: patients with and without response
fluctuations. Neurology 46: 10511054.
Djaldetti R, Inzelberg R, Giladi N et al. (2002). Oral solution
of levodopa ethylester for treatment of response fluctua-
tions in patients with advanced Parkinsons disease. Mov
Disord 17: 297302.
Djaldetti R, Giladi N, Hassin-Baer S et al. (2003). Pharmacoki-
netics of etilevodopa compared to levodopa in patients with
Parkinsons disease: an open-label, randomized, crossover
study. Clin Neuropharmacol 26: 322326.
62 T. D. HALBIG AND W. C. KOLLER
Dodd ML, Klos KJ, Bower JH et al. (2005). Pathological
gambling caused by drugs used to treat Parkinson disease.
Arch Neurol 62: 13771381.
Driver-Dunckley E, Samanta J, Stacy M (2003). Pathological
gambling associated with dopamine agonist therapy in
Parkinsons disease. Neurology 61: 422423.
Duan W, Ladenheim B, Cutler RG et al. (2002). Dietary
folate deficiency and elevated homocysteine levels endan-
ger dopaminergic neurons in models of Parkinsons
disease. J Neurochem 80: 101110.
Dufouil C, Alperovitch A, Ducros V et al. (2003). Homocys-
teine, white matter hyperintensities, and cognition in
healthy elderly people. Ann Neurol 53: 214221.
Dupont E, Andersen A, Boas J et al. (1996). Sustained-
release Madopar HBS compared with standard Madopar
in the long-term treatment of de novo parkinsonian
patients. Acta Neurol Scand 93: 1420.
Duty S, Brotchie JM (1997). Enhancement of the behavioral
response to apomorphine administration following
repeated treatment in the 6-hydroxydopamine-lesioned
rat is temporally correlated with a rise in striatal preproen-
kephalin-B, but not preproenkephalin-A, gene expression.
Exp Neurol 144: 423432.
Duvoisin RC (1972). Diphenidol for levodopa induced
nausea and vomiting. JAMA 221: 1408.
Edwards LL, Quigley EM, Pfeiffer RF (1992). Gastrointest-
inal dysfunction in Parkinsons disease: frequency and
pathophysiology. Neurology 42: 726732.
Ehringer H, Hornykiewicz O (1960). [Distribution of nora-
drenaline and dopamine (3-hydroxytyramine) in the
human brain and their behavior in diseases of the extrapyr-
amidal system]. Klin Wochenschr 38: 12361239.
Eisler T, Eng N, Plotkin C et al. (1981). Absorption of levo-
dopa after rectal administration. Neurology 31: 215217.
Emerit J, Edeas M, Bricaire F (2004). Neurodegenerative dis-
eases and oxidative stress. Biomed Pharmacother 58: 3946.
Emre M (2003). Dementia associated with Parkinsons
disease. Lancet Neurol 2: 229237.
Erni W, Held K (1987). The hydrodynamically balanced
system: a novel principle of controlled drug release. Eur
Neurol 27 (Suppl 1): 2127.
Evans AH, Katzenschlager R, Paviour D et al. (2004). Pund-
ing in Parkinsons disease: its relation to the dopamine
dysregulation syndrome. Mov Disord 19: 397405.
Fabbrini G, Mouradian MM, Juncos JL et al. (1988). Motor
fluctuations in Parkinsons disease: central pathophysiolo-
gical mechanisms, Part I. Ann Neurol 24: 366371.
Factor SA, Molho ES, Feustel PJ et al. (2001). Long-term
comparative experience with tolcapone and entacapone
in advanced Parkinsons disease. Clin Neuropharmacol
24: 295299.
Fahn S (1974). On-off phenomenon with levodopa therapy in
Parkinsonism. Clinical and pharmacologic correlations and
the effect of intramuscular pyridoxine. Neurology 24:
431441.
Fahn S, Elton R, Members of the UPDRS Development
Committee (1987). In: S Fahn, CD Marsden, DB Calne,
M Goldstein (Eds.), Recent Developments in Parkinsons
Disease, Vol. 2. Macmillan Health Care Information,
Florham Park, NJ, pp. 153163, 293304.
Fehling C (1966). Treatment of Parkinsons syndrome with L-
dopa. A double blind study. Acta Neurol Scand 42: 367372.
Feldman RG, Mosbach PA, Kelly MR et al. (1989). Double-
blind comparison of standard Sinemet and Sinemet CR in
patients with mild-to-moderate Parkinsons disease.
Neurology 39: 96101; discussion 105.
Fenelon G, Mahieux F, Huon R et al. (2000). Hallucinations
in Parkinsons disease: prevalence, phenomenology and
risk factors. Brain 123 (Pt 4): 733745.
Fernandez HH, Friedman JH (1999). Punding on L-dopa.
Mov Disord 14: 836838.
Fernandez HH, Friedman JH, Jacques C et al. (1999). Quetia-
pine for the treatment of drug-induced psychosis in Par-
kinsons disease. Mov Disord 14: 484487.
Fernandez HH, Trieschmann ME, Friedman JH (2004). Aripi-
prazole for drug-induced psychosis in Parkinson disease:
preliminary experience. Clin Neuropharmacol 27: 45.
Fiala KH, Whetteckey J, Manyam BV (2003). Malignant
melanoma and levodopa in Parkinsons disease: causality
or coincidence? Parkinsonism Relat Disord 9: 321327.
Fiorillo CD, Tobler PN, Schultz W (2003). Discrete coding
of reward probability and uncertainty by dopamine
neurons. Science 299: 18981902.
Fisher A, Croft-Baker J, Davis M et al. (2002). Entacapone-
induced hepatotoxicity and hepatic dysfunction. Mov
Disord 17: 13621365; discussion 13971400.
French Clozapine Parkinson Study Group (1999). Clozapine
in drug-induced psychosis in Parkinsons disease. The
French Clozapine Parkinson Study Group. Lancet 353:
20412042.
Friedman JH (1991). The management of the levodopa psy-
choses. Clin Neuropharmacol 14: 283295.
Friedman JH, Lannon MC (1989a). Clozapine in the treat-
ment of psychosis in Parkinsons disease. Neurology 39:
12191221.
Friedman JH, Lannon MC (1989b). An open trial of con-
trolled release carbidopa/L-dopa (sinemet CR) for the
treatment of mild-to-moderate Parkinsons disease. Clin
Neuropharmacol 12: 220223.
Gancher ST, Nutt JG, Woodward W (1988). Response to
brief levodopa infusions in parkinsonian patients with
and without motor fluctuations. Neurology 38: 712716.
Garcia Ruiz PJ, Meseguer E, Del Val J et al. (2004). Motor
complications in Parkinson disease: a prospective follow-
up study. Clin Neuropharmacol 27: 4952.
Genedani S, Rasio G, Cortelli P et al. (2004). Studies on
homocysteine and dehydroepiandrosterone sulphate
plasma levels in Alzheimers disease patients and in Par-
kinsons disease patients. Neurotox Res 6: 327332.
Gerfen CR, Engber TM, Mahan LC et al. (1990). D1 and D2
dopamine receptor-regulated gene expression of striatoni-
gral and striatopallidal neurons. Science 250: 14291432.
Giovannoni G, OSullivan JD, Turner K et al. (2000).
Hedonistic homeostatic dysregulation in patients with
Parkinsons disease on dopamine replacement therapies.
J Neurol Neurosurg Psychiatry 68: 423428.
 LEVODOPA
Giros B, Caron MG (1993). Molecular characterization of the
dopamine transporter. Trends Pharmacol Sci 14: 4349.
Goetz CG, Stebbins GT (1993). Risk factors for nursing
home placement in advanced Parkinsons disease. Neurol-
ogy 43: 22272229.
Goetz CG, Tanner CM, Shannon KM et al. (1988). Controlled-
release carbidopa/levodopa (CR4-Sinemet) in Parkinsons
disease patients with and without motor fluctuations. Neurol-
ogy 38: 11431146.
Goetz CG, Tanner CM, Gilley DW et al. (1989). Develop-
ment and progression of motor fluctuations and side
effects in Parkinsons disease: comparison of Sinemet
CR versus carbidopa/levodopa. Neurology 39: 6366; dis-
cussion 7263.
Goetz CG, Pappert EJ, Blasucci LM et al. (1998). Intravenous
levodopa in hallucinating Parkinsons disease patients:
high-dose challenge does not precipitate hallucinations.
Neurology 50: 515517.
Goetze O, Wieczorek J, Mueller T et al. (2005). Impaired
gastric emptying of a solid test meal in patients with Par-
kinsons disease using (13)C-sodium octanoate breath test.
Neurosci Lett 375: 170173.
Golbe LI (1991). Young-onset Parkinsons disease: a clinical
review. Neurology 41: 168173.
Goldberg LI, Rajfer SI (1985). Dopamine receptors: applica-
tions in clinical cardiology. Circulation 72: 245248.
Goldstein DS, Holmes CS, Dendi R et al. (2002). Orthostatic
hypotension from sympathetic denervation in Parkinsons
disease. Neurology 58: 12471255.
Gordin A, Kaakkola S, Teravainen H (2003). Position of
COMT inhibition in the treatment of Parkinsons disease.
Adv Neurol 91: 237250.
Gorell JM, Johnson CC, Rybicki BA (1994). Parkinsons dis-
ease and its comorbid disorders: an analysis of Michigan
mortality data, 1970 to 1990. Neurology 44: 18651868.
Grace AA (1991). Phasic versus tonic dopamine release and the
modulation of dopamine system responsivity: a hypothesis
for the etiology of schizophrenia. Neuroscience 41: 124.
Graham DG, Tiffany SM, Bell WR Jr et al. (1978). Autoxida-
tion versus covalent binding of quinones as the mechanism
of toxicity of dopamine, 6-hydroxydopamine, and related
compounds toward C1300 neuroblastoma cells in vitro.
Mol Pharmacol 14: 644653.
Grahnen A, Eckernas SA, Collin C et al. (1992). Comparative
multiple-dose pharmacokinetics of controlled-release
levodopa products. Eur Neurol 32: 343348.
Grandas F, Galiano ML, Tabernero C (1999). Risk factors
for levodopa-induced dyskinesias in Parkinsons disease.
J Neurol 246: 11271133.
Greenacre JK, Coxon A, Petrie A et al. (1976). Comparison
of levodopa with carbidopa or benserazide in parkinson-
ism. Lancet 2: 381384.
Gschwandtner U, Aston J, Renaud S et al. (2001). Pathologic
gambling in patients with Parkinsons disease. Clin Neuro-
pharmacol 24: 170172.
Guldberg HC, Marsden CA (1975). Catechol-O-methyl
transferase: pharmacological aspects and physiological
role. Pharmacol Rev 27: 135206.
63
Haglund L, Hoogkamer JFW (1995). MadoparW dispensible:
pharmacokinetics and bioavailability in healthy volun-
teers. J Neurol 242 (Suppl 2): S140.
Hakamaki T, Rajala T, Lehtonen A (1998). Ambulatory
24-hour blood pressure recordings in patients with Parkin-
sons disease with or without fludrocortisone. Int J Clin
Pharmacol Ther 36: 367369.
Han SK, Mytilineou C, Cohen G (1996). L-DOPA up-
regulates glutathione and protects mesencephalic cultures
against oxidative stress. J Neurochem 66: 501510.
Hardie RJ, Malcolm SL, Lees AJ et al. (1986). The pharma-
cokinetics of intravenous and oral levodopa in patients
with Parkinsons disease who exhibit on-off fluctuations.
Br J Clin Pharmacol 22: 429436.
Hardoff R, Sula M, Tamir A et al. (2001). Gastric emptying
time and gastric motility in patients with Parkinsons dis-
ease. Mov Disord 16: 10411047.
Hauser RA, Molho E, Shale H et al. (1998). A pilot evalua-
tion of the tolerability, safety, and efficacy of tolcapone
alone and in combination with oral selegiline in untreated
Parkinsons disease patients. Tolcapone De Novo Study
Group. Mov Disord 13: 643647.
Heikkinen H, Saraheimo M, Antila S et al. (2001). Phar-
macokinetics of entacapone, a peripherally acting cate-
chol-O-methyltransferase inhibitor, in man. A study
using a stable isotope technique. Eur J Clin Pharmacol
56: 821826.
Hely MA, Morris JG, Reid WG et al. (1994). The Sydney
multicentre study of Parkinsons disease: a randomised,
prospective five year study comparing low dose bromo-
criptine with low dose levodopa-carbidopa. J Neurol
Neurosurg Psychiatry 57: 903910.
Henry C, Wilson JA (1998). Catechol-O-methyltransferase
inhibitors in Parkinsons disease. Lancet 351: 19651966.
Hernan MA, Zhang SM, Rueda-deCastro AM et al. (2001).
Cigarette smoking and the incidence of Parkinsons dis-
ease in two prospective studies. Ann Neurol 50: 780786.
Hoehn M, Yahr M (1967). Parkinsonism: onset, progression
and mortality. Neurology 17: 427442.
Hoehn MM (1975). Levodopa-induced postural hypotension.
Treatment with fludrocortisone. Arch Neurol 32: 5051.
Hollander E, Evers M (2001). New developments in impul-
sivity. Lancet 358: 949950.
Holroyd S, Currie L, Wooten GF (2001). Prospective study
of hallucinations and delusions in Parkinsons disease.
J Neurol Neurosurg Psychiatry 70: 734738.
Horne MK, Cheng CH, Wooten GF (1984). The cerebral
metabolism of L-dihydroxyphenylalanine. An autoradio-
graphic and biochemical study. Pharmacology 28: 1226.
Hornykiewicz O (1974). The mechanisms of action of
L-dopa in Parkinsons disease. Life Sci 15: 12491259.
Hornykiewicz O (2002). L-DOPA: from a biologically inac-
tive amino acid to a successful therapeutic agent. Amino
Acids 23: 6570.
Howse PM, Matthews WB (1973). Brocresine in Parkinsons
disease. Action of a peripheral and central decarboxylase
inhibitor in potentiating levodopa. J Neurol Neurosurg
Psychiatry 36: 2729.
64 T. D. HALBIG AND W. C. KOLLER
Huang YC, Colaizzi JL, Bierman RH et al. (1986). Phar-
macokinetics and dose proportionality of domperidone in
healthy volunteers. J Clin Pharmacol 26: 628632.
Hutton JT, Morris JL (1991). Long-term evaluation of Sine-
met CR in parkinsonian patients with motor fluctuations.
Can J Neurol Sci 18: 467471.
Hutton JT, Morris JL, Bush DF et al. (1989). Multicenter
controlled study of Sinemet CR vs Sinemet (25/100) in
advanced Parkinsons disease. Neurology 39: 6772;
discussion 7263.
Inzelberg R, Kipervasser S, Korczyn AD (1998). Auditory
hallucinations in Parkinsons disease. J Neurol Neurosurg
Psychiatry 64: 533535.
Iwase H, Sudo J, Terui J et al. (2000). Transdermal absorp-
tion of L-dopa from a new system composed of two sepa-
rate layers of L-dopa and hydrogel in rats. Drug Dev Ind
Pharm 26: 755759.
Jankovic J, Schwartz K, Vander Linden C (1989). Compari-
son of Sinemet CR4 and standard Sinemet: double blind
and long-term open trial in parkinsonian patients with
fluctuations. Mov Disord 4: 303309.
Jankovic J, Gilden JL, Hiner BC et al. (1993). Neurogenic
orthostatic hypotension: a double-blind, placebo-controlled
study with midodrine. Am J Med 95: 3848.
Jellinger KA (2003). Prevalence of stroke in Parkinsons
disease. Mov Disord 18: 723724.
Jenner P (2002). Pharmacology of dopamine agonists in the
treatment of Parkinsons disease. Neurology 58: S1S8.
Jenner P (2003). The MPTP-treated primate as a model of
motor complications in PD: primate model of motor
complications. Neurology 61: S4S11.
Jensen NO, Dupont E, Hansen E et al. (1987). Madopar
HBS: slow-release levodopa and benserazide in parkinso-
nian patients presenting marked fluctuations in symptoms
on standard L-dopa treatment. Eur Neurol 27 (Suppl 1):
6872.
Jolkkonen J, Jenner P, Marsden CD (1995). L-DOPA
reverses altered gene expression of substance P but not
enkephalin in the caudate-putamen of common marmosets
treated with MPTP. Brain Res Mol Brain Res 32:
297307.
Jorga K, Fotteler B, Schmitt M et al. (1997). The effect of
COMT inhibition by tolcapone on tolerability and pharma-
cokinetics of different levodopa/benserazide formulations.
Eur Neurol 38: 5967.
Jorga K, Fotteler B, Sedek G et al. (1998a). The effect of tol-
capone on levodopa pharmacokinetics is independent of
levodopa/carbidopa formulation. J Neurol 245: 223230.
Jorga KM (1998a). Pharmacokinetics, pharmacodynamics,
and tolerability of tolcapone: a review of early studies in
volunteers. Neurology 50: S31S38.
Jorga KM (1998b). COMT inhibitors: pharmacokinetic and
pharmacodynamic comparisons. Clin Neuropharmacol
21 (Suppl 1): 916.
Jorga KM, Fotteler B, Heizmann P et al. (1998b). Pharmaco-
kinetics and pharmacodynamics after oral and intravenous
administration of tolcapone, a novel adjunct to Parkinsons
disease therapy. Eur J Clin Pharmacol 54: 443447.
Jorga KM, Kroodsma JM, Fotteler B et al. (1998c). Effect
of liver impairment on the pharmacokinetics of tolca-
pone and its metabolites. Clin Pharmacol Ther 63:
646654.
Jorga KM, Larsen JP, Beiske A et al. (1999). The effect of
tolcapone on the pharmacokinetics of benserazide. Eur J
Neurol 6: 211219.
Juncos JL, Mouradian MM, Fabbrini G et al. (1987). Levodopa
methyl ester treatment of Parkinsons disease. Neurology
37: 12421245.
Kaakkola S (2000). Clinical pharmacology, therapeutic use
and potential of COMT inhibitors in Parkinsons disease.
Drugs 59: 12331250.
Kaakkola S, Wurtman RJ (1993). Effects of catechol-O-
methyltransferase inhibitors and L-3,4-dihydroxyphenyla-
lanine with or without carbidopa on extracellular
dopamine in rat striatum. J Neurochem 60: 137144.
Kafka MP (2003). The monoamine hypothesis for the patho-
physiology of paraphilic disorders: an update. Ann N Y
Acad Sci 989: 8694; discussion 144153.
Kahn N, Freeman A, Juncos JL et al. (1991). Clozapine is
beneficial for psychosis in Parkinsons disease. Neurology
41: 16991700.
Kalir HH, Mytilineou C (1991). Ascorbic acid in mesence-
phalic cultures: effects on dopaminergic neuron develop-
ment. J Neurochem 57: 458464.
Kaneoke Y, Koike Y, Sakurai N et al. (1995). Gastrointest-
inal dysfunction in Parkinsons disease detected by
electrogastroenterography. J Auton Nerv Syst 50:
275281.
Kao HD, Traboulsi A, Itoh S et al. (2000). Enhancement of
the systemic and CNS specific delivery of L-dopa by the
nasal administration of its water soluble prodrugs. Pharm
Res 17: 978984.
Kaufmann H, Nahm K, Purohit D et al. (2004). Autonomic
failure as the initial presentation of Parkinson disease and
dementia with Lewy bodies. Neurology 63: 10931095.
Keranen T, Gordin A, Harjola VP et al. (1993). The effect of
catechol-O-methyl transferase inhibition by entacapone on
the pharmacokinetics and metabolism of levodopa in
healthy volunteers. Clin Neuropharmacol 16: 145156.
Keranen T, Gordin A, Karlsson M et al. (1994). Inhibition of
soluble catechol-O-methyltransferase and single-dose
pharmacokinetics after oral and intravenous administration
of entacapone. Eur J Clin Pharmacol 46: 151157.
Kincannon J, Boutzale C (1999). The physiology of pigmented
nevi. Pediatrics 104: 10421045.
Kleedorfer B, Poewe W (1992). Comparative efficacy of two
oral sustained-release preparations of L-dopa in fluctuating
Parkinsons disease. Preliminary findings in 20 patients. J
Neural Transm Park Dis Dement Sect 4: 173178.
Klein C, Kompf D, Pulkowski U et al. (1997). A study of
visual hallucinations in patients with Parkinsons disease.
J Neurol 244: 371377.
Koller WC, Hutton JT, Tolosa E et al. (1999). Immediate-
release and controlled-release carbidopa/levodopa in PD:
a 5-year randomized multicenter study. Carbidopa/Levo-
dopa Study Group. Neurology 53: 10121019.
 LEVODOPA
Korten A, Lodder J, Vreeling F et al. (2001). Stroke and idio-
pathic Parkinsons disease: does a shortage of dopamine
offer protection against stroke? Mov Disord 16: 119123.
Kostic V, Przedborski S, Flaster E et al. (1991). Early devel-
opment of levodopa-induced dyskinesias and response
fluctuations in young-onset Parkinsons disease. Neurol-
ogy 41: 202205.
Kostic VS, Marinkovic J, Svetel M et al. (2002). The effect
of stage of Parkinsons disease at the onset of levodopa
therapy on development of motor complications. Eur
J Neurol 9: 914.
Kuhn W, Roebroek R, Blom H et al. (1998). Elevated plasma
levels of homocysteine in Parkinsons disease. Eur Neurol
40: 225227.
Kurlan R (2004). Disabling repetitive behaviors in Parkinsons
disease. Mov Disord 19: 433437.
Kurth MC (1997). Using liquid levodopa in the treatment of
Parkinsons disease. A practical guide. Drugs Aging 10:
332340.
Kurth MC, Tetrud JW, Irwin I et al. (1993). Oral levodopa/
carbidopa solution versus tablets in Parkinsons patients
with severe fluctuations: a pilot study. Neurology 43:
10361039.
Kurth MC, Adler CH, Hilaire MS et al. (1997). Tolcapone
improves motor function and reduces levodopa require-
ment in patients with Parkinsons disease experiencing
motor fluctuations: a multicenter, double-blind, rando-
mized, placebo-controlled trial. Tolcapone Fluctuator
Study Group I. Neurology 48: 8187.
Lamberti P, Zoccolella S, Iliceto G et al. (2005). Effects of
levodopa and COMT inhibitors on plasma homocysteine
in Parkinsons disease patients. Mov Disord 20: 6972.
Lamberty Y, Klitgaard H (2000). Consequences of pentyle-
netetrazole kindling on spatial memory and emotional
responding in the rat. Epilepsy Behav 1: 256261.
Lang AE (2001). Acute orthostatic hypotension when start-
ing dopamine agonist therapy in parkinson disease: the
role of domperidone therapy. Arch Neurol 58: 835.
Langdon N, Malcolm PN, Parkes JD (1986). Comparison of
levodopa with carbidopa, and levodopa with domperidone
in Parkinsons disease. Clin Neuropharmacol 9: 440447.
Langer SZ (1980). Presynaptic regulation of the release of
catecholamines. Pharmacol Rev 32: 337362.
Larsen JP, Worm-Petersen J, Siden A et al. (2003). The toler-
ability and efficacy of entacapone over 3 years in patients
with Parkinsons disease. Eur J Neurol 10: 137146.
Lautala P, Ethell BT, Taskinen J et al. (2000). The specifi-
city of glucuronidation of entacapone and tolcapone by
recombinant human UDP-glucuronosyltransferases. Drug
Metab Dispos 28: 13851389.
Lawrence de Koning AB, Werstuck GH, Zhou J et al. (2003).
Hyperhomocysteinemia and its role in the development of
atherosclerosis. Clin Biochem 36: 431441.
Leenders KL, Palmer AJ, Quinn N et al. (1986). Brain dopa-
mine metabolism in patients with Parkinsons disease
measured with positron emission tomography. J Neurol
Neurosurg Psychiatry 49: 853860.
65
Lees AJ (1995). Comparison of therapeutic effects and mortal-
ity data of levodopa and levodopa combined with selegiline
in patients with early, mild Parkinsons disease. Parkinsons
Disease Research Group of the United Kingdom. BMJ 311:
16021607.
Lesser RP, Fahn S, Snider SR et al. (1979). Analysis of the
clinical problems in parkinsonism and the complications
of long-term levodopa therapy. Neurology 29: 12531260.
LeWitt PA, Nelson MV, Berchou RC et al. (1989).
Controlled-release carbidopa/levodopa (Sinemet 50/200
CR4): clinical and pharmacokinetic studies. Neurology 39:
4553; discussion 59.
Li ST, Dendi R, Holmes C et al. (2002). Progressive loss of
cardiac sympathetic innervation in Parkinsons disease.
Ann Neurol 52: 220223.
Lieberman A, Gopinathan G, Miller E et al. (1990). Rando-
mized double-blind cross-over study of Sinemet-controlled
release (CR4 50/200) versus Sinemet 25/100 in Parkinsons
disease. Eur Neurol 30: 7578.
Lieberman AN, Goldstein M, Gopinathan G et al.
(1984). Combined use of benserazide and carbidopa in
Parkinsons disease. Neurology 34: 227229.
Lipton SA, Kim WK, Choi YB et al. (1997). Neurotoxicity
associated with dual actions of homocysteine at the N-
methyl-D-aspartate receptor. Proc Natl Acad Sci USA
94: 59235928.
Lloyd KG, Davidson L, Hornykiewicz O (1975). The neuro-
chemistry of Parkinsons disease: effect of L-dopa therapy.
J Pharmacol Exp Ther 195: 453464.
Lotta T, Vidgren J, Tilgmann C et al. (1995). Kinetics of
human soluble and membrane-bound catechol O-methyl-
transferase: a revised mechanism and description of the
thermolabile variant of the enzyme. Biochemistry 34:
42024210.
Low PA, Gilden JL, Freeman R et al. (1997). Efficacy of
midodrine vs placebo in neurogenic orthostatic hypoten-
sion. A randomized, double-blind multicenter study.
Midodrine Study Group. JAMA 277: 10461051.
Lozano AM, Lang AE, Levy R et al. (2000). Neuronal
recordings in Parkinsons disease patients with dyskinesias
induced by apomorphine. Ann Neurol 47: S141S146.
Luchsinger JA, Tang MX, Shea S et al. (2004). Plasma
homocysteine levels and risk of Alzheimer disease.
Neurology 62: 19721976.
Lyons KE, Hubble JP, Troster AI et al. (1998). Gender dif-
ferences in Parkinsons disease. Clin Neuropharmacol
21: 118121.
Malcolm SL, Allen JG, Bird H et al. (1987). Single-dose
pharmacokinetics of Madopar HBS in patients and effect
of food and antacid on the absorption of Madopar HBS
in volunteers. Eur Neurol 27 (Suppl 1): 2835.
Mannisto PT, Kaakkola S (1999). Catechol-O-methyltransferase
(COMT): biochemistry, molecular biology, pharmacology,
and clinical efficacy of the new selective COMT inhibitors.
Pharmacol Rev 51: 593628.
Mannisto PT, Tuomainen P, Toivonen M et al. (1990). Effect
of acute levodopa on brain catecholamines after selective
66 T. D. HALBIG AND W. C. KOLLER
MAO and COMT inhibition in male rats. J Neural Transm
Park Dis Dement Sect 2: 3143.
Mannisto PT, Ulmanen I, Lundstrom K et al. (1992). Char-
acteristics of catechol O-methyl-transferase (COMT) and
properties of selective COMT inhibitors. Prog Drug Res
39: 291350.
Maratos EC, Jackson MJ, Pearce RK et al. (2001). Anti-
parkinsonian activity and dyskinesia risk of ropinirole
and L-DOPA combination therapy in drug naive MPTP-
lesioned common marmosets (Callithrix jacchus). Mov
Disord 16: 631641.
Marconi R, Lefebvre-Caparros D, Bonnet AM et al.
(1994). Levodopa-induced dyskinesias in Parkinsons
disease phenomenology and pathophysiology. Mov Disord
9: 212.
Mark MH, Sage JI (1989a). Long-term efficacy of controlled-
release carbidopa/levodopa in patients with advanced
Parkinsons disease. Ann Clin Lab Sci 19: 415421.
Mark MH, Sage JI (1989b). Controlled-release carbidopa-
levodopa (Sinemet) in combination with standard Sinemet in
advanced Parkinsons disease. Ann Clin Lab Sci 19: 101106.
Markham C, Diamond SG, Treciokas LJ (1974). Carbidopa
in Parkinson disease and in nausea and vomiting of
levodopa. Arch Neurol 31: 128133.
Markianos M, Hadjikonstantinou M, Bistolaki E (1982).
Urinary noradrenaline and serotonin metabolites in drug-
free Parkinson patients and the effect of L-dopa treatment.
Acta Neurol Scand 66: 267275.
Marsden CD, Parkes JD (1977). Success and problems of
long-term levodopa therapy in Parkinsons disease. Lancet
1: 345349.
Marsden CD, Parkes JP, Qinn N (1982). Fluctuations of
disability in Parkinsons disease. In: CD Marsden, S Fahn
(Eds.), Movement Disorders. Butterworth, London.
Mastaglia FL, Johnsen RD, Kakulas BA (2002). Prevalence
of stroke in Parkinsons disease: a postmortem study.
Mov Disord 17: 772774.
Meco G, Pratesi L, Bonifati V (1991). Cardiovascular
reflexes and autonomic dysfunction in Parkinsons
disease. J Neurol 238: 195199.
Melamed E, Hefti F, Wurtman RJ (1980). Nonaminergic
striatal neurons convert exogenous L-dopa to dopamine
in parkinsonism. Ann Neurol 8: 558563.
Melis MR, Argiolas A (1995). Dopamine and sexual behavior.
Neurosci Biobehav Rev 19: 1938.
Meltzer HY (1999). The role of serotonin in antipsychotic
drug action. Neuropsychopharmacology 21: 106S115S.
Mena MA, Pardo B, Casarejos MJ et al. (1992). Neurotoxi-
city of levodopa on catecholamine-rich neurons. Mov
Disord 7: 2331.
Mena MA, Pardo B, Paino CL et al. (1993). Levodopa toxi-
city in foetal rat midbrain neurones in culture: modulation
by ascorbic acid. Neuroreport 4: 438440.
Mena MA, Davila V, Sulzer D (1997a). Neurotrophic effects
of L-DOPA in postnatal midbrain dopamine neuron/corti-
cal astrocyte cocultures. J Neurochem 69: 13981408.
Mena MA, Casarejos MJ, Carazo A et al. (1997b). Glia
protect fetal midbrain dopamine neurons in culture from
L-DOPA toxicity through multiple mechanisms. J Neural
Transm 104: 317328.
Menza MA, Sage J, Marshall E et al. (1990). Mood changes
and on-off phenomena in Parkinsons disease. Mov
Disord 5: 148151.
Menza MA, Golbe LI, Cody RA et al. (1993). Dopamine-
related personality traits in Parkinsons disease. Neurology
43: 505508.
Merello M, Lees AJ (1992). Beginning-of-dose motor dete-
rioration following the acute administration of levodopa
and apomorphine in Parkinsons disease. J Neurol Neurosurg
Psychiatry 55: 10241026.
Merello M, Pirtosek Z, Bishop S et al. (1992). Cardiovascular
reflexes in Parkinsons disease: effect of domperidone and
apomorphine. Clin Auton Res 2: 215219.
Merims D, Shabtai H, Korczyn AD et al. (2004). Antiparkin-
sonian medication is not a risk factor for the development
of hallucinations in Parkinsons disease. J Neural Transm
111: 14471453.
Metman LV, Hoff J, Mouradian MM et al. (1994). Fluctua-
tions in plasma levodopa and motor responses with liquid
and tablet levodopa/carbidopa. Mov Disord 9: 463465.
Michel PP, Hefti F (1990). Toxicity of 6-hydroxydopamine
and dopamine for dopaminergic neurons in culture. J Neu-
rosci Res 26: 428435.
Miller JW (2002). Homocysteine, folate deficiency, and
Parkinsons disease. Nutr Rev 60: 410413.
Miller JW, Selhub J, Nadeau MR et al. (2003). Effect of
L-dopa on plasma homocysteine in PD patients: relation-
ship to B-vitamin status. Neurology 60: 11251129.
Molina JA, Sainz-Artiga MJ, Fraile A et al. (2000). Patholo-
gic gambling in Parkinsons disease: a behavioral manifes-
tation of pharmacologic treatment? Mov Disord 15:
869872.
Montastruc JL, Rascol O, Senard JM et al. (1994). A rando-
mised controlled study comparing bromocriptine to which
levodopa was later added, with levodopa alone in previously
untreated patients with Parkinsons disease: a five year
follow up. J Neurol Neurosurg Psychiatry 57: 10341038.
Montastruc JL, Schmitt L, Bagheri H (2003). [Pathological
gambling behavior in a patient with Parkinsons disease
treated with levodopa and bromocriptine.] Rev Neurol
(Paris) 159: 441443.
Moore H, Todd CL, Grace AA (1998). Striatal extracellular
dopamine levels in rats with haloperidol-induced depolar-
ization block of substantia nigra dopamine neurons. J Neu-
rosci 18: 50685077.
Morgante L, Epifanio A, Spina E et al. (2004). Quetiapine
and clozapine in parkinsonian patients with dopaminergic
psychosis. Clin Neuropharmacol 27: 153156.
Morris MS (2003). Homocysteine and Alzheimers disease.
Lancet Neurol 2: 425428.
Moskovitz C, Moses H 3rd, Klawans HL (1978). Levodopa-
induced psychosis: a kindling phenomenon. Am J Psychiatry
135: 669675.
Muenter MD, Tyce GM (1971). L-dopa therapy of Parkin-
sons disease: plasma L-dopa concentration, therapeutic
response, and side effects. Mayo Clin Proc 46: 231239.
 LEVODOPA
Muller T, Werne B, Fowler B et al. (1999). Nigral endothe-
lial dysfunction, homocysteine, and Parkinsons disease.
Lancet 354: 126127.
Muller T, Woitalla D, Hauptmann B et al. (2001). Decrease
of methionine and S-adenosylmethionine and increase of
homocysteine in treated patients with Parkinsons disease.
Neurosci Lett 308: 5456.
Murer MG, Dziewczapolski G, Menalled LB et al. (1998).
Chronic levodopa is not toxic for remaining dopamine
neurons, but instead promotes their recovery, in rats with
moderate nigrostriatal lesions. Ann Neurol 43: 561575.
Myllyla VV, Sotaniemi KA, Illi A et al. (1993). Effect of
entacapone, a COMT inhibitor, on the pharmacokinetics
of levodopa and on cardiovascular responses in patients
with Parkinsons disease. Eur J Clin Pharmacol 45:
419423.
Myllyla VV, Jackson M, Larsen JP (1997). Efficacy and
safety of tolcapone in levodopa-treated Parkinsons dis-
ease patients with wearing-off phenomenon: a multicen-
tre, double blind, randomized placebo-controlled trial. Eur
J Neurol 4: 333341.
Myllyla VV, Kultalahti ER, Haapaniemi H et al. (2001).
FILOMEN Study Group. Twelve-month safety of entaca-
pone in patients with Parkinsons disease. Eur J Neurol
8: 5360.
Mytilineou C, Han SK, Cohen G (1993). Toxic and protec-
tive effects of L-dopa on mesencephalic cell cultures.
J Neurochem 61: 14701478.
Naber D, Lambert M (2004). Aripiprazole: a new atypical
antipsychotic with a different pharmacological mechan-
ism. Prog Neuropsychopharmacol Biol Psychiatry 28:
12131219.
Nakaso K, Yasui K, Kowa H et al. (2003). Hypertrophy of
IMC of carotid artery in Parkinsons disease is associated
with L-DOPA, homocysteine, and MTHFR genotype.
J Neurol Sci 207: 1923.
Napolitano A, Zurcher G, Da Prada M (1995). Effects of tol-
capone, a novel catechol-O-methyltransferase inhibitor, on
striatal metabolism of L-dopa and dopamine in rats. Eur
J Pharmacol 273: 215221.
Nausieda PA, Tanner CM, Klawans HL (1983). Serotonergi-
cally active agents in levodopa-induced psychiatric toxicity
reactions. Adv Neurol 37: 2332.
Nausieda PA, Pfeiffer RF, Tagliati M et al. (2005). A multi-
center, open-label, sequential study comparing preferences
for carbidopa-levodopa orally disintegrating tablets and
conventional tablets in subjects with Parkinsons disease.
Clin Ther 27: 5863.
Nilsson D, Hansson LE, Johansson K et al. (1998). Long-
term intraduodenal infusion of a water based levodopa-
carbidopa dispersion in very advanced Parkinsons
disease. Acta Neurol Scand 97: 175183.
Nilsson D, Nyholm D, Aquilonius SM (2001). Duodenal
levodopa infusion in Parkinsons diseaselong-term
experience. Acta Neurol Scand 104: 343348.
Nissinen E, Kaheinen P, Penttila KE et al. (1997). Entaca-
pone, a novel catechol-O-methyltransferase inhibitor for
67
Parkinsons disease, does not impair mitochondrial energy
production. Eur J Pharmacol 340: 287294.
Nissinen E, Nissinen H, Larjonmaa H et al. (2005). The
COMT inhibitor, entacapone, reduces levodopa-induced
elevations in plasma homocysteine in healthy adult rats.
J Neural Transm 112 (9) 12131221.
Noble EP (2000). The DRD2 gene in psychiatric and neuro-
logical disorders and its phenotypes. Pharmacogenomics
1: 309333.
Nordera GP, Lorizio A, Lion P et al. (1987). Treatment of par-
kinsonian conditions with a controlled-release form of levo-
dopapreliminary study. Eur Neurol 27 (Suppl 1): 7680.
Novartis Pharmaceuticals Corporation (2000). COMTAN
Prescribing Information, East Hanover, New Jersey, USA.
Novartis Pharmaceuticals Corporation (2005). CLOZARIL
Prescribing Information, East Hanover, New Jersey.
Nutt JG (1987). On-off phenomenon: relation to levodopa
pharmacokinetics and pharmacodynamics. Ann Neurol
22: 535540.
Nutt JG (1990). Levodopa-induced dyskinesia: review,
observations, and speculations. Neurology 40: 340345.
Nutt JG (1992). Pharmacokinetics and pharmacodynamics of
levodopa. In: WC Koller, (Ed.), Handbook of Parkinsons
Disease. Marcel Dekker, New York, pp. 411732.
Nutt JG (1998). Catechol-O-methyltransferase inhibitors for
treatment of Parkinsons disease. Lancet 351: 12211222.
Nutt JG (2000). Effect of COMT inhibition on the phar-
macokinetics and pharmacodynamics of levodopa in par-
kinsonian patients. Neurology 55: S33S37; discussion
S38S41.
Nutt JG, Fellman JH (1984). Pharmacokinetics of levodopa.
Clin Neuropharmacol 7: 3549.
Nutt JG, Woodward WR, Anderson JL (1985). The effect of
carbidopa on the pharmacokinetics of intravenously admi-
nistered levodopa: the mechanism of action in the treat-
ment of parkinsonism. Ann Neurol 18: 537543.
Nutt JG, Gancher ST, Woodward WR (1988). Does an inhi-
bitory action of levodopa contribute to motor fluctuations?
Neurology 38: 15531557.
Nutt JG, Woodward WR, Beckner RM et al. (1994). Effect
of peripheral catechol-O-methyltransferase inhibition on
the pharmacokinetics and pharmacodynamics of levodopa
in parkinsonian patients. Neurology 44: 913919.
Nutt JG, Carter JH, Woodward WR (1995). Long-duration
response to levodopa. Neurology 45: 16131616.
Nyholm D, Askmark H, Gomes-Trolin C et al. (2003). Opti-
mizing levodopa pharmacokinetics: intestinal infusion ver-
sus oral sustained-release tablets. Clin Neuropharmacol
26: 156163.
Nyholm D, Nilsson Remahl AI, Dizdar N et al. (2005). Duo-
denal levodopa infusion monotherapy vs oral polyphar-
macy in advanced Parkinson disease. Neurology 64:
216223.
Obeso JA, Olanow CW (1997). Dopamine agonists in early
Parkinsons disease. In: CW Olanow, JA Obeso (Eds.),
Beyond the Decade of the Brain, Vol. 2. Wells Medical
Ltd, Tunbridge Wells, Kent, UK, pp. 1135.
68 T. D. HALBIG AND W. C. KOLLER
Obeso JA, Rodriguez-Oroz MC, Chana P et al. (2000). The
evolution and origin of motor complications in Parkinsons
disease. Neurology 55: S13S20; discussion S21S13.
Olanow CW (2000). Tolcapone and hepatotoxic effects.
Tasmar Advisory Panel. Arch Neurol 57: 263267.
Olanow CW, Hauser RA, Gauger L et al. (1995). The effect
of deprenyl and levodopa on the progression of Parkin-
sons disease. Ann Neurol 38: 771777.
Olanow CW, Watts RL, Koller WC (2001). An algorithm
(decision tree) for the management of Parkinsons disease
(2001): treatment guidelines. Neurology 56: S1S88.
Ondo WG, Levy JK, Vuong KD et al. (2002). Olanzapine
treatment for dopaminergic-induced hallucinations. Mov
Disord 17: 10311035.
Ondo WG, Tintner R, Dat Voung K et al. (2005). Double-
blind, placebo-controlled, unforced titration parallel
trial of quetiapine for dopaminergic-induced hallucina-
tions in Parkinsons disease. Mov Disord 20 (8):
958963.
Onofrj M, Thomas A, Iacono D et al. (2001). Switch-over
from tolcapone to entacapone in severe Parkinsons
disease patients. Eur Neurol 46: 1116.
OSuilleabhain PE, Bottiglieri T, Dewey RB Jr et al.
(2004a). Modest increase in plasma homocysteine follows
levodopa initiation in Parkinsons disease. Mov Disord 19:
14031408.
OSuilleabhain PE, Sung V, Hernandez C et al. (2004b).
Elevated plasma homocysteine level in patients with
Parkinson disease: motor, affective, and cognitive associa-
tions. Arch Neurol 61: 865868.
Pacchetti C, Martignoni E, Sibilla L et al. (1990). Effective-
ness of Madopar HBS plus Madopar standard in patients
with fluctuating Parkinsons disease: two years of follow-
up. Eur Neurol 30: 319323.
Pahwa R, Busenbark K, Huber SJ et al. (1993). Clinical
experience with controlled-release carbidopa/levodopa in
Parkinsons disease. Neurology 43: 677681.
Papa SM, Desimone R, Fiorani M et al. (1999). Internal
globus pallidus discharge is nearly suppressed during
levodopa-induced dyskinesias. Ann Neurol 46: 732738.
Papavasiliou PS, Cotzias GC, Duby SE et al. (1972). Levodo-
pa in Parkinsonism: potentiation of central effects with a
peripheral inhibitor. N Engl J Med 286: 814.
Papavasiliou PS, Cotzias GC, Lawrence WH (1973). Levodo-
pa and dopamine in cerebrospinal fluid. Neurology 23:
756759.
Pappert EJ, Goetz CG, Niederman F et al. (1996). Liquid
levodopa/carbidopa produces significant improvement in
motor function without dyskinesia exacerbation. Neurol-
ogy 47: 14931495.
Pappert EJ, Goetz CG, Niederman FG et al. (1999). Halluci-
nations, sleep fragmentation, and altered dream phenom-
ena in Parkinsons disease. Mov Disord 14: 117121.
Pardo B, Mena MA, Fahn S et al. (1993). Ascorbic acid
protects against levodopa-induced neurotoxicity on a cate-
cholamine-rich human neuroblastoma cell line. Mov
Disord 8: 278284.
Parker WD Jr, Boyson SJ, Parks JK (1989). Abnormalities of
the electron transport chain in idiopathic Parkinsons dis-
ease. Ann Neurol 26: 719723.
Parkinson Study Group (1989). Effect of deprenyl on the
progression of disability in early Parkinsons disease.
The Parkinson Study Group. N Engl J Med 321:
13641371.
Parkinson Study Group (1996a). Impact of deprenyl and
tocopherol treatment on Parkinsons disease in DATATOP
patients requiring levodopa. Ann Neurol 39: 3745.
Parkinson Study Group (1996b). Impact of deprenyl and
tocopherol treatment on Parkinsons disease in DATATOP
subjects not requiring levodopa. Ann Neurol 39: 2936.
Parkinson Study Group (1997). Entacapone improves motor
fluctuations in levodopa-treated Parkinsons disease
patients. Ann Neurol 42: 747755.
Parkinson Study Group (1999). Low-dose clozapine for the
treatment of drug-induced psychosis in Parkinsons dis-
ease. The Parkinson Study Group. N Engl J Med 340:
757763.
Parkinson Study Group (2000). Pramipexole vs levodopa as
initial treatment for Parkinson disease: a randomized
controlled trial. JAMA 284: 19311938.
Parkinson Study Group (2002a). Dopamine transporter
brain imaging to assess the effects of pramipexole vs levo-
dopa on Parkinson disease progression. JAMA 287:
16531661.
Parkinson Study Group (2002b). A controlled trial of rasagi-
line in early Parkinson disease: the TEMPO Study. Arch
Neurol 59: 19371943.
Parkinson Study Group (2004a). Levodopa and the progres-
sion of Parkinsons disease. N Engl J Med 351:
24982508.
Parkinson Study Group (2004b). Pramipexole vs levodopa as
initial treatment for Parkinson disease: a 4-year rando-
mized controlled trial. Arch Neurol 61: 10441053.
Parkinson Study Group (2004c). A controlled, randomized,
delayed-start study of rasagiline in early Parkinson
disease. Arch Neurol 61: 561566.
Parkinson Study Group (2005). A randomized placebo-con-
trolled trial of rasagiline in levodopa-treated patients with
Parkinson disease and motor fluctuations: the PRESTO
study. Arch Neurol 62: 241248.
Pearce RK, Banerji T, Jenner P et al. (1998). De novo
administration of ropinirole and bromocriptine induces
less dyskinesia than L-dopa in the MPTP-treated marmoset.
Mov Disord 13: 234241.
Perry EK, Kerwin J, Perry RH et al. (1990). Visual halluci-
nations and the cholinergic system in dementia. J Neurol
Neurosurg Psychiatry 53: 88.
Perry IJ, Refsum H, Morris RW et al. (1995). Prospective
study of serum total homocysteine concentration and risk
of stroke in middle-aged British men. Lancet 346:
13951398.
Perry TL, Godin DV, Hansen S (1982). Parkinsons disease:
a disorder due to nigral glutathione deficiency? Neurosci
Lett 33: 305310.
 LEVODOPA
Pezzoli G, Tesei S, Ferrante C et al. (1988). Madopar HBS in
fluctuating parkinsonian patients: two-year treatment.
Mov Disord 3: 3745.
Pfeiffer RF (1998). Gastrointestinal dysfunction in Parkinsons
disease. Clin Neurosci 5: 136146.
Pfeiffer RF (2003). Gastrointestinal dysfunction in Parkinsons
disease. Lancet Neurol 2: 107116.
Physicians Desk Reference (2003). 57th edn. Thomson PDR,
Montvale, NJ.
Piccini P, Brooks DJ, Korpela K et al. (2000). The catechol-O-
methyltransferase (COMT) inhibitor entacapone enhances
the pharmacokinetic and clinical response to Sinemet CR
in Parkinsons disease. J Neurol Neurosurg Psychiatry 68:
589594.
Poewe WH, Lees AJ, Stern GM (1986). Low-dose L-dopa
therapy in Parkinsons disease: a 6-year follow-up study.
Neurology 36: 15281530.
Poewe WH, Lees AJ, Stern GM (1987). Clinical and pharma-
cokinetic observations with Madopar HBS in hospitalized
patients with Parkinsons disease and motor fluctuations.
Eur Neurol 27 (Suppl 1): 9397.
Poewe WH, Deuschl G, Gordin A et al. (2002a). Efficacy
and safety of entacapone in Parkinsons disease patients
with suboptimal levodopa response: a 6-month rando-
mized placebo-controlled double-blind study in Germany
and Austria (Celomen study). Acta Neurol Scand 105:
245255.
Poewe WH, Deuschl G, Gordin A et al. (2002b). CELOMEN
Study Group. Efficacy and safety of entacapone in Parkinsons
disease patients with suboptimal levodopa response: a
6-month randomized placebo-controlled double-blind study
in Germany and Austria (Celomen study). Acta Neurol Scand
105: 245255.
Postuma RB, Lang AE (2004). Homocysteine and levodopa:
should Parkinson disease patients receive preventative
therapy? Neurology 63: 886891.
Quigley EM (1996). Gastrointestinal dysfunction in Parkinsons
disease. Semin Neurol 16: 245250.
Quinn N, Marsden CD, Parkes JD (1982). Complicated
response fluctuations in Parkinsons disease: response to
intravenous infusion of levodopa. Lancet 2: 412415.
Quinn NP, Toone B, Lang AE et al. (1983). Dopa dose-
dependent sexual deviation. Br J Psychiatry 142: 296298.
Quinn NP, Marion MH, Marsden CD (1987). Open study of
Madopar HBS, a new formulation of levodopa with
benserazide, in 13 patients with Parkinsons disease and
on-off fluctuations. Eur Neurol 27 (Suppl 1): 105113.
Rabey JM, Vardi J, Askenazi JJ et al. (1977). L-tryptophan
administration in L-dopa-induced hallucinations in elderly
Parkinsonian patients. Gerontology 23: 438444.
Rabey JM, Treves TA, Neufeld MY et al. (1995). Low-dose
clozapine in the treatment of levodopa-induced mental
disturbances in Parkinsons disease. Neurology 45:
432434.
Rabey JM, Sagi I, Huberman M et al. (2000). Rasagiline
mesylate, a new MAO-B inhibitor for the treatment of
Parkinsons disease: a double-blind study as adjunctive
therapy to levodopa. Clin Neuropharmacol 23: 324330.
69
Rajput AH, Stern W, Laverty WH (1984). Chronic low-dose
levodopa therapy in Parkinsons disease: an argument for
delaying levodopa therapy. Neurology 34: 991996.
Rajput AH, Martin W, Saint-Hilaire MH et al. (1997). Tolca-
pone improves motor function in parkinsonian patients
with the wearing-off phenomenon: a double-blind,
placebo-controlled, multicenter trial. Neurology 49:
10661071.
Rascol O, Brooks DJ, Korczyn AD et al. (2000). A five-year
study of the incidence of dyskinesia in patients with early
Parkinsons disease who were treated with ropinirole or
levodopa. 056 Study Group. N Engl J Med 342:
14841491.
Rascol O, Brooks DJ, Melamed E et al. (2005). Rasagiline as
an adjunct to levodopa in patients with Parkinsons disease
and motor fluctuations (LARGO, Lasting effect in Adjunct
therapy with Rasagiline Given Once daily, study): a ran-
domised, double-blind, parallel-group trial. Lancet 365:
947954.
Reinikainen K, Leinonen M, Isojarvi J (2002). Predicting the
need for levodopa dose reduction after entacapone initia-
tion in PD patients with end-of-dose wearing-off. Mov
Disord 17 (Suppl 5): P111.
Riederer P, Youdim MB, Rausch WD et al. (1978). On the
mode of action of L-deprenyl in the human central
nervous system. J Neural Transm 43: 217226.
Riederer P, Sofic E, Rausch WD et al. (1989). Transition
metals, ferritin, glutathione, and ascorbic acid in parkinso-
nian brains. J Neurochem 52: 515520.
Rinne UK, Molsa P (1979). Levodopa with benserazide
or carbidopa in Parkinson disease. Neurology 29:
15841589.
Rinne UK, Larsen JP, Siden A et al. (1998a). Entacapone
enhances the response to levodopa in parkinsonian
patients with motor fluctuations. Nomecomt Study Group.
Neurology 51: 13091314.
Rinne UK, Bracco F, Chouza C et al. (1998b). Early treat-
ment of Parkinsons disease with cabergoline delays the
onset of motor complications. Results of a double-blind
levodopa controlled trial. The PKDS009 Study Group.
Drugs 55 (Suppl 1): 2330.
Roberts JW, Cora-Locatelli G, Bravi D et al. (1993). Cate-
chol-O-methyltransferase inhibitor tolcapone prolongs
levodopa/carbidopa action in parkinsonian patients.
Neurology 43: 26852688.
Rodnitzky RL, Dickins QS, Dobson J (1989). Long-term
clinical efficacy of Sinemet CR in patients with Parkin-
sons disease. Neurology 39: 9295; discussion 95.
Rogers JD, Sanchez-Saffon A, Frol AB et al. (2003).
Elevated plasma homocysteine levels in patients treated
with levodopa: association with vascular disease. Arch
Neurol 60: 5964.
Rondot P, Ziegler M, Aymard N et al. (1989). Effect of con-
trolled-release carbidopa/levodopa on motor performance
in advanced Parkinsons disease. Neurology 39: 7477;
discussion 95.
Rouru J, Gordin A, Huupponen R et al. (1999). Pharmacoki-
netics of oral entacapone after frequent multiple dosing
70 T. D. HALBIG AND W. C. KOLLER
and effects on levodopa disposition. Eur J Clin Pharmacol
55: 461467.
Ruottinen HM, Rinne JO, Ruotsalainen UH et al. (1995).
Striatal [18F]fluorodopa utilization after COMT inhibition
with entacapone studied with PET in advanced Parkin-
sons disease. J Neural Transm Park Dis Dement Sect
10: 91106.
Ruottinen HM, Rinne UK (1996a). Effect of one months
treatment with peripherally acting catechol-O-methyltrans-
ferase inhibitor, entacapone, on pharmacokinetics and
motor response to levodopa in advanced parkinsonian
patients. Clin Neuropharmacol 19: 222233.
Ruottinen HM, Rinne UK (1996b). A double-blind pharma-
cokinetic and clinical dose-response study of entacapone
as an adjuvant to levodopa therapy in advanced Parkin-
sons disease. Clin Neuropharmacol 19: 283296.
Sachs C, Berglund B, Kaijser L (1985). Autonomic cardio-
vascular responses in parkinsonism: effect of levodopa
with dopa-decarboxylase inhibition. Acta Neurol Scand
71: 3742.
Sage JI, Mark MH (1988). Comparison of controlled-release
Sinemet (CR4) and standard Sinemet (25 mg/100 mg) in
advanced Parkinsons disease: a double-blind, crossover
study. Clin Neuropharmacol 11: 174179.
Sanchez-Ramos JR, Ortoll R, Paulson GW (1996). Visual
hallucinations associated with Parkinson disease. Arch
Neurol 53: 12651268.
Sasahara K, Nitanai T, Habara T et al. (1980). Dosage form
design for improvement of bioavailability of levodopa II:
bioavailability of marketed levodopa preparations in dogs
and parkinsonian patients. J Pharm Sci 69: 261265.
Sawle GV, Burn DJ, Morrish PK et al. (1994). The effect of
entacapone (OR-611) on brain [18F]-6-L-fluorodopa meta-
bolism: implications for levodopa therapy of Parkinsons
disease. Neurology 44: 12921297.
Schapira AH, Cooper JM, Dexter D et al. (1990). Mitochon-
drial complex I deficiency in Parkinsons disease.
J Neurochem 54: 823827.
Schonfeldt-Lecuona C, Connemann BJ (2004). Aripiprazole
and Parkinsons disease psychosis. Am J Psychiatry 161:
373374.
Schrag A, Quinn N (2000). Dyskinesias and motor fluctua-
tions in Parkinsons disease. A community-based study.
Brain 123 (Pt 11): 22972305.
Schultz E, Nissinen E (1989). Inhibition of rat liver and duo-
denum soluble catechol-O-methyltransferase by a tight-
binding inhibitor OR-462. Biochem Pharmacol 38:
39533956.
Schultz E, Nissinen E, Kaakkola S (1989). Determination of
catechol-O-methyltransferase activity in erythrocytes by
high performance liquid chromatography with electroche-
mical detection. Biomed Chromatogr 3: 6467.
Schultz W (1986). Responses of midbrain dopamine neurons
to behavioral trigger stimuli in the monkey. J Neurophy-
siol 56: 14391461.
Sedek G, Jorga K, Schmitt M et al. (1997). Effect of tolca-
pone on plasma levodopa concentrations after coadminis-
tration with levodopa/carbidopa to healthy volunteers.
Clin Neuropharmacol 20: 531541.
Seedat S, Kesler S, Niehaus DJ et al. (2000). Pathological
gambling behaviour: emergence secondary to treatment
of Parkinsons disease with dopaminergic agents. Depress
Anxiety 11: 185186.
Senard JM, Verwaerde P, Rascol O et al. (1995). Effects of
acute levodopa administration on blood pressure and heart
variability in never treated parkinsonians. Hypertens Res
18 (Suppl 1): S175S177.
Senard JM, Rai S, Lapeyre-Mestre M et al. (1997). Preva-
lence of orthostatic hypotension in Parkinsons disease.
J Neurol Neurosurg Psychiatry 63: 584589.
Seshadri S, Beiser A, Selhub J et al. (2002). Plasma homo-
cysteine as a risk factor for dementia and Alzheimers dis-
ease. N Engl J Med 346: 476483.
Shaffer H, Hall M (1996). Estimating the prevalence of ado-
lescent gambling disorders: a quantitative synthesis and
guide toward standard gambling nomenclature. J Gambl
Stud 12: 193214.
Sharf B, Moskovitz C, Lupton MD et al. (1978). Dream phe-
nomena induced by chronic levodopa therapy. J Neural
Transm 43: 143151.
Shoulson I, Glaubiger GA, Chase TN (1975). On-off
response. Clinical and biochemical correlations during
oral and intravenous levodopa administration in parkinso-
nian patients. Neurology 25: 11441148.
Siegfried J (1987). Therapeutic value of Madopar HBS: judg-
ment after 2 years experience. Eur Neurol 27 (Suppl 1):
98104.
Siemers ER, Shekhar A, Quaid K et al. (1993). Anxiety and
motor performance in Parkinsons disease. Mov Disord 8:
501506.
Sigurdardottir GR, Nilsson C, Odin P et al. (2001). Car-
diovascular effects of domperidone in patients with
Parkinsons disease treated with apomorphine. Acta
Neurol Scand 104: 9296.
Skibba JL, Pinckley J, Gilbert EF et al. (1972). Multiple pri-
mary melanoma following administration of levodopa.
Arch Pathol 93: 556561.
Smith LA, Gordin A, Jenner P et al. (1997). Entacapone
enhances levodopa-induced reversal of motor disability
in MPTP-treated common marmosets. Mov Disord 12:
935945.
Smith LA, Tel BC, Jackson MJ et al. (2002). Repeated
administration of piribedil induces less dyskinesia than
L-dopa in MPTP-treated common marmosets: a beha-
vioural and biochemical investigation. Mov Disord 17:
887901.
Smith LA, Jackson MJ, Hansard MJ et al. (2003). Effect of
pulsatile administration of levodopa on dyskinesia induc-
tion in drug-naive MPTP-treated common marmosets:
effect of dose, frequency of administration, and brain
exposure. Mov Disord 18: 487495.
Smith LA, Jackson MJ, Al-Barghouthy G et al. (2005). Multi-
ple small doses of levodopa plus entacapone produce con-
tinuous dopaminergic stimulation and reduce dyskinesia
 LEVODOPA
induction in MPTP-treated drug-naive primates. Mov
Disord 20: 306314.
Sofic E, Paulus W, Jellinger K et al. (1991). Selective
increase of iron in substantia nigra zona compacta of
parkinsonian brains. J Neurochem 56: 978982.
Squires RF (1972). Multiple forms of monoamine oxidase in
intact mitochondria as characterized by selective inhibitors
and thermal stability: a comparison of eight mammalian
species. Adv Biochem Psychopharmacol 5: 355370.
Steckler T, Sahgal A (1995). The role of serotonergic-choli-
nergic interactions in the mediation of cognitive beha-
viour. Behav Brain Res 67: 165199.
Steece-Collier K, Collier TJ, Sladek CD et al. (1990).
Chronic levodopa impairs morphological development of
grafted embryonic dopamine neurons. Exp Neurol 110:
201208.
Steiger MJ, Stocchi F, Bramante L et al. (1992). The clinical
efficacy of single morning doses of levodopa methyl ester:
dispersible Madopar and Sinemet plus in Parkinson dis-
ease. Clin Neuropharmacol 15: 501504.
Stern M, Dulaney E, Gruber SB et al. (1991). The epidemiol-
ogy of Parkinsons disease. A case-control study of young-
onset and old-onset patients. Arch Neurol 48: 903907.
Stocchi F, Barbato L, Bramante L et al. (1994). The clinical
efficacy of a single afternoon dose of levodopa methyl
ester: a double-blind cross-over study versus placebo.
Funct Neurol 9: 259264.
Stocchi F, Barbato L, Bramante L et al. (1996). Fluctuating
parkinsonism: a pilot study of single afternoon dose of
levodopa methyl ester. J Neurol 243: 377380.
Struck LK, Rodnitzky RL, Dobson JK (1990). Stroke and
its modification in Parkinsons disease. Stroke 21:
13951399.
Sudo J, Iwase H, Terui J et al. (1998). Transdermal absorp-
tion of L-dopa from hydrogel in rats. Eur J Pharm Sci 7:
6771.
Sweet RD, Lee JE, McDowell FH (1972). Methyldopa as an
adjunct to levodopa treatment of Parkinsons disease. Clin
Pharmacol Ther 13: 2327.
Syed N, Murphy J, Zimmerman T Jr et al. (1998). Ten years
experience with enteral levodopa infusions for motor fluc-
tuations in Parkinsons disease. Mov Disord 13: 336338.
Thompson JF, Scolyer RA, Kefford RF (2005). Cutaneous
melanoma. Lancet 365: 687701.
Tohgi H, Abe T, Takahashi S et al. (1993). Alterations in the
concentration of serotonergic and dopaminergic substances
in the cerebrospinal fluid of patients with Parkinsons dis-
ease, and their changes after L-dopa administration. Neurosci
Lett 159: 135138.
Tohgi H, Abe T, Yamazaki K et al. (1995). Effects of the
catechol-O-methyltransferase inhibitor tolcapone in Par-
kinsons disease: correlations between concentrations of
dopaminergic substances in the plasma and cerebrospinal
fluid and clinical improvement. Neurosci Lett 192:
165168.
Tolosa E, Marti MJ, Valldeoriola F et al. (1998). History of
levodopa and dopamine agonists in Parkinsons disease
treatment. Neurology 50: S2S10; discussion S44S18.
71
Tornwall M, Kaakkola S, Tuomainen P et al. (1994). Com-
parison of two new inhibitors of catechol O-methylation
on striatal dopamine metabolism: a microdialysis study
in rats. Br J Pharmacol 112: 1318.
Tretter L, Sipos I, Adam-Vizi V (2004). Initiation of neuro-
nal damage by complex I deficiency and oxidative stress
in Parkinsons disease. Neurochem Res 29: 569577.
Troconiz IF, Naukkarinen TH, Ruottinen HM et al. (1998).
Population pharmacodynamic modeling of levodopa in
patients with Parkinsons disease receiving entacapone.
Clin Pharmacol Ther 64: 106116.
Trugman JM, James CL, Wooten GF (1991). D1/D2 dopa-
mine receptor stimulation by L-dopa. A [14C]-2-deoxy-
glucose autoradiographic study. Brain 114 (Pt 3):
14291440.
U.K. Madopar CR Study Group (1989). A comparison of
Madopar CR and standard Madopar in the treatment of
nocturnal and early-morning disability in Parkinsons
disease. Clin Neuropharmacol 12: 498505.
Uitti RJ, Tanner CM, Rajput AH et al. (1989). Hypersexuality
with antiparkinsonian therapy. Clin Neuropharmacol 12:
375383.
Valeant Pharmaceuticals International (2006). Prescribing
information Tasmar (tolcapone) USA. Valeant Pharmaceu-
ticals International, Aliso Viejo, CA.
van Deelen RA, Rommers MK, Eerenberg JG et al.
(2002). [Hypersexuality during use of levodopa]. Ned
Tijdschr Geneeskd 146: 20952098.
Verhagen Metman L, Locatelli ER, Bravi D et al. (1997).
Apomorphine responses in Parkinsons disease and the
pathogenesis of motor complications. Neurology 48:
369372.
Vogel HP, Schiffter R (1983). Hypersexualitya complica-
tion of dopaminergic therapy in Parkinsons disease. Phar-
macopsychiatria 16: 107110.
von Bohlen und Halbach O, Dermietzel R (2002). Dopamine.
In: Neurotransmitters and Neuromodulators: Wiley-VCH
Verlag GmbH & Co. KGaA, Weinheim.
Wakabayashi K, Takahashi H (1997). Neuropathology of
autonomic nervous system in Parkinsons disease. Eur
Neurol 38 (Suppl 2): 27.
Wakabayashi K, Takahashi H, Ohama E et al. (1993). Lewy
bodies in the visceral autonomic nervous system in Parkin-
sons disease. Adv Neurol 60: 609612.
Waters CH, Kurth M, Bailey P et al. (1997). Tolcapone in
stable Parkinsons disease: efficacy and safety of long-
term treatment. The Tolcapone Stable Study Group. Neu-
rology 49: 665671.
Webster RA (2001). Dopamine (DA). In: RA Webster,
(Ed.), Neurotransmitters, Drugs and Brain Function. John
Wiley & Sons Ltd, New York.
Weiner WJ, Singer C, Sanchez-Ramos JR et al. (1993). Levo-
dopa, melanoma, and Parkinsons disease. Neurology 43:
674677.
Westin JE, Andersson M, Lundblad M et al. (2001). Persis-
tent changes in striatal gene expression induced by long-
term L-DOPA treatment in a rat model of Parkinsons
disease. Eur J Neurosci 14: 11711176.
72 T. D. HALBIG AND W. C. KOLLER
Whone AL, Watts RL, Stoessl AJ et al. (2003). Slower pro-
gression of Parkinsons disease with ropinirole versus
levodopa: the REAL-PET study. Ann Neurol 54: 93101.
Wick MM (1979). Levodopa and dopamine analogs: melanin
precursors as antitumor agents in experimental human and
murine leukemia. Cancer Treat Rep 63: 991997.
Wick MM (1980). Levodopa and dopamine analogs as DNA
polymerase inhibitors and antitumor agents in human mel-
anoma. Cancer Res 40: 14141418.
Wick MM (1987). Inhibition of transformation by levodopa-
carbidopa in lymphocytes derived from patients with mel-
anoma. J Invest Dermatol 88: 535537.
Wick MM (1989). Levodopa/dopamine analogs as inhibitors
of DNA synthesis in human melanoma cells. J Invest Der-
matol 92: 329S331S.
Wikberg T, Ottoila P, Taskinen J (1993a). Identification of
major urinary metabolites of the catechol-O-methyltrans-
ferase inhibitor entacapone in the dog. Eur J Drug Metab
Pharmacokinet 18: 359367.
Wikberg T, Vuorela A, Ottoila P et al. (1993b). Identification
of major metabolites of the catechol-O-methyltransferase
inhibitor entacapone in rats and humans. Drug Metab
Dispos 21: 8192.
Wilde MI, Markham A (1996). Ondansetron. A review of its
pharmacology and preliminary clinical findings in novel
applications. Drugs 52: 773794.
Wilding IR, Hardy JG, Davis SS et al. (1991). Characterisation of
the in vivo behaviour of a controlled-release formulation of
levodopa (Sinemet CR). Clin Neuropharmacol 14: 305321.
Wolters EC, Tesselaar HJ (1996). International (NL-UK)
double-blind study of Sinemet CR and standard Sinemet
(25/100) in 170 patients with fluctuating Parkinsons
disease. J Neurol 243: 235240.
Wolters EC, Horstink MW, Roos RA et al. (1992). Clinical
efficacy of Sinemet CR 50/200 versus Sinemet 25/100 in
patients with fluctuating Parkinsons disease. An open,
and a double-blind, double-dummy, multicenter treatment
evaluation. The Dutch Sinemet CR Study Group. Clin
Neurol Neurosurg 94: 205211.
Wright CB, Lee HS, Paik MC et al. (2004). Total homocys-
teine and cognition in a tri-ethnic cohort: the Northern
Manhattan Study. Neurology 63: 254260.
Yahr MD, Duvoisin RC, Mendoza MR et al. (1971). Modifi-
cation of L-dopa therapy of Parkinsonism by alpha-
methyldopa hydrazine (MK-486). Trans Am Neurol Assoc
96: 5558.
Yamamoto M, Yokochi M, Kuno S et al. (1997). Effects of
tolcapone, a catechol-O-methyltransferase inhibitor, on
motor symptoms and pharmacokinetics of levodopa in
patients with Parkinsons disease. J Neural Transm 104:
229236.
Yasui K, Kowa H, Nakaso K et al. (2000). Plasma homocys-
teine and MTHFR C677T genotype in levodopa-treated
patients with PD. Neurology 55: 437440.
Yasui K, Nakaso K, Kowa H et al. (2003). Levodopa-
induced hyperhomocysteinaemia in Parkinsons disease.
Acta Neurol Scand 108: 6667.
Yeh KC, August TF, Bush DF et al. (1989). Pharmacoki-
netics and bioavailability of Sinemet CR: a summary of
human studies. Neurology 39: 2538.
Zeng BY, Pearce RK, MacKenzie GM et al. (2000). Altera-
tions in preproenkephalin and adenosine-2a receptor
mRNA, but not preprotachykinin mRNA correlate with
occurrence of dyskinesia in normal monkeys chroni-
cally treated with L-DOPA. Eur J Neurosci 12:
10961104.
Ziv I, Zilkha-Falb R, Offen D et al. (1997). Levodopa
induces apoptosis in cultured neuronal cellsa possible
accelerator of nigrostriatal degeneration in Parkinsons
disease? Mov Disord 12: 1723.
Zoldan J, Friedberg G, Livneh M et al. (1995). Psychosis
in advanced Parkinsons disease: treatment with ondanse-
tron, a 5-HT3 receptor antagonist. Neurology 45:
13051308.
Zurcher G, Colzi A, Da Prada M (1990). Ro 407592: inhi-
bition of COMT in rat brain and extracerebral tissues.
J Neural Transm Suppl 32: 375380.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 33

Dopamine agonists

OLIVIER RASCOL1,2*, TARIK SLAOUI2, WAFA REGRAGUI2, FABIENE ORY-MAGNE2,

CHRISTINE BREFEL-COURBON1,2 AND JEAN-LOUIS MONTASTRUC1

1
Department of Clinical Pharmacology, Clinical Investigation Center, University Hospital, Toulouse, France
2
Department of Neurosciences, University Hospital, Toulouse, France

The discovery of a dopaminergic deficit in the nigros-
triatal pathway of patients with Parkinsons disease
led to the introduction of levodopa therapy (Birkmayer
and Hornykiewicz, 1970). After 40 years, levodopa
remains the gold-standard antiparkinsonian treament.
Nevertheless, the initial good therapeutic efficacy of
levodopa is often confounded within a few years of
the start of treatment by the development of motor
complications (fluctuations, abnormal movements) and
other problems (Marsden et al., 1987; Nutt, 1990; Ras-
col et al., 2003). Because of these limitations, the treat-
ment of patients with Parkinsons disease has expanded
to incorporate additional pharmacologic approaches.
Among these other therapeutic options, dopamine-
receptor agonists are widely used. This chapter will
focus on the use of dopamine agonists as antiparkinso-
nian medications. It will not cover their role in the treat-
ment of other movement disorders, such as the restless-
legs syndrome (Happe and Trenkwalder, 2004; Hening
et al., 2004).
Bromocriptine was the first agonist to be indicated as
an adjunct to levodopa therapy for patients with Parkin-
sons disease experiencing motor fluctuations (Calne
et al., 1974). There are now nine different dopamine ago-
nists presently approved and marketed for the treatment
of Parkinsons disease: apomorphine, bromocriptine,
cabergoline, dihydroergocryptine, lisuride, pergolide, pir-
ibedil, pramipexole and ropinirole (alphabetical order).
Among these nine dopamine agonists, five are ergot deri-
vatives (bromocriptine, cabergoline, dihydroergocryp-
tine, lisuride and pergolide) whereas the four others are
not (apomorphine, piribedil, pramipexole and ropinirole).
All are used as oral medications, except apomorphine,
which is used as subcutaneous injections or infusions.
All share the property of binding to the D2-like family
of dopamine receptors (D2, D3, D4). All have specific
pharmacodynamic and pharmacokinetic profiles (Mon-
tastruc et al., 1993; Uitti and Ahlskog, 1996; Deleu
et al., 2002). There are many randomized controlled
trials (RCTs) and a large body of clinical experience to
support the usefulness of dopamine agonists in the treat-
ment of Parkinsons disease. However several issues
remain a matter of controversy. Among these, important
ones are the place of the agonists (as a class) in the
global strategy of Parkinsons disease therapy (before
or after levodopa) and the potential advantages or disad-
vantages of a given agonist versus another one.
33.1. Pharmacological properties of dopamine
agonists
33.1.1. Pharmacokinetic properties (for review, see
Deleu et al., 2002; Tintner and Jankovic, 2003)
33.1.1.1. Absorption and bioavailability
Most dopamine agonists, except apomorphine, are
absorbed orally. The systemic bioavailability of the
ergot agonists is low, due to an extensive first-pass
hepatic metabolism. This is also true for piribedil.
Because of poor oral absorption and low bioavailability,
apomorphine is only used via the subcutaneous route.
The second generation of non-ergot agonists, including
pramipexole and ropinirole, has a better bioavailability
(Table 33.1). The usually recommended range of daily
doses for the different dopamine agonists is listed in
Table 33.1. Rotigotine, a dopamine agonist designed

*
Correspondence to: Professor Olivier Rascol, Clinical Investigation Center, Department of Clinical Pharmacology and
Department of Neurosciences, Faculty of Medicine, 37 Allees Jules Guesde, Toulouse 31073, France. E-mail: rascol@cict.fr,
Tel: 33-(0)-5-61-14-5962, Fax: 33-(0)-5-61-25-5116.
74 O. RASCOL ET AL.
Table 33.1
Main pharmacokinetic and pharmacodynamic (binding) properties of dopamine agonists

Binding affinity
Recommended Times Oral bioavail- Elimination
Agonists daily dose (mg) daily ability (%) half-life (h) D1-like D2-like 5-HT a1 a2

Apomorphine * * * 0.5 0/ 0/
Bromocriptine 1060 3 6 38
Cabergoline 26 1 50 65110 0/
Dihydroergo-
cryptine 30120 3 5 15 /
Lisuride 15 3 1020 23 0/
Pergolide 1.54 3 2050 20
Piribedil 150300 3 10 20 0/ 0 0/
Pramipexole 1.54.5 3 >90 812 0/ 0/ 0/
Ropinirole 624 3 50 68 0 0 0 0

*Subcutaneous route.
5-HT, serotonin.

to be administered transdermally rather than orally, is
currently under development for the treatment of Par-
kinsons disease (Mucke, 2003; Jenner, 2005; Poewe
and Lussi, 2005; Rascol, 2005). This drug is not yet
approved for this indication.
33.1.1.2. Elimination half-life
Interest has focused recently in Parkinsons disease on
drug plasma elimination half-lives because continuous
dopamine stimulation (CDS) is an appealing hypothesis
to explain the development of motor complications
(fluctuations and abnormal involuntary movements) that
are frequently associated with long-term dopatherapy.
According to this theory, levodopa, when administrated
orally, is supposed to stimulate in a pulsatile non-
physiological way the striatal dopamine receptors. This
induces in turn a cascade of molecular and cellular
downstream events that change the basal ganglia outflow
and lead to abnormal motor programs (Chase, 1998; Ola-
now et al., 2000).
All orally active dopamine agonists have longer
elimination half-lives than levodopa. Apomorphine has
the shortest one (30 minutes), but this is overcome in
clinical practice when the drug is delivered using con-
tinuous subcutaneous pumps (Neef and van Laar,
1999; LeWitt, 2004). The shortest half-life for an orally
active agonist is that of lisuride (26 hours). Cabergo-
line has the longest one (65110 hours) (Fariello,
1998), and the other ones have intermediate half-lives,
ranging from 6 to 20 hours (Rascol, 1997; Matheson
and Spencer, 2000; Di Marco et al., 2002; Biglan and
Holloway, 2002; Blin, 2003; Albanese and Colosimo,
2003; Curran and Perry, 2004) (Table 33.1). Globally,
dopamine agonists are thus supposed to offer a more
continuous stimulation of dopamine receptors than
levodopa. At present, there is however no convincing
evidence that this difference in elimination half-lives
correlates with specific efficacy or safety clinical
parameters. For example, empirical practice does not
suggest that cabergoline, with its long elimination
half-life, is more efficacious in reducing the risk of
long-term motor complications than lisuride, an agonist
with a much shorter elimination half life. The sole prac-
tical clinical difference that might be related to elimina-
tion half-life is that cabergoline is used once daily to
treat the patients, whereas the other agonists are gener-
ally used on a t.i.d. regimen. In theory, it is also concei-
vable that cabergoline-induced adverse drug reactions,
such as psychosis for example, could persist for longer
periods of time than with other agonists when the drug
is withdrawn. Conversely, wearing-off effects have
been observed in some patients on monotherapy with
shorter elimination half-life agonists like ropinirole
(F. Stocchi, personal communication).
33.1.1.3. Metabolism and drug interactions (for
review, see Pfeiffer, 1996)
Ergot derivatives as well as ropinirole and piribedil
have an extensive hepatic metabolism. Enzymatic
inhibitors, like macrolide antibacterials, have been
reported to increase some adverse drug reactions
induced by ergot agonists like bromocriptine (Montas-
truc and Rascol, 1984; Periti et al., 1992). Ropinirole
is metabolized extensively by the hepatic microsomal
enzyme system (CYP1A2, CYP3A4 and CYP2D6)
 DOPAMINE AGONISTS
(Kaye and Nicholls, 2000). Ciprofloxacin, which is an
inhibitor of CYP1A2, can increase the area under the
curve of ropinirole plasma levels. In this case, a dose
reduction of the agonist might be considered. Estro-
gens will decrease ropinirole clearance by about
36%. Conversely, pramipexole, which undergoes mini-
mal hepatic biotransformation and is excreted virtually
unchanged in the urine by the renal tubular secretion,
is not exposed to such interaction. It is devoid of
any CYP interaction. On the other hand, this drug can
theoretically lead to potential interactions with drugs
excreted by renal tubular secretion (H2-antagonists,
diuretics, verapamil, quinidine) and this may require
dose adjustment. The same is true in patients with
impaired renal function. Apomorphine is partly metabo-
lized by the catechol-O-methyltransferase (COMT)
enzyme (LeWitt, 2004). However, no relevant interac-
tion has been reported with a COMT inhibitor such as
entacapone (Durif et al., 2004). Overall, there is no
evidence that the co-prescription of levodopa with
any orally active dopamine agonist will modify the
pharmacokinetic properties of any of these compounds
and vice versa.
33.1.2. Pharmacodynamics and receptor selectivity
33.1.2.1. Binding to non-dopamine receptors
The dopamine agonists that belong to the ergot deriva-
tive family (bromocriptine, lisuride, pergolide, cabergo-
line) have high to moderate affinity for a variety of
non-dopaminergic receptors such as a-adrenergic (a1
and a2) and serotonergic (5-HT1 and 5-HT2) receptors
(Montastruc et al., 1993; Piercey et al., 1996; Fariello,
1998; Piercey, 1998). These compounds, therefore, are
less selective than non-ergot agents like ropinirole, pra-
mipexole and piribedil (Tulloch, 1997; Piercey, 1998)
(Table 33.1). It is not clear whether such differences
influence clinical outcomes. A drug with actions at nor-
adrenergic or serotonergic receptors might theoretically
induce better antiparkinsonian efficacy than selective
dopaminergic agents, since the transformation of levo-
dopa into norepinephrine and not solely into dopamine
could explain why this drug has such potent sympto-
matic antiparkinsonian effects. However, acting on
non-dopamine receptors could also lead to adverse
reactions such as psychosis or dysautonomic symptoms.
Clinical studies have not yet provided undisputable
evidence to support these assumptions.
33.1.2.2. Relative affinity for dopamine-receptor
subtypes
Dopamine agonists differ in their relative affinities for
D1- and D2-like receptors (Table 33.1). Bromocriptine
is a D2-agonist and a weak D1-antagonist (partial ago-
75
nist). Apomorphine and pergolide are known as mixed
D2- and D1-agonists. Other agonists, such as ropinirole
and pramipexole, are reported to be selective D2-like
(and preferentially D3-) agonists (Piercey, 1998; Tul-
loch, 1997) (Table 33.1). Such differences could theo-
retically have clinical correlates, but the literature is
quite controversial on that topic. It has been proposed,
for example, that a synergistic activation of both D1-
and D2-receptors may be necessary to induce a full
antiparkinsonian effect (Luquin et al., 1992; Robert-
son, 1992). According to this theory, mixed D1/D2
agents could then be more potent antiparkinsonian
medications than the D2-selective ones. An action at
D1-receptors has also been implicated in the genesis
of adverse drug reactions, like dyskinesias for exam-
ple. Some authors have proposed that clozapine, an
atypical neuroleptic, could exert antidyskinetic proper-
ties because of its antagonistic effects at D1-receptors
(Bennett et al., 1994). This claim is however incompa-
tible with the observation that selective D2-agonists
can induce dyskinesia by themselves, even in non-
primed levodopa-naive monkeys (Gomez-Mancilla
and Bedard, 1992; Luquin et al., 1992) and that the
selective D1-agonist, A-86929, has a lower propensity
than D2-agonists to induce abnormal movements in the
primate model of levodopa-induced dyskinesias
(Grondin et al., 1997). However the prodrug of this
last compound, ABT-431, induced the same amount
of dyskinesias as levodopa when tested in dyskinetic
patients with Parkinsons disease (Rascol et al., 2001).
Potentially beneficial effects of preferential selec-
tivity for D3-receptors have also been speculated.
The highest concentrations of D3-receptor mRNA are
found in the mesolimbic pathways, which are thought
to be involved in motivation (Wise and Rompre,
1989). Some psychopharmacologic experiments in
animals suggest that D3-agonists might have antide-
pressant properties (Maj et al., 1997). This led to the
proposal that drugs like pramipexole and ropinirole
could have antidepressant effects, but clinical evidence
is still weak to support this assumption.
33.1.2.3. In vivo antiparkinsonian efficacy of
dopamine agonists in experimental models of
Parkinsons disease
Most D2-agonists have demonstrated that they can
reverse the motor deficit that mimics the motor parkinso-
nian symptoms in different in vivo models of Parkinsons
disease. This is true for the akinetic syndrome induced in
the rodent by reserpine, a dopamine-depleting agent, for
the abnormal rotational behavior induced by the unilat-
eral striatal injection of 6-hydroxydopamine in the rat
and for the parkinsonian-like motor syndrome induced
76 O. RASCOL ET AL.
by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) intoxication of various species of primates
(Eden et al., 1991; Arai et al., 1995; Domino et al.,
1998; Pearce et al., 1998). An intriguing finding in these
animal models is that most agonists, when used as mono-
therapy, are as efficacious as levodopa in reversing the
symptoms, whereas in clinical practice, it is common
observation that orally active agonists have a less potent
symptomatic antiparkinsonian activity than levodopa.
The reason for this discrepancy and for the non-predict-
ability of the model on this aspect remains unknown.
It may be due to tolerability-related dose limitations
in humans.
Dopamine agonists induce significantly fewer dys-
kinesias than levodopa in levodopa-naive MPTP-
intoxicated monkey (Bedard et al., 1986; Grondin et al.,
1996; Pearce et al., 1998). This property, which is also
observed in patients with Parkinsons disease, as long
as they have not been previously exposed and primed
by levodopa for dyskinesias, may result from the long
elimination half-life of the agonists, but other mechanisms
could also be implicated (see section 33.1.1.2).
33.1.2.4. Neuroprotective properties of dopamine
agonists in experimental models of neuronal death
Current theories on the pathogenesis of Parkinsons
disease have centered for many years on the formation
of reactive oxygen species and the onset of oxidative
stress, leading to oxidative damage in the substantia
nigra pars compacta (Jenner and Olanow, 1996).
Dopamine may produce toxic metabolites, via auto-
oxidation to toxic semiquinones, that lead to the pro-
duction of reactive oxygen species (Olanow, 1990).
Levodopa decarboxylation to dopamine may enhance
this phenomenon. For this reason, dopamine agonists,
which allow delay and reduction of levodopa needs,
have been speculated to have a positive impact on
the disease progression. However, levodopa toxicity
is highly questioned in vivo and there are no clinical
data to support the concept that this drug could
accelerate the progression of the disease in patients
(Olanow et al., 2004).
Independent of levodopa toxicity, there are other
reasons why a dopamine agonist might be neuropro-
tective. Activity at presynaptic dopamine autorecep-
tors might reduce the amount of dopamine released
into the synapse, thus reducing the rate of firing and
dopamine turnover in the neuron (Sethy et al., 1997).
Several dopamine agonists also have free radical-
scavenging activity (Yoshikawa et al., 1994; Hall
et al., 1996). In addition, they protect cells in vitro
and ex vivo from oxidative damage (Iida et al., 1999;
Ogawa et al., 1999) and excitotoxicity and demon-
strate antiapoptotic effects in a variety of cell models
(Schapira and Olanow, 2003). In the laboratory,
dopamine agonists protect dopaminergic and non-
dopaminergic neurons from a variety of toxins in both
in vitro and in vivo models of parkinsonism (Olanow
et al., 1998; Le and Jankovic, 2001; Schapira, 2002).
However, to date, none of these promising preclinical
data have yet translated into undisputable clinical
benefit (see below).
33.2. Clinical trials on dopamine agonists:
clinical efficacy in the treatment of Parkinsons
disease
Under the auspices of the Movement Disorders Society
(MDS), a group of experts that included author O. Rascol
of the present chapter has performed an evidence-based
systematic review to assess all antiparkinsonian thera-
peutic interventions. The conclusions of this review
are based on the robustness of clinical evidence (Goetz
et al., 2002; Rascol et al., 2002) and have recently
been updated (Goetz et al., 2005). This MDS review
includes, among other interventions, the nine dopamine
agonists discussed in this chapter. It extensively sum-
marizes the level of evidence supporting the use of each
individual agonist according to a number of different
clinical objectives: (1) prevention of disease progres-
sion; (2) symptomatic control of parkinsonism as mono-
therapy; (3) symptomatic control of parkinsonism as
adjunct to levodopa; (4) prevention of motor complica-
tions; (5) control of motor complications; and (6) man-
agement of non-motor complications, each drug being
rated according to standardized definitions of efficacy,
safety and implications for clinical practice. The pre-
sent chapter will synthesize the conclusions of this
review and the reader is invited to refer to the original
documents for a more comprehensive and detailed
description of the methods as well as for an extensive
description and citation of the level of evidence, agonist
by agonist and trial by trial. These data will be pre-
sented here according to the use of dopamine agonists
in two clinical situations: (1) the early de novo patient
not previously exposed to levodopa; and (2) the patient
suffering from more advanced disease and already
treated with levodopa.
33.2.1. Evidence for the use of dopamine agonists in
levodopa-naive patients with early Parkinsons
disease
There are generally three main reasons to consider
using a dopamine agonist in this situation: (1) to slow
down disease progression; (2) to control the parkinso-
nian symptoms of the patients; and (3) to reduce the
 DOPAMINE AGONISTS
risk of motor complications associated with the long-
term use of levodopa.
33.2.1.1. Dopamine agonists and the prevention of
disease progression
Our basic understanding of Parkinsons disease is that
the disorder is caused by the progressive death of
dopamine nigrostriatal neurons. It is therefore in the
earliest stages of the disease that one expects that the
largest number of dopamine neurons remain spared
by the pathological process and could be available
for neuroprotection. Consequently, neuroprotective
strategies are often discussed at this stage.
The clinical demonstration that a drug could posi-
tively influence the progression of Parkinsons disease
is a major therapeutic challenge. This objective
remains an unsolved question. Up to now, even the
design of the trials assessing the putative disease-mod-
ifying effects of a given drug remains a matter of
controversies. There is no way to measure directly
neuronal loss in vivo and it is unclear how clinical
symptoms correlate with neuronal death. Clinical end-
points, such as measuring the hazard function of early
untreated patients to reach the need for symptomatic
treatment, are biased by the intrinsic symptomatic anti-
parkinsonian properties of many drugs, including
dopamine agonists. The use of imaging biomarkers
which quantify for example the amount of dopamine
transporters or the production of dopamine in the stria-
tum with single-photon or positron emission tomogra-
phy does not allow more definite conclusions because
of other potential biases.
Bromocriptine, pramipexole and ropinirole have
been tested in RCTs specifically designed to assess
their potential impact on disease progression (Olanow
et al., 1995; Parkinson Study Group, 2002a; Whone
et al., 2003). Due to methodological shortcomings,
none of these studies produced sufficiently convincing
evidence to establish that the drugs had a positive
effect on disease progression. It has been reported in
two long-term (24-year) RCTs comparing pramipex-
ole or ropinirole to levodopa that two different neuroi-
maging biomarkers of striatal dopaminergic function
declined more slowly over time in patients treated with
an agonist than in those who received levodopa. This
can be interpreted as an indirect index of a neuropro-
tective effect. However, in these trials, the same
patients had a better clinical outcome on levodopa than
on agonists. Moreover, it was impossible to disentan-
gle in these studies if: (1) the imaging differences were
due to a faster decline of the biomarker on levodopa or
to a slower one on the agonist; and if (2) the difference
was related or not to a more pronounced downregula-
77
tion of the biomarker by levodopa than by the agonists
(Schapira and Olanow, 2004).
In summary, according to these findings, neuropro-
tection remains an unmet need in Parkinsons disease.
In spite of a seducing rationale, there is not strong
enough evidence definitely to recommend the use of
a dopamine agonist for this purpose in clinical prac-
tice. This remains an investigational topic. Interest-
ingly, in line with this negative conclusion, the few
available controlled data assessing mortality after
10 years of follow-up showed that the early use of an
agonist like bromocriptine rather than levodopa in
Parkinsons disease patients did not improve patients
life expectancy (Hely and Morris, 1999; Lees et al.,
2001; Montastruc et al., 2001a). No data are available
with other agonists.
33.2.1.2. Dopamine agonists as monotherapy and
the symptomatic control of parkinsonian symptoms
Parkinsonism (tremor, bradykinesia and rigidity) is the
core of the clinical syndrome of Parkinsons disease.
It progressively causes motor disability in patients
with early Parkinsons disease who are not already
on levodopa. A dopamine agonist used as initial mono-
therapy can be proposed to control such symptoms and
there are a number of RCTs to support this property.
Such RCTs are usually parallel short-term (6-month)
comparisons with placebo or an active comparator
(levodopa or another agonist). The most widely stan-
dardized scale used to assess parkinsonism in these
trials is the Unified Parkinsons Disease Rating Scale
(UPDRS) (Fahn et al., 1987).
33.2.1.2.1. Randomized controlled trials comparing
agonist monotherapy versus placebo (Table 33.2)
There is at least one good-quality RCT and sometimes
several to support the efficacy of dihydroergo-
cryptine (Bergamasco et al., 2000), pergolide (Barone
et al., 1999), pramipexole (Shannon et al., 1997) and
ropinirole (Adler et al., 1997) on parkinsonism in early
Parkinsons disease (for a complete list of references,
see the MDS evidence-based review: Goetz et al.,
2002, 2005; Rascol et al., 2002). Pergolide is no longer
used as a first-line agonist for safety reasons (see sec-
tion 33.3). There is less convincing but still supportive
evidence for bromocriptine. This conclusion is mainly
based on levodopa-controlled RCTs showing, as a sec-
ondary endpoint, that the drug was as efficacious as
levodopa (Riopelle, 1987; Montastruc et al., 1994)
(although these studies were not powered to demon-
strate non-inferiority) or only slightly less efficacious
(in a proportion suggesting that the difference in
functional improvement was not important enough to
78 O. RASCOL ET AL.
Table 33.2
Level of evidence supporting the efficacy of the different dopamine agonists in levodopa-naive patients with early
Parkinsons disease based on the conclusions of the Movement Disorders Society evidence-based review (see Goetz et al.,
2002, 2005; Rascol et al., 2002)

Symptomatic control Prevention of motor

Agonists Disease progression of parkinsonism complications

Apomorphine* Insufficient Not used Not used

Bromocriptine Insufficient Likely Likely
Cabergoline Insufficient Insufficient Efficacious
Dihydroer-
gocryptine Insufficient Efficacious Insufficent
Lisuride Insufficient Likely Insufficient
Pergolide{ Insufficient Efficacious Insufficient
Piribedil Insufficient Insufficient Insufficient
Pramipexole Insufficient Efficacious Efficacious
Ropinirole Insufficient Efficacious Efficacious

*Apomorphine is not used in early Parkinsons disease because it is only active via the subcutaneous route.
{
Pergolide cannot be recommended as a first-line treatment for early Parkinsons disease because of the risk of valvular heart disorder.
Efficacious, positive effect of the agonists on studied outcomes in at least one high-quality randomized controlled trial (RCT) and no
conflicting data from other RCT(s); likely, efficacy likely, i.e. evidence suggests, but is not sufficient to show, that the agonist has a positive
effect on studied outcomes, based on any RCT and no conflicting data from other RCTs; insufficient, insufficient evidence, i.e. there are no
data or available data do not provide enough evidence either for or against the use of the agonist.

suggest that the choice of the treatment was critical
within the first 3 years of follow-up; Parkinsons Dis-
ease Research Group of the United Kingdom, 1993).
The same is true for cabergoline (Rinne et al., 1997,
1998). There are only open-label studies to support
the effect of lisuride (Rinne, 1989) and piribedil
(Rondot and Ziegler, 1992) in early Parkinsons dis-
ease. Apomorphine, being only used subcutaneously,
has never been tested as monotherapy for the treatment
of Parkinsons disease at this early stage.
33.2.1.2.2. Randomized controlled trials comparing
agonist monotherapy versus levodopa
Levodopa is more efficacious than any orally active
dopamine agonist monotherapy. This common clinical
practice observation is documented in RCTs assessing
agonists like cabergoline (Rinne et al., 1997), pramipex-
ole (Parkinson Study Group, 2000), ropinirole (Rascol
et al., 1998) and bromocriptine (Parkinsons Disease
Research Group of the United Kingdom, 1993; Olanow
et al., 1995). There are no published levodopa-controlled
head-to-head RCTs with the other agonists.
The proportion of patients with early Parkinsons
disease capable of remaining on agonist monotherapy
falls progressively over years to less than 20% after
5 years of treatment with bromocriptine (Parkinsons
Disease Research Group of the United Kingdom,
1993; Montastruc et al., 1994), cabergoline (Rinne
et al., 1998), pramipexole (Parkinson Study Group,
2000) and ropinirole (Rascol et al., 2000). For this rea-
son, after some years of treatment, most patients who
start on an agonist will receive levodopa as a replacing
or an adjunct treatment to keep control on the motor
parkinsonian syndrome. The optimal timing when
combining both drugs has never been assessed. In the
last decade, the most frequently tested strategy has
been to start with an agonist and to postpone the
adjunction of levodopa as late as possible as a second
step of the therapeutic strategy. However, in the pre-
vious decade, it was common practice to combine
early an agonist like bromocriptine or lisuride with
levodopa within the first months of treatment (early
combination strategy) (Przuntek et al., 1996; Allain
et al., 2000). There are no data to assess if one strategy
is better than the other one.
33.2.1.2.3. Randomized controlled trials comparing an
agonist monotherapy versus another agonist
There are only few trials comparing the efficacy of
a dopamine agonist versus that of another one as
monotherapy. When such data are available (bromo-
criptine versus ropinirole (Korczyn et al., 1998, 1999)
and versus pergolide (Mizuno et al., 1995), the clinical
relevancy of the reported difference, if any, remains
questionable, especially since the exact dose equiva-
lence between the different agonists remains unknown.
Such drugs should then be considered from a clinical
perspective as having basically a comparable efficacy.
 DOPAMINE AGONISTS
33.2.1.2.4. Randomized controlled trials comparing an
agonist monotherapy versus another antiparkinsonian
medication
There are no published direct head-to-head compari-
sons between any agonist monotherapy and other anti-
parkinsonian medications in early Parkinsons disease
(monoamine oxidase-B (MAO-B) inhibitors, amanta-
dine, anticholinergics). The changes in UPDRS scores
reported in placebo-controlled RCTs are usually
greater on agonists than on MAO-B inhibitors (Par-
kinson Study Group, 1989, 2002b). This could be
interpreted as an indirect indication of a greater symp-
tomatic efficacy of the agonists, but one cannot firmly
establish if this putative difference is of clinical
importance.
33.2.1.3. Prevention of motor complications
The incidence of motor complications is 10% per year
on levodopa therapy. Over time, they usually become
more disabling and difficult to manage. Symptomatic
control of symptoms is therefore not the only factor
to be considered when initiating an antiparkinsonian
treatment and doctors and patients are also often inter-
ested in considering the impact of an initial therapeutic
strategy on the incidence of long-term motor compli-
cations. The strategy of using early a dopamine agonist
and to keep levodopa as a second-line rescue medica-
tion to delay the problem of motor complication has
been a growing matter of interest in the last decade.
Several RCTs compared the probability of developing
motor complications for up to 5 years in previously
untreated patients who received an agonist versus
levodopa-treated patients. There was no standardized
method used to define when a patient began motor
complications and each trial used its own definition,
with consequent variable numbers from one study to
another.
33.2.1.3.1. Randomized controlled trials comparing an
agonist monotherapy versus levodopa (Table 33.2)
Prospective RCTs lasting 25 years and demonstrating
the ability of the early use of an agonist to reduce the
incidence of motor complications versus levodopa are
available for cabergoline (Rinne et al., 1998), prami-
pexole (Parkinson Study Group, 2000) and ropinirole
(Rascol et al., 2000; Whone et al., 2003). Similar con-
clusions were reported according to less methodologi-
cally convincing trials with bromocriptine (Parkinson
Diseases Research Group of the United Kingdom,
1993; Hely et al., 1994; Montastruc et al., 1994). Con-
flicting results have been reported with lisuride
(Rinne, 1989; Allain et al., 2000) and published con-
trolled data are lacking for other orally active agonists
79
(dihydroergocryptine, pergolide, piribedil), apomor-
phine not having been used and tested in this situation.
The ability of several dopamine agonists to reduce
or to delay time to motor complications versus levo-
dopa is therefore based on a good level of evidence.
However, the clinical importance and usefulness of
such results in the global management strategy of
patients with early Parkinsons disease remain a matter
of controversy (see section 33.4).
33.2.1.3.2. Randomized controlled trials comparing
agonist monotherapy versus another agonist
There is no indication that one agonist might be more
efficacious than another one in preventing or delaying
time to motor complications. The only published head-
to-head RCT comparing two agonists in this situation
(ropinirole versus bromocriptine) (Korczyn et al.,
1999) did not show any difference at 3 years in the
incidence of dyskinesias.
33.2.1.3.3. Randomized controlled trials with
agonist monotherapy versus other antiparkinsonian
medications
No data are available to assess whether the early use of
an agonist could be more efficacious in delaying time
to motor complications than other drugs like MAO-B
inhibitors, anticholinergics, amantadine or the early
combination of a COMT inhibitor with levodopa. Such
trials should be performed in the future.
33.2.2. Evidence to use dopamine agonists as
adjunct to levodopa in patients with moderate to
advanced Parkinsons disease
Adding a dopamine agonist in patients already on
levodopa therapy is a strategy that is generally consid-
ered and has been assessed for three main reasons:
(1) to improve the symptomatic control of parkinso-
nian motor signs (parkinsonism); (2) to improve motor
complications; and (3) to try to improve non-motor
signs.
33.2.2.1. Symptomatic control of parkinsonism as
adjunct to levodopa
The symptomatic efficacy of several agonists has been
assessed in RCTs in patients with moderate to severe
forms of Parkinsons disease already treated with levo-
dopa. As for early monotherapy, such RCTs are
usually limited to 36 months of follow-up and use
the UPDRS as an endpoint to assess the symptomatic
effect of the drug on the cardinal signs of parkinson-
ism, in the off and/or in the on condition if the
patients are fluctuating.
80
33.2.2.1.1. Randomized controlled trials comparing an
agonist versus placebo (Table 33.3)
Most agonists have shown to be effective in improving
the cardinal motor signs of parkinsonism in patients
already treated with levodopa. This is true for apomor-
phine (Dewey et al., 2001), bromocriptine (Guttman
et al., 1997; Mizuno et al., 2003), cabergoline (Hutton
et al., 1996), pergolide (Olanow et al., 1994), piribedil
(Ziegler et al., 2003) and pramipexole (Pinter et al.,
1999; Pogarell et al., 2002). Due to lower-quality
trials, the available evidence is less convincing but still
supportive for dihydroergocryptine (Martignoni et al.,
1991), lisuride (Allain et al., 2000) and ropinirole
(Lieberman et al., 1998). Some trials suggested that
agonists such as pramipexole and ropinirole might
have a special impact on tremor (Pogarell et al.,
2002; Schrag et al., 2002), but there is no clear ratio-
nale for such a specific effect and this can probably
apply to any efficacious symptomatic dopaminergic
medication (Navan et al., 2005).
33.2.2.1.2. Randomized controlled trials comparing an
agonist versus another agonist
There are a number of RCTs of variable methodologi-
cal quality that compare in cross-over or parallel
designs the symptomatic effect of two different dopa-
mine agonists on parkinsonism when adjunct to levo-
dopa. In all these trials, bromocriptine has been used
as the reference comparator. Such data cannot have a
O. RASCOL ET AL.
strong impact on clinical practice because most studies
raised methodological problems (insufficient power,
surrogate endpoints, arbitrary definition of dose
equivalences) and because they reported only mod-
est intergroup differences, posing the question of
their relevance in clinical practice. This applies to
trials with cabergoline (Inzelberg et al., 1996), lisur-
ide (LeWitt et al., 1982; Laihinen et al., 1992),
pergolide (LeWitt et al., 1983; Pezzoli et al., 1994;
Mizuno et al., 1995; Boas et al., 1996), pramipexole
(Mizuno et al., 2003) and ropinirole (Brunt et al., 2002).
33.2.2.1.3. Randomized controlled trials comparing an
agonist versus other antiparkinsonian medications
Bromocriptine (Tolcapone Study Group, 1999) and per-
golide (Koller et al., 2001) have been the sole agonists
compared to the COMT inhibitor tolcapone in open-
label RCTs. No significant difference was reported in
terms of efficacy on the parkinsonian cardinal signs,
although the safety profile was somehow different
between the drugs. No data are available for other
agonists and other antiparkinsonian drugs.
33.2.2.2. Symptomatic treatment of motor
complications
Motor complications are frequent and can be disabling
after several years of treatment with levodopa. They
involve fluctuations, erratic or unstable responses to
medications, also known as the wearing-off or onoff

Table 33.3
Level of evidence supporting the efficacy of the different dopamine agonists as an adjunct to levodopa in moderate to
advanced Parkinsons disease according to the conclusions of the evidence-based review on antiparkinsonian
interventions (Goetz et al., 2002; Rascol et al., 2002)

Symptomatic control Control of motor Non-motor

Agonists of parkinsonism fluctuations symptoms

Apomorphine* Efficacious Efficacious Insufficient

Bromocriptine Efficacious Likely Insufficient
Cabergoline Efficacious Likely Insufficient
Dihydroergocryptine Insufficient Insufficient Insufficient
Lisuride Likely Insufficient Insufficient
Pergolide{ Efficacious Efficacious Insufficient
Piribedil Efficacious Insufficient Insufficient
Pramipexole Efficacious Efficacious Insufficient
Ropinirole Insufficient Efficacious Insufficient

*Apomorphine is used as subcutaneous route.

{
Pergolide cannot be recommended as a first-line treatment for Parkinsons disease because of the risk of valvular heart disorder.
Efficacious, positive effect of the agonists on studied outcomes in at least one high-quality randomized controlled trial (RCT) and no conflict-
ing data from other RCT(s); likely, efficacy likely, i.e. evidence suggests, but is not sufficient to show, that the agonist has a positive effect on
studied outcomes, based on any RCT and no conflicting data from other RCTs; insufficient, insufficient evidence, i.e. there are no data or avail-
able data and do not provide enough evidence either for or against the use of the agonist.
 DOPAMINE AGONISTS
phenomena, and dyskinesias or involuntary move-
ments. Completing dopamine stimulation with drugs
like dopamine agonists is expected to be potentially
useful for such symptoms. RCTs have thus been
implemented to assess the effects of various agonists
on motor complications. Such trials were usually
short-term (36-month) studies using home diaries as
an endpoint (Hausser et al., 2000). Because agonists
have differing effects on fluctuations and dyskinesias,
these behaviors are considered separately.
33.2.2.2.1. Motor fluctuations
There are several good-quality RCTs to support the
use of a number of dopamine agonists to reduce the
duration of off episodes (Table 33.3). This is true for
pergolide (Olanow et al., 1994; Clarke and Speller,
2000a), pramipexole (Guttman et al., 1997; Clarke
et al., 2000a; Mizuno et al., 2003), ropinirole (Rascol
et al., 1996; Lieberman et al., 1998; Clarke and Deane,
2001a) and apomorphine (Ostergaard et al., 1995; Dewey
et al., 2001). For safety reasons (see section 33.3), it is
not recommended to use pergolide as a first-line agonist.
Less convincing RCTs or less consistent results have
been reported with bromocriptine (Hoehn and Elton,
1985; Toyokura et al., 1985; Guttman et al., 1997) and
cabergoline (Hutton et al., 1996). There are only
open-label or anecdotal data to suggest that other ago-
nists like dihydroergocriptine, lisuride or piribedil can
also improve motor fluctuations.
Comparative trials, when available, did not show
major differences between bromocriptine and other
agonists such as cabergoline (Inzelberg et al., 1996),
lisuride (Laihinen et al., 1992), pergolide (Mizuno et al.,
1995; Clarke and Speller, 2000b) ropinirole (Clarke and
Deane, 2001b; Brunt et al., 2002) and pramipexole
(Clarke et al., 2000b; Mizuno et al., 2003). The same
was true when comparing bromocriptine (Tolcapone
Study Group, 1999) and pergolide (Koller et al., 2001)
with the COMT inhibitor tolcapone. No other compari-
sons have been published.
33.2.2.2.2. Dyskinesias
When levodopa-treated patients with advanced Parkin-
sons disease receive an agonist to reduce off episodes,
this is usually at the cost of some worsening of dyskine-
sia. This has been quite constantly observed in any RCT
assessing any agonist in this situation (see previous
paragraph for references). In clinical practice, the daily
dose of levodopa is then partly reduced when the
agonist is adjunct in order to minimize this problem.
On longer follow-up, in line with the CDS hypoth-
esis, there are theoretical reasons to expect that high
doses of dopamine agonists might permit the reduction
81
of the duration and severity of levodopa-induced dys-
kinesias, since agonists could deliver a more stable
stimulation than levodopa and therefore reverse the
underlying mechanisms causing dyskinesias. There
are only few open-label and generally uncontrolled
reports in small cohorts of patients to support this
practice. The most convincing data have been
published with continuous subcutaneous infusions of
apomorphine (Colzi et al., 1998; Manson et al., 2002;
Katzenschlager et al., 2005). Some positive anecdotal
studies have also been presented with oral administra-
tion of pergolide (Facca and Sanchez-Ralos, 1996) and
ropinirole (Cristina et al., 2003).
33.2.2.3. Symptomatic control of non-motor
problems
Although Parkinsons disease is often considered a pro-
totypic movement disorder, most patients have addi-
tional non-motor symptoms. These include autonomic
dysfunction, depression, cognitive decline, sleep pro-
blems, sensory complaints and pain. Available trials
on non-motor features of Parkinsons disease, when
available, usually have major methodological limita-
tions. As a result, the evidence is weak in most
instances and does not allow the use of an agonist to
be supported or recommended in such indications.
In RCTs conducted in non-parkinsonian subjects
with major or bipolar depression, pramipexole was
superior to placebo (Corrigan et al., 2000; Zarate
et al., 2004), but convincing data are missing in Parkin-
sons disease patients. The only available evidence in
Parkinsons disease is weak, limited to uncontrolled or
low-quality RCT trials with agonists like pergolide, pra-
mipexole and ropinirole (Izumi et al., 2000; Perugi
et al., 2001; Lattanzi et al., 2002; Rektorova et al.,
2003). This does not allow any firm conclusions to be
drawn.
The same is true for cognition, although it is com-
mon empirical knowledge that any agonist can aggra-
vate cognitive and behavioral dysfunction in patients
with Parkinsons disease dementia or Lewy body dis-
ease. Agonists are therefore not recommended or should
even be withdrawn in such conditions. There is no
strong evidence that symptoms like frozen gait, balance
problems, anxiety, sleep disturbances or pain are
responsive to the effects of dopamine agonists. It is con-
ceivable that such symptoms, if partly dopa-responsive
and occurring or worsening during off episodes, might
be improved by such drugs as by any other dopaminer-
gic medication. No convincing undisputable clinical
data are available however. Conversely, dysautonomic
parkinsonian symptoms, like orthostatic hypotension,
are often aggravated by dopamine agonist (as by any
82 O. RASCOL ET AL.
dopaminergic medication), probably through dopami-
nergic sympatholytic mechanisms.
33.3. Safety issues on dopamine agonists
Adverse drug reactions are defined as any appreciably
harmful or unpleasant reaction resulting from an inter-
vention related to the use of a medicinal product which
predicts hazard from future administration and war-
rants prevention or specific treatment, or alteration of
the dosage regime, or withdrawal of the product
(Edwards and Aronson, 2000). They can be classified
as type A and type B reactions (Rawlins and Thomson,
1977). Type A reactions are generally expected and
predictable, since they are frequently related to the
known pharmacological properties of the drug. Their
prevalence is relatively high. They are usually non-
serious, non-lethal, dose-dependent and can be managed
with dose adjustment. Conversely, type B reactions are
unexpected, unpredictable, rare, often serious reactions
and most of the time they lead to drug withdrawal.
33.3.1. Dopamine agonist type A adverse reactions
Such adverse reactions are usually classified as periph-
eral (gastrointestinal reactions such as nausea and
vomiting, cardiovascular reactions such as orthostatic
hypotension and leg edema) or central ones (psychia-
tric reactions and sedative reactions). These type A
reactions are shared by other active dopamine-mimetic
medications and are generally believed to be the con-
sequence of the stimulation of dopamine receptors
out of the basal ganglia. There is no convincing evi-
dence that any agonist is associated with a lower risk
than another one for such type A reactions and this is
true for peripheral as well as central effects.
33.3.1.1. Peripheral type A adverse reactions
Gastrointestinal and cardiovascular adverse reactions
are common at the onset of therapy with any dopamine
agonist and usually tolerate out over time. They are
explained by the agonistic effect of the drugs on dopa-
mine receptors in the gut and in the area postrema
(gastrointestinal effects) and at the presynaptic level
of the orthosympathetic system (orthostatic hypoten-
sion). They can be managed by slow titration. Anti-
emetics like domperidone, a dopamine-blocker agent
that does not cross the bloodbrain barrier, help to
treat nausea in countries where this drug is available.
In large levodopa-controlled double-blind RCTs, gas-
trointestinal and cardiovascular adverse drug reactions
are not necessarily reported to be more frequent on
agonists than on levodopa (Rascol et al., 2000),
although it is frequently empirically believed that this
is the case in clinical practice.
Leg edema is known to be associated with both
ergot and non-ergot dopamine agonists. Reported inci-
dences vary widely and this reaction is more frequent
on agonists than on levodopa. For example, the inci-
dence of leg edema reported in levodopa-controlled
trials was 14% on ropinirole versus 6% on levodopa
(Rascol et al., 2000), 42% on pramipexole versus
15% on levodopa (Holloway et al., 2004) and 16%
on cabergoline versus 3% on levodopa (Bracco et al.,
2004). The mechanism of this side-effect is unknown.
This adverse drug reaction is sometimes reported as
dose-dependent but can also be idiosyncratic. It is
reversible with discontinuation of the agonist and the
use of a diuretic therapy should be discouraged because
it is not efficacious and can induce or aggravate other
problems like orthostatic hypotension.
Subcutaneous nodules at the injection site of apo-
morphine are another type A adverse reaction. This
adverse reaction seems unrelated to the dopaminergic
effects of the drug but rather to its intrinsic physical
properties, since problems of local toxicity have been
reported at any site of administration (subcutaneous,
sublingual, intranasal). Such subcutaneous nodules
are frequent, sometimes painful and may become
infected, especially when the drug is delivered by
subcutaneous continuous pump. Changing the site of
injection every day and careful local hygiene reduce
the incidence and severity of such a reaction (Poewe
et al., 1993; Bowron, 2004).
33.3.1.2. Central type A adverse reactions
Psychiatric symptoms are among the most disabling
dopamine agonist-related adverse drug reactions
(Factor et al., 1995). This is true for any efficacious
dopaminergic medications. The prevalence of these
symptoms on agonists varies according to the reports
and usually ranges between 5 and 20%. In most
levodopa-controlled double-blind trials, psychiatric
adverse reactions are reported to be more common
on agonists than on levodopa (Rascol et al., 2000;
Parkinson Study Group, 2000) and this is also empiri-
cally observed in clinical practice. Such psychotic
symptoms can present as delusions, usually paranoid,
or hallucinations, predominantly visual, though audi-
tory component is common. Abnormal behaviors such
as hypersexuality, pathological gambling and other
related syndromes have also been reported. Such psy-
chiatric reactions generally develop after a period of
treatment and are dose-related. Predisposing factors
such as age, individual psychopathological back-
ground, cognitive impairment and polytherapy are
 DOPAMINE AGONISTS
sometimes reported. These adverse reactions are a fre-
quent reason for withdrawing an agonist after some
years of therapy. The development of such psychiatric
reactions might indeed represent an early indicator of
cognitive decline in such a patient, although hallucina-
tions and delusion can occur in cognitively normal
subjects. The usual management of such psychiatric
adverse reactions is to reduce the dose or even stop the
agonist. It may take weeks before the effect clears.
If downtitration or withdrawal of the agonist leads to an
unacceptable worsening of motor function, the atypical
neuroleptic clozapine proved to improve hallucinations
without worsening parkinsonism in two short-term pla-
cebo-controlled RCTs (French Clozapine Parkinson
Study Group, 1999; Parkinson Study Group, 1999).
However, due to safety hematological problems, cloza-
pine is not easy to use and other atypical neuroleptics,
like quetiapine, for example, are sometimes empirically
proposed, although convincing RCTs are not available
to provide a good level of evidence to support this prac-
tice (Matheson and Lamb, 2000).
Abnormal daytime somnolence was not listed
among common type A adverse reactions of antiparkin-
sonian medications like dopamine agonists until the
publication in 1999 of cases of sleep attacks at the
wheel in patients with Parkinsons disease treated with
ropinirole or pramipexole (Frucht et al., 1999). It was
thereafter realized that such problems are common with
any dopamine agonist, including ergot and non-ergot
ones. This is based on postmarketing surveillance case
reports with apomorphine (Homann et al., 2000),
bromocriptine (Ferreira et al., 2000), cabergoline
(Ebersbach et al., 2000), lisuride (Ferreira et al.,
2000), pergolide (Ferreira et al., 2000; Schapira,
2000), piribedil (Ferreira et al., 2000; Tan, 2003),
pramipexole (Frucht et al., 1999; Ryan et al., 2000),
ropinirole (Frucht et al., 1999; Paladini, 2000) and
other antiparkinsonian medications than agonists, like
entacapone (Ebersbach et al., 2000) and levodopa
(Ferreira et al., 2001). Pharmacoepidemiological
surveys confirmed that all agonists share the risk of
daytime somnolence (Hobson et al., 2002; Paus
et al., 2003; Ferreira et al., 2006). In levodopa-con-
trolled double-blind RCTs, the agonists usually
induce greater somnolence than levodopa (Etminan
et al., 2001). The prevalence of abnormal daytime
somnolence varies greatly according to the studies
(6% according to Paus et al., 2003; 16%: Tandberg
et al., 1999; 18%: Razmy et al., 2004; 27%: Ferreira
et al., 2006; 30%: Montastruc et al., 2001b; 32%:
Manni et al., 2004; 34%: Schlesinger and Ravin,
2003; 43%: Korner et al., 2004; 76%: Brodsky
et al., 2003). This is probably mainly due to different
definitions (sleep attacks, sudden onset of sleep, and Suri, 2000). These adverse reactions are usually
83
unintended sleep episodes, irresistible sleep
episodes, abnormal daytime sleepiness, excessive
daytime sleepiness), different populations (non-
demented parkinsonians, parkinsonians on agonists
only, driving parkinsonians, normal population) and
different methods of assessment (questionnaires,
scales like the Epworth scale, electrophysiological
techniques like the Multiple Sleep Latency Test)
according to the studies. Initially, it has been difficult
to demonstrate the exact responsibility of the agonists
in causing such symptoms because multiple factors
can induce daytime somnolence in patients with Par-
kinsons disease. These factors are mainly related to
the disease itself, comorbidities and comedications.
In placebo-controlled RCTs conducted in healthy
volunteers, an agonist like ropinirole induced somnolence
(Ferreira et al., 2002). This was also true for levodopa
(Andreu et al., 1999). These experiments strongly
document the link between the drugs and the sedative
symptoms, regardless of the disease itself. Risk fac-
tors are poorly known and may be related to the
patient (age, gender, genetic susceptibility), the dis-
ease (severity, duration, associated symptoms such as
dysautonomia, dementia, depression) or the drug
(dose, duration of exposure, comedications). It must
now be recognized that somnolence is a frequent
dopaminergic type A adverse reaction, shared by
most, if not all, dopaminergic medications (Homann
et al., 2002), although dopamine agonists appear to
be at greater risk than levodopa (Etminan et al.,
2001). Patients should be informed of this potential
effect and be advised not to drive if it is present.
The practical management of agonist-induced day-
time inappropriate sleepiness is poorly known and
remains empirical. In some instances, dose reduction
is efficacious. Switching from one agonist to another
can be proposed, but the same reaction can occur
with the other agonist. There are no convincing pla-
cebo-controlled RCTs on which to base the prescrip-
tion of specific therapies, such as modafinil for
example (Montastruc and Rascol, 2001).
33.3.2. Dopamine agonist type B adverse reactions
Examples of rare but potentially severe type B reac-
tions on dopamine agonists are numerous.
Fibrosis has been detected in postmarketing surveil-
lance studies with all ergot derivatives, including bromo-
criptine, lisuride, cabergoline and pergolide. Classically,
such fibrotic reactions have been reported as pleuropul-
monary, pericardiac and/or retroperitoneal syndromes
(Todman et al., 1990; Bhatt et al., 1991; Ling et al.,
1999; Shaunak et al., 1999; Ben-Noun, 2000; Mondal
84 O. RASCOL ET AL.
considered as rare events, although their exact preva-
lence is unknown. Their mechanism is possibly related
to the dose and duration of exposure to the ergot
compounds. Erythrocyte sedimentation and protein C-
reactive inflammatory markers are usually increased
and may be helpful for an early diagnosis. The risk of
developing such a fibrosis on non-ergot agonists is much
lower, if it exists. These reactions are sometimes
life-threatening, although they can be at least partially
reversible after withdrawal of the drug. In general,
when a patient develops this kind of adverse reaction
on an ergot agonist, the strategy is to switch to a
non-ergot one.
Recently, several cases of another type of fibrotic
adverse reaction, severe multivalvular heart disease,
have been reported on pergolide and other ergot deri-
vative agonists, namely bromocriptine and cabergoline
(Vergeret et al., 1984; Agarwal et al., 2004; Horvath
et al., 2004). For the moment, the risk is better docu-
mented with pergolide (Van Camp et al., 2004). For
this reason, this drug is now generally only used as a
second-line alternative option, when other agonists,
especially the non-ergot ones, have not provided a
satisfying response. Operational definitions (clinical
syndrome versus echocardiographic detection), sever-
ity grading, prevalence, mechanism of action (related
for some authors to 5-HT2B effects), management
and reversibility after drug withdrawal of such valvu-
lar heart reactions remain a matter of debate and it is
too early at this stage to conclude definitely on their
true impact on the benefit/risk ratio of the ergot
agonists (Rascol et al., 2004a, b).
Another example of type B adverse reaction is
Coombs-positive hemolytic anemia that has been
reported with apomorphine, especially in patients
receiving continuous subcutaneous infusions. This is a
rare adverse reaction and the usefulness of blood count
monitoring for this purpose remains uncertain (Poewe
et al., 1993; Pinter et al., 1998). Other examples of type
B reactions due to agonists are alopecia, which has been
reported with bromocriptine (Fabre et al., 1993), visual
cortical disturbances on bromocriptine (Lane and
Routledge, 1983), loss of vision color on pramipexole
(Muller et al., 2003) and hypersensitivity (allergic
reactions) to many agonists (Martindale, 2002). These
adverse reactions are rare, but their real prevalence
and mechanisms often remain unknown.
33.4. Dopamine agonists in clinical practice
and their place in the management of patients
with Parkinsons disease
Treatment of Parkinsons disease has become increas-
ingly complex, due to the growing number of medical
and surgical treatment options that can be offered to
patients. There are different ways to introduce and
combine antiparkinsonian medications, according to
various therapeutic strategies. Regardless of these dif-
ferences, the global usefulness of dopamine agonists is
well established and there is a good level of evidence
to document that this class of drugs, as a whole, pro-
vides substantial help in the management of patients
with Parkinsons disease. Nevertheless, the exact place
of the dopamine agonists, as a class, versus other
medications and the best choice among the different
agonists within this class (except subcutaneous
injections of apomorphine) often remains a matter
of empirical preferences that differ according to
individual opinions.
In de novo patients, the main question is to decide
if and when to start levodopa. Should levodopa be
used as soon as possible or as a second step, after an
initial dopamine agonist early therapy? For each
patient, the choice is based on a subtle combination
of subjective and objective factors, including concerns
related to the drug (efficacy, safety, practicality, cost),
the patient (symptoms, age, needs, expectations,
experience, comorbidity, socioeconomic level) and
his/her environment (variability of drugs availability
according to national markets, variability in econom-
ical and health care systems). There is thus not a single
and unequivocal algorithm applicable to all patients
worldwide (Clarke and Guttman, 2002; Ahlskog,
2003; Schwarz, 2003).
Starting a patient on one of the available orally
active dopamine agonists is now considered as a useful
strategy by a growing number of specialists, because
agonists are effective antiparkinsonian medications
and are associated with a lower risk of motor compli-
cations than levodopa. The benefit of this strategy
must be balanced however by the fact that: (1) the ben-
efit of the early use of an agonist on motor complica-
tions has been assessed only up to 5 years and
remains questionable on longer follow-up, especially
in terms of quality of life; (2) agonists have a smaller
symptomatic effect than levodopa on UPDRS scores
according to RCTs (but the difference is only marginal
and probably clinically not relevant when small doses
of levodopa are allowed as a supplement as soon as
the agonist monotherapy becomes insufficient);
(3) agonists are more expensive than levodopa; and
(4) there is a greater incidence of psychiatric adverse
reactions, somnolence and edema on agonists than on
levodopa. Patients must be informed of these risks,
especially somnolence for drivers. As older patients
(70 years of age and above) are less prone to develop
motor complications on levodopa and more sensitive
to cognitive and psychotic adverse reactions, the
 DOPAMINE AGONISTS
early use of levodopa rather than that of an agonist is
often preferred as first-line therapy in this population.
Conversely, as younger patients (< 70 years) are at
greater risk for motor complications, this is the popula-
tion where initial treatment with an agonist is
especially considered. In most patients, agonist mono-
therapy cannot control parkinsonian symptoms for
more than a few years, even when increasing the
dose over time, and must thereafter be complemen-
ted with levodopa. In this case, it is recommended
to continue agonist therapy and to supplement it with
the lowest possible dose of levodopa rather than to
switch to levodopa monotherapy in order to maintain
as much as possible the long-term benefit on motor
complications.
In more advanced levodopa-treated patients, the
usefulness of dopamine agonists is established to treat
onoff problems. Clinical empirical experience and
some comparative studies suggest that the adjunction
of an orally active dopamine agonist to levodopa
reduces the time spent off in a comparable way than
other pharmacological options such as COMT or
MAO-B inhibitors. On average, there is a 12-hour
reduction in time spent off, at the cost of some worsen-
ing of dyskinesias that can be managed by adjusting
concomitantly the dose of levodopa. Interestingly, the
efficacy of the three different types of adjunct medica-
tions to levodopa (agonists, MAO-B and COMT inhi-
bitors) does not seem to be mutually exclusive and
rather appears to be complementary. Therefore, many
patients with advanced Parkinsons disease will hap-
pen to receive a combination of these drugs after some
years of management. Starting with one of them first,
rather than with one of the others, remains a matter
of personal experience and preference. MAO-B inhibi-
tors have the advantage of practicality (no titration,
once-daily dose and only one dosage for all patients).
COMT inhibitors do not require titration either and
are used at a unique dosage. Conversely, dopamine
agonists must be titrated but their dosage can then be
tailored to individual need. Safety profiles are also dif-
ferent between the three therapeutic classes of comple-
mentary drugs to levodopa. A special place must be
allocated to apomorphine in the management of
advanced patients with Parkinsons disease (Poewe
and Wenning, 2000; Deleu et al., 2004). This is so
because of the effect size of apomorphine on parkinso-
nian symptoms. It is strong, similar to that of levo-
dopa, and this is unique for a dopamine agonist. The
group of Lees and coworkers first reported the benefi-
cial effects of apomorphine in patients with advanced
Parkinsons disease (Stibe et al., 1988). As already
mentioned, this drug can only be used via subcuta-
neous route. Intermittent penjet injections can thus be
85
proposed to treat off episodes (Factor, 2004). The clin-
ical effect of a single apomorphine injection usually
develops within 10 minutes and lasts 45 minutes on
average, because of the short elimination half-life of
the drug. The concomitant use of domperidone, where
available, reduces the risk of gastrointestinal and
hypotensive adverse reactions. Apomorphine penjet
injections are recommended in patients with severe
fluctuations resistant to other medical therapies, on
top of the regular oral treatment (including an oral
agonist). When the need for apomorphine injections
exceeds 810 injections per day, or when dyskinesias
are too difficult to manage, continuous subcutaneous
infusion with apomorphine pumps is then considered.
This requires a clinical team with sufficient expertise
in order to train the patient and the care-giver correctly
to a relatively complex procedure. A proportion of dif-
ficult patients who failed on oral medications will
profit from this treatment, with a reduction of time
spent off, a reduction in dyskinesia and a reduction
of the daily dose of oral therapies, including levodopa
(Hagell and Odin, 2001). In the centers where deep
brain (subthalamic stimulation) surgery is available,
these patients are nowadays frequently offered a surgi-
cal approach and apomorphine pumps are rather pro-
posed as a second-line alternative option, in cases of
surgical contraindication. However, the benefit/risk
and cost/effectiveness ratios of both techniques have
never been carefully compared in parallel and this
should be assessed objectively in the future.
Another important matter of interest for clinical
practice is to compare the advantages and disadvan-
tages of the different orally active agonists (Tan and
Jankovic, 2001). Four aspects can help in comparing
drugs: efficacy, safety, practicality and costs. Overall,
excluding apomorphine, all orally active dopamine
agonists share the same efficacy profile (global class
effect) (Bonuccelli, 2003; Inzelberg et al., 2003).
However, the level of evidence differs from one drug
to the other, because the effect of some agonists has
been poorly or never assessed in several indications
(Tables 33.2 and 33.3). The best level of evidence is
clearly offered by the two most recently marketed ago-
nists, pramipexole and ropinirole. There is however lit-
tle evidence that an older agonist, like bromocriptine,
is less useful than the newer ones. The few trials iden-
tified with older medications were conducted in times
when technical solutions to plan such trials had not yet
been developed. This historical factor explains why
such trials are less convincing. Unfortunately, there is
no present interest in studying these old drugs again,
using modern designs, since their patents have expired
and these molecules thus do not offer any more suffi-
cient economical retrieval. As pointed out above, the
86 O. RASCOL ET AL.
evidence to document a substantial superiority of the
new agonists over bromocriptine turns out to be rather
weak and poorly convincing. In several countries, bro-
mocriptine is much cheaper than the newer agonists,
especially now that generics are available, and this
deserves to be considered. Safety is another important
matter. Overall, all agonists expose the patients to the
same risk of peripheral and central type A adverse
reactions. There is no evidence that one of them is
safer than another one on these aspects. Conversely,
fibrotic type B reactions appear to be more frequent
on ergot than non-ergot agonists and this is why pergo-
lide, for example, is no longer considered as a first-line
choice when starting a treatment with a dopamine ago-
nist. From a practicality perspective, all orally active
agonists are usually administered t.i.d. except cabergo-
line, which is administrated once daily. All must be
titrated over weeks up to the minimal dose that is suf-
ficient to control symptoms. The impracticality of apo-
morphine subcutaneous injections precludes the use of
this drug in patients with early Parkinsons disease and
limits its indications to patients with severe levodopa-
induced motor complications.
Switching from an agonist to another one for effi-
cacy or safety reasons is sometimes considered in clin-
ical practice, although global efficacy and safety
profiles (except fibrosis) are similar among the drugs.
Most of the available data is based on open-label
non-randomized trials with an overnight switch from
bromocriptine to the other agonist. An empirical
conversion chart of dose equivalence is sometimes
proposed with 10 mg bromocriptine 1 mg pergolide
1 mg pramipexole 2 mg cabergoline 5 mg ropi-
nirole (Reichmann et al., 2003; Grosset et al., 2004;
Stewart et al., 2004). Using such equivalent daily
doses, some patients appear to enjoy or not switch-
ing from bromocriptine to another agonist. This might
be related to the placebo or nocebo effect, but this
strategy is sometimes interesting in the practical man-
agement of a given patient. Combining two dopamine
agonists is another issue that is sometimes considered
in clinical practice. There is no real convincing phar-
macological rationale to combine in the same subject
two different orally active dopamine agonists, which
are supposed to act on the same D2-receptors. How-
ever, some movement disorder specialists believe that
such a combination regimen (for example, an agonist
with a long elimination half-life, like cabergoline a
non-ergot agonist with a shorter elimination half-life,
like ropinirole or pramipexole) is useful in some
patients. Such a practice warrants more studies and
a more objective evaluation before any conclusions
can be drawn. It is common pharmacological observa-
tion that combining two compounds belonging to the
same family frequently increases the risk of adverse
reactions.
33.5. Conclusions
In summary, dopamine agonists are useful medications
for the management of patients with Parkinsons dis-
ease in the early stages as well as in more advanced
stages of the disorder. Although their symptomatic
effect is well established on the cardinal signs of par-
kinsonism and on motor fluctuations, their clinical
impact on disease progression and on non-motor signs
such as depression remains to be documented. All
orally active dopamine agonists have globally quite a
comparable benefit/risk profile, although: (1) cabergo-
line can be used once daily whereas others are usually
prescribed t.i.d.; (2) apomorhine is used subcuta-
neously in patients with severe refractory motor fluc-
tuation; and (3) ergot compounds are at greater risk
than the non-ergot compounds for rare but potentially
severe fibrotic complications. Future developments
for dopamine agonists in the treatment of Parkinsons
disease might come from new compounds having
novel pharmacokinetic profiles, such as the transder-
mal patch of rotigotine (Rascol, 2005) and the slow-
release formulations of already marketed agonists like
ropinirole, or from new agonists with novel pharmaco-
dynamic profiles (more selective on dopamine D1-like
or D2-like receptor subtypes) and partial agonists such
as SLV 308 (Wolf, 2003). In the next few years,
the clinical use of dopamine agonists will extend to
novel indications in disorders with greater prevalence
than Parkinsons disease, such as the restless-legs
syndrome, for example.
References
Adler CH, Sethi KD, Hauser RA et al. (1997). for the Ropi-
nirole Study Group. Ropinirole for the treatment of early
Parkinsons disease. Neurology 49: 393399.
Agarwal P, Fahn S, Frucht SJ (2004). The diagnosis and
management of pergolide-induced fibrosis. Mov Disord
19: 699704.
Ahlskog JE (2003). Parkinsons disease: is the initial treat-
ment established? Curr Neurol Neurosci Rep 3: 289295.
Albanese A, Colosimo C (2003). Dihydroergocriptine in Par-
kinsons disease: clinical efficacy and comparison with other
dopamine agonists. Acta Neurol Scand 107: 349355.
Allain H, Destee A, Petit H et al. (2000), and the French
Lisuride Study Group. Five-year follow-up of early lisur-
ide and levodopa combination therapy versus levodopa
monotherapy in de novo Parkinosns disease. Eur Neurol
44: 2230.
Andreu N, Chale JJ, Senard JM et al. (1999), L-dopa-induced
sedation: a double-blind cross-over controlled study versus
 DOPAMINE AGONISTS
triazolam and placebo in healthy volunteers. Clin Neuro-
pharmacol 22: 1523.
Arai N, Isaji M, Miyata H et al. (1995). Differential effects
of three dopamine receptor agonists in MPTP-treated
monkeys. J Neural Transm 10: 5562.
Barone P, Bravi D, Bermejo-Pareja F et al. (1999), and the
Pergolide Monotherapy Study Group. Pergolide monother-
apy in the treatment of early Parkinsons disease: a rando-
mized, controlled study. Neurology 53: 573579.
Bedard PJ, Di Paolo T, Falardeau P et al. (1986). Chronic
treatment with L-dopa but not bromocriptine induces dys-
kinesia in MPTP-parkinsonian monkeys. Correlation with
[3H]spiperone binding. Brain Res 379: 294299.
Bennett JP, Landrow ER, Dietrich S et al. (1994). Suppres-
sion of dyskinesias in advanced Parkinsons disease: mod-
erate daily clozapione doses provide long-term dyskinesia
reduction. Mov Disord 9: 404414.
Ben-Noun L (2000). Drug-induced respiratory disorders: inci-
dence, prevention and management. Drug Saf 23: 143164.
Bergamasco B, Frattola L, Muratorio A et al. (2000).
Alpha-dihydroergocryptine in the treatment of de novo
parkinsonian patients: results of a multicentre, rando-
mised, double-blind, placebo-controlled study. Acta
Neurol Scand 101: 372380.
Bhatt MH, Keenan SP, Fleetham JA et al. (1991). Pleuropul-
monary disease associated with dopamine agonist therapy.
Ann Neurol 30: 613616.
Biglan KM, Holloway RG (2002). A review of pramipexole
and its clinical utility in Parkinsons disease. Expert Opin
Pharmacother 3: 197210.
Birkmayer W, Hornykiewicz O (1970). Der L-3,4 dioxyphe-
nylalanin DOPA: effect bie der Parkinson akinese.
Wien Klin Wochenschr 74: 787788 [Engl transl Parkin-
sonism Rel Dis 1998; 4(2): 6162].
Blin O (2003). The pharmacokinetics of pergolide in Parkin-
sons disease. Curr Opin Neurol 16: S9S12.
Boas J, Worm-Petersen J, Dupont E et al. (1996). The levo-
dopa dose-sparing capacity of pergolide compared with
that of bromocriptine in an open-label, cross-over study.
Eur J Neurol 3: 4449.
Bonuccelli U (2003). Comparing dopamine agonists in
Parkinsons disease. Curr Opin Neurol 16: S13S19.
Bowron A (2004). Practical considerations in the use of
apomorphine injectable. Neurology 62: S32S36.
Bracco F, Battaglia A, Chouza C et al. (2004). PKD009
Study Group. The long-acting dopamine receptor agonist
cabergoline in early Parkinsons disease: final results of
a 5-year, double-blind, levodopa-controlled study. CNS
Drugs 18: 733746.
Brodsky MA, Godbold J, Roth T et al. (2003). Sleepiness in
Parkinsons disease: a controlled study. Mov Disord 18:
668672.
Brunt ER, Brooks DJ, Korczyn AD et al. (2002). on behalf of
the 043 Study Group. A six-month multicentre, double-
blind, bromocriptine-controlled study of the safety and
efficacy of ropinirole in the treatment of patients with Par-
kinsons disease not optimally controlled by L-dopa.
J Neural Transm 109: 489502.
87
Calne DB, Teychenne PF, Leigh PN et al. (1974). Treatment
of Parkinsons disease with bromocriptine. Lancet 2:
13551356.
Chase TN (1998). The significance of continuous dopami-
nergic stimulation in the treatment of Parkinsons disease.
Drug 55: S1S9.
Clarke CE, Deane KH (2001a). Ropinirole for levodopa-
induced complications in Parkinsons disease. Cochrane
Database Syst Rev 1 CD001516.
Clarke CE, Deane KH (2001b). Ropinirole versus bromo-
criptine for levodopa-induced complications Parkinsons
disease. Cochrane Database Syst Rev 1: CD001517.
Clarke CE, Guttman M (2002). Dopamine agonist early
therapy in Parkinsons disease. Lancet 360: 17671769.
Clarke CE, Speller JM (2000a). Pergolide for levodopa-
induced complications in Parkinsons disease. Cochrane
Database Syst Rev 2: CD000235.
Clarke CE, Speller JM (2000b). Pergolide versus bromocrip-
tine for levodopa-induced motor complications in Parkin-
sons disease. Cochrane Database Syst Rev 2: CD000236.
Clarke CE, Speller JM, Clarke JA (2000a). Pramipexole for
levodopa-induced complications in Parkinsons disease.
Cochrane Database Syst Rev 3: CD002261.
Clarke CE, Speller JM, Clarke JA (2000b). Pramipexole
versus bromocriptine for levodopa-induced complications
in Parkinsons disease. Cochrane Database Syst Rev 3:
CD002259.
Colzi A, Turner K, Lees AJ (1998). Continuous subcuta-
neous waking day apomorphine in the long term treatment
of levodopa induced interdose dyskinesia in Parkinsons
disease. J Neurol Neurosurg Psychiatry 64: 573576.
Corrigan MH, Denahan AQ, Wright CE et al. (2000). Com-
parison of pramipexole, fluoxetine, and placebo in patients
with major depression. Depress Anxiety 11: 5865.
Cristina S, Zangaglia R, Mancini F et al. (2003). High-dose
ropinirole in advanced Parkinsons disease with severe
dyskinesias. Clin Neuropharmacol 26: 146150.
Curran MP, Perry CM (2004). Cabergoline. A review of its
use in the treatment of Parkinsons disease. Drugs 64:
21252141.
Deleu D, Northway MG, Hanssens Y (2002). Clinical phar-
macokinetic and pharmacodynamic properties of drugs
used in the treatment of Parkinsons disease. Clin Pharma-
cokinet 41: 261309.
Deleu D, Hanssens Y, Northway MG (2004). Subcutaneous
apomorphine: an evidence-based review of its use in
Parkinsons disease. Drugs Aging 21: 687709.
Dewey RB, Hutton JT, LeWitt PA et al. (2001). A rando-
mised double-blind placebo-controlled trial of subcuta-
neously injected apomorphine for parkinsonian off-stat
events. Arch Neurol 58: 13851392.
Di Marco A, Appiah-Kubi LS, Chaudhuri KR (2002). Use of
the dopamine agonist cabergoline in the treatment of
movement disorders. Expert Opin Pharmacother 3:
14811487.
Domino EF, Ni L, Zang H et al. (1998). Effects of prami-
pexole on contraversive rotation and functional motor
88 O. RASCOL ET AL.
impairments in l-methyl-4-phenyl-1,2,3,6-tetrahydro-
pyridine-induced chronic hemiparkinsonian monkeys.
J Pharmacol Exp Ther 287: 983987.
Durif F, Debilly B, Galitzky M et al. (2004). Clozapine
improves dyskinesias in Parkinson disease: a double-blind,
placebo-controlled study. Neurology 62: 381388.
Ebersbach G, Norden J, Tracik F (2000). Sleep attacks in
Parkinsons disease: polysomnographic recordings. Mov
Disord 15 (Suppl 3): P504.
Eden RJ, Costall B, Domeney AM et al. (1991). Preclinical
pharmacology of ropinirole (SK-&-F-101468-A) a novel
dopamine-D2 agonist. Pharmacol Biochem Behav 38:
147154.
Edwards IR, Aronson JK (2000). Adverse drug reactions:
definitions, diagnosis, and management. Lancet 356:
12551259.
Etminan M, Samii A, Takkouche B et al. (2001). Increased
risk of somnolence with the new dopamine agonsits in
patients with Parkinsons disease: a meta-analysis of rando-
mised controlled trials. Drug Saf 24: 863888.
Fabre N, Montastruc JL, Rascol O (1993). Alopecia: an
adverse effect of bromocriptine. Clin Neuropharmacol
16: 266268.
Facca A, Sanchez-Ramos J (1996). High-dose pergolide
monotherapy in the treatment of severe levodopa-induced
dyskinesias. Mov Disord 11: 327329.
Factor SA (2004). Literature review: intermittent subcuta-
neous apomorphine therapy in Parkinsons disease. Neu-
rology 62: S12S17.
Factor SA, Molho ES, Podskalny GD et al. (1995). Parkin-
sons disease: drug-induced psychiatric states. Adv Neurol
65: 115138.
Fahn S, Elton R (1987), and the members of the UPDRS
Development Committee. Unified Parkoinsons disease rat-
ing scale. In: S Fahn, CD Marsden, DB Calne, M Goldstein
(Eds.), Vol. 2, Macmillan Publishing Co Inc, New-York,
pp. 293304.
Fariello RG (1998). Pharmacodynamic and pharmacokinetic
features of cabergoline. Rationale for use in Parkinsons
disease. Drugs 55: 1016.
Ferreira JJ, Galitzky M, Montastruc JL et al. (2000). Sleep
attacks and Parkinsons disease treatment. Lancet 355:
13331334.
Ferreira JJ, Thalamas C, Montastruc JL et al. (2001). Levodo-
pa monotherapy can induce sleep attacks in Parkinsons
disease patients. J Neurol 248: 426427.
Ferreira JJ, Galitzky M, Thalamas C et al. (2002). Effect of
ropinirole on sleep onset: a randomized, placebo-controlled
sutdy in healthy volunteers. Neurology 58: 460462.
Ferreira JJ, Desboeuf K, Galitzky M et al. (2006). Sleep disrup-
tion, daytime somnolence and sleep attacks in Parkinsons
disease: a clinical survey in Parkinsons disease patients and
age-matched healthy volunteers. Eur J Neurol 13: 209214.
French Clozapine Parkinson Study Group (1999). Clozapine
in drug-induced psychosis in Parkinsons disease. The
French Clozapine Parkinson Study Group. Lancet 353:
20412042.
Frucht S, Rogers JD, Greene PE et al. (1999). Falling asleep
at the wheel: motor vehicule mishaps in persons taking
pramipexole and ropinirole. Neurology 52: 19081910.
Goetz CG, Koller WC, Poewe W et al. (2002). Management
of Parkinsons disease: an evidence-based review. Mov
Disord 17: S1S166.
Goetz CG, Poewe W, Rascol O et al. (2005). Evidence-based
medical review update: pharmacological and surgical
treatments of Parkinsons disease: 2001 to 2004. Mov
Disord 20: 395411.
Gomez-Mancilla B, Bedard PJ (1992). Effect of chronic
treatment with ()-PHNO, a D2 agonist in MPTP-treated
monkeys. Exp Neurol 117: 185188.
Grondin R, Goulet M, Di Paolo T et al. (1996). Cabergoline
a long-acting dopamine D2-like receptor agonist, produces
a sustained antiparkinsonian effect with transient dyskine-
sias in parkinsonian drug-naive primates. Brain Res 735:
298306.
Grondin R, Bedard PJ, Britton DR et al. (1997). Potential
therapeutic use of the selective dopamine D1 receptor
agonist, A-86929: an acute study in parkinsonian levo-
dopa-primed monkeys. Neurology 49: 421426.
Grosset K, Needleman F, Macphee G et al. (2004). Switching
from ergot to nonergot dopamine agonists in Parkinsons
disease: a clinical series and five-drug dose conversion
table. Mov Disord 19: 13701374.
Guttman M (1997). and the International Pramipexole-
Bromocriptine Study Group. Double-blind comparison of
pramipexole and bromocriptine treatment with placebo in
advanced Parkinsons disease. Neurology 49: 10601065.
Hagell P, Odin P (2001). Apomorphine in the treatment of
Parkinsons disease. J Neurosci Nurs 33: 21343738.
Hall ED, Andrus PK, Oostveen JA et al. (1996). Neuroprotec-
tive effects of the dopamine D2/D3 agonist pramipexole
against postischemic or metamphetamine induced degen-
eration of nigrostriatal neurons. Brain Res 742: 8088.
Happe S, Trenkwalder C (2004). Role of dopamine receptor
agonists in the treatment of restless legs syndrome. CNS
Drugs 18: 2736.
Hausser RA, Friedlander J, Zesiewicz TA et al. (2000).
A home diary to assess functional status in patients with
Parkinsons disease with motor fluctuations and dyskine-
sia. Clin Neuropharmacol 23: 7581.
Hely MA, Morris JGL (1999). The Sydney multicentre study
of Parkinsons disease: progression and mortality at 10
years. J Neurol Neurosurg Psychiatry 67: 300307.
Hely MA, Morris JGL, Reid WGJ (1994). The Sydney multi-
centre study of Parkinsons disease: a randomized, prospec-
tive five year study comparing low dose bromocriptine
with low dose levodopa-carbidopa. J Neurol Neurosurg
Psychiatry 57: 903910.
Hening WA, Allen RP, Earley CJ et al. (2004). Restless Legs
Syndrome Task Force of the Standards of Practice Com-
mittee of the American Academy of Sci Medicine. An
update on the dopaminergic treatment of restless legs syn-
drome a periodic limb movement disorder. Sleep 27:
560583.
 DOPAMINE AGONISTS
Hobson DE, Lang AE, Martin WR et al. (2002). Excessive
daytime sleepniness and sudden-onset sleep in Parkinson
disease: a survey by the Canadian Movement Disorders
Group. JAMA 287: 455463.
Hoehn MM, Elton RL (1985). Low dosages of bromocriptine
added to levodopa in Parkinsons disease. Neurology 35:
199206.
Holloway RG, Shoulson I, Fahn S et al. (2004). Parkinson
Study Group. Pramipexole vs levodopa as initial treatment
for Parkinson disease: a 4-year randomized controlled
trial. Arch Neurol 61: 10441053.
Homann CN, Wenzel K, Suppan K et al. (2000). Sleep
attacks after acute administration of apomorphine. Mov
Disord 15 (Suppl 3): P585.
Homann CN, Wenzel K, Suppan K et al. (2002). Sleep
attacks in patients taking dopamine agonists: review.
BMJ 324: 14831487.
Horvath J, Fross RD, Kleiner-Fisman G et al. (2004). Severe
multivalvular heart disease: a new complication of the ergot
derivative dopamine agonists. Mov Disord 19: 656661.
Hutton JT, Koller WC, Ahlskog JE et al. (1996). Multicenter,
placebo-controlled trial of cabergoline taken once daily in
the treatment of Parkinsons disease. Neurology 46:
10621065.
Iida M, Miyazaki I, Tanaka KI et al. (1999). Dopamine D2
receptor-mediated antioxidant and neuroprotective effects
of ropinirole, a dopamine agonist. Brain Res 838: 5159.
Inzelberg R, Nisipeanu P, Rabey JM et al. (1996). Double-blind
comparison of cabergoline and bromocriptine in Parkinsons
disease patients with motor fluctuations. Neurology 47:
785788.
Inzelberg R, Schechtman E, Nisipeanu P (2003). Cabergoline,
pramipexole and ropinirole used as immunotherapy in
early Parkinsons disease. Drugs Aging 20: 847855.
Izumi T, Inoue T, Kitagawa N et al. (2000). Open pergolide
treatment of tricyclic and heterocyclic antidepressant-
resistant depression. J Affect Disord 61: 127132.
Jenner P (2005). A novel dopamine agonist for the transder-
mal treatment of Parkinsons disease. Neurology 65:
S3S5.
Jenner P, Olanow CW (1996). Oxidative stress and the patho-
genesis of Parkinsons disease. Neurology 47: S161S170.
Katzenschlager R, Hughes A, Evans A et al. (2005). Contin-
uous subcutaneous apomorphine therapy improves dyski-
nesias in Parkinsons disease: a prospective study using
single-dose challenges. Mov Disord 20: 151157.
Kaye CM, Nicholls B (2000). Clinical pharmacokinetics of
ropinirole. Clin Pharmacokinet 39: 243254.
Koller W, Lees A, Doder M et al. (2001). Tolcapone/Pergo-
lide Study Group. Randomized trial of tolcapone versus
pergolide as add-on to levodopa therapy in Parkinsons
disease patients with motor fluctuations. Mov Disord 16:
858866.
Korczyn AD, Brooks DJ, Brunt ER et al. (1998), on behalf of
the 053 Study Group. Ropinirole versus bromocriptine in
the treatment of early Parkinsons disease: 6-month
interim report of a 3-year study. Mov Disord 13: 4651.
89
Korczyn AD, Brunt ER, Larsen JP et al. (1999). A 3-year
randomized trial of ropinirole and bromocriptine in early
Parkinsons disease. The 053 Study Group. Neurology
53: 364370.
Korner Y, Meindorfner C, Moller JC et al. (2004). Predictors
of sudden onset of sleep in Parkinsons disease. Mov Dis-
ord 19: 129812305.
Laihinen A, Rinne UK, Suchy I (1992). Comparison of lisur-
ide and bromocriptine in the treatment of advanced Par-
kinsons disease. Acta Neurol Scand 86: 593595.
Lane RJ, Routledge PA (1983). Bromocriptine has been
reported to cause visual cortical disturbances. Drug-
induced neurological disorders. Drugs 26: 124147.
Lattanzi L, DellOsso L, Cassano P et al. (2002). Pramipexole
in treatment-resistant depression: a 16-week naturalistic
study. Bipolar Disord 4: 307314.
Le WD, Jankovic J (2001). Are dopamine receptor agonists
neuroprotective in Parkinsons disease? Drugs Aging 18:
389396.
Lees AJ, Katzenschlager R, Head J et al. (2001), on behalf of
the Parkinsons Disease Research Group on the United King-
dom. Ten-year follow-up of three different initial treatments in
de-novo PD. A randomized trial. Neurology 57: 16871694.
LeWitt PA (2004). Subcutaneously administered apomor-
phine: pharmacokinetics and metabolism. Neurology 62:
S8S11.
LeWitt PA, Gopinathan G, Ward CD et al. (1982). Lisuride
versus bromocriptine treatment in Parkinson disease: a
double-blind study. Neurology 32: 6972.
LeWitt PA, Ward CD, Larsen TA et al. (1983). Comparison
of pergolide and bromocriptine therapy in parkinsonism.
Neurology 33: 1091014.
Lieberman A, Olanow CW, Sethi K et al. (1998), and the
Ropinirole Study Group. A multicenter trial of ropinirole
adjunct treatment for Parkinsons disease. Neurology 51:
10571062.
Ling LH, Ahlskog JE, Munger TM et al. (1999). Constrictive
pericarditis and pleuropulmonary disease linked to ergot
dopamine agonist therapy (cabergoline) for Parkinsons
disease. Mayo Clin Proc 74: 371375.
Luquin RM, Laguna J, Obeso JA (1992). Selective D2 recep-
tor stimulation induces dyskinesia in parkinsonian mon-
keys. Ann Neurol 31: 551554.
Maj J, Rogoz Z, Skuza G et al. (1997). Antidepressant
effects of pramipexole, a novel dopamine receptor agonist.
J Neural Transm 104: 525533.
Manni R, Terzaghi M, Sartori I et al. (2004). Dopamine ago-
nists and sleepiness in PD: review of the literature and per-
sonal findings. Sleep Med 5: 189193.
Manson AJ, Turner K, Lees AJ (2002). Apomorphine mono-
therapy in the treatment of refractory motor complications
of Parkinsons disease: long-term follow-up study of 64
patients. Mov Disord 17: 12351241.
Marsden CD, Parkes JD, Quinn N (1987). Fluctuations of
disability in Parkinsons disease: pathophysiological
aspects. In: CD Marsden, S Fahn (Eds.), Movement Dis-
orders. Butterworth, London, pp. 96122.
90 O. RASCOL ET AL.
Martignoni E, Pacchetti C, Sibilla L et al. (1991). Dihy-
droergocryptine in the treatment of Parkinsons disease:
a six months double-blind clinical trial. Clin Neurophar-
macol 14: 7883.
Martindale (2002). Edited by Sean C. Sweetman. The Com-
plete Drug Reference 33rd edition, Pharmacological Press
London, Chicago, pp. 11601179.
Matheson AJ, Lamb HM (2000). Quetiapine: a review of its
clinical potential in the management of psychotis symp-
toms in Parkinsons disease. CNS Drugs 14: 157172.
Matheson AJ, Spencer CM (2000). Ropinirole. A review of
its use in the management of Parkinsons disease. Drugs
60:115137.
Mizuno Y, Kondo T, Narabayashi H (1995). Pergolide in the
treatment of Parkinsons disease. Neurology 45: S13S21.
Mizuno Y, Yanagisawa N, Kuno S et al. (2003). and the
Pramipexole Study Group. Randomized, double-blind
study of pramipexole with placebo and bromocriptine
in advanced Parkinsons disease. Mov Disord 18:
11491156.
Mondal BK, Suri S (2000). Pergolide-induced retroperitoneal
fibrosis. Int J Clin Pract 54: 403.
Montastruc JL, Rascol A (1984). Treatment of Parkinsons
disease with high doses of bromocriptine. Possible interac-
tion with josamycin. Presse Med 13: 22672268.
Montastruc JL, Rascol O (2001). Modafinil and pramipex-
ole-associated somnolence. Mov Disord 15: 783784.
Montastruc JL, Rascol O, Senard JM (1993). Current status
of dopamine agonists in Parkinsons disease management.
Drugs 46: 384393.
Montastruc JL, Rascol O, Senard JM et al. (1994). A rando-
mised controlled study comparing bromocriptine to which
levodopa was later added, with levodopa alone in previously
untreated patients with Parkinsons disease: a five year
follow-up. J Neurol Neurosurg Psychiatry 57: 10341038.
Montastruc JL, Desboeuf K, Lapeyre-Mestre M et al.
(2001a). Long-term mortality results on the randomized
controlled study comparing bromocriptine to which levo-
dopa was later added with levodopa alone in previously
untreated patients with Parkinsons disease. Mov Disord
16: 511514.
Montastruc JL, Brefel-Courbon C, Senard JM et al.
(2001b). Sleep attacks and antiparkinsonian drugs: a pilot
prospective pharmacoepidemiologic study. Clin Neuro-
pharmacol 24: 181183.
Mucke HAM (2003). Rotigotine Schwarz Pharma. Drugs 6:
894899.
Muller T, Przuntek H, Kuhlmann A (2003). Loss of color
vision during long-term treatment with pramipexole.
J Neurol 250: 101102.
Navan P, Findley LJ, Undy MB et al. (2005). A randomly
assigned double-blind cross-over study examining the
relative anti-parkinsonian tremor effects of pramipexole
and pergolide. Eur J Neurol 12: 18.
Neef C, van Laar T (1999). Pharmacokinetic-pharmacody-
namic relationship of apomorphine in patients with Par-
kinsons disease. Clin Pharmacokinet 37: 257271.
Nutt JG (1990). Levodopa-induced dyskinesia. Neurology
40: 340345.
Ogawa N, Miyazaki I, Tanaka K et al. (1999). Dopamine D2
receptor mediated antioxidant and neuroprotective effects
of ropinirole. Parkinsonism Relat Disord 5: S1S81.
Olanow CW (1990). Oxidation reactions in Parkinsons dis-
ease. Neurology 40: S32S39.
Olanow CW, Fahn S, Muenter M et al. (1994). A multicenter
double-blind placebo-controlled trial of pergolide as an
adjunct to Sinemet in Parkinsons disease. Mov Disord
9: 4047.
Olanow CW, Hauser RA, Gauger L et al. (1995). The effect
of deprenyl and levodopa on the progression of Parkin-
sons disease. Ann Neurol 38: 771777.
Olanow CW, Jenner P, Brooks D (1998). Dopamine agonists
and neuroprotection in Parkinsons disease. Ann Neurol
44: 167174.
Olanow CW, Schapira AHV, Rascol O (2000). Continuous
dopamine-receptor stimulation in early Parkinsons dis-
ease. Trends Neurosci 23: S117S126.
Olanow CW, Agid Y, Mizuno Y et al. (2004). Levodopa in
the treatment of Parkinsons disease: current controver-
sies. Mov Disord 19: 9971005.
Ostergaard L, Werdelin L, Odin P et al. (1995). Pen injected
apomorphine against off phenomena in late Parkinsons
disease: a double blind, placebo controlled study. J Neurol
Neurosurg Psychiatry 58: 681687.
Paladini D (2000). Sleep attacks in two Parkinsons disease
patients taking ropinirole. Mov Disord 15 (Suppl 3): P671.
Parkinson Study Group (1989). Effect of deprenyl on the
progression of disability in early Parkinsons disease.
N Engl J Med 321: 13641371.
Parkinson Study Group (1999). Low-dose clozapine for the
treatment of drug-induced psychosis in Parkinsons dis-
ease. N Engl J Med 340: 757763.
Parkinson Study Group (2000). Pramipexole versus levodopa
as initial treatment for Parkinsons disease: a randomized
controlled trial. JAMA 284: 19311938.
Parkinson Study Group (2002a). Dopamine transporter brain
imaging to assess the effects of pramipexole vs. levodopa
on Parkinsons disease progression. JAMA 287: 16531661.
Parkinson Study Group (2002b). A controlled trial of rasagi-
line in early Parkinson disease: the TEMPO study. Arch
Neurol 59: 19371943.
Parkinsons Disease Research Group in the United Kingdom
(1993). Comparisons of therapeutic effects of levodopa,
levodopa and selegiline, and bromocriptine in patients
with early, mild Parkinsons disease: three year interim
report. BMJ 307: 469472.
Paus S, Brecht HM, Koster J et al. (2003). Sleep atatcks,
daytime sleepiness, and dopamine agonists in Parkinsons
disease. Mov Disord 18: 659667.
Pearce RKB, Banerji T, Jenner P et al. (1998). De novo
administration of ropinirole and bromocriptine induces
less dyskinesia than L-dopa in the MPTP-treated marmo-
set. Mov Disord 13: 234241.
 DOPAMINE AGONISTS
Periti P, Mazzei T, Mini E et al. (1992). Pharmacokinetic
drug interactions of macrolides. Clin Pharmacokinet 23:
106131.
Perugi G, Toni C, Ruffolo G et al. (2001). Adjunctive dopa-
mine agonists in treatment-resistant bipolar II depression:
an open case series. Pharmacopsychiatry 34: 137141.
Pezzoli G, Martignoni E, Pachetti C et al. (1994). Pergolide
compared with bromocriptine in Parkinsons disease: a
multicenter, cross-over, controlled study. Mov Disord 9:
431436.
Pfeiffer RE (1996). Antiparkinsonian agents: drug interac-
tions of clinical significance. Drug Saf 14: 343354.
Piercey MF (1998). Pharmacology of pramipexole, a dopa-
mine D3-preferring agonist useful in treating Parkinsons
disease. Clin Neuropharmacol 21: 141151.
Piercey MF, Hoffmann WE, Smith HW et al. (1996). Inhibi-
tion of dopamine neuron firing by pramipexole, a D3-pre-
fering dopamine agonist: comparison to other dopamine
agonists. Eur J Pharmacol 312: 3544.
Pinter MM, Helscher RJ, Mundsperger N et al. (1998). Transi-
ent increase of pancreatic enzymes evoked by apomorphine
in Parkinsons disease. J Neural Transm 105: 12371244.
Pinter MM, Pogarell O, Oertel WH (1999). Efficacy, safety
and tolerance of the non-ergoline dopamine agonist prami-
pexole in the treatment of advanced Parkinsons disease:
double-blind, placebo-controlled, randomized, multicenter
study. J Neurol Neurosurg Psychiatry 66: 436441.
Poewe W, Lussi F (2005). Clinical studies with transdermal
rotigotine in early Parkinsons disease. Neurology 65:
S11S14.
Poewe W, Wenning GK (2000). Apomorphine: an underuti-
lized therapy for Parkinsons disease. Mov Disord 15:
789794.
Poewe WP, Kleedorfer B, Wagner M et al. (1993). Continu-
ous subcutaneous apomorphine infusions for fluctuating
Parkinsons disease. Long-term follow-up in 18 patients.
Adv Neurol 60: 656659.
Pogarell O, Gasser T, Van Hilten JJ et al. (2002). Pramipex-
ole in patients with Parkinsons disease and marked drug
resistant tremor: a randomized, double-blind, placebo-con-
trolled multicentre trial. J Neurol Neurosurg Psychiatry
72: 713720.
Przuntek H, Welzel D, Gerlach M et al. (1996). Early institu-
tion of bromocriptine in Parkinsons disease inhibits the
emergence of levodopa-associated motor side effects:
long-term results of the results of the PRADO study.
J Neural Transm 103: 699715.
Rascol O (1997). Ropinirole: clinical profile. In: CW
Olanow, JA Obeso (Eds.), Beyond the Decade of the
Brain: Dopamine Agonists in Early Parkinsons disease.
Wells Medical Ltd, Royal Tunbridge Wells, pp. 163176.
Rascol O (2005). Transdermal delivery of dopaminergic
agents. Neurology 65: S1S2.
Rascol O, Lees AJ, Senard JM et al. (1996). Ropinirole
in the treatment of levodopa-induced motor fluctuations
in patients with Parkinsons disease. Clin Neuropharmacol
19: 234245.
91
Rascol O, Brooks DJ, Brunt ER et al. (1998), on behalf of
the 056 Study Group. Ropinirole in the treatment of early
Parkinsons disease: a 6-month interim report of a 5-year
levodopa-controlled study. Mov Disord 13: 3945.
Rascol O, Brooks DJ, Korczyn AD et al. (2000), for the 056
Study Group. A five-year study of the incidence of dyski-
nesia in patients with early Parkinsons disease who were
treated with ropinirole or levodopa. N Engl J Med 342:
14841491.
Rascol O, Nutt JG, Blin O et al. (2001). Induction by dopa-
mine D1 receptor agonist ABT-431 of dyskinesia similar
to levodopa in patients with Parkinsons disease. Arch
Neurol 58: 249254.
Rascol O, Goetz C, Koller W et al. (2002). Treatment inter-
ventions for Parkinsons disease: an evidence based
assessment. Lancet 359: 15891598.
Rascol O, Payoux P, Ory F et al. (2003). Limitations of current
Parkinsons disease therapy. Ann Neurol 53 (Suppl 3),
S3S12, discussion S12S15.
Rascol O, Pathak A, Bagheri H et al. (2004a). New concerns
about old drugs: valvular heart disease on ergot derivative
dopamine agonists as an exemplary situation on pharma-
covigilance. Mov Disord 19: 611613.
Rascol O, Pathak A, Bagheri H et al. (2004b). Dopaminago-
nists and fibrotic valvular heart disease: further considera-
tions. Mov Disord 19: 15241525.
Rawlins MD, Thomson JW (1977). Pathogenesis of adverse
drug reactions. In: DM Daines, (Ed.), Text Book of
Adverse Drug Reactions. Oxford University Press, p. 44.
Razmy A, Lang AE, Shapiro CM (2004). Predictors of
impaired daytime sleep and wakefulness in patients with
Parkinson disease treated with older (ergot) vs newer
(nonergot) dopamine agonists. Arch Neurol 61: 97102.
Reichmann H, Herting B, Muller A et al. (2003). Switching
and combining dopamine agonists. J Neural Transm 110:
13931400.
Rektorova I, Rektor I, Bares M et al. (2003). Pramipexole
and pergolide in the treatment of depression in Parkinsons
disease: a national multicentre prospective randomized
study. Eur J Neurol 10: 399406.
Rinne U (1989). Lisuride a dopamine agonist in the treatment
of early Parkinsons disease. Neurology 39: 336339.
Rinne UK, Bracco F, Chouza C (1997), on behalf of the
PKD009 Collaborative Study Group. Carbergoline in the
treatment of early Parkinsons disease: results of the first
year of treatment in a double-blind comparison of caber-
goline and levodopa. Neurology 48: 363368.
Rinne UK, Bracco F, Chouza C et al. (1998), and the
PKDS009 Study Group. Early treatment of Parkinsons
disease with cabergoline delays the onset of motor compli-
cations. Drugs 55: 2330.
Riopelle RJ (1987). Bromocriptine and the clinical spectrum
of Parkinsons disease. Can J Neurol Sci 14: 455459.
Robertson HA (1992). Dopamine receptor interactions: some
implications for the treatment of Parkinsons disease.
Trends Neurosci 15: 201206.
92 O. RASCOL ET AL.
Rondot P, Ziegler M (1992). Activity and acceptability of
piribedil in Parkinsons disease: a multicentre study.
J Neurol 239 (Suppl 1): 2834.
Ryan M, Slevin JT, Wells A (2000). Non-ergot dopamine
agonist-induced sleep attacks. Pharmacotherapy 20:
724726.
Schapira AH (2000). Sleep attacks (sleep episodes) with
pergolide. Lancet 355: 13321333.
Schapira AH (2002). Neuroprotection and dopamine
agonists. Neurology 58: S9S18.
Schapira AH, Olanow CW (2003). Rationale for the use of
dopamine agonists as neuroprotective agents in Parkin-
sons disease. Ann Neurol 53: S149S159.
Schapira AHV, Olanow CW (2004). Neuroprotection in Par-
kinsons disease. Mysteries, Myths, and Misconceptions.
JAMA 291: 358364.
Schlesinger I, Ravin PD (2003). Dopamine agonist induce epi-
sode of irresistible daytime sleepiness. Eur Neurol 49: 3033.
Schrag A, Keens J, Warner J (2002). Ropinirole Study
Group. Ropinirole for the treatment of tremor in early Par-
kinsons disease. Eur J Neurol 9: 253257.
Schwarz J (2003). Rationale for dopamine agonist use as
immunotherapy in Parkinsons disease. Curr Opin Neurol
16: S27S33.
Sethy VH, Wu H, Oostveen JA et al. (1997). Neuroprotective
effects of the dopamine agonists pramipexole and bromo-
criptine in 3-acetylpyridine-treated rats. Brain Res 754:
181186.
Shannon KM, Bennett JP, Friedman JH (1997). for the Pra-
mipexole Study Group. Efficacy of pramipexole, a novel
dopamine agonist, as monotherapy in mild to moderate
Parkinsons disease. Neurology 49: 724728.
Shaunak S, Wilkins A, Pilling JB et al. (1999). Pericardial,
retroperitoneal, and pleural fibrosis induced by pergolide.
J Neurol Neurosurg Psychiatry 66: 7981.
Stewart D, Morgan E, Burn D et al. (2004). Dopamine ago-
nist switching in Parkinsons disease. Hosp Med 65:
215219.
Stibe CM, Lees AJ, Kempster PA et al. (1988). Subcutaneous
apomorphine in parkinsonian on-off oscillations. Lancet 1:
403406.
Tan EK (2003). Piribedil-induced sleep attacks in Parkin-
sons disease. Fundam Clin Pharmacol 17: 117119.
Tan EK, Jankovic J (2001). Choosing dopamine agonists in
Parkinsons disease. Clin Neuropharmacol 24: 247253.
Tandberg E, Larsen JP, Karlsen K (1999). Excessive daytime
sleepiness and sleep benefit in Parkinsons disease: a com-
munity-based study. Mov Disord 14: 922927.
Tintner R, Jankovic J (2003). Dopamine agonists in Parkin-
sons disease. Expert Opin Investig Drugs 12: 18031820.
Todman DH, Oliver WA, Edwards RL (1990). Pleuropul-
monary fibrosis due to bromocriptine treatment for Parki-
nosns disease. Clin Exp Neurol 27: 7982.
Tolcapone Study Group (1999). Efficacy and tolerability of
tolcapone compared with bromocriptine in levodopa-trea-
ted parkinsonian patients. Mov Disord 14: 3844.
Toyokura Y, Mizuno Y, Kase M et al. (1985). Effects of bro-
mocriptine on parkinsonism. A nation-wide collaborative
double-blind study. Acta Neurol Scand 72: 157170.
Tulloch IF (1997). Pharmacologic profile of ropinirole: a
nonergoline dopamine agonist. Neurology 49: S58S62.
Uitti RJ, Ahlskog JE (1996). Comparative review of dopa-
mine receptor agonist in Parkinsons disease. CNS Drugs
5: 369388.
Van Camp G, Flamez A, Cosyns B et al. (2004). Treatment
of Parkinsons disease with pergolide and relation to
restrictive valvular heart disease. Lancet 363: 11791183.
Vergeret J, Barat M, Taytard A et al. (1984). Pleuropulmon-
ary fibrosis and bromocriptine. Sem Hop 60: 741744.
Whone AL, Watts RL, Stoessl AJ et al. (2003). REAL-PET
Study Group. Slower progression of Parkinsons disease
with ropinirole versus levodopa: the REAL-PET study.
Ann Neurol 54: 93101.
Wise RA, Rompre PP (1989). Brain dopamine and reward.
Annu Rev Psychol 40: 191225.
Wolf WA (2003). SLV-308. Solvay. Curr Opin Investig
Drugs 4: 878882.
Yoshikawa T, Minamiyama Y, Naito Y et al. (1994). Antiox-
idant properties of bromocriptine, a dopamine agonist.
J Neurochem 62: 10341038.
Zarate CA, Payne JL, Singh J et al. (2004). Pramipexole for
bipolar II depression: a placebo-controlled proof of con-
cept study. Biol Psychiatry 56: 5460.
Ziegler M, Castro-Caldas A, Del Signore S et al. (2003).
Efficacy of piribedil as early combination to levodopa
in patients with stable Parkinsons disease: a 6-month,
randomized placebo-controlled study. Mov Disord 18:
418425.
Further Reading
Etminan M, Gill S, Samii A (2003). Comparison of the risk
of adverse events with pramipexole and ropinirole in
patients with Parkinsons disease: a meta-analysis. Drug
Saf 26: 439444.
Hunziker T, Bruppacher R, Kuenzi UP et al. (2002). Classifi-
cation of ADRs: a proposal for harmonization and differ-
entiation based on the experience of the Comprehensive
Hospital Drug Monitoring Bern/St. Gallen, 19741993.
Pharmacoepidemiol Drug Saf 11: 159163.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 34

Monoamine oxidase A and B inhibitors in Parkinsons disease

MOUSSA B. H. YOUDIM1* AND PETER F. RIEDERER2

1
Department of Pharmacology, Technion-Bruce Rappaport Faculty of Medicine, Eve Topf and NPF Neurodegenerative
Diseases Centers, Rappaport Family Research Institute, Haifa, Israel
2
Clinical Neurochemistry, Department of Psychiatry and Psychotherapy, National Parkinson Foundation (USA) Center of
Excellence Research Laboratories, University of Wurzburg, Wurzburg, Germany

34.1. Introduction indirectly acting sympathomimetic amines, present in

Monoamine oxidase (MAO), which catalyzes primary,
secondary and tertiary amines (Fig. 34.1), was discov-
ered in 1928 by Hare Bernhiem and later identified by
Balschko as one of the most important enzymes in
neurotransmitter metabolism (Youdim et al., 2005a,
2006). Its physiological roles and inhibitors have
played major roles in our understanding of the func-
tional roles of dopamine (DA), norepinephrine and ser-
otonin (5-HT) neurotransmission in the central nervous
system (CNS). One of the first psychotropic drugs to be
identified was iproniazid, the first MAO inhibitor to
be discovered by serendipity and introduced into clinic
as an antidepressant. Although this drug and other non-
selective MAO inhibitors demonstrated remarkable
antidepressant action in the late 1950s and 1960s
(Table 34.1), their usefulness as antidepressants was
seriously challenged in earlier clinical studies, mainly
because of limited dosage employed. In addition some
drugs, such as iproniazid, caused liver toxicity and
others, such as tranylcypromine, induced what became
known as the cheese reaction. These side-effects ser-
iously hampered the development and assessment of
other MAO inhibitors as antidepressants and anti-
parkinson drugs. Although the problem of hepatotoxi-
city, which was associated with hydrazine-derived
drugs, was resolved with the development of other
non-hydrazine MAO inhibitors, the cheese reaction
remained the major source of problems.
What became known as the cheese reaction is
associated with the presence of tyramine and other
food (cheeses and many diverse foodstuffs) and drinks
(beer and wine), especially those that are fermented.
Most such amines are metabolized by MAO. Tyramine,
a substrate of MAO, if present in ingested food cannot
be metabolized as a consequence of MAO inhibition.
It can gain access to the circulatory system and induce
a significant release of norepinephrine from peripheral
adrenergic neurons (Fig. 34.2). The consequence of this
can be severe cardiovascular response, resulting in
hypertensive reaction, and which can be fatal in some
cases. The search for an understanding of the mechan-
ism of the cheese reaction by MAO inhibitors and
development of inhibitors devoid of this fatal side-effect
continued with the identification of multiple forms of
MAO with different substrate specificity and inhibitor
sensitivity (Youdim and Weinstock, 2001).
34.2. Multiple forms of brain monoamine
oxidase
The demonstration that MAO was not a single enzyme
but existed in several forms in the liver and brain
tissues of rats (Youdim and Sourkes, 1965) was
strengthened by the observation that the MAO inhibitor
clorgyline (Johnston, 1968) could differentiate between
two forms of MAO in brain and most tissues of animals
and humans. Johnston termed these enzymes type A and
type B and where clorgyline (Table 34.1, Fig. 34.3)
was a selective irreversible inhibitor of MAO-A, an
enzyme responsible for oxidative deamination of
norepinephrine and 5-HT. By contrast, MAO-B was

*Correspondence to: Professor Moussa B. H. Youdim, Centers of Excellence for Neurodegenerative Diseases Research,
Technion-Rappaport Family Faculty of Medicine and Institute, Efron St., PO Box 9697, Haifa 31096, Israel. Email:
youdim@tx.technion.ac.il, Tel: 972-4-8295-290, Fax: 972-4-8513-145.
94 M. B. H. YOUDIM AND P. F. RIEDERER

H2O2 O2 + H+

FAD FADH2
H
R2 + R2 OH2 C + R2
R N R N R O + HN
MAO
R1 R1 R1
Fig. 34.1. Reaction pathway of monoamine oxidase (MAO) catalyzes oxidative deamination of monoamine neurotransmitters.

(Youdim et al., 1988a). Nevertheless, the consistent

Table 34.1 cheese reaction observed with this drug in pharmacolo-
Monoamine oxidase (MAO) inhibitors with application gical and clinical studies led to its abandonment.
in depression and Parkinsons disease The reports by Youdim and colleagues (Collins
et al., 1970; Youdim et al., 1972) for the presence of
MAO type MAO-A and B in postmortem human brains led to
the suggestion that by mapping human brain MAO
AB A B
and distribution according to its isoenzymes, it would
Irreversible be possible to develop effective selective MAO inhibi-
Iproniazid AD tors directed at each form for the treatment of depres-
Phenelzine AD sion and other neuropsychiatric diseases, yet without
Isocarboxazid AD the occasional dangerous side-effects (cheese reaction)
Tranylcypromine AD inherent with older MAO inhibitors (Youdim et al.,
APD? 1972). L-Deprenyl (selegiline), the selective irreversi-
Nialamide AD
ble MAO inhibitor was the first such drug to be shown
Pargyline*
Clorgyline AD
to have MAO inhibitory activities opposite to that of
Deprenyl APD clorgyline, namely being a MAO-B inhibitor that
(selegiline) inhibited the metabolism of phenylethylamine, but
Rasagiline AD, APD? APD not 5-HT and norepinephrine, and to be devoid of the
TV3326 (brain- cheese reaction in isolated pharmacological preparations
selective, and in vivo animal studies (Knoll and Magyar, 1972).
phase II The second such inhibitor was AGN1135 and its
clinical) R-optical isomer, rasagiline (Finberg et al., 1981; Kalir
Reversible et al., 1981; Youdim et al., 2001a). Since then several
Moclobemide AD, other MAO-A and B inhibitors, such as irreversible
APD
(rasagiline) and reversible (moclobemide, lazabemide,
Brofaromine AD
Caroxazone
milacemide and safinamide) inhibitors have also been
Toloxatone AD shown not to induce a cheese reaction in animal and
BW 137OU87 human studies when used at their selective MAO-B-inhi-
Befloxatone AD bitory dosage (Table 34.1, Fig. 34.3). Yet selective irre-
Lazabemide APD versible inhibition of MAO-A is associated with the
Milacemide cheese reaction and studies of Finberg et al. (Finberg
Safinamide APD et al., 1981; Finberg and Tenne, 1982; Youdim et al.,
1988a, b) have clearly illuminated and established that
*Shows slight degree of selectivity for MAO-B. the cheese reaction is the consequence of irreversible
AD, antidepressant; APD, antiparkinsonian.
MAO-A inhibition by at least 80%, an enzyme predomi-
nantly present in the gut, portal system and peripheral
resistant to inhibition by clorgyline and metabolized and central aminergic neurons (Fig. 34.2). However,
benzylamine and, as shown later, phenylethylamine. selective irreversible MAO-B inhibitors, when used at
Tyramine and DA were equally well metabolized by concentrations that lose their selectivity for MAO-B
both forms of the enzyme (Table 34.2) (Youdim et al., and inhibit MAO-A, can also initiate such reactions. In
1988a, 2005; Cesura and Pletscher, 1992). Clorgyline vivo inhibition of MAO-A with irreversible non-selec-
was shown to increase brain levels of norepinephrine tive or irreversible selective MAO-A allows the uptake
and 5-HT and possess antidepressant activity in a series of unmetabolized tyramine into the circulation, which
of double-blind clinical trials in depressed patients eventually gains access to peripheral adrenergic neurons,
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE 95

Fig. 34.2. For full color figure, see plate section. The mechanism of potentiation of cardiovascular effects of tyramine the
cheese reaction. The prevention of metabolism of tyamine by irreversible monoamine oxidase (MAO)-AB or MAO-A inhibi-
tors results in the uptake of dietary tyramine in circulation by cardiovascular adrenergic neurons, which initiates the release of
norepinephrine (NA), a substrate for inhibitied MAO-A. L-DOPA, levodopa; COMT, catechol-O-methyltransferase.

thereby releasing norepinephrine (Fig. 34.2). These stu-
dies were the impetus for the development of reversible
MAO-A inhibitor antidepressants lacking the ability to
cause a cheese reaction. The rationale was that in the
case of MAO-A inhibition and tyramine ingestion, the
latter would displace the reversible inhibitor from the
enzyme active site and thus be metabolized itself by the
MAO-A (Fig. 34.4). However, reversible MAO-A
(moclobemide) and B (lazabemide, milacemide and safi-
namide) inhibitors are devoid of the cheese reaction by
the virtue of the ability of tyramine to displace the inhibi-
tor from its binding site on MAO-A and to be metabo-
lized by it. Indeed, these reversible inhibitors have very
high specificity for the enzymes they inhibit and there is
little cross-over for inactivation of the other enzyme.
Moclobemide, a reversible MAO-A inhibitor, was
the first such drug to be developed and introduced into
clinics as an antidepressant (Da Prada et al., 1981;
Korn et al., 1988; Youdim et al., 1988a, b; Haefely
et al., 1992, 1993; Priest, 1992; Paykel and Youdim,
1993; Angst et al., 1995; Youdim, 1995). Several other
similar drugs, such as brofaromine and befloxatone
(Table 34.1), have undergone preclinical and clinical
studies. Their preclinical and clinical pharmacology
has shown similar activity to that of moclobemide
(Paykel and Youdim, 1993; Youdim, 1995). These
drugs, including moclobemide, have a limited cardio-
vascular tyramine potentiation and do not cause a
cheese reaction, even in excess tyramine ingestion,
which is far beyond doses that may be present in food
(Bieck et al., 1988; Da Prada et al., 1988). The lack of
cheese reaction by these reversible MAO-A inhibitors
(Table 34.1) relies on the concept that, during reversible
MAO-A inhibition, the presence of tyramine near the
active site of the enzyme results in the displacement
of the inhibitor, which leads to metabolism of tyramine
by this enzyme in the body and, since tyramine does not
cross the bloodbrain barrier, central MAO-A will
continue to be inhibited, thus inducing increased brain
levels of MAO-A substrates 5-HT and norepinephrine.
The consequence of this is long-term adaptation at post-
synaptic sites, leading to alleviation of depression, since
these neurotransmitters have been implicated in the
pathophysiology of depressive illness and drugs that
increase their functional activity induce antidepressant
activity.
34.3. Distribution of MAO-A and MAO-B
in systemic organs and brain
MAO is a ubiquitous enzyme and is found in all tissues
in different concentrations and forms. MAO-B is more
abundant, accounting for about 80% of total MAO
activity in the human basal ganglia, which is in contrast
to rat brain, where the ratio is roughly 1:1 (Table 34.3).
In the human brain the distribution of MAO-A and
96 M. B. H. YOUDIM AND P. F. RIEDERER
CH3 CH3
O N N
CH3 H
CI CI Clorgyline Selegiline

CH3 H
N N
H3C N H H
CH CH3 H CH3 H

Methamphetamine Amphetamine

N O
N N
Rasagiline H Ladostigil H
(Agilect)

HO
NH2 NH2
N
Aminoindane Hydroxyaminoindane

N
OH NH2
NH
M30 F
Brain selective O O
MAO-AB
inhibitor
Safinamide C17H18N2O2F NW=301
Fig. 34.3. Structures of monoamine oxidase (MAO)-A, B and MAO-AB inhibitors in clinical use or under development.
Unlike selegiline, rasagiline is not metabolized to amphetamine or methamphetamine but rather to aminoindane. Ladostigil,
a cholinesterase brain-selective MAO-AB inhibitor derivative of rasagiline, is metabolized to hydroxyaminoindane, a conse-
quence of carbamate oxidation. Both ladostigil and M30 are brain-selective MAO-AB inhibitors that do not potentiate the
cardiovascular effect of tyramine (cheese effect). Safinamide is a selective reversible MAO-B inhibitor with other pharmaco-
logical attributes, including its interaction with K channel.

MAO-B differs in various regions (Collins et al.,
1970; OCarroll et al., 1983). Dopaminergic neurons
of the substantia nigra reveal extremely low staining
of MAO. This is in contrast to noradrenergic neurons
of the locus ceruleus, which stain positively with the
MAO-A substrate 5-HT and serotoninergic neurons
of the raphe nuclei which stain for MAO-B. Glial
cells stain predominantly for MAO-B, whereas astro-
cytes contain both enzyme forms (Konradi et al.,
1989). Nevertheless, non-selective inhibition of
MAO results in a highly significant increase of DA
in human and rodent brains regions. Furthermore,
both reversible and irreversible MAO-A inhibitors
increase brain levels of 5-HT and norepinephrine,
indicating that, even though the activity of MAO in
these neurons may be low, the enzyme has a meta-
bolic regulatory role.
An increase in MAO-B with age and in both pla-
telets (Murphy et al., 1976; Bridge et al., 1985) and
human brains with Parkinsons and Alzheimers
disease is detected (Adolfsson et al., 1980). Trans-
mitter analyses of three different age groups (09.9
years, 1059.9 years and 60 years and older) defined
according to previous studies on ontogenesis and senes-
cence in human brain showed a decrease in the 5-hy-
droxyindole acetic acid (5-HIAA)/5-HT ratio after the
first decade of life. Changes in the dopaminergic system
were seen in senescene with decreasing DA levels and
an increase in the homovanillic acid/DA ratio, whereas
the dihydroxyphenylacetic acid/DA ratio was unaf-
fected. Norepinephrine was not changed over the life-
time (Konradi et al., 1992). In rodents and humans,
MAO-A is present in the extraneuronal compartment
and within the dopaminergic terminals, where it is
involved in the metabolism of intraneuronal and
released DA respectively (Fig. 34.5). Its role is to main-
tain the neurotransmitter concentration low within the
neuron (Youdim et al., 1988a, b; Cesura and Pletscher,
1992). However, it should be remembered that DA is
equally well metabolized by both MAO-A and B.
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE 97
Table 34.2 Table 34.3
Some natural and synthetic substrates of monoamine Distribution of monoamine oxidase (MAO)-A and MAO-B
oxidase (MAO) in humans and in the brains of selected species

MAO type Total activity (%)

AB A B Tissue MAO-A MAO-B

Neurotransmitters Brain
and metabolites Human (striatum: 20 80
Epinephrine all regions)
Norepinephrine Monkey 25 75
Dopamine Guinea pig 20 80
Serotonin (5-HT) Cat 25 75
Metanephrine Pig 40 60
Normetanephrine Rat 55 45
Tele-N-methylhistamine Mice 50 50
1-methyl-4- Aminergic neurons 100 0
phenyl-4-propionoxy Glia and astrocytes 50 50
-piperidine (MPTP) Other tissues
Milacemide Liver 55 45
Trace amines, dietary (human, rat, rabbit)
amines, drugs Small intestine
75 25
Tyramine Kidney (rat) 25 75
Octopamine Lings (rat) 55 45
Phenylethylamine Human platelet 5 95
Tryptamine Chromaffin cell 5 95
Phenylethanolamine Pheochromocytoma 95 5
Synephrine PC-12 cells 95 5
Phenylephrine

Note: The above selectivity for MAO subtypes is based on determi-

nation in cell-free preparations.

FAD SRS FAD

SRS

MAO-A RIMA MAO-A--RIMA

SRS FAD
SRS FAD

Tyramine Tyramine displacement of RIMA

FAD FAD RIMA and

SRS SRS
tyramine
metabolites

Fig. 34.4. The mechanism of interaction of reversible monoamine oxidase (MAO)-A inhibitor (RIMA, moclobemide) with
monoamine oxidase, its displacement by tyramine and their eventual metabolism by MAO and drug-metabolizing enzyme
respectively.
98 M. B. H. YOUDIM AND P. F. RIEDERER

Dopamine
Glia receptor D2
Entacapone
agonists
MAO-A & B

3OMD
Selegiline
Rasagiline

COMT Bloodbrain barrier Ladostigil, M30

D2
DT
SV
SV
Tyrosine DDC
L-dopa Dopamine
L-DOPA DA
SV
MAO A AR
DDC
D1

Dopamine

MAO-A & B
Benzerezide Moclobarmide
carbidopa
Astrocyte Postsynaptic terminal
Presynaptic terminal
substantia nigra origin Striatum

Fig. 34.5. The pathway of dopamine (DA) synthesis from tyrosine via hydroxylation by tyrosine hydroxylase to levodopa
(L-dopa) and subsequent decarboxylation by dopa decarboxylase (DDC) to DA and its metabolism by interaneuronal monoa-
mine oxidase (MAO)-A and by glia and asotrocyte MAO-A and B extraneuronally. The selective inhibition of MAO by various
selective MAO-A (moclobemide) or MAO-B (selegiline, rasagiline) does not alter the steady state of striatal dopamine. On the
other hand, non-selective MAO-AB (ladostigil and M30) inhibitors induce highly significant increases in striatal dopamine and
in other brain regions. D1 and D2, dopamine receptors; DAT, dopamine transporter; AR, amine reuptake; SV, synaptic vesicle;
COMT, catechol-O-methyltransferase; 3OMD, O-methyldopa; DT, dopamine transporter; SV, vesicle.

34.4. MAO-B inhibitors in Parkinsons disease
Selegiline (L-deprenyl), a selective irreversible inhibi-
tor of MAO-B, without the ability to cause a cheese
reaction at its selective dosage, was identified for the
treatment of PD because of the latter property and pro-
minence of MAO-B in extrapyramidal brain regions of
human brain (Birkmayer et al., 1975, 1977; Lees et al.,
1977). It has been widely used in the treatment of Par-
kinsons disease and has been shown to postpone the
need for levodopa in early Parkinsons disease and to
be useful in the management of end-of-dose akinesia
in fully developed disease (Birkmayer et al., 1975,
1977; Lees et al., 1977; Parkinson Study Group,
1993; Szeleny, 1993). Since then several other reversi-
ble and irreversible MAO-B inhibitors have been
developed. The reversible MAO-B inhibitors lazabe-
mide and milacemide, which showed great promise
as antiparkinsonian drugs, had systemic toxicology.
However a recent addition is the antiparkinsonian
drug rasagiline, a selective potent irreversible MAO-B
with more than 1015-fold the potency of selegiline
(Youdim et al., 2001a; Finberg and Youdim, 2002;
Parkinson Study Group, 2002, 2004, 2005; Rascol
et al., 2005) which, unlike selegiline, does not give rise
to methamphetamine metabolites, nor does it have
the sympathomimetic activity of selegiline (Finberg
et al., 1981; Finberg and Youdim, 2002) or cause
cardiovascular complications (Youdim, and Riederer,
1993a; Finberg et al., 1999; Abassi et al., 2004) or
orthostatic hypotension observed with selegiline. The
orthostatic hypotension of selegiline has now been
shown to be related to the methamphetamine metabolite
(Abassi et al., 2004). Rasagiline increases the production
of DA following levodopa treatment in monkeys, as mea-
sured by microdialysis (Finberg et al., 1998a, b) and on
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE
chronic treatment in rats it induced increased release of
DA (Lammensdorf et al., 1996).
Safinamide is a recently developed reversible
selective MAO-B inhibitor with iron channel property
that does not induce a cheese reaction (Marzo et al.,
2004). This drug has anticonvulsant activity. It im-
proves motor function in early Parkinsons disease
(Stocchi et al., 2004). A median safinamide dose of
70 mg/day (range 4090 mg/day) has been shown to
increase the percentage of parkinsonian patients
improving their motor scores by 30% from baseline
(responders). In a subgroup of 101 patients under
stable treatment with a single DA agonist, the addition
of safinamide potentiated the response (47.1% respon-
ders, mean 4.7-point motor score decrease; P  0.05).
These results suggest that doses of safinamide exerting
ion channel block and glutamate release inhibition
add to its symptomatic effect and warrant further
exploration of this drug in Parkinsons disease.
In parkinsonian brains obtained at autopsy from
2 weeks or 4 years of L-selegiline-treated subjects, a
highly significant (>3000%) and moderate (4070%)
increase in phenylethylamine and DA was respectively
observed in substantia nigra, caudate nucleus, putamen
and globus pallidus, without any changes in 5-HT,
norepinephrine or their metabolite contents (Riederer
et al., 1986; Riederer and Youdim, 1986; Youdim
and Riederer, 1993a). By contrast, clorgyline (an
MAO-A inhibitor) increases both norepinephrine and
5-HT highly significantly with a slight increase of DA
in human basal ganglia and animal striatum (Youdim
et al., 1972). However, tranylcypromine, a non-selec-
tive MAO inhibitor, increases the three neurotransmit-
ters in human and rat brain. Indeed, in rat brain
clorgyline, selegline and rasagiline are unable to in-
crease striatal DA or alter its metabolism (Finberg and
Youdim, 2002). Only when both enzymes are inhibited
does striatal DA increase, resulting in DA functional
activity potentiation (Green et al., 1977).
34.5. MAO-A inhibitors in Parkinsons disease
Most investigators forget that DA is equally well
metabolized by MAO-B and -A and that the latter
enzyme is located intraneuronally and regulates the
cytoplasmic concentration of DA with neurons and
the extend DA is released. Nevertheless, little attention
has been paid to MAO-A inhibition by MAO-A inhibi-
tors in the treatment of PD, even though it has clearly
been established that DA is equally well metabolized
by MAO-A and MAO-B in the striatum (Collins
et al., 1970; OCarroll et al., 1983). There is no indica-
tion as to what is the contribution of MAO-A or MAO-
B inhibition or MAO-A compartmentalization to DA
99
metabolism in the human striatum. This is mainly
because the effect of L-selegiline or clorgyline on DA
elevation in parkinsonian brains and brains obtained at
autopsy from depressed subjects on MAO inhibitors
(Youdim et al., 1972) is not as profound as the increase
in 5-HT and norepinephrine or the selective MAO-B
substrate, phenylethylamine, observed respectively
with these inhibitors. These data have clearly indicated
that when one form of the enzyme is fully inhibited in
human basal ganglia, the other MAO can equally meta-
bolize DA and thus its level will not change drastically
in the striatum (Youdim and Riederer, 1993a).
The major reason why MAO-A inhibitors have not
received attention as antiparkinsonian drugs is because
its irreversible inhibitors cause the cheese reaction.
However, the reversible MAO-A inhibitor antidepres-
sant (RIMA) does not possess this side-effect
(Da Prada et al., 1988; Youdim et al., 1988a, b). The
antiparkinsonian effects of a RIMA, moclobemide,
when added to the standard therapy with levodopa
and dopaminergic agonists, on motor performance of
patients with idiopathic PD has been studied (Sier-
adzan et al., 1995). The influence of the drug on the
mood and cognitive function of non-depressed parkin-
sonians has been evaluated. This was also considered
valid, since 2060% of parkinsonian patients suffer
from depression and many factors could account for
this, including the reported degeneration of raphe
nucleus 5-HT and locus ceruleus noradrenergic neu-
rons. Nevertheless, depression has a biological basis
and in PD the main monoaminergic systems in the
brain are disturbed. Indeed, besides the deficit in stria-
tal DA, significant reductions in locus ceruleus, nore-
pinephrine and raphe nucleus 5-HT have consistently
been reported. The involvement of the latter two
monoamines in the pathogenesis of depression would
suggest that PD may be a useful model for the study
of depression. Recent molecular genetic studies
demonstrate that polymorphism in the 5-HT transpor-
ter, as observed in endogenous depression, is identical
to that in parkinsonian patients with severe and fre-
quent episods of depression. It could be shown that
the 5-HT transporter gene-linked polymorphic region,
but not the MAO-A gene promoter-associated poly-
morphism, may be a risk factor for depression in par-
kinsonian patients, whereas neither polymorphism
increases the risk for development of Parkinsons dis-
ease itself (Mossner et al., 2001).
However, moclobemide was well tolerated by
healthy volunteers when administered with levodopa
and benserazide. Its safety and tolerance in parkinso-
nians treated with levodopa and a peripheral decarbox-
ylase inhibitor were evaluated (Sieradzan et al., 1995).
In these studies moclobemide was used as 450 mg
100 M. B. H. YOUDIM AND P. F. RIEDERER
daily dosage in parkinsonian subjects (Sieradzan et al.,
1995). More recent studies indicate that the dosage of
moclobemide can be increased to 900 mg, without
unwanted side-effects, with a better clinical response
in depressed subjects and greater efficacy for MAO-A
inhibition, and presumably the same could be true for
PD subjects. The low dosage, as used in moclobemide-
treated PD studies (Sieradzan et al., 1995), may also
explain why a relatively mild symptomatic antiparkin-
sonian response was obtained. Such a problem does
not occur with L-selegiline or rasagiline, since they
bind covalently to the enzyme and fully inhibit
MAO-B. In this context, treatment with moclobemide
and selegiline or rasagiline should be avoided, without
application of tyramine restriction. Nevertheless, sev-
eral studies with such combinations have not shown
unwanted side-effects, whereas moclobemide can be
safely prescribed to patients on levodopa/decarboxy-
lase inhibitor therapy. A combination of reversible
MAO-A (e.g. moclobemide) and reversible MAO-B
(e.g. lazabemide) inhibitor may be worth considering
as a therapeutic means. However, caution may need to
be taken with regard to a combination of MAO inhibitors
(even selective ones) with classical antidepressants and
especially serotonin selective reuptake inhibitors
(SSRIs). Such combined treatment strategies may
provoke the serotonin syndrome, which is a serious
adverse reaction in human brains. In the treatment of
therapy-resistant depression, MAO inhibitors are an
important therapeutic strategy. The combined treatment
of MAO inhibitors with tricyclic antidepressants or
SSRIs should be avoided (Bijl, 2004; Izumi et al.,
2006; Nieuwstraten et al., 2006) due to the possibility
of initiating the deleterious serotonin syndrome.
The mild antiparkinsonian action of moclobemide
(Sieradzan et al., 1995) is matched by its true antide-
pressant activity in several double-blind studies as
compared with other antidepressants such as fluoxe-
tine, imipramine and desimipramine (Bieck et al.,
1988; Priest, 1992; Paykel and Youdim, 1993; Angst
et al., 1995; Youdim, 1995). Recent studies on moclo-
bemides antidepressant action in depressive parkinso-
nian subjects has shown that the drug can be a useful
additional antidepressant and is well tolerated with
standard therapy. Thus, the RIMA antidepressant
moclobemide could influence the function of the ami-
nergic neurotransmitters, as well as depression in Par-
kinsons disease. Moclobemide, originally developed
as an antidepressant, is effective in the treatment of
depression. A number of studies have assessed its
effects on cognition, but the differences in subject
samples and experimental designs render their results
inconclusive. In major depression, moclobemide was
found to improve vigilance, psychomotor speed and
long-term memory. There have also been reports on
improvement in memory and choice reaction time in the
elderly subjects. In other studies in non-depressed elderly
people and in healthy young volunteers, moclobemide
had no significant effects on cognitive functions. Most
importantly, it does not produce hypertensive reactions
due to interaction with dietary tyramine (cheese reac-
tion). Numerous animal (rats and mice) studies have
shown that inhibition of MAO-A with either reversible
(moclobemide) or irreversible (clorgyline) inhibitors of
this enzyme induce little change in DA, suggesting that
at first glance DA metabolism does not appear to be
affected by this inhibitor. Nevertheless, striatal microdia-
lysis studies in rats have shown that, after moclobemide
or clorgyline or rasagiline, the release of DA occurs,
and this is highly significant (Haefely et al., 1992, 1993;
Lamensdorf et al., 1996; Finberg et al., 1998a). This would
indicate that, although MAO-A or B inhibition does
affect brain DA steady state, it affects its release. This
may explain the antiparkinsonian effects of such drugs.
Thus, the increased release of DA during MAO-A inhibi-
tion may account for the prolonged duration of motor
response to single levodopa challenge in response to
moclobemide (Szeleny, 1993; Sieradzan et al., 1995;
Sternic et al., 1998). The relatively mild symptomatic
effect of moclobemide in PD may be associated with
the pharmacokinetic properties of this inhibitor. Moclo-
bemide, being a reversible inhibitor, could be displaced
from its binding site on MAO-A present intraneuronally
and extraneuronally by DA formed from levodopa. Thus,
disinhibition of the enzyme could occur. Haefely et al.
(1992, 1993), examining the effect of moclobemide on
DA metabolism in microdialysis studies, have indeed
shown that DA can displace the inhibitor from its
MAO-A binding site. Under such conditions, namely
lack of MAO-A inhibition, reductions in DA accumula-
tion and release could occur. Thus, it is evident that
special attention needs to be paid to the pharmacoki-
netics of the ratio of daily dosage of moclobemide
or other reversible MAO-A inhibitors to levodopa
for a more effective action of moclobemide on DA
metabolism and its antiparkinsonian activity.
The studies so far done with the MAO-A inhibitor
moclobemide have shown it to be well tolerated and
safe in levodopa-treated parkinsonians (Sieradzan
et al., 1995). The observed shortening of latency and
prolonged duration of motor response to single-dose
levodopa challenge may be explained by the known
effects of moclobemide on the metabolism of exogen-
ous levodopa to DA and oxidative deamination by
MAO-A. Moclobemide seems to have a mild sympto-
matic benefit in PD (Sieradzan et al., 1995; Sternic
et al., 1998). In particular, the baseline motor condi-
tions after overnight withdrawal of medication
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE
improved during moclobemide treatment. The results
suggest that bradykinesia may be more amenable to
moclobemide than other parkinsonian disabilities. In
non-depression parkinsonians, moclobemide does not
significantly influence cognitive measures of mood.
Further controlled studies are required to evaluate the
place of moclobemide and other reversible selective
MAO-A inhibitors such as brofaromine and befloxa-
tone, which are more powerful inhibitors with greater
affinity for MAO-A.
34.6. Selective MAO-B inhibitors in
Parkinsons disease with depressive illness
Selegiline was originally developed as a psychoenergi-
zer antidepressant. However, earlier uncontrolled open
studies with large doses (100 mg) and later control
studies with higher doses (> 15 mg) established a sig-
nificant antidepressant action. However, in monother-
apy and in combination with the 5-HT precursor 5-
hydroxytryptophan (5-HTP), it had significant antide-
pressant activity in controlled studies (Mendlewicz
and Youdim, 1978, 1979, 1983; Mann and Gershon,
1980; Mann, 1989). An antidepressant activity with a
selegiline patch at high doses is reported in recent
studies. It is most likely that at high doses, selegiline
loses its MAO-B inhibitory selectivity and also inhi-
bits MAO-A, as has been regularly observed in animal
studies, but it bypasses system inhibition of MAO-A.
However, consideration should be given to a com-
bination of selegiline or rasagiline with 5-HTP as anti-
depressant since three double-blind studies have
shown that the selegiline5-HTP combination is sig-
nificantly more effective than 5-HTP alone in bipolar
depressed subjects (Mendlewicz and Youdim, 1978,
1979, 1983) and little evidence was obtained for the
efficacy of selegiline monotherapy at its selective
MAO-B-inhibitory concentrations as antidepressant
(Mendlewicz and Youdim, 1978). These studies
require confirmation. The highly significant antide-
pressant action of the combination of 5-HTP plus
L-deprenyl (selegiline) has been attributed to its action
in human brain on DA metabolism, where selegiline
significantly increases DA and phenylethylamine (a
releaser of DA) in various regions. It has been shown
that the functional activity of 5-HT (i.e behavioral
response in rats to increased levels of brain 5-HT)
formed from tryptophan or 5-HTP is DA-dependent
(Green and Grahame-Smith, 1975; Green and Youdim,
1975; Youdim et al., 1976). This may explain why
alpha-methyl-p-tyrosine, an inhibitor of tyrosine
hydroxylase, is able to block 5-HT functional activity
in response to the 5-HT precursors tryptophan and
5-HTP in rats (Green and Grahame-Smith, 1975).
101
Thus, although DA may not be directly involved in
the pathophysiology of depression or the mechanism
of the action of MAO inhibitors as antidepressants, it
may modulate serotonergic activity (Green and Gra-
hame-Smith, 1975, Green and Youdim, 1975; Youdim
et al., 1976). Thus, this may be one reason why it has
been suggested that a non-selective reversible MAO-
A-B inhibitor that blocks DA metabolism might be
more effective as an antidepressant than a selective
reversible MAO-A inhibitor, such as moclobemide,
which is thought to be a milder antidepressant and bet-
ter tolerated by older patients (Sternic et al., 1998;
Amrein et al., 1999; Erfurth and Back, 1999; Jansen
and Ballering, 1999).
Depression has a biological basis of its own, but
particularly in Parkinsons disease, where the main
monoaminergic systems are degenerating. It is now
well recognized that some 4060% of parkinsonian
subjects suffer from endogenous depression (Bosboom
and Wolters, 2004; Lauterbach, 2004; Leentjens, 2004;
Rihmer et al., 2004). Most often it is forgotten that, in
addition to the deficit in striatal DA, highly significant
reductions in locus ceruleus norepinephrine and raphe
nucleus 5-HT have consistently been reported in par-
kinsonian brains. The association of diminished nora-
drenergic and serotoninergic neurotransmission in the
pathogenesis of depressive illness would suggest that:
(1) Parkinsons disease may be an ideal condition for
the study of depression and its treatment; and (2) a
drug such as moclobemide and other RIMAs could
exhibit dual pharmacological activities as antiparkin-
sonian drug and antidepressant in the same patients
suffering from the two diseases. Several studies have
shown that in depressed parkinsonian patients moclo-
bemide is a useful antidepressant and it is well toler-
ated with standard therapy. The fact that RIMA can
be safely prescribed to parkinsonian patients on levo-
dopa/decarboxylase inhibitor therapy may be an ideal
situation for the symptomatic treatment of parkinso-
nian subjects with episodes of depression. RIMA are
considered to be not as effective antidepressants as the
non-selective MAO inhibitors, even though selective
inhibition of MAO-A results in increased norepinephr-
ine and 5-HT, with little change in DA. However,
non-selective MAO inhibitors induce a much greater
increase in brain levels of these neurotransmitters
(Green and Youdim, 1975; Green et al., 1977). This
has been attributed to the observation that, when
MAO-A is selectively inhibited, the intact MAO-B
can continue to metabolize these amines, albeit at a
slower rate, when their elevated concentrations satisfy
the Km (Michaelis constant) of MAO-B for these
amines (Green and Youdim, 1975; Green et al., 1977).
Since selective MAO-B inhibitors do not increase brain
102 M. B. H. YOUDIM AND P. F. RIEDERER
levels of the three neurotransmitters, they have limited
effect in their full functional neurotransmission. Thus,
if we are to understand the contribution of MAO-A and
B inhibition to DA metabolism and neurotransmission
in PD and the contribution of DA neurotransmission to
increased functional activity of 5-HT in the prevention
of depression in Parkinsons disease, there is a need for
either non-selective reversible or brain-selective irrever-
sible MAO-A and B inhibitors as antidepressant antipar-
kinsonian agents, devoid of tyramine potentiation,
namely the cheese reaction.
34.7. Novel brain-selective irreversible
MAO-AB inhibitors with limited tyramine
potentiation in the treatment of Parkinsons
disease comorbid with dementia and
depressive illness
There are no profound clinical studies for the combined
treatment with selective MAO inhibitors and acetylcho-
line esterase inhibitors in patients with (Alzheimers)
dementia or parkinsonian patients developing dementia
(Lewy body disease). However, recent studies have
shown that patients with Lewy body disease on levo-
dopa therapy for their extrapyramidal disorder respond
cognitively to anti-Alzheimer acetylcholinesterase inhi-
bitors (Benecke, 2003; Mosimann and McKeith, 2003;
Wild et al., 2003) without loss of response to dopami-
nergic antiparkinsonian drugs. A significant number of
these patients, as well as subjects with Alzheimers dis-
ease and Parkinsons disease, have a predisposition to
depression (Chan-Palay, 1992).
To overcome this problem, a series of neuroprotective
bifunctional cholinesterase brain-selective MAO-AB
inhibitors (Weinstock et al., 2000; Youdim and Bucca-
fesco, 2005a, b) from the pharmacophore of antiparkin-
sonian drugs selegiline and rasagiline (Sterling et al.,
2002) by introducing a carbamate cholinesterase
inhibitory moiety in such compounds to increase choli-
nergic activity (Fig. 34.3). This was done to retain the
neuroprotective and antiparkinsonian activities of these
compounds. Among the compounds identified, ladostigil
([TV3326 (N-propargyl)-(3R)-aminoindan-5-yl]-ethyl
methyl carbamate) (Fig. 34.3) (Weinstock et al., 2000;
Sterling et al., 2002), a derivative of rasagiline, is show-
ing remarkable pharmacological activities that may
make this compound ideal for the treatment of Parkin-
sons disease comorbid with depressive illness and
dementia. Ladostigil is a butryl and acetylcholinesterase
inhibitor and possesses the anti-Alzheimer drug proper-
ties of other cholinesterase inhibitors, such as rivastig-
mine and galantamine, by attenuating the deficit in
spatial learning in rats and monkeys in response to sco-
polamine (Weinstock et al., 2000; Buccafusco et al.,
2003). Compartive cognitive studies with other choli-
nesterase inhibitors (galantamine, rivastigmine) in
monkey have shown that it is superior to these inhibi-
tors. This may be accounted for by its ability to increase
both acetylcholine and DA and cognitive enhancement
by the latter neurotransmitter. Being weaker than rivas-
tigmine and galantamine, its toxicity is limited as com-
pared to the latter cholinesterase inhibitors. It retains the
neuroprotective antiapoptotic activity of rasagiline
(Weinstock et al., 2001; Youdim and Weinstock,
2001; Maruyama et al., 2003).
Ladostigil does not exhibit either MAO-A or B
inhibition in vitro or in acute in vivo studies. However,
on chronic treatment in mice, rats, rabbits and mon-
keys, it shows remarkable selectivity for the inhibition
of both enzymes in the brain, with little effects
on MAO-A and B in the liver and small intestine
(Weinstock et al., 2000, 2002a, b, 2003). Its in vivo
MAO-AB inhibitory activity is explained by the obser-
vation that ladostigil acts as a prodrug. The oxidation
of its carbamate cholinesterase inhibitory moiety gives
rise to hydroxyl rasagiline that inhibits both MAO and
B and may be selectively accumulated in the aminer-
gic neurons. This novel property explains its limited
tyramine potentiation in rats and rabbits, as compared
to tranylcypromine, clorgyline and moclobemide
(Weinstock et al., 2002b). It induces highly significant
increases in norepinephrine, 5-HT and DA in the hip-
pocampus and striatum of rats and mice (Weinstock
et al., 2000; Sagi et al., 2003) and, in the forced-swim
test model for antidepressant activity, it is equivalent
to amitryptiline, clorgyline, tranylcypromine and
moclobemide (Weinstock et al., 2002a). Furthermore,
being an MAO-AB inhibitor, similar to MAO-B inhi-
bitors (selegiline, rasagiline and lazabemide), it pre-
vents the striatal dopaminergic neuron degeneration
and DA depletion induced by the parkinsonism neuro-
toxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP), in the mouse model of Parkinsons disease
(Sagi et al., 2003). And, unlike selegiline and rasagi-
line, it highly significantly increases brain DA in
MPTP-treated mice above the level of control. The
fact that it inhibits both forms of MAO is a bonus for
preventing metabolism of DA by either form of MAO.
34.8. Combined treatment of MAO inhibitors
with COMT inhibitors
The combined treatment of MAO inhibitors and the
peripherally and centrally acting catechol-O-methyl-
transferase (COMT) inhibitors entacapone and tolca-
pone has not been sufficiently evaluated in clinical
studies with patients suffering from Parkinsons dis-
ease. However, preclinical data let us assume that such
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE
combined treatment would not be harmful because
catecholamines could still be metabolized in the CNS
by COMT activity.
34.9. Neuroprotection
Selegiline and rasagiline increase neuronal survival in
a variety of in vitro and in vivo models of neural
insult, often independently of MAO-B inhibition
(for review, see Tatton and Chalmers-Redman, 1996;
Foley et al., 2000; Youdim et al., 2005, 2006). These
results have provoked excitement with respect to their
potential as disease-modifying agents. The neurotoxins
MPTP and 6-hydroxydopamine (6-OHDA) selectively
damage dopaminergic neurons and MPTP elicits par-
kinsonian syndromes in mice, goldfish and primates,
including humans. MPTP is both a substrate and a
weak, partially reversible inhibitor of MAO-B, and
a reasonably good substrate and potent, reversible
inhibitor of MAO-A. The neurotoxic mechanism of
MPTP is its conversion by astrocytic MAO-B to the
toxin, 1-methyl-4-phenylpyridinium (MPP), a rever-
sible inhibitor of both MAO-A and MAO-B (Singer
and Ramsay, 1991), which enters the neuron via the
DA transporter (for review, see Gerlach et al., 1991).
There are also a range of endogenous substances, such
as the b-carbolines and tetrahydroisoquinolines, that
are metabolized to neurotoxic compounds by MAO-B
(Glover and Sandler, 1993). All MAO-B inhibitors
protect DA neurons against MPTP and such toxins
by inhibiting their activation and, in some cases, neu-
ronal uptake. This has been demonstrated in animal
models for selegiline, pargyline and rasagiline at the
cellular, neurochemical and behavioral levels (for
review, see Glover and Sandler, 1993; Tatton and
Chalmers-Redman, 1994). A neuroprotective effect
against intrastriatally injected MPP has been demon-
strated (Wu et al., 1995, 1996). Selegiline antagonizes
MPP-induced apoptosis in a dopaminergic hybrid
cell line, and this protection is independent of MAO-
B inhibition; higher concentrations (1 mM), however,
induced apoptosis (Le et al., 1997), although this could
not be confirmed by Vaglini et al. (1996). Sautter
et al. (1994) reported that both rasagiline and selegi-
line protected marmosets against the effects of MPTP.
In contrast to MPTP, 6-OHDA must be applied
directly to the nigrostriatal system in order to elicit a
toxic effect and its neurotoxicity does not require meta-
bolism by MAO-B for its activation. However, rasagi-
line has been shown to protect against this neurotoxin
(Blandini et al., 2004), against spontaneous central adre-
nergic degeneration in spontaneously hypertensive SHR
rats (Eliash et al., 2005) and in cerebellar granule cells
(Bonneh-Barkay et al., 2005). The neurotoxic mechan-
103
ism of 6-OHDA is believed to be associated with oxida-
tive stress, possibly mediated by release of bound iron
(II). A neuroprotective effect of high-dose selegiline
and rasagiline is suggested by the normalization of 6-
OHDA-induced release of acetylcholine from striatal
slices and DA neurons (Knoll, 1987).
Selegiline, pargyline and 2-hexyl-N-methylpropargy-
lamine (Gibson, 1987; Finnegan et al., 1990; Yu et al.,
1994; Zhang et al., 1996) but not mofegiline (Magyar,
1994) or the MAO-A inhibitor clorgyline (Knoll,
1987) protect noradrenergic neurons in rodent hippo-
campus and locus ceruleus against the toxin N-(2-chlor-
oethyl)-N-ethyl-2-bromobenzylamine (DSP-4; toxic
effect due to its derivative, the aziridinium ion), and
selegiline reversibly inhibits DSP-4-stimulated norepi-
nephrine release in rat hippocampus (Magyar et al.,
1998). It is not clear whether this capacity depends on
inhibition of MAO-B, and inhibition of monoamine
transport appears not to be involved (Hallman and Jons-
son, 1984; Yu et al., 1994). However, Magyar (1993)
attributed the protective effects of selegiline and its
p-fluoro-derivative to the prevention of aziridinium
ion uptake. Selegiline and mofegiline are also effective
against 3,4-methyenedioxymethamphetamine (MDMA)-
induced serotonergic toxicity in rats (Mytilineou et al.,
1997a, b). Both selegiline and rasagiline, but not pargy-
line, protect cultured mesencephalic dopaminergic
neurons against glutamate receptor-mediated toxicity
(Sprague and Nichols, 1995; Mytilineou et al., 1997b;
Finberg et al., 1996, 1999a, b). For a review on the neu-
roprotective activity of rasagiline and selegiline in other
in vivo models, see Youdim et al., (2003, 2005, 2006).
34.9.1. Neurorescuing effects
It is recognized that lesions of the CNS activate a
chain of responses which result in greater damage than
might be expected from the magnitude of the initial
insult. These processes are only incompletely under-
stood, but it is hoped that it might be possible to slow,
halt or even reverse such processes after their initia-
tion. Such intervention is the major hope for the more
effective management of central neurodegenerative
disorders, including Parkinsons and Alzheimers dis-
ease.
Selegiline has been reported to protect dopaminergic
neurons from MPTP-induced cell death, even when
applied 3 days after exposure to the toxin, and prevent
the neurodegeneration of tyrosine hydroxylase-reactive
cells in the rat substantia nigra by subchronic administra-
tion of selegiline (Tatton and Wadia, 1991). Tatton
coined the term neurorescuing to describe this phenom-
enon, because at the time of selegiline administration,
the MAO-B-catalyzed generation of MPP is completed
104 M. B. H. YOUDIM AND P. F. RIEDERER
within 36 hours of exposure to MPTP and neurodegen-
eration had already commenced. The same laboratory
was unable to observe this effect with other MAO-A
and B inhibitors (with the possible exception of pargy-
line and rasagiline (Tatton et al., 1996; Youdim et al.,
2006). Both selegiline and rasagiline are able to
increase the survival rate of motor neurons following
axotomy of the rat facial nerve (Salo and Tatton,
1992) or subjection to spinal cord ischemia (Ravi-
kumar et al., 1998) of rat retinal ganglion cells follow-
ing damage to the optic nerve (Buys et al., 1995), of
cultured mouse mesencephalic cells following with-
drawal of growth factors and serum (Roy and Bdard,
1993) and of cultured mesencephalic neurons from
rodents (Koutsilieri et al., 1996) and dogs (Schmidt
et al., 1997) treated with MPP.
These effects are seen at concentrations where
MAO-B inhibitors do not inhibit the enzyme and
PC12 and SHSY-5Y cells contain only MAO-A, and
which can be blocked by protein synthesis inhibitors
(Tatton et al., 1994). Their mechanism has been attri-
butable to neurotrophic and antiapoptotic properties
of selegiline and rasagiline (Tatton et al., 1996; Pater-
son and Tatton, 1998; Paterson et al., 1998; Maruyama
et al., 2004; Youdim et al., 2005). They noted that the
observed neuroprotective action was accompanied by
reduced intramitochondrial Ca2 levels and reduced
cytoplasmic radical concentrations, as well as by a
decrease in the DNA fragmentation characteristic of
apoptotic cell death. The authors also recorded the
altered expression of a number of cellular mRNAs
and proteins (discussed below), and suggested that
the ultimate result of these changes is the prevention
of mitochondrial swelling, a stabilization of the mito-
chondrial membrane potential (cM), thus inhibiting
one of the processes thought to be among the earliest
events in apoptosis (Figs. 34.6 and 34.7) (Tatton and
Chalmers-Redman, 1996; Akao et al., 2002a, b). In a
further investigation, they demonstrated that a signifi-
cant decline in cM could be measured in nerve growth

Fig. 34.6. The mechanism of neurotoxin-induced neuronal death and its prevention by propargylamines. Mitochondria are responsi-
ble for cell survival/death via the regulation of Bcl-2 family antiaptotic (Bcl-2) and proapoptotic (Bad, Bax) proteins. Rasagiline, sele-
giline and propargylamine have been shown to induce cell survival in response to serum withdrawal or neurotoxins in neuronal cell
cultures (SHSY-5Y and PC-12) through the activation of Bcl-2 and Bcl-Xl, and the downregulation of Bad and Bax. These propargy-
lamines produce their neuroprotective activity by interacting with the mitochondrial outer membrane. The propargylamine moiety in
these inhibitors prevents neurotoxin-induced collapse of mitochondrial membrane potential, mitochondria permeability transition and
the opening of the voltage-dependent channel, as a consequence of antiapoptoic Bcl-2 family protein upregulation. The consequence
of this is the prevention of ubiquitin-proteasome inhibition, release of cytochrome c and activation of proapoptotic caspases, resulting
in cell survival. SOD, superoxide dismutase; PKC, protein kinase; AIF, apoptotic inducing factor; PT, permeability transition.
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE 105

Fig. 34.7. For full color figure, see plate section. Mitochondria are responsible for cell survival/death via the regulation of BCl-2
family antiapoptotic (Bcl-2) and proapoptotic (Bad, Bax) family proteins. Rasagiline, selegiline and propargylamine have been
shown to induce cell survival in response to serum withdrawal or neurotoxins in neuronal cell cutltures (SHSY-5Y and PC-12)
via activation of Bcl-2 and Bcl-Xl and downregulation of Bad and Bax. These propargylamines produce their neuroprotective
activity by interaction with the outer-mitochondrial out membrane. They prevent neurotoxins inducing the collapse of mito-
chondrial membrane potential, mitochondrial permeability transition and the opening of the voltage-dependent channel
(VDAC) as a consequence of Bcl-2 and Bcl-Xl activation. OM, outer mitochondria; IM, inner mitochondria; GAPDH, glycer-
aldehyde-3-phosphate dehydrogenase; ROS, reactive oxygen species; HK, hexokinase; CK, creatine kinase; ANT, adenosine
nucleotide translocase; CyD, cyclophilin D; CsA, ciclosporin A; PBR, peripheral benzodiazepine receptor.

factor-deprived PC12 cells 3 hours after the withdra-
wal of trophic support; this could be reversed by both
nerve growth factor restoration and by selegiline and
rasagiline (Wadia et al., 1998; Bar-Am et al., 2005).
It is suggested that selegiline and rasagiline alter the
relationship between Ca2 levels and cM, perhaps
by stimulation of protein synthesis, including that of
BCL-2 (Wadia et al., 1998) (Figs. 34.6 and 34.7).
Both rasagiline and selegiline prevent the transloca-
tion of proapoptic glyceraldehyde-3-phosphate dehy-
drogenase (GAPDH) in neuronal cells from
cytoplasm to the nucleus (Maruyama et al., 2001).
Paterson et al. (1990) reported that the R-isomers of
selegiline and 2-heptyl-N-methylpropargylamine
inhibited cytosine arabinoside (ara C)-induced apop-
tosis in a primary cerebellar granule neuronal culture,
but not that elicited by low K levels. It is perhaps
significant that ara C-, but not K-induced apoptosis
is associated with impaired mitochondrial function.
Rasagiline shares all the properties of selegiline in
terms of the molecular mechanisms described for
selegiline in its neuroprotection and neurorescue
activity (Figs. 34.6 and 34.7: see Youdim et al.,
2005 for review). Recent studies have clearly indi-
cated that the neuroprotective neurorescue activity
of these propargylamine resides in the propargyl moi-
ety, since propargylamine itself has a similar mechan-
ism of action with almost identical potency (Weinreb
et al., 2004; Bar-Am et al., 2005) (Fig. 34.8).
Tatton and Chalmers-Redman (1996) reported that
desmethylselegiline (DMS), not selegiline, was respon-
sible for the antiapoptotic effect in their cell culture
systems. Given the kinetics of selegiline metabolism
and its oral bioavailibility, however, they considered
it unlikely that DMS would play a major part in the
observed clinical benefits of selegiline, as oral delivery
allows it to exhibit only an estimated 520% of its anti-
apoptotic potential. DMS is also an MAO-B inhibitor,
but less potent than selegiline (Borbe et al., 1990). It
is therefore unlikely that MAO-B inhibition accounts
for its actions. In contrast, Magyar et al. (1998) found
DMS to be only weakly antiapoptotic in a human mel-
anoma cell line. The amphetamine metabolites of sele-
giline, on the other hand, antagonize the antiapoptotic
effects of selegiline and rasagiline (Bar-Am et al.,
2004a) (Fig. 34.9), and at high concentrations are proa-
poptotic (Tatton and Chalmers-Redman, 1996). Salo
and Tatton (1992) compared the rescue phenomena
they had observed with those which can be achieved
with ciliary neurotrophic factor, and demonstrated
that astrocytic ciliary neurotrophic factor mRNA
expression is, in fact, upregulated by selegiline
(Seniuk et al., 1994). Further, Kragten et al. (1998)
reported that the selegiline analog CGP 3466 lacks
MAO-B-inhibitory activity but is neuroprotective
in a human neuroblastoma cell line; this activity
was shown to be dependent on specific binding to
the enzyme glyceraldehyde-3-phosphatase. Thiffault
106 M. B. H. YOUDIM AND P. F. RIEDERER

Fig. 34.8. For full color figure, see plate section. The proposed schematic pathway of the neuroprotective-neurorescue activity
of rasagiline and propargylamine and their ability to process amyloid precursor protein (APP) via activation of a-secretase to
release the neuroprotective-neurotrophic soluble amyloid protein-alpha (sAPPa). Both propargylamines activate PKC and ERK
pathways and the inhibitors of PKC (GF109203X and Calpbestin) and ERK1/2 (PD98059 and UO126) prevent
their neuroprotective activity. P-PKC, pan protein kinase C; P-ERK, extracellular signal regulation kinase; BDNF, brain-
derived neurotrophic factor; GMDF, glia-derived neurotrophic factor.

1200

1000
Cell death (% of control)

*
800

** *
600 ** **
**
400

200

0
C SF R R+A R+AI S S+A A+AI A AI
Fig. 34.9. Neurorescue of partially differentiated PC-12 cells in serum-free cultures by rasagiline and selegiline and their pre-
vention by methamphetamine metabolites of selegiline. but not by aminoindan. C, control; R, rasagiline; S, selegiline; A,
methamphetamine; AI, aminoindan; SF, serum free.
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE
et al. (1997), however, found that no long-term benefit
(30 days posttreatment) was affected by either selegi-
line or mofegiline with respect to MPTP-induced
nigral cell loss in mice. A recent similar study with
post-MPTP chronic rasagiline treatment has shown
neurorescue of DA neurons, which has been attributed
to its ability to induce protein kinase C (PKC)-depen-
dent-mitogen-activated protein (MAP) kinase path-
way resulting from activation and translocation of
PKCa and b and phosphorylation of ERK1/2
(Yogev-Falach et al., 2003; Weinreb et al., 2004; Sagi
et al., 2006) (Fig. 34.8).
Rasagiline has demonstrated neuroprotective prop-
erties in a variety of models of neuroinsult, including
closed-head injury in mice and facial nerve axotomy
in newborn rats, and in several models of acute drug-
induced dopaminergic motor and cognition impair-
ment; selegiline was also effective in several of these
models, but there was no correlation between the
potency of the two inhibitors (Mytilineou et al.,
1997a, b; Speiser et al., 1998a, b). In vitro, rasagiline
rescued nerve cells and increased the percentage of
tyrosine hydroxylase-positive cells in serum depriva-
tion-induced apoptosis (Finberg et al., 1996) and selegi-
line increased the proportion of tyrosine hydroxylase-
positive cells without increasing total cell number,
whereas mofegiline and Ro 166491 were ineffective
in similar experiments (Tatton et al., 1994). Both rasa-
giline and selegiline were found to promote the survival
of rat E14 mesencephalic dopaminergic cells in culture,
but not of co-cultured GABAergic cells; rasagiline,
but not selegiline, also displayed this effect under
serum-free conditions (Finberg et al., 1998a, b).
The effects of the rasagiline metabolite L-aminoin-
dane, only observed at high doses, were distinct from
those of rasagiline itself (Speiser et al., 1997). L-Ami-
noindane has no amphetamine-like properties, but its
structural similarity to benzylamine suggests that it
may be a reversible MAO-B inhibitor (Fowler et al.,
1980). Unlike the methamphetamine metabolite of sele-
giline, which interferes with neuroprotective and neuror-
escue activity of rasagiline and selegiline, such an effect
is not seen with aminoindane and aminoindane may have
neuroprotective activity (Bar-Am et al., 2004b).
Tatton and Chalmers-Redman (1996) reported that
selegiline alters the expression of some 50 or more
glial and neuronal proteins whose synthesis is modu-
lated. Of these, 10 have been identified: the levels of
both forms of superoxide dismutase, glutathione per-
oxidase, tyrosine hydroxylase, BCL-2, BCL-XL and
c-FOS mitochondrial NADH dehydrogenase were
increased; however the levels of BAX and c-JUN,
two proteins associated with the initiation of apoptosis,
were decreased. Very similar results have also been
107
obtained with rasagiline (Maruyama et al., 2002,
2004; Naoi et al., 2003; Youdim et al., 2003, 2005).
These changes were selective and did not represent a
general increase in cellular synthetic activity. It was
therefore proposed that the propargyl moiety of rasagi-
line initiates a transcriptional program which removes
the cell from the apoptotic pathway, probably by stabi-
lizing the mitochondrial membrane and reducing oxi-
dative stress (Tatton and Chalmers-Redman, 1996).
These changes are not attributable to MAO-B inhibi-
tion, since propargylamine is a very poor MAO inhibi-
tor. Furthermore, the recent studies with the S-optical
isomer of rasagiline, TVP-1022, a drug that is 1000
times less potent than MAO inhibitors, have shown
that MAO inhibition is not a prerequisite for neuropro-
tection. TVP 1022 shares a similar molecular mechan-
ism of neuroprotection (Youdim et al., 2001b). It has
now been established that the neuroprotective activity
resides in the propargyl moiety, since propargylamine
has similar activity, with the same potency in neuronal
cell culture studies (Weinreb et al., 2004; Bar-Am
et al., 2005).
Selegiline increases the number of glial fibrillary
acidic protein (GFAP)-immunoreactive astrocytes in
rat striatum (Biagini et al., 1993) and subchronic treat-
ment with selegiline lead to an increase in the number
of GFAP- and basic fibroblast growth factor (bFGF)-
positive astrocytes following a mechanical lesion of
the rat brain (Biagini et al., 1994). The proliferation
of such cells is normally associated with CNS injury,
and represents the first stage of the neurotrophin-
mediated repair process. Revuelta et al. (1997) treated
rats with selegiline 3 weeks before and 3 weeks after
the unilateral transection of the medial forebrain bun-
dle; although the density of GFAP-positive astrocytes
was elevated in the drug-treated animals in both the
lesioned and unlesioned substantia nigra (but not stria-
tum), the treatment did not reduce the axotomy-
induced degeneration of the nigrostriatal system.
In dopaminergic cell cultures exposed to MPP,
high-dose selegiline (110 M), administered on the
day following toxin exposure, improved cell survival
rate significantly, possibly via stimulation of neurotro-
phin synthesis (Koutsilieri et al., 1996). Selegiline is
also reported to stimulate synthesis of interleukins-1
and -6 in cultured peripheral blood mononuclear cells
from healthy volunteers (Wilfried et al., 1997; Muller
et al., 1998). Elevated cerebrospinal fluid levels of
these trophins have been reported in untreated de novo
Parkinsons and Alzheimers disease patients (Blum-
Degen et al., 1996), suggesting that their increased
synthesis may be an early response to the underlying
disease process. Furthermore, selegiline and rasagiline
elevated the nerve growth factor GDNF and BDNF
108 M. B. H. YOUDIM AND P. F. RIEDERER
concentration in an astrocyte and SHSY-5Y cell cul- symptomatic control of parkinsonism the safety profile
tures (Semokova et al., 1996; Maruyama et al., 2004). of selegiline (510 mg/day) is good and no precaution is
necessary at these dosages. Clinical studies designed to
34.10. Other properties of MAO-B inhibitors identify clinical neuroprotection point to the prevention
of disease progression. This conclusion was drawn from
Selegiline suppresses the degradation of putrescine, a key an evidence-based review (Goetz et al., 2002) of the
molecule in the regulation of polyamine synthesis. Poly- Movement Disorder Society, in which levels of therapeu-
amines, such as spermine and spermidine, are stored and tic measures in Parkinsons disease were analyzed.
synthesized in brain microglia, and are believed to play a Tables 34.434.6 (from Riederer et al., 2004) give a
number of roles in the CNS (for review, see Zappia and closer view on prospective, randomized, double-blind
Pegg, 1988), including the modulation of N-methyl-D- and placebo-controlled studies with 510 mg/day selegi-
aspartate (NMDA) receptor activity (Williams et al., line monotherapy in Parkinsons disease (Table 34.4), of
1991), whose activation plays a central role in excito- selegiline as an adjunct to levodopa (Table 34.5) and sele-
toxic damage to the CNS. The N1-acetylated versions gilines efficacy for clinical neuroprotection in Parkin-
of these polyamines are themselves good MAO-B sons disease (Table 34.6). Forty years of experience
substrates; the suppression of the metabolism of these with selegiline in the treatment of Parkinsons disease
precursors and of putrescine should therefore lead to have indicated that selective inhibition of MAO is a useful
diminished sensitivity of the NMDA receptor, and thus therapeutic concept for both the early and advanced
offer a direct connection between MAO-B inhibition phases of this progressive disorder. In addition, basic
and neuroprotection by selegiline and rasagiline (Youdim research points to the efficacy of selegiline as a possible
and Riederer, 1993b). neuroprotective drug. However, this could not be demon-
strated by the state-of-the-art clinical trials designed at the
34.11. Clinical aspects of MAO-B inhibitors
in Parkinsons disease
Table 34.4
The major clinical indications of selective MAO-A Symptomatic efficacy of selegiline monotherapy
inhibitors are for depressive disorders, anxiety disorders in Parkinsons disease
and, more recently, Parkinsons disease. In addition, the
selective reversible MAO-A inhibitor moclobemide has Author (year) N Results
shown minor indications for attention-deficit hyperac- Parkinson Study 800 Motor UPDRS (1 vs 3 months)
tivity syndrome, smoking cessation and cognitive Group (1989) Placebo 16.8 / 17.5
deficits in dementia. By contrast, selective MAO-B Selegiline 15.7 / 15.8
inhibitors have primarily found use in Parkinsons dis- Myllyla et al. 52 Disability significant less in the
ease and there may be some indications in Alzheimers (1992) selegiline group up to 12
disease. Nevertheless, high dosage of selegiline, which months
loses its selectivity and inhibits MAO, has been Allain et al. 93 Significant better motor UPDRS
reported to possess antidepressant activity. (1993) and depression scores at 3
The clinical applications of MAOIs in depressive dis- months in the selegiline group
Mally et al. 20 Significant change in motor
orders and anxiety disorders have been reviewed in
(1995) behavior and daily activity
detail by Riederer et al. (2004): the focus here is on the (UPDRS) after 3 weeks at 10
clinical use of the new irreversible type B-MAO inhibi- mg selegiline. Total UPDRS
tor rasagiline. Also some comparison has been made to scores and North Western
selegiline, which has been in clinical use since 1975. ratings were changed
significantly after 4 weeks.
34.11.1. Selegiline Greatest changes in walking
and in hypokinesia, rigidity
Selegilines potential as an antiparkinson drug has been were not modified by selegiline
reviewed in numerous studies (Riederer and Lachen- Palhagen et al. 157 Change in total UPDRS at 6
mayer, 2003; Riederer et al., 2004). From these clinical (1998) weeks and 3 months:
Placebo 25.3 / 1.75.4
studies it has been concluded that selegiline is efficacious
Selegiline 0.45.0 / 15.3
as monotherapy and that there is evidence for a sympto-
matic effect as adjunct therapy (Goetz et al., 2002). There Prospective, randomized, double-blind, placebo-controlled studies.
is, however, insufficient evidence for the ability of selegi- UPDRS, Unified Parkinsons Disease Rating Scale.
line to prevent or control motor complications. In the From Riederer et al. (2004).
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE 109
Table 34.5
Selegiline as adjunct to levodopa (symptomatic efficacy)

Author (year) N Results

Przuntek and Kuhn 21 Significant improvement in CURS and Schoppe motor performance series in 2/3 of cases
(1987) on adjunct selegiline
Sivertsen et al. (1989) 38 No significant difference in total CURS and scores for rigidity and funcitonal performance
Larsen et al. (1999) 163 Patients treated with levodopa selegiline developed markedly less severe parkinsonism
and required lower doses of levodopa during the 5-year study period
Przuntek et al. (1999) 116 Over 5 years, only a slight rise of levodopa dose in the selegiline group, but marked rise in
the placebo group. Equal therapeutic efficacy in the selegiline group with lower
levodopa dose
Shoulson et al. (2002) 368 During 2-year follow-up:
Selegiline: 34% dyskinesias, 16% freezing,
change in total UPDRS 7.0612.7
Placebo: 19% dyskinesia, 29% freezing,
change in total UPDRS 1.5110.4

Prospective, randomized, double-blind, placebo-controlled studies.

CURS, Columbia University Rating Scale; UPDRS, Unified Parkinsons Disease Rating Scale.
From Riederer et al. (2004).

Table 34.6
Neuroprotection in Parkinsons disease by selegiline

Authors (year) Name of the study N Result

Tetrud and Langston (1990) Pilot study for 54 Endpoint (levodopa)

DATATOP
Parkinson Study Group DATATOP
(1993a, b, 1989)
Myllyla et al. (1992) Finnish trial
Allain et al. (1993) French selegiline
multicentre trial
Olanow et al. (1995) SINDEPAR
Przuntek et al. (1999) SELEDO
Placebo 312. days
Selegiline 548.9 days
800 Endpoint (levodopa)
After 12 months:
Placebo 47%
Selegiline 26%
47 Endpoint (levodopa)
Placebo 37228 days
Selegiline 54590 days
93 Endpoint (levodopa)
After 3 months:
Placebo 18.4%
Selegiline 4.5%
101 Deterioration in UPDRS between
baseline and final visit (14 months)
Placebo 5.81.4 points
Selegiline 0.41.3 points
116 Primary endpoint: need for >50%
increase in levodopa dose
Placebo 2.6 years
Selegiline 4.9 years

UPDRS, Unified Parkinsons Disease Rating Scale.

From Riederer et al. (2004).
110 M. B. H. YOUDIM AND P. F. RIEDERER
time selegiline was being studied (Riederer and Lachen-
mayer, 2003).
34.11.2. Zydis selegiline
Zydis selegiline is a new galenic form of selegiline
HCl, a freeze-dried product which is taken as a melt
tablet (Clarke et al., 2003a). The reason for develop-
ing this drug derives from the fact that selegiline is a
sympathomimetic agent and it is administered orally.
It undergoes a first-pass metabolization in the liver,
which leads to 90% breakdown of the parent com-
pound into its metabolites amphetamine and metam-
phetamine. These metabolites and selegiline itself are
thought to be responsible for its side-effects cardio-
vascular disturbances (Churchyard et al., 1997). This
may not be a selegiline-specific problem according to
the numerous clinical publications over the last 40
years (Birkmayer et al., 1985, Gerlach et al., 2003).
Nevertheless it is important to avoid amphetamine
and metamphetamine cardiovascular effects (Abassi
et al., 2004). Zydis selegiline, in a dose of 1.25 mg/
day, avoids the first-pass breakdown and produces a
plasma concentration to inhibit irreversibly platelet
MAO-B. This inhibition corresponds to the effect of
10 mg selegiline. Zydis selegiline is well tolerated and
reduces Unified Parkinsons Disease Rating Scale
(UPDRS) scores significantly within 12 weeks of start-
ing treatment (Clarke et al., 2003b). Double-blind, mul-
ticenter trials show that Zydis selegiline significantly
reduces daily off time at 46 weeks of treatment with
1.25 mg dose by 9.9% (P 0.003) and at 1012 weeks
with the 2.5 mg dose by 13.2% (P < 0.001). The total
number of off hours could be reduced by 2.2 hours/
day at week 12 from baseline, whereas this value was
only 0.6 hours/day in the placebo group. Dyskinesia-
free time increased by 1.8 hours/day at week 12. There
was no difference in adverse reactions between the
patient groups receiving Zydis selegiline and placebo
(Waters et al., 2004).
34.11.3. Rasagiline (Azilect, Agilect)
In a phase II evaluation, rasagiline mesylate has been
administered to de novo parkinsonian patients in a
10-week, placebo-controlled and randomized trial
using dosages of up to 4 mg/day. Specific attention
has been given to cardiovascular parameters, since this
inhibitor, unlike selegiline, has no sympathomimetic
activity and is metabolized to aminoindan rather than
amphetamine derivatives (Abassi et al., 2004). Rasagi-
line is 1015 times more active than selegiline and was
well tolerated in all doses (0.52 mg/day) used. There
was no evidence of side-effects like hypertension, brady-
cardia or other cardiovascular adverse reactions (Marek
et al., 1997) and side-effects are no more frequent than
with placebo.
Based on these data, a controlled trial of rasagiline in
early Parkinsons disease, the TEMPO study (Parkinson
Study Group, 2002) has been performed. The goal of this
clinical examination was to demonstrate the efficacy,
safety and tolerability of rasagiline in untreated patients
with early Parkinsons disease by conducting a rando-
mized, placebo-controlled and double-blind trial over 6
months. A first report was published by the Parkinson
Study Group in 2002. A total of 138 patients entered
the study taking placebo, whereas 134 were receiving 1
mg/day rasagiline and another 132 were receiving 2
mg/day monotherapy respectively. In the placebo group
112 patients completed 26 weeks without additional
therapy: this figure was 111 in the group receiving 1
mg/day rasagiline and 105 patients in the group on 2
mg/day rasagiline. The TEMPO study clearly demon-
strated that rasagiline monotherapy was effective in this
26-week clinical trial. Table 34.7 shows this significant
improvement in UPDRS scores and subscales for rasagi-
line at 1 and 2 mg/day versus placebo. Table 34.8 gives
evidence that there were no adverse events experienced
by either treatment group.
In a second phase of that trial (Parkinson Study
Group, 2004) subjects randomized to 1 or 2 mg/day
of rasagiline continued to receive this dosage, whereas
patients previously taking placebo received rasagiline
at 2 mg/day. This clinical design is named delayed-
onset clinical trial and considers symptomatic effi-
cacy of a drug as well as possible disease-modifying
related activity to neuroprotective effect (Leber,
1997). This study demonstrated that rasagiline is effec-
tive even 1 year after start of treatment. Subjects treated
with rasagiline, 2 and 1 mg/day, for 12 months showed
less functional decline than subjects whose treatment
was delayed for 6 months, suggesting its possible dis-
ease-modifying activity (Table 34.9). Again, there was
no evidence for group differences with regard to
adverse events (Parkinson Study Group, 2004).
In the PRESTO study (Parkinson Study Group,
2005), safety, tolerability and efficacy of rasagiline
in levodopa-treated parkinsonian patients and motor
fluctuations have been studied. A total of 472 patients
were enrolled with at least 2.5 hours off time each day,
despite being on optimized antiparkinsonian therapy.
In this multicenter, randomized placebo-controlled,
double-blind, parallel-group clinical trial, rasagiline
was used in doses of 1.0 or 0.5 mg/day in comparison
to placebo. Outcome measures were changed from
baseline in total daily off time during the 26-week
treatment, in the percentage of patients completing
the 26-week trial and in adverse event frequency.
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE 111
Table 34.7
Primary analysis of changes between baseline and 26 weeks

Effect size (95% confidence interval)

Characteristic Rasagiline 1 mg/day groups vs placebo Rasagiline 2 mg/day group vs placebo

Total UPDRS score 4.20 (5.66 to 2.73) 3.56 (5.04 to 2.08)

UPDRS motor subscale 2.71 (3.86 to 1.55) 1.68 (2.84 to 0.51)
ADL subscale 1.04 (1.60 to 0.48) 1.22 (1.78 to 0.65)
Mental subscale 0.14 (0.44 to 0.15) 0.26 (0.56 to 0.04)
PIGD subscale 0.15 (0.41 to 0.11) 0.20 (0.46 to 0.06)
Rigidity 0.38 (0.80 to 0.039) 0.39 (0.81 to 0.02)
Tremor 0.63 (1.03 to 0.23) 0.38 (0.78 to 0.02)
Bradykinesia 1.51 (2.19 to 0.82) 0.77 (1.47 to 0.08)
Schwab and England ADL stage 0.77 (0.42 to 1.96) 0.39 (0.81 to 1.58)
Hoehn and Yahr stage 0.04 (0.13 to 0.04) 0.04 (0.13 to 0.04)
PDQUALIF scale 2.91 (5.19 to 0.64) 2.74 (5.02 to 0.45)
Beck Depression Inventory 0.35 (0.86 to 0.16) 0.21 (0.72 to 0.30)
Timed motor score 0.55 (1.19 to 0.08) 0.36 (1.00 to 0.28)

UPDRS, Unified Parkinsons Disease Rating Scale; ADL, activities of daily living; PIGD, postural instability/gait disorder; PDQUALIF,
Parkinsons Disease Quality of Life.
Primary outcome variable adjusted according to the primary model.
Center-treatment interaction included if significant.
Reproduced from Parkinson Study Group (2002), with permission from Archives of Neurology.

Table 34.8
Adverse events by treatment group*

Placebo group Rasagiline 1 mg/day Rasagiline 2 mg/day Combined rasagiline

Adverse events (n 138) group (n 134) group (n 132) groups (n 266)

Any event 110 (79.7) 109 (81.3) 111 (84.1) 220 (82.7)
Any event (moderate or 63 (45.7) 58 (43.3) 60 (45.5) 118 (44.4)
severe intensity)
Infection 22 (15.9) 20 (14.9) 21 (15.9) 41 (15.4)
Headache 14 (10.1) 19 (14.2) 16 (12.1) 35 (13.2)
Accidental injury 14 (10.1) 10 (7.5) 10 (7.6) 20 (7.5)
Dizziness 15 (10.9) 9 (6.7) 10 (7.6) 19 (7.1)
Astheniay 15 (10.9) 6 (4.5) 6 (4.5) 12 (4.5)
Nausea 10 (7.2) 7 (5.2) 9 (6.8) 16 (6.0)
Arthralgia 6 (4.3) 5 (3.7) 14 (10.6) 19 (7.1)
Back pain 7 (5.1) 7 (5.2) 8 (6.1) 15 (5.6)
Pain 8 (5.8) 8 (6.0) 6 (4.5) 14 (5.3)

*Data are presented as the number (percentage) of patients. Between-groups differences were not statistically significant, unless otherwise indicated.
yP 0.03 for the difference between placebo and combined treatment groups; P 0.05, difference between placebo and each of the individual
treatment groups.
Reproduced from Parkinson Study Group (2002), with permission from Archives of Neurology.

In general, the efficacy of rasagiline at 1 mg/day
was greater than within the patient group receiving
0.5 mg/day. However, the primary outcome measure,
reduction of daily off time, could be reached in both
treatment groups, although it was much better in
the 1 mg/day patient group. UPDRS subscores were
significant with respect to improvement of activities
of daily living during off time, motor performance
during on time, rigidity and tremor in both treatment
groups.
112 M. B. H. YOUDIM AND P. F. RIEDERER
Table 34.9
Change from baseline in efficacy variables between the 371 subjects receiving 6 months and 1 year of treatment*

Rasagiline, 1 mg/day vs delayed rasagiline, Rasagiline, mg/day, vs delayed rasagiline,

Variable 2 mg/day 2 mg/day

UPDRS
Totaly 1.82 (3.64 to 0.01){ 2.29 (4.11 to 0.48)}
Motory 1.06 (2.47 to 0.34) 0.99 (2.39 to 0.41)
ADL 0.48 (1.15 to 0.19) 0.96 (2.39 to 0.29)k
Mentaly 0.16 (0.09 to 0.42) 0.07 (0.33 to 0.19)
Hoehn and Yahr scale score 0.08 (0.01 to 0.17) 0.04 (0.05 to 0.13)
Schwab and England scale score 0.21 (1.47 to 1.04) 0.15 (1.41 to 1.11)

*Data are given as effect size (95% confidence interval). Rasagiline was administered as rasagiline mesylate.
yThe model used to determine effect size includes a treatment  center interaction.
{P 0.05.
}P 0.01.
kP 0.005.
Reproduced from Parkinson Study Group (2004), with permission from Archives of Neurology.

Bradykinesia and dyskinesia improved in only the 1
mg/day group. With regard to side-effects, there was a
significant increase at 1 mg/day rasagiline in weight
loss, anorexia and vomiting. There were no group dif-
ferences with regard to blood pressure or pulse rate.
The most common serious side-effects in all three
groups were related to accidental injury (n 6), arthri-
tis, worsening Parkinsons disease, stroke, melanoma
(n 3) and urinary tract infection (n 3). One patient
was identified as having a melanoma before initiating
study medication and its occurrence is no more than
is seen with levodopa.
A further clinical trial was set up to demonstrate the
effectiveness of rasagiline as an adjunct to levodopa.
The Lasting effect in Adjunct therapy with Rasagiline
Given Once daily (LARGO) study was an 18-week,
randomized, placebo-controlled, double-blind, double-
dummy, parallel-group multicenter trial. A total of 687
outpatients were randomly assigned to oral rasagiline:
231 individuals received 1 mg once daily, 227 received
entacapone, a peripheral COMT inhibitor, 200 mg with
every levodopa dose and 229 individuals were on pla-
cebo. Primary outcomes were change in daily off time,
clinical global improvement and UPDRS scores (Rascol
et al., 2005). Table 34.10 shows that rasagiline improves
daily off time significantly and at the same rate as enta-
capone. In addition, daily on time without troublesome
dyskinesia improved significantly in both groups at
similar rates. UPDRS secondary analyses and ancillary
study efficacy assessment showed equipotency of rasagi-
line and entacapone adjunct to levodopa (unpublished
data). There were no differences whatsoever between
placebo-, rasagiline- and entacapone-treated individuals
with regard to adverse events (Rascol et al., 2005). In
addition, rasagiline is well tolerated in patients older
than 70 years. There is no evidence for typical side-
effects of dopaminergic treatment such as daytime som-
nolence, leg edema or nausea. Treatment with rasagiline
is simple once daily without the need for titration.
Rasagiline is easy to handle as an adjunct to levodopa.
In conclusion, rasagiline may be a relatively ideal
drug once a day for the treatment of Parkinsons dis-
ease both in the early stages as monotherapy and in
advanced stages in combination with levodopa. Its
efficacy is equal to that of entacapone. Rasagiline
reduces significantly off-time periods in patients with
motor fluctuations and improves daily on time without
troublesome dyskinesias. The drug is well tolerated
and does not show adverse events, even after long-
term treatment. Rasagiline has the potential to demon-
strate clinical neuroprotection as assumed from the
1-year delayed-onset clinical trial.
34.12. Conclusion
After more than 30 years of experience with MAO and
its inhibitors, we are now in a better position to under-
stand the importance of this enzyme in brain function
and how MAO inhibitors alter the function of central
actions of monoaminergic neurotransmitters norepi-
nephrine, 5-HT and DA. The experiences gained with
selegiline (L-deprenyl), rasagiline and moclobemide
as antiparkinsonian drugs and other RIMAs have
shown that we can synthesize selective MAO-A or
MAO-B inhibitors directed at the active sites of each
enzyme, and such drugs are devoid of the unwanted
hazardous side-effects associated with the earlier
MAO inhibitors. The many clinical experiences have
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE
Table 34.10
Primary and associated efficacy assessments

Adjusted mean change from baseline to treatment (SE)

Rasagilin Entacapone Placebo Difference, rasagiline vs Difference, entacapone

(n 222) (n 218) (n 218) placebo (95% CI) P vs placebo (95% CI) P

Daily off time (h) 1.18 (015) 1.20 (015) 0.40 (015) 0.78 (1.18 to 0.39) 0.0001 0.80 (1.20 to 0.41) < 0.0001
Daily on time without troublesome dyskinesia (h) 0.85 (0.17) 0.85 (0.17) 0.03 (017) 0.82 (0.36 to 1.27) 0.0005 0.82 (0.36 to 1.27) 0.0005
Daily on time with troublesome dyskinesia (h) 0.23 (0.13) 0.18 (0.13) 0.14 (0.13) 0.09 (0.28 to 0.46) 0.6209 0.04 (0.32 to 0.41) 0.8157
Responder rate (number [%])* 113 (51%) 99 (45%) 70 (32%) 2.5y (1.62 to 3.85) < 0.0001 2.0y (1.29 to 3.06) 0.0019

Assessments measured by entries in 24-h diaries. Off-time period of poor overall function (i.e. increasing signs of Parkinsons disease). On-time period of good overall function and mobility.
*Responders were defined as patients showing an improvement of 1 h or more in the change from baseline in mean total daily off time.
yOdds ratio.
From Rascol et al. (2005).

113
114 M. B. H. YOUDIM AND P. F. RIEDERER
also educated us how to use these drugs, for an ade-
quate period and with the right dosage these were
the features that contained the inherent problems in
earlier studies with non-selective MAO inhibitors.
The present experiences with reversible MAO-A inhi-
bitors, especially moclobemide, are demonstrating
remarkable activities in different clinical settings.
The most prominent aspect of these is that moclobe-
mide is a true antidepressant with few side-effects, is
well tolerated and shows clinical antidepressant effi-
cacy and has antiparkinsonian activity. Because rever-
sible MAO-A inhibitors such as moclobemide are
showing remarkably safe action and relatively low
incidents of side-effects, it is being considered in the
treatment of mental functions in Parkinsons and Alz-
heimers diseases, in which a significant number of
these subjects (4060%) suffer from endogenous
depression. However, RIMAs are considered as mild
antidepressants and may be useful for the treatment
of subtypes of major depressions. The availability of
the novel brain-selective MAO-AB inhibitor ladosti-
gil, with limited tyramine potentiation and equivalent
or better than RIMA, will indicate whether MAO-AB
inhibition would be more effective than antiparkinso-
nian and antidepressant drugs than the selective
MAO-A or B inhibitors so far examined in PD.
Furthermore, recent clinical studies with cholinester-
ase inhibitors have demonstrated that introduction of
such drugs in Lewy body disease patients does not
interfere with their response to levodopa antiparkinso-
nian drug therapy. However, the therapeutic effects of
MAO-A or B inhibitors in Lewy body disease have not
been investigated. Thus, therapeutically there may be
a greater advantage with the use of a drug such as
ladostigil, which has multiple pharmacological
actions, namely the ability to inhibit both forms of
MAO and cholinesterase, related to the comorbidity
of neurological neurodegenerative diseases with
depressive illness.
Acknowledgments
This work was supported by National Parkinson Foun-
dation (Miami, USA), Michael J. Fox foundation (New
York), Golding Parkinson Research Fund and Eve
Topf Neurodegenerative Diseases Center (Technion,
Haifa). We are grateful for their support.
References
Abassi ZA, Binah O, Youdim MB (2004). Cardiovascular
activity of rasagiline, a selective and potent inhibitor of
mitochondrial monoamine oxidase B: comparison with
selegiline. Br J Pharmacol 143 (3): 371378.
Adolfsson R, Gottfries CG, Oreland L et al. (1980). Increased
activity of brain and platelet monoamine oxidase in
dementia of Alzheimer type. Life Sci 27: 10291034.
Akao Y, Maruyama W, Yi H et al. (2002a). An anti-Parkin-
sons disease drug, N-propargyl-1(R)-aminoindan (rasagi-
line), enhances expression of anti-apoptotic bcl-2 in
human dopaminergic SH-SY5Y cells. Neurosci Lett
326 (2): 105108.
Akao Y, Maruyama W, Shimizu S et al. (2002b). Mitochon-
drial permeability transition mediates apoptosis induced
by N-methyl(R)salsolinol, an endogenous neurotoxin,
and is inhibited by Bcl-2 and rasagiline, N-propargyl-1
(R)-aminoindan. J Neurochem 82 (4): 913923.
Allain H, Pollak P, Neukirch HC (1993). Symptomatic effect
of selegiline in de novo parkinsonian patients. The French
Selegiline Multicenter Trial. Mov Disord 8(Suppl 1):
3640.
Amrein R, Martin JR, Cameron AM (1999). Moclobemide in
patients with dementia and depression. Adv Neurol 80:
509519.
Angst J, Amrein R, Stabl M (1995). Moclobemide and tricyclic
antidepressants in severe depression: meta analysis and
prospective studies. J Clin Psychopharmacol 15: 16S23S.
Bar-Am O, Yogev-Falach M, Amit T et al. (2004a). Regulation
of protein kinase C by the anti-Parkinson drug, MAO-B
inhibitor, rasagiline and its derivatives, in vivo. J Neurochem
89 (5): 11191125.
Bar-Am O, Amit T, Youdim MB (2004b). Contrasting
neuroprotective and neurotoxic actions of respective
metabolites of anti-Parkinson drugs rasagiline and selegi-
line. Neurosci Lett 355 (3): 169172.
Bar-Am O, Weinreb O, Amit T et al. (2005). Regulation of
Bcl-2 family proteins, neurotrophic factors, and APP pro-
cessing in the neurorescue activity of propargylamine.
FASEB J 19 (13): 18991901.
Benecke R (2003). Diffuse Lewy body diseasea clinical
syndrome or a disease entity? J Neurol 250 (Suppl 1):
I39I42.
Biagini G, Zoll M, Fuxe K et al. (1993). L-deprenyl increases
GFAP immunoreactivity selectively in inactivated astro-
cytes in rat brain. Neuroreport 5: 955958.
Biagini G, Frasoldati A, Fuxe K et al. (1994). The concept of
astrocyte-kinetic drug in the treatment of neurodegenera-
tive diseases: evidence for Ldeprenyl-induced activation
of reactive astrocytes. Neurochem Int 25: 1722.
Bijl D (2004). The serotonin syndrome. Neth J Med 62 (9):
309313.
Birkmayer W, Riederer P, Youdim MB et al. (1975). The
potentiation of the anti akinetic effect after L-dopa treat-
ment by an inhibitor of MAO-B, Deprenil. J Neural
Transm 36: 303326.
Birkmayer W, Riederer P, Ambrozi L et al. (1977). Implications
of combined treatment with Madopar and L-deprenil in
Parkinsons disease. A long-term study. Lancet 1: 439443.
Birkmayer W, Knoll J, Riederer P et al. (1985). Increased
life expectancy resulting from addition of L-deprenyl to
Madopar treatment in Parkinsons disease: a longterm
study. J Neural Transm 64 (2): 113127.
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE
Blandini F, Armentero MT, Fancellu R et al. (2004).
Neuroprotective effect of rasagiline in a rodent model of
Parkinsons disease. Exp Neurol 187 (2): 455459.
Blum-Degen D, Muller T, Kuhn W et al. (1996). Interleukin-
1 beta and interleukin-6 are elevated in the cerebrospinal
fluid of Alzheimer and de novo Parkinsons disease
patients. Neurosci Lett 202: 1720.
Bonneh-Barkay D, Ziv N, Finberg JP (2005). Characteriza-
tion of the neuroprotective activity of rasagiline in
cerebellar granule cells. Neuropharmacology 48 (3):
406416.
Borbe HO, Niebch G, Nickel B (1990). Kinetic evaluation of
MAO-B-activity following oral administration of selegi-
line and desmethyl-selegiline in rat. J Neural Transm
Suppl 32: 131137.
Bosboom JL, Wolters ECh (2004). Psychotic symptoms in
Parkinsons disease: pathophysiology and management.
Expert Opin Drug Saf 3 (3): 209220.
Bridge TP, Soldo BJ, Phelps BH et al. (1985). Platelet mono-
amine oxidase activity: demographic characteristics con-
tribute to enzyme activity variability. J Gerontol 40:
2328.
Buccafusco JJ, Terry AV Jr, Goren AVJr et al. (2003). Potential
cognitive actions of (n-propargly-(3r)-aminoindan-5-yl)-
ethyl, methyl carbamate (tv3326), a novel neuroprotective
agent, as assessed in old rhesus monkeys in their perfor-
mance of versions of a delayed matching task. Neuroscience
119 (3): 669678.
Buys YM, Trope GE, Tatton WG (1995). ()-Deprenyl
increases the survival of rat retinal ganglion cells after optic
nerve crush. Curr Eye Res 14: 119126.
Cesura AM, Pletscher A (1992). The new generation of mono-
amine oxidase inhibitors. Prog Drug Res 38: 171297.
Chan-Palay V (1992). Depression and senile dementia of
Alzheimers type: a role for moclobemide. Psychopharma-
cology 106: S137S139.
Churchyard A, Mathias CJ, Boonkongchuen P et al. (1997).
Autonomic effects of selegiline: possible cardiovascular toxi-
city in Parkinsons disease. J Neurol Neurosurg Psychiatry
63 (2): 228234.
Clarke A, Johnson ES, Mallard N et al. (2003a). A new low-
dose formulation of selegiline: clinical efficacy, patient
preference and selectivity for MAO-B inhibition. J Neural
Transm 110 (11): 12571271.
Clarke A, Brewer F, Johnson ES et al. (2003b). A new formu-
lation of selegiline: improved bioavailability and selectivity
for MAO-B inhibition. J Neural Transm 110 (11):
12411255.
Collins GG, Sandler M, Williams ED et al. (1970). Multiple
forms of human brain mitochondrial monoamine oxidase.
Nature 225: 817820.
Da Prada M, Keller H, Keller R et al. (1981). Ro 111163, a
specific short acting MAO inhibitor with antidepressant
properties. In: Monoamine Oxidase. Basic and Clinical
Frontiers. Excerpta Medica, Amsterdam, pp. 183196.
Da Prada M, Zurcher G, Wuthrich I et al. (1988). On tyra-
mine, food beverages and reversible MAO inhibitor moclo-
bemide. J Neural Transm Suppl 26: 3156.
115
Eliash S, Shteter N, Eilam R (2005). Neuroprotective effect
of rasagiline, a monoamine oxidase-B inhibitor, on sponta-
neous cell degeneration in a rat model. J Neural Transm
112 (8): 9911003.
Erfurth AB, Back T (1999). Severe therapy refractory
depression as initial mainstream of Parkinsons disease.
Psychiatr Prax 26: 4647.
Finberg JP, Tenne M (1982). Relationship between tyramine
potentiation and selective inhibition of monoamine oxi-
dase types A and B in the rat vas deferens. Br J Pharmacol
77 (1): 1321.
Finberg JP, Youdim MB (2002). Pharmacological properties of
the anti-Parkinson drug rasagiline; modification of endogen-
ous brain amines, reserpine reversal, serotonergic and dopa-
minergic behaviours. Neuropharmacology 43 (7): 11101118.
Finberg JP, Tenne M, Youdim MB (1981). Tyramine antag-
onistic properties of AGN 1135, and irreversible inhibitor
of monoamine oxidase type B. Br J Pharmacol 73: 6574.
Finberg JP, Lamensdorf I, Commissiong JW et al. (1996).
Pharmacology and neuroprotective properties of rasagi-
line. J Neural Transm Suppl 48: 95101.
Finberg JP, Wang J, Bankiewicz K et al. (1998a). Increased
striatal dopamine production from L-DOPA following
selective inhibition of monoamine oxidase B by R()-N-
propargyl-1-aminoindan (rasagiline) in the monkey.
J Neural Transm Suppl 52: 279285.
Finberg JP, Takeshima T, Johnston JM et al. (1998b).
Increased survival of dopaminergic neurons by rasagiline,
a monoamine oxidase B inhibitor. Neuroreport 9: 703707.
Finberg JP, Lamensdorf I, Weinstock M et al. (1999). Pharma-
cology of rasagiline (N-propargyl-1R-aminoindan). Adv
Neurol 80: 495499.
Finnegan KT, Skratt JJ, Irwin I et al. (1990). Protection against
DSP-4-induced neurotoxicity by deprenyl is not related to its
inhibition of MAO B. Eur J Pharmacol 184: 119126.
Foley P, Gerlach M, Youdim MBH et al. (2000). MAO-B
inhibitors: multiple roles in the therapy of neurodegenera-
tive disorders? Parkinsonism Rel Disord 6 (1): 2547.
Fowler CJ, Oreland L, Marcusson J et al. (1980). Titration of
human brain monoamine oxidase -A and -B by clorgyline
and L-deprenil. Naunyn Schmiedebergs Arch Pharmacol
311: 263272.
Gerlach M, Riederer R, Przuntek R et al. (1991). MPTP
mechanisms of neurotoxicity and their implications for
Parkinsons disease. Eur J Pharmacol 208: 273286.
Gerlach M, Reichmann H, Riederer P (2003). Die Parkinson-
Krankheit Grundlagen, Klinik, Therapie. Unter Mitarbeit
von W. Gotz und U. Sommer. Dritte, uberarbeitete und
erweiterte Auflage. XVII, 368 Seiten.
Gibson CJ (1987). Inhibition of MAO-B, but not MAO-A,
blocks DSP-4 toxicity on central NE neurons. Eur J Pharma-
col 141: 135138.
Glover V, Sandler M (1993). Neurotoxins and monoamine
oxidase B inhibitors: possible mechanisms for the neuro-
protective effect of ()-deprenyl. In: I Szelenyi, (Ed.),
Inhibitors of Monoamine Oxidase B. Pharmacology and
Clinical use in Neurodegenerative Disorders. Birkhauser,
Basel, pp. 169181.
116 M. B. H. YOUDIM AND P. F. RIEDERER
Goetz CG, Koller WC, Poewe W et al. (2002). Treatment
intervention for Parkinsons disease: an evidence based
assessment. Mov Disord 17 (4): 3839.
Green AR, Grahame-Smith DG (1975). In: DG Grahame
Smith (Ed.), Handbook of Psychopharmacology, Vol. 3,
Plenum, New York, pp. 350388.
Green AR, Youdim MB (1975). Effects of monoamine oxi-
dase inhibition by clorgyline, deprenil or tranylcypromine
on 5-hydroxytryptamine concentrations in rat brain and
hyperactivity following subsequent tryptophan administra-
tion. Br J Pharmacol 55 (3): 415422.
Green AR, Mitchell BD, Tordoff AF et al. (1977). Evidence
for dopamine deamination by both type A and type B
monoamine oxidase in rat brain in vivo and for the degree
of inhibition of enzyme necessary for increased functional
activity of dopamine and 5-hydroxytryptamine. Br J Phar-
macol 60 (3): 343349.
Haefely W, Burkard WP, Cesura AM et al. (1992). Biochem-
istry and pharmacology of moclobemide, a prototype
RIMA. Psychopharmacology (Berl) 106: S6S14.
Haefely W, Burkard WP, Cesura A et al. (1993). Pharmacology
of moclobemide. Clin Neuropharmacol 16 (Suppl 2): S8S18.
Hallman H, Jonsson G (1984). Pharmacological modifications
of the neurotoxic action of the noradrenaline neurotoxin
DSP4 on central noradrenaline neurons. Eur J Pharmacol
103 (34): 269278.
Izumi T, Iwamoto N, Kitaichi Y et al. (2006). Effects of co-
administration of a selective serotonin reuptake inhibitor
and monoamine oxidase inhibitors on 5-HT-related beha-
vior in rats. Eur J Pharmacol 532 (3): 258264.
Jansen Steur EN, Ballering LA (1999). Combined and selective
monoamine oxidase inhibition in the treatment of depression
in Parkinsons disease. Adv Neurol 80: 505509.
Johnston JP (1968). Some observations upon a new inhibitor
of monoamine oxidase in brain tissue. Biochem Pharma-
col 17: 12851297.
Kalir A, Sabbagh A, Youdim MB (1981). Selective acetylenic
suicide and reversible inhibitors of monoamine oxidase
A and B. Br J Pharmacol 73: 5564.
Knoll J (1987). R-()-deprenyl (Selegiline, Movergan) facil-
itates the activity of the nigrostriatal dopaminergic neuron.
J Neural Transm Suppl 25: 4566.
Knoll J, Magyar K (1972). Some puzzling pharmacological
effects of monoamine oxidase inhibitors. Adv Biochem
Psychopharmacol 5: 393408.
Konradi C, Kornhuber J, Froelich L et al. (1989). Demonstration
of monoamine oxidase-A and -B in the human brainstem by a
histochemical technique. Neuroscience 33 (2): 383400.
Konradi C, Kornhuber J, Sofic E et al. (1992). Variations of
monoamines and their metabolites in the human brain
putamen. Brain Res 579 (2): 285290.
Korn A, Da Prada M, Raffesberg W et al. (1988). Tyramine
pressor effect in man: studies with moclobemide, a novel,
reversible monoamine oxidase inhibitor. J Neural Transm
Suppl 26: 5771.
Koutsilieri E, Chen TS, Rausch WD et al. (1996). Selegiline
is neuroprotective in primary brain cultures treated with
1-methyl-4-phenylopyridinium. Eur J Pharmacol 306:
181186.
Kragten E, Lalande I, Zimmermann K et al. (1998). Glyceral-
dehyde-3-phosphate dehydrogenase, the putative target of
the antiapoptotic compounds CGP 3466 and R-()-depre-
nyl. J Biol Chem 273: 58215828.
Lamensdorf I, Youdim MB, Finberg JP (1996). Effect of
long-term treatment with selective monoamine oxidase
A and B inhibitors on dopamine release from rat striatum
in vivo. J Neurochem 67 (4): 15321539.
Larsen JP, Boas J, Erdal JE (1999). Does selegiline modify
the progression of early Parkinsons disease? Results from
a five-year study. The Norwegian-Danish Study Group.
Eur J Neurol 6: 539547.
Lauterbach EC (2004). The neuropsychiatry of Parkinsons
disease and related disorders. Psychiatr Clin North Am
27 (4): 801825.
Le W, Jankovic J, Xie W et al. (1997). ()-Deprenyl protec-
tion of 1-methyl-4-phenylpyridium ion (MPP)-induced
apoptosis independent of MAO-B inhibition. Neurosci
Lett 224: 197200.
Leber P (1997). Slowing the progression of Alzheimer dis-
ease: methodologic issues. Alzheimer Dis Assoc Disord
11 (Suppl 5): S10S21; discussion S37S39.
Leentjens AF (2004). Depression in Parkinsons disease:
conceptual issues and clinical challenges. J Geriatr
Psychiatry Neurol 17 (3): 120126.
Lees AJ, Shaw KM, Kohout LL et al. (1977). Deprenyl in
Parkinsons disease. Lancet 2 (8042): 791795.
Magyar K (1993). Pharmacology of monoamine oxidase type
B inhibitors. In: I Szelenyi, (Ed.), Inhibitors of Monoamine
Oxidase B. Pharmacology and Clinical Use in Neurodegen-
erative Disorders. Birkhauser, Basel, pp. 125143.
Magyar K (1994). Behaviour of ()-deprenyl and its analo-
gues. J Neural Transm Suppl 41: 167175.
Magyar KB, Szende J, Lengyel J et al. (1998). The neuropro-
tective and neuronal rescue effects of ()-deprenyl. J Neural
Transm 52 (Suppl): 109123.
Mally J., Kovacs AB., Stone TW. (1995). Delayed develop-
ment of symptomatic improvement by ()-deprenyl in
Parkinsons disease. J. Neurol. Sci., 134: 143145.
Mann J, Gershon S (1980). L-deprenyl, a selective monoa-
mine oxidase type-B inhibitor in endogenous depression.
Life Sci 26: 877882.
Mann JJ (1989). A controlled study of antidepressant efficacy
and side effects of ()-deprenyl. A selective monoamine
oxidase inhibitor. Arch Gen Psychiatry 46: 4550.
Marek KL, Friedman J, Hauser R et al. (1997). Phase II
evaluation of rasagiline mesylate (TVP-1012), a novel
anti-parkinsonian drug, in parkinsonian patients not using
levodopa/carbidopa. Mov Disord 12: 838846.
Maruyama W, Akao Y, Youdim MB et al. (2001). Transfec-
tion-enforced Bcl-2 overexpression and an anti-Parkinson
drug, rasagiline, prevent nuclear accumulation of glyceral-
dehyde-3-phosphate dehydrogenase induced by an endo-
genous dopaminergic neurotoxin, N-methyl(R)salsolinol.
J Neurochem 78 (4): 727735.
Maruyama W, Akao Y, Carrillo MC et al. (2002). Neuropro-
tection by propargylamines in Parkinsons disease: sup-
pression of apoptosis and induction of prosurvival genes.
Neurotoxicol Teratol 24 (5): 675682.
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE
Maruyama W, Weinstock M, Youdim MB et al. (2003).
Anti-apoptotic action of anti-Alzheimer drug, TV3326
[(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carba-
mate, a novel cholinesterase-monoamine oxidase inhibitor.
Neurosci Lett 341 (3): 233236.
Maruyama W, Nitta A, Shamoto-Nagai M et al. (2004).
N-Propargyl-1(R)-aminoindan, rasagiline, increases glial
cell line-derived neurotrophic factor (GDNF) in neuroblas-
toma SH-SY5Y cells through activation of NF-kappaB
transcription factor. Neurochem Int 44 (6): 393400.
Marzo A, Dal Bo L, Monti NC et al. (2004). Pharmacokinetics
and pharmacodynamics of safinamide, a neuroprotectant
with antiparkinsonian and anticonvulsant activity. Pharma-
col Res 50 (1): 7785.
Mendlewicz J, Youdim MB (1978). Anti-depressant poten-
tiation of 5-hydroxytryptophan by L-deprenyl, an MAO
type B inhibitor. J Neural Transm 43: 279286.
Mendlewicz J, Youdim MBH (1979). Anti-depressant poten-
tiation of 5-hydroxytrytophan by l-deprenyl in affective
disorder. J Aff Disord 2: 137146.
Mendlewicz J, Youdim MBH (1983). L-Deprenil, a selective
monoamine oxidase type B inhibitor, in the treatment of
depression: a double blind evaluation. Br J Psychiatry
142: 508511.
Mosimann UP, McKeith IG (2003). Dementia with Lewy
bodiesdiagnosis and treatment. Swiss Med Wkly
133 (910): 131142.
Mossner R, Henneberg A, Schmitt A et al. (2001). Allelic
variation of serotonin transporter expression is associated
with depression in Parkinsons disease. Mol Psychiatry
6 (3): 350352.
Murphy DL, Wright C, Buchsbaum M et al. (1976). Platelet
and plasma amine oxidase activity in 680 normals: sex and
age differences and stability over time. Biochem Med 16:
254265.
Muller T, Kuhn W, Kruger R et al. (1998). Selegiline as
immunostimulanta novel mechanism of action? J Neural
Transm Suppl 52: 321328.
Myllyla VV., Sotaniemie KA., Vuorinen JA., Heinonen EH.
(1992). Neurology, 42: 339343.
Mytilineou C, Radcliffe PM, Olanow CW (1997a). L-()-
desmethylselegiline, a metabolite of selegiline [L-()-
deprenyl], protects mesencephalic dopamine neurons
from excitotoxicity in vitro. J Neurochem 68 434436
Clarke A, Brewer F, Johnson ES et al. (1997a). A new
formulation of selegiline: improved bioavailability and
selectivity for MAO-B inhibition. J Neural Transm
110 (11): 12411255.
Mytilineou C, Radcliffe P, Leonardi EK et al. (1997b).
L-deprenyl protects mesencephalic dopamine neurons
from glutamate receptor-mediated toxicity in vitro. J Neu-
rochem 68: 3339.
Naoi M, Maruyama W, Youdim MB et al. (2003). Anti-apoptotic
function of propargylamine inhibitors of type-B monoamine
oxidase. Inflammopharmacology 11 (2): 175181.
Nieuwstraten C, Labiris NR, Holbrook A (2006). Systematic
overview of drug interactions with antidepressant medica-
tions. Can J Psychiatry 51 (5): 300316.
117
OCarroll AM, Fowler CJ, Phillips JP et al. (1983). The dea-
mination of dopamine by human brain monoamine oxidase.
Arch Pharmacol 322: 198223.
Olanow C.W. Hauser R.A., Gauger L, Malaparia T, Koller W,
Hubble J, Bushenbark K, Lilienfeld D, Esterlitz J (1995).
The effect of deprenyl and levodopa on the progression of
Parkinsons disease. J. Ann. Neurol, 38: 771777.
Palhagen S, Heinonen EH., Hagglund J, Kaugesaar T., Kontants
H, Maki-Ikola O, Palm R., Turunen j. (1998). Selegiline
delays the onset of disability in de novo parkinsonian patients.
Swedish Parkinson Study Group. J Neurol 51: 520525.
Parkinson Study Group (1989). Effect of deprenyl on the
progression of disability in early Parkinsons disease. The
Parkinson Study Group. N. Engl. J. Med., 321: 13641371.
Parkinson Study Group (1993a). A controlled trial of lazabe-
mide (RO196327) in untreated Parkinsons disease. Ann.
Neurol., 33: 350356.
Parkinson Study Group (1993b). Effects of Tocopherol and
Deprenyl on the Progression of Disability in Early Parkin-
sons Disease. New Engl. J. Med., 328: 176183.
Parkinson Study Group (2002). A controlled trial of rasagi-
line in early Parkinson disease: the TEMPO Study. Arch
Neurol 59 (12): 19371943.
Parkinson Study Group (2004). A controlled, randomized,
delayed-start study of rasagiline in early Parkinson dis-
ease. Arch Neurol 61 (4): 561566.
Parkinson Study Group (2005). A randomized placebo-
controlled trial of rasagiline in levodopa-treated patients
with Parkinson disease and motor fluctuations: the PRE-
STO study. Arch Neurol 62 (2): 241248.
Paterson IA, Tatton WG (1998). Antiapoptotic actions of mono-
amine oxidase B inhibitors. Adv Pharmacol 42: 312315.
Paterson IA, Boulton AA, Juorio AV (1990). Phenylethyla-
mine in the CNS: effects of monoamine oxidase inhibiting
drugs, deuterium substitution and lesions and its role in the
neuromodulation of catecholaminergic neurotransmission.
J Neural Transm Suppl 29: 119129.
Paterson IA, Zhang D, Warrington RC et al. (1998).
R-deprenyl and R-2-heptyl-N-methylpropargylamine pre-
vent apoptosis in cerebellar granule neurons induced by
cytosine arabinoside but not low extracellular potassium.
J Neurochem 70: 515523.
Paykel E, Youdim MBH (Eds.) (1993). Monoamine oxidase
inhibitors: new developments. Clin Neuropharmacol 16
(Suppl 2): 96212.
Priest RG (1992). Moclobemide: a range of opportunities.
Psychopharmacology (Berl) 106: S140S141.
Przuntek H., Kuhn W. (1987). The effect of R-()-deprenyl
in de novo Parkinson patients on combination therapy with
levodopa and decarboxylase inhibitor. J. Neural Transm
25: 97104.
Przuntek H., Conrad B., Dichgans J., Kraus PH., Krauseneck P.,
Pergande G., Rinne U., Schimrigk K., Schnitker J., Vogel
HP. (1999). SELEDO: a 5-year long-term trial on the effect
of selegiline in early Parkinsonian patients treated with
levodopa. J. Neurol. 6: 141150.
Rascol O, Brooks DJ, Melamed E et al. (2005). LARGO Study
Group. Rasagiline as an adjunct to levodopa in patients with
118 M. B. H. YOUDIM AND P. F. RIEDERER
Parkinsons disease and motor fluctuations (LARGO, Last-
ing effect in Adjunct therapy with Rasagiline Given Once
daily, study): a randomised, double-blind, parallel-group
trial. Lancet 365 (9463): 947954.
Ravikumar R, Lakshmana MK, Rao BS et al. (1998).
()-Deprenyl attenuates spinal motor neuron degeneration
and associated locomotor deficits in rats subjected to spinal
cord ischemia. Exp Neurol 149: 123129.
Revuelta M, Venero JL, Machado A et al. (1997). Deprenyl
induces GFAP immunoreactivity in the intact and injured
dopaminergic nigrostriatal system but fails to counteract
axotomy-induced degenerative changes. Glia 21: 204216.
Riederer P, Lachenmayer L (2003). Selegilines neuroprotective
capacity revisited. J Neural Transm 110 (11): 12731278.
Riederer P, Youdim MBH (1986). Human brain monoamine
oxidase activity and monoaminemetabolism in Parkinso-
nian patients treated with L-deprenyl. J Neurochem 45:
13491356.
Riederer P, Konradi C, Schay V et al. (1986). Location of
MAO-A and MAO-B in human brain, a step in under-
standing the therapeutic action of L-deprenyl. Adv Neurol
45: 111119.
Riederer P, Lachenmayer L, Laux G (2004). Clinical applica-
tions of MAO-inhibitors. Curr Med Chem 11: 20332043.
Rihmer Z, Seregi K, Rihmer A (2004). Parkinsons disease
and depression. Neuropsychopharmacol Hung 6 (2): 8285.
Roy E, Bdard PJ (1993). Deprenyl increases survival of rat
foetal nigral neurones in culture. Neuroreport 4: 11831186.
Sagi Y, Weinstock M, Youdim MB (2003). Attenuation of
MPTP-induced dopaminergic neurotoxicity by TV3326,
a cholinesterase-monoamine oxidase inhibitor. J Neuro-
chem 86 (2): 290297.
Sagi Y, Mandel S, Amit L et al. (2006). Activation of tyro-
sine kinase receptor signaling pathway by rasagiline facil-
itates neurorescue and restoration of nigrostriatal
dopamine neurons in post-MPTP-induced parkinsonism.
Neurobiol Dis 25 (1): 3544.
Salo PT, Tatton WG (1992). Deprenyl reduces the death of moto-
neurons caused by axotomy. J Neurosci Res 31: 394400.
Sautter J, Gerlach M, Schwarz J et al. (1994). TVP-1012, an
irreversible MAO-B-inhibitor protects against MPTP-
neurotoxicity in the monkeycomparison with deprenyl.
11th International Symposium on Parkinsons Disease,
Rome, March 2630.
Schmidt DE, Ebert MH, Lynn JC et al. (1997). Attenuation
of 1-methyl-4-phenylpyridinium (MPP) neurotoxicity
by deprenyl in organotypic canine substantia nigra cul-
tures. J Neural Transm 104: 875885.
Semokova I, Wolz P, Schilling M et al. (1996). Selegiline
enhances NGF synthesis and protects central nervous sys-
tem (CNS) neurons from excitotoxic and ischemic damage.
Eur J Pharmacol 315: 1930.
Seniuk NA, Henderson JT, Tatton WG et al. (1994). Increased
CNTF gene expression in process-bearing astrocytes fol-
lowing injury is augmented by R()-deprenyl. J Neurosci
Res 37: 278286.
Shoulson I., Oakes D., Fahn S., Lang A., Langston J.W.,
LeWitt P., Olanow C.W., Penney J.B., Tanner C., Kieburtz
K., Rudolpha A., Parkisnon Study Group. (2002). Impact of
sustained deprenyl (selegiline) in levodopa-treated Parkin-
sons disease: a randomized placebo-controlled extension
of the deprenyl and tocopherol antioxidative therapy of par-
kinsonism trial. J. Ann. Neurol., 51: 604612.
Sieradzan K, Chanon S, Stern G et al. (1995). The therapeu-
tic potential of moclobemide, a reversible selective mono-
amine oxidase A inhibitor in Parkinsons disease. Clin
Psychopharmacol 15: 51S60S.
Singer TP, Ramsay RR (1991). The interaction of monoa-
mine oxidases with tertiary amines. Biochem Soc Trans
19: 211215.
Sivertsen B., Dupont E., Mikkelsen B., Mogensen P., Ras-
mussen C., Boesen F., Heinonen E. (1989). Selegiline
and levodopa in early of moderately advanced Parkinsons
disease: a double-blind controlled short- and longterm
study. E. Acta Neurol. Scand. 126: 147152.
Speiser Z, Katzir O, Rehavi M et al. (1998a). Sparing by rasagi-
line (TVP-1012) of cholinergic functions and behavior in the
postnatal anoxia rat. Pharmacol Biochem Behav 60: 387393.
Speiser Z, Levy R, Cohen S (1998b). Effects of N-propargyl-
1-(R)aminoindan (rasagiline) in models of motor and cog-
nition disorders. J Neural Transm Suppl 52: 287300.
Sprague JE, Nichols DE (1995). Inhibition of MAO-B
protects against MDMA-induced neurotoxicity in the stria-
tum. Psychopharmacology (Berl) 118: 357364.
Sternic N, Kacar A, Filipovic S et al. (1998). The therapeutic
effect of moclobemide, a reversible selective monoamine
oxidase A inhibitor, in Parkinsons disease. Clin Neuro-
pharmacol 21: 9396.
Sterling J, Tamas T, Toth G et al. (2002). Novel dual inhibi-
tors of AChE and MAO derived from hydroxyl aminoindan
and phenetylamine as potential treatment for Alzheimers
disease. J Med Chem 45 (24): 52605279.
Stocchi F, Arnold G, Onofrj M et al. (2004). Safinamide
Parkinsons Study Group. Improvement of motor function in
early Parkinson disease by safinamide. Neurology 63 (4):
746748.
Szeleny I (Ed.) (1993). Inhibitors of Monoamine Oxidase
B. Birkhauser, Boston.
Tatton WG, Chalmers-Redman RM (1996). Modulation of
gene expression rather than monoamine oxidase inhibition:
()-deprenyl-related compounds in controlling neurodegen-
eration. Neurology 47 (Suppl 3): S171S183.
Tatton WG, Ju WY, Holland DP et al. (1994). ()-Deprenyl
reduces PC12 apoptosis by inducing new protein synth-
esis. J Neurochem 63: 15721575.
Tatton WG, Wadia JS, Ju WY et al. (1996). ()-Deprenyl
reduces neuronal apoptosis and facilitates neuronal out-
growth by altering protein synthesis without inhibiting
monoamine oxidase. J Neural Transm 48: 4559.
Tetrud JW, Langston JW. (1990). The effect of deprenyl
(selegiline) on the natural history of Parkinsons disease.
J. W. Science, 245: 519522.
Thiffault C, Lamarre-Theroux L, Quirion R et al. (1997).
L-deprenyl and MDL72974 do not improve the recovery
of dopaminergic cells following systemic administration
of MPTP in mouse. Mol Brain Res 44: 238244.
 MONOAMINE OXIDASE A AND B INHIBITORS IN PARKINSONS DISEASE
Vaglini F, Pardini C, Cavalletti M et al. (1996). L-deprenyl
fails to protect mesencephalic dopamine neurons and
PC12 cells from the neurotoxic effects of 1-methyl-4-
phenylpyridinium ion. Brain Res 741: 6874.
Wadia JS, Chalmers-Redman RM, Ju WJ et al. (1998).
Mitochondrial membrane potential and nuclear changes
in apoptosis caused by serum and nerve growth factor
withdrawal: time course and modification by ()-depre-
nyl. J Neurosci 18: 932947.
Waters CH, Sethi KD, Hauser RA et al. (2004). Zydis Sele-
giline Study Group. Zydis selegiline reduces off time in
Parkinsons disease patients with motor fluctuations: a 3-
month, randomized, placebo-controlled study. Mov Disord
19: 426432.
Weinreb O, Bar-Am O, Amit T et al. (2004). Neuroprotection
via pro-survival protein kinase C isoforms associated with
Bcl-2 family members. FASEB J 18 (12): 14711473.
Weinstock M, Bejar C, Wang RH et al. (2000). TV 3326,
a novel neuroprotective drug with cholinesterase and mono-
amine oxidase inhibitory activities for the treatment of
Alzheimers disease. J Neural Transm Suppl 60: 157169.
Weinstock M, Kirschbaum-Slager N, Lazarovici P et al. (2001).
Neuroprotective effects of novel cholinesterase inhibitors
derived from rasagiline as potential anti-Alzheimer drugs.
Ann NY Acad Sci 939: 148161.
Weinstock M, Poltyrev T, Bejar C et al. (2002a). Effect of TV
3326, a novel monoamine-oxidase cholinesterase inhibitor,
in rat models of anxiety and depression. Psychopharmacol-
ogy (Berl) 160 (3): 318324.
Weinstock M, Gorodetsky E, Wang RH et al. (2002b).
Limited potentiation of blood pressure response to oral
tyramine by brain-selective monoamine oxidase A-B inhi-
bitor, TV-3326 in conscious rabbits. Neuropharmacology
43 (6): 9991005.
Weinstock M, Gorodetsky E, Poltyrev T et al. (2003). A novel
cholinesterase and brain-selective monoamine oxidase inhi-
bitor for the treatment of dementia comorbid with depres-
sion and Parkinsons disease. Prog Neuropsychopharmacol
Biol Psychiatry 27 (4): 555561.
Wild R, Pettit T, Burns A (2003). Cholinesterase inhibitors
for dementia with Lewy bodies. Cochrane Database Syst
Rev 3: CD003672.
Wilfried K, Muller T, Kruger R et al. (1997). Selegiline
stimulates biosynthesis of cytokines interleukin-1 beta
and interleukin-6. Neuroreport 7: 28472848.
Williams K, Romano C, Dichter MA et al. (1991). Modula-
tion of the NMDA receptor by polyamines. Life Sci 48:
469498.
Wu RM, Murphy DL, Chiueh CC (1995). Neuronal protec-
tive and rescue effects of deprenyl against MPPdopami-
nergic toxicity. J Neural Transm 100: 5361.
Wu RM, Murphy DL and Chiueh CC (1996). Suppression of
hydroxyl radical formation and protection of nigral neu-
rons by l-deprenyl (selegiline). Ann NY Acad Sci 786:
379390.
Yogev-Falach M, Amit T, Bar-Am O et al. (2003). The
importance of propargylamine moiety in the anti-Parkinson
drug rasagiline and its derivatives in MAPK-dependent
119
amyloid precursor protein processing. FASEB J 17 (15):
23252327.
Youdim MBH (Ed.) (1995). Reversible and Selective
Inhibitors of Monoamine Oxidase: New Findings. Acta
Psyuchiat, Scand 91:143.
Youdim MB, Buccafusco JJ (2005a). Multi-functional drugs
for various CNS targets in the treatment of neurodegenera-
tive disorders. Trends Pharmacol Sci 26 (1): 2735.
Youdim MB, Buccafusco JJ (2005b). CNS Targets for multi-
functional drugs in the treatment of Alzheimers and Par-
kinsons diseases. J Neural Transm 111: 519537.
Youdim MB, Riederer P (1993a). Dopamine metabolism and
neurotransmission in primate brain in relationship to
monoamine oxidase A and B inhibition. J Neural Transm
91: 181195.
Youdim MB, Riederer P (1993b). The relevance of glial mono-
amine oxidase-B and polyamines to the action of selegiline
in Parkinsons disease. Mov Disord 8 (Suppl 1): S8S13.
Youdim MB, Weinstock M (2001). Molecular basis of neuro-
protective activities of rasagaline and the anti-Alzheimer
drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl
methyl carbamate.] Cell Mol Neurobiol 21 (6): 555573.
Youdim MBH, Sourkes TL (1965). The effect of heat, pH
and riboflavin deficiency on monoamine oxidase activity.
Can J Biochem 43: 13051318.
Youdim MB, Collins GG, Sandler M et al. (1972). Human
brain monoamine oxidase, multiple forms and selective
inhibitors. Nature 236: 225228.
Youdim MBH, Green AR, Grahame-Smith DG (1976). The
role of 5-hydroxytryptamine, dopamine and MAO in the pro-
duction of hyperactivity. In: W Birkmayer, O Hornykiewicz
(Eds.) Advances in Parkinsonism. Editiones Roche, Base,
pp. l155163.
Youdim MBH, Finberg JPM, Tipton KF (1988a). Monoamine
oxidase. In: U Trendelengurg , U Weiner (Eds.), Catechola-
mine II. Springer-Verlag, Berlin, pp. 119192.
Youdim MBH, Da Prada M, Amrein R (Eds.) (1988b). The
cheese effect and new reversible MAO-A inhibitors.
J Neural Transm (Suppl 26).
Youdim MB, Gross A, Finberg JP (2001a). Rasagiline [N-pro-
pargyl-1R()-aminoindan], a selective and potent inhibitor
of mitochondrial monoamine oxidase B. Br J Pharmacol
132 (2): 500506.
Youdim MB, Wadia A, Tatton W et al. (2001b). The
anti-Parkinson drug rasagiline and its cholinesterase
inhibitor derivatives exert neuroprotection unrelated to
MAO inhibition cell culture and in vivo. Ann NY Acad
Sci 939: 450458.
Youdim MB, Amit T, Falach-Yogev M (2003). The essenti-
ality of Bcl-2, PKC and proteasome-ubiquitin complex
activations in the neuroprotective-antiapoptotic action of
the anti-Parkinson drug, rasagiline. Biochem Pharmacol
66 (8): 16351641.
Youdim MB, Maruyama W, Naoi M (2005). Neurophar-
macological, neuroprotective and amyloid precursor
processing properties of selective MAO-B inhibitor anti-
parkinsonian drug, rasagiline. Drugs Today (Barc)
41 (6): 369391.
120 M. B. H. YOUDIM AND P. F. RIEDERER
Youdim MBH, Edmondson D, Tipton KF (2006). Monoa-
mine oxidases. Nat Rev Neurosci 7: 295309.
Yu PH, Davis BA, Fang J et al. (1994). Neuroprotective
effects of some monoamine oxidase-B inhibitors against
DSP-4-induced noradrenaline depletion in the mouse
hippocampus. J Neurochem 63: 18201828.
Zappia V, Pegg AE (Eds.) (1998b). Progress in Polyamine
Research. Plenum Press, New York.
Zhang X, Zuo DM, Davis BA et al. (1996). Immuno-
histochemical evidence of neuroprotection by R(-)-deprenyl
and N-(2-hexyl)-N-methylpropargylamine on DSP-4-induced
degeneration of rat brain noradrenergic axons and terminals.
J Neurosci Res 43: 482489.
Further Reading
Bieck PR, Antonin KH, Schmidt E (1993). Clinical pharma-
cology of reversible monoamine oxidase inhibitors. Clin
Neuropharmacol 16 (Suppl 2): S34S41.
Fuller RW, Hemrick-Luecke SK (1985). Inhibition of types
A and B monoamine oxidase A and B by 1-methyl-
4-phenyl-1,2,3,6-dihydropyridine. J Pharmacol Exp Ther
232: 696701.
Gerlach M, Riederer P (1996). Animal models of Parkinsons
disease: an empirical comparison with the phenomenology
of the disease in man. J Neural Transm 103: 9871041.
Gotz ME, Breithaupt W, Sautter J et al. (1998). Chronic
TVP-1012 (rasagiline) doseactivity response of monoa-
mine oxidases A and B in the brain of the common
marmoset. J Neural Transm Suppl 52: 271278.
Green AR, Youdim MBH (1976). Use of animal models to
study the action of monoamine oxidase inhibitors. In:
Monoamine Oxidase and Its Inhibition, Ciba Foundation
Symposium No. 39 Elsevier, Amsterdam, pp. 231246.
Lai CT, Yu PH (1997). R()-deprenyl potentiates dopamine-
induced cytotoxicity toward catecholaminergic neuro-
blastoma SH-SY5Y cells. Toxicol Appl Pharmacol 142:
186191.
Larsen JP, Boas J (1997). The effects of early selegiline ther-
apy on long-term levodopa treatment and parkinsonian
disability: an interim analysis of a NorwegianDanish
5-year study. Norwegian-Danish Study Group. J. Move-
ment Disord 12: 175182.
Schmauss M (2002). Kontrolluntersuchungen. In: Riederer P,
Laux, G, Poldinger (Hrsg.). Neuro-Psychopharmaka,
Band 3: Antidepressiva, Phasenpophylaktika und Stim-
mungsstabilisierer, 2. neubearbeitete Auflage. Springer,
Wien, pp. 538539.
Tatton WG, Greenwood CE (1991). Rescue of dying neurons:
a new action for deprenyl in MPTP parkinsonism. J Neurosci
Res 30: 666672.
Zreik MJ, Fozard MJR, Dudley MW et al. (1989). MDL
72.974A: a potent and selective enzyme activated irreversi-
ble inhibitor of monoamine oxidase type B with potential
for use in Parkinsons disease (Parkinsons disease and
dementia section). J Neural Transm 1: 243254.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 35

Anticholinergic medications

YAROSLAU COMPTA AND EDUARDO TOLOSA*

Neurology Service, Hospital Clinic, University of Barcelona, Barcelona, Spain

35.1. Introduction an antiparkinsonian effect, confirming the aforemen-

Ordenstein, following the observations of his professor,
Jean-Martin Charcot, first described the beneficial
effect of the belladonna alkaloids (mainly containing
atropine as active component) on tremor and other
Parkinson disease (PD) symptoms (Ordenstein, 1867).
Subsequent investigators, such as Gowers (1888) at
the end of the 19th century, agreed that other substances
like Indian hemp (containing Cannabis sativa), scopol-
amine (hyoscine) and hyoscyamine (duboisine) were
effective in mitigating tremor and muscular rigidity.
Ordenstein suggested that parkinsonian symptoms
resulted from peripheral parasympathetic overactivity,
after the vagolyitic effect exerted by belladonna alka-
loids. It was not until 1945 that Feldburg discovered
that acetylcholine was also a central neurotransmitter
which was abundant in the striatum at the synaptic vesi-
cles of nerve terminals, and suggested a central effect
for anticholinergic drugs. A few years later, Barbeau
(1962) proposed that an altered dopaminergiccholi-
nergic balance exists in the striatum in PD with the
primary deficit in dopamine leading to a secondary
relative overactivity of acetylcholine. Normalization
of this striatal imbalance would explain the beneficial
effect of anticholinergics in PD. Another proposed
mechanism of action for anticholinergics in PD is the
inhibition of dopamine reuptake in the striatum (Coyle
and Snyder, 1969).
For over half a century the belladonna alkaloids
formed the mainstay of the medical management of
the Parkinson syndrome. These natural products
were substituted in the 1960s by a series of synthetic
anticholinergics and antihistaminics (Strang, 1965).
Synthetic anticholinergic drugs with selective periph-
eral effects (Duvoisin, 1966, 1967) proved not to have
tioned Feldburgs (1945) hypothesis.
35.2. Mechanism of action and clinical trials
Anticholinergics appear to improve symptoms of
PD through a central anticholinergic effect exerted in
the striatum. Duvoisin showed that cholinesterase inhi-
bitors, which can penetrate the brain, increase the
severity of PD symptoms (Barbeau, 1962; Coyle and
Snyder, 1969), an effect that can be reversed by anti-
cholinergics, such as benzotropine. This observation
provides a rationale for the use of anticholinergics
in PD and supports the notion that a state of striatal
cholinergic preponderance exists in PD secondary
to the striatal dopamine deficiency (Barbeau, 1962).
It is thought that the antimuscarinic properties of the
anticholinergics mediate their antiparkinsonian pro-
perties. In two studies with direct mesencephalic and
pallidal administration of drugs, atropine was found
to have an antiparkinsonian action (Nashold, 1959;
Velasco et al., 1982).
Centrally active anticholinergics (muscarinic recep-
tor antagonists) exert a modest improvement on PD
symptoms, but the percentage of patients reported to
improve with these drugs has varied greatly, from 40
to 77% in open trials (Corbin, 1949; Strang, 1965)
and from 20 to 40% in double-blind studies (Parkes
et al., 1974).
It is frequently stated that anticholinergics are more
effective in alleviating resting tremor and rigidity than
akinesia and that the major benefit derived from their
use is precisely from their tremorolytic effects (Doshay
and Constable, 1957; Burns et al., 1964; Strang, 1965;
Ebling, 1971; Obeso and Martnez-Lage, 1987). Such
affirmation has its origin in the observation that the

*Correspondence to: Professor Eduardo Tolosa, Neurology Service, Hospital Clinic, Esc 8, 4 planta, Villarroel 170, 08036
Barcelona, Spain. E-mail: ETOLOSA@clinic.ub.es, Tel: 0034-93-227-5785, Cell: 0034-227-5783.
122 Y. COMPTA AND E. TOLOSA
injection of the cholinomimetic drug tremorine elicited
tremor and rigidity in animals (Everett et al., 1956),
symptoms that improved after the administration of
atropine or scopolamine. Reports suggesting that antic-
holinergics do not have a specific antitremor effect,
however, abound in the literature. Thus, Marshall
(1968) was of the opinion that anticholinergics had
little or no effect upon the tremor of PD, and Yahr
and Duvoisin (1968), in a review on the subject,
concluded that the modest improvement achieved
with anticholinergics is derived from a greater effect
in relieving muscular rigidity and akinesia rather than
tremor.
Still, although a specific tremolytic effect of the
anticholinergics in PD has not been well documented,
most investigators report improvement in tremor with
anticholinergic monotherapy. A double-blind study
using objective evaluation of tremor with accelero-
metry (Koller, 1986) clearly showed a reduction in tre-
mor amplitude of about 60% from baseline in a group
of 10 de novo patients with early parkinsonism, after
treatment with trihexyphenidyl. However, other stu-
dies using quantitative measures of tremor differed
in their results, showing both improvement (Agate
et al., 1956) and lack of tremolytic effect (Norris and
Vas, 1967).
The differences described in the effect of anticholi-
nergics on tremor and other symptoms of the PD have
been attributed to differences in patient selection, drug
dosages, specific drugs studied and on methods of
assessment. Whether patients with early mild disease
respond better or worse than those with more advanced
parkinsonism has not been clarified, and it appears that
the use of higher doses of anticholinergics does not
yield better results than lower doses. Marsden (1969),
in a placebo-controlled study, compared different
doses of two anticholinergics and found no evidence
of increased benefit from higher doses with either
of the two, a failure that did not seem to be related
to the appearance of side-effects. Burns et al. (1964)
also found no evidence of increasing benefit with
increasing dosage of trihexyphenidyl in a carefully
controlled clinical trial. Therapeutic differences among
the various synthetic anticholinergics are probably
minor, but some patients may tolerate one better than
the other.
Studies of trihexyphenidyl (Martin et al., 1974), ben-
zotropine (Tourtellotte et al., 1982) and bornaprine
(Cantello et al., 1986) in levodopa-treated patients, and
two reviews indicate that adjunctive anticholinergics
have only a minor effect on PD symptoms in patients
on levodopa therapy (Goetz et al., 2002; Katzenschlager
et al., 2003).
35.3. Adverse effects
Peripheral adverse effects of these agents include
tachycardia, constipation (rarely leading to paralytic
ileus), urinary retention, blurred vision and dry mouth
(Duvoisin, 1965; Ebling, 1971). Gingivitis and caries,
rarely leading to loss of teeth, may occur (Lang and
Blair, 1989) and reduced sweating may interfere with
body temperature regulation. These effects are all
reversible when diminishing or with discontinuation
of the drug, and can even show some tolerance after
prolonged exposure. Rarely, some of these side-effects
can be beneficial at times, as is the case for dry mouth,
which can be advantageous in patients with prominent
drooling. Caution must be exercised in elder male
patients with comorbid prostate hypertrophy, due to a
high risk for urinary retention. Blurred vision is a com-
mon side-effect, attributed to reduced accommodation
due to parasympathetic blockade. Extremely rare is
the occurrence of acute narrow-angle glaucoma, which
can be precipitated in predisposed patients.
The usefulness of anticholinergics is also limited by
central side-effects. These include sedation, confusion
and psychiatric disturbances, such as hallucina-
tions and psychosis (Porteous and Ross, 1956; Koller,
1984). Impaired mental function (mainly immediate
memory and memory acquisition) is a well-documented
central side-effect that resolves after drug withdrawal
(van Herwaarden et al., 1993). Anticholinergics can
lead to an exacerbation of frontal lobe dysfunction in
PD patients (Syndulko et al., 1981; Sadeh et al., 1982;
Dubois et al., 1987). An impairment of higher cortical
functions has been found in non-demented PD subjects
with an acute subclinical dose of scopolamine (Bedard
et al., 1998) and impaired neuropsychiatric function
has been demonstrated even in patients without cog-
nitive impairment (Syndulko et al., 1981; Sadeh et al.,
1982). These central effects are more likely to occur
with advanced age and in patients with dementia (De
Smet et al., 1982). The marked involvement of the
cholinergic system (i.e. nucleus basalis of Meynert) in
PD (Forster and Lewy, 1912; Braak and Braak, 2000)
and in dementia with Lewy bodies (Tiraboschi et al.,
2002) pathology is probably the basis of the cognitive
changes induced by anticholinergics.
35.4. Anticholinergic use in clinical practice
The anticholinergics currently in use are listed in
Table 35.1. One of the first introduced synthetic drugs
is a piperidine compound, trihexyphenidyl. It was initi-
ally developed as a gastrointestinal antispasmodic
agent, shown in trials in the late 1940s to be as effective
 ANTICHOLINERGIC MEDICATIONS
Table 35.1
Anticholinergic drugs commonly used to treat tremor in
Parkinsons disease
Generic name Daily dose (mg)
Trihexyphenidyl 120
Benztropine 0.56
Ethopropazine 100800
Procyclidine 7.520
Diphenhydramine 25200
Bornaprine 88.25
as belladonna alkaloids in the management of PD, with
one-half of patients achieving an average of 20%
improvement (Rix and Fisher, 1972). The most repre-
sentative drugs of the antihistamines are diphenhydra-
mine (Montuschi, 1949) and orphenadrine (Strang,
1965); orphenadrine is thought to be more potent
because of its more potent anticholinergic activity.
Another widely used anticholinergic drug is benztro-
pine, a combination of the atropine molecule and the
benzhydryl group of the diphenhydramine molecule
(Doshay et al., 1952). Developed in the 1950s, this drug
is more potent than trihexyphenidyl and less sedative
than antihistaminics. Other less commonly used antic-
holinergics are phenothiazine derivatives (i.e. ethopro-
pazine), which, despite being neuroleptics, show
prominent anticholinergic activity and, hence, some
degree of antiparkinsonian effects (Young, 1972).
Nowadays, due to the propensity to induce adverse
effects, the anticholinergics have been progressively
substituted as first-line treatment of the early stages
of PD (Yahr, 1990) by other drugs such as the mono-
amine oxidase-B inhibitors or the modern dopamine
agonists, which have better tolerability and have
been shown to be associated with fewer motor com-
plications when compared with levodopa (Rascol
et al., 2002). However, no trials have directly com-
pared the effects of dopamine agonists with those of
the anticholinergics in PD.
Despite a lack of definite data to confirm a special
role in the management of tremor, anticholinergics
are also recommended in patients in whom other thera-
pies such as the agonists amantadine or levodopa have
failed to control tremor sufficiently.
In patients on long-term levodopa therapy and
more advanced disease, e.g. patients with associated
motor complications such as fluctuations or dyskine-
sias, the beneficial effect from adding anticholinergics
has been questioned (Martin et al., 1974), but some
authors believe that in some instances the addition of
anticholinergics may convey some benefit (Parkes
123
et al., 1974; Tourtellotte et al., 1982; Yahr et al.,
1982; Koller, 1986).
Development of tolerance to the effects of benefi-
cial effects of anticholinergics is said to occur fre-
quently. Such loss of therapeutic benefit is indeed a
common clinical observation after months of treat-
ment, but should be attributed, at least in part, to
disease progression. Withdrawal of anticholinergics,
even in patients in whom it is thought that the drugs
are no longer effective, invariably results in worsening
of the parkinsonian symptoms, at times to a level
worse than the patients baseline state (Hughes et al.,
1971; Horrocks et al., 1973).
In PD anticholinergic drugs have been reported to
alleviate dystonic spasms resulting from chronic levo-
dopa administration, as is the case in early-morning
dystonia (Poewe et al., 1987). In another study by
Poewe et al. (1988), challenge with procyclidine in 9
PD patients with foot dystonia resulted in abolition
of dystonia in 6, amelioration in 1 and no effect in
the remaining 2 patients.
35.5. Summary
The anticholinergics have been shown to improve the
main symptoms of PD modestly. They are used as
initial treatment in the early stages of the disease. Less
commonly they are administered as adjuncts to levo-
dopa or other therapeutic agents in more advanced
stages. Levodopa-induced dystonia is another situation
where anticholinergics could be helpful.
In recent years the use of anticholinergics for the
symptomatic treatment of PD has decreased signifi-
cantly, mostly due to the successful introduction into
therapy of a variety of new dopamine agonists and
enzyme inhibitors that help to control symptoms and
have been shown to be efficacious in delaying the intro-
duction of levodopa or minimizing motor complica-
tions of chronic levodopa administration. Such studies
have not been performed with the anticholinergics.
Because of their side-effect profile, with both periph-
eral and central adverse effects, the anticholinergics
should be always started at low doses and upward titra-
tion of doses done gradually. Due to their negative
effects on memory and cognition, their use should be
avoided in elderly patients. Therapeutic differences
among the various synthetic anticholinergics are prob-
ably minor, but some patients may tolerate one better
than another.
References
Agate FJ, Dosahy LJ, Curtis FK (1956). Quantitative measure-
ment of therapy in paralysis agitans. JAMA 160: 353354.
124 Y. COMPTA AND E. TOLOSA
Barbeau A (1962). The pathogenesis of Parkinsons disease:
a new hypothesis. Can Med Assoc J 87: 802807.
Bedard MA, Lemay S, Gagnon JF et al. (1998). Induction of
a transient dysexecutive syndrome in Parkinsons disease
using a subclinical dose of scopolamine. Behav Neurol
11: 187195.
Braak H, Braak E (2000). Pathoanatomy of Parkinsons
disease. J Neurol 247 (Suppl 2): II310.
Burns D, DeJong D, Solis-Quiroga OH (1964). Effects of
trihexyphenidyl hydrochloride (Artane) on Parkinsons
disease. Neurology 14: 1323.
Cantello R, Riccio A, Gilli M (1986). Bornaprine vs placebo
in Parkinson disease: double-blind controlled cross-over
trial in 30 patients. Ital J Neurol Sci 7 (1): 139143.
Corbin KB (1949). Trihexyphenidyl: evaluation of a new
agent in treatment of parkinsonism. JAMA 141: 377382.
Coyle JT, Snyder SH (1969). Antiparkinsonian drugs: inhibi-
tion of dopamine uptake in the corpus striatum as a possi-
ble mechanism of action. Science 166: 899901.
De Smet Y, Ruberg M, Serdaru M et al. (1982). Confusion,
dementia, and anticholinergics in Parkinsons disease. J
Neurol Neurosurg Psychiatry 45: 11611164.
Doshay LJ, Constable K (1957). Treatment of paralysis
agitans with orphenadrine (Disipal) hydrochloride. JAMA
163: 13521357.
Doshay LJ, Constable K, Fromer S (1952). Preliminary study
of a new antiparkinsonian. Neurology 2: 233243.
Dubois B, Danze F, Pillon B et al. (1987). Cholinergic-
dependent cognitive deficits in Parkinsons disease. Ann
Neurol 22: 2630.
Duvoisin RC (1965). A review of drug therapy in parkinson-
ism. Bull NY Acad Med 41: 898910.
Duvoisin RC (1966). The mutual antagonism of cholinergic
and anticholinergic agents in parkinsonism. Trans Am
Neurol Assoc 91: 7379.
Duvoisin RC (1967). Cholinergic-anticholinergic antagonism
in parkinsonism. Arch Neurol 17: 124136.
Ebling P (1971). The medical management of Parkinsons
disease before the introduction of L-dopa. Aust N Z J
Med 1 (Suppl): 3538.
Everett GM, Blockus LE, Shepperd IM (1956). Tremor induced
by tremorine and its antagonism by anti-parkinsonian drugs.
Science 124: 79.
Feldburg W (1945). Present views on the mode of action
of acetylcholine in the central nervous system. Physiol
Rev 25: 596642.
Forster E, Lewy FH (1912). Paralysis agitans. In: M Lewan-
dowsky (Ed.), Pathologische Anantomie. Handbuch der
Neurologie. Springer Verlag, Berlin, pp. 920933.
Goetz CG, Koller WC, Poewe W et al. (2002). Management
of Parkinsons disease: an evidence-based review. Mov
Disord 17 (Suppl 4): S1S166.
Gowers WR (1888). A Manual of Disease of the Nervous
System. P. Blakistons Sons and Company, Philadelphia.
Horrocks PM, Vicary DJ, Rees JE et al. (1973). Anticholiner-
gic withdrawal and benzhexol treatment in Parkinsons
disease. J Neurol Neurosurg Psychiatry 36: 936941.
Hughes RC, Polgar JG, Weightman D et al. (1971). Levodopa
in Parkinsonism: the effects of withdrawal of anticholinergic
drugs. Br Med J 2 (760): 487491.
Katzenschlager R, Sampaio C, Costa J et al. (2003). Antic-
holinergics for symptomatic management of Parkinsons
disease. Cochrane Database Syst Rev. (2): CD003735.
Koller WC (1984). Disturbance of recent memory functions
in parkinsonian patients on anticholinergic therapy. Cortex
20: 307311.
Koller WC (1986). Pharmacologic treatment of parkinsonian
tremor. Arch Neurol 43: 126127.
Lang AE, Blair RDG (1989). Anticholinergic drugs and
amantadine in the treatment of Parkinsons Disease. In:
DB Calne, (Ed.), Handbook of Experimental Pharmacology,
Vol. 88: Drugs for the Treatment of Parkinsons Disease.
Springer Verlag, Berlin, Heidelberg.
Marsden CD (1969). Extending the use of anticholinergic
drugs in Parkinsons disease. In: FJ Gillingham, IM
Donaldson (Eds.), Third Symposium on Parkinsons
Disease. E & S Livingstone, Edinburgh, pp. 185192.
Marshall J (1968). Tremor. In: PJ Vinken, GW Bruyn (Eds.),
Handbook of Clinical Neurology: Diseases of Basal Ganglia.
Elsevier North-Holland, Amsterdam, pp. 809825.
Martin WE, Lowenson RB, Resch JA et al. (1974). A con-
trolled study comparing trihexyphenidyl hydrochloride
plus levodopa with placebo plus levodopa in patients with
Parkinsons disease. Neurology 24: 912919.
Montuschi E (1949). Benadryl in parkinsonism. The Lancet
1: 546.
Nashold BS (1959). Cholinergic stimulation of globus
pallidus in man. Proc Soc Exp Biol Med 101: 6869.
Norris JW, Vas CJ (1967). Mehixene hydrochloride and
parkinsonian tremor. Acta Neurol Scand 43: 535538.
Obeso JA, Martnez-Lage M (1987). Anticholinergics and
amantadine. In: W Koller (Ed.), Handbook of Parkinsons
Disease. Marcel Dekker, New York, pp. 309316.
Ordenstein L (1867). Sur la paralysie et la sclerose en plaque
generalise. Martinet, Paris.
Parkes JD, Baxter RC, Marsden CD et al. (1974). Com-
parative trial of benzhexol, amantadine and levodopa in
the treatment of Parkinson disease. J Neurol Neurosurg
Psychiatry 37: 422426.
Poewe W, Lees AJ, Steiger D et al. (1987). Foot dystonia in
Parkinsons disease: clinical phenomenology and neuro-
pharmacology. Adv Neurol 45: 357360.
Poewe W, Lees AJ, Stern GM (1988). Dystonia in Parkinsons
disease: clinical and pharmacological features. Ann Neurol
235: 7378.
Porteous HB, Ross DDN (1956). Mental symptoms in
parkinsonism following benzhexol hydrochloride therapy.
Br Med J 2: 138140.
Rascol O, Goetz C, Koller W et al. (2002). Treatment inter-
ventions for Parkinsons disease: an evidence based
assessment. Lancet 359 (9317): 15891598.
Rix A, Fisher RG (1972). Comparison of trihexyphinidyl and
dihydromorphanthridine derivative in control of tremor of
parkinsonism. South Med J 65: 13851389.
 ANTICHOLINERGIC MEDICATIONS
Sadeh M, Braham J, Modan M (1982). Effects of anticholi-
nergic drugs on memory in Parkinsons disease. Arch
Neurol 39: 666667.
Strang RR (1965). Orphenadrine (Disipal) in the treatment
of parkinsonism: a two year study of 150 patients. Med J
Aust 2 (11): 448450.
Syndulko K, Gilden ER, Hansch EC et al. (1981). Decreased
verbal memory associated with anticholinergic treatment
in Parkinsons disease patients. Int J Neurosci 14: 6166.
Tiraboschi P, Hansen LA, Alford M et al. (2002). Early and
widespread cholinergic losses differentiate dementia with
Lewy bodies from Alzheimer disease. Arch Gen Psy-
chiatry 59 (10): 946951.
Tourtellotte WW, Potvin AR, Syndulko K et al. (1982). Parkin-
sons disease: Congentin with Sinemet, a better response.
Prog Neuropsychopharmacol Biol Psychiatry 6: 5155.
van Herwaarden G, Berger HJ, Horstink MW (1993). Short-
term memory in Parkinsons disease after withdrawal of
125
long-term anticholinergic therapy. Clin Neuropharmacol
16 (5): 438443.
Velasco F, Velasco M, Romo R (1982). Effect of carbachol
and atropine perfusions in the mesencephalic tegmentum
and caudate nucleus of experimental tremor in monkeys.
Exp Neurol 78: 450460.
Yahr M (1990). Principles of medical treatment. In: G Stern
(Ed.), Parkinsons disease. Chapman and Hall, Baltimore,
pp. 495508.
Yahr M, Duvoisin RC (1968). Medical therapy of parkinson-
ism. In: PJ Vinken, GW Bruyn (Eds.), Handbook of Clin-
ical Neurology: Diseases of Basal Ganglia. Elsevier
North-Holland, Amsterdam, pp. 283300.
Yahr MD, Clough CG, Bergman KJ (1982). Cholinergic
and dopaminergic mechanisms in Parkinsons disease after
long term levodopa administration. Lancet 1: 709710.
Young RR (1972). Treatment of parkinsonism. N Engl J Med
287: 10471048.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 36

Antiglutamatergic drugs in the treatment of Parkinsons disease

MARIA GRACIELA CERSOSIMO* AND FEDERICO EDUARDO MICHELI

Program of Parkinsons Disease and Other Movement Disorders, Hospital de Clnicas, University of
Buenos Aires, Buenos Aires, Argentina

36.1. Introduction associated with an increase in the phosphorylation of

In the last two decades drugs targeting glutamatergic
pathways have been a matter of growing interest
for the treatment of a wide variety of neurologic dis-
orders, including Parkinsons disease (PD) (Lipton
and Rosenberg, 1994). In the vertebrate brain gluta-
mate is the main excitatory neurotransmitter and med-
iates neurotransmission of most excitatory synapses
(Miller, 1998; Kemp and Mc Kernan, 2002).
Hyperactivity of glutamatergic transmission app-
ears to be involved in different aspects of PD. First,
glutamate-mediated excitotoxicity is one of the mech-
anisms proposed in the cascade of events leading to
neuronal cell death (Olney, 1969; Olney and Ho,
1970); therefore, agents capable of avoiding this could
be good candidates for neuroprotection (Lange and Rie-
derer, 1994). Second, glutamatergic pathways from the
subthalamic nucleus to the globus pallidus pars interna
are enhanced in the parkinsonian state, which might
contribute in the development of PD symptoms (Nash
and Brotchie, 2002). And third, overactivity of the str-
iatal glutamatergic receptors has been implicated as
one of the mechanisms underlying levodopa-induced
dyskinesias (Chase et al., 1996).
There are three types of glutamate ionotropic chan-
nels: (1) N-methyl-D-aspartate (NMDA); (2) alpha-
amino-3-hydroxy-5-methyl-4-isoxazolepropionate
(AMPA); and (3) kainate. The NMDA subtype recep-
tor is composed of two subunits: NR1, whose presence
is mandatory, NR2A-D and in some cases NR3A or B
subunits (McBain and Mayer, 1994). The functional
characteristics of these ionotropic receptors are regu-
lated by their phosphorylation state. In animal models,
lesions of the nigrostriatal dopaminergic system are
serine and tyrosine residues of the striatal NMDA
receptors (Chase et al., 2000).
Glutamate is such a powerful excitatory transmitter
that stimulation of the NMDA receptors for prolonged
periods of time or in excessive amounts leads to neuro-
nal cell death as a result of a massive calcium influx,
overproduction of free radicals, mitochondrial dys-
function and apoptosis (Olney, 1969; Bonfoco et al.,
1995). In addition, excitotoxicity can take place in
the presence of normal levels of glutamate when the
NMDA receptor activity is pathologically increased
(Zeevalk and Nicklas, 1992).
On the other hand, glutamate-mediated synaptic trans-
mission is essential for the normal functioning of the cen-
tral nervous system. In fact, compounds with a very strong
antiglutamatergic action can also block the normal neuro-
nal function resulting in unacceptable side-effects
(Schmidt and Bubser, 1989; Kaur and Starr, 1997). Unfor-
tunately, the clinical use of potent glutamate antagonists,
such as MK-801 which has remarkable excitotoxicity-
blocking properties in experimental models, is limited
because of its side-effects (Lipton, 2004). The ideal anti-
glutamatergic drug should be able to block the NMDA
receptor in situations of excessive activation but without
altering glutamatergic transmission during normal condi-
tions. It was recently noticed that agents with low affinity
for the Mg-binding site like the L-aminoadamatane deri-
vatives amantadine and memantine only enter the NMDA
channel under conditions of pathological glutamate
exposure (Dingledine et al., 1999).
At present, the only antiglutamatergic agent used in
the management of PD patients is amantadine, an old
compound that has proved to be particularly useful
for the treatment of levodopa-induced dykinesias.

*Correspondence to: Dr Maria Graciela Cersosimo, Pena 2225 5
C (CP 1126), Argentina. E-mail: mgracersosimo@arnet.com.
ar, Tel: 54-11-4806-2217, Fax: 54-11-4811-3076.
128 M. G. CERSOSIMO AND F. E. MICHELI
So far, despite the effort in developing new agents
with glutamate antagonist properties it has only been
possible for a few of them, such as memantine, dextro-
methorphan, budipine, remacemide and riluzole, to be
tried in clinical studies but results were poor.
36.2. Amantadine
Amantadine hydrocloride was initially introduced as
an antiviral agent effective against A2 influenza
(Jackson et al., 1963). Its antiparkinsonian effect was
discovered fortuitously in a 58-year-old woman with
PD who experienced a remission of her symptoms
while taking amantadine to prevent influenza. After
this single case, the authors conducted a trial with
163 patients with PD and observed improvement in
66% of them. Since then it has been acknowledged
that the beneficial effects on PD are usually short-lived
(Schwab et al., 1969).
Over the years, the introduction of a number of
other different agents, including dopamine agonists,
resulted in a more limited use of amantadine in part
due to its modest antiparkinsonian action but also
because of the short duration of the clinical benefit
(Factor and Molho, 1999). Many clinical trials have
investigated the efficacy of amantadine and recent
reviews on PD treatment placed amantadine as a
second-line therapy for PD.
The interest in this agent has recently reappeared
since Shannon et al. (1987) reported that amantadine
improved motor fluctuations and Stoof et al. (1992)
demonstrated amantadines activity at glutamate
receptors, suggesting that its antiparkinsonian effects
might be related to NMDA receptor blockade.
Factor et al. (1998) reported that amantadine with-
drawal in patients treated for longer than 1 year may
result in a substantial increase of motor disability or
delirium. In addition, several controversial and unre-
solved issues regarding the mechanism of action of
amantadine as well as the duration of the beneficial
response are still open questions.
36.2.1. Basic pharmacology and mechanism
of action
Amantadine hydrocloride is L-amino adamantamine,
the salt of a symmetric 10-carbon primary amine. It
is a stable, white, crystalline compound that is freely
soluble in water (Schwab et al., 1969). In humans, it
is well absorbed after oral administration. Blood levels
peak 14 hours after an oral dose of 2.5 mg/kg. The
drug has a plasma half-life of 1028.5 hours and is
excreted largely unmetabolized in the urine. Amanta-
dine hydrocloride is used clinically as 100-mg cap-
sules and recommended doses for PD treatment are
100 mg b.i.d. or t.i.d. (Aoki and Sitar, 1988; Goetz,
1998).
Amantadine interacts with several different neuro-
transmitters systems; however the exact mechanism
of action is not established. It is classically described
that the drug has dopaminergic and anticholinergic
properties and more recently amantadines antagonist
activity of NMDA glutamatergic receptors has been
reported (Stoof et al., 1992). Amantadine exerts its
dopaminergic effects, acting at presynaptic and postsy-
naptic levels. Presynaptically, the drug interacts with
dopaminergic neurotransmission in two ways: first,
enhancing the release of dopamine and other cathecho-
lamines from dopaminergic terminals and second,
inhibiting the reuptake process. Postsynaptically, a
direct action of the drug on dopamine receptors has
been described, resulting in changes in dopamine
receptor affinity. Additionally, studies on the chronic
effect of amantadine showed an increased striatal spir-
operidol binding, suggesting D2 dopamine receptor
blockade (Von Voigtlander and Moore, 1971; Bailey
and Stone, 1975; Gianutsos et al., 1985).
Stoof and colleagues (1992) reported amantadines
antiglutamatergic properties as demonstrated by
NMDA receptor blockade in the rat neostriatum
at therapeutic doses. It has been demonstrated that
amantadine acts as a non-competitive NMDA antagonist
producing a concentration-, time- and voltage-dependent
blockade of open NMDA channels (Kornhuber et al.,
1991; Sobolevski et al., 1998). Recently it has been
recognized that amantadine belongs to the type of
blocker manifesting the so-called trapping block of
NMDA channels. These drugs enter an open NMDA
channel and bind to its blocking site located deep in
the pore. The blocking molecules remain in the pore
for a relatively long time, being trapped behind the
closed activation gate. Agonist reapplication opens the
gate and allows the blocker to leave the channel. The
molecular mechanisms of the trapping of blockers are
at present unclear (Banplied et al., 1997; Sobolevski
et al., 1998).
Interestingly, despite the many different pharmaco-
logical properties attributed to this drug, it is not clear
how they contribute to its clinical effect.
Furthermore, the classic idea that the antipar-
kinsonian effect of amantadine is secondary to its dopa-
minergic or anticholinergic activities is not supported
by more recent studies. In fact, therapeutic doses of
amantadine in vitro are not associated with increased
extracellular brain dopamine levels. Similarly, the pre-
sumed anticholinergic effect is also unlikely as amanta-
dine only binds to acetylcholine receptors at very high
 ANTIGLUTAMATERGIC DRUGS IN THE TREATMENT OF PARKINSONS DISEASE
concentrations (Brown and Redfern, 1976; Verhagen
Metman et al., 1998a).
Regarding the antidyskinetic effect of amantadine,
compelling data support the hypothesis that it is related
to the anti-NMDA properties of the drug. Furthermore,
some authors propose NMDA antagonism of amantadine
as the mechanism for its antiparkinsonian effect (Stoof
et al., 1992).
36.2.2. Symptomatic treatment of parkinsonism
Amantadine has a mild antiparkinsonian effect and
appears to be more effective in the control of bradykine-
sia and rigidity and less effective in tremor. Schwab
et al. (1969) conducted the first clinical experience to
assess the efficacy of amantadine in 163 patients with
PD. This was an open-label non-controlled study;
patients received a maximum daily dose of 200 mg
amantadine in addition to their usual antiparkinsonian
medication. The authors found improvement of akinesia,
rigidity and tremor in 66% of patients and noted that in
58% the benefit was sustained for a period of 38 months.
Since that first report, several trials were performed
to investigate amantadines effectiveness in the treat-
ment of PD as monotherapy or associated with other
antiparkinsonian drugs.
A double-blind, placebo-controlled cross-over study
was performed on 30 PD patients, all but 3 who were
on anticholinergic or antihistaminic drugs; patients
received amantadine as monotherapy. Clinical assess-
ments included evaluations of tremor, rigidity, all phy-
sical signs, daily activities, repetitive motions and an
overall average. Amantadine resulted in a statistically
significant 12% overall improvement over placebo.
Ten patients continued treatment for 1012 months.
Improvements in tremor and rigidity remained rela-
tively constant although there was some apparent loss
of efficacy in timed tests (Butzer et al., 1975).
Fahn and Isgreen (1975) conducted a randomized
double-blind, cross-over, placebo-controlled trial
in 23 Parkinsons disease patients. During the first
cross-over period the patients were randomized to pla-
cebo or amantadine 200 mg/day. The authors reported
a favorable response in 16 patients (70%). The most
common adverse reactions were insomnia, anorexia,
dizziness, nervousness, irritability, depression and
sleepiness.
Parkes and colleagues (1974) compared the efficacy
of amantadine (200 mg/day) and anticholinergics
(benzhexol 8 mg/day) or both in 17 PD patients in a
randomized, double-blind cross-over trial. The clinical
improvement observed with amantadine or benzhexol
as monotherapy was a reduction of 15% in functional
disability without significant differences between the
129
two drugs: both drugs in combination resulted in a
reduction of 40% of total disability.
Walker et al. (1972) also showed that amantadine is
superior to placebo when administered in patients
receiving anticholinergics. In a double-blind, cross-
over trial in 42 PD patients they found amantadine
was 74% superior to placebo.
As adjunct therapy of levodopa, amantadine is
somewhat efficacious in the symptomatic treatment
of PD. In a double-blind, randomized cross-over study,
Savery (1977) added amantadine to 42 PD patients
treated with levodopa/carbidopa. The clinical eva-
luation after a period of 9 weeks resulted in a signi-
ficant improvement in symptoms. Similarly, Fehling
(1973) in a double-blind, randomized cross-over study
compared the effect of amantadine or placebo in 21
patients receiving levodopa/carbidopa and found
amantadine to be significantly more effective than
placebo in improving PD symptoms. Nonetheless,
these findings could not be confirmed by other authors
who found no differences in the evaluation of patients
treated with levodopa/carbidopa with and without
amantadine (Millac et al., 1970; Callagham et al.,
1974).
It is generally described that amantadine produces
a transient clinical benefit with a loss of efficacy after
612 months, probably due to a tachyphylaxis phe-
nomenon (Schwab et al., 1969). Nonetheless, some
authors have questioned the validity of this concept.
Factor et al. (1998) in a critical review of 22 studies
of amantadine found that many of them had included
patients with postencephalitic parkinsonism, multiple
system atrophy or progressive supranuclear palsy.
The length of amantadine therapy ranged from 4 days
to 12 months and in 13 studies a decline of efficacy
was not mentioned, suggesting there are not enough
reliable data to support this notion (Marsden, 1988;
Factor and Molho, 1999). Zeldowicz and Huberman
(1973) performed a clinical trial on 77 PD patients to
evaluate whether there is a decline in efficacy. A total
of 19 patients had good to excellent response to aman-
tadine monotherapy and maintained that improvement
for an average of 21 months, with the longest duration
being 30 months. In addition, a marked deterioration
took place when amantadine was switched in a random
fashion to placebo.
36.2.3. Treatment of motor complications
Amantadine was found to be effective in the treatment
of levodopa-induced dyskinesias in patients with PD.
Preclinical studies suggest that the development of
levodopa-induced motor complications is associated
with an increase in phosphorylation state of NMDA
130 M. G. CERSOSIMO AND F. E. MICHELI
receptors in striatal medium spiny neurons; as a res-
ult, synaptic efficacy is enhanced and corticostriatal
glutamatergic input is amplified, affecting striatal
GABAergic output and probably leading to motor res-
ponse complications. Therefore, it is conceivable that
amantadine exerts its antidyskinetic effect by normal-
izing striatal NMDA receptor hyperfunction (Chase
et al., 1996; Dunah et al., 2000). Verhagen Metman
and colleagues (1998a) conducted the first controlled
clinical trial to evaluate the effects of amantadine on
levodopa-associated dyskinesias and motor fluctua-
tions in 18 advanced PD patients (average age 60
years, Hoehn and Yahr stage IIV) in a double-blind,
cross-over, placebo-controlled study during a 6-week
period. All patients received amantadine or placebo
for 3 weeks. Amantadine doses ranged from 100 to
400 mg/day depending on age, renal function and tol-
erance. At the end of each study period the patients
received an intravenous levodopa infusion for 7 hours
at an individually determined optimal rate, defined as
the lowest rate producing the maximal antiparkinso-
nian effect. The evaluations were performed during
the last 2 hours of the levodopa infusion and chorei-
form dyskinesias and parkinsonian symptoms were
scored every 10 minutes. Dyskinesias were also video-
taped and subsequently scored by a second blinded
neurologist. Parkinsonian symptoms and dyskinesias
were assessed using the Unified Parkinsons Disease
Rating Scale (UPDRS) part III, items 20, 22, 23, 26
and 31 and a modified Abnormal Involuntary Move-
ment Scale (AIMS). Motor fluctuations were assessed
with the UPDRS part IV, items 32 (duration of dyski-
nesias), 33 (severity of dyskinesias) and 39 (proportion
of the day in the off state), as well as patient diaries
on the last 2 or 3 days of each study arm. The sta-
tistical analysis of measures showed a significant
(P < 0.001) reduction in the severity of dyskinesias
which was 60% lower with amantadine as compared
to placebo. In this study amantadine substantially ame-
liorated levodopa-induced peak-dose dyskinesias with-
out worsening parkinsonian symptoms. Dysphasic
dyskinesias could not be evaluated as they did not occur
during optimal levodopa infusion rate. Only 4 patients
withdrew from the study because of adverse reactions
(confusion 1, hallucinations 1, palpitations 1 and nausea
1) (Verhagen Metman et al., 1998a). One year later
Metman et al. (1999) reported the results of a 1-year
follow-up of the previously reported study. Of the initial
18 patients, 17 participated in this study with a non-
randomized, double-blind, placebo-controlled design.
Ten days prior to the follow-up assessment, amantadine
was replaced by capsules containing either amantadine
or placebo. On the test day, the patients received an
intravenous infusion of levodopa followed by motor
assessments. Results showed that the reduction in dyski-
nesias severity was 56% compared with 60% 1 year
before. The authors conclude that the beneficial effect
of amantadine on levodopa-induced dyskinesias is
maintained for at least 1 year after treatment initiation
(Metman et al., 1999).
In the two previous studies amantadine was admini-
strated orally and onset of benefit was observed from
days to weeks after treatment initiation. Del Dotto and
colleagues (2001) investigated the possible occurrence
of an acute effect of amantadine after an intravenous
infusion. They conducted a randomized, double-blind,
placebo-controlled study including 9 PD patients with
peak-dose levodopa-induced choreiform dyskinesias.
Their mean age was 59.7 years, disease duration was
8.4 years, Hoehn and Yahr stage III in the off condi-
tion and the daily dose of levodopa immediately prior
to study was 860 mg. All patients were evaluated on 2
different days for 5 hours while taking their usual anti-
parkinsonian medications. The 9 patients received their
first morning levodopa dose, followed by a 2-hour in-
travenous amantadine (200 mg) or placebo infusion.
Parkinsonian symptoms and dyskinesias were assessed
every 15 minutes during the infusion and 3 hours post-
infusion using the UPDRS scale part III, tapping test
and the AIMS. Results showed that the average of dys-
kinesia scores during amantadine infusion was 50%
lower when compared to placebo (P < 0.01). These
results indicate that the antidyskinetic effect of amanta-
dine occurs acutely and does not require days or weeks
to develop (Del Dotto et al., 2001).
The antidyskinetic effect of amantadine was also con-
firmed by other authors. Snow et al. (2000) performed a
double-blind, placebo-controlled, cross-over study to
assess the effect of amantadine (200 mg/day oral) versus
placebo on levodopa-induced dyskinesias in 24 patients
with PD showing a significant (P < 0.004) reduction
of 24% in the total dyskinesia score after amantadine
administration.
36.2.4. Prevention of disease progression
Several recent studies suggest that amantadine has neu-
roprotective properties in addition to its symptomatic
effects. It has been suggested that the enhanced excita-
tory amino acid neurotransmission may play a role in
the pathogenesis of several chronic neurodegenerative
diseases, including PD (Kornhuber et al., 1994; Danysz
et al., 1997). Studies in monkeys indicate that excitatory
amino acids such as glutamate are involved in the path-
ophysiological cascade of 1-methyl-4-phenyl-1236-
tetrahydropyridine (MPTP)-induced neuronal cell death.
This observation supports the hypothesis that glutamate
antagonists such as amantadine may be able to delay
 ANTIGLUTAMATERGIC DRUGS IN THE TREATMENT OF PARKINSONS DISEASE
the progression of the disease (Lange et al., 1997). In
addition, multiple in vitro studies have recently shown
the neuroprotective properties of amantadine and its
congener compound memantine at therapeutically used
doses (Kornhuber et al., 1994).
Uitti and colleagues (1996) studied survival in
patients with PD and other parkinsonian syndromes
employing standard survival curves and a Cox regres-
sion model to identify independent predictive variables
for survival. Patients treated with and without aman-
tadine were similar in terms of age, gender, type of
parkinsonism, Hoehn and Yahr staging and cognitive
status. The authors found that the use of amantadine
is an independent predictor of improved survival.
Glutamate receptor antagonist drugs appear to be
promising agents for the neuroprotective therapy of
PD (Kornhuber and Weller, 1996).
Several compounds with antiparkinsonian effects,
such as amantadine, memantine and budipine, have
been shown to be non-competitive NMDA receptor
antagonists, are candidates for clinical trials (Lange
et al., 1997) and appear to be promising agents for
the neuroprotective therapy of PD (Kornhuber and
Weller, 1996).
36.2.5. Side-effects
Amantadine is usually well tolerated. The more fre-
quent adverse reactions associated with the use of
amantadine include: insomnia, anxiety, dizziness,
impaired coordination, nervousness, nausea and vomit-
ing. These side-effects are usually mild, although they
can be severe in elderly patients. In fewer than 5% of
patients, irritability, headaches, depression, ataxia,
confusion, hallucinations, nightmares, somnolence,
agitation, diarrhea, constipation, livedo reticularis and
xerostomia are reported. Dry mouth and blurred vision
are considered peripheral anticholinergic side-effects.
Livedo reticularis is more often in women and is fre-
quently associated with persistent ankle edema (Lof-
fler et al., 1998). Unusual adverse effects include
hyperkinesias, urinary retention, rash and decreased
libido whereas toxic manifestations of amantadine
include acute psychosis, coma, cardiovascular
toxicity and death.
More rare adverse reactions have been reported as
isolated cases such as vocal myoclonus, heart failure
or peripheral neuropathy (Vale and Maclean, 1977;
Pfeiffer, 1996). Shulman and colleagues (1999)
reported a case of sensory motor peripheral neuropathy
secondary to chronic administration of amantadine in a
48-year-old woman where the discontinuation of the
drug resulted in the resolution of trophic skin ulcers,
paresthesias and distal weakness.
131
Amantadine toxicity may be associated with over-
dose or renal insufficiency as 90% of an oral dose
is excreted unchanged in the urine (Macchio et al.,
1993). These toxic effects may be exacerbated by the
concomitant use of anticholinergic agents.
Withdrawal effects of amantadine are not frequent
but may be serious. Factor and colleagues (1998)
reported 3 PD patients who, after gradually tapering
amantadine, experienced acute delirium, paranoia and
agitation in addition to worsening of motor symptoms.
In all of them the syndrome rapidly resolved after
amantadine restitution. Some characteristics were
common among the 3 patients. They were elderly
and had hallucinations in the past, dementia, advanced
PD and a long duration of amantadine therapy, repre-
senting possible risk factors for this complication
(Factor et al., 1998).
36.3. Other antiglutamatergic drugs
36.3.1. Memantine
Memantine (1-amino-3,5-dimethyladamantane) is an
L-aminoadamantane derivative first synthesized in
1968. It has been proposed that memantine may be
useful for the treatment of PD symptoms (Fischer
et al., 1977; Schneider et al., 1984). Also, some case
reports have suggested the utility of memantine in
levodopa-induced dyskinesia therapy (Hanagasi et al.,
2000) However, evidence to conclude about its effi-
cacy in any indication for PD is so far insufficient.
Clinical trials have shown that memantine is effective
in the treatment of Alzheimers disease (Reisberg
et al., 2003).
Memantine is an uncompetitive and low-affinity
NMDA receptor antagonist with voltage-dependent
binding (Bormann, 1989). Unlike amantadine, meman-
tine has no dopaminergic or anticholinergic actions.
Memantine has a three-ring structure with a bridge-
head amine that binds to the Mg binding site of the
NMDA receptor (Bormann, 1989; Lipton, 1993).
Memantine is completely absorbed from gastroin-
testinal tract with peak blood levels occurring 2030
minutes after an oral dose of 5 mg/kg. The mean
half-life of memantine is 60100 hours and approxi-
mately 80% of the drug circulates unchanged. The
usual recommended dose for patients with PD is 10
mg t.i.d. (Jarvis and Figgit, 2003; Lundbeck, 2002).
Only a few qualified studies assessing the efficacy
of memantine in PD are found in the literature. Merello
et al. (1999) performed a randomized, placebo-controlled,
cross-over study in 12 PD patients with motor fluctuations
to asses the effect of memantine on the cardinal symptoms
of PD and levodopa-induced dyskinesias.
132 M. G. CERSOSIMO AND F. E. MICHELI
A significant improvement of motor symptoms in the
off and on states evaluated by means of the UPDRS in a second phase of the study, with a double-blind,
motor scale was observed. No significant effect of
memantine on levodopa-induced dyskinesias was
reported (Merello et al., 1999).
Memantine is usually well tolerated; reported side-
effects included diarrhea, dizziness, headache, hallu-
cinations, agitation, insomnia and urinary incontinence
(Jarvis and Figgitt, 2003).
There are no data available regarding the utility of
memantine in the prevention of PD progression.
36.3.2. Dextromethorphan
Dextromethorphan is a widely used and safe antitus-
sive agent with low affinity and uncompetitive antago-
nist properties of the NMDA receptors. Based on this
knowledge, dextromethorphan was tried in PD and a
variety of conditions where glutamate overactivity is
supposed to play a pathogenic role (Wong et al.,
1988; Church et al., 1989).
Dextromethorphan is well absorbed in the gastroin-
testinal tract with peak blood levels occurring 14 hours
after an oral dose of 2.5 mg/kg and a median half-life of
2 hours. There is genetic polymorphism for the oxida-
tive O-demethylation being both extensive and poor
metabolizers. Half-life in poor metabolizers can reach
up to 45 hours. Recommended dosage varies between
100 and 200 mg/day (Woodworth et al., 1987; Schadel
et al., 1995).
Only two open-label and non-controlled studies
assessing the efficacy of dextromethorphan for the
treatment of motor symptoms of PD in non-fluctuating
patients have been carried out. Montastruc et al. (1994)
performed a study to investigate the effect of adding
dextromethorphan 90 mg/day to the therapy of 13 PD
patients. Evaluations with the UPDRS motor scale done
at baseline and after 1 month of treatment did not show
any change in the scores (Montastruc et al., 1994).
Conversely, Bonuccelli et al. (1992) found signifi-
cant improvement on UPDRS motor scale scores of
6 de novo PD patients and another 6, in which dex-
tromethorphan was added to their previous treatment.
In this study doses of 180 mg/day were associated
with significant improvement in tremor, rigidity and
finger-tapping.
Verhagen Metman et al. (1998b) conducted a study
with dextromethorphan in patients with levodopa-
induced dyskinesia and motor fluctuations. Eighteen
patients were included to initial open-label dose esca-
lation screening. The dose of dextromethorphan was
increased up to 180 mg/day or until side-effects occurred.
All patients in addition received quinidine 100 mg b.i.d.
to inhibit O-demethylation of dextromethorphan. Pati-
ents reporting subjective improvement were included
placebo-controlled, cross-over design consisting of
2-week arms separated by 1-week washout. Six patients
were included in the second part of the study. Although
parkinsonian scores were not modified by dextrometh-
orphan, dyskinesias improved by 25 % (P  0.05). The
severity of motor fluctuations also improved significantly
by 66% (P  0.05), according to the UPDRS part IV-item
39. Adverse events included decreased levodopa effi-
cacy, increased dystonia, increase in pre-existing impo-
tence, nausea, perspiration and drowsiness (Verhagen
Metman et al., 1998b).
At present data are insufficient to conclude on effi-
cacy and safety of dextromethorphan in any indication
of PD.
36.3.3. Budipine
Budipine (1-t-butyl-4,4-diphenylpiperidine) has a com-
plex pharmacological profile interacting with different
neurotransmitter systems. Besides its NMDA receptor
antagonist properties it also influences GABAergic,
noradrinergic, serotoninergic and cholinergic transmis-
sion (Jackisch et al., 1993; Kolckgether et al., 1996;
Eltze, 1999).
Up to 2000 budipine was still available in some
European countries but cardiac side-effects, including
arrhythmias due to an acquired long QT syndrome,
led to important restrictions, further limiting its use
in clinical practice (Scholz et al., 2003).
Przuntek et al. (2002) conducted a multicenter,
placebo-controlled, double-blind study in 84 PD patients
to assess the efficacy of 20 mg budipine three times a
day in addition to a stable optimum dopaminergic regi-
men. Duration of the study was 4 months and patients were
evaluated with the Columbia University Rating Scale
(CURS). Budipine significantly (P  0.01) decreased
the CURS subscores for rigidity, tremor and akinesia com-
pared with placebo. Adverse events reported in the budi-
pine group were dizziness, dry mouth, loss of appetite,
nervousness and visual dysfunction (Przuntek et al., 2002).
The usefulness of budipine in the treatment of
patients with motor fluctuations was investigated by
Spieker et al. (1999) in an open-label study performed
in 7 PD patients medicated with budipine at doses of
40 mg/day in addition to their dopaminergic therapy.
The duration of the study was 8 weeks and assess-
ments were UPDRS motor section in the on state
and a diary over 7 days recording hours of on/off
states, dyskinesias or dystonia. Results showed that
time off decreased in 5 of the 7 patients; also motor
scores during the on period improved. Peak-dose
dyskinesias did not occur in any of the patients.
 ANTIGLUTAMATERGIC DRUGS IN THE TREATMENT OF PARKINSONS DISEASE
At present there is agreement that the risk-to-
benefit ratio for the use of budipine is unfavorable
because of the significant increased risk of cardiac
arrhythmias. This is the reason why the use of budipine
in the treatment of PD is not recommended.
36.3.4. Remacemide
Remacemide hydrochloride is a low-affinity, non-
competitive NMDA channel antagonist which has
shown antiparkinsonian efficacy in rodent and primate
models. The active metabolite of remacemide AR-R
12495 also has a moderate affinity for the NMDA
receptor and both interact with voltage-dependent neu-
ronal sodium channels (Greenamyre et al., 1994;
Schachter and Tarsy, 2000).
A multicenter randomized, placebo-controlled,
double-blind, parallel-group, dose-ranging study of
remacemide was performed in 200 early PD patients
who were not receiving levodopa or dopamine agonists.
Subjects were randomized to remacemide 150, 300 or
600 mg daily, or matching placebo for 5 weeks. The
study failed to demonstrate any symptomatic effect of
remacemide as monotherapy in patients with early PD
(Parkinson Study Group, 2000).
Shoulson et al. (2001) assessed the safety, tolerabil-
ity and efficacy of remacemide adjunct treatment in
279 PD patients with motor fluctuations receiving
levodopa. The authors conducted a randomized, dou-
ble-blind, placebo-controlled, parallel-dose-ranging
study during a 7-week treatment period. Remacemide
doses were 300 mg b.i.d. and 600 mg q.i.d. Results
showed that remacemide was safe and well tolerated
as adjunct to dopaminergic therapy in patients with
PD and motor fluctuations. However, UPDRS motor
scores and percentage of on time did not show any
significant improvement in the remacemide group
compared with placebo (Shoulson et al., 2001).
The Parkinson Study Group (2001) evaluated the
effect of remacemide hydrochloride in the treatment
of levodopa-induced dyskinesias. A total of 39 PD
subjects with disabling dyskinesias were included in
a multicenter, randomized double-blind, placebo-
controlled, parallel-group study during a period of 2
weeks. Daily doses of remacemide were 150, 300 or
600 mg or matching placebo. The study failed to
demonstrated any significant changes in dyskinesia
measures, but a statistically significant improvement
in the off state UPDRS motor score (P 0.01)
and in the UPDRS part II (P 0.04) was observed
in patients receiving remacemide 150 mg/day. In sub-
jects receiving remacemide 300 mg/day a significant
(P 0.004) improvement in the percentage of on
state daily hours was found and in the UPDRS part II
133
scores in the off state (P 0.04). Finally, the group
of remacemide 600 mg/day only showed significant
(P 0.04) improvement in the UPDRS part II scores
in the on state.
The most common dose-related adverse events
associated with remacemide were nausea and dizziness
(Shoulson et al., 2001). More rarely, headache, abnor-
mal vision, vomiting and hypokinesia can ocur (Clarke
et al., 2001).
Remacemide appears to be a safe and well-tolerated
drug; however, larger trials are required to establish
its efficacy in the treatment of levodopa-induced
dyskinesias and parkinsonian symptoms.
36.3.5. Riluzole
The antiglutamatergic agent riluzole (2-amino-6-trifluor-
omrthoxy-benzothiazole) is currently the only drug
approved for the treatment of amyotrophic lateral sclero-
sis and its effect can only extend the survival of patients
for a few months (Bensimon et al., 1994). Riluzole has
multiple mechanisms of action: (1) inactivation of vol-
tage-dependent sodium channels (Benoit and Escande,
1991; Hubert et al., 1994); (2) non-competitive blockade
of postsynaptic excitatory amino acid receptors (Bena-
vides et al., 1985; Debono et al., 1993); and (3) presynap-
tic inhibition of glutamate release (Cheramy et al., 1986,
1992). Preclinical data suggest that riluzole has a neuro-
protective effect in animal models of PD (Boireau
et al., 1994; Bezard et al., 1998).
Jankovic and Hunter (2002) assessed neuroprotec-
tive properties of riluzole in a double-blind placebo-
controlled study in 20 patients with early PD. Subjects
were randomized to 50 mg b.i.d. of riluzole or matching
placebo. All patients were evaluated at baseline, 1, 3
and 6 months and following a 6-week washout period.
After the washout, all subjects were offered to enroll
in a 1-year extension study. Assessments included
UPDRS scale, Hoehn and Yahr stage and Schwab
and England scale. Results did not show any sympto-
matic effect of riluzole on the UPDRS score and no
changes in the Hoehn and Yahr stage. Among the 17
patients who decided to continue in the extension phase
of the study, the deterioration in the UPDRS score was
more pronounced in the placebo group but this differ-
ence was not significant. The study failed to show
evidence of symptomatic or neuroprotective effects of
riluzole (Jankovic and Hunter, 2002).
The effect of riluzole in PD patients with dyskine-
sias was investigated by Braz et al. (2004) in a dou-
ble-blind, placebo-controlled pilot study. A total of
16 patients were randomly treated with riluzole 50
mg b.i.d. or matching placebo during 7 consecutive
days. The patients were evaluated at baseline and at
134 M. G. CERSOSIMO AND F. E. MICHELI
the end of the treatment period. Assessments included
UPDRS part III and IV, Hoehn and Yahr stage and the
Larsen scale for dyskinesia. On the day of the evaluations
the patients were asked to assist after a washout period
of at least 8 hours without taking levodopa or any other
antiparkinsonian medication. For the evaluation all
subjects were treated with subcutaneous apomorphine
1 mg every 15 minutes until the on condition was
achieved. No significant differences were found between
the two groups. Riluzole was not able to reduce apomor-
phine-induced dykinesia (Braz et al., 2004).
References
Aoki FY, Sitar DS (1988). Clinical pharmacokinetics of aman-
tadine hydrochloride. Clin Pharmacokinet 14: 3551.
Bailey EV, Stone TW (1975). The mechanism of action of
amantadine in parkinsonism: a review. Arch Int Pharma-
codyn Ther 216: 246262.
Banplied TA, Boeckman FA, Aizenman E et al. (1997). Trap-
ping channel block of NMDA receptors activated
responses by amantadine and memantine. J Neurophysiol
77 (1): 309323.
Benavides J, Camelin JC, Mitrani N et al. (1985). 2-Amino-
6-trifluoromethoxy benzothiazole, a possible antagonist of
excitatory amino acid neurotransmission. Biochemical
properties. Neuropharmacology 24: 10851092.
Benoit E, Escande D (1991). Riluzole specifically blocks
inactivated Na channels in myelinated nerve fibre.
Pflugers Arch 419: 603609.
Bensimon G, Lacomblez L, Meininger V (1994). The ALS
Riluzole Study Group. A controlled trial of riluzole in
amyotrophic lateral sclerosis. N Engl J Med 330: 585601.
Bezard E, Stutzmann JM, Imbert C et al. (1998). Riluzole
delayed appearance of parkinsonian motor abnormalities
in a chronic MPTP monkey model. Eur J Pharmacol
356: 101104.
Boireau A, Miquet JM, Dubedat P et al. (1994). Riluzole and
experimental parkinsonism: partial antagonism of MPP
induced increase in striatal extracellular dopamine in rats
in vivo. Neuroreport 5: 21572160.
Bonfoco E, Krainc D, Ankarcrona M et al. (1995). Apoptosis
and necrosis: two distinct events induced respectively by
mild and intense insults with NMDA or nitric oxide/super-
oxide in cortical cell cultures. Proc Natl Acad Sci USA 92:
71627166.
Bonuccelli U, Del Dotto P, Piccini P et al. (1992). Dex-
tromethorphan and parkinsonism. Lancet 340: 53.
Bormann J (1989). Memantine is a potent blocker of
N-methyl-D-aspartate (NMDA) receptor channels. Eur J
Pharmacol 166 (3): 591592.
Braz CA, Borges V, Ferraz HB (2004). Effect of riluzole on
dyskinesia and duration of the on state in Parkinsons dis-
ease patients: a double blind, placebo controlled pilot
study. Clin Neuropharmacol 27 (1): 2529.
Brown F, Redfern PH (1976). Studies on mechanism of
action of amantadine. Br J Pharmacol 58: 561567.
Butzer JF, Silver DE, Sahs AL (1975). Amantadine in Par-
kinsons disease. A double blind, placebo controlled,
crossover study with long term follow up. Neurology
25 (7): 603606.
Callagham N, McIlroy M, OConnor M (1974). Treatment of
Parkinsons disease with levodopa and amantadine used as
a single drugs and in combined therapy. Ir J Med Sci 143:
6778.
Chase TN, Engber TM, Mouradian MM (1996). Contribution
of dopaminergic and glutamatergic mechanisms to the
pathogenesis of motor response complications in Parkin-
sons disease. Adv Neurol 69: 497501.
Chase TN, Oh JD, Konitsiotis S (2000). Antiparkinsonian and
antidiskynetic activity of drugs targeting central glutama-
tergic mechanisms. J Neurol 247 (Suppl 2): II/36II/42.
Cheramy A, Romo R, Godeheu G et al. (1986). In vivo pre-
synaptic control of dopamine release in the cat caudate
nucleus. Facilitatory or inhibition influence of L-gluta-
mate. Neuroscience 19: 10811090.
Cheramy A, Barbeito L, Godeheu G et al. (1992). Riluzole
inhibits the release of glutamate in the caudate nucleus
of the cat in vivo. Neurosci Lett 147: 209212.
Church J, Jones MG, Davies SN et al. (1989). Antitussive
agents as N-methylaspartate antagonists: further studies.
Can J Physiol Pharmacol 67: 561567.
Clarke CE, Cooper JA, Holdich TA (2001). TREMOR Study
Group. A randomized, double blind, placebo controlled,
ascending dose tolerability and safety study of remacemide
as adjuvant therapy in Parkinsons disease with response
fluctuations. Clin Neuropharmacol 24 (3): 133138.
Danysz W, Parsons CG, Kornhuber J et al. (1997). Ami-
noadamantanes as NMDA receptors antagonists and
antiparkinsonian agents preclinical studies. Neurosci
Biobehav Rev 21 (4): 455468.
Debono MW, Le Guern J, Canton T et al. (1993). Inhibition
by riluzole of electrophysiological responses mediated by
rat kainite and NMDA receptors expressed in Xenopus
oocytes. Eur J Pharmacol 235: 283289.
Del Dotto P, Pavese N, Gambaccini G et al. (2001). Intrave-
nous amantadine improves levodopa-induced dyskinesias:
an acute double blind placebo controlled study. Mov Dis-
ord 16 (3): 515520.
Dingledine R, Borges K, Bowie D et al. (1999). The gluta-
mate receptor ion channels. Pharmacol Rev 51: 851.
Dunah AW, Wang Y, Yasuda RP et al. (2000). Alteration in
subunit expression, composition, and phosphorylation of
striatal N-methyl-D-aspartate glutamate receptors in a rat
6-hydroxidopamine model of Parkinsons disease. Mol
Pharmacol 57: 342352.
Eltze M (1999). Multiple mechanisms of action: the pharma-
cological profile of budipine. J Neural Transm Suppl 56:
83105.
Factor SA, Molho ES (1999). Tansient benefit of amantadine
in Parkinsons disease: the facts about the myth. Mov Dis-
ord 14 (3): 515517.
Factor SA, Molho ES, Brown DL (1998). Acute delirium
after withdrawal of amantadine in Parkinsons disease.
Neurology 50: 14561458.
 ANTIGLUTAMATERGIC DRUGS IN THE TREATMENT OF PARKINSONS DISEASE
Fahn S, Isgreen WP (1975). Long term evaluation of aman-
tadine and levodopa combination in parkinsonism by
double blind crossover analyses. Neurology 25 (8):
695700.
Fehling C (1973). The effect of adding amantadine to
optimum L-dopa dosage in Parkinsons syndrome. Acta
Neurol Scand 49: 245251.
Fischer PA, Jacobi P, Schneider E, Schonberger B
(1977). Effects of intravenous administration of meman-
tine in parkinsonian patients. Arzneimittelforschung 27:
10221023.
Gianutsos G, Chute S, Dunn JP (1985). Pharmacological
changes in dopaminergic systems induced by long term
administration of amantadine. Eur J Pharmacol 110:
357361.
Goetz C (1998). New lessons from old drugs. Amantadine
and Parkinsons disease. Neurology 50: 12111212.
Greenamyre JT, Eller RV, Zhang Z et al. (1994). Antiparkin-
sonian effect of remacemide hydrochloride, a glutamate
antagonist in rodent and primate models of Parkinsons
disease. Ann Neurol 35: 655661.
Hanagasi HA, Kaptanoglu G, Sahin HA et al. (2000).
The use of the NMDA antagonist memantine in drug resis-
tant dyskinesias resulting from L-dopa. Mov Disord
15 (5): 10161017.
Hubert JP, Delumeau JC, Glowinski J et al. (1994). Antagon-
ism by riluzole of entry of calcium evoked by NMDA and
veratridine in rat cultured granule cells: evidence for a
dual mechanism of action. Br J Pharmacol 113: 261267.
Jackisch R, Huang HY, Reimann W et al. (1993). Effects of
the antiparkinsonian drug budipine on neurotransmitter
release in central nervous system tissue in vitro. J Pharma-
col Exp Ther 264: 889898.
Jackson GG, Muldoon RL, Akers LW (1963). Serological
evidence for prevention of influenza infection in volun-
teers by and anti-influenza drug adamantanamine hydro-
chloride. Antimicrob Agents Chemother 3: 703707.
Jankovic J, Hunter C (2002). A double blind, placebo con-
trolled and longitudinal study of riluzole in early Parkin-
sons disease. Parkinsonism Relat Disord 8 (4): 271276.
Jarvis B, Figgitt DP (2003). Memantine. Drugs Aging 20 (6):
465476.
Kaur S, Starr MS (1997). Differential effects of intrastriatal
and intranigral injections of glutamate antagonists on
motor behaviour in the reserpine treated rat. Neuroscience
76: 345354.
Kemp JA, McKernan RM (2002). NMDA receptor pathways
as drug targets. Nat Neurosci 5: 10391042.
Kolckgether T, Wullner U, Steinbach JP et al. (1996). Effects
of the antiparkinsonian drug central neurotransmitter sys-
tems. Eur J Pharmacol 301: 6773.
Kornhuber J, Weller M (1996). New therapeutic possibilities
with low affinity MNDA receptors antagonists. Nerve-
narzt 67 (1): 7782.
Kornhuber J, Bormann J, Hubers M et al. (1991). Effects of
1-amino-adamantanes at the MK-801 binding site of the
NMDA-receptor-gated ion channel: a human postmortem
brain study. Eur J Pharmacol 206: 297300.
135
Kornhuber J, Weller M, Schoppmeyer K et al. (1994). Aman-
tadine and memantine are NMDA receptors antagonists
with neuroprotective properties. J Neural Transm Suppl
43: 91104.
Lange KW, Riederer P (1994). Glutamatergic drugs in
Parkinsons disease. Life Sci 55 (2526): 20672075.
Lange KW, Kornhuber J, Riederer P (1997). Dopamine/glu-
tamate interactions in Parkinson s disease. Neurosci Bio-
behav Rev 21 (4): 393400.
Lipton SA (1993). Prospects for clinically tolerated NMDA
antagonists: open channel blockers and alternative redox
states of nitric oxide. Trends Neurosci 16: 527532.
Lipton SA (2004). Failures and successes of NMDA receptor
antagonists: molecular basis for the use of open-channel
blockers like memantine in the treatment of acute and
chronic neurologic insults. NeuroRx 1: 101110.
Lipton SA, Rosenberg RA (1994). Mechanisms of disease:
excitatory amino acids as a final common pathway in neu-
rologic disorders. N Eng J Med 330: 613622.
Loffler H, Habermann B, Effendy I (1998). Amantadine
induced livedo reticularis. Hautarzt 49 (3): 224227.
Lundbeck H (2002). Summary of product characteristics.
Ebixa (memantine hydrochloride). Lunbeck H A/S, Valby,
Denmark, 113.
McBain CL, Mayer ML (1994). N-methyl-aspartic-acid
receptor structure and function. Physiol Rev 74: 723760.
Macchio GJ, Ito V, Sahgal V (1993). Amantadine-induced
coma. Arch Phys Med Rehabil 74 (10): 11191120.
Marsden CD (1988). The drug therapy of early Parkinsons
disease. In: MB Stern, HH Hurtig (Eds.), The Compre-
hensive Management of Parkinsons disease. PMA Pub-
lishing Corp, New York, NY, pp. 7988.
Merello M, Nouzeilles MI, Cammarota A et al. (1999). Effect
of memantine (NMDA antagonist) on Parkinsons disease:
a double blind crossover randomized study. Clin Neuro-
pharmacol 22 (5): 273276.
Metman LV, Del Dotto P, LePoole K et al. (1999). Amanta-
dine for levodopa induced dyskinesias: a 1-year follow up
study. Arch Neurol 56 (11): 13831386.
Millac P, Hasan I, Espir ML et al. (1970). Treatment of Par-
kinsonism with L-dopa and amantadine. Lancet 2: 720.
Miller C (1998). Glutamate receptor activation: a four step
program. Neuroscience 280 (5): 15471548.
Montastruc JL, Fabre N, Rascol O et al. (1994). N-methyl-D-
aspartate antagonist (NMDA) and Parkinsons disease:
a pilot study with dextromethorphan. Mov Disord 9: 242243.
Nash JE, Brotchie JM (2002). Characterisation of striatal
NMDA receptors involved in the generation of parkinso-
nian symptoms: intrastriatal microinjection studies in the
6-OHDA-lesioned rat. Mov Disord 17 (3): 455466.
Olney JW (1969). Glutamate induced retinal degeneration in
the neonatal mice: electron microscopy if the acutely evol-
ving lesion. J Neuropathol Exp Neurol 28: 455474.
Olney JW, Ho OL (1970). Brain damage in infant mice fol-
lowing oral intake of glutamate, aspartate, or cysteine.
Nature 227: 609611.
Parkes JD, Baxter RC, Marsden CD et al. (1974). Compara-
tive trial of benzhexol, amantadine, and levodopa in
136 M. G. CERSOSIMO AND F. E. MICHELI
the treatment of Parkinsons disease. J Neurol Neurosurg
Psychiatry 37: 422426.
Parkinson Study Group (2000). A multicenter controlled trial
of remacemide hydrochloride as monotherapy for PD.
Neurology 54 (8): 15831588.
Parkinson Study Group (2001). Evaluation of dyskinesias in a
pilot, randomized, placebo controlled trial of remacemide in
advanced Parkinsons disease. Arch Neurol 58: 16601668.
Pfeiffer RF (1996). Amantadine-induced vocal myoclonus.
Mov Disord 11 (1): 104106.
Przuntek H, Bittkau S, Bliesath H et al. (2002). Budipine
provides additional benefit in patients with Parkinsons
disease receiving a stable optimum dopaminergic drug
regimen. Arch Neurol 59: 803806.
Reisberg B, Doody R, Stoffler A et al. (2003). Memantine
Study Group. Memantine in moderate to severe Alzhei-
mers disease. N Engl J Med 348 (14): 13331341.
Savery F (1977). Amantadine and a fixed combination of
levodopa and carbidopa in the treatment of Parkinsons
disease. Dis Nerv Syst 38: 605608.
Schachter SC, Tarsy D (2000). Remacemide: current status
and clinical applications. Expert Opin Investig Drugs
9 (4): 871873.
Schadel M, Wu D, Otton SV et al. (1995). Pharmacokinetics
of dextromethorphan and metabolites in humans: influ-
ence of CYP2D6 phenotype and quinidine inhibition.
J Clin Psychopharmacol 15: 263269.
Scholz EP, Kiesecker C, Lueck S et al. (2003). Drug binding
to aromatic residues in the HERG channel pore cavity as
possible explanation for acquired Long QT syndrome by
antiparkinsonian drug budipine. Naunyn Schmiedebergs
Arch Pharmacol 368: 404414.
Schmidt WJ, Bubser M (1989). Anticataleptic effects of the
N-methyl-D-aspartate antagonist MK-801 in rats. Pharma-
col Biochem Behav 32: 621623.
Schneider E, Fischer PA, Clemens R et al. (1984). Effects of
oral memantine administration on Parkinson symptoms.
Results of a placebo controlled multicenter study. Dtsch
Med Wochenschr 109: 987990.
Schwab RS, England AC, Poskanzer DC et al. (1969). Aman-
tadine in the treatment of Parkinsons disease. JAMA 208:
11681170.
Shannon KM, Goetz CG, Carroll VS et al. (1987). Amanta-
dine and motor fluctuations in chronic Parkinsons dis-
ease. Clin Neuropharmacol 10: 522526.
Shoulson I, Penney J, McDermott M et al. (2001). Parkinson
Study Group. A randomized, controlled trial of remace-
mide for motor fluctuations in Parkinsons disease. Neu-
rology 56: 455462.
Shulman LM, Minagar A, Sharma K et al. (1999). Amanta-
dine-induced peripheral neuropathy. Neurology 53 (8):
18621865.
Snow BJ, Macdonald L, Mcauley D et al. (2000). The effect
of amantadine in levodopa induced dyskinesias in Parkin-
sons disease: a double blind, placebo controlled study.
Clin Neuropharmacol 23 (2): 8285.
Sobolevski AI, Koshelev SG, Khodorov BI (1998). Interac-
tion of memantine and amantadine with agonist inbound
NMDA-receptor channels in acutely isolated rat hippo-
campal neurons. J Physiol 512 (1): 4760.
Spieker S, Loschmann PA, Klockgether T (1999). The
NMDA antagonist budipine can alleviate levodopa
induced motor fluctuations. Mov Disord 14 (3): 517519.
Stoof JC, Booij J, Drukarch B (1992). Amantadine as N-
methyl-D-aspartic acid receptor antagonist: new possibili-
ties for therapeutic applications. Clin Neurol Neurosurg
94: S4S6.
Uitti RJ, Rajput AH, Ahlskog JE et al. (1996). Amantadine
treatment is an independent predictor of improved survival
in Parkinsons disease. Neurology 46 (6): 15511552.
Vale JA, Maclean KS (1977). Amantadine-induced heart
failure. Lancet 1 (8010): 548.
Verhagen Metman L, Del Dotto P, Van den Munckhof
P et al. (1998a). Amantadine as treatment for dyskinesias
and motor fluctuations in Parkinsons disease. Neurology
50: 13231326.
Verhagen Metman L, Blanchet PJ, Van den Munckhof
P et al. (1998b). A trial of dextromethorphan in parkinso-
nian patients with motor response complications. Mov
Disord 13 (3): 414417.
Von Voigtlander PF, Moore KE (1971). Dopamine release
from the brain in vivo by amantadine. Science 174:
408410.
Walker JE, Albers JW, Tourtellotte WW et al. (1972). A
qualitative and quantitative evaluation of amantadine in
the treatment of Parkinsons disease. J Chronic Dis 25:
149182.
Wong BY, Coulter DA, Choi DW et al. (1988). Dextrorphan
and dextromethorpham common antitussives, are antiepi-
leptic and antagonize N-methyl-D-asparatate in brain
slices. Neurosci Lett 85: 261266.
Woodworth JR, Dennis SRK, Moore L et al. (1987). The
polymorphic metabolism of dextromethorphan. J Clin
Pharmacol 27: 139143.
Zeevalk GD, Nicklas WJ (1992). Evidence that the
loss of the voltage dependent Mg block of the N-
methyl-D-aspartate receptor underlies activation during
inhibition of neuronal metabolism. J Neurochem 59:
12111220.
Zeldowicz LR, Huberman J (1973). Long term therapy of
Parkinsons disease with amantadine alone and combined
with levodopa. Can Med Assoc J 109: 588593.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 37

Investigational drugs

CARLO COLOSIMO* AND GIOVANNI FABBRINI

Dipartimento di Scienze Neurologiche, Universita La Sapienza, Rome, Italy

37.1. Introduction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

The introduction of the dopamine precursor levodopa
(LD) as the mainstay of treatment of Parkinsons dis-
ease (PD) has provided excellent symptomatic benefit
for the majority of patients. However, the effects of
dopaminergic therapy are limited by the fact that LD
has not been shown to slow the progression of the dis-
ease and that PD patients still face major shortcomings
in the chronic phase of the disease.
Fluctuations and levodopa-induced dyskinesia (LID)
are the major complications in the current therapeutic
approach to the treatment of PD, deeply affecting patients
quality of life. More than 50% of all patients treated with
LD for 5 years or more develop motor response fluctua-
tions, which are usually associated with the appearance
of LID (Nutt and Holford, 1996; Colosimo and De
Michele, 1999; Brotchie, 2000). The exact pathophysiol-
ogy of fluctuations and LID is not fully understood, but
they are probably related to striatal dopamine receptor
changes following dopaminergic denervation and chronic
exposure to LD (Crossman, 1990). These receptor altera-
tions include changes of sensitivity, relative balance
between different dopamine receptor subtypes and differ-
ent translational and neuromodulatory-system responses
(Crossman, 1990; Colosimo et al., 1996; Brotchie, 2000;
Bezard et al., 2001).
Duration of the disease and early initiation of LD
therapy are key factors for the development of motor
complications, though the poor pharmacokinetics of
LD (very short half-life, inconsistent absorption) also
plays an important role. As a result, the dopamine ago-
nists, compounds with a better pharmacokinetic profile
than LD, were developed. Based on experimental data
showing that de novo administration of dopamine ago-
nists to non-human primates rendered parkinsonian
(MPTP) induced less dyskinesia than LD (Bedard
et al., 1992; Pearce et al., 1998), several clinical stu-
dies have been conducted, all showing that dopamine
agonists can alleviate parkinsonian symptoms in pre-
viously untreated patients with a much reduced inci-
dence of fluctuations and dyskinesia (Rascol et al.,
2000; Parkinson Study Group, 2004b).
Unfortunately, this strategy has its limitations since
only approximately 30% of parkinsonian patients show
a good and durable response to dopamine agonists as
monotherapy. Chronic use of dopamine agonists is also
associated with frequent psychiatric side-effects,
including visual hallucinations, delusions and paranoid
psychosis. Furthermore, dopamine agonists more easily
elicit dyskinesia when administered together with LD
or following priming with LD. Therefore, in the fore-
seeable future, dopamine replacement in the form of
LD is likely to remain the mainstay of therapeutic
approaches for PD. Attempts to reduce dyskinesia by
means of drug holidays, controlled-release LD prepara-
tions, long-acting dopamine agonists (cabergoline), or
other adjunct therapies such as monoamine oxidase-B
(MAO-B) or catechol-O-methyl-transferase inhibitors,
have generally met with limited success in the clinic
(Colosimo and De Michele, 1999). Continuous waking-
day subcutaneous apomorphine infusion is effective in
the long term, though not easily applicable to the major-
ity of patients (Colosimo et al., 1994). As a result, several
new treatment strategies for PD are currently being
investigated, particularly those targeting non-dopaminer-
gic pathways.
Furthermore, in PD there is still no satisfactory
approach to the treatment of cognitive disturbances
and dementia (Brown and Marsden, 1990), autonomic
dysfunction (Senard et al., 2001), balance, walking

*Correspondence to: Carlo Colosimo, Dipartimento di Scienze Neurologiche, Universita La Sapienza, Viale dellUniversita
30, I-00185 Rome, Italy, E-mail: carlo.colosimo@uniroma1.it, Tel: 39-06-4991-4511, Fax: 39-06-4991-4700.
138 C. COLOSIMO AND G. FABBRINI
difficulties and the risk of falling (Bloem et al., 2004),
speech disorders (Pinto et al., 2004), psychiatric and
behavioral symptoms (Wint et al., 2004) and sleep
problems (Brotini and Gigli, 2004). Based on all the
previous observations, therapeutic research in the
future is expected to be moving in several different
directions. Among these are: (1) development of so-
called neuroprotective drugs, capable of blocking or
at least slowing down the degenerative process respon-
sible for neuron death, or even of restorative strategies,
which would allow to normal brain function to be
regained; (2) further improvement in the replacement
of dopaminergic loss; (3) antidyskinetic drugs; and
(4) symptomatic drugs acting on neurotransmitters
other than dopamine, or which may target the brain
in other areas rather than only in the striatum.
37.2. Neuroprotective therapies
gies will derive directly from studies directed to an
understanding of the pathogenesis and mechanisms of
cell death. Current information suggests that neurode-
generation in PD is associated with a cascade of events
that includes oxidant stress, mitochondrial abnormal-
ities, failure in the ubiquitin-proteasome system to clear
unwanted proteins, excitotoxicity, inflammation and
possible other still not identified mechanisms (Dawson
and Dawson, 2003). Considerable evidence suggests that
cell death in PD, regardless of cause, occurs by way of
signal-mediated apoptosis (Hirsch et al., 1999). Devel-
opment of new drugs for neuroprotection is very fast.
In a recent survey of potential neuroprotective agents
for clinical trials in PD (Ravina et al., 2003), several
compounds have been identified as potential effective
neuroprotective agents, but only a few are real candi-
dates for phase II or III studies. The development status
of these compounds is summarized in Table 37.1.

Interventions that can slow or halt the progression of
PD remain a crucial unmet need.
Several promising approaches are under development
for the potential of neuroprotection in PD. However, the
confounding fact of the possible symptomatic effects of
the drugs tested, the placebo effect, the choice of optimal
endpoint and the need for validated surrogate markers
are all significant issues when studying a putative neuro-
protective intervention in PD, which have not been
completely addressed until now. Neuroprotection strate-
37.2.1. Monoamine oxidase inhibitors
37.2.1.1. Rasagiline
Rasagiline is a propargylamine and is a potent, irreversi-
ble, selective inhibitor of MAO-B with no amphetamine-
like metabolites and with the capability of increasing DA
release. Beside its activity on MAO enzymes, the neu-
roprotective properties of rasagiline may be linked to
other factors, such as the capability of inhibiting apop-
tosis at three levels: (1) intranuclear translocation of

Table 37.1
Development status of neuroprotective/neurorestorative agents

Compound Company/institution Class of compound Phase of development

CEP-1347 Cephalon/H Lundbeck Mixed-lineage kinase inhibitor Withdrawn

Kyowa Hakko Kogyo
Leteprinim Spectrum Pharmaceuticals Nerve growth factor agonist Phase II
V-10367 Vertex Pharmaceuticals Neuroimmunophilin ligand
Schering
Liatermine Amgen Growth factor agonist Withdrawn
GPI-1485 Guildford Pharmaceuticals Neuroimmunophilin-ligand Phase II
PAN-408 Panacea Pharmaceuticals a-Synuclein oligomerization Preclinical
inhibitors
PYM-50028 Phytopharm plc/Yamanouchi Dopamine modulator Phase II
Pharmaceutical
TCH-346 Novartis GAPDH inhibitor Withdrawn
MITO-4509 Mitokor Estrogen analog Phase I
Sonic hedgehog Curis/Wyeth Pharmaceuticals Hedgehog agonist Preclinical
protein agonist
ONO-2506 ONO Pharmaceutical Astrocyte modulator Phase II
E-2007 Eisai AMPA antagonist Phase II

Adapted with permission from The Thomson Corporation and Johnston and Brotchie (2004). # 2004 The Thomson Corporation.
GAPDH, glyceraldehyde-3-phosphate dehydrogenase; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid.
 INVESTIGATIONAL DRUGS
the glycolytic enzyme glyceraldehyde-3-phosphate
dehydrogenase; (2) induction of bcl-2; and (3) activa-
tion of mitochondrial permeability transition. Clinical
studies on rasagiline have also confirmed the potential
usefulness of this drug in the symptomatic treatment of
PD. In early patients (TEMPO study) rasagiline was
superior to placebo in improving Unified Parkinsons
Disease Rating Scale (UPDRS) motor and activities of
daily living scores. More patients in the placebo group
(16.7%) than those in rasagiline treatment (11.2%)
needed LD within 12 months of the beginning of the
study, although this difference was not significant. This
study also included an initial 6-month placebo phase
(delayed treatment) which showed that patients treated
for 6 months with placebo and then allowed to receive
the active drug did not catch up with those patients
who were in active treatment since the beginning of the
study. These data, although preliminary, suggest a dis-
ease-modifying effect rather than symptomatic benefit
only (Parkinson Study Group, 2002, 2004a).
37.2.1.2. Zydis selegiline
The usefulness of conventional selegiline is confounded
by low bioavailability, extensive first-pass metabolism
and production of amphetamine metabolites. Zydis sele-
giline (a rapidly disintegrating tablet) dissolves in the
mouth on contact with saliva and undergoes pregastric
absorption, providing high plasma levels of selegiline,
almost completely avoiding first-pass metabolism and
markedly reducing the production of amphetamine meta-
bolites (Seager, 1998). Few studies have shown the
potential usefulness of the drug in the treatment of
advanced patients with motor fluctuations, increasing
the time spent in the on phase. Side-effects more com-
monly reported were dizziness, dyskinesia, hallucina-
tions, headache and dyspepsia, usually in the first
6 weeks of treatment (Waters et al., 2004). The possible
role of zydis selegiline as a neuroprotective agent has not
been tested.
37.2.2. Modulators of mitochondrial function
Coenzyme Q1 is a health supplement which is able to
increase the activity of mitochondrial complex I activity
and may act as an antioxidant. Preliminary evidence
suggests that doses of 1200 mg/day, which are well toler-
ated, may slow functional decline as measured by
UPDRS scores (Shults et al., 2002).
Creatine is also a nutritional supplement which is
converted to phosphocreatine, a metabolite functioning
as an energy buffer able to transfer a phosphoryl group
to adenosine diphosphate. Creatine has been shown to
be protective in MPTP rodent models (Matthews et al.,
139
1999). A pilot study using creatine and minocycline is
under way.
37.2.3. Other mechanisms
37.2.3.1. Estrogens
Epidemiological data suggest a reduced incidence of
PD in women (Currie et al., 2004) and there are also
several animal models in which estrogens appear as pro-
mising neuroprotective agents. The mechanism may
involve neurotrophic effects as well as antioxidant
effects (Dluzen and Horstink, 2003).
37.2.3.2. GM1 ganglioside
GM1 ganglioside is a component of neuronal mem-
branes, may facilitate the neurotrophic actions of
brain-derived nerve growth factor (BDNF) and glial-
derived neurotrophic factor (GDNF), may inhibit
apoptosis and may protect against excitotoxicity. Some
preliminary data in PD have shown that the compound
is well tolerated and has short-term symptomatic ben-
efit (Schneider, 1998). However concerns still exist
about its immunogenicity and the relationship with
GuillainBarre syndrome.
37.2.3.3. Neuroimmunophilin
Neuroimmunophilin ligands (NILs) are drugs derived
from the immunosuppressant FK506 (tacrolimus) that
have been shown to have variable efficacy in reversing
neuronal degeneration and preventing cell death (Gold
and Nutt, 2002). In animal models mimicking PD they
induce resprouting and are neurotrophic. Some evi-
dence suggests that NILs may act through regulation
of steroid hormone receptors. Other evidence suggests
that NILs may protect neurons by upregulating the
antioxidant glutathione and stimulating nerve regrowth
by inducing the production of neurotrophic factors.
Initial clinical trials have had mixed success. In one,
patients with moderately severe PD showed no overall
improvement in fine motor skills following 6 months
of treatment with the neuroimmunophilin GPI 1485,
although there was a decreased loss of dopaminergic
nerve terminals or eventually an increase in dopami-
nergic terminals within 6 months of the higher dose
of GPI 1485 drug treatment (Poulter et al., 2004).
37.2.3.4. Inhibitors of microglial inflammation
(antiapoptotic kinase inhibitors)
The c-Jun NH2-terminal kinase (JNK) signaling path-
way is frequently induced by cellular stress and corre-
lated with neuronal death. JNK signaling is therefore a
promising target in PD for developing pharmacologi-
cal intervention. CEP-1347 blocks the activation of
140 C. COLOSIMO AND G. FABBRINI
the c-Jun/JNK apoptotic pathway in neurons exposed to
various stressors and attenuates neurodegeneration in
animal models of PD, eventually associated with micro-
glial activation. CEP-1347 reduced cytokine production
in primary cultures of human and murine microglia and
in monocyte/macrophage-derived cell lines, stimulated
with various endotoxins or the plaque-forming peptide
Abeta140. Moreover, CEP-1347 inhibited brain tumor
necrosis factor (TNF) production induced by intracereb-
roventricular injection of lipopolysaccharide in mice.
As expected from a mixed linear inhibitor (MLK),
CEP-1347 acted upstream of p38 and c-Jun activation
in microglia by dampening the activity of both pathways
(Lund et al., 2005). These data infer that MLKs may be
important, yet unrecognized, modulators of microglial
inflammation and demonstrate a novel anti-inflamma-
tory potential of CEP-1347 (Johnston and Brotchie,
2004). The safety and tolerability of CEP-1347 have
recently been studied in 30 patients with PD. Overall
the drug was well tolerated and had no acute effect
on parkinsonian symptoms or LD pharmacokinetics
(Parkinson Study Group, 2004c).
37.2.3.5. Minocycline
Minocycline is a semisynthetic, second-generation tet-
racycline derivative which crosses the bloodbrain
barrier and may inhibit microglial-related inflamma-
tory events and also the apoptotic cascade. Several stu-
dies have shown that minocycline is neuroprotective in
animal models of central nervous system trauma and
neurodegenerative diseases; in particular, this com-
pound has greatly enhanced survival in nigrostriatal
dopaminergic neurons in the MPTP model of PD (Du
et al., 2001). Minocycline has, therefore, been incorpo-
rated into an ongoing clinical investigation in
untreated PD patients (Ravina et al., 2003).
37.3. Improvement of dopaminergic drugs
Several strategies have been proposed and developed
in order to improve the pharmacokinetics and pharma-
codynamics of dopaminergic agents used in PD.
The development status of all these compounds is
summarized in Table 37.2.
37.3.1. Improvement of levodopa bioavailability
Absorption of LD is very sensitive and depends on the
state of the stomach and gastrointestinal system.
Therefore efforts are under way to improve LD
absorption. Recent attempts have shown that methyl-
ester LD (melevodopa) is effective as standard LD
and may have the additional advantage of a faster
absorption (Johnston and Brotchie, 2004).
Another approach is currently under investigation
through the intraduodenal infusion delivery of LD.
Advanced parkinsonian patients may benefit from this
form of treatment in order to achieve more stable
plasma LD levels (Nyholm et al., 2005).
37.3.2. Increase in the synaptic availability
of dopamine
Dopamine reuptake blockers, by enhancing and stabi-
lizing intrasynaptic transmitter levels, could help palli-
ate motor dysfunction in PD, in both early and
advanced disease. In experimental animals with severe
neurotoxin-induced dopaminergic neuron loss mimick-
ing conditions in advanced PD, LD treatment after an
effective pharmacologic dopamine transporter (DAT)
blockade produces far higher elevations in extracellu-
lar DA than normally occur (Pearce et al., 2002). Thus,
DAT inhibitors should act clinically to potentiate the
antiparkinsonian action of LD. Moreover, because a
reduction in DA reuptake prolongs its striatal half-life,
motor fluctuations as well as dyskinesia and other
adverse consequences of the intermittent stimulation
of striatal DA receptors might diminish in the long
term (Nutt and Holford, 1996). A randomized, dou-
ble-blind, placebo-controlled study compared the acute
effects of the monoamine uptake inhibitor NS 2330
with those of placebo in 9 fluctuating parkinsonian
patients (Bara-Jimenez et al., 2004). Individuals ran-
domly assigned to NS 2330 treatment were given an
initial 1-week placebo run-in, followed by a treatment
phase consisting of eight doses of 1.5 mg each, admi-
nistered three times weekly. The cumulative total dose
of 12 mg was selected to achieve plasma drug concen-
trations in therapeutic range, based on preliminary
pharmacokinetic data obtained by the drug manufac-
turer. Remaining patients received placebo throughout
the entire study. At the dose administered, no change
in parkinsonian scores was found when NS 2330 was
given alone or with LD. Moreover, NS 2330 coadmi-
nistration did not appear to reduce the severity of dys-
kinesia or the duration of the antiparkinsonian
response to LD. Since, under the conditions of this
study, results failed to support the usefulness of dopa-
mine reuptake inhibition in the treatment of advanced
PD, this compound was withdrawn from clinical trials.
37.3.3. Dopamine agonists
There is still work to be done to understand better the
effects of selective D1 dopamine agonists in PD
(Rascol et al., 1999, 2001a). It is realistic to hope for
further innovations through the development of new
 INVESTIGATIONAL DRUGS 141
Table 37.2
Development status of symptomatic antiparkinsonian agents

Phase of
Compound Company/Institution Class of compound development Other potential actions

Dopaminergic
Melevodopa Chiesi Farmaceutici Methyl-l-dopa/ Launched
carbidopa
SR-57667 Sanofi-Synthelabo Irreversible MAO-B Phase IIb Neuroprotective
inhibitor?
Safinamide Newron MAO-B inhibitor Phase III Neuroprotective
Pharmaceuticals Na/Ca channel
blocker
Rasagiline Teva Pharmaceutical Irreversible MAO-B Launched Neuroprotective
Industries/H inhibitor
Lundbeck/Eisai
NS-2330 NeuroSearch/ Monoamine Withdrawn Cognitive enhancement
Boehringer Ingelheim reuptake inhibitor Antidepressant
SPD-473 Shire Pharmaceutical Monoamine reuptake Phase II Cognitive enhancement
Group inhibitor Antidepressant
Sumanirole Pfizer D2-agonist Withdrawn
Rotigotine Schwarz Pharma/Otsuka D2-agonist Launched
Pharmaceutical
SLV-308 Solvay D2 partial agonist/ Phase II Antidepressant
5-HT1A agonist
Talipexole Boehringer Ingelheim D2-agonist/a2- Launched
adrenoceptor agonist
DU-127090 Solvay/H Lundbeck/Wyeth D2 partial agonist/ Phase III
Pharmaceuticals 5-HT1A agonist
BIA-3202 BIAL Group COMT inhibitor Phase I Neuroprotective
Non-dopaminergic
Istradefylline Kyowa Hakko Kogyo A2A antagonist Phase III Neuroprotective
KF-17837 Kyowa Hakko Kogyo A2A antagonist Preclinical Neuroprotective
VR-2006 Vernalis Group A2A antagonist Phase I Neuroprotective
Donepezil Eisai/Pfizer/Wyeth-Ayerst AChE inhibitor Launched Cognitive
International enhancement

Adapted with permission from The Thomson Corporation and Johnston and Brotchie (2004). # 2004 The Thomson Corporation.
MAO-B, monoamine oxidase-B; COMT, catechol-O-methyltransferase; AChE, acetylcholinesterase.

dopamine agonists, fully or partially selective or non-
selective (Bezard et al., 2003a). D2-selective agonists
such as sumanirole were developed based on the con-
cept that the D3 component action of the previous
generation of dopamine agonists, such as pramipexole,
may be detrimental to the antiparkinsonian effect
(Stephenson et al., 2005).
The concept of constant dopaminergic stimulation
(Chase, 1998) is now leading to the study of new ways
of administering dopaminomimetics, such as the trans-
dermal route, for the possibility of giving particularly
stable plasma levels (Parkinson Study Group, 2003).
Rotigotine is a non-ergot dopamine agonist, acting
selectively on D2-receptors, which has been formulated
in a silicone-based transdermal system. The rationale
behind this transdermal delivery system is based on the
option of having a non-oral DA agonist which may be
useful in terms of compliance in patients already assum-
ing many drugs for the oral route and the capability of
stable blood levels of a dopamine agonist. Rotigotine
patch reaches the steady state in 24 hours and allows
stable drug release in the 24-hour period (Metman et al.,
2001). Early PD patients (n 242) were treated in a phase
III double-blind, placebo-controlled study against four dif-
ferent doses of rotigotine (4.5, 9.0, 13.5 or 18 mg). The
doses of 13.5 and 18.0 mg were superior to placebo at
week 11. Side-effects were also more frequent in the
active-treatment groups and were qualitatively similar to
142 C. COLOSIMO AND G. FABBRINI
those reported in other studies of dopamine agonists in
early PD patients (nausea, application-site reaction, dizzi-
ness, somnolence, insomnia, vomiting and fatigue) (Par-
kinson Study Group, 2003). Local skin reactions were
not uncommon (39%), leading to early withdrawal in a
few cases. Preliminary positive data are also available
for the transdermal delivery of lisuride (Woitalla et al.,
2004).
37.3.3.1. Slv-308
SLV-308 is a partial D2D3 agonist and an agonist of 5-
HT1A receptors, a profile which suggests a good anti-
parkinsonian action with reduced capability of indu-
cing dyskinesia. Phase II trials in the treatment of PD
are under way (Wolf, 2003).
37.3.3.2. Safinamide
This is a novel experimental drug combining several
pharmacological properties that are potentially useful
in the treatment of PD. This drug has the capability of
blocking voltage-dependent sodium and N-type cal-
cium channel, therefore inhibiting glutamate release.
Safinamide is also a highly selective and reversible
inhibitor of MAO-B, decreasing dopamine break-
down and the production of toxic free radicals
(Fariello et al., 1998). The peculiarity of this dual
mechanism of action offers the possibility that safina-
mide might be used in PD, but also in the treatment of
epilepsy. A recent double-blind trial has shown that
safinamide increased in respect to placebo (37.5
versus 21.4%) the percentage of early PD patients
improving their motor score by >30% and also
improved the motor scores in a subgroup of patients
under stable treatment with dopamine agonists
(Stocchi et al., 2004).
37.4. Antidyskinetic drugs
The pathophysiology underlying treatment-related
dyskinesia is not well known and cannot easily be
fitted into current models of basal ganglia dysfunction
in PD. It may involve altered activity in the projection
pathways from the striatum to the globus pallidus,
resulting in reduced activity in the output regions of
the basal ganglia, i.e. the internal segment of the glo-
bus pallidus and the substantia nigra pars reticulata
(Papa et al., 1999). Several experimental and clinical
studies in parkinsonism have shown that motor fluc-
tuations and LID can be modulated by drugs acting
on neurotransmitters other than dopamine, including
glutamate, g-aminobutyric acid, norepinephrine, acet-
ylcholine, serotonin, adenosine and cholecystokinin.
In numerous cases, the prospect of using specific drugs
to counteract LID was raised by the previously shown
efficacy of such compounds in the treatment of other
types of dyskinesia.
37.4.1. Glutamatergic drugs
Amantadine is an antiviral compound, which has been
widely used as a first-line antiparkinsonian drug since
1969, but has only recently been found to act as a non-
competitive N-methyl-D-aspartate (NMDA) glutama-
tergic antagonist (Chase et al., 2000). Findings from
basic science suggesting that NMDA receptor block-
ade may improve the dyskinetic complications of LD
therapy have thus prompted the use of this compound
as a specific antidyskinetic drug (Metman et al.,
1998a). Following pilot studies showing that amanta-
dine has a favorable effect on LID in a significant per-
centage of patients with PD, further work has
confirmed the beneficial effects of amantadine on
motor response complications (Pourcher et al., 1989;
Metman et al., 1999; Luginger et al., 2000; Snow
et al., 2000; Del Dotto et al., 2001), although some
authors have shown that benefit may be short-lived
(Thomas et al., 2004). The hope of better-tolerated
glutamate antagonists is driving the development of the
non-competitive a-amino-3-hydroxy-5-methylisoazole-
4-propionate (AMPA) antagonists, for example
talampanel. Since AMPA antagonists may also have
neuroprotective actions, some of the companies now
appear to be developing AMPA antagonists for this
use, rather than as antidyskinetic drugs (Johnston and
Brotchie, 2004).
The results of other trials in which familiar drugs
have been used in LID are less convincing. For
instance, the efficacy of a combination of LD and
anticholinergic drugs in parkinsonian patients to
reduce both parkinsonian symptoms and biphasic
dyskinesia was only demonstrated in a single trial
(Pourcher et al., 1989). The addition of 5-methoxy
5-N, N-dimethyl-tryptamine, a non-selective serotonin
agonist, slightly reduced dyskinesia but also reduced
the antiparkinsonian benefit of LD (Gomez-Mancilla
and Bedard, 1993). More recently, alleviation of par-
kinsonian symptoms without the development of dys-
kinesia has been reported in both MPTP-lesioned
monkeys and other experimental animals by using ade-
nosine A2A receptor antagonists and NR2B-selective
NMDA glutamatergic antagonists (Kanda et al.,
1998, 2000; Grondin et al., 1999; Steece-Collier
et al., 2000; Bibbiani et al., 2002; Lundblad et al.,
2003). The potential symptomatic use in PD of drugs
acting on serotonergic and adenosine receptors will
be discussed in more detail in the next part of this
chapter.
 INVESTIGATIONAL DRUGS 143
A summary of the various drugs which have been of searches, using the search terms Parkinsons dis-
successfully tested in LID in controlled trials on ease, levodopa and dyskinesia on Medline and
humans is shown in Table 37.3 (Colosimo and Craus, references from relevant articles; numerous articles
2003). Data for this synopsis were identified by means were also identified through searches in the authors

Table 37.3
Symptomatic drugs for LID as proven by controlled trials

Compound Mechanism of action Reference and study design Dose*

Ritanserin Selective serotonergic 5-HT2 Meco et al. (1988): Single-blind, Mean dosage of
antagonist placebo-controlled, cross-over study 21.4 mg (range
1030 mg), 3 a day
Buspirone Serotonergic 5-HT1A-agonist Bonifati et al. (1994): Double-blind, 10 mg, 2 a day
placebo-controlled, cross-over study
Fluoxetine Selective serotonin reuptake Durif et al. (1995): Videotape 20 mg, 2 a day
inhibitor randomized evaluation
Propranolol b-Adrenergic blocker Carpentier et al. (1996): Videotape Up to 60 mg a day
randomized evaluation
Clozapine Dopaminergic D4/D1- Durif et al. (1997): Videotape 50 mg/day
antagonist, serotonergic 5-HT2 randomized evaluation
antagonist, anticholinergic? Durif et al. (2004): Double-blind, Up to 50 mg a day
parallel-group, placebo-controlled,
multicenter trial
Amantadine Non-competitive NMDA Metman et al. (1998a): Double-blind, 100 mg, 34 a day
glutamatergic antagonist placebo-controlled, cross-over study
Metman et al. (1999): Double-blind, 100 mg, 34 a day
placebo-controlled, cross-over study
Luginger et al. (2000): Double-blind, 100 mg, 3 a day
placebo-controlled, cross-over trial
Snow et al. (2000): Double-blind, 100 mg, 2 a day
placebo-controlled, cross-over trial
Del Dotto et al. (2001): Acute double- 200 mg in a 2-hour
blind, placebo-controlled study intravenous infusion
Dextromethorphan NMDA glutamatergic antagonist Metman et al. (1998b): Double-blind, Range, 60120 mg/day
placebo-controlled, cross-over study
Metman et al. (1998c): Double-blind, Up to 180 mg a day
placebo-controlled, cross-over study
Olanzapine Dopaminergic D1/D2/D4- Manson et al. (2000a): Randomized, Up to 7. 5 mg/day
antagonist placebo-controlled, double-blind,
cross-over trial
Idazoxan a2-Adrenergic antagonist Rascol et al. (2001b): Randomized, 10, 20, 40 mg, in
double-blind, placebo-controlled single dose
study
Nabilone Cannabinoid receptor agonist Sieradzan et al. (2001): Randomized, 0.03 mg/kg in two
double-blind, placebo-controlled, doses
cross-over trial
Sarizotan Serotonergic 5-HT1A full agonist, Olanow et al. (2004): Prospective, 6- Up to 10 mg/day
dopaminergic D2/D3/D4 weak month multicenter open-label dose-
antagonist? rising study and videotape evaluation
Naloxone Opioid antagonist Fox et al. (2004): Randomized, double- 0.4 mg/kg per min in
blind, placebo-controlled, cross-over, intravenous infusion
acute-challenge study

*Unless indicated, the dose was given orally; when available, the number of doses per day was given.
Adapted with permission from Colosimo and Craus (2003).
NMDA, N-methyl-d-aspartate.
144 C. COLOSIMO AND G. FABBRINI
extensive files. Abstracts and reports from meetings
were also included. Several other drugs have been
reported to improve LID in case series or uncontrolled
trials, e.g. methysergide (Gomez-Mancilla and Bedard,
1993), physostigmine (Tarsy et al., 1974; Gomez-Man-
cilla and Bedard, 1993), estrogens (Gomez-Mancilla
and Bedard, 1992), progesterone (Gomez-Mancilla and
Bedard, 1992), riluzole (Merims et al., 1999), mirtazapine
(Meco et al., 2003), quetiapine (Oh et al., 2002), magne-
sium sulfate (Chassain et al., 2002), alpha-amino-3-
hydroxy-5-methyl-4-isoxazole (a propionic acid receptor
antagonist) (Silverdale et al., 2002), 3,4-methylenedioxy-
methamphetamine (ecstasy) (Iravani et al., 2003) and
cannabis (Venderova et al., 2004). These pilot studies
should encourage, when appropriate, larger double-blind
controlled trials.
37.4.2. Noradrenergic drugs
A key abnormality most likely underlying LID is the
overactivity of the direct striatal output pathway con-
necting the striatum with the output regions of the
basal ganglia. Adrenergic a2-receptors are present in
the basal ganglia and several experimental studies
have shown that they occur in high density in the rat
and mouse striatum, in a position likely to influence
the direct or indirect striatal motor outputs (Scheinin
et al., 1994; Holmberg et al., 1999; Papa et al., 1999;
Bezard et al., 2001; Zhang and Ordway, 2003).
As it has also been suggested that activation of a2-
adrenergic receptors can facilitate movements pro-
duced by activation of the direct pathway, it is possible
that enhanced a2-adrenergic receptor stimulation may
contribute to the pathophysiology of LID (Hill and
Brotchie, 1999). Other studies have indicated that
dopaminergic transmission in the striatum can also be
influenced by -adrenergic activity; the density of -
adrenergic receptors is one of the highest in the stria-
tum and the local release of dopamine is increased
by isoproterenol when applied in vivo into the caudate
nucleus or in vitro on rat striatal slices, an effect that is
prevented by propranolol (Reisine et al., 1982).
In addition, motor behavior studies in animals on
dopaminenorepinephrine interactions have shown that
the noradrenergic systems in PD are impaired and this
probably contributes to both motor and affective symp-
toms observed in this condition (Burn, 2002).
These observations have encouraged studies on
drugs acting on the noradrenergic system. Ever since
the 1980s, the coadministration of yohimbine and LD
to MPTP-treated primates has been known to reduce
LID without influencing the antiparkinsonian efficacy
of this compound (Chopin et al., 1986). Yohimbine
reduces the dyskinetic effect produced by LD, whereas
the antiparkinsonian effect is not altered regardless of
the dosage. Yohimbine has a variety of pharmacologi-
cal properties: it is mainly an a-adrenergic receptor
antagonist with low selectivity between a1 and a2 sub-
types, but also acts as an antagonist at dopamine D2, 5-
HT1A and peripheral 5-HT2B receptors and as an ago-
nist at 5-HT1D receptors. On the other hand the combi-
nation of LD with clonidine, an a2-adrenoreceptor
agonist, also reduced LID, whereas at higher doses
clonidine blocked both the antiparkinsonian and the
dyskinetic effects of LD (Nishikawa et al., 1984;
Gomez-Mancilla and Bedard, 1993; Hill and Brotchie,
1999). More recent are the data concerning fipamezole
(JP-1730), a 2-indane imidazole a2-adrenergic receptor
antagonist which was also able to reduce LID in the
MPTP-lesioned marmoset model of PD (Savola
et al., 2003): this compound is currently in phase III
clinical trials (Peltonen et al., 2002). Besides, in a
single clinical trial it has been suggested that adminis-
tration of low doses of propranolol, a non-selective -
adrenergic blocker, may improve LID in patients with
advanced PD (Carpentier et al., 1996).
On the basis of these data, idazoxan, a new selec-
tive a2-adrenoreceptor antagonist, was developed and
tested in animals with experimental parkinsonism and
subsequently in patients with LID. Two reports, one
experimental and the other clinical, have confirmed
that idazoxan has an interesting pharmacological pro-
file, improving LID without a return to parkinsonian
symptoms (Fox et al., 2001; Rascol et al., 2001b). Pre-
vious experimental data in animals have suggested
that, although idazoxan as a monotherapy displays no
antiparkinsonian effect, when given in combination
with LD it not only reduces the dyskinetic side-effects
of LD, but may even extend the antiparkinsonian
action of this compound (Henry et al., 1999).
The purpose of the experimental study by Fox and
coworkers (2001) was to compare the effect of ida-
zoxan on dyskinesia produced by both LD and apomor-
phine in the MPTP experimental model of PD. The
marmosets were treated with MPTP to induce a parkin-
sonian syndrome. In the first part of the study, only LD
(8 mg/kg) or apomorphine (0.0750.3 mg/kg) was
administered in order to establish the severity of the
dyskinesia each drug produced. In the second part of
the study, doses of apomorphine and LD were individu-
ally administered along with either idazoxan (2.5 mg/kg)
or vehicle. A neurologist with clinical experience in
movement disorders who was blinded to the animals
treatment then analyzed the videotapes.
Part one of the study demonstrated that both apo-
morphine and LD increased mobility and improved
 INVESTIGATIONAL DRUGS
bradykinesia and posture scores, when compared with
vehicle-treated marmosets. Administration with either
apomorphine or LD resulted in a dose-dependent
increase in dyskinesia, with dyskinesia present for
the entire period of maximal antiparkinsonian action.
When idazoxan was coadministered with LD, the
median peak-dose dyskinesia score was significantly
lower than that observed with LD alone (4 versus 16;
P < 0.05), whereas peak posture, bradykinesia or
mobility scores were not significantly different. There
were no significant differences between LD/idazoxan
versus LD alone in the duration of dyskinesia, nor
were there any significant differences between the
coadministration of idazoxan and apomorphine and
apomorphine alone in the median peak-dose dyskine-
sia score. Idazoxan had no effect on the antiparkinso-
nian action of apomorphine or in the duration of
dyskinesia induced by this compound. By contrast,
the action of LD, following the coadministration of
idazoxan and LD, lasted longer than when LD was
administered alone (250
20 minutes on time versus
130
10 minutes on time; P < 0.05). The authors
concluded that the dyskinesia resulting from LD
involves adrenoreceptor activation, whereas dyskinesia
resulting from apomorphine does not. Indeed, the
action of a2-adrenergic antagonists may involve the
blockade of the action of norepinephrine synthesized
from LD; the hypothesis is that, since dopamine ago-
nists are not metabolized to norepinephrine, idazoxan
does not reduce dyskinesia produced by such agents.
This should be taken into consideration when trials
with new antidyskinetic agents based on acute
challenges with apomorphine are planned.
In a clinical study, Rascol and coworkers (2001b)
assessed the effects of idazoxan on LID in patients
with advanced PD. A total of 18 patients were enrolled
in this single-oral-dose randomized double-blind pla-
cebo-controlled study. The study tested three different
idazoxan doses (10, 20 and 40 mg) and placebo.
Assessment consisted of a single oral dose of either
idazoxan or placebo, followed an hour later by the
patients usual first morning dose of LD plus an addi-
tional 50 mg. A trained physician used the UPDRS to
monitor the treatment effect. Patients were videotaped
for the assessment of dyskinesia and were identified as
either peak-dose or biphasic. Data were analyzed by
means of three different measurements: (1) calculation
of the area under the curve (AUC) of the changes from
baseline in the dyskinesia and UPRDS scores; (2) cal-
culation of the score distribution; and (3) an analysis
of the peak-dose and biphasic dyskinesia scores.
The AUC analysis revealed a statistically insignifi-
cant dose-related reduction for the mean dyskinesia
145
AUC in the 10- and 20-mg idazoxan treatment groups
(20 and 40%) as compared to the placebo group. No
AUC trend was found in the 40-mg idazoxan treatment
group. The severity score distribution indicated a
statistically significant treatment effect in favor of
idazoxan (20 mg) when compared with placebo
(P 0.01). No significant treatment effects were
found in the biphasic and dyskinesia distribution
analysis. The antiparkinsonian effects of LD were
similar in both the idazoxan and the placebo groups,
whereas adverse events were more frequent with
idazoxan than with placebo. The results of this study
seem to indicate that idazoxan, by blocking a2-receptors,
may reduce levels of dyskinesia in PD patients
without affecting the antiparkinsonian efficacy of LD
treatment.
Although the data obtained in these two studies are
consistent with each other, they are in contrast with the
only other available clinical trial, which recently
reported that idazoxan was not beneficial for LID in
8 PD patients (Manson et al., 2000b). Moreover,
although not published, a subsequent multi-institu-
tional trial investigating idazoxan as a treatment for
LID was negative. The reasons for the negative results
were complex and at least partly due to the capacity of
trial centers to comply with the protocol and to the
safety profile of the drug (early drop-outs), maybe
due to inadequate titration (O. Rascol, personal
communication).
These studies with idazoxan are of theoretical and
clinical interest, but they do have several drawbacks:
the results of the clinical trial, in particular, are based
on a relatively small number of PD patients and only
following an acute oral challenge of LD. Moreover,
since idazoxan may induce several adverse events,
such as hypertension, tachycardia, flushing and head-
ache, it is difficult to ascertain what are the usefulness
and benefit-to-risk ratio of idazoxan in the long-term
management of dyskinetic parkinsonian patients.
In summary, it seems that, though the mechanisms
underlying the manifestations and the priming process
for dyskinesia have yet to be fully elucidated, non-
dopaminergic compounds may provide an effective
way of limiting the expression of involuntary move-
ments in PD.
37.5. Symptomatic non-dopaminergic drugs
Dopamine replacement therapy effectively treats the
early motor symptoms of PD. However, its association
with the development of motor complications limits
its usefulness in late stages of the disease (Nutt and
Holford, 1996; Colosimo and De Michele, 1999) and
146 C. COLOSIMO AND G. FABBRINI
a non-dopaminergic approach to therapy might thus
provide an effective way of preventing the development
of these complications in PD.
37.5.1. Drugs acting at adenosine receptors
Adenosine A2A receptors are localized to the indirect
striatal output function and control motor behavior.
They are active in predictive experimental models of
PD and appear to be promising as the first major
non-dopaminergic therapy for PD (Johnston and
Brotchie, 2004). The initial results from a controlled
clinical trial of an adenosine A2A antagonist, theophyl-
line, conducted on 10 patients with PD, have been
contrasting (longer beneficial response on akinesia
without significant changes in the other clinical
parameters of the disease) (Kulisevsky et al., 2002).
Istradefylline (KW-6002) is a novel adenosine A2A
receptor antagonist designed to treat patients with
motor fluctuations and dyskinesias (Jenner, 2005).
Istradefylline is currently in phase III clinical trials
for efficacy in patients with PD; results from phase II
clinical trials demonstrated that it provides a signifi-
cant reduction in off time and increased on time in dyskinesia and particularly in troublesome dyski-
with non-troublesome dyskinesia in LD-treated
patients with established motor complications and is
safe and well tolerated. In a 12-week, double-blind,
randomized, placebo-controlled, exploratory study
(Hauser et al., 2003), patients with motor fluctuations
and peak-dose dyskinesias were randomly assigned to
placebo (n 29), istradefylline (maximum of 20 mg/
day: n 26), or istradefylline (maximum 40 mg/day:
n 28). As assessed by patient home diary, off time
was reduced and severity of dyskinesia was unchanged,
whereas the on time with dyskinesia increased.
In addition, there is increasing preclinical evidence that
A2A receptor antagonists may also have neuroprotective
properties (Johnston and Brotchie, 2004). Thus, their
eventual use as symptomatic therapy may lead to the
identification of disease-modifying properties.
37.5.2. Serotonergic drugs
With progressive degeneration of dopaminergic neu-
rons in PD, dopamine formation from exogenous LD
increasingly takes place in striatal serotonergic nerve
terminals (Bezard et al., 2003b). It is thus not surpris-
ing that pharmacologic agents affecting serotonergic
nerve impulse activity, by interacting with 5-HT1A
autoreceptors, can regulate serotonin release under
normal conditions and dopamine release in LD-treated
parkinsonian animals. In the latter circumstances,
drugs that stimulate these autoreceptors tend to attenu-
ate peak striatal concentrations of dopamine and
prolong its half-life. If 5-HT1A agonists produce the
same pharmacologic effects in PD patients, then a
reduction in peak-dose dyskinesias and wearing-off
fluctuations might be expected. Recent observations
in parkinsonian animals support this possibility
(Bibbiani et al., 2001).
To evaluate this hypothesis, the effects of a selective
5-HT1A agonist, sarizotan, given orally at 2 and 5 mg
twice daily to 18 relatively advanced parkinsonian
patients, were recently compared with baseline placebo
function during a 3-week, double-blind, placebo-
controlled, proof-of-concept study (Bara-Jimenez
et al., 2005). Sarizotan alone or with intravenous
LD had no effect on parkinsonian severity. But at
safe and tolerable doses, sarizotan coadministration
reduced LID and prolonged its antiparkinsonian
response (P < 0.05). The findings suggest that 5-
HT1A receptor stimulation in LD-treated parkinsonian
patients can modulate striatal dopaminergic function
and that 5-HT1A agonists may be useful as LD adju-
vants in the treatment of advanced PD. In another
open-label trial on 64 patients with advanced PD,
sarizotan treatment induced a significant reduction
nesia (Olanow et al., 2004). These benefits were
obtained without change in total off time or change
in UPDRS or activities of daily living scores. Unfor-
tunately, this compound was recently withdrawn from
clinical trials.
37.5.3. Drugs acting at synaptic vesicular proteins
Levetiracetam (LEV; (S)-alpha-ethyl-2-oxo-1-pyrro-
lidine acetamide) is an antiepileptic drug that is
approved as add-on therapy in the treatment of par-
tial-onset seizures (Kumar and Smith, 2004). LEV
has been shown to reduce LID in preclinical studies
of animal models of PD (Bezard et al., 2003c).
Furthermore, a few case reports and small open-label
studies indicate that LEV may reduce various abnor-
mal involuntary movements, including myoclonus,
paroxysmal kinesiogenic choreoathetosis and
Meiges syndrome. The tolerability and preliminary
efficacy of LEV in reducing LID in PD patients were
evaluated in a prospective open-label pilot study
(Zesiewicz et al., 2005). Nine PD patients who were
experiencing peak-dose dyskinesias for at least 25%
of the awake day and were at least moderately dis-
abled were treated with LEV in doses up to 3000
mg for up to 60 days. The primary outcome measure
was the percentage of the awake day that patients
spent on without dyskinesia or with non-troublesome
dyskinesia (good on time). The mean dose of LEV at
endpoint was 625
277 mg/day. LEV significantly
 INVESTIGATIONAL DRUGS
improved the percentage of the awake day on without
dyskinesia or with non-troublesome dyskinesia at
endpoint compared to baseline (43
12% versus 61

17%; P 0.02). Percentage on time with trouble-
some dyskinesia decreased from 23
10% at base-
line to 11
6% at endpoint, although not
significantly. There was no significant increase in
off time from baseline to endpoint. There was a
56% drop-out rate, in most of the cases due to somno-
lence. These preliminary data suggest that LEV is a
promising drug in PD patients who experience severe
peak-dose dyskinesia; as a result, LEV is currently in
phase III clinical trials.
37.6. Conclusions
Future developments in drug therapy of PD appear to
be exciting and it is likely that PD will remain one
of the most active areas of drug development in neu-
rology for many years to come. In the near future it
will probably be feasible to demonstrate in vivo if
drugs act as neuroprotective or even restorative. It is
also very likely that there will be improvements in
the way physicians may be able to replace dopaminer-
gic loss and more and more attention is expected on
new ways of treating non-dopaminergic symptoms.
Efforts are expected too in a better characterization
and treatment of cognitive disturbances which fre-
quently accompany PD. This chapter is by definition
a section which must be intended in evolution. It is
possible that by the time of publication some studies
will have appeared showing the efficacy or the failure
of a certain treatment. We have tried to give an overview
of the closest prospective in the new pharmacological
strategies in PD.
Acknowledgments
The authors thank W. Poewe and O. Rascol for their
data on ongoing trials in Parkinsons disease.
M. Bologna and C. Aurilia helped with the manuscript
preparation.
References
Bara-Jimenez W, Dimitrova T, Sherzai A et al. (2004). Effect
of monoamine reuptake inhibitor NS2330 in advanced
Parkinsons disease. Mov Disord 19: 11831186.
Bara-Jimenez W, Bibbiani F, Morris MJ et al. (2005). Effects
of serotonin 5-HT1A agonist in advanced Parkinsons dis-
ease. Mov Disord 20 (8): 932936.
Bedard PJ, Mancilla BG, Blanchet P et al. (1992). Levodopa-
induced dyskinesia: facts and fancy. What does the MPTP
monkey model tell us? Can J Neurol Sci 19: 134137.
147
Bezard E, Brotchie JM, Gross CE (2001). Pathophysiology
of levodopa-induced dyskinesia: potential for new thera-
pies. Nat Rev Neurosci 2: 577588.
Bezard E, Ferry S, Mach U et al. (2003a). Attenuation of
levodopa-induced dyskinesia by normalizing dopamine
D3 receptor function. Nat Med 9: 762767.
Bezard E, Gross CE, Brotchie JM (2003b). Presymptomatic
compensation in Parkinsons disease is not dopamine-
mediated. Trends Neurosci 26: 215221.
Bezard E, McGuire SG, Crossman AR et al. (2003c). Novel
antiepileptic drug levetiracetam decreases dyskinesia
elicited by L-dopa and ropinirole in the MPTP-lesioned
marmoset. Mov Disord 18: 13011305.
Bibbiani F, Oh JD, Chase TN (2001). Serotonin 5-HT1A ago-
nist improves motor complications in rodent and primate
parkinsonian models. Neurology 57: 18291834.
Bibbiani F, Oh JD, Petzer JP et al. (2002). A2A receptor
antagonist prevents the development of dopamine agonist-
induced motor complications in primate and rodent models
of Parkinsons disease. Mov Disord 17 (Suppl 5): S78S79.
Bloem BR, Hausdorff JM, Visser JE et al. (2004). Falls and
freezing of gait in Parkinsons disease: a review of two
interconnected, episodic phenomena. Mov Disord 19:
871884.
Bonifati V, Fabrizio E, Cipriani R et al. (1994). Buspirone in
levodopa-induced dyskinesias. Clin Neuropharmacol 17:
7382.
Brotchie JM (2000). The neural mechanisms underlying
levodopa-induced dyskinesia in Parkinsons disease. Ann
Neurol 47 (4 Suppl 1): S105S114.
Brotini S, Gigli GL (2004). Epidemiology and clinical fea-
tures of sleep disorders in extrapyramidal disease. Sleep
Med 5: 169179.
Brown RG, Marsden CD (1990). Cognitive function in
Parkinsons disease: from description to theory. Trends
Neurosci 13: 2129.
Burn DJ (2002). Depression in Parkinsons disease. Eur
J Neurol 9 (Suppl 3): 4454.
Carpentier AF, Bonnet AM, Vidailhet M et al. (1996).
Improvement of levodopa-induced dyskinesia by propra-
nolol in Parkinsons disease. Neurology 46: 15481551.
Chase TN (1998). The significance of continuous dopami-
nergic stimulation in the treatment of Parkinsons disease.
Drugs 55 (Suppl 1): 19.
Chase TN, Oh JD, Konitsiotis S (2000). Antiparkinsonian
and antidyskinetic activity of drugs targeting central
glutamatergic mechanisms. J Neurol 247 (Suppl 2):
II36II42.
Chassain C, Eschalier A, Durif F (2002). Magnesium sul-
phate potentiates the antiparkinsonian levodopa effect
and has antidyskinetic effect in MPTP-lesioned monkeys.
Mov Disord 17 (Suppl 5): S22S23.
Chopin P, Pellow S, File SE (1986). The effects of yohimbine
on exploratory and locomotor behaviour are attributable to
its effects at noradrenaline and not at benzodiazepine recep-
tors. Neuropharmacology 25: 5357.
Colosimo C, Craus A (2003). Noradrenergic drugs for levodopa-
induced dyskinesia. Clin Neuropharmacol 26: 299305.
148 C. COLOSIMO AND G. FABBRINI
Colosimo C, De Michele M (1999). Motor fluctuations in
Parkinsons disease: pathophysiology and treatment. Eur
J Neurol 6: 121.
Colosimo C, Merello M, Albanese A (1994). Clinical useful-
ness of apomorphine in movement disorders. Clin Neuro-
pharmacol 17: 243259.
Colosimo C, Merello M, Hughes AJ et al. (1996). Motor
response to acute dopaminergic challenge with apomor-
phine and levodopa in Parkinsons disease: implications
for the pathogenesis of the on-off phenomenon. J Neurol
Neurosurg Psychiatry 60: 634637.
Crossman AR (1990). An hypothesis on the pathophysiological
mechanisms that underlie levodopa- or dopamine agonist-
induced dyskinesia in Parkinsons disease: implications for
future strategies in treatment. Mov Disord 5: 100108.
Currie LJ, Harrison MB, Trugman JM et al. (2004). Postmeno-
pausal estrogens use affects the risk of Parkinson disease.
Arch Neurol 61: 886888.
Dawson TM, Dawson VL (2003). Molecular pathways of neuro-
degeneration in Parkinsons disease. Science 302: 819822.
Del Dotto P, Pavese N, Gambaccini G et al. (2001). Intrave-
nous amantadine improves levadopa-induced dyskinesias:
an acute double-blind placebo-controlled study. Mov
Disord 16: 515520.
Dluzen D, Horstink M (2003). Estrogens as neuroprotectant
of nigrostriatal dopaminergic system: laboratory and clin-
ical studies. Endocrine 21: 6775.
Du Y, Ma Z, Lin S (2001). Minocycline prevents nigrostria-
tal dopaminergic neurodegeneration in the MPTP model
of Parkinsons disease. Proc Natl Acad Sci USA 98:
1466914674.
Durif F, Vidailhet M, Bonnet AM et al. (1995). Levodopa-
induced dyskinesias are improved by fluoxetine. Neurol-
ogy 45: 18551858.
Durif F, Vidailhet M, Assal F et al. (1997). Low-dose cloza-
pine improves dyskinesias in Parkinsons disease.
Neurology 48: 658662.
Durif F, Debilly B, Galitzky M et al. (2004). Clozapine
improves dyskinesias in Parkinson disease: a double-blind,
placebo-controlled study. Neurology 62: 381388.
Fariello RG, McArthur RA, Bonsignori A et al. (1998). Pre-
clinical evaluation of PNU-151774E as a novel anticon-
vulsivant. J Pharmacol Exp Ther 285: 397403.
Fox S, Silverdale M, Kellett M et al. (2004). Non-subtype-
selective opioid receptor antagonism in treatment of levo-
dopa-induced motor complications in Parkinsons disease.
Mov Disord 19: 554560.
Fox SH, Henry B, Hill MP et al. (2001). Neural mechanisms
underlying peak-dose dyskinesia induced by levodopa and
apomorphine are distinct: evidence from the effects of the
alpha(2) adrenoceptor antagonist idazoxan. Mov Disord
16: 642650.
Gold BG, Nutt JG (2002). Neuroimmunophilin ligands in the
treatment of Parkinsons disease. Curr Opin Pharmacol 2:
8286.
Gomez-Mancilla B, Bedard PJ (1992). Effect of estrogen and
progesterone on L-dopa induced dyskinesias in MPTP-
treated monkeys. Neurosci Lett 135: 129132.
Gomez-Mancilla B, Bedard PJ (1993). Effect of nondopami-
nergic drugs on L-dopa-induced dyskinesias in MPTP-
treated monkeys. Clin Neuropharmacol 16: 418427.
Grondin R, Bedard PJ, Hadj Tahar A et al. (1999). Anti-
parkinsonian effect of a new selective adenosine A2A
receptor antagonist in MPTP-treated monkeys. Neurology
52: 16731677.
Hauser RA, Hubble JP, Truong DD (2003). Istradefylline
US-001 Study Group. Randomized trial of the adenosine
A (2A) receptor antagonist istradefylline in advanced
PD. Neurology 61: 297303.
Henry B, Fox SH, Peggs D et al. (1999). The alpha2-adrener-
gic receptor antagonist idazoxan reduces dyskinesia and
enhances anti-parkinsonian actions of L-dopa in the
MPTP-lesioned primate model of Parkinsons disease.
Mov Disord 14: 744753.
Hill MP, Brotchie JM (1999). The adrenergic receptor ago-
nist, clonidine, potentiates the anti-parkinsonian action
of the selective kappa-opioid receptor agonist, enadoline,
in the monoamine-depleted rat. Br J Pharmacol 128:
15771585.
Hirsch EC, Hunot S, Faucheux B et al. (1999). Dopaminergic
neurons degenerate by apoptosis in Parkinsons disease.
Mov Disord 14: 383385.
Holmberg M, Scheinin M, Kurose H et al. (1999). Adrenergic
alpha2C-receptors reside in rat striatal GABAergic projec-
tion neurons: comparison of radioligand binding and
immunohistochemistry. Neuroscience 93: 13231333.
Iravani MM, Jackson MJ, Kuoppamaki M et al. (2003).
3,4-Methylenedioxymethamphetamine (ecstasy) inhibits
dyskinesia expression and normalizes motor activity in
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated
primates. J Neurosci 23: 91079115.
Jenner P (2005). Istradefylline, a novel adenosine A2A recep-
tor antagonist, for the treatment of Parkinsons disease.
Expert Opin Investig Drugs 14: 729738.
Johnston TH, Brotchie JM (2004). Drugs in development for
Parkinsons disease. Curr Opin Investig Drugs 5 (7):
720726.
Kanda T, Jackson MJ, Smith LA et al. (1998). Adenosine
A2A antagonist: a novel antiparkinsonian agent that does
not provoke dyskinesia in parkinsonian monkeys.
Ann Neurol 43: 507513.
Kanda T, Jackson MJ, Smith LA et al. (2000). Combined use
of the adenosine A(2A) antagonist KW-6002 with
L-DOPA or with selective D1 or D2 dopamine agonists
increases antiparkinsonian activity but not dyskinesia in
MPTP-treated monkeys. Exp Neurol 162: 321327.
Kulisevsky J, Barbanoj M, Gironell A et al. (2002). A dou-
ble-blind crossover, placebo-controlled study of the ade-
nosine A2A antagonist theophylline in Parkinsons
disease. Clin Neuropharmacol 25: 2531.
Kumar SP, Smith PE (2004). Levetiracetam as add-on ther-
apy in generalised epilepsies. Seizure 13: 475477.
Luginger E, Wenning GK, Bosch S et al. (2000). Beneficial
effects of amantadine on L-dopa-induced dyskinesias in
Parkinsons disease. Mov Disord 15: 873878.
 INVESTIGATIONAL DRUGS
Lund S, Porzgen P, Mortensen AL et al. (2005). Inhibition of
microglial inflammation by the MLK inhibitor CEP-1347.
J Neurochem 92: 14391451.
Lundblad M, Vaudano E, Cenci MA (2003). Cellular and
behavioural effects of the adenosine A2a receptor
antagonist KW-6002 in a rat model of L-DOPA-induced
dyskinesia. J Neurochem 84: 13981410.
Manson AJ, Schrag A, Lees AJ (2000a). Low-dose olanza-
pine for levodopa induced dyskinesias. Neurology 55:
795799.
Manson AJ, Iakovidou E, Lees AJ (2000b). Idazoxan is inef-
fective for levodopa-induced dyskinesia in Parkinsons
disease. Mov Disord 15: 336337.
Matthews RT, Ferrante RJ, Klivenyi P et al. (1999). Creatine
and cyclocreatine attenuate MPTP neurotoxicity. Exp
Neurol 157: 142149.
Meco G, Marini S, Lestingi L et al. (1988). Controlled
single-blind cross-over study of ritanserin and placebo in
L-dopa induced dyskinesias in Parkinsons disease.
Curr Ther Res 43: 262270.
Meco G, Fabrizio E, Di Rezze S et al. (2003). Mirtazapine in
L-dopa-induced dyskinesias. Clin Neuropharmacol 26:
179181.
Merims D, Ziv I, Djaldetti R et al. (1999). Riluzole for
levodopa-induced dyskinesias in advanced Parkinsons
disease. Lancet 353: 17641765.
Metman LV, Del Dotto P, van de Munckhof P et al. (1998a).
Amantadine as treatment for dyskinesias and motor fluctua-
tions in Parkinsons disease. Neurology 50: 13231326.
Metman LV, Blanchet PJ, van den Munckhof P et al. (1998b).
A trial of dextromethorphan in parkinsonian patients with
motor response complications. Mov Disord 13: 414417.
Metman LV, Del Dotto P, Natt R et al. (1998c). Dextro-
methorphan improves levodopa-induced dyskinesias in Par-
kinsons disease. Neurology 51: 203206.
Metman LV, Del Dotto P, LePoole K et al. (1999). Amanta-
dine for levodopa-induced dyskinesias: a 1-year follow-up
study. Arch Neurol 56: 13831386.
Metman LV, Gillespie M, Farmer C et al. (2001). Continuous
transdermal dopaminergic stimulation in advanced Parkin-
sons disease. Clin Neuropharmacol 24: 163169.
Nishikawa T, Tanaka M, Tsuda A et al. (1984). Clonidine
therapy for tardive dyskinesia and related syndromes. Clin
Neuropharmacol 7: 239245.
Nutt JG, Holford NH (1996). The response to levodopa in
Parkinsons disease: imposing pharmacological law and
order. Ann Neurol 39: 561573.
Nyholm D, Nilsson Remahl AI, Dizdar N et al. (2005). Duo-
denal levodopa infusion monotherapy vs oral polyphar-
macy in advanced Parkinson disease. Neurology 64:
216223.
Oh JD, Bibbiani F, Chase TN (2002). Quetiapine attenuates
levodopa-induced motor complications in rodent and pri-
mate parkinsonian models. Exp Neurol 177: 557564.
Olanow CW, Damier P, Goetz CG et al. (2004). Multicenter,
open-label, trial of sarizotan in Parkinson disease patients
with levodopa-induced dyskinesias (the SPLENDID
Study). Clin Neuropharmacol 27: 5862.
149
Papa SM, Desimone R, Fiorani M et al. (1999). Internal
globus pallidus discharge is nearly suppressed during
levodopa-induced dyskinesias. Ann Neurol 46: 732738.
Parkinson Study Group (2002). A controlled trial of rasagi-
line in early Parkinson disease: the TEMPO Study.
Arch Neurol 59: 19391943.
Parkinson Study Group (2003). A controlled trial of rotigo-
tine monotherapy in early Parkinsons disease.
Arch Neurol 60: 17211728.
Parkinson Study Group (2004a). A controlled, randomized,
delayed-start study of rasagiline in early Parkinson
disease. Arch Neurol 61: 561566.
Parkinson Study Group (2004b). Pramipexole vs levodopa as
initial treatment for Parkinson disease: a 4-year rando-
mized controlled trial. Arch Neurol 61: 10441053.
Parkinson Study Group (2004c). The safety and tolerability
of a mixed lineage kinase inhibitor (CEP-1347) in PD.
Neurology 62: 330332.
Pearce RK, Banerji T, Jenner P et al. (1998). De novo
administration of ropinirole and bromocriptine induces
less dyskinesia than LD in the MPTP-treated marmoset.
Mov Disord 13: 234241.
Pearce RK, Smith LA, Jackson MJ et al. (2002). The mono-
amine reuptake blocker brasofensine reverses akinesia
without dyskinesia in MPTP-treated and levodopa-primed
common marmosets. Mov Disord 17: 877886.
Peltonen JM, Huupponen R, Ahokoski O et al. (2002). Tolerabil-
ity and safety of buccal JP-1730. A phase I study in healthy
male volunteers. Mov Disord 17 (Suppl 5): S100S101.
Pinto S, Ozsancak C, Tripoliti E et al. (2004). Treatments for
dysarthria in Parkinsons disease. Lancet Neurol 3: 547556.
Poulter MO, Payne KB, Steiner JP (2004). Neuroimmunophi-
lins: a novel drug therapy for the reversal of neurodegen-
erative disease? Neuroscience 128: 16.
Pourcher E, Bonnet AM, Kefalos J et al. (1989). Effects of ety-
benzatropine and diazepam on levodopa-induced diphasic
dyskinesias in Parkinsons disease. Mov Disord 4: 195201.
Rascol O, Blin O, Thalamas C et al. (1999). ABT-431, a D1
receptor agonist prodrug, has efficacy in Parkinsons
disease. Ann Neurol 45 (6): 736741.
Rascol O, Brooks DJ, Korczyn AD et al. (2000). A five-year
study of the incidence of dyskinesia in patients with early
Parkinsons disease who were treated with ropinirole or
levodopa. 056 Study Group. N Engl J Med 342: 14841491.
Rascol O, Nutt JG, Blin O et al. (2001a). Induction by dopa-
mine D1 receptor agonist ABT-431 of dyskinesia similar
to levodopa in patients with Parkinson disease. Arch
Neurol 58: 249254.
Rascol O, Arnulf I, Peyro-Saint Paul H et al. (2001b). Ida-
zoxan, an alpha-2 antagonist, and L-DOPA-induced dyski-
nesias in patients with Parkinsons disease. Mov Disord
16: 708713.
Ravina BM, Fagan SC, Hart RG et al. (2003). Neuroprotec-
tive agents for clinical trials in Parkinsons disease: a sys-
tematic assessment. Neurology 60: 12341240.
Reisine TD, Chesselet MF, Lubetzki C et al. (1982). A role
for striatal beta-adrenergic receptors in the regulation of
dopamine release. Brain Res 241: 123130.
150 C. COLOSIMO AND G. FABBRINI
Savola JM, Hill M, Engstrom M et al. (2003). Fipamezole
(JP-1730) is a potent alpha2 adrenergic receptor antagonist
that reduces levodopa-induced dyskinesia in the MPTP-
lesioned primate model of Parkinsons disease. Mov
Disord 18: 872883.
Scheinin M, Lomasney JW, Hayden-Hixson DM et al.
(1994). Distribution of alpha2-adrenergic receptor subtype
gene expression in rat brain. Brain Res Mol Brain Res 21:
133149.
Schneider JS (1998). GM1 ganglioside in the treatment of
Parkinsons disease. Ann NY Acad Sci 845: 363373.
Seager H (1998). Drug-delivery products and the Zydis fast-
dissolving dosage form. J Pharm Pharmacol 50: 375382.
Senard JM, Brefel-Courbon C, Rascol O et al. (2001). Orthostatic
hypotension in patients with Parkinsons disease: pathophy-
siology and management. Drugs Aging 18: 495505.
Shults CW, Oakes D, Kieburtz K et al. (2002). Parkinson
study group. Effects of coenzyme Q10 in early Parkinson
disease: evidence of slowing of the functional decline.
Arch Neurol 59: 15411550.
Sieradzan KA, Fox SH, Hill M et al. (2001). Cannabinoids
reduce levodopa-induced dyskinesia in Parkinsons dis-
ease: a pilot study. Neurology 57: 21082111.
Silverdale MA, Nicholson SL, Crossman AR et al. (2002).
Anti-dyskinetic actions of AMPA receptor antagonists in
the MPTP-lesioned marmoset model of Parkinsons dis-
ease. Mov Disord 17 (Suppl 5): S41.
Snow BJ, Macdonald L, Mcauley D et al. (2000). The effect
of amantadine on levodopa-induced dyskinesias in Parkin-
sons disease: a double-blind, placebo-controlled study.
Clin Neuropharmacol 23: 8285.
Steece-Collier K, Chambers LK, Jaw-Tsai SS et al. (2000).
Antiparkinsonian actions of CP-101,606, an antagonist of
NR2B subunit-containing N-methyl-d-aspartate receptors.
Exp Neurol 163: 239243.
Stephenson DT, Meglasson MD, Connell MA et al. (2005).
The effects of a selective D2 receptor agonist on beha-
vioral and pathological outcome in 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine-treated squirrel monkeys.
J Pharmacol Exp Ther 314 (3): 12571266.
Stocchi F, Arnold G, Onofrj M et al. (2004). Improvement of
motor function in early Parkinson disease by safinamide.
Neurology 63: 746748.
Tarsy D, Leopold N, Sax DS (1974). Physostigmine in chor-
eiform movement disorders. Neurology 24: 2833.
Thomas A, Iacono D, Luciano AL et al. (2004). Duration of
amantadine benefit on dyskinesia of severe Parkinsons
disease. J Neurol Neurosurg Psychiatry 75: 141143.
Venderova K, Ruzicka E, Vorisek V et al. (2004). Survey on
cannabis use in Parkinsons disease: subjective improve-
ment of motor symptoms. Mov Disord 19: 11021106.
Waters CH, Sethi KD, Hauser RA et al. (2004). Zydis selegi-
line reduces off time in Parkinsons disease with motor
fluctuations: a 3-month, randomized, placebo-controlled
study. Mov Disord 19: 426432.
Wint DP, Okun MS, Fernandez HH (2004). Psychosis in Par-
kinsons disease. J Geriatr Psychiatry Neurol 17: 127136.
Woitalla D, Muller T, Benz S et al. (2004). Transdermal
lisuride delivery in the treatment of Parkinsons disease.
J Neural Transm Suppl 68: 8995.
Wolf WA (2003). SLV-308. Solvay. Curr Opin Investig
Drugs 4: 878882.
Zesiewicz TA, Sullivan KL, Maldonado JL et al. (2005).
Open-label pilot study of levetiracetam (Keppra) for the
treatment of levodopa-induced dyskinesias in Parkinsons
disease. Mov Disord 20 (9): 12051209.
Zhang W, Ordway GA (2003). The alpha2C-adrenoceptor
modulates GABA release in mouse striatum. Brain Res
Mol Brain Res 112: 2432.
Further Reading
Holloway RG, Shoulson I, Fahn S et al. (2004). Parkinson
Study Group. Pramipexole vs levodopa as initial treatment
for Parkinson disease: a 4-year randomized controlled
trial. Arch Neurol 61: 10441053.
Parkes JD, Debono AG, Marsden CD (1976). Bromocriptine
in parkinsonism: long-term treatment dose response, and
comparison with levodopa. J Neurol Neurosurg Psychiatry
39: 11011108.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 38

The importance of patient groups and collaboration

MARY BAKER1* AND JILL RASMUSSEN2

1
European Parkinsons Disease Association (EPDA), Sevenoaks, Kent, UK
2
Merstham Clinic, Redhill, Surrey, UK

38.1. Introduction
Historically, patient groups (PGs) were formed to offer
mutual support, not only for patients with serious
or chronic debilitating disorders, but also for their rela-
tives and friends, who in many cases undertook primary
responsibility for day-to-day care. As these groups
expanded, they focused first on access to professional
and institutional care as needed and to improving insofar
as possible patients quality of life and a dignified and
peaceful end. The next logical step soon followed when
PGs became legal charities to raise funds to increase pub-
lic awareness of particular diseases, to lobby policy-
makers to direct public attention and resources to obtain
better access to treatment and to promote the search for
more effective remedies. In essence, they became patient
advocacy groups (PAGs) providing a public voice for
patients and lobbying for their particular interests.
There is little doubt that PAGs have made major contri-
butions to patients well-being and quality of life. In some
cases, PAGs have developed resources of their own that
have made material contributions to the discovery of more
effective treatments and sometimes to cures. However,
the majority of such development has depended and con-
tinues to depend upon commercial interests, academic
institutions or publicly funded resources.
Not only because both charitable and public finan-
cial resources are limited, but also because the research
infrastructure required for both fundamental and applied
research into complex disorders, often with poorly
understood etiology, is equally limited, there is compe-
tition for the available resources. This occurs against a
background where worldwide expenditure on health
care falls well short of demand and, in many cases,
short of actual need as well. For the general well-being,
it is essential that the economic, social and policy issues
that arise are settled in such ways that deliver an opti-
mal balance between patients needs and available
resources. PAGs hold the keys to this balance, but if
these are to be properly applied, PAGs must broaden
their perspectives to consider a patients general wel-
fare, not just that related to a specific disease that,
in many cases, will be complicated by comorbid or
consequential disorders.
38.2. The burden of diseases
The World Health Organization (WHO) has developed
methods to assess generally the burden of disease on
societies (Murray and Lopez, 1996). The diseases
underlying this burden vary significantly from region
to region, with the burden in developing countries aris-
ing mainly from perinatal disorders, malnutrition, com-
municable disease and violence, whereas in developed
areas the burden arises mainly from non-communicable
diseases (Murray and Lopez, 1996).
The WHO summarizes the burden of disease in terms
of disability-adjusted life-years (DALYs) which, in
turn, is the sum of years of life lost (YLL) and years of
life with disability (YLD). YLL represents the reduction
in life expectancy whereas YLD represents the number
of years lived with disability adjusted for the incidence
of disease and the severity of associated disability, a
factor ranging from none (0) to death (1) (Olesen and
Leonardi, 2003).
Considering the European region (roughly, all
European countries west of Russia plus a few others),
Olesen and Leonardi (2003) using the WHO data have

*Correspondence to: Dr. Mary Baker, c/o Lizzie Graham, European Parkinsons Disease Association (EPDA), 4 Golding Road,
Sevenoaks, Kent TN13 3NJ, UK. E-mail: lizzie@epda.demon.co.uk, Tel/Fax: 44-(0)-1732-457-683, Cell: 44-(0)-7787-554-
856, Website: http://www.epda.eu.com
152 M. BAKER AND J. RASMUSSEN
calculated that brain diseases are responsible for 23%
of the years of healthy life lost and 50% of YLDs. In this
context, brain disease included neurological, neurosur-
gical and psychiatric disorders together with half of the
burden of injuries and congenital problems. Considering
the key summary measure of lost health, DALY, 35%
was related to brain diseases (Olesen and Leonardi,
2003). Based on these data, these authors suggested that
a third of the curriculum at medical school should deal
with the brain and that a like proportion of life-science
funding should go to basic and clinical neuroscience
and that overall a third of health care expenditure should
be allocated to the prevention, diagnosis and treatment of
brain disease.
Given that brain disease underlies a significant pro-
portion of health care costs in Europe, a proportion
probably similar in other developed areas of the world,
it will be incumbent upon PAGs to prioritize the actual
needs rather than the demands of patients so that
resources that may be available are applied most effec-
tively. In this respect, all PAGs, not just those represent-
ing neuroscience, hold the key to resolving insofar as
possible the resource/demand dilemma.
38.3. Responsible advocacy
In representing patients, PAGs have a duty to listen to
their patients wants, to filter out trivial wants and to
translate the remainder into prioritized needs consider-
ing in that process what is most probably achievable in
the short, medium and longer term. For such an assess-
ment, scientific and medical expertise will be required
and for this most PAGs will require collaborators.
Having established a set of priorities that is scientifi-
cally, clinically and financially credible in terms of a
specific disease, a PAG has an equal duty to consider
whether the resource demands of its priorities are not
disproportionate in light of the burden of disease.
Whereas PAGs naturally have a self-centered focus
on specific diseases, this must necessarily be tempered
by a wider social responsibility to share equitably the
limited resource pool. PAGs must share with govern-
ments, policy-makers as well as with medical and
scientific communities the responsibility for achieving
an optimum balance between resources and the needs
of all patients, not just the few.
Even though brain disorders underlie more than a
third of DALYs, they remain rather a poor relation
when it comes to research. If health care is to have
any hope of efficient delivery, public policy and
research must target big ticket issues such as brain
disease. Although a policy change of this sort would
constitute something of a paradigm shift, especially
in Europe, it requires no less a shift in the perspectives
of the PAGs whose principal goals of health care
advocacy are to raise awareness of specific issues
and make them national priorities (Carroll, 2004).
Instead of competing with one another for scarce
resources, PAGs must recognize that many specific dis-
orders have important perhaps critical features in
common and that synergy, especially at the level of
fundamental science, is very likely. Rather than com-
peting on narrowly defined disease entities, the PAGs
must coalesce in broadly based consortia that have a
much greater opportunity to influence public policy
and to define the objectives of basic research that is
certainly necessary to achieve breakthrough therapies
for many, if not most, brain diseases. Application to
specific disorders could then follow.
38.4. Need for collaboration and partnerships
PAGs must recognize that their roles and responsibil-
ities, if first to their members, are not just for this par-
ticular group of patients, but also for society for
intelligent and equitable policy, for politics, friends,
families, supporters, employers, scientists, health care
professionals, and no less for those who produce and
supply pharmaceuticals and devices. We are all fellow
travelers on a challenging journey. And we will all be
patients.
If PAGs are to fulfill their wider responsibilities to
public welfare, they must achieve a difficult balance
between representing the needs of their patient consti-
tuency and the needs of the wider community of
patients and society generally.
There can be no doubt that the primary objective for
any PAG is to listen to and recognize the needs of its
members. There is otherwise no point in its existence.
However, the needs of patients and their best interests
are unlikely to be most effectively served by a narrow
focus that excludes the interests of other patients or
those of the larger society. Although its member
patients may applaud such an exclusive focus simply
because their own disorder looms largest in the frame-
work of scientific or medical issues that urgently
require resolution, such resolution is most likely to be
achieved not only through collaboration with the whole
range of individuals and organizations with specific
expertise, but also with other PAGs and groups that
share similar representative and advocacy objectives.
38.5. Need for research partnerships and
coalitions
Because PAGs in general have neither the expertise nor
the financial resources to conduct primary research them-
selves, when representing the interests of patients, PAGs
 THE IMPORTANCE OF PATIENT GROUPS AND COLLABORATION
must seek and facilitate collaboration. Although PAGs
have recognized this, collaborations are usually limi-
ted to individuals or entities that are able and willing to
focus narrowly on the particular disease entity the PAG
represents.
For example, in a workshop for PAGs sponsored
by the American Society for Experimental Neuro
Therapeutics, a speaker suggesting ways of engaging
academic partners (Benderly, 2004) recommended
that PAGs should try to attract promising young
academic researchers who were just starting their
careers. A small grant might be used to direct their
attention toward areas specific to the PG. Having
thus captured an academic, the PAG could encou-
rage continued loyalty by contributing to the indivi-
duals professional career by supporting grant
applications to other funding bodies, by offering
opportunities to publish and by other similar means.
However, such methods are inherently competitive,
pitting PAGs against one another in the attempt to
harness the next generation of scientific and clinical
expertise.
Rather than competing, albeit with the best of
motives, greater progress is likely to arise from colla-
boration between PAGs. In many chronic, disabling
conditions and certainly in neurology and psychiatry
the disparate disease states as defined in the current
nosology have more in common than not and separat-
ing one from another can be very problematic in vivo.
On this basis, common pathological mechanisms and
perhaps of etiology seem likely and the disease-
focused PAGs should join forces to support the
search for those underlying mechanisms that could
allow earlier identification of risk or that may be
interrupted or modified before irreversible damage
has finally overwhelmed the compensating resources
of the brain.
For example, a number of neurodegenerative disor-
ders associated with dementia (Alzheimers disease,
dementia of the Lewy body type, frontotemporal
dementia, prion disease) have a different predominant
pathology, but share a common mechanism of produc-
tion of the hallmark pathology, namely protein mis-
folding (Hammarstrom et al., 2001; Hardy, 2003).
What distinguishes their specific development is
unclear, but is probably important in the search for
therapies or prevention. Coalitions of all PAGs repre-
senting the disparate diseases should be formed to
support research in such cases. It would also be rea-
sonable to expect that an alliance of PAGs represent-
ing disparate diseases with some common features
could encourage thinking outside the box that often
seems to produce breakthrough concepts.
153
38.6. Partnerships for policy change
Beyond partnerships of PAGs to promote progress on
issues of common interest, even wider alliances with
other professional organizations undoubtedly improve
both credibility and leverage when advancing the
social and economic justifications for directing public
policy and resources. Whether or not within an alli-
ance, PAGs must be effective at enabling, at bringing
people of disparate interests together to spawn original
thinking and to induce change.
When attempting to influence both public percep-
tion and by extension public policy, the size of the pro-
blem obviously matters. Groups representing a large
patient population with significant demands on state
or other resources will have greater success in getting
their message across. They will be more able to high-
light the burden of illness substantiated by economic
evidence, including both direct and indirect personal,
financial and societal costs.
Having got the attention of the public and policy-
makers, the PAGs must mediate between conflicting
interests and perspectives. For example, they need to
engage clinicians and health economists (who are not
natural bedfellows) with patients who have a sharp
focus on their distress, but very little idea of the cost.
Such engagement presents real potential for conflict,
as the various interests are not easily reconciled.
Even apart from economics, patients and doctors
have different perspectives and priorities. PAGs have
an important mediating role in listening to patients
and helping them to express their needs clearly and
to encourage partnership in their care. Doctors typi-
cally focus on the specific disease, the site of pathol-
ogy and upon symptomatology. They measure illness,
its progression and response to treatment, for example,
according to neurological parameters. Patients, by con-
trast, focus on the effect of the illness and its treatment
on their daily lives (mood, pain, sleep, bodily function,
disability). Patients look at things in terms of their
self-respect (work, independence) and relationships
with others. From that highly personalized perspective,
specialized clinical assessments are largely meaning-
less and the primary debilitating effects often arise
not from the underlying disease, but from such comor-
bid conditions as depression or anxiety, from employ-
ment or financial concerns, or from sensitivity to
public stigma.
To insure that patients have access to management
of all of their problems, not simply access to specia-
lized care, important as that is, PAGs need on the
one hand to engender evidence-based policies, treat-
ment guidelines and management practices based on
154 M. BAKER AND J. RASMUSSEN
mass statistics whilst on the other hand representing
the spectrum of disease and the real problems that par-
ticular cohorts experience. These problems often cross
specialist boundaries.
38.7. Advocacy is not enough
Although advocacy is a necessary, important and chal-
lenging function, it is not in itself sufficient. It is
equally important that PAGs also take responsibility
to inform and educate their members. They must pro-
vide their members not only with encouragement and
support, but also with realistic expectations. Patients
have a right to see a doctor who understands their dis-
ease, but also a team that can recognize associated
problems and address them. Patients have a right to
expect continuity of care, that is, to see the same doc-
tor and team at successive visits. But patients also
have a duty to educate themselves about their disease,
to recognize and understand its possible complications
and to have reasonable expectations concerning their
care and to be prepared to participate fully and effec-
tively in their own treatment. It is a prime responsibil-
ity of the PAGs to provide and deliver this sort of
patient education.
As part of this educational responsibility, PAGs
need to make it clear to their members that there is
fierce competition for health care resources and that
patients with a particular disorder have no intrinsic
right to a disproportionate share of the limited
resources. Distribution of available resources is inher-
ently political. As such, politicians and policy-makers
are tempted to respond to the views of the much larger
population of the generally healthy who tend to con-
sider most serious those disorders that they believe
present the greatest immediate risk to them personally.
PAGs representing patients with disorders that predo-
minantly affect the elderly, including most of the
degenerative neurological diseases, are disadvantaged
in the competition for resources simply because the
general public consider these to be remote risks.
Neurological disorders are often considered a threat
only to the old and victims are largely hidden from
society, whereas psychiatric disorders are associated
with public stigma and likewise hidden or denied
wherever possible. PAGs representing these patients
must strive to illustrate the burden of these disorders
and to raise their profile in public perception. In terms
of DALYs and consequent direct and indirect costs
to society, brain diseases are very important. In the
past, spouses or other members of the immediate
family have absorbed much of this personal as well
as financial cost. However, increasing dispersion of
the extended family as well as dissolution of the
nuclear family coupled with increasing full-time em-
ployment for both sexes results in an increasing
responsibility of the state to provide care. This is
inherently expensive and exacerbated by the demo-
graphic reality of an increasing proportion of older
people in the population.
It is perhaps natural and certainly understandable
that diseases that lead to premature death are frighten-
ing for most people. Understanding the personal
impact of an illness that gradually erodes the senses,
intellectual function or the ability to perform simple
motor tasks is much harder for healthy people to ima-
gine. It therefore devolves to the PAGs to use every
possible tool at their disposal to educate the healthy
not only to recognize their personal risk, but more
importantly, to gain some concept of the impact of
living with a disability that will only become more
severe. It must be obvious that the risk of a single dis-
order such as Parkinsons disease is small compared
to the risk of one of the range of equally or more
debilitating degenerative neurological conditions.
Again, fragmenting the message among many specific
disorders, each equally devastating, can hardly be as
effective as a coordinated message. The PAGs have a
duty to their members, if not to society generally, to
collaborate in the effort to educate the public, the
politicians and the policy-makers.
38.8. Research and development issues
In the same way, the PAGs have a duty to collaborate
when representing their members in the many areas of
common interest such as the ethical dimensions of
stem cell or animal research. The effort to relieve the
suffering of patients should not be compromised by
the fact that some necessary aspects of scientific and
clinical research may offend the sensibilities of those
with dogmatic views, however fervently held.
Collaboration of PAGs is also necessary if a uni-
form standard of care is to be accessible to members
regardless of their disease, their station in life or where
they live. There are, for example, significant differ-
ences in reimbursement and in the time lags for access
to new treatments.
Regulatory requirements and the associated time-
costs of drug development coupled with a high risk of
failure and short patent terms constrain the develop-
ment of new drugs. In particular, development for rela-
tively rare conditions is unlikely. In addition, the cost
of new drugs is necessarily high to recoup development
costs not only for the one registered drug, but also for
the three or four that failed in development. Short
patent terms mean that most cost recovery has to be
achieved before the patent expires and manufacturers
 THE IMPORTANCE OF PATIENT GROUPS AND COLLABORATION
of generics who contribute nothing to research or
development flood the market. If the PAGs wish to
encourage new therapies, they need to collaborate to
lobby for regulatory changes that will encourage rather
than stifle research and development.
38.9. What next for patient advocacy?
Finally, although there is no doubt that PAGs have
made major contributions to the well-being of their
patients and that continuing such contributions will be
required in future, changing times now require that the
PAGs should seriously consider altering their operating
methods in areas of mutual interest.
In the encouragement and/or sponsorship of research
into the underlying mechanisms of neurological disor-
ders, a broader scope of enquiry that could promote lat-
eral thinking should prove more productive than one
based upon a narrow focus on a single disease entity.
Close collaboration of several PAGs would be most
appropriate and perhaps necessary to engender such
research.
In particular, there is compelling evidence from the
WHO for the importance of brain disorders, mainly
neurological and psychiatric, among the diseases con-
tributing most significantly to the global burden of dis-
ease. Fragmenting the voice of all affected patients
along disease-specific lines is counterproductive in
155
the competition for an equitable distribution of limited
research, development and care-centered resources.
Although it may well be desirable that disease-
centered PAGs should retain a measure of individual
identity and autonomy, a much greater measure of
association and collaboration among the PAGs dealing
with brain-related diseases will be necessary if they
are to serve most effectively the needs of patients and
to achieve a share of resources commensurate with the
impact of brain diseases on individuals, society and
the health care systems.
References
Benderly BL (2004). Advocacy groups are crucial players in
developing new neurotherapeutics. NeuroRx 1: 500502.
Carroll PR (2004). The impact of patient advocacy: the
University of California-San Francisco experience. J Urol
172 (5 Pt 2): S58S61.
Hammarstrom P, Schneider F, Kelly JW (2001). Trans-
suppression of misfolding in an amyloid disease. Science
293: 24592462.
Hardy J (2003). Impact of genetic analysis on Parkinsons
disease research. Mov Disord 18 (Suppl 6): S96S98.
Murray CJ, Lopez AD (1996). Evidence-based health policy
lessons from the Global Burden of Disease Study. Science
274: 740743.
Olesen J, Leonardi M (2003). The burden of brain diseases in
Europe. Eur J Neurol 10: 471477.
 Section 6

Complications of therapy
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 39

Motor and non-motor fluctuations

SUSAN H. FOX* AND ANTHONY E. LANG

Division of Neurology, University of Toronto, Toronto, ON, Canada

39.1. Introduction gait seen in response to a dose of levodopa (Table 39.1).

The cardinal symptoms of Parkinsons disease (PD),
bradykinesia, rigidity and tremor, occur in large part
secondary to progressive degeneration of the dopami-
nergic neurons within the substantia nigra pars com-
pacta of the midbrain. Treatment of PD is therefore
based on dopamine replacement, either in the form of
the dopamine precursor, levodopa (co-administered
with a peripheral dopa-decarboxylase inhibitor) or via
directly acting dopamine receptor agonists. Early treat-
ment of PD with these agents results in effective and
sustained control of motor symptoms which may last
for several years. With the progression of the disease
and the requirement for higher doses of levodopa, the
vast majority of patients start to experience a reduced
and variable benefit from medication. At this stage,
patients often experience fluctuations in response to
medication in both the motor symptoms (motor fluctua-
tions), but also in non-motor symptoms (non-motor
fluctuations), such as psychiatric/behavioral problems,
autonomic dysfunction and sensory/pain symptoms. In
addition, PD patients may also experience spontaneous
fluctuations in symptoms, unrelated to levodopa dos-
ing. The presence of fluctuations in motor and non-
motor symptoms is almost invariable in PD patients
and as such the absence of fluctuations may suggest that
a patient does not have idiopathic PD (Quinn, 1998).
39.2. Levodopa-induced motor fluctuations
39.2.1. Definitions
The commonest fluctuations to emerge in advancing PD
are the variable and often unpredictable benefits on the
motor symptoms of bradykinesia, rigidity, tremor and
A PD patient exhibiting parkinsonian symptoms is
described as being off and an improvement in symp-
toms after dopaminergic medication is termed on.
The doseresponse to levodopa is often divided into
three timeframes: (1) the initial improvement or begin-
ning of dose, when the patient first begins to notice an
improvement in symptoms and switches on; (2) the
maximal time of improvement in parkinsonian symp-
toms, called peak dose; and (3) the beginning of loss
of benefit and re-emergence of parkinsonian symptoms
or end of dose. Motor fluctuations can affect all or part
of these levodopa dose-related timeframes. Thus a care-
ful history of the patients problems in relation to the
timing of a dose of levodopa is critical to management
and treatment of motor fluctuations. Measurement of
motor fluctuations in response to medication is incorpo-
rated into the Unified Parkinsons Disease Rating Scale
(UPDRS).
39.2.1.1. Predictable wearing-off
Motor fluctuations tend to begin with a predictable
shortening in the duration of response to levodopa with
gradual emergence of parkinsonian symptoms, called
wearing-off. This is usually apparent when the dura-
tion of levodopa benefit is 4 hours or less (Muenter
and Tyce, 1971; Shoulson et al., 1975; Fahn, 1982).
The earliest manifestation of this is usually morning
akinesia, since the time between doses is generally
longest overnight before the morning dose.
39.2.1.2. Unpredictable, sudden offs
Patients can also experience wearing-off that is fast,
random and unrelated to the timing of the last dose
of levodopa, called unpredictable offs. Such patients

*Correspondence to: Susan H. Fox, Toronto Western Hospital, Movement Disorders Clinic, Division of Neurology, University
of Toronto, 399 Bathurst Street MCL7412, Toronto, ON M5T 2S8, Canada. E-mail: sfox@uhnresearch.ca, Tel: 1-416-603-
5383, Fax: 1-416-603-5004.
160 S. H. FOX AND A. E. LANG
Table 39.1
Levodopa-induced motor fluctuations in Parkinsons disease
Predictable wearing-off
Unpredictable, sudden offs
Dose failure, delayed or partial on response
Beginning-of-dose worsening
End-of-dose rebound
On- and off-period freezing (motor blocks)
Tachyphemia and running gait
Dyskinesia
Peak dose/square-wave dyskinesia
Wearing-off/off-period dystonia
Diphasic dyskinesia
Onoff fluctuations/yo-yoing
can suffer off-periods that come on over a few seconds
with resultant severe akinesia, called a sudden off
(Fahn, 1974).
39.2.1.3. Dose failure, beginning-of-dose worsening,
end-of-dose rebound
Patients may also experience delay in benefit
(delayed on) or absence of benefit from a dose of
levodopa, called dose failure (Melamed and Bitton,
1984). Some patients can experience a transient wor-
sening of symptoms at the beginning of dose, often
as an increase in tremor (beginning-of-dose worsen-
ing) (Merello and Lees, 1992). In some cases, the off
state may be worse than in the untreated state or after
longer periods of drug withdrawal (super off) and
these patients may experience an exacerbation or
rebound in their symptoms at the end of dose (end-
of-dose rebound) (Nutt et al., 1988).
39.2.1.4. On- and off-period freezing (motor blocks)
One particular problem that can occur is a transient
difficulty initiating a movement a sudden transient
freezing (also called motor blocks) that may occur when
starting to walk (start hesitation), while turning (turning
hesitation) or going through a narrow doorway (Giladi
et al., 1992; Fahn, 1995). Once the block is overcome
then the activity can be completed smoothly. In addi-
tion, freezing can occur during other activities such as
speech and writing (Fahn, 1995). Motor blocks can also
occur due to sudden stress or anxiety (startle hesitation).
Such freezing episodes most commonly occur when the
patient is in the off state but may also occur in the on
state (on-period freezing).
39.2.1.5. Tachykinetic problems
Some patients with PD may experience increased
speed of speaking (tachyphemia) that also becomes
lower-volume and increasingly inaudible; this is often
associated with high doses of levodopa and is an on-
period phenomenon. Tachyphemia is often associated
with a similar phenomenon in walking: an increasing
speed of walking even to the point of running, with
smaller steps, which may lead to falls (Giladi et al.,
1997).
39.2.1.6. Dyskinesia
At the same time as the above fluctuations start to
occur, patients often experience involuntary move-
ments or dyskinesia. Dyskinesia can occur at variable
times in response to levodopa. Thus dyskinesia most
commonly occurs at the peak dose of levodopa action
(peak-dose dyskinesia) or throughout the duration of
the on-period (square-wave dyskinesia) and can be a
mixture of chorea, ballism and dystonia and to a lesser
extent myoclonus (Nutt, 1990). Choreiform move-
ments in the limbs are most common but dystonic pos-
turing in the limbs and craniocervical dystonia and
chorea are also common (Luquin et al., 1992). Off-per-
iod or wearing-off-period dyskinesia is predominantly
dystonic and tends to affect the limbs, particularly
the legs and feet (Poewe et al., 1988; Bravi et al.,
1993). Patients often experience a more fixed posture
(e.g. ankle intorsion with toe flexion or extension),
especially early morning, often associated with pain
(early-morning dystonia) (Melamed, 1979). Less com-
mon is dyskinesia occurring at the beginning and end
of dose, when the levels of levodopa are rising and
falling, respectively. This is known as diphasic dyski-
nesia, or beginning-of-dose and end-of-dose dyskine-
sia. This has also been referred to as dystonia
improvementdystonia or DID pattern (Muenter
et al., 1977). Diphasic dyskinesia tends to affect the
legs predominantly (Marsden et al., 1982) and can
involve stereotypical rapid alternating leg movements,
as well as unusual ballistic kicking or dystonia
(Luquin et al., 1992).
39.2.1.7. Onoff fluctuations
With further disease progression and levodopa treat-
ment, patients can experience predictable or unpre-
dictable switching from being on and mobile with
dyskinesia to being off and immobile, known as
onoff fluctuations (Duvoisin, 1974; Fahn, 1974).
The term onoff implies a transition from one state
to the other akin to switching on and off a light.
Patients with advanced PD can develop a yo-yoing
effect where they rapidly, unpredictably and repeat-
edly switch from being on with dyskinesia to off
and then on again (Fahn 1974, 1982; Marsden and
Parkes, 1976).
 MOTOR AND NON-MOTOR FLUCTUATIONS
39.3. Spontaneous motor fluctuations
Motor fluctuations can also occur spontaneously as
part of the disease and not necessarily related to
long-term levodopa therapy. There is often a diurnal
variation in symptoms with improvement in the morn-
ing and deterioration through the day (Struck et al.,
1990; Nutt and Holford, 1996). Marked diurnal varia-
tion is seen in young-onset PD patients with mutations
in the parkin gene (Khan et al., 2003). Another sponta-
neous motor fluctuation, first observed in the prelevo-
dopa era, is paradoxical kinesia. This was particularly
apparent in postencephalitic parkinsonism. Paradoxical
kinesia is a sudden improvement in motor activity in
response to a mental stress, e.g. a fire alarm or as a
reflex response to being thrown a ball (Quinn, 1998).
Although some fluctuations mentioned earlier can be
exacerbated by levodopa, they can also be a feature
of the underlying disease; these include motor blocks
and tachykinetic symptoms.
39.4. Epidemiology of motor fluctuations
The incidence of motor fluctuations in PD has been
consistently shown to increase with both duration of
levodopa therapy and duration of disease. The earliest
reports estimated that 10% of patients per year devel-
oped motor fluctuations after the initiation of levodopa
therapy (Marsden and Parkes, 1977). The frequency of
wearing-off/onoff motor fluctuations and dyskinesia
has been estimated from a cumulative literature review
(between 1966 and 2000) to be 40% and 50%, respec-
tively, after 46 years of levodopa treatment (Ahlskog
and Muenter, 2001). In recent prospective randomized
clinical trials comparing initiation of levodopa with a
dopamine agonist, where the development of motor
fluctuations was the primary endpoint of the study,
4054% experienced dyskinesia and 3462.7% wear-
ing-off after 45.5 years of follow-up (Rascol et al.,
2000; Parkinson Study Group, 2004).
Accurate measurement of the current prevalence of
motor fluctuations experienced by PD patients, how-
ever, is marred by variability in ascertainment (Marras
and Lang, 2003) and the effect of changes in treatment
practice over the past two decades. A community-based
study of 124 PD patients found that 20% were experien-
cing dyskinesia and 30% response fluctuations after a
mean disease duration of 6 (
4.3) years (Schrag et al.,
2002).
39.5. Pathophysiology of motor fluctuations
Motor fluctuations are due to a combination of pre- and
postsynaptic changes in the nigrostriatal dopaminergic
161
system and possibly other dopamine pathways, e.g. the
nigropallidal pathway, together with peripheral pharma-
cokinetic factors. Disease progression with loss of
nigrostriatal dopaminergic terminals results in altered
central pharmacokinetics of levodopa (presynaptic
changes); peripheral pharmacokinetics of levodopa and
the duration and dose of levodopa therapy result in
changes to postsynaptic dopamine receptor signaling
(central pharmacodynamic or postsynaptic changes).
These factors result in abnormal intrasynaptic dopamine
concentration with loss of normal constant stimulation
of postsynaptic dopamine receptors.
39.5.1. Central pharmacokinetics of levodopa
In early PD, the clinical response to a single dose of
levodopa is stable and lasts for several hours, despite
the half-life of levodopa being only 6090 minutes
(Muenter and Tyce, 1971). Thus if a patient misses a
dose of levodopa, there is no recurrence of symptoms.
This is called the long-duration response (LDR) to
levodopa (Nutt and Holford, 1996; Obeso et al.,
2000a). The duration of the LDR, i.e. the time to com-
plete loss of drug effect after stopping levodopa, is
thought to last 12 weeks (Olanow et al., 1995; Hauser
et al., 2000), but recent studies have suggested that this
may extend for up to 4 weeks (Hauser and Holford,
2002; Fahn et al., 2004) or even longer. The exact ori-
gin of this LDR is unknown but it may be partly due to
levodopa conversion to dopamine in remaining nigros-
triatal terminals and storage in synaptic vesicles for
release as required, thus mimicking the normal physio-
logical function of the dopamine terminals (Quattrone
et al., 1995; Zappia et al., 1999). The LDR may also
be due to postsynaptic changes in dopamine receptor
pharmacology and second-messenger systems, as the
LDR is similar in dopa-responsive dystonia where
there is no presynaptic loss of dopamine terminals
(Nutt and Nygaard, 2001) (see below). In PD patients
with motor fluctuations, the duration of the LDR short-
ens and the rate of decline in LDR after stopping levo-
dopa is greatest in more severely affected patients
(Quattrone et al., 1995; Zappia et al., 1999; Nutt
et al., 2002).
In advanced PD, the response to levodopa is domi-
nated by a short-duration response (SDR), which is
the loss of benefit, typically less than 4 hours following
a dose of levodopa. At this stage, patients start to
experience fluctuations in their response to levodopa
with wearing-off and thus become more dependent on
the timing of each levodopa dose. These wearing-off
symptoms are probably due to a progressive loss of pre-
synaptic dopaminergic terminals with a loss of dopa-
mine storage (Fabbrini et al., 1988; Chase et al., 1993;
162 S. H. FOX AND A. E. LANG
Verhagen Metman et al., 2000). Loss of dopaminergic
terminals means levodopa is converted to dopamine in
other aromatic acid-decarboxylase-containing cells,
such as serotonergic and endothelial cells (Ng et al.,
1971; Melamed et al., 1980). These cells lack the ability
to store dopamine and thus non-regulated release of
dopamine into the synaptic space may cause fluctua-
tions. In patients with motor fluctuations, compared to
those without, there is decrease in the latency to onset
and peak response of levodopa (Nutt et al., 1992,
2002; Colosimo et al., 1996). In early PD there is a lin-
ear relationship between dose of levodopa and response;
however, in advanced PD with motor fluctuations, this
doseresponse switches to a sigmoid curve; thus
patients switch on at a critical level, below which they
are off and above which they are essentially fully on
(Mouradian et al., 1988).
Altered synaptic dopamine turnover has also been
suggested to underlie motor fluctuations (Torstenson
et al., 1997). [11C]Raclopride positron emission
tomography (PET) studies have shown that PD
patients who subsequently develop motor fluctua-
tions, even before these occur, have three times
greater levels of synaptic dopamine 1 hour after levo-
dopa administration compared to non-fluctuators and,
after 4 hours, only the non-fluctuators were able to
maintain a stable level of synaptic dopamine (de la
Fuente-Fernandez et al., 2001). However, in PD patients
experiencing peak-dose dyskinesia, synaptic dopamine
levels were higher 1 hour post-levodopa but there was
no difference after 4 hours with non-dyskinetic patients
(de la Fuente-Fernandez et al., 2004). Thus, it is unclear
if levodopa-induced changes in synaptic dopamine are
compensatory to underlying disease or a cause of motor
fluctuations.
39.5.2. Peripheral pharmacokinetics of levodopa
Gastrointestinal factors may also play an important role
in motor fluctuations due to variability of levodopa
delivery to the brain. Levodopa crosses the wall of
the small intestine and the bloodbrain barrier via a
saturable carrier-mediated transporter. Competition
for this transporter between dietary amino acids and
levodopa can result in delayed switching on or failure
of a dose of levodopa to have any benefit (Nutt et al.,
1984). Other factors that affect levodopa absorption
include slow or erratic gastric emptying, which may
occur secondary to concurrently used anticholinergics
and food (Nutt and Fellman, 1984), as well as to age
and PD itself (see section 39.6.2.2). All of these fac-
tors combined can result in an important contribution
of peripheral pharmacokinetics to the chance of erratic
and unpredictable responses to levodopa.
39.5.3. Central pharmacodynamics
Central pharmacodynamics or postsynaptic mechan-
isms are probably the most important factor in the
development of motor fluctuations. Thus, wearing-off
and dose failures also occur following long-term levo-
dopa therapy in animal models of parkinsonism, where
there is no progressive loss of nigrostriatal terminals
(Papa et al., 1994; Chase, 1998a). In normal primates,
long-term treatment with levodopa can induce dyski-
nesia which is dose-dependent; thus nigrostriatal
degeneration is not a prerequisite for motor fluctua-
tions to develop (Pearce et al., 2001; Togasaki et al.,
2001). (However, fluctuations will develop quicker
with a greater loss of nigrostriatal terminals: see
below.) In addition, the shortening of the LDR as mea-
sured by the rate of antiparkinsonian response decline
following withdrawal of medication (turning off a
constant intravenous infusion of levodopa), which
becomes increasingly faster from mild, untreated PD
patients to those with severe onoff fluctuations, is
also seen using infusions of the dopamine agonists
apomorphine and lisuride, which act predominantly
on postsynaptic dopamine receptors, independent of
presynaptic terminals (Bravi et al., 1994; Verhagen
Metman et al., 1997; Stocchi et al., 2001a). In addi-
tion, eliminating variability in synaptic dopamine
levels with a constant infusion of levodopa still results
in fluctuations as measured by changes in tapping
speed as an indicator of bradykinesia (Nutt et al.,
1997). Thus central pharmacokinetics of levodopa is
not the only factor in the development of a fluctuating
response. This implies that the basis for the develop-
ment of motor fluctuations is probably due to erratic
or pulsatile stimulation of the postsynaptic dopamine
receptor and consequent downstream processes.
However, the extent of presynaptic denervation
clearly contributes by altering the frequency of dopa-
mine receptor stimulation, which then sets up changes
within the postsynaptic signaling pathways. Thus in
PD patients, dyskinesia occurs earlier and is more
severe on the most affected side (Horstink et al.,
1990). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) parkinsonism, with a greater degree of dopami-
nergic denervation than idiopathic PD, dyskinesia
occurs earlier, on average 6 months, after initiation of
levodopa (Ballard et al., 1985).
The exact postsynaptic mechanisms responsible for
inducing motor fluctuations are unclear but probably
consist of multiple changes to neurotransmitter signal-
ing pathways within the basal ganglia (Crossman,
1990; Obeso et al., 2000b; Bezard et al., 2001). To date,
most investigations into postsynaptic mechanisms have
evaluated levodopa-induced dyskinesia specifically.
 MOTOR AND NON-MOTOR FLUCTUATIONS
On the other hand, animal models of PD with levodopa-
induced dyskinesia also exhibit wearing-off fluctuations
(Papa et al., 1994) and, in advanced PD, patients with
dyskinesia invariably exhibit other types of motor
fluctuations, thus the neural mechanisms underlying
dyskinesia may be similar to those underlying other
motor fluctuations. However, postmortem studies have
suggested that some differences exist between PD
patients who experience dyskinesia only compared to
those with wearing-off only. For example, in patients
with wearing-off only, putaminal dopamine was mainly
metabolized intraneuronally whereas in patients with
dyskinesia only, the dopamine was mainly extraneuro-
nal (Rajput et al., 2004). In addition, increased GABAA
receptors in the putamen have been linked to the patho-
physiology of wearing-off but not to dyskinesia (Calon
et al., 2003). To date, however, the exact distinction,
if any, between the neural mechanisms underlying dys-
kinesia, wearing-off and other on/off fluctuations (that
are unrelated solely to the peripheral pharmacokinetics
of levodopa, such as delayed-on) is unknown.
The phasic stimulation of postsynaptic dopamine
receptors by repeated doses of levodopa is clearly a
factor in the development of motor fluctuations. Con-
sistent with this is the observation in animal models
of PD that de novo treatment with chronic continuous
levodopa results in fewer or no motor fluctuations
compared to repeat dosing with intermittent levodopa
(Engber et al., 1989; Blanchet et al., 1995). In PD
patients, de novo therapy with long-acting dopamine
agonists reduces motor fluctuations compared to
short-acting levodopa (Rascol et al., 2000; Parkinson
Study Group, 2004). Thus, less pulsatile dopaminergic
stimulation reduces the risk of developing motor fluc-
tuations by preventing postsynaptic changes that occur
with intermittent stimulation.
To date, no consistent changes have been demon-
strated in dopamine D1-, D2- or D3-receptor subtype
number or affinity in levodopa-treated PD patients to
account for the development of motor fluctuations
(Rinne et al., 1991; Turjanski et al., 1997). The old
explanation of dopamine receptor supersensitivity,
as a consequence of dopamine depletion, causing
motor fluctuations and particularly dyskinesia, is unli-
kely, as dyskinesia rarely appears with the first doses
of levodopa, even in severely affected patients, or in
MPTP-lesioned primates with profound dopamine
terminal loss. Some recent evidence suggests that there
may be increased signaling downstream of striatal
dopamine D1-receptors in MPTP-lesioned primates
with dyskinesia compared to non-dyskinetic animals,
despite the absence of receptor number changes
(Aubert et al., 2005). As dopamine D1-receptor signal-
ing regulates the activity of the so-called direct
163
pathway, which is an inhibitory GABAergic pathway
from the caudate putamen (striatum) to the internal
segment of the globus pallidus, this may lead to
increased activation of this pathway, which is thought
to underlie levodopa-induced dyskinesia (Bezard et al.,
2001) (see Ch. 40).
Non-dopaminergic neurotransmitter systems have
also been shown to be associated with the develop-
ment of motor fluctuations. In animal models of PD
with motor fluctuations, activation of the dopamine
D1-receptor results in enhanced phosphorylation of
N-methyl-d-aspartate (NMDA) glutamate receptor
subunits within the striatum (Oh et al., 1999; Dunah
and Standaert, 2001; Calon et al., 2002a). NMDA
receptor antagonists will reduce motor fluctuations
in animal models of PD (Papa et al., 1995; Papa and
Chase, 1996) and the non-selective NMDA receptor
antagonist amantadine is effective in reducing the
severity of dyskinesia in clinical practice (Verhagen-
Metman et al., 1998). The NMDA receptor is critical
to synaptic plasticity and in levodopa-induced
dyskinesia it appears that stimulation of striatal dopa-
minergic receptors functionally linked to NMDA
neurotransmission may lead to a form of synaptic plas-
ticity similar to long-term potentiation (LTP) in the
hippocampus involved in memory and learning. Thus
in the striatum in levodopa-induced dyskinesia, exces-
sive LTP may contribute to the development of motor
fluctuations (Calabresi et al., 2000, Picconi et al.,
2003).
Increases in the opioid peptides within the striatum
may also be associated with motor fluctuations, as
shown by evidence from animal models (Henry and
Brotchie, 1996; Andersson et al., 1999; Henry et al.,
1999; Klinteberg et al., 2002), human postmortem stu-
dies (Calon et al., 2002b; Henry et al., 2003) and PET
studies (Piccini et al., 1997). In PD patients with motor
fluctuations, non-selective opioid receptor antagonists
extend on-time (Fox et al., 2004) but have no effect on
established dyskinesia (Rascol et al., 1994; Manson
et al., 2001; Fox et al., 2004). The exact role of opioids
in dyskinesia is unclear, as recent studies in MPTP-
lesioned primates have shown that opioid antagonists
can increase dyskinesia (Samadi et al., 2003). Evidence
that other non-dopaminergic neurotransmitter systems
are involved in motor fluctuations comes from preclinical
studies in animal models of PD (Brotchie et al., 2005)
and from clinical studies (Silverdale et al., 2003) using
selective a2-adrenoceptor antagonists (Bara Jimenez
et al., 2004); 5HT1A-receptor agonists (Olanow et al.,
2004) and cannabinoids (Sieradzan et al., 2001). Thus a
range of non-dopaminergic neurotransmitter systems are
probably involved in the pathophysiology of motor
fluctuations.
164 S. H. FOX AND A. E. LANG
39.6. Treatment of levodopa-induced motor
fluctuations
39.6.1. Predictable wearing-off
39.6.1.1. Alter dose interval or preparation of
levodopa
End-of-dose or wearing-off phenomenon, if mild, can
be initially treated by decreasing the time interval
between dosing of levodopa to give the next dose just
before the beneficial effects have worn off. Alterna-
tively or in addition, if the patient is not experiencing
dyskinesia and off-periods predominate, then the dose
of levodopa can be increased. As discussed earlier,
because of the change in the doseresponse curve to
levodopa in advanced PD, increasing individual doses
of levodopa will not improve the quality of the on-
period, but will simply increase the duration (Marsden,
1994).
Longer-acting levodopa preparations such as Sine-
met CR or Madopar CR may help improve on-time
by 11.5 hours (Ahlskog et al., 1988; MacMahon
et al., 1990). However, the bioavailability of these
longer-acting preparations is 2030% less than stan-
dard-release preparations and patients usually end up
on higher overall daily doses of levodopa, with a risk
of exacerbating dyskinesia, particularly later in the
day (Lieberman et al., 1990). In addition, these pre-
parations also typically have a longer latency to bene-
fit so patients may experience delayed-on problems;
especially if doses are not overlapping (i.e. the patient
wears off before the next dose). The problem with all
the above strategies is that, because the dose of levo-
dopa is increased, there is a risk of exacerbating motor
fluctuations in the future.
39.6.1.2. Add a dopamine receptor agonist
Adding an oral dopamine receptor agonist is a better
option as it minimizes the need to increase the dose
of levodopa. All dopamine agonists in clinical prac-
tice, such as bromocriptine, ropinirole, pergolide, pra-
mipexole and cabergoline, reduce off-time and
improve the duration of on-time when combined with
levodopa (Hoehn and Elton, 1985; Lieberman et al.,
1993; Olanow et al., 1994; Rascol et al., 1996; Pinter
et al., 1999). In addition, it may be possible to reduce
the dose of levodopa. Systematic review and analysis
of clinical trials comparing bromocriptine with ropinir-
ole, cabergoline and pramipexole as add-on therapy
have shown no significant differences in efficacy
(Clarke et al., 2000; Clarke and Deane, 2001a, b;
Goetz, 2003). In two trials, pergolide was more effica-
cious at reducing motor impairment and disability
compared to bromocripine (Clarke and Speller,
2000). A new patch formulation of the dopamine ago-
nist rotigotine is in clinical development (Parkinson
Study Group, 2003). To date, there are no comparisons
of efficacy between the newer dopamine agonists.
Side-effects of dopamine agonists have been discussed
earlier (see Ch. 33).
39.6.1.3. Add a catechol-O -methytransferase
(COMT) inhibitor
COMT is an enzyme involved in the breakdown of
levodopa and dopamine to methylated derivatives.
Inhibition of this enzyme therefore increases the elim-
ination half-life of levodopa, thus increasing bioavail-
ability (Ruottinen and Rinne, 1996a). The other
pharmacological effect of repeated dosing with COMT
inhibitors is a reduction in the usual peaks and troughs
of levodopa levels, i.e. a smoothing-out of levodopa
levels through the course of the day, resulting in an
increase in mean daily plasma levodopa levels (Nutt
et al., 1994).
There are currently two COMT inhibitors available,
entacapone and tolcapone. However, tolcapone is una-
vailable in many European countries and Canada due
to concerns regarding liver toxicity and, in those coun-
tries where available, restrictions apply to its use.
Tolcapone is administered three times daily, usually
in 100-mg doses, irrespective of levodopa dosing.
The shorter half-life of entacapone (1 hour) means that
each 200-mg dose has to be co-administered with
levodopa. A combined preparation of levodopa/carbi-
dopa and entacapone (Stalevo) in a single tablet is
now available and is undergoing clinical trials (Koller
et al., 2005). Many clinical trials have demonstrated
improved on-time with the addition of entacapone
(Ruottinen and Rinne, 1996b; Parkinson Study Group,
1997) or tolcapone (Kurth et al., 1997; Rajput et al.,
1997) to levodopa, on average by 12 hours. There
are no differences in the responses obtained using
levodopa/carbidopa, levodopa/benserazide prepara-
tions or with controlled-release preparations of levo-
dopa (Poewe et al., 2002). Although randomized
comparative studies have not been performed, it is
common clinical impression that tolcapone may be
more efficacious than entacapone in controlling motor
fluctuations (Factor et al., 2001). This may relate
to the purely peripheral effects of entacapone on
degradation of levodopa as compared to the additional
central effects of tolcapone on dopamine metabolism
(Kaakkola et al., 1994; Forsberg et al., 2003).
Early side-effects of COMT inhibitors include
prolongation of existing on-period dyskinesia, usually
without an increase in severity, as there is no change
in peak levodopa level after a single dose. However,
 MOTOR AND NON-MOTOR FLUCTUATIONS
as the level of levodopa may accumulate following
repeated dosing, then severity of dyskinesia may also
increase (Ruottinen and Rinne, 1996a; Kurth et al.,
1997; Muller et al., 2000). The dyskinesia can be
improved by reducing the dose of levodopa (Myllyla
et al., 2001). Later side-effects include abdominal pain
and severe diarrhea that can occur after a few weeks of
treatment and may lead to discontinuation in 510% of
patients (Rajput et al., 1997; Myllyla et al., 2001). Tol-
capone requires liver enzyme monitoring; significant
elevation of transaminases can occur in about 3% of
patients and 3 unmonitored patients died of acute
hepatic failure before this complication was recog-
nized (Rajput et al., 1997; Assal et al., 1998). Entaca-
pone does not cause elevation of liver enzymes
(Myllyla et al., 2001). The difference between tolca-
pone and entacapone in inducing liver enzymes does
not relate to the COMT inhibition per se but rather to
an effect on other metabolic pathways, possibly via
inhibition of mitochondrial adenosine triphosphate
synthesis (Korlipara et al., 2004) (see Ch. 32).
39.6.1.4. Add a monoamine oxidase B inhibitor
Monoamine oxidase B (MAO-B) inhibition can extend
the duration of action of levodopa by inhibiting the
metabolism of dopamine and increasing dopamine
levels by up to 70% in the brain (Riederer and Youdim,
1986). Several early clinical studies demonstrated that
the MAO-B inhibitor, selegiline (510 mg/day) had a
mild effect on PD patients with wearing-off motor fluc-
tuations (Lees et al., 1977; Golbe et al., 1988). There
was no benefit in patients with marked, disabling on
off fluctuations and the main side-effects related to
increased dopamine levels, such as nausea and dyskine-
sia, which improved on reduction of levodopa dose.
A new transmucosal preparation of selegiline
(Zydis selegiline) is now available. This is placed on
the tongue and is rapidly absorbed directly into the
systemic circulation, resulting in more reliable and
higher blood levels of selegiline (Seager, 1997; Clarke
et al., 2003). This bypasses first-pass hepatic metabo-
lism and reduces production of theoretically toxic
amphetamine-like metabolites (Clarke et al., 2003).
A single double-blind, randomized, placebo-controlled
trial (RCT) has shown that Zydis selegiline (2.5 mg/
day) significantly reduced total daily off-time in PD
patients, with predictable wearing-off, by 2.2 hours
compared to 0.6 hours for placebo (Waters et al.,
2004). The main side-effects were dizziness, halluci-
nations, headache and dyskinesia, although there was
no significant difference in on-time with dyskinesia
between placebo and Zydis selegiline. Levodopa doses
were reduced by 20% with Zydis selegiline, although
165
not specifically due to worsening of dyskinesia (Tetrud
and Koller, 2004). To date, no comparisons have been
made with conventional selegiline in terms of improv-
ing wearing-off symptoms.
Rasagiline, a newly developed irreversible MAO-B
inhibitor, is 1015 times more potent than selegiline
and is not associated with amphetamine metabolites
(Finberg et al., 1999). A double-blind RCT showed
that in PD patients with onoff fluctuations, rasagiline
up to 2 mg/day improved motor and activities of daily
living on-period UPDRS scores compared to placebo,
but there was no significant decrease in off-periods
(Rabey et al., 2000). However, a more recent study
found that rasagiline 0.5 and 1 mg/day reduced total
daily off-time by 1.41 and 1.85 hours, respectively
(Parkinson Study Group, 2005) (see Ch. 34).
39.6.2. Dose failure, delayed or partial On
39.6.2.1. Improve gastric emptying by taking
levodopa on an empty stomach
Impaired absorption of levodopa in the small intestine
may cause either a delayed or partial improvement of
parkinsonian symptoms or result in no benefit a dose
failure or no-on. Levodopa absorption may be impaired
by delay in gastric emptying secondary to the presence of
food (Fahn, 1977; Baruzzi et al., 1987). Initially patients
are advised to take levodopa with food to prevent nausea
but with time this requirement diminishes. Thus advising
a patient to take levodopa on an empty stomach will
improve absorption and reduce dose failures (Contin
et al., 1998).
39.6.2.2. Improve gastric emptying by stopping
anticholinergics and treating constipation
Gastric emptying is also erratic and slow in PD due to
the underlying disease per se as well as secondary to
dopaminergic and anticholinergic medications (Evans
et al., 1981; Edwards et al., 1992). In addition, consti-
pation via a cologastric reflex leads to delayed gastric
emptying (Bojo and Cassuto, 1992). A slower speed of
gastric emptying has been demonstrated to correlate
with the presence of motor fluctuations (Djaldetti
et al., 1996).
39.6.2.3. Liquid/soluble levodopa preparations
Soluble levodopa preparations are more rapidly and
reliably absorbed compared with conventional levodopa
(Stocchi et al., 1994). Preparations that exist include
levodopa/benserazide (Madopar dispersible), levodopa
methyl ester and levodopa/carbidopa (Parcopa). Alter-
natively, patients can crush oral levodopa preparations
and take them with a carbonated beverage. Patients
166 S. H. FOX AND A. E. LANG
requiring frequent smaller doses to control complicated
fluctuations and disabling dyskinesias can take liquid
levodopa preparations by crushing tablets in water
combined with ascorbic acid; however, the solutions
are unstable after 24 hours (Kurth et al., 1993a). Such
soluble preparations of levodopa are more rapidly and
reliably absorbed than conventional tablets but have a
shorter duration of action 11.5 hours.
39.6.2.4. Bypass gastric problems
There have been several attempts at delivering levo-
dopa, in various preparations, directly into the duode-
num as a way of circumventing the stomach and so
improving absorption (Kurlan et al., 1986; Kurth
et al., 1993b; Nyholm et al., 2005). One preparation of
levodopa used is Duodopa, a stable suspension of levo-
dopa and carbidopa in methylcellulose, which improves
levodopa solubility (Nyholm et al., 2005). These studies
have been performed in small numbers of patients and
have not been double-blind or placebo-controlled, so
the true efficacy is unclear. However, these studies have
shown improved on-time without an increase in dyski-
nesia in advanced PD patients (see later). One study
followed patients for 10 years and noted particular ben-
efit in reducing dyskinesia (Syed et al., 1998). In all
cases, however, technical and mechanical issues may
limit widespread use.
39.6.2.5. Take levodopa when still in On state
Occasionally patients with advanced PD experiencing
motor fluctuations may report that the first dose of
the day is less effective (Melamed and Bitton, 1984)
(in general, however, PD patients tend to notice that
their response to medication is usually better in the
morning and deteriorates over the course of the day).
Some patients need a larger dose to kick in; or if they
become very parkinsonian or super off, then a
usually effective dose of levodopa does not switch
them on. This can often be observed when performing
acute levodopa challenges in the practically defined
off-state after an overnight withdrawal of PD medica-
tions. Studies have shown that patients taking Sinemet
CR have a better response to the second dose com-
pared to the first morning dose, suggesting there is a
delay in absorption in the off-state (Yeh et al., 1989).
One explanation for these observations has been that
PD patients with fluctuations have an increase in gas-
tric emptying in the on-state but decreased gastric
emptying in the off-state (Hardoff et al., 2001). The
authors suggest that taking the next dose of levodopa
while still partly on may reduce dose failures as the
increased gastric emptying will improve absorption
via the small intestine.
39.6.3. Unpredictable OnOff fluctuations
Unpredictable onoff fluctuations appear in more
advanced disease and are more resistant to treatment
than predictable wearing-off. Patients are unable to
correlate on- and off-periods with their levodopa dos-
ing schedule and they may suddenly switch from one
to the other over a few seconds. Such fluctuations are
typically associated with concurrent dyskinesia, thus
pharmacological treatment is difficult and often such
patients will require surgical intervention to allow a
reduction in levodopa dosage.
39.6.3.1. Increase oral dopaminergic agents (as for
predictable wearing-off)
Increasing dopaminergic stimulation with increased
frequency and/or dosing of levodopa may reduce sud-
den onoff fluctuations by smoothing out dopamine
levels. However, these unpredictable onoff fluctua-
tions do not appear to correlate with levodopa timing
or levels. Patients often have associated on-period
choreiform dyskinesia and so this regime can exacer-
bate involuntary movements. Specific therapies to
reduce on- and off-period dyskinesias are discussed
in Chapter 40.
Increasing the dose of a dopamine agonist is a better
option as this may permit a reduction in the levodopa
dose. The addition of entacapone is less helpful for
unpredictable sudden offs compared to predictable
wearing-off (Gordin et al., 2003). Whatever approach
is taken, PD patients with advanced disease often
cannot tolerate even small increases in dopaminergic
stimulation because of a disabling increase in dyskine-
sia or the development of behavioral and psychiatric
problems. At this stage, the response to intermittent oral
medication becomes brittle and unpredictable.
More frequent, smaller doses attempting to address
the shortening response without aggravating dyskine-
sias sometimes result in a more unpredictable response
pattern with a greater number of dose failures. At this
stage many patients seem to have an all-or-none
response to levodopa that requires a threshold level
of dopaminergic stimulation to obtain (see section
39.5.1). Frequent small doses may undershoot this
threshold. In such patients with very complicated,
unpredictable fluctuations, simplifying the dosage
schedule using fewer but larger doses will often result
in a return to a more predictable response pattern.
39.6.3.2. Use liquid/soluble preparations
The more rapidly absorbed, fast-acting soluble levo-
dopa preparations may be helpful for rapid reversal
of off-periods (see above).
 MOTOR AND NON-MOTOR FLUCTUATIONS
39.6.3.3. Modify dietary protein
Onoff fluctuations have been suggested to be second-
ary to impaired absorption of levodopa across the gut
and bloodbrain barrier due to competition with large
neutral amino acids found in dietary protein (Nutt
et al., 1984; Leenders et al., 1986; Alexander et al.,
1994). As such, either reducing protein intake or leav-
ing large protein meals to the end of the day may
reduce onoff fluctuations (Pincus and Barry, 1987;
Karstaedt and Pincus, 1992). This effect is probably
not at the level of the gut as the neutral amino acid
transporter capacity is unlikely to become saturated
and there is no difference in plasma levodopa kinetics
following administration of levodopa after a low-
protein meal compared to a normal-protein meal in
advanced PD patients (Carter et al., 1989; Simon
et al., 2004).
39.6.3.4. Add apomorphine
The injectable mixed dopamine D1/D2-receptor ago-
nist, apomorphine, has been used in Europe for many
years as a treatment for onoff motor fluctuations
(Stibe et al., 1988; Stocchi et al., 2001b) and has
recently been approved for use in the USA. Due to
the proemetic action of apomorphine, prior treatment
for 23 days and continued treatment using the oral
antiemetics domperidone (20 mg t.i.d.) or trimethoben-
zamide hydrochloride (300 mg t.i.d.) is required. Some
patients can discontinue the antiemetic after a few
weeks.
A single subcutaneous injection of apomorphine
alleviates parkinsonian symptoms within 515 minutes
for 6090 minutes and so can be used as a rescue
for off-period disability (Chaudhuri et al., 1988; Frankel
et al., 1990; Dewey et al., 2001). Apomorphine can be
used either as intermittent subcutaneous injections
(28 mg per injection, average daily total dose approxi-
mately100 mg/day) and/or as an infusion (20160 mg)
ranging over 1024 hours (Manson et al., 2002; Tyne
et al., 2004). The antiparkinsonian actions of apomor-
phine and levodopa are equivalent (Cotzias et al.,
1970). Long-term use of apomorphine does not result
in loss of benefit (Hughes et al., 1993; Gancher et al.,
1995). For patients with frequent off-periods, infusion
of apomorphine is useful. This is more practical when
patients are requiring several injections per day.
Continuous infusion of apomorphine not only
markedly reduces off-time but also reduces on-period
dyskinesia. This reduction in dyskinesia is partly due
to a concomitant reduction in levodopa dose (Colzi
et al., 1998; Manson et al., 2002). However, continuous
dopaminergic stimulation of striatal dopamine receptors
in animal models of established motor fluctuations and
167
dyskinesia also results in changes within neurotransmit-
ter signaling pathways in the basal ganglia circuitry
(Chase, 1998b; Hadj Tahar et al., 2000; Bezard et al.,
2001). In effect this results in a depriming of the
system with a reduction in motor fluctuations and dys-
kinesia. In clinical studies, continuous dopaminergic
stimulation using infusions of levodopa (Sage et al.,
1988; Kurth et al., 1993b; Nutt et al., 2000) or lisuride
(Stocchi et al., 2002) can also reduce established on
off fluctuations and dyskinesia. However, in terms of
ease of use and tolerability, infusion of apomorphine
subcutaneously is a better option. Unfortunately, this
depriming is short-lived and patients who have to stop
the infusions and return to intermittent doses of oral
medication often experience a rapid return to their
motor complications. Thus such patients may need to
be considered for surgery to treat motor fluctuations
(see later).
The main side-effect of apomorphine is formation
of skin nodules. These can occur in 2078% of
patients (Colzi et al., 1998; Tyne et al., 2004) but are
only bothersome in about a third of these patients
(Manson et al., 2002). Management includes rotating
the injection site, ensuring strict aseptic technique;
diluting the apomorphine 1:1 with normal saline,
massage or local skin ultrasound. Neuropsychiatric
side-effects appear to be less common than with oral
dopamine agonists but hallucinations and confusion
can occur at high doses. In a small proportion of
patients with PD, addictive behaviors develop and
include excessive use of their dopaminergic medica-
tions (see later). Escalating doses of apomorphine
and levodopa in such patients may result in major
behavioral and psychiatric side-effects such as hyper-
sexuality and gambling, termed hedonistic homeo-
static dysregulation (Giovannoni et al., 2000).
Management of this may require hospitalization and
an aggressive reduction in medication doses. On the
other hand, in some cases, a reduction in neuropsy-
chiatric problems, such as depression, occurs with apo-
morphine (Manson et al., 2002).
New methods of administering apomorphine are
being developed in an attempt to reduce the problems
associated with injections. To date, sublingual (Montas-
truc et al., 1991), intranasal (Kapoor et al., 1990) and
rectal administration (Hughes et al., 1991) have all been
tried but with suboptimal absorption and tolerability.
A recent epicutaneous transdermal (ApoMTD) route
has been developed and a preliminary study has shown
improved off-periods with mild side-effects, including
some transient skin erythema (Priano et al., 2004). In
all cases, however, the rate of absorption of apomor-
phine is much slower than via an injection and as such
limits use as a rescue therapy for off-periods.
168 S. H. FOX AND A. E. LANG
Despite the obvious advantages, there has been a
general underusage of apomorphine (Chaudhuri and
Clough, 1998). In many countries, this has been
because of a lack of a peripheral dopamine receptor
antagonist such as domperidone. Another common
reason also relates to the practicalities of using apo-
morphine as most patients will need support from
family and specialist PD nurses (Manson et al., 2002;
Tyne et al., 2004). The efficacy of bilateral subthala-
mic nucleus deep brain stimulation (STN DBS) for
motor fluctuations has resulted in this becoming the
preferred option, particularly since doses of dopami-
nergic medication can often be substantially reduced
(Moro et al.,1999), with resultant reduced risk of, or
an improvement in, other adverse side-effects (see
later). However, in elderly patients where the risks of
surgery are thought too great, apomorphine infusion
for treatment of motor fluctuations is a viable option.
To date, no direct comparison of apomorphine infusion
with bilateral STN DBS has been made.
39.6.3.5. Bilateral Subthalamic Nucleus Deep Brain
Stimulation
In patients with advanced PD, bilateral STN DBS is cur-
rently the most effective treatment for all motor fluctua-
tions (Limousin et al., 1998; Kumar et al., 1998;
Lagrange et al., 2002; see Ch. 43). In particular, predict-
able and unpredictable onoff motor fluctuations,
as measured by the UPDRS part IV subscale, are signif-
icantly reduced by about 50% and on-period dyskinesia
is reduced by > 50 % (Kumar et al., 1998; Limousin
et al., 1998; Moro et al., 1999). As discussed in the next
section, due to the profound reduction in off-periods,
patients may also experience significant benefit in other
non-motor off-period symptoms, such as pain and auto-
nomic symptoms. Long-term follow-up to 5 years has
demonstrated that patients continue to have fewer motor
fluctuations (Krack et al., 2003). In most patients, there
is a reduction in dopaminergic medication of about
50% and in rare instances no dopaminergic drugs are
required after surgery (Kumar et al., 1998; Limousin
et al., 1998; Moro et al., 1999; Molinuevo et al., 2000).
This in part accounts for the reduction in on-period dys-
kinesia. However, even when challenged with the same
preoperative dose of levodopa, patients will have signif-
icantly less levodopa-induced dyskinesia, thus suggest-
ing that continuous STN DBS has a depriming effect
on the basal ganglia circuitry in a similar fashion to con-
tinuous dopaminergic stimulation (Bejjani et al., 2000;
Moro et al., 2002; Varma et al., 2003).
Bilateral internal globus pallidus (GPi) DBS is also
effective at improving off-periods and especially in les-
sening dyskinesia, even without a concurrent reduction
in dopaminergic medication (Kumar et al., 2000; Loher
et al., 2002; Volkmann et al., 2004). Although there
have been no large RCTs comparing STN to GPi
DBS, there is a general belief that the benefit obtained
with STN DBS is on the whole greater and more sus-
tained than that obtained with GPi DBS (Deep-Brain
Stimulation for Parkinsons Disease Study Group,
2001; Boucai et al., 2004; Peppe et al., 2004).
39.6.4. Treatment of sudden transient
motor blocks
PD patients with off-period freezing may respond to
various approaches designed to reduce the off-periods,
as outlined above. However, freezing of gait is often
more resistant to increasing dopaminergic stimulation
compared to other parkinsonian symptoms. In addi-
tion, freezing can occur during on-periods (on-period
freezing) and this can be extremely difficult to treat.
At times this on-period freezing worsens in response
to increasing the dose of dopaminergic drugs. Bilateral
STN DBS may have no effect on on-period freezing
(Stolze et al., 2001). Reductions in dopaminergic
agents may help the problem but can also result in an
increase in other parkinsonian symptoms. Such
patients may respond by developing tricks that utilize
a variety of sensory cues, such as having to step over
an object, whether the foot of another person, lines
drawn on the floor, a specifically designed cane
or walker with either a laser or modified lower part
of the cane at right angles, or other cues such as play-
ing music, marching in time or counting that can then
trigger a movement (Quinn, 1998; Kompoliti et al.,
2000).
39.7. Non-motor fluctuations
39.7.1. Definitions
In addition to fluctuations in the motor symptoms of
parkinsonism, patients can also experience fluctuations
in non-motor symptoms, which may be as debilitating,
or more so, than immobility and akinesia (Lang and
Lozano, 1998). These fluctuations have been classed
into three groups of symptoms: neuropsychiatric, auto-
nomic and sensory/pain (Riley and Lang, 1993; Hillen
and Sage, 1996) (Table 39.2). These non-motor symp-
toms appear to follow a similar pattern to the wearing-
off phenomena seen in parkinsonian symptoms and
may appear during wearing-off and off-periods and
improve after taking levodopa or dopaminergic drugs.
In addition, some symptoms may be associated with
elevated levels of levodopa and so appear during the
on-periods.
 MOTOR AND NON-MOTOR FLUCTUATIONS
Table 39.2
Non-motor fluctuations
1. Neuropsychiatric
(a) Mood
Anxiety, depression, irritability, panic attacks, screaming
Apathy
Fatigue
(b) Psychotic symptoms
Euphoria, agitation, dopamine dysregulation syndrome
Visual hallucinations, delusion, paranoia
(c) Cognitive functions
2. Autonomic
(a) Thermoregulation: sweating, facial flushing, pallor,
hyperthermia
(b) Sphincter function: urinary disturbances, bloating,
abdominal discomfort, constipation
(c) Dysphagia and drooling of saliva; dry mouth
(d) Orthostatic hypotension, tachycardia
(e) Dyspnea
(f) Peripheral edema
3. Sensory
(a) Pain
(b) Numbness, paresthesia
(c) Restless-legs syndrome; akathisia
39.7.2. Epidemiology
The epidemiology of these non-motor fluctuations is not
well defined. On the current UPDRS scale, Activities of
Daily Living part II subscale, only three questions speci-
fically address non-motor symptoms related to on- and
off-periods: sensory symptoms, swallowing and drooling
saliva. Attempts have been made to determine the extent
of non-motor symptoms with questionnaires (Riley and
Lang, 1993; Hillen and Sage, 1996; Gunal et al., 2002;
Witjas et al., 2002). These studies have shown that
fluctuations in neuropsychiatric symptoms are probably
the most common, with mood fluctuations, especially
off-period anxiety, occurring in up to 75% of patients
(Quinn, 1998; Witjas et al., 2002). PD patients with
non-motor fluctuations usually experience more than
one symptom and often have multiple symptoms
(Shulman et al., 2001). However, the exact incidence
and prevalence are not known.
To try and address this problem, the new UPDRS
rating scale currently under development has incorpo-
rated more non-motor aspects, such as apathy, sleep
patterns and various autonomic functions (Movement
Disorder Society Task Force, 2003). New non-motor
questionnaires are also being developed (Gulati et al.,
2004; Brown et al., 2005; Stacy et al., 2005). These tools
require clinimetric testing but represent an increased
169
awareness of the non-motor complications and fluctua-
tions experienced by PD patients.
39.7.3. Neuropsychiatric fluctuations
39.7.3.1. Mood fluctuations
39.7.3.1.1. Anxiety/depression
PD patients commonly experience fluctuations in mood,
generally with worsening in the off-periods and improve-
ment in the on-periods (Brown et al., 1984; Cantello et al.,
1986; Nissenbaum et al., 1987; Menza et al., 1990). The
commonest symptoms experienced are off-period anxi-
ety, irritability and depression (Menza et al., 1990; Riley
and Lang, 1993; Siemers et al., 1993; Witjas et al.,
2002). PD patients can also have panic attacks (Vazquez
et al., 1993) and off-period moaning and screaming
episodes have been reported (Steiger et al., 1991).
39.7.3.1.2. Apathy
Apathy is a distinct neurobehavioral syndrome experi-
enced by PD patients that consists of reduced interest
and motivation, behavioral changes with reduced
initiative and decreased spontaneous action and emo-
tional changes with a flattened affect (Pluck and
Brown, 2002). PD patients may experience fluctua-
tions in apathy with worsening in off-periods (Witjas
et al., 2002). Apathy is thought to involve limbic basal
ganglia anterior cingulate cortical loops (Isella et al.,
2002). Patients who have undergone STN DBS and
have a reduction in their levodopa dose are reported
to develop apathy, suggesting a dopaminergic etiology
(Funkiewiez et al., 2004).
39.7.3.1.3. Fatigue
Fatigue is a common symptom in PD patients, and is
defined according to the patients own perceived state
of lack of energy (Krupp and Pollina, 1996; Herlofson
and Larsen, 2002). The cause is unclear but fatigue is
usually distinct from depression or sleepiness, not asso-
ciated with disease severity (Friedman and Friedman,
1993; van Hilten et al., 1993; Alves et al., 2004) and
is probably an independent symptom of PD (Herlofson
and Larsen, 2002). Single-photon emission computed
tomography (SPECT) studies have suggested that PD
patients with fatigue have impaired frontal-lobe perfu-
sion (Abe et al., 2000). In questionnaire studies, the fre-
quency of fatigue in PD patients is over 50% and
fluctuates through the day, and is predominantly worse
in off-periods (Witjas et al., 2002; Zenzola et al., 2003).
39.7.3.1.4. Pathophysiology
As outlined in the sections above, the origin of mood
symptomatology varies and includes frontal, basal
170 S. H. FOX AND A. E. LANG
ganglia and limbic circuits as well as brainstem bioa-
mine nuclei and their projections. The pathophysiol-
ogy underlying fluctuations of these mood disorders
is unclear. Improvements in mood have been demon-
strated to be proportional to levodopa dose, suggesting
a relationship to brain dopamine concentration (Maricle
et al., 1995). In addition, the improvements in mood
with infusion of levodopa precede the improvement in
motor function, suggesting that patients do not simply
feel better because they are more mobile (Maricle
et al., 1995). Mood fluctuations have also been shown
to be associated with a longer disease duration and
younger age at onset, as well as with the presence and
severity of motor fluctuations (Cantello et al., 1986;
Vazquez et al., 1993; Racette et al., 2002; Witjas
et al., 2002; Richard et al., 2004), thus the underlying
pathophysiology may be similar to that causing fluc-
tuations in parkinsonian symptoms. However, there
is not always a consistent relationship between motor
and mood fluctuations (Richard et al., 2004). In addi-
tion it is not entirely clear whether fluctuations in
mood are related to an underlying persistent, comor-
bid mood disorder. The limited conflicting available
evidence derives from case reports or small series
(Menza et al., 1990; Racette et al., 2002; Richard
et al., 2004).
39.7.3.1.5. Management
Mood deterioration, which is a wearing-off or off-
period phenomenon, may respond to treatment of the
off-periods. There have been no clinical trials formally
assessing treatment of fluctuations in anxiety or depres-
sion. Patients with persistent anxiety and depression
despite reduced off-periods may benefit from specific
anxiolytic or antidepressant therapy. However, the
influence of this treatment on off-period-related exacer-
bations of mood is unknown.
39.7.3.2. Fluctuations in psychotic symptoms
39.7.3.2.1. Euphoria, agitation, dopamine dysregula-
tion syndrome
In the on-periods, PD patients can experience an eleva-
tion in mood that may be associated with alertness and
euphoria (Keshavan et al., 1986; Nissenbaum et al.,
1987; Lees, 1989). Some patients report a feeling of
euphoria that just precedes the motor on-state (Witjas
et al., 2002). An extreme form of mood elevation asso-
ciated with on-periods may result in psychomotor agi-
tation and hyperactivity, increased excitability and
even a hypomanic or true manic state. This has been
described in a small number of patients, predominantly
male, and has been termed the dopamine dysregula-
tion syndrome (Giovanni et al., 2000; Lawrence
et al., 2003). These patients consume much larger
doses of levodopa and other dopaminergic drugs than
they require to maintain a good on-state, and can
experience a range of symptoms that occur with on-
periods, including hypersexuality, pathological gam-
bling and shopping, aggression and compulsive eating
(Molina et al., 2000; Lawrence et al., 2003; Kurlan,
2004). In addition to or separate from the dopamine
dysregulation syndrome, patients may demonstrate
stereotypical behavior termed punding. Here patients
will perform the same, meaningless, seemingly purpo-
seless task over and over again (Friedman, 1994;
Evans et al., 2004). These behaviors, usually related
to a prior trade or hobby, occur at the expense of sleep
and patients may spend hours with a single purposeless
activity followed by severe exhaustion and fatigue.
39.7.3.2.2. Visual hallucinations, delusions, paranoia
Psychotic symptoms of illusions, well-formed visual
hallucinations, paranoia and delusions are often
reported in PD and are associated with disease severity,
age, depression and cognitive impairment (Goetz and
Stebbins, 1993; Factor et al., 2003). Visual hallucinations
will fluctuate through the day and are most commonly
reported in the evening and overnight (Sanchez-Ramos
et al., 1996; Fenelon et al., 2000). In questionnaire studies
of prevalence of non-motor fluctuations, patients have
reported hallucinations specifically related to on-periods
(Witjas et al., 2002) but others experience them specifi-
cally related to off-periods (Nissenbaum et al., 1987;
Witjas et al., 2002).
39.7.3.2.3. Pathophysiology
The underlying pathophysiology of psychotic symp-
toms in PD may relate to alterations in neurotransmit-
ter pathways, particularly involving mesolimbic
dopamine and serotonin (Meltzer, 1992; Breier, 1995).
Pathological studies have suggested that the inferotem-
poral cortex may be implicated as Lewy bodies are
increased in the amygdala and parahippocampus of
the temporal lobe in PD patients with hallucinations
compared to those without (Harding et al., 2002).
The cause of fluctuations in psychotic symptoms, how-
ever, is unclear, although it may relate to changes in
mesolimbic dopaminergic stimulation as all dopami-
nergic agents can cause psychosis and reducing or dis-
continuing dopaminergic medication can resolve the
symptoms (Friedman and Sienkiewicz, 1991; Poewe,
2003). However, psychotic symptoms such as halluci-
nations are not always related to the level of dopami-
nergic stimulation, since infusion of levodopa in
hallucinating patients did not trigger hallucinations in
one study (Goetz et al., 1998) and several reports have
 MOTOR AND NON-MOTOR FLUCTUATIONS
found no relationship between either type or dose of
dopaminergic drug and psychosis (Sanchez-Ramos
et al., 1996; Graham et al., 1997; Fenelon et al.,
2000; Merims et al., 2004). Disturbances in the
sleepwake cycle are often found in patients with psy-
chotic symptoms and may account for fluctuations in
these symptoms. Thus, patients with psychotic symp-
toms have more daytime somnolence and have vivid
dreams or nightmares (Moskovitz et al., 1978; Nau-
sieda et al., 1982; Pappert et al., 1999; Fenelon et al.,
2000), although the exact nature of this relationship
is not entirely clear (Goetz et al., 2005). In addition,
there is a disturbance in rapid-eye movement (REM)
sleep pattern in PD patients with hallucinations
(Comella et al., 1993; Arnulf et al., 2000). Indeed, in
some patients hallucinations may relate to intrusions
of REM sleep into wakefulness comparable to hypna-
gogic hallucinations in narcolepsy. Thus pathology
in brainstem structures controlling sleep may also
cause fluctuating hallucinations in PD (Manford and
Andermann, 1998).
39.7.3.2.4. Management
On-period elevations in mood and psychotic symptoms
may resolve with reduction in levodopa or dopamine
agonist dose. Some studies have suggested that dopa-
mine agonists are more likely to be associated with
psychotic symptoms than levodopa (Saint Cyr et al.,
1993), but the relationship to dopaminergic stimulation
is not entirely clear (see above). In the case of the
dopamine dysregulation syndrome, patients benefit
from a reduction and rationing of levodopa and dopa-
mine agonists (Lawrence et al., 2003; Evans et al.,
2004). In general, psychotic symptoms usually require
specific treatment with atypical neuroleptics such as
quetiapine or clozapine. Other patients may have coex-
istent depression and sleep disturbances which will
require specific treatment (Lawrence et al., 2003;
Evans et al., 2004).
39.7.3.3. Fluctuations in cognitive function
Cognitive problems ranging from mild cognitive
impairment to dementia are common in advanced PD
(Aarsland et al., 1996; see Ch. 18). Patients with
dementia with Lewy bodies often demonstrate quite
prominent fluctuations in cognition and alertness
(McKeith et al., 1996; see Ch. 60). However, fluctua-
tions in cognition can also occur in PD patients with-
out dementia (Delis et al., 1982; Girotti et al., 1986;
Cooper et al., 1991; Meco et al., 1991). Thus some
patients report on-period slowing of thoughts or brady-
phrenia and difficulty or delay in memory retrieval,
sometimes referred to as the tip of the tongue
171
phenomenon (Brown et al., 1984; Poewe et al., 1991;
Green et al., 2002). Other patients report slowing of
thoughts predominantly in the off-periods (Matison
et al., 1982; Witjas et al., 2002). Indeed, in our experi-
ence, patients complain of cognitive slowing and
difficulty concentrating more often related to the off-
periods. Some patients show reduction in selective areas
of cognitive function in off-periods such as delayed
recall of complex verbal material (Mohr et al., 1989)
and verbal fluency (Gotham et al., 1988). However, this
has been suggested to be more related to a reduction in
attention/arousal than a true cognitive effect (Brown
et al., 1984).
39.7.3.3.1. Pathophysiology
Patients with fluctuating cognition and no dementia
often have dysfunctions in frontal lobe function, sug-
gesting impaired basal gangliaprefrontal cortical
loops (Gotham et al., 1988; Green et al., 2002). The
exact circuitry involved or underlying mechanisms,
however, remain unclear. Memory function in PD
has been shown to correlate with changes in dopamine
levels, rather than with a constant high or low level
(Huber et al., 1987, 1989), suggesting that fluctuations
in cognitive function may relate to levodopa dosing.
39.7.4. Autonomic symptoms
Patients with PD develop a variety of symptoms of
dysautonomia as part of the underlying disease process
(Koike and Takahashi, 1997; see Ch. 14). These com-
monly include sweating and thermoregulatory dys-
function, sphincter disturbances, abdominal bloating
and discomfort, drooling, dry mouth, orthostatic hypo-
tension, peripheral edema and a range of other rarer
symptoms. Many patients report fluctuations in these
symptoms predominantly occurring with off-periods
(Riley and Lang, 1993; Hillen and Sage, 1996). How-
ever, in other studies, many autonomic symptoms were
independent of on- or off-periods (Gunal et al., 2002;
Witjas et al., 2002). Patients with fluctuations in auto-
nomic symptoms usually have a collection of symp-
toms that occur together consistently, usually in the
off-periods (Raudino, 2001; Swinn et al., 2003).
39.7.4.1. Disturbances of thermoregulation
One of the commonest types of non-motor fluctuation
reported by patients is off-period sweats, which can be
sudden and drenching, sometimes referred to as
sweating crises (Sage and Mark, 1995; Raudino,
2001; Gunal et al., 2002). In one study, 64% of patients
experienced sweating in the off-period, whereas 16%
reported symptoms when on with dyskinesia (Witjas
172 S. H. FOX AND A. E. LANG
et al., 2002). In a cohort of PD patients all reporting
sweating, 35% had sweating episodes in the off-period,
18% when on with dyskinesia but 39% apparently unre-
lated to their motor state (Swinn et al., 2003). Patients
also often complain of facial flushing or a sensation of
feeling hot occurring during the off-periods (Hillen
and Sage, 1996; Gunal et al., 2002; Witjas et al.,
2002). During formal autonomic function testing in
the off-state, PD patients have increased sweating and
lower skin temperatures to a heat stimulus which
reverses with levodopa therapy (Goetz et al., 1986a).
There have been rare reports of severe hyperthermia
induced by off-periods in patients with motor fluctua-
tions, similar to the neuroleptic malignant syndrome-like
state that may occur in response to sudden withdrawal
of levodopa (Pfeiffer and Sucha, 1989; Keyser and
Rodnitzky, 1991).
39.7.4.2. Disturbance of sphincter function
Off-period urinary urgency is a common problem (Riley
and Lang, 1993; Raudino, 2001; Gunal et al., 2002).
Urodynamic studies in the on- and off-state have shown
that apomorphine will improve voiding by decreasing
bladder outflow resistance (Christmas et al., 1988),
whereas levodopa gives inconsistent results (Fitzmaurice
et al., 1985; Uchiyama et al., 2003; Winge et al., 2004).
Another sphincter problem occurring predominantly in
the off-period is constipation (Witjas et al., 2002), rarely
to the extent of anismus. Apomorphine has been demon-
strated to relieve paradoxical striated muscle contraction
during defecation (Mathers et al., 1989). Some patients
report fluctuating abdominal discomfort and bloating
due to suppression of peristalsis that occurs during off-
periods (Hillen and Sage, 1996; Raudino, 2001; Gunal
et al., 2002; Witjas et al., 2002).
39.7.4.3. Dysphagia and drooling of saliva
Swallowing difficulties with choking on food can
occur in PD in the off-periods (Bushmann et al.,
1989; Witjas et al., 2002). Some patients experience
an improvement in symptoms with levodopa, although
it is not consistent. Barium studies before and after
administration of levodopa have demonstrated that
about 50% of PD patients experience improved oro-
pharyngeal or esophageal function (Bushmann et al.,
1989). Off-period belching secondary to esophageal
motility dysfunction, relieved by apomorphine, has
also been reported (Kempster et al., 1989). PD patients
often report drooling of saliva secondary to dysphagia,
which can range from mild to severe with a constantly
wet face and clothes (Bateson et al., 1973). Patients
often report fluctuations in salivation with worsening
in the off-periods (Raudino, 2001; Gunal et al.,
2002). Alternatively some patients report a dry mouth
during off-periods (Witjas et al., 2002), possibly
related to breathing through a persistently open mouth.
39.7.4.4. Orthostatic hypotension
PD patients can experience a symptomatic postural fall
in blood pressure (BP) which may cause a range of
symptoms, including dizziness, fainting, fatigue, slee-
piness, shoulder pain or falls (Senard et al., 1997;
Mathias and Kimber, 1998). Generally this is second-
ary to pathological involvement of the sympathetic
nervous system but also occurs de novo or is aggra-
vated by dopaminergic medication since all such
agents are capable of lowering BP (Wakabayashi
et al., 1993; Korchounov et al., 2004). However, the
presence of motor fluctuations appears to be an addi-
tional independent risk factor for fluctuations in BP
control. In one study, PD patients with wearing-off
fluctuations compared to a group without motor fluc-
tuations had significantly higher supine and erect
BP during the off-phase as compared to the on-phase
(Baratti and Calzetti, 1984).
39.7.4.5. Dyspnea
Dyspnea occurring as an off-period phenomenon has
been reported in PD patients with fluctuations (Hillen
and Sage, 1996; Raudino. 2001; Gunal et al., 2002;
Witjas et al., 2002) and may be accompanied by a
bothersome, subjective sense of air hunger. Alterna-
tively, some patients may demonstrate tachypnea with-
out much in the way of accompanying complaints,
although the care-giver may express concerns about
the symptoms. These symptoms may occur due to
upper-airway obstruction (Vincken et al., 1984). How-
ever, a study by Weiner et al. (2002) has shown that
patients perception of dyspnea is improved by levo-
dopa without any objective change in pulmonary func-
tion. In addition, off-period dystonia of the cervical or
laryngeal musculature can also induce stridor (Corbin
and Williams, 1987). Breathing difficulties can also
occur as an on-period problem and may be a form of
respiratory dyskinesia (De Keyser and Vincken, 1985;
Jankovic and Nour, 1986).
39.7.4.6. Pathophysiology
Dysautonomic features in PD are related to pathologi-
cal involvement of the peripheral and central sympa-
thetic and parasympathetic nervous systems that
occurs with advancing disease (Edwards et al., 1992;
Wakabayashi et al., 1993). Fluctuations in autonomic
function have been shown to correlate with both dis-
ease duration and severity of disease (Gunal et al.,
2002; Witjas et al., 2002). Patients with fluctuating
 MOTOR AND NON-MOTOR FLUCTUATIONS
autonomic symptoms tend to have higher daily levo-
dopa doses compared to non-fluctuators (Gunal et al.,
2002). Fluctuations in these autonomic functions may
relate to fluctuating peripheral dopaminergic stimula-
tion (Goetz et al., 1986a). Dopamine D1- and D2-
receptor agonists can reduce the bladder threshold for
the micturition reflex in the MPTP-lesioned primate
(Yoshimura et al., 1993, 1998), suggesting improved
bladder function in the on-state. Dopamine plays a role
in the regulation of BP by inhibition of sodium trans-
port in renal proximal tubules and relaxation of vascu-
lar smooth muscles (Velasco and Luchsinger, 1998),
thus accounting for fluctuating orthostatic and cardio-
vascular symptoms. However, some symptoms, such
as sweating, are not related to disease severity or dura-
tion or to levodopa dose. In these cases the pathophy-
siology is less clear but may relate to disease
involvement of more central autonomic stuctures such
as the hypothalamus (Langston and Forno, 1978;
Braak et al., 2004).
39.7.4.7. Management
In general, off-period autonomic dysfunction will
respond to treatment of the off-periods (Sage and
Mark, 1995; Olanow and Koller, 1998). Urinary
dysfunction related to a hyperactive bladder may be
helped with anticholinergic medications such as
oxybutinin or tolteradine. Bilateral STN DBS is also
effective at reducing urinary symptoms due to detrusor
hyperreflexia (Seif et al., 2004). Sweating episodes
may respond to beta-blockers (Stocchi et al., 1997;
Olanow and Koller, 1998). Sialorrhea may respond to
botulinum toxin injections into the salivary glands
(Mancini et al., 2003; Ondo et al., 2004).
39.7.5. Sensory
PD patients can experience a number of fluctuating
symptoms that have been loosely termed sensory to
distinguish them from symptoms that may occur due
to the motor features of parkinsonism. Such symptoms
may include pain, numbness and paresthesias, akathisia
and restless-legs syndrome. These symptoms can fluctu-
ate and are either most often experienced exclusively
during off-periods or are accentuated during these
times. Such symptoms are often the most distressing
to patients and in some cases become more disabling
and bothersome than the motor fluctuations.
39.7.5.1. Pain
Pain is a common symptom in PD and fluctuations in
pain are reported in 2346% of PD patients (Goetz
et al., 1986b; Quinn et al., 1986; Gunal et al., 2002;
173
Witjas et al., 2002). Fluctuations in pain are due to a
number of factors. One important cause is the presence
of dystonia and rigidity associated with off-periods.
Pain associated with dystonia most commonly occurs
accompanying early-morning dystonia, typically
affecting the feet and toes, and improving when the
patient switches on (Melamed, 1979; Currie et al.,
1998). Painful dystonic spasms may also occur as an
end-of-dose or off-period pattern (Ilson et al., 1984)
or in a diphasic pattern (Luquin et al., 1992).
Patients also report painful sensations without evi-
dence of dystonia, most often associated with off-
periods (Quinn et al., 1986). Such pain can be severe
and have a burning, aching or stabbing quality. Often
the symptoms are diffuse and poorly localized, but
may be more severe on the more affected parkinsonian
side. Non-specific oral and genital pain related to off-
periods has also been reported, in all cases responding
to treatment with levodopa (Ford et al., 1996). On-
period pain is also a recognized problem and may be
secondary to peak-dose dyskinesia; however, it has
not been well characterized (Goetz et al., 1986b;
Quinn, 1998). In some patients, this may simply relate
to a combination of a musculoskeletal cause (e.g.
arthritis) with prominent choreoathetoid involuntary
movements.
39.7.5.2. Numbness/dysesthesia
PD patients with motor fluctuations can also experi-
ence fluctuating sensory symptoms without objective
sensory loss. These symptoms include numbness, cold-
ness, tightening or paresthesia that is most often asso-
ciated with off-periods (Snider et al., 1976; Koller,
1984). Patients are reported to experience symptoms
more in the legs than the arms, with the neck and face
being rarely affected (Snider et al., 1976).
39.7.5.3. Restless-legs syndrome/akathisia
Restlessness is a common complaint among patients
with PD; however, it may be difficult to distinguish
restlessness due to leg pain or discomfort as a wearing-
off phenomenon from true restless-legs syndrome and
akathisia (Poewe and Hogl, 2004). Fluctuations in symp-
toms of restlessness, with a predominantly off-period
distribution, have been reported in a number of case
series; however, the term was often not clearly defined
(Gunal et al., 2002; Witjas et al., 2002).
Akathisia is a sensation of inner restlessness and
inability to sit still that has been reported to occur in
26% of PD patients, when underlying factors such as
discomfort due to parkinsonism-related symptoms are
excluded (Lang and Johnson, 1987). Fluctuations in
akathisia are common among PD patients with motor
174 S. H. FOX AND A. E. LANG
fluctuations (Witjas et al., 2002). The relationship to
the motor state is not consistent: some patients report
akathisia related to off-periods but also when switch-
ing on or in an end-of-dose pattern (Lang and Johnson,
1987; Comella and Goetz, 1994; Witjas et al., 2002).
39.7.5.4. Pathophysiology
Fluctuating pain and other sensory symptoms in PD
may be secondary to peripheral mechanisms asso-
ciated with sustained muscle contraction in dystonia,
rigidity or musculoskeletal problems as well as to
primary central mechanisms, the nature of which
remains unclear. Off-period fluctuating pain and other
sensory symptoms are often dramatically alleviated by
dopaminergic medication, suggesting that the patho-
physiology is associated with the neural mechanisms
generating the underlying parkinsonian symptoms
and dystonic symptoms. In addition, pain, which may
or may not be associated with dystonia, can be a pre-
senting feature of untreated PD (LeWitt et al., 1986).
The basal ganglia are involved in pain processing,
via the ventral anterior and ventrolateral thalamic
nuclei (Chudler and Dong, 1995; Tracey et al.,
2000). The pathways involved in primary parkinsonian
pain are unknown; however a PET study has shown
that increased pain perception correlates with lower
numbers of striatal dopamine D2-receptors (Hagelberg
et al., 2002), suggesting a link between the dopaminer-
gic system and pain processing. Spinal cord dopami-
nergic pathways have also been suggested to play a
role in fluctuating pain, since spinal anesthesia but
not sympathetic or epidural block effectively alle-
viated diphasic leg pain in one PD patient (Sage
et al., 1990). More recently it has been demonstrated
that, in PD, there is increased sensitivity to some pain-
ful stimuli such as heat threshold; however, this did
not change between the on- and off-state in PD
patients with motor fluctuations (Djaldetti et al.,
2004). This suggests that some painful sensory symp-
toms may be secondary to involvement of non-dopa-
minergic systems such as noradrenergic structures
(Buzas and Max, 2004).
39.7.5.5. Management
Sensory symptoms clearly related to off-periods,
or low levels of levodopa as in diphasic dyskinesia,
will improve with increased dopaminergic medication
and treatment of onoff fluctuations (Sage, 2004).
Early-morning off-period dystonia will respond to the
use of long-acting dopamine agonists or controlled-
release levodopa prior to bedtime (Lees, 1987). Rescue
medication for severe off-period pain includes soluble
levodopa preparations or apomorphine (Lees, 1993;
Factor et al., 2000). Severe nocturnal pain may be
helped by apomorphine infusion (Reuter et al., 1999).
Bilateral STN DBS and pallidotomy are also an effec-
tive therapy for fluctuating off-period sensory symp-
toms (Honey et al., 1999; Krack et al., 1999; Loher
et al., 2002). Other treatment options for off-period
dystonia include specifically targeted botulinum toxin
injections ((Pacchetti et al., 1995), baclofen (Lees
et al., 1978) and lithium (Quinn and Marsden, 1986).
On-period pain and sensory symptoms may respond
to a reduction in dopaminergic mediation. Sensory
symptoms unrelated to dystonia and unresponsive to
manipulations in dopaminergic therapy are often
intractable and difficult to treat. There are no published
clinical trials to date and thus treatment options are
based on case reports and include opiates (Stein and
Read, 1997) and clozapine (Factor and Freidman,
1997; Trosch et al., 1998). It should be noted that,
although bilateral STN DBS is extremely effective at
treating motor fluctuations in PD and thus reducing
many off-period-related non-motor symptoms (Funkie-
wiez et al., 2004), the concomitant reduction in dopami-
nergic medications can often induce or unmask new
non-motor symptoms that were not present prior to the
surgery, such as restless-legs syndrome (Kedia et al.,
2004). The short- and long-term influence of bilateral
STN DBS on the broad spectrum of non-motor
fluctuations outlined above is at present unknown.
References
Aarsland D, Tandberg E, Larsen JP et al. (1996). Frequency of
dementia in Parkinson disease. Arch Neurol 53: 538542.
Abe K, Takanashi M, Yanagihara T (2000). Fatigue in
patients with Parkinsons disease. Behav Neurol 12:
103106.
Ahlskog JE, Muenter MD (2001). Frequency of levodopa-
related dyskinesias and motor fluctuations as estimated
from the cumulative literature. Mov Disord 16: 448458.
Ahlskog JE, Muenter MD, McManis PG et al. (1988). Con-
trolled-release Sinemet (CR-4): a double-blind crossover
study in patients with fluctuating Parkinsons disease.
Mayo Clin Proc 63: 876886.
Alexander GM, Schwartzman RJ, Grothusen JR et al. (1994).
Effect of plasma levels of large neutral amino acids and
degree of parkinsonism on the blood-to-brain transport of
levodopa in naive and MPTP parkinsonian monkeys. Neu-
rology 44: 14911499.
Alves G, Wentzel-Larsen T, Larsen JP (2004). Is fatigue an
independent and persistent symptom in patients with Par-
kinson disease? Neurology 63: 19081911.
Andersson M, Hilbertson A, Cenci MA (1999). Striatal fosB
expression is causally linked with l-DOPA-induced abnor-
mal involuntary movements and the associated upregula-
tion of striatal prodynorphin mRNA in a rat model of
Parkinsons disease. Neurobiol Dis 6: 461474.
 MOTOR AND NON-MOTOR FLUCTUATIONS
Arnulf I, Bonnet AM, Damier P et al. (2000). Hallucinations,
REM sleep, and Parkinsons disease: a medical hypoth-
esis. Neurology 55: 281288.
Assal F, Spahr L, Hadengue A et al. (1998). Tolcapone and
fulminant hepatitis. Lancet 352: 958.
Aubert I, Guigoni C, Hakansson K et al. (2005). Increased
D1 dopamine receptor signaling in levodopa-induced
dyskinesia. Ann Neurol 57: 1726.
Ballard PA, Tetrud JW, Langston JW (1985). Permanent
human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP): seven cases. Neurology 35:
949956.
Bara-Jimnez W, Morris M, Dimitrova T et al. (2004). Alpha
2A adrenergic antagonistic effects in advanced Parkin-
sons diseases. 8th International Congress of Parkinsons
Disease and Movement Disorders, 14th17th June 2004,
Rome, Italy.
Baratti M, Calzetti S (1984). Fluctuation of arterial blood
pressure during end-of-dose akinesia in Parkinsons disease.
J Neurol Neurosurg Psychiatry 47: 12411243.
Baruzzi A, Contin M, Riva R et al. (1987). Influence of meal
ingestion time on pharmacokinetics of orally administered
levodopa in parkinsonian patients. Clin Neuropharmacol
10: 527537.
Bateson MC, Gibberd FB, Wilson RS (1973). Salivary symp-
toms in Parkinson disease. Arch Neurol 29: 274275.
Bejjani BP, Arnulf I, Demeret S et al. (2000). Levodopa-
induced dyskinesias in Parkinsons disease: is sensitization
reversible? Ann Neurol 47: 655658.
Bezard E, Brotchie JM, Gross CE (2001). Pathophysiology
of levodopa-induced dyskinesia: potential for new thera-
pies. Nat Rev Neurosci 2: 577588.
Blanchet PJ, Calon F, Martel JC et al. (1995). Continuous
administration decreases and pulsatile administration
increases behavioral sensitivity to a novel dopamine
D2 agonist (U-91356A) in MPTP-exposed monkeys.
J Pharmacol Exp Ther 272: 854859.
Bojo L, Cassuto J (1992). Gastric reflex relaxation by colo-
nic distension. J Auton Nerv Syst 38: 5764.
Boucai L, Cerquetti D, Merello M (2004). Functional surgery
for Parkinsons disease treatment: a structured analysis of a
decade of published literature. Br J Neurosurg 18: 213222.
Braak H, Ghebremedhin E, Rub U et al. (2004). Stages in the
development of Parkinsons disease-related pathology.
Cell Tissue Res 318: 121134.
Bravi D, Mouradian MM, Roberts JW et al. (1993). End-of-
dose dystonia in Parkinsons disease. Neurology 43:
21302131.
Bravi D, Mouradian MM, Roberts JW et al. (1994). Wear-
ing-off fluctuations in Parkinsons disease: contribution
of postsynaptic mechanisms. Ann Neurol 36: 2731.
Breier A (1995). Serotonin, schizophrenia and antipsychotic
drug action. Schizophr Res 14: 187202.
Brotchie JM, Lee J, Venderova K (2005). Levodopa-induced
dyskinesia in Parkinsons disease. J Neural Transm
112 (3): 359391.
Brown RG, Marsden CD, Quinn N et al. (1984). Alterations
in cognitive performance and affect-arousal state during
175
fluctuations in motor function in Parkinsons disease.
J Neurol Neurosurg Psychiatry 47: 454465.
Brown RG, Dittner A, Findley L et al. (2005). The Parkinson
fatigue scale. Parkinsonism Relat Disord 11: 4955.
Bushmann M, Dobmeyer SM, Leeker L et al. (1989). Swal-
lowing abnormalities and their response to treatment in
Parkinsons disease. Neurology 39: 13091312.
Buzas B, Max MB (2004). Pain in Parkinson disease.
Neurology 62: 21562157.
Calabresi P, Giacomini P, Centonze D et al. (2000). Levodo-
pa-induced dyskinesia: a pathological form of striatal
synaptic plasticity? Ann Neurol 47 (4 Suppl 1): S60S68.
Calon F, Morissette M, Ghribi O et al. (2002a). Alteration of
glutamate receptors in the striatum of dyskinetic 1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine-treated monkeys following
dopamine agonist treatment. Prog Neuropsychopharmacol
Biol Psychiatry 26: 127138.
Calon F, Birdi S, Rajput AH et al. (2002b). Increase of pre-
proenkephalin mRNA levels in the putamen of Parkinson
disease patients with levodopa-induced dyskinesias.
J Neuropathol Exp Neurol 61: 186196.
Calon F, Morissette M, Rajput AH et al. (2003). Changes of
GABA receptors and dopamine turnover in the postmor-
tem brains of parkinsonians with levodopa-induced motor
complications. Mov Disord 18: 241253.
Cantello R, Gilli M, Riccio A et al. (1986). Mood changes
associated with end-of-dose deterioration in Parkinsons
disease: a controlled study. J Neurol Neurosurg Psychiatry
49: 11821190.
Carter JH, Nutt JG, Woodward WR et al. (1989). Amount and
distribution of dietary protein affects clinical response to
levodopa in Parkinsons disease. Neurology 39: 552556.
Chase TN (1998a). Levodopa therapy: consequences of the
nonphysiologic replacement of dopamine. Neurology
50 (5 Suppl 5): S17S25.
Chase TN (1998b). The significance of continuous dopami-
nergic stimulation in the treatment of Parkinsons disease.
Drugs 55 (Suppl 1): 19.
Chase TN, Mouradian MM, Engber TM (1993). Motor
response complications and the function of striatal efferent
systems. Neurology 43 (12 Suppl 6): S23S27.
Chaudhuri KR, Clough C (1998). Subcutaneous apomor-
phine in Parkinsons disease. BMJ 316: 641.
Chaudhuri KR, Critchley P, Abbott RJ et al. (1988). Subcuta-
neous apomorphine for on-off oscillations in Parkinsons
disease. Lancet 2 (8622): 1260.
Christmas TJ, Kempster PA, Chapple CR et al. (1988). Role
of subcutaneous apomorphine in parkinsonian voiding
dysfunction. Lancet 2: 14511453.
Chudler EH, Dong WK (1995). The role of the basal ganglia
in nociception and pain. Pain 60: 338.
Clarke A, Brewer F, Johnson ES et al. (2003). A new for-
mulation of selegiline: improved bioavailability and
selectivity for MAO-B inhibition. J Neural Transm 110:
12411255.
Clarke CE, Deane K (2001a). Ropinirole versus bromocrip-
tine for levodopa-induced complications in Parkinsons
disease. Cochrane Database Syst Rev CD001517.
176 S. H. FOX AND A. E. LANG
Clarke CE, Deane K (2001b). Cabergoline versus bromocrip-
tine for levodopa-induced complications in Parkinsons
disease. Cochrane Database Syst Rev CD001519.
Clarke CE, Speller JM (2000). Pergolide versus bromocrip-
tine for levodopa-induced motor complications in Parkin-
sons disease. Cochrane Database Syst Rev CD000236.
Clarke CE, Speller JM, Clarke JA (2000). Pramipexole ver-
sus bromocriptine for levodopa-induced complications in
Parkinsons disease. Cochrane Database Syst Rev
CD002259.2000.
Colosimo C, Merello M, Hughes AJ et al. (1996). Motor
response to acute dopaminergic challenge with apomor-
phine and levodopa in Parkinsons disease: implications
for the pathogenesis of the on-off phenomenon. J Neurol
Neurosurg Psychiatry 60: 634637.
Colzi A, Turner K, Lees AJ (1998). Continuous subcuta-
neous waking day apomorphine in the long term treatment
of levodopa induced interdose dyskinesias in Parkinsons
disease. J Neurol Neurosurg Psychiatry 64: 573576.
Comella CL, Goetz CG (1994). Akathisia in Parkinsons
disease. Mov Disord 9: 545549.
Comella CL, Tanner CM, Ristanovic RK (1993). Polysomno-
graphic sleep measures in Parkinsons disease patients
with treatment-induced hallucinations. Ann Neurol 34:
710714.
Contin M, Riva R, Martinelli P et al. (1998). Effect of meal
timing on the kinetic-dynamic profile of levodopa/carbi-
dopa controlled release [corrected] in parkinsonian
patients. Eur J Clin Pharmacol 54: 303308.
Cooper JA, Sagar HJ, Jordan N et al. (1991). Cognitive
impairment in early, untreated Parkinsons disease and
its relationship to motor disability. Brain 114: 20952122.
Corbin DO, Williams AC (1987). Stridor during dystonic
phases of Parkinsons disease. J Neurol Neurosurg Psy-
chiatry 50: 821822.
Cotzias GC, Papavasiliou PS, Fehling C et al. (1970). Simila-
rities between neurologic effects of L-dipa and of apomor-
phine. N Engl J Med 282: 3133.
Crossman AR (1990). A hypothesis on the pathophysiologi-
cal mechanisms that underlie levodopa- or dopamine
agonist-induced dyskinesia in Parkinsons disease: impli-
cations for future strategies in treatment. Mov Disord 5:
100108.
Currie LJ, Harrison MB, Trugman JM et al. (1998). Early
morning dystonia in Parkinsons disease. Neurology 51:
283285.
De Keyser J, Vincken W (1985). L-dopa-induced respiratory
disturbance in Parkinsons disease suppressed by tiapride.
Neurology 35: 235237.
de la Fuente-Fernandez R, Lu JQ, Sossi V et al. (2001).
Biochemical variations in the synaptic level of dopamine
precede motor fluctuations in Parkinsons disease: PET
evidence of increased dopamine turnover. Ann Neurol
49: 298303.
de la Fuente-Fernandez R, Sossi V, Huang Z et al. (2004).
Levodopa-induced changes in synaptic dopamine levels
increase with progression of Parkinsons disease: implica-
tions for dyskinesias. Brain 127: 27472754.
Deep-Brain Stimulation for Parkinsons Disease Study
Group (2001). Deep-brain stimulation of the subthalamic
nucleus or the pars interna of the globus pallidus in
Parkinsons disease. N Engl J Med 345: 956963.
Delis D, Direnfeld L, Alexander MP et al. (1982). Cognitive
fluctuations associated with on-off phenomenon in Parkin-
son disease. Neurology 32: 10491052.
Dewey RB Jr, Hutton RB, LeWitt PA et al. (2001). A rando-
mized, double-blind, placebo-controlled trial of subcuta-
neously injected apomorphine for parkinsonian off-state
events. Arch Neurol 58: 13851392.
Djaldetti R, Baron J, Ziv I et al. (1996). Gastric emptying in
Parkinsons disease: patients with and without response
fluctuations. Neurology 46: 10511054.
Djaldetti R, Shifrin A, Rogowski Z et al. (2004). Quantitative
measurement of pain sensation in patients with Parkinson
disease. Neurology 62: 21712175.
Dunah AW, Standaert DG (2001). Dopamine D1 receptor-
dependent trafficking of striatal NMDA glutamate receptors
to the postsynaptic membrane. J Neurosci 21: 55465558.
Duvoisin RC (1974). Variations in the on-off phenomena.
Adv Neurol 5: 339340.
Edwards LL, Quigley EM, Pfeiffer RF (1992). Gastrointest-
inal dysfunction in Parkinsons disease: frequency and
pathophysiology. Neurology 42: 726732.
Engber TM, Susel Z, Juncos JL et al. (1989). Continuous and
intermittent levodopa differentially affect rotation induced
by D-1 and D-2 dopamine agonists. Eur J Pharmacol
168 (3): 291298.
Evans MA, Broe GA, Triggs EJ et al. (1981). Gastric empty-
ing rate and the systemic availability of levodopa in the
elderly parkinsonian patient. Neurology 31: 12881294.
Evans AH, Katzenschlager R, Paviour D et al. (2004). Pund-
ing in Parkinsons disease: its relation to the dopamine
dysregulation syndrome. Mov Disord 19: 397405.
Fabbrini G, Mouradian MM, Juncos JL et al. (1988). Motor
fluctuations in Parkinsons disease: central pathophysiolo-
gical mechanisms, Part I. Ann Neurol 24: 366371.
Factor SA, Friedman JH (1997). The emerging role of cloza-
pine in the treatment of movement disorders. Mov Disord
12: 483496.
Factor SA, Brown DL, Molho ES (2000). Subcutaneous apo-
morphine injections as a treatment for intractable pain in
Parkinsons disease. Mov Disord 15: 167169.
Factor SA, Molho ES, Feustel PJ et al. (2001). Long-term
comparative experience with tolcapone and entacapone
in advanced Parkinsons disease. Clin Neuropharmacol
24: 295299.
Factor SA, Feustel PJ, Friedman JH et al. (2003). Longitudinal
outcome of Parkinsons disease patients with psychosis.
Neurology 60: 17561761.
Fahn S (1974). On-off phenomenon with levodopa therapy
in parkinsonism: clinical and pharmacologic correlations
and the effects of intramuscular pyridoxine. Neurology
24: 431441.
Fahn S (1977). Episodic failure of absorption of levodopa: a
factor in the control of clinical fluctuations in the treat-
ment of parkinsonism. Neurology 27: 390.
 MOTOR AND NON-MOTOR FLUCTUATIONS
Fahn S (1982). Fluctuations of disability in Parkinsons dis-
ease: pathophysiological aspects. In: CD Marsden, S Fahn
(Eds.), Movement Disorders. Butterworth Scientific,
London, pp. 123145.
Fahn S (1995). The freezing phenomenon in parkinsonism.
Adv Neurol 67: 5363.
Fahn S, Oakes D, Shoulson I et al. (2004). Parkinson Study
Group. Levodopa and the progression of Parkinsons dis-
ease. N Engl J Med 351: 24982508.
Fenelon G, Mahieux F, Huon R et al. (2000). Hallucinations
in Parkinsons disease: prevalence, phenomenology and
risk factors. Brain 123: 733745.
Finberg JP, Lamensdorf I, Weinstock M et al. (1999). Phar-
macology of rasagiline (N-propargyl-1R-aminoindan).
Adv Neurol 80: 495499.
Fitzmaurice H, Fowler CJ, Rickards D et al. (1985). Micturi-
tion disturbance in Parkinsons disease. Br J Urol 57:
652656.
Ford B, Louis ED, Greene P et al. (1996). Oral and genital
pain syndromes in Parkinsons disease. Mov Disord 11:
421426.
Forsberg M, Lehtonen M, Heikkinen M et al. (2003). Phar-
macokinetics and pharmacodynamics of entacapone and
tolcapone after acute and repeated administration: a com-
parative study in the rat. J Pharmacol Exp Ther 304:
498506.
Fox S, Silverdale M, Kellett M et al. (2004). Non-subtype-
selective opioid receptor antagonism in treatment of
levodopa-induced motor complications in Parkinsons
disease. Mov Disord 19: 554560.
Frankel JP, Lees AJ, Kempster PA et al. (1990). Subcutaneous
apomorphine in the treatment of Parkinsons disease.
J Neurol Neurosurg Psychiatry 53: 96101.
Friedman A, Sienkiewicz J (1991). Psychotic complications
of long-term levodopa treatment of Parkinsons disease.
Acta Neurol Scand 84: 111113.
Friedman J, Friedman H (1993). Fatigue in Parkinsons
disease. Neurology 43: 20162018.
Friedman JH (1994). Punding on levodopa. Biol Psychiatry
36: 350351.
Funkiewiez A, Ardouin C, Caputo E et al. (2004). Long term
effects of bilateral subthalamic nucleus stimulation on
cognitive function, mood, and behaviour in Parkinsons
disease. J Neurol Neurosurg Psychiatry 75: 834839.
Gancher ST, Nutt JG, Woodward WR (1995). Apomorphine
infusional therapy in Parkinsons disease: clinical utility
and lack of tolerance. Mov Disord 10: 3743.
Giladi N, McMahon D, Przedborski S et al. (1992).Motor
blocks in Parkinsons disease Neurology 42: 333339.
Giladi N, Kao R, Fahn S (1997). Freezing phenomenon in
patients with parkinsonian syndromes. Mov Disord 12:
302305.
Giovannoni G, OSullivan JD, Turner K et al. (2000). Hedo-
nistic homeostatic dysregulation in patients with Parkin-
sons disease on dopamine replacement therapies.
J Neurol Neurosurg Psychiatry 68: 423428.
Girotti F, Carella F, Grassi MP et al. (1986). Motor and cog-
nitive performances of parkinsonian patients in the on and
177
off phases of the disease. J Neurol Neurosurg Psychiatry
49: 657660.
Golbe LI, Lieberman AN, Muenter MD et al. (1988). Depre-
nyl in the treatment of symptom fluctuations in advanced
Parkinsons disease. Clin Neuropharmacol 11: 4555.
Goetz CG (2003). Treatment of advanced Parkinsons disease:
an evidence-based analysis. Adv Neurol 91: 213228.
Goetz CG, Stebbins GT (1993). Risk factors for nursing
home placement in advanced Parkinsons disease. Neurol-
ogy 43: 22272229.
Goetz CG, Lutge W, Tanner CM (1986a). Autonomic dys-
function in Parkinsons disease. Neurology 36: 7375.
Goetz CG, Tanner CM, Levy M et al. (1986b). Pain in Par-
kinsons disease. Mov Disord 1: 4549.
Goetz CG, Pappert EJ, Blasucci LM et al. (1998). Intravenous
levodopa in hallucinating Parkinsons disease patients:
high-dose challenge does not precipitate hallucinations.
Neurology 50: 515517.
Goetz CG, Wuu J, Curgian LM et al. (2005). Hallucinations
and sleep disorders in PD: six-year prospective longitudi-
nal study. Neurology 64: 8186.
Gordin A, Kaakkola S, Teravainen H (2003). Position of
COMT inhibition in the treatment of Parksons disease.
In: A Gordin, S Kaakkola, H Teravainen (Eds.), Vol. 91.
Lippincott Williams and Williams, USA, pp. 237250.
Gotham AM, Brown RG, Marsden CD (1988). Frontal cog-
nitive function in patients with Parkinsons disease on
and off levodopa. Brain 111: 299321.
Graham JM, Grunewald RA, Sagar HJ (1997). Hallucinosis
in idiopathic Parkinsons disease. J Neurol Neurosurg Psy-
chiatry 63: 434440.
Green J, McDonald WM, Vitek JL et al. (2002). Cognitive
impairments in advanced PD without dementia. Neurology
59: 13201324.
Gulati A, Alison F, Frauke S et al. (2004). A clinical obser-
vational study of the patterns and occurrence of non-motor
symptoms in Parkinsons disease ranging from early to
advanced disease. Mov Disord 19 (Suppl 9): 406.
Gunal DI, Nurichalichi K, Tuncer N et al. (2002). The clinical
profile of nonmotor fluctuations in Parkinsons disease
patients. Can J Neurol Sci 29: 6164.
Hadj Tahar A, Gregoire L, Bangassoro E et al. (2000). Sus-
tained cabergoline treatment reverses levodopa-induced
dyskinesias in parkinsonian monkeys. Clin Neuropharma-
col 23: 195202.
Harding AJ, Stimson E, Henderson JM et al. (2002). Clini-
cal correlates of selective pathology in the amygdala
of patients with Parkinsons disease. Brain 125:
24312445.
Hardoff R, Sula M, Tamir A et al. (2001). Gastric emptying
time and gastric motility in patients with Parkinsons disease.
Mov Disord 16: 10411047.
Hagelberg N, Martikainen IK, Mansikka H et al. (2002).
Dopamine D2 receptor binding in the human brain is
associated with the response to painful stimulation and
pain modulatory capacity. Pain 99: 273279.
Hauser RA, Holford NH (2002). Quantitative description
of loss of clinical benefit following withdrawal of
178 S. H. FOX AND A. E. LANG
levodopa-carbidopa and bromocriptine in early Parkinsons
disease. Mov Disord 17: 961968.
Hauser RA, Koller WC, Hubble JP et al. (2000). Time course
of loss of clinical benefit following withdrawal of levo-
dopa/carbidopa and bromocriptine in early Parkinsons
disease. Mov Disord 15: 485489.
Henry B, Brotchie JM (1996). Potential of opioid antagonists
in the treatment of levodopa-induced dyskinesias in Par-
kinsons disease. Drugs Aging 9: 149158.
Henry B, Crossman AR, Brotchie JM (1999). Effect of
repeated L-DOPA, bromocriptine, or lisuride administra-
tion on preproenkephalin-A and preproenkephalin-B
mRNA levels in the striatum of the 6-hydroxydopamine-
lesioned rat. Exp Neurol 155: 204220.
Henry B, Duty S, Fox SH et al. (2003). Increased striatal
pre-proenkephalin B expression is associated with dyski-
nesia in Parkinsons disease. Exp Neurol 183: 458468.
Herlofson K, Larsen JP (2002). Measuring fatigue in patients
with Parkinsons diseasethe Fatigue Severity Scale. Eur
J Neurol 9: 595600.
Hillen ME, Sage JL (1996). Nonmotor fluctuations in patients
with Parkinsons disease. Neurology 47: 11801183.
Hoehn MM, Elton RL (1985). Low dosages of bromocriptine
added to levodopa in Parkinsons disease. Neurology 35:
199206.
Holloway RG, Shoulson I, Fahn S et al. (2004). Parkinson
Study Group. Pramipexole vs levodopa as initial treatment
for Parkinson disease: a 4-year randomized controlled
trial. Arch Neurol 61: 10441053.
Honey CR, Stoessl AJ, Tsui JK et al. (1999). Unilateral
pallidotomy for reduction of parkinsonian pain. J Neuro-
surg 91: 198201.
Horstink MW, Zijlmans JC, Pasman JW et al. (1990).
Severity of Parkinsons disease is a risk factor for peak-
dose dyskinesia. J Neurol Neurosurg Psychiatry 53:
224226.
Huber SJ, Shulman HG, Paulson GW et al. (1987). Fluctua-
tions in plasma dopamine level impair memory in Parkin-
sons disease. Neurology 37: 13711375.
Huber SJ, Shulman HG, Paulson GW et al. (1989). Dose-
dependent memory impairment in Parkinsons disease.
Neurology 39: 438440.
Hughes AJ, Bishop S, Lees AJ et al. (1991). Rectal apomor-
phine in Parkinsons disease. Lancet 337: 118.
Hughes AJ, Bishop S, Kleedorfer B et al. (1993). Subcuta-
neous apomorphine in Parkinsons disease: response to
chronic administration for up to five years. Mov Disord
8: 165170.
Ilson J, Fahn S, Cote L (1984). Painful dystonic spasms in
Parkinsons disease. Adv Neurol 40: 395398.
Isella V, Melzi P, Grimaldi M et al. (2002). Clinical, neurop-
sychological, and morphometric correlates of apathy in
Parkinsons disease. Mov Disord 17: 366371.
Jankovic J, Nour F (1986). Respiratory dyskinesia in Parkin-
sons disease. Neurology 36: 303304.
Kaakkola S, Gordin A, Mannisto PT (1994). General proper-
ties and clinical possibilities of new selective inhibitors
of catechol-O-methyltransferase. Gen Pharmacol 25:
813824.
Kapoor R, Turjanski N, Frankel J et al. (1990). Intranasal
apomorphine: a new treatment in Parkinsons disease.
J Neurol Neurosurg Psychiatry 53: 1015.
Karstaedt PJ, Pincus JH (1992). Protein redistribution diet
remains effective in patients with fluctuating parkinson-
ism. Arch Neurol 49: 149151.
Kedia S, Moro E, Tagliati M et al. (2004). Emergence of
restless legs syndrome during subthalamic stimulation for
Parkinson disease. Neurology 63: 24102412.
Kempster PA, Lees AJ, Crichton P et al. (1989). Off-period
belching due to a reversible disturbance of oesophageal
motility in Parkinsons disease and its treatment with apo-
morphine. Mov Disord 4: 4752.
Keshavan MS, David AS, Narayanen HS et al. (1986). On-
off phenomena and manic-depressive mood shifts: case
report. J Clin Psychiatry 47: 9394.
Keyser DL, Rodnitzky RL (1991). Neuroleptic malignant
syndrome in Parkinsons disease after withdrawal or
alteration of dopaminergic therapy. Arch Intern Med
151: 794796.
Khan NL, Graham E, Critchley P et al. (2003). Parkin disease:
a phenotypic study of a large case series. Brain 126:
12791292.
Klintenberg R, Svenningsson P, Gunne L et al. (2002).
Naloxone reduces levodopa-induced dyskinesias and
apomorphine-induced rotations in primate models of
parkinsonism. J Neural Transm 109: 12951307.
Koike Y, Takahashi A (1997). Autonomic dysfunction in
Parkinsons disease. Eur Neurol 38 (Suppl 2): 812.
Koller W, Guarnieri M, Hubble J et al. (2005). An open-label
evaluation of the tolerability and safety of Stalevo (carbi-
dopa, levodopa and entacapone) in Parkinsons disease
patients experiencing wearing-off. J Neural Transm 112:
221230.
Koller WC (1984). Sensory symptoms in Parkinsons dis-
ease. Neurology 34: 957959.
Kompoliti K, Goetz CG, Leurgans S et al. (2000). On
freezing in Parkinsons disease: resistance to visual cue
walking devices. Mov Disord 15: 309312.
Korchounov A, Kessler KR, Schipper HI (2004). Differential
effects of various treatment combinations on cardiovascu-
lar dysfunction in patients with Parkinsons disease. Acta
Neurol Scand 109: 4551.
Korlipara LV, Cooper JM, Schapira AH (2004). Differences
in toxicity of the catechol-O-methyl transferase inhibitors,
tolcapone and entacapone to cultured human neuroblas-
toma cells. Neuropharmacology 46: 562569.
Krack P, Pollak P, Limousin P et al. (1999). From off-period
dystonia to peak-dose chorea. The clinical spectrum of vary-
ing subthalamic nucleus activity. Brain 122: 11331146.
Krack P, Batir A, Van Blercom N et al. (2003). Five-year
follow-up of bilateral stimulation of the subthalamic
nucleus in advanced Parkinsons disease. N Engl J Med
349: 19251934.
 MOTOR AND NON-MOTOR FLUCTUATIONS
Krupp LB, Pollina DA (1996). Mechanisms and manage-
ment of fatigue in progressive neurological disorders. Curr
Opin Neurol 9: 456460.
Kumar R, Lozano AM, Kim YJ et al. (1998). Double-blind
evaluation of subthalamic nucleus deep brain stimulation
in advanced Parkinsons disease. Neurology 51: 850855.
Kumar R, Lang AE, Rodriguez-Oroz MC et al. (2000). Deep
brain stimulation of the globus pallidus pars interna in
advanced Parkinsons disease. Neurology 55 (12 Suppl 6):
S34S39.
Kurlan R (2004). Disabling repetitive behaviors in Parkinsons
disease. Mov Disord 19: 433437.
Kurlan R, Rubin AJ, Miller C et al. (1986). Duodenal deliv-
ery of levodopa for on-off fluctuations in parkinsonism:
preliminary observations. Ann Neurol 20: 262265.
Kurth MC, Tetrud JW, Irwin I et al. (1993a). Oral levodopa/
carbidopa solution versus tablets in Parkinsons patients
with severe fluctuations: a pilot study. Neurology 43:
10361039.
Kurth MC, Tetrud JW, Tanner CM et al. (1993b). Double-
blind, placebo-controlled, crossover study of duodenal infu-
sion of levodopa/carbidopa in Parkinsons disease patients
with on-off fluctuations. Neurology 43: 16981703.
Kurth MC, Adler CH, Hilaire MS et al. (1997). Tolcapone
improves motor function and reduces levodopa require-
ment in patients with Parkinsons disease experiencing
motor fluctuations: a multicenter, double-blind, rando-
mized, placebo-controlled trial. Tolcapone Fluctuator
Study Group I. Neurology 48: 8187.
Lagrange E, Krack P, Moro E et al. (2002). Bilateral subtha-
lamic nucleus stimulation improves health-related quality
of life in PD. Neurology 59: 19761978.
Lang AE, Johnson K (1987). Akathisia in idiopathic Parkin-
sons disease. Neurology 37: 477481.
Lang AE, Lozano AM (1998). Parkinsons disease. First of
two parts. N Engl J Med 339: 10441053.
Langston JW, Forno LS (1978). The hypothalamus in Parkin-
son disease. Ann Neurol 3: 129133.
Lawrence AD, Evans AH, Lees AJ (2003). Compulsive use
of dopamine replacement therapy in Parkinsons disease:
reward systems gone awry? Lancet Neurol 2: 595604.
Leenders KL, Poewe WH, Palmer AJ et al. (1986). Inhibition
of L-[18F]fluorodopa uptake into human brain by amino
acids demonstrated by positron emission tomography.
Ann Neurol 20: 258262.
Lees AJ (1987). A sustained-release formulation of L-dopa
(Madopar HBS) in the treatment of nocturnal and early-
morning disabilities in Parkinsons disease. Eur Neurol
27 (Suppl 1): 126134.
Lees AJ (1989). The on-off phenomenon. J Neurol Neurosurg
Psychiatry (Suppl) Jun: 2937.
Lees AJ (1993). Dopamine agonists in Parkinsons disease: a
look at apomorphine. Fundam Clin Pharmacol 7 (34):
121128.
Lees AJ, Shaw KM, Kohout LJ et al. (1977). Deprenyl in
Parkinsons disease. Lancet 2 (8042): 791795.
Lees AJ, Shaw KM, Stern GM (1978). Baclofen in Parkin-
sons disease. J Neurol Neurosurg Psychiatry 41: 707708.
179
LeWitt PA, Burns RS, Newman RP (1986). Dystonia in
untreated parkinsonism. Clin Neuropharmacol 9: 293297.
Lieberman A, Gopinathan G, Miller E et al. (1990). Rando-
mized double-blind cross-over study of Sinemet-controlled
release (CR4 50/200) versus Sinemet 25/100 in Parkinsons
disease. Eur Neurol 30: 7578.
Lieberman A, Imke S, Muenter M et al. (1993). Multicenter
study of cabergoline, a long-acting dopamine receptor agonist,
in Parkinsons disease patients with fluctuating responses to
levodopa/carbidopa. Neurology 43: 19811984.
Limousin P, Krack P, Pollak P et al. (1998). Electrical stimu-
lation of the subthalamic nucleus in advanced Parkinsons
disease. N Engl J Med 339: 11051111.
Loher TJ, Burgunder JM, Pohle T et al. (2002). Long-term
pallidal deep brain stimulation in patients with advanced
Parkinson disease: 1-year follow-up study. J Neurosurg
96: 844853.
Luquin MR, Scipioni O, Vaamonde J et al. (1992). Levodo-
pa-induced dyskinesias in Parkinsons disease: clinical and
pharmacological classification. Mov Disord 7: 117124.
MacMahon DG, Sachdev D, Boddie HG et al. (1990). A
comparison of the effects of controlled-release levodopa
(Madopar CR) with conventional levodopa in late Par-
kinsons disease. J Neurol Neurosurg Psychiatry 53:
220223.
Mancini F, Zangaglia R, Cristina S et al. (2003). Double-
blind placebo controlled study to evaluate the efficacy
and safety of botulinum toxin type A in the treatment of
drooling in parkinsonism. Mov Disord 18: 685688.
Manford M, Andermann F (1998). Complex visual halluci-
nations. Clinical and neurobiological insights. Brain 121:
18191840.
Manson AJ, Katzenschlager R, Hobart J et al. (2001). High
dose naltrexone for dyskinesias induced by levodopa.
J Neurol Neurosurg Psychiatry 70: 554556.
Manson AJ, Turner K, Lees AJ (2002). Apomorphine mono-
therapy in the treatment of refractory motor complications
of Parkinsons disease: long-term follow-up study of 64
patients. Mov Disord 17: 12351241.
Maricle RA, Nutt JG, Valentine RJ et al. (1995). Dose-response
relationship of levodopa with mood and anxiety in fluctuat-
ing Parkinsons disease: a double-blind, placebo-controlled
study. Neurology 45: 17571760.
Marras C, Lang AE (2003). Measuring motor complications
in clinical trials for early Parkinsons disease. J Neurol
Neurosurg Psychiatry 74: 143146.
Marsden CD (1994). Parkinsons disease. J Neurol Neuro-
surg Psychiatry 57: 672681.
Marsden CD, Parkes JD (1976). On-off effects in patients
with Parkinsons disease on chronic levodopa therapy.
Lancet 1: 292296.
Marsden CD, Parkes JD (1977). Success and problems of
long-term levodopa therapy in Parkinsons disease. Lancet
1 (8007): 345349.
Marsden CD, Parkes JD, Quinn N (1982). Fluctuations of dis-
ability in Parkinsons diseaseclinical aspects. In: CD
Marsden, S Fahn (Eds.), Movement Disorders. Butterworth
Scientific, London, pp. 96122.
180 S. H. FOX AND A. E. LANG
Mathers SE, Kempster PA, Law PJ et al. (1989). Anal
sphincter dysfunction in Parkinsons disease. Arch Neurol
46: 10611064.
Mathias CJ, Kimber JR (1998). Treatment of postural hypo-
tension. J Neurol Neurosurg Psychiatry 65: 285289.
Matison R, Mayeux R, Rosen J et al. (1982). Tip-of-the-
tongue phenomenon in Parkinson disease. Neurology 32:
567570.
McKeith IG, Galasko D, Kosaka K et al. (1996). Consensus
guidelines for the clinical and pathologic diagnosis of demen-
tia with Lewy bodies (DLB): report of the consortium on
DLB international workshop. Neurology 47: 11131124.
Meco G, Bonifati V, Bedini L et al. (1991). Relations
between on-off phenomena and cognitive functions in
Parkinson disease. Ital J Neurol Sci 12: 5762.
Melamed E (1979). Early morning dystonia. A late side effect
of long-term levodopa therapy in Parkinsons disease. Arch
Neurol 36: 308310.
Melamed E, Bitton V (1984). Delayed onset of responses to
individual doses of L-dopa in parkinsonian fluctuators:
an additional side effect of long-term L-dopa therapy.
Neurology 34 (Suppl 2): 270.
Melamed E, Hefti F, Wurtman RJ (1980). Nonaminergic
striatal neurons convert exogenous L-dopa to dopamine
in parkinsonism. Ann Neurol 8: 558563.
Meltzer HY (1992). The importance of serotonin-dopamine
interactions in the action of clozapine. Br J Psychiatry
Suppl 17: 2229.
Menza MA, Sage J, Marshall E et al. (1990). Mood changes
and on-off phenomena in Parkinsons disease. Mov Disord
5: 148151.
Merello M, Lees AJ (1992). Beginning-of-dose motor dete-
rioration following the acute administration of levodopa
and apomorphine in Parkinsons disease. J Neurol Neuro-
surg Psychiatry 55: 10241026.
Merims D, Shabtai H, Korczyn AD et al. (2004). Antiparkin-
sonian medication is not a risk factor for the development
of hallucinations in Parkinsons disease. J Neural Transm
111: 14471453.
Mohr E, Fabbrini G, Williams J et al. (1989). Dopamine and
memory function in Parkinsons disease. Mov Disord
4: 113120.
Molina JA, Sainz-Artiga MJ, Fraile A et al. (2000). Pathologic
gambling in Parkinsons disease: a behavioral manifestation
of pharmacologic treatment? Mov Disord 15: 869872.
Molinuevo JL, Valldeoriola F, Tolosa E et al. (2000). Levo-
dopa withdrawal after bilateral subthalamic nucleus
stimulation in advanced Parkinson disease. Arch Neurol
57: 983988.
Montastruc JL, Rascol O, Senard JM et al. (1991). Sublingual
apomorphine in Parkinsons disease: a clinical and phar-
macokinetic study. Clin Neuropharmacol 14: 432437.
Moro E, Scerrati M, Romito LM et al. (1999). Chronic
subthalamic nucleus stimulation reduces medication
requirements in Parkinsons disease. Neurology 53: 8590.
Moro E, Esselink RJ, Benabid AL et al. (2002). Response to
levodopa in parkinsonian patients with bilateral subthala-
mic nucleus stimulation. Brain 125: 24082417.
Moskovitz C, Moses H 3rd, Klawans HL (1978). Levodopa-
induced psychosis: a kindling phenomenon. Am J Psychiatry
135: 669675.
Mouradian MM, Juncos JL, Fabbrini G et al. (1988). Motor
fluctuations in Parkinsons disease: central pathophysiolo-
gical mechanisms, Part II. Ann Neurol 24: 372378.
Movement Disorder Society Task Force on Rating Scales for
Parkinsons Disease (2003). The Unified Parkinsons
Disease Rating Scale (UPDRS): status and recommenda-
tions. Mov Disord 18: 738750.
Muenter MD, Tyce GM (1971). L-dopa therapy of Parkin-
sons disease: plasma L-dopa concentration, therapeutic
response, and side effects. Mayo Clin Proc 46: 231239.
Muenter MD, Sharpless NS, Tyce GM et al. (1977). Patterns of
dystonia (I-D-I and D-I-D-) in response to I-dopa therapy
in Parkinsons disease. Mayo Clin Proc 52: 163174.
Muller T, Woitalla D, Schulz D et al. (2000). Tolcapone
increases maximum concentration of levodopa. J Neural
Transm 107: 113119.
Myllyla VV, Kultalahti ER, Haapaniemi H et al. (2001). FILO-
MEN Study Group. Twelve-month safety of entacapone in
patients with Parkinsons disease. Eur J Neurol 8: 5360.
Nausieda PA, Weiner WJ, Kaplan LR et al. (1982). Sleep
disruption in the course of chronic levodopa therapy: an
early feature of the levodopa psychosis. Clin Neurophar-
macol 5: 183194.
Ng KY, Colburn RW, Kopin IJ (1971). Effects of L-dopa on
efflux of cerebral monoamines from synaptosomes. Nature
230: 331332.
Nissenbaum H, Quinn NP, Brown RG et al. (1987). Mood
swings associated with the on-off phenomenon in
Parkinsons disease. Psychol Med 17: 899904.
Nutt JG (1990). Levodopa-induced dyskinesia:review, obser-
vation and speculations. Neurology 40: 340345.
Nutt JG, Fellman JH (1984). Pharmacokinetics of levodopa.
Clin Neuropharmacol 7: 3549.
Nutt JG, Holford NH (1996). The response to levodopa in
Parkinsons disease:imposing pharmacological law and
order. Ann Neurol 39: 561573.
Nutt JG, Nygaard TG (2001). Response to L-DOPA in
DOPA-responsive dystonia. Arch Neurol 58 (6): 905910.
Nutt JG, Woodward WR, Hammerstad JP et al. (1984). The
on-off phenomenon in Parkinsons disease. Relation to
levodopa absorption and transport. N Engl J Med 310:
483488.
Nutt JG, Gancher ST, Woodward WR (1988). Does an inhi-
bitory action of levodopa contribute to motor fluctuations?
Neurology 38: 15531557.
Nutt JG, Woodward WR, Carter JH et al. (1992). Effect of
long-term therapy on the pharmacodynamics of levodopa.
Relation to on-off phenomenon. Arch Neurol 49: 11231130.
Nutt JG, Woodward WR, Beckner RM et al. (1994). Effect
of peripheral catechol-O-methyltransferase inhibition on
the pharmacokinetics and pharmacodynamics of levodopa
in parkinsonian patients. Neurology 44: 913919.
Nutt JG, Carter JH, Lea ES et al. (1997). Motor fluctuations
during continuous levodopa infusions in patients with
Parkinsons disease. Mov Disord 12: 285292.
 MOTOR AND NON-MOTOR FLUCTUATIONS
Nutt JG, Obeso JA, Stocchi F (2000). Continuous dopamine-
receptor stimulation in advanced Parkinsons disease.
Trends Neurosci 23 (10 Suppl): S109S115.
Nutt JG, Carter JH, Lea ES et al. (2002). Evolution of the
response to levodopa during the first 4 years of therapy.
Ann Neurol 51: 686693.
Nyholm D, Nilsson Remahl AI, Dizdar N et al. (2005).
Duodenal levodopa infusion monotherapy vs oral
polypharmacy in advanced Parkinson disease. Neurology
64: 216223.
Obeso JA, Rodriguez-Oroz MC, Chana P et al. (2000a). The
evolution and origin of motor complications in Parkin-
sons disease. Neurology 55 (11 Suppl 4): S13S20.
Obeso JA, Rodriguez-Oroz MC, Rodriguez M et al. (2000a).
Pathophysiology of the basal ganglia in Parkinsons
disease. Trends Neurosci 23 (10 Suppl): S8S19.
Oh JD, Vaughan CL, Chase TN (1999). Effect of dopamine
denervation and dopamine agonist administration on ser-
ine phosphorylation of striatal NMDA receptor subunits.
Brain Res 821: 433442.
Olanow CW, Koller WC (1998). An algorithm (decision
tree) for the management of Parkinsons disease: treatment
guidelines. American Academy of Neurology. Neurology
50 (3 Suppl 3): S1S57.
Olanow CW, Fahn S, Muenter M et al. (1994). A multicenter
double-blind placebo-controlled trial of pergolide as an
adjunct to Sinemet in Parkinsons disease. Mov Disord
9: 4047.
Olanow CW, Hauser RA, Gauger L et al. (1995). The effect
of deprenyl and levodopa on the progression of Parkin-
sons disease. Ann Neurol 38: 771777.
Olanow CW, Damier P, Goetz CG et al. (2004). Multicenter,
open-label, trial of sarizotan in Parkinson disease patients
with levodopa-induced dyskinesias (the SPLENDID
Study). Clin Neuropharmacol 27: 5862.
Ondo WG, Hunter C, Moore W (2004). A double-blind
placebo-controlled trial of botulinum toxin B for sialor-
rhea in Parkinsons disease. Neurology 62: 3740.
Pacchetti C, Albani G, Martignoni E et al. (1995). Off
painful dystonia in Parkinsons disease treated with botuli-
num toxin. Mov Disord 10: 333336.
Papa SM, Chase TN (1996). Levodopa-induced dyskinesias
improved by a glutamate antagonist in Parkinsonian mon-
keys. Ann Neurol 39: 574578.
Papa SM, Engber TM, Kask AM et al. (1994). Motor fluc-
tuations in levodopa treated parkinsonian rats: relation to
lesion extent and treatment duration. Brain Res 662:
6974.
Papa SM, Boldry RC, Engber TM et al. (1995). Reversal of
levodopa-induced motor fluctuations in experimental
parkinsonism by NMDA receptor blockade. Brain Res
701: 1318.
Pappert EJ, Goetz CG, Niederman FG et al. (1999). Hallucina-
tions, sleep fragmentation, and altered dream phenomena in
Parkinsons disease. Mov Disord 14: 117121.
Parkinson Study Group (1997). Entacapone improves motor
fluctuations in levodopa-treated Parkinsons disease
patients. Ann Neurol 42: 747755.
181
Parkinson Study Group (2003). A controlled trial of rotigotine
monotherapy in early Parkinsons disease. Arch Neurol 60:
17211728.
Parkinson Study Group (2005). A randomized placebo-con-
trolled trial of rasagiline in levodopa-treated patients with
Parkinson disease and motor fluctuations: the PRESTO
study. Arch Neurol 62: 241248.
Pearce RK, Heikkila M, Linden IB et al. (2001). L-dopa
induces dyskinesia in normal monkeys: behavioural and
pharmacokinetic observations. Psychopharmacology
(Berl) 156: 402409.
Peppe A, Pierantozzi M, Bassi A et al. (2004). Stimulation of
the subthalamic nucleus compared with the globus pallidus
internus in patients with Parkinson disease. J Neurosurg
101: 195200.
Pfeiffer RF, Sucha EL (1989). On-off-induced lethal
hyperthermia. Mov Disord 4: 338341.
Piccini P, Weeks RA, Brooks DJ (1997). Alterations in opioid
receptor binding in Parkinsons disease patients with levo-
dopa-induced dyskinesias. Ann Neurol 42: 720726.
Picconi B, Centonze D, Hakansson K et al. (2003). Loss of
bidirectional striatal synaptic plasticity in L-DOPA-
induced dyskinesia. Nat Neurosci 6: 501506.
Pincus JH, Barry K (1987). Influence of dietary protein on
motor fluctuations in Parkinsons disease. Arch Neurol
44: 270272.
Pinter MM, Pogarell O, Oertel WH (1999). Efficacy, safety,
and tolerance of the non-ergoline dopamine agonist prami-
pexole in the treatment of advanced Parkinsons disease:
a double blind, placebo controlled, randomised, multicentre
study. J Neurol Neurosurg Psychiatry 66: 436441.
Pluck GC, Brown RG (2002). Apathy in Parkinsons disease.
J Neurol Neurosurg Psychiatry 73: 636642.
Poewe W (2003). Psychosis in Parkinsons disease. Mov
Disord 18 (Suppl 6): S80S87.
Poewe W, Hogl B (2004). Akathisia, restless legs and periodic
limb movements in sleep in Parkinsons disease. Neurology
63 (8 Suppl 3): S12S16.
Poewe W, Berger W, Benke T et al. (1991). High-speed
memory scanning in Parkinsons disease: adverse effects
of levodopa. Ann Neurol 29: 670673.
Poewe WH, Lees AJ, Stern GM (1988). Dystonia in Parkin-
sons disease: clinical and pharmacological features. Ann
Neurol 23: 7378.
Poewe WH, Deuschl G, Gordin A et al. (2002). Celomen
Study Group. Efficacy and safety of entacapone in Parkin-
sons disease patients with suboptimal levodopa response:
a 6-month randomized placebo-controlled double-blind
study in Germany and Austria (Celomen study). Acta
Neurol Scand 105: 245255.
Priano L, Albani G, Brioschi A et al. (2004). Transdermal
apomorphine permeation from microemulsions: a new
treatment in Parkinsons disease. Mov Disord 19: 937942.
Quattrone A, Zappia M, Aguglia U et al. (1995). The suba-
cute levodopa test for evaluating long-duration response
in Parkinsons disease. Ann Neurol 38: 389395.
Quinn N, Marsden CD (1986). Lithium for painful dystonia
in Parkinsons disease. Lancet 1: 1377.
182 S. H. FOX AND A. E. LANG
Quinn NP (1998). Classification of fluctuations in patients
with Parkinsons disease. Neurology 51 (2 Suppl 2):
S25S29.
Quinn NP, Koller WC, Lang AE et al. (1986). Painful Par-
kinsons disease. Lancet 1 (8494): 13661369.
Rabey JM, Sagi I, Huberman M et al. (2000). Rasagiline
Study Group. Rasagiline mesylate, a new MAO-B inhibi-
tor for the treatment of Parkinsons disease: a double-blind
study as adjunctive therapy to levodopa. Clin Neurophar-
macol 23: 324330.
Racette BA, Hartlein JM, Hershey T et al. (2002). Clinical
features and comorbidity of mood fluctuations in Parkinsons
disease. J Neuropsychiatry Clin Neurosci 14: 438442.
Rajput AH, Martin W, Saint-Hilaire MH et al. (1997). Tolca-
pone improves motor function in parkinsonian patients with
the wearing-off phenomenon: a double-blind, placebo-
controlled, multicenter trial. Neurology 49: 10661071.
Rajput AH, Fenton ME, Di Paolo T et al. (2004). Human
brain dopamine metabolism in levodopa-induced dyskinesia
and wearing-off. Parkinsonism Relat Disord 10: 221226.
Rascol O, Fabre N, Blin O et al. (1994). Naltrexone, an opi-
ate antagonists, fails to modify motor symptoms in
patients with Parkinsons disease. Mov Disord 9: 437440.
Rascol O, Lees AJ, Senard JM et al. (1996). Ropinirole in
the treatment of levodopa-induced motor fluctuations in
patients with Parkinsons disease. Clin Neuropharmacol
19: 234245.
Rascol O, Brooks DJ, Korczyn AD et al. (2000). A five-year
study of the incidence of dyskinesia in patients with early
Parkinsons disease who were treated with ropinirole or
levodopa. 056 Study Group. N Engl J Med 342:
14841491.
Raudino F (2001). Non motor off in Parkinsons disease.
Acta Neurol Scand 104: 312315.
Reuter I, Ellis CM, Ray Chaudhuri K (1999). Nocturnal sub-
cutaneous apomorphine infusion in Parkinsons disease
and restless legs syndrome. Acta Neurol Scand 100:
163167.
Richard IH, Frank S, McDermott MP et al. (2004). The ups
and downs of Parkinson disease: a prospective study of
mood and anxiety fluctuations. Cogn Behav Neurol 17:
201207.
Riederer P, Youdim MB (1986). Monoamine oxidase acti-
vity and monoamine metabolism in brains of parkinsonian
patients treated with l-deprenyl. J Neurochem 46:
13591365.
Riley DE, Lang AE (1993). The spectrum of levodopa-
related fluctuations in Parkinsons disease. Neurology 43:
14591464.
Rinne JO, Laihinen A, Lonnberg P et al. (1991). A post-mor-
tem study on striatal dopamine receptors in Parkinsons
disease. Brain Res 556: 117122.
Ruottinen HM, Rinne UK (1996a). Effect of one months
treatment with peripherally acting catechol-O-methyl-
transferase inhibitor, entacapone, on pharmacokinetics
and motor response to levodopa in advanced parkinsonian
patients. Clin Neuropharmacol 19: 222233.
Ruottinen HM, Rinne UK (1996b). Entacapone prolongs
levodopa response in a one month double blind study in
parkinsonian patients with levodopa related fluctuations.
J Neurol Neurosurg Psychiatry 60: 3640.
Sage JI (2004). Pain in Parkinsons disease. Curr Treat
Options Neurol 6: 191200.
Sage JI, Mark MH (1995). Drenching sweats as an off phe-
nomenon in Parkinsons disease: treatment and relation
to plasma levodopa profile. Ann Neurol 37: 120122.
Sage JI, Trooskin S, Sonsalla PK et al. (1988). Long-term
duodenal infusion of levodopa for motor fluctuations in
parkinsonism. Ann Neurol 24: 8789.
Sage JI, Kortis HI, Sommer W (1990). Evidence for the role
of spinal cord systems in Parkinsons disease-associated
pain. Clin Neuropharmacol 13: 171174.
Saint-Cyr JA, Taylor AE, Lang AE (1993). Neuropsychological
and psychiatric side effects in the treatment of Parkinsons
disease. Neurology 43 (12 Suppl 6): S47S52.
Samadi P, Gregoire L, Bedard PJ (2003). Opioid antagonists
increase the dyskinetic response to dopaminergic agents in
parkinsonian monkeys: interaction between dopamine and
opioid systems. Neuropharmacology 45: 954963.
Sanchez-Ramos JR, Ortoll R, Paulson GW (1996). Visual
hallucinations associated with Parkinson disease. Arch
Neurol 53: 12651268.
Schrag A, Ben-Shlomo Y, Quinn N (2002). How common are
complications of Parkinsons disease? J Neurol 249: 419423.
Seager H (1997). Drug delivery products and the Zydis fast-
dissolving dosage form. J Pharm Pharmacol 50: 375382.
Seif C, Herzog J, van der Horst C et al. (2004). Effect of
subthalamic deep brain stimulation on the function of the
urinary bladder. Ann Neurol 55: 118120.
Senard JM, Rai S, Lapeyre-Mestre M et al. (1997). Preva-
lence of orthostatic hypotension in Parkinsons disease.
J Neurol Neurosurg Psychiatry 63: 584589.
Shoulson I, Glaubiger GA, Chase TN (1975). On-off
response. Clinical and biochemical correlations during
oral and intravenous levodopa administration in parkinso-
nian patients. Neurology 25: 11441148.
Shulman LM, Taback RL, Bean J et al. (2001). Comorbidity
of the nonmotor symptoms of Parkinsons disease. Mov
Disord 16: 507510.
Siemers ER, Shekhar A, Quaid K et al. (1993). Anxiety and
motor performance in Parkinsons disease. Mov Disord 8:
501506.
Sieradzan KA, Fox SH, Hill M et al. (2001). Cannabinoids
reduce levodopa-induced dyskinesia in Parkinsons
disease: a pilot study. Neurology 57: 21082111.
Silverdale MA, Fox SH, Crossman AR et al. (2003). Potential
nondopaminergic drugs for Parkinsons disease. Adv
Neurol 91: 273291.
Simon N, Gantcheva R, Bruguerolle B et al. (2004). The
effects of a normal protein diet on levodopa plasma
kinetics in advanced Parkinsons disease. Parkinsonism
Relat Disord 10: 137142.
Snider SR, Fahn S, Isgreen WP et al. (1976). Primary sen-
sory symptoms in parkinsonism. Neurology 26: 423429.
 MOTOR AND NON-MOTOR FLUCTUATIONS
Stacy M, Bowron A, Guttman M et al. (2005). Identification
of motor and nonmotor wearing-off in Parkinsons
disease: comparison of a patient questionnaire versus a
clinician assessment. Mov Disord 20 (6): 726733.
Steiger MJ, Quinn NP, Toone B et al. (1991). Off-period
screaming accompanying motor fluctuations in Parkin-
sons disease. Mov Disord 6: 8990.
Stein WM, Read S (1997). Chronic pain in the setting of
Parkinsons disease and depression. J Pain Symptom
Manage 14: 255258.
Stibe CM, Lees AJ, Kempster PA et al. (1988). Subcutaneous
apomorphine in parkinsonian on-off oscillations. Lancet
1 (8582): 403406.
Stolze H, Klebe S, Poepping M et al. (2001). Effects of bilat-
eral subthalamic nucleus stimulation on parkinsonian gait.
Neurology 57: 144146.
Stocchi F, Quinn NP, Barbato L et al. (1994). Comparison
between a fast and a slow release preparation of levodopa
and a combination of the two: a clinical and pharmacoki-
netic study. Clin Neuropharmacol 17: 3844.
Stocchi F, Nordera G, Marsden CD (1997). Strategies for
treating patients with advanced Parkinsons disease with
disastrous fluctuations and dyskinesias. Clin Neurophar-
macol 20: 95115.
Stocchi F, Vacca L, Berardelli A et al. (2001a). Long-duration
effect and the postsynaptic compartment: study using a
dopamine agonist with a short half-life. Mov Disord 16:
301305.
Stocchi F, Vacca L, De Pandis MF et al. (2001b). Subcuta-
neous continuous apomorphine infusion in fluctuating
patients with Parkinsons disease: long-term results. Neurol
Sci 22: 9394.
Stocchi F, Ruggieri S, Vacca L et al. (2002). Prospective ran-
domized trial of lisuride infusion versus oral levodopa in
patients with Parkinsons disease. Brain 125 (Pt 9):
20582066.
Struck LK, Rodnitzky RL, Dobson JK (1990). Circadian
fluctuations of contrast sensitivity in Parkinsons disease.
Neurology 40: 467470.
Swinn L, Schrag A, Viswanathan R et al. (2003). Sweating
dysfunction in Parkinsons disease. Mov Disord 18:
14591463.
Syed N, Murphy J, Zimmerman TJr et al. (1998). Ten years
experience with enteral levodopa infusions for motor fluc-
tuations in Parkinsons disease. Mov Disord 13: 336338.
Tetrud JW, Koller WC (2004). A novel formulation of sele-
giline for the treatment of Parkinsons disease. Neurology
63 (7 Suppl 2): S2S6.
Togasaki DM, Tan L, Protell P et al. (2001). Levodopa
induces dyskinesias in normal squirrel monkeys. Ann
Neurol 50: 254257.
Torstenson R, Hartvig P, Langstrom B et al. (1997). Differential
effects of levodopa on dopaminergic function in early and
advanced Parkinsons disease. Ann Neurol 41: 334340.
Tracey I, Becerra L, Chang I et al. (2000). Noxious hot and
cold stimulation produce common patterns of brain activa-
tion in humans: a functional magnetic resonance imaging
study. Neurosci Lett 288: 159162.
183
Trosch RM, Friedman JH, Lannon MC et al. (1998). Cloza-
pine use in Parkinsons disease: a retrospective analysis
of a large multicentered clinical experience. Mov Disord
13: 377382.
Turjanski N, Lees AJ, Brooks DJ (1997). In vivo studies on
striatal dopamine D1 and D2 site binding in L-dopa-trea-
ted Parkinsons disease patients with and without dyskine-
sias. Neurology 49: 717723.
Tyne HL, Parsons J, Sinnott A et al. (2004). A 10 year retro-
spective audit of long-term apomorphine use in Parkin-
sons disease. J Neurol 251: 13701374.
Uchiyama T, Sakakibara R, Hattori T et al. (2003). Short-
term effect of a single levodopa dose on micturition distur-
bance in Parkinsons disease patients with the wearing-off
phenomenon. Mov Disord 18: 573578.
van Hilten JJ, Weggeman M, van der Velde EA et al. (1993).
Sleep, excessive daytime sleepiness and fatigue in Parkin-
sons disease. J Neural Transm Park Dis Dement Sect 5:
235244.
Varma TR, Fox SH, Eldridge PR et al. (2003). Deep brain
stimulation of the subthalamic nucleus: effectiveness in
advanced Parkinsons disease patients previously reliant
on apomorphine. J Neurol Neurosurg Psychiatry 74:
170174.
Vazquez A, Jimenez-Jimenez FJ, Garcia-Ruiz P et al. (1993).
Panic attacks in Parkinsons disease. A long-term compli-
cation of levodopa therapy. Acta Neurol Scand 87: 1418.
Velasco M, Luchsinger A (1998). Dopamine: pharmacologic
and therapeutic aspects. Am J Ther 5: 3743.
Verhagen Metman L, Locatelli ER, Bravi D et al. (1997).
Apomorphine responses in Parkinsons disease and the patho-
genesis of motor complications. Neurology 48: 369372.
Verhagen-Metman L, Del Dotto P, van den Munckhof P et al.
(1998). Amantadine as treatment for dyskinesias and motor
fluctuations in Parkinsons disease. Neurology 50:
13231326.
Verhagen Metman L, Konitsiotis S, Chase TN (2000).
Pathophysiology of motor response complications in
Parkinsons disease: hypotheses on the why, where, and
what. Mov Disord 15: 38.
Vincken WG, Gauthier SG, Dollfuss RE et al. (1984). Invol-
vement of upper-airway muscles in extrapyramidal dis-
orders. A cause of airflow limitation. N Engl J Med 311:
438442.
Volkmann J, Allert N, Voges J et al. (2004). Long-term
results of bilateral pallidal stimulation in Parkinsons
disease. Ann Neurol 55: 871875.
Waters CH, Sethi KD, Hauser RA et al. (2004). Zydis
Selegiline Study Group. Zydis selegiline reduces off time
in Parkinsons disease patients with motor fluctuations:
a 3-month, randomized, placebo-controlled study. Mov
Disord 19: 426432.
Wakabayashi K, Takahashi H, Ohama E et al. (1993). Lewy
bodies in the visceral autonomic nervous system in Parkin-
sons disease. Adv Neurol 60: 609612.
Weiner P, Inzelberg R, Davidovich A et al. (2002). Respira-
tory muscle performance and the Perception of dyspnea in
Parkinsons disease. Can J Neurol Sci 29: 6872.
184 S. H. FOX AND A. E. LANG
Winge K, Werdelin LM, Nielsen KK et al. (2004). Effects of
dopaminergic treatment on bladder function in Parkinsons
disease. Neurourol Urodyn 23: 689696.
Witjas T, Kaphan E, Azulay JP et al. (2002). Nonmotor
fluctuations in Parkinsons disease: frequent and disabling.
Neurology 59: 408413.
Yeh KC, August TF, Bush DF et al. (1989). Pharmacoki-
netics and bioavailability of Sinemet CR: a summary of
human studies. Neurology 39 (11 Suppl 2): 2538.
Yoshimura N, Mizuta E, Kuno S et al. (1993). The dopamine
D1 receptor agonist SKF 38393 suppresses detrusor
hyperreflexia in the monkey with parkinsonism induced
by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
Neuropharmacology 32: 315321.
Yoshimura N, Mizuta E, Yoshida O et al. (1998). Therapeutic
effects of dopamine D1/D2 receptor agonists on detrusor
hyperreflexia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-
dine-lesioned parkinsonian cynomolgus monkeys. J Phar-
macol Exp Ther 286: 228233.
Zappia M, Oliveri RL, Montesanti R et al. (1999). Loss of
long-duration response to levodopa over time in PD:
implications for wearing-off. Neurology 52: 763767.
Zenzola A, Masi G, De Mari M et al. (2003). Fatigue in
Parkinsons disease. Neurol Sci 24: 225226.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 40

Levodopa-induced dyskinesias in Parkinsons disease

JOSE A. OBESO1*, MARCELO MERELLO2, MARIA C. RODRIGUEZ-OROZ1, CONCEPCIO MARIN3,

JORGE GURIDI1 AND LAZARO ALVAREZ4

1
Department of Neurology and Neurosurgery, University Clinic and Medical School and Neuroscience Division,
University of Navarra and CIMA, Pamplona, Spain
2
Movement Disorders Section, Raul Carrea Institute for Neurological Research, FLENI, Buenos Aires, Argentina
3
Laboratori de Neurologia Experimental, Fundacio Clnic-Hospital Clnic, Institut dInvestigacions Biomediques August Pi i
Sunyer (IDIBAPS), Hospital Clnic, Barcelona, Spain
4
Movement Disorders Unit, Centro Internacional de Restauracion Neurologica (CIREN), La Habana, Cuba

40.1. Introduction biochemical studies have been conducted with tissue

Hyperkinetic or dyskinetic disorders are characterized
by excessive motor activity that interferes with normal
motor control mechanism. The early literature during
the 1950s and 1960s used the term hyperkinesia
to designate wild involuntary movements like chorea,
ballism, choreoathetosis or action tremor, all of which
are currently embraced under the global denomina-
tion of dyskinesias This comprises chorea and ball-
ism, dystonic movements and postures, myoclonus,
tics and tremor. The capacity for levodopa to induce
involuntary movements (i.e. levodopa-induced dyski-
nesias or LID) never witnessed before in Parkinsons
disease (PD) patients was established soon after its
introduction in the early 1970s (Cotzias et al., 1969;
Barbeau, 1976).
LID are associated with several molecular, biochem-
ical and physiological changes in the basal ganglia
(BG). Among these, molecular and neuronal firing are
the ones that have been studied in greater depth. It has
not yet been possible to decipher which changes
are compensatory, causally linked to LID or induced
as a consequence of the involuntary movements.
Animal models of PD, mainly the 6-hydroxydopamine
(6-OHDA) lesioned rat and the 1-methyl-4-phenyl-
1,2,3,6-tetrayhydropyridine (MPTP)-intoxicated mon-
key, have been used to elicit LID, allowing the study
of biochemical changes and modifications of neuro-
nal firing activity in the BG. More recently, a few
derived from well-characterized PD patients and the
revitalization of surgery has permitted the recording
of BG activity in vivo. Thus, a wealth of information
is now available to put together findings in animal mod-
els and in patients, leading to a more comprehensive
understanding of LID.
This review will generically concentrate on LID but
dopamine agonists are also capable per se of inducing
dyskinesias, as shown in MPTP monkeys and de novo
PD patients.
40.2. Clinical presentation
LID generally occur in patients with motor fluctua-
tions (i.e. wearing-off or end-of-dose deterioration)
and are therefore better described in relation to the
motor state achieved in response to levodopa (Marsden
and Parkes, 1977; Marsden et al., 1981; Obeso et al.,
1989; Fahn, 2000). Accordingly, LID may be divided
into three main groups: (1) peak-dose choreic or dys-
tonic movements; (2) diphasic dyskinesias; and (3)
off-period dystonia. This is a convenient classification
that relates phenomenology (i.e. type of dyskinesia) and
temporal onset with the degree of dopaminergic activity
and motor state (Fig. 40.1), thus allowing the character-
ization of the underlying pharmacological origin of the
dyskinesia by clinical inspection. Admittedly, in a large
proportion of patients, more than one type of LID is

*Correspondence to: Jose A. Obeso, Neurologia, Clinica Universitaria, Avenida Pio XII 36, Pamplona 31180, Spain. E-mail:
jobeso@unav.es, Tel: 34-948-255400, Fax: +34-948-194700.
186 J. A. OBESO ET AL.

Fig. 40.1. Relationship between onset and type of levodopa-induced dyskinesia and the dopaminergic response. Off-period
dystonia and diphasic dyskinesias occur while dopaminergic activity is low and should, therefore, disappear when higher levels
are reached. In contrast, peak-dose chorea is related to excessive dopaminergic stimulation.

present and the assessment and pharmacological solution
are more problematic.
40.2.1. Choreic and dystonic movements
Choreic and dystonic movements occur during the per-
iod of peak plasma level and maximal clinical benefit
(on dyskinesias or peak-dose dyskinesias). On-period
dyskinesias are associated with levodopa in a dose-
related manner. Typically, movements are choreiform
and involve the face, neck and proximal upper limbs.
A smaller proportion of patients exhibit other move-
ment disorders such as ballism, myoclonic jerks and
tic-like movements. Involuntary upward saccadic eye
movements are seen in a minority of patients.
40.2.2. Diphasic dyskinesias
These are repetitive movements, usually of the legs,
that occur at the beginning and end of the levodopa
dose effect (diphasic) and disappear or transform into
a choreic (peak-dose) pattern during the on period
(Muenter et al., 1977). Diphasic dyskinesias are asso-
ciated with low or intermediate levodopa plasma
levels that are insufficient to achieve a full on anti-
parkinonian effect. Labeling and classifying diphasic
dyskinesias have been permanent sources
of confusion. Muenter et al., (1977) applied the term
DID for dystoniaimprovementdystonia but the
movements are also frequently labeled as ballistic or
choreic. In reality, they typically consist of repetitive
stereotypic flexor and extensor movements of the
lower limbs (Fig. 40.2) due to alternating contractions
of agonist and antagonist muscles (Obeso et al., 1989;
Luquin et al., 1992b). This well-established pattern is
incompatible with the definitions of chorea or dysto-
nia. In severe patients, the repetitive pattern of muscle
contraction may become disrupted and reach large
amplitude, giving rise to a more disorganized move-
ment, resembling ballism.
40.2.3. Off-period dystonia
Dystonic postures are due to sustained co-contraction of
agonist and antagonist muscles, twisting the body into
fixed postures. Off-period dystonia commonly consists
of focal dystonic postures of a limb, such as extension
of the foot and big toe or flexion of the toes, but may
also be generalized. Dystonic postures may also have
a diphasic evolution (Luquin et al., 1992b) and may be
the initial manifestation of PD, before treatment is intro-
duced. In fact, dystonic postures in PD were well recog-
nized before levodopa became available. Nowadays,
however, they are more frequently seen and characteris-
tic of off periods and therefore readily subside when
the on response ensues.
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE 187

Fig. 40.2 Phenomenology of diphasic dyskinesias. Movements typically consist of repetitive, kicking of the leg (left). The
characteristic electromyogram pattern, recorded with surface electromyographic electrodes, consists of alternating contraction
of antagonist muscles of the lower limb (right). Note the typical 5 Hz resting tremor in the upper limb. ff, finger flexors; fe,
finger extensors; quad, quadriceps; ham, hamstrings; gastroc, gastronemius; tib ant, tibialis anterior muscles. Modified from
Obeso et al. (1989) and Luquin et al. (1992).

40.2.4. Special presentations 40.2.4.3. Dyskinesias without benefit

There are some special circumstances when the clinical
presentation of LID does not follow the typical patterns
described above (see below).
40.2.4.1. Nocturnal myoclonus
Spontaneous myoclonic jerking of the leg at night occurs
in the normal population but more frequently in patients
with PD treated with dopaminergic drugs and usually
coincides with nightmares and other parasomnias. The
importance of nocturnal myoclonus, besides its potential
inconvenience for the spouse, is that it generally heralds
the beginning of psychiatric complications. It therefore
demands early recognition and treatment.
40.2.4.2. Dyskinesiasparkinsonism
In patients with severe PD who require large doses of
levodopa, motor fluctuations and dyskinesias may not
strictly follow the typical patterns described above. The
combination of one body part exhibiting dyskinesias
while the other half is off is one of the most troublesome
presentations. Typically, the upper half of the body
exhibits dyskinesias and coincidentally the patient is
incapable of walking due to severe freezing of gait.
Dyskinesias without benefit were described in the
1970s and early 1980s but are not so frequently
encountered nowadays. In this situation patients suffer
dyskinetic movements without having the antiparkin-
sonian benefit of levodopa, similar to off dyskine-
sias. However, we believe from our experience with
chronic infusion of dopamine agonists that such pre-
sentation mainly corresponds to diphasic dyskinesias
without the characteristic short-lasting and beginning
and end-of-dose dual presentation.
40.2.4.4. Graft-induced off dyskinesias
This is a new problem in the field of dyskinesias in
PD. Focal or segmental dyskinesias similar to typical
LID have now been reported in two transplantation
studies and were not observed in any of the placebo-
treated patients (Freed et al., 2001; Olanow et al.,
2003). These dyskinesias thus appear to be specifically
related to the grafted cells. Dyskinesias can persist for
days or even weeks following withdrawal of dop-
aminergic medication, hence the use of the term off-
medication dyskinesias. However, careful evaluation
indicates that in fact patients are not really off as com-
pared to their baseline (pregrafting) state. Indeed, in the
188 J. A. OBESO ET AL.
study by Freed et al. (2001), those patients who dev-
eloped dyskinesias after transplantation greatly im-
proved, reaching motor scores comparable to those
present during on dyskinesia. On the other hand, pat-
ients in the study by Olanow et al. (2003) showed a very
modest improvement and the clinical features and evo-
lution of the dyskinesias were more compatible with a
diphasic-like pattern.
40.3. Biochemical and molecular
characteristics
Striatal dopaminergic depletion and the discontinuous
or pulsatile activation associated with levodopa ther-
apy are the two major factors determining the develop-
ment of dyskinesias. Together they induce alterations
in the expression of dopamine receptors and in the vast
majority of neurotransmission systems acting at the
striatal level. The following section summarizes the
major findings.
40.3.1. Dopaminergic receptors
There are five subtypes of dopaminergic receptors
grouped into two main families. D1 and D5 subtypes
constitute the D1 family of dopaminergic receptors
and D2, D3 and D4 subtypes form the D2 family. Many
studies have been focused on possible changes in the
dopaminergic receptors in the striatum of parkinsonian
and dyskinetic PD patients and in a possible differen-
tial role of these receptor subtypes in the genesis of
LID. It has been proposed that LID surges as an imbal-
ance in activity of the two striatal output pathways,
possibly through activation of D1 and inhibition of
D2-receptors on the direct and indirect pathways,
respectively (Obeso et al., 2000b; Bezard et al.,
2001). Despite numerous experimental investigations,
however, a clear relationship between dyskinesia and
D1- or D2-receptor expression is not established.
Numerous studies have shown that dopamine
denervation causes an increase in striatal D2-receptors
in the postmortem tissue of untreated PD patients and
animal models of parkinsonism (Lee et al., 1978;
Bezard et al., 2001; Aubert et al., 2005; Guigoni
et al., 2005a). Chronic levodopa treatment induces a
normalization of the D2-receptor in patients with PD,
as assessed in postmortem tissue (Lee et al., 1978)
and by positron emission tomography (PET) (Brooks
et al., 1992; Shinotoh et al., 1993) and in MPTP
monkeys (Graham et al., 1993; Herrero et al., 1996a).
However, no difference in the expression of D2-receptors
was observed between non-dyskinetic and dyskinetic
groups of MPTP-treated monkeys (Aubert et al., 2005;
Guigoni et al., 2005a).
The D1 subtype of dopamine receptor was found to
be increased in the 6-OHDA rat model (Gerfen et al.,
1990). However, no marked changes induced by levo-
dopa were encountered in MPTP monkeys and PD
patients (Lee et al., 1978; Graham et al., 1993). Recent
findings suggest that LID may be more related to
changes at the level of D1-receptor transmission. There
is now evidence that downstream D1-mediated signal
transduction cascade (Gerfen, 1995) is abnormal in
LID. These include increased phosphorylation of cyclic
adenosine monophosphate-regulated phosphoprotein of
32 kDa (DARPP-32) (Picconi et al., 2003), an increase
in D1-agonist-induced G-protein-coupled receptor
kinases and high levels of cyclin-dependent kinase-5
(Cdk5) (Aubert et al., 2005; Guigoni et al., 2005a). These
data suggest that LID are closely related to augmented
D1-receptor-mediated transmission at the level of the
direct pathway. In addition, D3-receptors may play a
role in LID. This was initially proposed based on the
observation that striatal expression of this receptor is
highly dependent on afferent dopamine innervation
(Sokoloff et al., 1990; Levesque et al., 1995). Thus,
D3-receptor expression is reduced in the striatum of
parkinsonian rats and in the caudate nucleus of MPTP
monkeys (Levesque et al., 1995; Bordet et al., 1997).
Levodopa compensates for this reduction (Morissette
et al., 1998; Quik et al., 2000, Bezard et al., 2003) but
D3 putaminal receptors are only increased in animals
that developed LID (Bordet et al., 2000; Bezard et al.,
2003). Importantly, the overexpression of D3-receptor
was confined to medium spiny striatal neurons, giving
rise to the direct striatopallidal projection (Bordet
et al., 2000). These findings have led to suggest an
important role of D3 activation and the direct pathway
in the pathophysiology of dyskinesias. On the other
hand, other studies have failed to define significant
abnormalities of D3-receptors in LID in both the MPTP
monkey model (Hurley et al., 1996a) and PD patients
(Hurley et al., 1996b) and pharmacological studies
using the partial D3-agonist BP 897 induced reduction
of LID, but at the expense of increased parkinsonism
(Hsu et al., 2004).
40.3.2. Glutamatergic receptors
Striatal medium spiny output neurons receive massive
glutamatergic inputs from the cerebral cortex and the
thalamus and are the site of close interaction between
dopamine and glutamate receptors (Calabresi et al.,
2000). Accordingly, striatal glutamate receptors have
been suspected to be implicated in the development of
LID (Chase and Oh, 2000; Calabresi et al., 2000; Calon
et al., 2002). The actions of glutamate on target neurons
are mediated by four classes of receptors: three types
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
of channel-forming ionotropic receptors and one group
of metabotropic, or G-protein-coupled, glutamate recep-
tors (Hollmann and Heinemann, 1994; Dingledine et al.,
1999).
40.3.2.1. Glutamatergic ionotropic receptors
In the striatum, the majority of fast excitatory synaptic
transmission is mediated by ionotropic glutamate recep-
tors, which are ligand-gated ion channels. These recep-
tors are named according to the synthetic agonists that
are most effective in activating them and classified into
N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-
methylisoxasole-4-propionate (AMPA) and kainate
receptors (Dingledine et al., 1999). Striatal dopamine
depletion increases the concentration and release of glu-
tamate from corticostriatal terminals (Lindefors and
Ungerstedt, 1990) but neither intrinsic membrane prop-
erties nor the response to exogenous application of glu-
tamate agonists are altered in medium spiny neurons
(Calabresi et al., 1993, 2000).
40.3.2.1.1. NMDA receptors
NMDA receptors are the more densely expressed sub-
type in the striatum and their synaptic localization
appears to be exclusively on the dendritic spines of
the medium spiny gamma-aminobutyric acid (GABA)-
ergic neurons. The NMDA receptor is a heterodimeric
protein essentially composed of two distinct subunits,
namely NR1 and NR2 (Monyer et al., 1992). The
expression of at least one NR1 subunit is required to
form a functional channel and the combinations of dis-
tinct NR1 and NR2 subunits confer diversity of NMDA
receptors. In the striatum, the NMDA receptor subtype
containing NR2B is predominantly present (Standaert
et al., 1994).
Dopamine depletion in animal models (6-OHDA
and MPTP monkeys) induces a redistribution of
NMDA receptor subunits in two biochemical separate
compartments. Thus, in unfractionated homogenates
prepared from striatal tissue, the abundance of NR1,
NR2A and NR2B subunit proteins was unchanged
(Menegoz et al., 1995; Dunah et al., 2000; Calon
et al., 2002) or minimally increased for the NR2A sub-
unit proteins (Oh et al., 1997). In contrast, in striatal
synaptosomal membrane fractions, dopamine deple-
tion results in decreased NR1 and NR2B subunits
(Dunah et al., 2000; Hallett et al., 2005) and no change
in the NR2A subunit. It has been suggested that an
underlying mechanism for this distribution may be a
rapid D1-receptor- and tyrosine kinase-dependent traf-
ficking system, which regulates delivery of NMDA
receptor to synaptic sites in striatal neurons (Dunah
et al., 2004).
189
Chronic levodopa treatment in 6-OHDA-lesioned
rats, eliciting behavioral sensitization, increases NR1,
NR2A and NR2B subunits in homogenate and synap-
tosomal membrane fractions (Oh et al., 1997; Dunah
et al., 2000; Dunah and Standaert, 2001). In MPTP
monkeys, levodopa treatment causing dyskinesias
restored or increased the NR2B levels in synaptosomal
membranes but in addition increased the abundance of
the NR2A subunit (Calon et al., 2002; Hallett et al.,
2005). Similar studies from postmortem tissue of
patients (treated chronically with levodopa) showed
unchanged (Calon et al., 2003a) or increased (Lange
et al., 1997) NR2A binding and increased NR2B
binding (Calon et al., 2003a).
Phosphorylation of ion channels plays a role in
mediating synaptic plasticity and serves to increase
molecular and functional heterogeneity of NMDA
receptors (Betarbet et al., 2004). In animal studies
there is a controversy over the phosphorylation state
of these receptors either in the parkinsonian state or
in the levodopa-treated condition. Thus, a number of
changes in the rat parkinsonian model, such as
increase in the proportion of NR2B subunits that are
tyrosine-phosphorylated (Menegoz et al., 1995; Oh
et al., 1997), reduced serine phosphorylation of NR1
subunit (Dunah et al., 2000) or increased serine phos-
phorylation of NR2A but not NR2B receptor subunit
(Oh et al., 1997), have been described. Chronic levo-
dopa treatment enhanced serine phosphorylation of
NR1 and NR2A subunits and increasing tyrosine phos-
phorylation of NR2A and NR2B subunits (Oh et al.,
1997; Dunah et al., 2000). However, these alterations
have not been confirmed in parkinsonian MPTP and
dyskinetic monkeys (Hallett et al., 2005).
The efficacy of antagonists of the NMDA receptors
in animal models of PD has been widely examined.
These studies have revealed the ability of NMDA-
receptor blockade to alleviate the symptoms of parkin-
sonism and augment the effectiveness of dopaminergic
therapy preventing or reversing the induction of LID.
For example, the competitive antagonist LY345959
and the NR2B-selective antagonists Co101244 and
CI-1041 administered as coadjutants to levodopa
diminished LID (Papa and Chase, 1996; Blanchet
et al., 1999; Had Tahar et al., 2004) and CI-1041
prevented the development of LID in MPTP monkeys
(Morissette et al., 2006).
In summary, NMDA receptor subunit expression is
altered in both the parkinsonian and dyskinetic states
in the MPTP monkey model and PD patients. These
changes may mediate a putative deregulation of corti-
costriatal activity underlying LID. The involvement of
D1 dopamine receptor activation in the cascade of
intracellular changes summarized above and the fact
190 J. A. OBESO ET AL.
that the NR2A subtype of receptor is mostly expressed
in striatal neurons projecting to the substantia nigra
pars reticulata (SNpr) in the rat are in keeping with
the suggested pivotal role of the direct pathway in
the pathophysiology of LID (Bezard et al., 2003;
Aubert et al., 2005).
40.3.2.1.2. AMPA receptors
The role of AMPA receptors in LID is still controver-
sial. AMPA receptors in the striatum of MPTP monkeys
with LID have been reported as normal (Silverdale
et al., 2002) or moderately increased (Calon et al.,
2002). No alterations were found in the abundance of
striatal GluR2/3 AMPA receptor subunits in synaptoso-
mal membrane fractions following MPTP lesion and
repeated levodopa treatment (Hallett et al., 2005). The
absence of changes in AMPA receptor subunit proteins
in monkeys confirmed previous studies in 6-OHDA-
lesioned rats (Dunah et al., 2000; Picconi et al., 2004).
In postmortem tissue from levodopa-treated parkinso-
nian patients, no change of AMPA binding was
observed (Ulas et al., 1994) but recently, a small eleva-
tion in AMPA receptors restricted to the lateral putamen
has been reported (Calon et al., 2003a). The notion that
AMPA receptor-mediated mechanisms are involved in
LID is further suggested by the observation that
AMPA-receptor antagonists can reduce the expression
of LID when administered as an adjuvant to levodopa
in the MPTP monkeys (Konitsiotis et al., 2000).
40.3.2.2. Glutamatergic metabotropic receptors
In contrast to ionotropic glutamate receptors, the meta-
botropic glutamate receptors (mGluRs) are coupled to
second-messenger systems through G-proteins. They
have been classified into three groups: group I (mGluR1
and mGluR5), group II (mGluR2 and mGluR3) and
group III (mGluR4, 6, 7 and 8) and have been identified
in the striatum. In particular, group I mGluRs have been
localized throughout the whole striatum at postsynaptic
level, whereas group II and III mGluRs have been found
at presynaptic level of corticostriatal terminals (Pisani
et al., 2002). Indeed, induction of plastic changes in cor-
ticostriatal synapse depends upon activation of metabo-
tropic receptors. In particular, long-term potentiation
(LTP) is partially mediated by mGluR1 and mGluR5
(Gubellini et al., 2004) and the activation of mGluR2/
3 is required for inducing long-term depression (LTD)
(Sung et al., 2001). The meaning of these physiological
changes with respect to LID is discussed in more detail
in section 40.4 below.
The experimental evidence suggests that metabotro-
pic receptors represent another important point in the
regulation of the excessive corticostriatal glutamatergic
transmission in PD (Gubellini et al., 2004). Modulation
of these receptors can alleviate some parkinsonian
motor features in the 6-OHDA rat (Murray et al.,
2002; Picconi et al., 2002). However, there are no
direct data at present regarding the possible involve-
ment of these receptors in the pathophysiology of LID.
Future research on the possible role of mGluR on the
development of dyskinesias is clearly warranted.
40.3.3. Neuropeptides and adenosine receptors
40.3.3.1. Enkephalin, dynorphin and substantia P
Enkephalin, dynorphin and substantia P are opiod pep-
tides acting as cotransmitters in the striatopallidal sys-
tem. The striatal GABAergic projection neurons are
segregated with respect to the opioid peptides used as
cotransmitters. Thus, striatal neurons projecting to the
globus pallidum externa (GPe) in the indirect pathway
express enkephalin derived from the precursor pre-
proenkephalin A (PPE-A), whereas striatal neurons
projecting to the globus pallidum interna (GPi) and
SNpr in the direct pathway express dynorphin derived
from PPE-B (Henry et al., 1999; Steiner and Gerfen,
1999) (Fig. 40.3). Dopamine modulates the activity
of striatal neurons and the expression of these neuro-
peptides. Dopamine depletion increases PPE-A mRNA
and enkephalin peptide levels and reduces PPE-B
mRNA and dynorphin. These findings have been well
established in rat and monkey models as well as in tis-
sue from patients with PD (Augood et al., 1989; Ger-
fen et al., 1990; Asselin et al., 1994; Herrero et al.,
1995; Nisbet et al., 1995).
Chronic treatment with levodopa increases PPE-B
mRNA over basal levels but has little or no effect on
the elevated levels of PPE-A mRNA expression (Her-
rero et al., 1995; Nisbet et al., 1995; Cenci et al., 1998;
Henry et al., 1999; Tel et al., 2002). In LID, PPE-A is
either unchanged or further increased whereas PPE-B
is increased (Herrero et al., 1995; Morissette et al.,
1997; Henry et al., 1999; Calon et al., 2000; Zeng
et al., 2000; Tel et al., 2002; Henry et al., 2003). Inter-
estingly, increase of PPE-A mRNA expression in dys-
kinetic patients appears restricted to the lateral part of
the putamen, which receives dense projections from
the sensorimotor cortex. In humans, Piccini et al.
(1997) found significantly reduced striatal and thala-
mic opioid binding in dyskinetic but not in non-dyski-
netic PD patients. Unexpectedly, there has been no
follow-up study to gain further understanding of these
findings.
Opioid receptor antagonists were shown to reduce
LID in MPTP monkeys (Henry et al., 2001) but clini-
cal studies have produced controversial results. Two
studies have reported an antidyskinetic action of the
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
non-selective opioid receptor antagonist naloxone
(Trabucchi et al., 1982; Sandyk and Snider, 1986),
whereas oral administration of naltrexone, a longer-
acting analog of naloxone, was ineffective in alleviating
levodopa or apomorphine-induced dyskinesias (Rascol
et al., 1994; Manson et al., 2001). None of these studies
were placebo-controlled.
40.3.3.2. Adenosine receptors
The adenosinergic activity in the striatum has also
been investigated in PD and LID. The A2A subtype
of adenosine receptor is abundantly expressed in the
medium spiny neurons of the striatum (Martinez-Mir
et al., 1991), particularly in dendrites, and appears to
signal, in part, through activation of serine/threonine
kinases known to modulate the phosphorylation state
of ionotropic glutamate receptors (Swope et al.,
1999; Carvalho et al., 2000). Adenosine receptors are
mainly expressed in GABAergic neurons projecting
to the GPe (indirect pathway) and that also coexpress
PPE-A and D2-receptors (Svenningsson et al., 1998).
Dopaminergic lesion in the 6-OHDA rat model pro-
duces either no change or 20% increase of A2A receptor
in the striatum (Kaelin-Lang et al., 2000; Pinna et al.,
2002). In a recent study, enhancement of striatal A2A
adenosine receptors was shown in 6-OHDA-lesioned
rats and also in MPTP monkeys with LID (Zeng et al.,
2000; Tekumalla et al., 2001), although the finding
could not be replicated in squirrel monkeys (Quik
et al., 2002). In human studies, adenosine A2A recep-
tors are increased in the lateral putamen, without
changes in the caudate nucleus, of dyskinetic PD
patients compared with non-dyskinetic patients. A2A
receptors are also increased in the GPe of parkinsonian
patients with and without dyskinesia (Calon et al.,
2004). There was a positive correlation between the
expression of PPE-A and A2A receptors in the putamen
of these patients, which represents the motor region of
the striatum (Calon et al., 2004). It is known that PPE-
A is regulated by A2A receptor activity. Thus, A2A-
receptor antagonists reverse the PPE-A increment
induced in the rat striatum by 6-OHDA lesions and
dopaminergic drugs (Carta et al., 2002; Lundblad
et al., 2003). This has led to the suggestion that A2A-
receptor activation could precede PPE-A increment
and play a prominent causative role in the origin of LID.
Pharmacological studies in animal models suggest
that the A2A-antagonist KW-6002 has antiparkinso-
nian activity and potentates the action of levodopa
(Kanda et al., 1998, 2000; Grondin et al., 1999; Lund-
blad et al., 2003; Pinna et al., 2005). A2A antagonism
attenuates the overactivity of the striatopallidal
pathway in the parkinsonian rat, but this effect is
191
variable and may not even be present in some instances
(Bove et al., 2005). A2A-receptor blockade did not
attenuate or prevent LID in 6-OHDA-lesioned rats
(Lundblad et al., 2003). Similarly, it did not modify
the upregulation in prodynorphin elicited by chronic
levodopa treatment in rodents (Lundblad et al., 2003).
40.3.3.3. Early genes
Early genes and transcription factors that regulate the
expression of other genes could also be involved in
the increment of PPE and A2A-receptor (Calon et al.,
2000). PPE and A2A gene expression in LID may be
amplified by a common transcription factor such as

fosB, one of the most thoroughly studied factors. In
the striatum of the MPTP monkey there is an increment
in
fosB not seen after chronic treatment with very
long-acting D2-agonists such as cabergoline or continu-
ous administration of the D1-agonist SKF-82958, which
provided sustained antiparkinsonian efficacy without
dyskinesias (Doucet et al., 1996). In animals receiving
pulsatile stimulation with the D1-agonist SKF-82958,
dyskinesias appeared in 2 out of 3 monkeys within 1
week of administration along with a marked induction
of
fosB in the striatum of dyskinetic animals. Thus,

fosB is found to be increased in the striatum of dyski-
netic monkeys (Doucet et al., 1996; Calon et al., 2000)
and rats (Cenci, 2002), suggesting it could be a key fac-
tor in the development of LID. Interestingly, adminis-
tration of an antisense directed to
fosB blocked LID
in the rat (Andersson et al., 1999). However, no differ-
ences in
fosB expression have been found between
dyskinetic and non-dyskinetic PD patients (Tekumalla
et al., 2001). Clearly, the meaning and functional
changes of transcription factors in LID are not fully
understood at present.
40.3.4. GABA receptors
GABA is the major neurotransmitter of the BG. GABA
receptors are classified into two major subtypes:
ionotropic (GABAA and GABAC) and metabotropic.
GABAergic neurons are abundantly present in the BG,
including striatal interneurons, medium spiny neurons,
pallidal and SNpr efferent neurons. They are enriched
by GABAA and GABAB receptor subtypes.
GABAA receptors are increased in the GPi of dyski-
netic MPTP monkeys and in PD patients with LID
(Calon et al., 1995, 1999, 2003b; Calon and Di Paulo,
2002). GABAA receptor upregulation in GPi correlates
with the development of dyskinesias induced by D1-
and D2-agonists in MPTP monkeys (Calon et al.,
1995, 1999). This was not the case in MPTP monkeys
chronically treated with dopamine agonists which did
192 J. A. OBESO ET AL.
Motor Cortex

Thalamus

A NORMAL STATE

Motor Cortex

Thalamus

B PARKINSONISM
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE 193

Fig. 40.3. Schematic representation of the main basal ganglia circuits. (A) Normal state; (B) Parkinsonian state due to dopa-
minergic striatal depletion. Dopamine depletion induces a dual, opposite effect, on medium spiny neurons. D1-expressing neu-
rons are inhibited whereas D2-containing neurons are overactive. (C) Levodopa-induced dyskinetic state in Parkinsons
disease. This represents the changes elicited by levodopa on a denervated striatum (summarized in B). SNpc-DA, substantia
nigra pars compactadopamine; NMDA, N-methyl-D-aspartate; SP, substance P.

not induce dyskinesias. The main changes in the ex-
pression of GABAA receptors occurred in the motor
(posteroventral) region of the GPi (Calon et al., 2002).
On the other hand, no significant change was found in
GABAA receptors in the putamen of dyskinetic PD
patients. Patients with LID had increased expression of
GABAB receptors in the ventral GPe compared with
non-dyskinetic patients, but in absolute terms there was
no difference from control values (Calon et al., 2003b).
Overall, these data suggest abnormal deviation of GABA
receptors in the motor area of both segments of the GP
but the precise relationship with the parkinsonian and
dyskinetic states is not well depicted.
40.3.5. Serotoninergic receptors
The BG receive a rich serotoninergic innervation from
the dorsal and medial raphe nuclei which could play a
role in their motor and behavioral functions (Jacobs
and Fornal, 1993). The action of serotonin (5-hydroxy-
tryptamine: 5-HT) is mediated by a variety of 5-HT-
receptors, including G-protein-coupled subtypes (5-HT1,
5-HT2, 5HT47) and a ligand-gated ion channel (5-HT3)
(Hoyer et al., 2002).
Under normal circumstances levodopa is decar-
boxylated to dopamine in the striatal terminals of
nigrostriatal dopaminegic neurons. However, the site
of levodopa decarboxylation in parkinsonism remains
obscure, as most dopamine terminals have degen-
erated. There is now evidence that 5-HT neurons are
primarily responsible for the storage and release of
levodopa-derived dopamine into the striatum where
dopaminergic terminals are lost (Tanaka et al., 1999;
Kannari et al., 2001). In animal models and in pati-
ents with PD striatal dopaminergic mechanisms can be
influenced by drugs that selectively interact with seroto-
ninergic neurons, including those that stimulate 5-HT1A
receptors (Santiago et al., 1998). Interestingly, it has been
shown that in 6-OHDA-lesioned rats, pretreatment with
the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propyla-
mino) tetralin (8-OH-DPAT) attenuates the excessively
high extracellular dopamine levels that occur in the
dopamine-denervated striatum after levodopa treatment
(Kannari et al., 2001). This effect was mediated by stimu-
lation of 5-HT1A-receptors since the co-administration of
WAY-100635, a 5-HT1A-receptor antagonist, attenuated
the effect of 8-OH-DPAT on dopamine levels (Kannari
et al., 2001).
194 J. A. OBESO ET AL.
Based on these observations, it has been suggested
that the administration of 5-HT1A-receptor agonists
with levodopa may prevent the deleterious effects of
pulsatile stimulation of dopamine receptors associated
with levodopa treatment and reverse LID. Recent
results have shown that the co-administration of
8-OH-DPAT prevents behavioral sensitization to levo-
dopa in the 6-OHDA model (Tomiyama et al., 2005),
in association with a decrease in the striatal expression
of mRNA coding for dynorphin and acid decarboxylase,
both of which are established markers of levodopa-
induced motor complications (Tomiyama et al., 2005).
Moreover, the 5-HT1A agonists buspiron and sarizotan
have been found to reduce LID in two open trials with
PD patients (Bonifati et al., 1994; Bara-Jimenez et al.,
2005) and MPTP monkeys (Bibbiani et al., 2001). This
therapeutic effect was not associated with a reduction of
levodopa efficacy. Moreover, in 6-OHDA-lesioned rats,
sarizotan reversed the shortening in motor response
duration induced by intermittent administration of
levodopa (Bibbiani et al., 2001).
The clinical effects observed with sarizotan are most
likely related to the potent ability of the drug to activate
5-HT1A-receptors since its effects disappeared when the
5-HT1A antagonist WAY-100635 was co-administered
in rat and monkey models (Bibbiani et al., 2001).
Other potential mechanisms for the antidyskinetic
effect of sarizotan may also be taken into account. In
principle, sarizotans ability to diminish dyskinesias
does not seem to be related to its capability to block
D2, D3 or D4 dopaminergic receptors (Rabiner et al.,
2002; Bartoszyk et al., 2004). Recently, the effects of
sarizotan on the corticostriatal glutamate pathways
have been investigated and the results indicate that
sarizotan produces a reduction in cortical and striatal
glutamate levels when systemically administered or
perfused into the motor cortex (Antonelli et al., 2005).
Of particular interest are recent reports that indicate
the influence of 5-HT-receptors on subthalamic nucleus
(STN) activity. The intrasubthalamic administration of
5-HT-induced contralateral rotational behavior sug-
gests an inhibitory effect of 5-HT on STN neurons
(Bellforte and Pazo, 2004). Furthermore, extracellular
single-unit recordings in mouse brain slices demon-
strates that 5-HT elicits two distinct effects in STN neu-
rons, the first being an excitation and the second an
inhibition; the latter effect is attenuated by the adminis-
tration of WAY-100635, indicating a 5-HT1A-receptor-
mediated inhibition (Stanford et al., 2005).
40.4. Pathophysiology
40.4.1. The classic model
In the late 1980s a pathophysiological model of the
BG was established (Figure 40.3) based on observa-
tions in animal models of PD and dyskinesias
(Crossman, 1987; Albin et al., 1989; DeLong, 1990).
The main idea underlying the model is that corticos-
triatal afferent activity influences the output of the
BG, the GPi and SNpr, by two relatively segregated
striopallidal projections: the indirect pathway and the
direct pathway. The indirect pathway or circuit con-
sists of GABA medium spiny striatal neurons expres-
sing D2 and enkephalin and inhibiting the GPe,
which in turn inhibits the STN. The STN projection
is excitatory, i.e. glutamatergic, onto the GPi and
SNpr. The direct pathway also arises from GABA
striatal neurons bearing D1-receptors and expressing
substance P and dynorphin and projecting monosynap-
tically to the GPi/SNpr. These functional arrangements
sustain a dual functional effect of dopamine on striatal
medium spiny neurons and on the output of the BG
(Fig. 40.3A). Thus, increased activity in the direct path-
way and indirect pathway produces inhibition and
excitation respectively of GPi/SNpr neurons. Pauses
of neuronal activity in the GPi/SNpr are associated
with movement facilitation (Hikosaka and Wurtz,
1983; DeLong, 1990) whereas firing is more related
to the end and halting of movement (Brotchie et al.,
1991; Mink and Thach, 1991). Dopamine striatal defi-
ciency secondary to loss of the nigrostriatal projection
leads to increased activity in GABA medium spiny
neurons expressing D2 and enkephalin and overinhibi-
tion of the GPe, resulting in exaggerated activity of the
STN in the indirect pathway (Fig. 40.3B). In the direct
pathway dopamine deficiency induces a reduction of
activity in GABAergic neurons bearing D1-receptors
and expressing substance P and dynorphin (Gerfen
et al., 1990). Together, these changes in the indirect
and direct pathways combine to produce a state of
abnormally increased activity in the inhibitory output
of the BG (Fig. 40.3B), which is a main pathophysiolo-
gical feature of the parkinsonian state. The opposite
functional picture (Fig. 40.3C), on the other hand,
characterizes dyskinesias.
Initial evidence indicated a paramount role of the
indirect pathway in the induction of dyskinesias. In nor-
mal monkeys, choreic dyskinesias are produced by dis-
inhibition of the GPe and blockade or lesion of the STN
(Carpenter et al., 1950; Crossman et al., 1988; Hamada
and DeLong, 1992). Thus, blockade of the striato-GPe
inhibitory projection (with bicuculline) leads to
increased GPe efferent activity, which results in overin-
hibition of the STN (Crossman et al., 1988; Mitchell
et al., 1989, Grably et al., 2004), and reduction in STN
glutamatergic efferent activity induces hypoactivity of
the GPi, both causing dyskinesias (Mitchell et al.,
1989; Robertson et al., 1989; Hamada and DeLong,
1992). Hypoactivity of the GPi may also occur by
increased GABAergic input from the GPe and the direct
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
striatopallidal pathway. Direct administration of the
GABA agonist muscimol into the GPi has mainly been
associated with dystonic co-contraction of antagonist
muscles and secondary slowness of movement initiation
(Mink and Thach, 1991; Kato and Kimura, 1992; Inase
et al., 1996). There is only one report of choreic dyski-
nesias of the contralateral limbs provoked by overinhi-
bition (with muscimol) of the GPi (Burbaud et al.,
1998). In addition, permanent lesion of the GPi (Horak
and Anderson, 1984; Mink and Thach, 1991) is not
associated with any dyskinetic movement; on the con-
trary (see below) it eliminates dyskinesias.
Hypoactivity of the GPi leads to disinhibition of
the thalamocortical projection in the motor circuit,
releasing the motor thalamic nuclei and thereby facil-
itating the abnormal recruitment of cortical motor
areas and the development of involuntary move-
ments (Crossman, 1987; Albin et al., 1989; DeLong,
1990; Obeso et al., 2000b). This summary reflects
the underlying notion of the classic model. A similar
sequence of events is supposed to take place due to
excessive striatal dopaminergic stimulation in the
levodopa-treated parkinsonian state (Crossman, 1990;
Obeso et al., 2000b). In recent years, newer evidence
has arisen which has forced the revision and adapta-
tion of several assumptions of the original model.
We discuss in detail all these different developments
in the subsections below.
40.4.2. Synaptic plasticity
LTP and LTD are forms of synaptic plasticity that may
be critically involved in learning and memory pro-
cesses and are mediated by glutamatergic NMDA
receptors. In addition to the hippocampus, where it
was described for the first time, this phenomenon is
also present in a variety of brain structures, including
the striatum. Repetitive stimulation of the corticostria-
tal pathway can induce both LTP (in response to
high-frequency stimulation) and LTD (in response to
low-frequency stimulation) of synaptic transmission
in the striatum. Glutamatate released by corticostriatal
stimulation excites striatal medium spiny neurons,
which are modulated by the nigrostriatal dopaminergic
projection. Dendritic spines of striatal neurons are the
anatomical locus of interaction between glutamate
and dopamine with the dopaminergic terminal loca-
lized at the necks and the glutamatergic terminals at
the head of the spines respectively (Smith et al.,
1996). LID exhibit some features that are highly sug-
gestive of plastic changes. The gradual development,
persistency and dependence of glutamate receptor
mechanism suggest that LID may be aberrant forms
of motor learning (Centonze et al., 1999). Accord-
195
ingly, abnormal synaptic plasticity at corticostriatal
synapses may play a role in the pathophysiology of
parkinsonism and LID (Calabresi et al., 1996, 2000;
Picconi et al., 2003; Pisani et al., 2005).
In parkinsonian rats after dopaminergic denervation
with 6-OHDA or in animals treated with a D1-selective
antagonist, LTP is blocked (Calabresi et al., 2000; Pisani
et al., 2005). Chronic levodopa treatment restores this
response in dyskinetic and non-dyskinetic animals. After
induction of LTP, the delivery of low-frequency stimula-
tion in normal rats produces a reversal of synaptic
strength to pre-LTP levels, named depotentiation. Par-
kinsonian rats chronically treated with levodopa but
without dyskinesias exhibited the same response as
normal rats, whereas dyskinetic rats did not show the
depotentiation response (Picconi et al., 2003). Thus,
LTP cannot be reversed by low-frequency stimulation
in the 6-OHDA animals that developed LID after chronic
treatment, in contrast to levodopa-treated rats without
LID. Synaptic depotentiation is thought to increase the
efficiency of information storage in neuronal networks
and may play a prominent role in eliminating irrelevant
information underlying the process of forgetting. Thus,
the lack of depotentiation in the dyskinetic animals can
represent a failure in erasing inadequate motor informa-
tion, leading to the development of abnormal involuntary
movements (Picconi et al., 2003).
Striatal LTP mainly depends on activation of
NMDA and D1-receptors (Calabresi et al., 1996) but
it is also modulated by mGluR2/3 metabotropic recep-
tors and endocannainoids (Genderman et al., 2002). As
already indicated in section 40.3 above, NR2A recep-
tors are overexpressed in the striatum of MPTP mon-
keys with LID (Calon et al., 2002; Hallett et al.,
2005) whereas NR1 and NR2B are normalized by
levodopa treatment. This set of changes could be
responsible for a reinforcement of LTP leading to aug-
mented threshold for its reversion, or depotentiation, in
the dyskinetic animals.
Dendritic spines are the locus of the interaction
between glutamate and dopamine responsible for the
LTP and LTD. It could be that dopaminergic deple-
tion induces a redistribution of the subtypes of NMDA
receptors, along the cellular membrane, that might
cause an impairment of corticostriatal synaptic plasti-
city. An increase in the percentage of glutamatergic
synapses has been found (Anglade et al., 1996) in
the striatum of rats with 6-OHDA-induced lesion
and in PD patients. Moreover, the same studies have
shown that dendritic spines of striatal neurons are
reduced numerically and show abnormal length, size
and shape (Anglade et al., 1996; Meshul et al.,
1999; Stephens et al., 2005). At present, there are no
data either in the MPTP monkey model or in PD
196 J. A. OBESO ET AL.
patients regarding the synaptic or extrasynaptic alloca-
tion of the NR2A and NR2B subtypes of NMDA
receptors in the dyskinetic state. The exact meaning
of the changes so far encountered needs further stu-
dies. In perirhinal cortex, the NR2B NMDA receptors
responsible for LTD are allocated extrasynaptically,
whereas NR2A NMDA receptors, responsible for
LTP and depotentiation, are located synaptically
(Massey et al., 2004). Thus, it is possible that LID
in PD could similarly involve relocation of NR2
receptors underlying the formation of abnormal
changes in synaptic plasticity. This could be a promi-
nent feature of striatal physiology and LID.
40.4.3. Neurophysiology: neuronal firing
The parkinsonian state is associated with increased fir-
ing rate in the STN and GPi (Filion and Tremblay,
1991; Bergman et al., 1994; Merello et al., 1999a;
Vitek and Giroux, 2000). LID are associated with
reduction in the STN and GPi firing rate in the MPTP
monkey model (Filion et al., 1991; Papa et al., 1999)
and in patients with PD (Merello et al., 1999a; Lozano
et al., 2000; Boraud et al., 2001; Levy et al., 2001).
Levodopa treatment is associated with an increment
in the firing rate of GPe neurons (Filion et al., 1991;
Boraud et al., 1998). However, precise data regarding
120
80
Hertz
40
0
0 2 23 24
Off On
Fig. 40.4. Recording of neuronal extracellular activity in the globus pallidus internal segment of one representative 1-methyl-
4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey. In the off state there is increased firing rate, which is reduced when the
animal turns on after administration of a dopaminergic drug. The rate decreases to near zero, coinciding with the ensuing of
dyskinesias. Reproduced from Papa et al. (1999) with permission from the American Neurological Association.
GPe neuronal activity and the presence of LID are
strikingly limited (Filion et al., 1991).
Firing rate in the STN and GPi is therefore, appar-
ently well correlated with the parkinsonian and dyski-
netic motor states (Fig. 40.4). At odds with the model
is the fact that the lesion of the GPi (pallidotomy),
instead of aggravating LID, is associated with the
suppression of these undesired movements. A more
detailed analysis of neuronal activity in the GPi dur-
ing LID has shown that not every single neuron
decreased its firing rate during LID (Filion et al.,
1991; Boraud et al., 2001; Levy et al., 2001). Simi-
larly, in the STN (Levy et al., 2001), there was a
reduction in the overall firing rate of the nucleus but
a proportion of neurons had no change. Importantly,
the proportion of neurons discharging in bursts and
irregularly is increased in the STN and GPi during
LID (Filion et al., 1991; Merello et al., 1999a;
Lozano et al., 2000; Boraud et al., 2001). Accord-
ingly, the averaged firing frequency is not the only
physiological determinant of the dyskinetic state with
respect to the parkinsonian motor condition. Thus, it
is now believed that it is the pattern of neuronal activ-
ity in the output of the BG that is relevant to the
development of dyskinesias (Vitek et al., 1999; Vitek
and Giroux, 2000; Obeso et al., 2000b; Bezard et al.,
2001; Boraud et al., 2001).
100
90
80
70
60
Hertz
50
40
30
20
10
0
Off On On with
Dyskinesias
30 34
On with Dyskinesias Minutes
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE 197

Oscillatory Activity in the STN

5-10 Hz
2
1 qa
0

2,5
10-20 Hz

1,5
0,5

0,25
20-30 Hz

b 1,2
0,15
0,05

0,05
30-40 Hz

0,03
0,01 g1

0,07
>60 Hz

0,05
0,03
g2
0,01
(mV2) L-DOPA

OFF DD ON-Dyskinesias

Fig. 40.5. Recording oscillatory activity in the subthalamic nucleus of a patient with Parkinsons disease through implanted
electrodes. In the off state there is a predominant peak of activity in the beta band. The onset of diphasic dyskinesias (left vertical
line) is associated with drastic attenuation of beta activity and onset of theta activity (upper row). At the time of on dyskinesias
(right vertical line), there is an additional peak in the gamma band.

The importance of oscillations and patterns of neuro-
nal activity in LID is starting to be clarified (Fig. 40.5).
In patients submitted to surgery for deep brain stimula-
tion (DBS) it is possible to record local field potentials
(LFP) from the implanted electrodes in the STN or GPi.
Typically, in the off state there is a predominant peak
in the 1130 Hz (beta) band and, when patients are trea-
ted with dopaminergic drugs, the beta rhythm is drasti-
cally attenuated and activity in the 6080 Hz gamma
band predominates (Levy et al., 2002; Brown, 2003). A
recent study has shown that the dyskinetic state is asso-
ciated with a predominant oscillatory activity at 410
Hz in the STN of PD patients who developed LID
(Alonso-Frech et al., 2006) and that such theta/alpha
peaks are absent in patients without dyskinesias. Indeed,
stimulating the STN at this 48 Hz frequency in patients
treated with DBS in the STN elicited dyskinesias (Liu
et al., 2002). In the 6-OHDA rat with LID the Bordeaux
group (Meissner et al., 2006) recorded from the SNpr
and found precisely the same correlation between dyski-
nesias and slow oscillations. The peak activity in the
theta/alpha band coincided with a reduction in neuronal
firing rate in the SNpr and increased dopamine levels in
the striatum. It appears, therefore, that reduction in
single-cell neuronal activity allows synchronization at
around 48 Hz, which facilitates the onset of dyskinesias.
Interestingly, a similar predominance around 48 Hz
coinciding with LID has been recorded in the GPi in 1
patient with PD (Foffani et al., 2005) and in a group of
patients with torsion dystonia (Silberstein et al., 2003).
How this pattern of activity in the output nuclei of the
BG releases involuntary movements is not understood.
40.4.4. Anatomofunctional basis
Loss of nigrostriatal terminals is associated with large
and uncontrolled oscillations in dopamine levels after
exogenous administration of levodopa (Miller and
198 J. A. OBESO ET AL.
Abercrombie, 1999; Brotchie et al., 2005), which
increases with disease progression (De la Fuente-
Fernandez et al., 2004; Obeso et al., 2004). The stria-
tum has been classically assumed to be the site where
abnormal dopaminergic activation takes place in
patients chronically treated with levodopa, but direct
evidence had not existed until recently. This has come
from experience regarding fetal mesencephalic trans-
plants in patients with PD. Two double-blind studies
have conclusively shown that increasing dopaminergic
levels in the putamen (revealed by PET) is associated
with dyskinesias, which are otherwise identical to the
ones provoked by levodopa (Ma et al., 2002; Olanow
et al., 2003).
In line with the prevailing pathophysiological
explanation for LID discussed in the previous section,
excessively large amounts of dopamine induce plastic
changes in medium spiny striatal (i.e. putaminal) neu-
rons, giving rise to the indirect and direct pathways.
The relative importance of either striatopallidal projec-
tion is not well defined and, in fact, it has changed
over the years.
Direct data for the participation of the indirect
pathway in LID are relatively scarce. In normal pri-
mates dyskinesias are evoked by reducing STN activ-
ity (see above) and 2-deoxyglucose uptake is
increased in the STN and GPi of MPTP monkeys with
LID (Mitchell et al., 1992). Neuronal activity in the
STN from PD patients with dyskinesias elicited by
apomorphine during surgery is reduced compared with
the off parkinsonian state (Lozano et al., 2000; Vitek
and Giroux, 2000). Interestingly, the distribution of the
410 Hz oscillatory activity recently associated with
LID in PD patients (Alonso-Frech et al., 2006) and
the increment in glucose uptake in dyskinetic MPTP
monkeys predominate over the ventral region of the
STN (Mitchell et al., 1992; Guigoni et al., 2005b).
These results are in keeping with the classic model
and the role of the indirect pathway in the pathophy-
siology of LID. However, there is controversy over
the functional state of the GPe and its role in the
reduction of STN activity that mediates dyskinesias
(Obeso et al., 1997). On the one hand, recording neu-
ronal activity in the GPe of dyskinetic animals has
shown increased firing rate (Filion et al., 1991; Boraud
et al., 2001). However, metabolic markers are not in
keeping with such findings. Expression of mRNA for
striatal met-enkephalin remains increased (Herrero
et al., 1995) and expression of glutamic acid decarbox-
ylase (GAD) mRNA (an index of GABA activity) and
cytochrome oxidase mRNA (an index of cellular
activation) were not above normal in the GPe of dyski-
netic monkeys (Vila et al., 1997; Herrero et al.,
1996b). Importantly, lesions of the GPe did not block
previously installed LID in MPTP monkeys who actu-
ally deteriorated further (Blanchet et al., 1994). Thus,
the prediction of the model whereby levodopa induces
hyperactivity of the GPe leading to the expected over-
inhibition of the STN is not supported by metabolic
data. In this regard, it is worth noticing that there is a
direct dopaminergic innervation of the STN, GPe and
GPi (Hedreen, 1999) which is impaired in animal models
and patients with PD (Francois et al., 2000; Jan et al.,
2000). It is therefore possible that modulation of STN
output activity occurs not only from the GPe but also
by a direct effect of dopaminergic drugs.
The involvement of the direct pathway in the devel-
opment of LID has been substantiated in recent years,
particularly by studies related with modifications of
D1 striatal receptors signal transduction, as discussed
in section 40.3 above. Animal models gave variable
results regarding the expression of D1-receptors in
the striatum but importantly, no modification was pre-
sent in PD patients (Lee et al., 1978). A recent study
concluded that the expression of D1 striatal receptors
is unchanged in relation to LID in MPTP monkeys
but recognized an increment in binding of [(35)S]
GTP gamma, indicating functionally active receptors.
Moreover, levels of Cdk5 and DARPP-32, two pivotal
players in the D1 signal transduction pathway, are
increased in the striatum of dyskinetic monkeys
(Aubert et al., 2005). These findings were not present
in monkeys with a similar degree of parkinsonism
and dopaminergic depletion and without dyskinesias,
despite the fact that they received the same regimen
of levodopa treatment. The severity of LID also corre-
lated linearly with D3-receptor binding levels. Thus,
two markers of the medium spiny neurons at the origin
of the direct pathway, such as D1- and D3-receptors,
indicate a prominent role of the direct pathway in LID.
In contrast, levodopa treatment reduced and normalized
the increased expression of D2-receptors in MPTP mon-
keys with and without dyskinesias (Herrero et al.,
1996a; Bezard et al., 2001). PET studies in PD patients
showed a similar pattern of striatal D2-receptor after
receiving levodopa treatment (Brooks et al., 1992).
We believe that the dichotomy between the direct and
indirect pathways in the pathophysiology of LID is fruit-
less and unrealistic. Manipulation of either pathway at
the level of the GPi can induce dyskinesias. Thus, in nor-
mal monkeys dyskinesias can be elicited either by injec-
tion of glutamatergic antagonists into the GPi, blocking
the STN glutamatergic excitation (Robertson et al.,
1989), or by local injection of the GABAergic agonist
muscimol (Burbaud et al., 1998), mimicking inhibition
from the GPe and the direct pathway. There are several
other sources of evidence indicating participation of both
striatopallidal projections in the 6-OHDA rat and MPTP
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
monkeys. For instance, to restore striatal LTP in the
denervated striatum activation of both D1- and D2-recep-
tors is necessary (Calabresi et al., 2000). Dyskinesias
may be elicited by a D2-agonist (i.e. PHNO, 4-pro-
pyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho(1,2-b)(1,4)
oxazin-9-ol) after co-administration of a D1-antago-
nist (i.e. SCH-233390) and vice versa, a D1-agonist
may evoke dyskinesias in the presence of a D2-
antagonist (Luquin et al., 1992a). Finally, and more
importantly, administration of a D1-agonist in the
primed MPTP monkey induces dyskinesias and
causes changes in neuronal activity in the GPi which
are the same as those caused by a D2-agonist that also
provokes dyskinesias (Boraud et al., 2001). This sug-
gests that reduction of GPi firing frequency and slow
oscillatory synchronization responsible for LID may
occur through functional changes in several circuits
influencing GPi output activity. In fact, recent anato-
mical data strongly indicate that the concept of the
direct or indirect pathways cannot be sustained based
on connectivity among the different BG nuclei (Lev-
esque and Parent, 2005). Our own view is, therefore,
that the available data do not suggest the exclusive
participation of a given striatopallidal pathway in
the pathophysiology of LID. More likely, changes in
afferent activity to the GPi from the GPe, STN and
putamen are all involved in setting the firing patterns
and oscillatory activity that give rise to LID.
Lesions of the GPi and the pallidal receiving area of
the thalamus may eradicate LID. This conclusively
indicates that the abnormal signals are conveyed
through the pallidothalamic projection to the cortical
motor areas. Indeed, regional cerebral blood flow mea-
sured by PET or single-photon emission computed
tomography (SPECT) was increased in the motor
thalamus in patients with LID (Hershey et al., 1998)
or hemichorea (Kim et al., 2002), indicating increased
input, presumably from the GPi. Two other studies
compared regional activation during the performance
of manual activity. A PET study with O15H2O com-
pared levodopa-treated PD patients with and without
dyskinesia and found increased activation of the BG,
area 4, area 6, supplementary motor area and dorsolat-
eral prefrontal cortex at rest and during a joystick task
coinciding with on dyskinesias (Brooks et al., 2000).
Using 133Xe SPECT to measure blood flow during a
finger movement task, Rascol et al. (1998) described
similar findings at the cortical level.
In conclusion, it appears that LID depend upon
uncontrolled dopaminergic signaling at the putaminal
level, leading to abnormal generation of firing patterns
and oscillations in the output of the BG, which is con-
veyed via the thalamus to the cortical motor areas. LID
may represent the dysfunction of primary BG mechan-
199
isms involved in the suppression of unwanted actions
and the running of automatic movements (Marsden
and Obeso, 1994; Obeso et al., 2000a). Normally,
actions are limited to a few movements at a time.
The motor apparatus guarantees that other body seg-
ments are not recruited. The BG are thought to contri-
bute fundamentally to this operation by setting the
right balance between movement facilitation and inhi-
bition (Mink and Thach, 1991; Marsden and Obeso,
1994; Obeso et al., 2000a; Mink, 2003). Dyskinesias
represent a deviation of this essential mechanism
whereby voluntary motor acts are performed with rela-
tive accuracy, but unwanted, involuntary fragments of
movements are also simultaneously recruited. It is as
if the motor system has lost the capacity to focus and
appropriately select just the correct and desired move-
ment pattern, a typical function of the BG (Denny-
Brown and Yanagisawa, 1976; Marsden, 1982).
40.5. Treatment
LID are highly prevalent in the overall PD population
and may be very disabling, interfering with quality of
life (Chapuis et al., 2005). This is especially relevant
in patients with younger age at disease onset. For
example, in PD beginning before the age of 45 years
old, LID are severe and present in almost all patients
after 5 years of treatment.
The optimal therapeutic approach for LID is to avoid
their development. Advances in such an approach have
been gained over the last few years but the outcome is
still quite limited. This is due to the fact that LID are
directly related to disease progression, a problem that
has no realistic therapy yet and the inevitable need to
use levodopa during the evolution of PD.
40.5.1. Pharmacological treatments
Three main therapeutic strategies are used to manage LID
in parkinsonian patients: (1) prevention of the sensitiza-
tion or priming phenomenon by early use of a dopamine
agonist; (2) symptomatic treatment, once LID have
developed, with putative antidyskinetic interventions;
and (3) continuous dopaminergic stimulation to reverse
the functional changes underlying dyskinesias.
40.5.1.1. Prevention of priming
The use of neuroprotective drugs to slow disease pro-
gression has been extensively explored. L-deprenyl
(in an extension of the Deprenyl and Tocopherol Anti-
oxidative Therapy of Parkinsons disease (DATATOP)
study) failed to produce a significant reduction in the
incidence of dyskinesias (Shoulson, 1998).
200 J. A. OBESO ET AL.
The only group of drugs that has convincingly
demonstrated a reduction in the risk of developing dys-
kinesias is the dopamine agonists. Three placebo-con-
trolled studies comparing the evolution of patients
initiated with a dopamine agonist (ropinirol, pramipexol
and cabergoline) and standard levodopa have shown
that the former provided significant symptomatic relief,
although slightly less than levodopa, with less risk
for developing dyskinesia after a follow-up period of
25 years.
Rascol et al. (2000), in a comprehensive, double-
blind parallel study, compared the efficacy of ropinirol
and levodopa over a period of 5 years in 268 patients
with early PD. The analysis of the time to onset of
dyskinesia showed a significant difference in favor
of ropinirol. At 5 years, the cumulative incidence of
dyskinesia, regardless of levodopa supplementation,
was 20% in the ropinirol group and 45% in the levo-
dopa group. This confirmed clinically experimental
data in the MPTP monkey (Maratos et al., 2001),
showing that ropinirol alone or in combination with
low-dose levodopa delayed dyskinesia onset while
improving motor performance. The mean daily dose
of ropinirol was 15 mg but the majority of patients
enrolled in that arm required supplementary treatment
with levodopa (Rascol et al., 2000).
Holloway et al. (2004) compared the incidence of
motor complications between pramipexole and levodopa
as initial treatment in early PD. Patients allocated to pra-
mipexole treatment showed a significant reduction in
the risk of developing dyskinesias (24.5% versus 54%;
P < 0.001). Cabergoline is an ergoline derivative with a
very long half-life (
72 hours) that can therefore be
administered once daily. In a double-blind multicenter
trial on 419 patients naive to treatment, comparing caber-
goline and levodopa as initial therapy for PD, motor
complications were significantly delayed and occurred
less frequently in cabergoline-treated patients compared
to levodopa-treated patients (Bracco et al., 2004).
An evidence-based review (Inzelberg et al., 2003)
compared the results of studies published on early
treatment of PD with dopamine agonists (cabergoline,
ropinirol or pramipexole) with similar studies using
levodopa. Cabergoline, pramipexole and ropinirol
were similarly effective in reducing the risk for dyski-
nesia relative to levodopa. Dyskinesia risk reduction
was slightly greater for pramipexole and ropinirol than
for cabergoline. A concern encountered in the three stu-
dies was that, whereas treatment with a dopamine ago-
nist reduced the risk of dyskinesia, this was associated
with less antiparkinsonian benefit.
It remains open to future analysis if the initial ben-
efit on LID of treatment with a dopamine agonist is
carried forward over the long-term evolution, once
levodopa is added to the regimen. In addition, several
issues related to the design of the studies have been
raised by critical voices. Our own view is that the
severity of LID observed in clinical practice has been
considerably reduced in the last decade or so, coincid-
ing with the earlier use of dopamine agonist and the
associated possibility of reducing levodopa daily dose.
In addition, neuroimaging studies with PET and
SPECT suggested that dopamine agonists may be
associated with a reduction in the decline of dopami-
nergic striatal terminals when used in the early stages
of the disease, raising the possibility of a neuroprotec-
tive effect (Marek et al., 2002; Whone et al., 2003).
Thus, while sufficient and definitive data are being
compiled, we favor the prevailing concept of starting
therapy with a dopamine agonist, particularly in
patients who are 65 years old or younger, at the time
of diagnosis.
40.5.1.2. Dyskinesias in patients already primed:
symptomatic treatments
This is the commonest clinical scenario. Patients have
already developed LID and the clinician has to attempt
to control the dyskinesias by adjusting the antiparkin-
sonian drugs or adding agents capable of reducing
LID without increasing motor disability. The difficulty
in achieving therapeutic efficacy is directly related to
the severity and complexity of PD in each individual
subject. Thus, LID are relatively easy to control when
they are mild and occur in patients with a wide thera-
peutic window but may be very difficult (or impossi-
ble) to treat pharmacologically in severe patients who
exhibit all forms of LID and fall into severe off
episodes when they are not dyskinetic. We shall
review here the different individual pharmacologi-
cal approaches available to treat LID but, in many
instances of clinical practice, one needs to combine
several options.
40.5.1.2.1. Dopamine agonists
A dopamine agonist is added with the intention of
reducing levodopa dose and avoiding peak of dose
on-dyskinesias associated with high levodopa plasma
levels. Belanger et al. (2003) examined the possibility
of reducing LID by using a small dose of cabergoline.
During treatment, they observed LID in the levodopa
group but not in the levodopa cabergoline group,
which suggests that a small dose of a long-acting D2-
agonist combined with low doses of levodopa could
reduce the incidence of LID in patients with PD. This
study supports a commonly applied clinical strategy.
Another approach is to achieve an antidyskinetic
effect with a partial dopamine agonist. These drugs,
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
characterized by having lower intrinsic activity at the
receptor level than full agonists, act as either func-
tional agonist or antagonist, depending on the levels
of endogenous dopamine. A partial D2-receptor ago-
nist may represent an interesting alternative for the
treatment of PD and dyskinesias.
Preclamol, the ()enantiomer of 3(3-hydroxyphenyl)-
N-n-propyl piperidine (3-PPP), has a selective dopamine
mixed agonistantagonist profile for both pre and post-
synaptic receptors. Its action in patients with disabling
onoff fluctuations was compared against placebo a slight reduction in dyskinesia severity was observed
and subcutaneous apomorphine (Pirtosek et al., 1993).
Preclamol had a mild but unequivocal antiakinetic effect,
less than that achieved with subcutaneous apomorphine,
but caused less dyskinesia. Aripiprazole is a new
antipsychotic drug showing partial agonist activity for
D2 and 5-HT1A-receptors and antagonist activity for
5-HT2A-receptors. Lieberman (2004) postulated that
this drug may be able to reduce dyskinesias without
producing akinesia, but further studies are required to
investigate its antidyskinetic capacity.
40.5.1.2.2. Dopamine antagonists
The use of drugs that block the dopaminergic system has
been a classical approach for the treatment of dyskinesias
in general. D2-antagonists, like haloperidol, tiapride and
sulpiride, and presynaptic dopamine-depleting drugs,
like reserpine and tetrabenazine, have all proven useful
in the management of hemichorea-ballism (HCB), tard-
ive dyskinesias and tics. These same drugs are also effec-
tive in reducing or stopping LID in PD, but this effect
is invariably associated with marked motor worsening
after a variable period (ranging from hours to weeks).
In clinical practice, therefore, they are not useful.
Recent observations increasingly suggest that atypi-
cal neuroleptic drugs, which are able to block D3-
receptors preferentially, can be beneficial for patients
with movement disorders. Oh et al. (2002) evaluated
the effects of quetiapine, an atypical antipsychotic
with 5-HT2A/C and D2/3-antagonistic activity, on motor
behavior in the 6-OHDA-lesioned rat and in MPTP
monkeys. In unilaterally lesioned rats, quetiapine
(5 mg/kg p.o.) reversed the shortening of the motor
response to levodopa challenge produced by treatment
during 3 weeks with levodopa twice daily. Quetiapine
(5 mg/kg p.o.) also normalized the short-duration
response to acute injection of either a D1-receptor
agonist (SKF-38392) or a D2-agonist (quinpirole) in
rats that had received chronic levodopa treatment.
Quetiapine had no effect on parkinsonian manifesta-
tions when given alone to 6-OHDA-lesioned rats or
MPTP monkeys but did substantially reduce LID when
administered together with levodopa.
201
Katzenschlager et al. (2005) assessed the effect of
quetiapine on dyskinesias in a double-blind placebo-
controlled cross-over study in 9 patients with PD,
receiving 25 mg quetiapine or placebo at night, for 2
weeks, in prerandomized fashion, with a 1-week wash-
out between treatment periods. Patients subsequently
went on open-label quetiapine at 50 mg/day for a mean
duration of 30 days. During the double-blind phase,
dyskinesias remained unmodified with either 25 mg
quetiapine or with placebo. On 50 mg/day quetiapine,
on a visual analog scale. This improvement was not
reflected in the patients overall impression of treat-
ment effect. Thus, no antidyskinetic effect was per-
ceived with the low dose (25 mg) of quetiapine, but
a possible antidyskinetic effect was described with
higher doses.
Durif et al. (2004) investigated the efficacy and
safety of clozapine in the treatment of LID in 50
patients during a 10-week, double-blind, parallel-
group, placebo-controlled, multicenter trial. Mean clo-
zapine dose was 39.4  4.5 mg/day. The maximal LID
score at rest during the levodopa challenge was signif-
icantly decreased in the clozapine group. The authors
concluded that clozapine is effective in the treatment
of LID in severe PD. In another study, Manson et al.
(2000) assessed the usefulness of 2.57.5 mg/day of
olanzapine versus placebo for LID in 10 patients with
PD during a 2-week course. There was a 41% dyskine-
sia reduction in the olanzapine-treated group compared
to placebo as measured by objective dyskinesia rating,
but it resulted in a significant increment in off time
as measured by patient diaries (30% versus 2%) and
increased parkinsonism. These authors therefore con-
cluded that olanzapine is effective in reducing dys-
kinesias in PD but, even at a very low dose, it
may lead to unacceptable increases in parkinsonism
and off time.
40.5.1.2.3. Drugs acting on the opioid system
The opioid striatal neurons may play a role in the
induction of dyskinesias. Samadi et al. (2004) investi-
gated the effect of different doses of the opioid recep-
tor antagonists naloxone and naltrexone on the
dyskinetic response to the D1-agonist SKF-82958, the
D2-agonist quinpirole and levodopa in MPTP cyno-
molgus monkeys. They found that conjunct adminis-
tration of naloxone or naltrexone together with
dopaminergic agents led to a significant reduction in
the severity of dyskinesias without losing antiparkinso-
nian efficacy. Carroll et al. (2004) conducted a rando-
mized, double-blind, placebo-controlled cross-over
trial to examine the hypothesis that cannabis may have
202 J. A. OBESO ET AL.
a beneficial effect on dyskinesias in PD. Seventeen
patients completed the trial and cannabis was well toler-
ated with no pro- or antiparkinsonian action, but no evi-
dence of a treatment effect on LID as assessed by
Unified Parkinsons Disease Rating Scale (UPDRS) or
any secondary outcome measurements. Thus, despite
many experimental suggestions, there is no drug
currently employed clinically to manipulate the opioid
system for the treatment of LID (Manson et al., 2001).
40.5.1.2.4. Glutamatergic antagonists
The use of NMDA antagonists in humans has been
generally limited because of adverse effects associated
with non-selective NMDA receptor blockade.
Verhagen Metman et al. (1998b) in a double-blind
cross-over study showed that 3 weeks treatment with
dextrometorphan was able to reduce dyskinesias by
3040% while maintaining the response to levodopa.
In recent years, amantadine has become popular as a
possible antidyskinetic drug based on its putative
anti-NMDA action (Verhagen Metman et al., 1998a).
However, it is worth noticing that there is no definitive
evidence indicating such a mechanism of action. Del
Dotto et al. (2001) evaluated the effect of a 2-hour intra-
venous amantadine (200 mg) or placebo infusion against
LID in 9 PD patients with motor fluctuations and
severely disabling peak-dose dyskinesias. Intravenous
amantadine acutely improved LID by 50%, without los-
ing the antiparkinsonian benefit of levodopa in a 5-week,
double-blind cross-over trial. In another study Luginger
et al. (2000) assessed dyskinetic severity following oral
levodopa challenges as well as with self-scoring dyskine-
sia diaries and found them to be reduced by approxi-
mately 50% after amantadine treatment compared with
baseline or placebo control. Snow et al. (2000) evaluated
the effect of amantadine on LID in a double-blind, pla-
cebo-controlled study and found a 24% reduction in the
total dyskinesia score.
The above clinical data indicate that amantadine is
an effective treatment for LID. However, the duration
and magnitude of its antidyskinetic effect remain to be
established. Thomas et al. (2004) performed a 12-month
double-blind study including 40 patients suffering peak-
dose and diphasic dyskinesias in an attempt to elucidate
the duration of the antidyskinetic effect. After 15 days
of amantadine treatment, a reduction of 45% in the total
dyskinesia scores was detected, but the benefit lasted
less than 8 months. Moreover, in a systematic review
on the efficacy and safety of amantadine for LID treat-
ment, Crosby et al. (2003) concluded that there was
not enough evidence to determine whether amantadine
was effective. Our view is that, on an individual basis,
amantandine may result in a drastic amelioration of
LID and is therefore worth trying in the absence of con-
traindications. The antidyskinetic effect is probably
exerted at the level of the STN as amantandine failed
to control dyskinesias evoked by subthalamotomy in
patients who had previously responded markedly well
(Merello et al., 2006).
Merello et al. (1999b) evaluated the efficacy of
memantine (1-amino 3,5-dimethyl-adamantane hydro-
chloride) on cardinal symptoms of PD, the pharmaco-
logical response to levodopa (latency, duration and
magnitude) and the induction of dyskinesias. In 12
patients and contrary to recent findings with amantadine,
no effect on LID was observed. However, in a recent
report by Lokk (2004), memantine was given to 3 PD
patients with cognitive impairment and LID and 2 of
them benefited with regard to dyskinesia control.
Riluzole is an inhibitor of glutamatergic transmis-
sion in the central nervous system currently given to
patients with lateral amyotrophic sclerosis in an
attempt to improve prognosis. Braz et al. (2004) eval-
uated the effect of riluzole on dyskinesia in 16 patients
with PD and found no effect against apomorphine-
induced dyskinesias.
In general, the high expectations (Chase et al.,
2000) that were raised with the potential therapeutic
impact of antiglutamatergic drugs for PD have failed
to become a reality.
40.5.1.2.5. Drugs acting on the serotoninergic system
The serotoninergic system projects quite profusely to
the striatum and also to other key BG nuclei (i.e.
STN, GPe, GPi) and exerts an inhibitory control on
dopamine striatal transmission. Durif et al. (1995)
found a 47% improvement in the severity of dyskine-
sias evoked by apomorphine in 7 patients with PD
treated with fluoxetine. There was no reduction in
levodopa antiparkinsonian benefit.
Buspirone has a complex mechanism of action,
which aside from its 5-HT1A properties includes par-
tial dopamine agonism and mild opiate and noradre-
nergic antagonism (Kleedorfer et al., 1991). Bonifati
et al. (1994), in a double-blind, placebo-controlled,
cross-over study, found that buspirone (20 mg) signif-
icantly lessened the severity of LID in 5 out of 7
patients. Mirtazapine is an a2-antagonist, 5-HT1A ago-
nist and 5-HT2 antagonist, potentially useful for LID.
Meco et al. (2003) found in an open-label study
including 20 parkinsonian patients that mirtazapine
may be effective in reducing LID.
40.5.1.2.6. Noradrenergic drugs
The close relationship between the dopaminergic,
adrenergic and noradrenergic systems has led to the
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
assessment of a possible antidyskinetic effect of a few
drugs acting on those systems. Two studies have
shown how the a2-adrenoreceptor antagonist idazoxan
can significantly reduce LID in MPTP monkeys as
well as in patients with advanced PD (Grondin et al.,
2000). Rascol et al. (2001) reported improvement of
LID without reappearance of parkinsonian symptoms
in 18 patients treated with idazoxan. Carpentier et al.
(1996) found a significant 40% improvement in dyski-
nesia scores in PD patients treated with a low dose of
propranolol (1020 mg/day).
40.5.1.2.7. Practical considerations
There appear to be many drugs that are capable of
reducing the severity of LID. In some occasional
patients, the therapeutic impact of any one of the treat-
ments summarized above may be strikingly positive,
but in the majority it is limited to mild or short-lasting
improvement. Nevertheless, they are generally well
tolerated and worth trying in patients in whom other
therapeutic measurements cannot be afforded. In our
experience, the degree of symptomatic control of
LID mainly depends upon the complexity of dyskine-
sias and severity of off periods. This may be schema-
tically summarized as follows: (1) in patients with
mild but bothersome peak-dose dyskinesias, read-
just the levodopa schedule, and consider adding a
dopamine agonist and any one of the drugs discussed
above; (2) for patients with severe peak-dose dyskine-
sias, consider switching treatment to provide continu-
ous dopaminergic stimulation; and (3) patients with
severe peak-dose dyskinesias and diphasic dyskinesias
probably require surgical treatment.
40.5.1.3. Reversing priming: continuous
dopaminergic stimulation
Since the introduction of the concept of continuous
dopaminergic stimulation in the 1980s (Horowski
et al., 1988; Chase et al., 1989; Obeso et al., 1989,
1994), it was realized that constant delivery of dopami-
nergic drugs was associated with a reduction in the
severity of LID. Over the past decade, further evidence
has accumulated to support the notion that continuous
stimulation of dopamine receptors may even reverse
part of the changes induced by chronic pulsatile levo-
dopa administration. The initial pivotal study in this
regard was conducted by Mouradian et al. (1990),
who continuously delivered levodopa intravenously
for 712 days to a small group (n 12) of patients with
severe PD. They found a progressive attenuation of LID
and amelioration of the onoff fluctuations. More
recently, 24 patients with motor fluctuations and dyski-
nesia were randomized in a cross-over design to com-
pare conventional oral treatments and intraduodenal
203
infusion of a levodopa/carbidopa gel (Nyholm et al.,
2005). The time spent in the on state was increased
81100% by infusion therapy with no increase in
dyskinesias. This was associated with improvement in
quality-of-life scores. This approach is now commer-
cially available and may be a valid option for some
patients, despite the obvious practical limitations.
Similarly, continuous delivery of dopamine ago-
nists by the subcutaneous route, such as lisuride and
apomorphine, is associated with a reduction in LID.
The majority of trials used infusions during the day-
time but stopped at nighttime to reduce the risk of
severe psychiatric complications.
Manson et al. (2002) reviewed their experience in
64 patients treated with apomorphine infusions.
Forty-five patients were successfully converted to
monotherapy and discontinued all other dopaminergic
drugs during the daytime treatment period with apo-
morphine. Patients were followed for a mean of 33.8
months, with a mean maintenance dose of apomor-
phine of 98 mg/day. Dyskinesias were reduced by
64% in the monotherapy group compared to 30%
in those on polytherapy. These results confirmed that
subcutaneous apomorphine monotherapy can reset
peak-dose dyskinesia threshold in levodopa-treated
patients, while further reducing off-period disability.
Katzenschlager et al. (2005) prospectively assessed
the antidyskinetic effect of continuous subcutaneous
apomorphine using subjective and objective measures
and the response to a levodopa challenge. At 6 months,
the mean levodopa dose had been reduced by 55% and
the daily off time in patients diaries was reduced
by 38%. Levodopa challenge showed a reduction of
4044% in the dyskinesia scores. Patients self-assess-
ment scores reflected these significant changes. The
improvement correlated with a reduction in oral
drug therapy and with final apomorphine dose. This
prospective study confirmed a marked reduction in
dyskinesia with continuous subcutaneous apomorphine
therapy, paralleled by reduced dyskinesias during
dopaminergic challenge tests. Similarly, Stocchi et al.
(2002) compared the long-term incidence of dyskine-
sias in patients treated with subcutaneous infusion of
lisuride (plus supplementary oral levodopa as needed)
versus patients treated with standard levodopa orally
and showed that patients receiving lisuride infusions
experienced a significant reduction in the incidence of
both motor fluctuations and dyskinesia, compared with
patients receiving standard dopaminergic therapies.
Benefits persisted for the 4-year duration of the study.
This study also confirmed earlier results indicating that
continuous lisuride infusion can be fairly well tolerated
and beneficial for patients motor complications (Obeso
et al., 1986), provided they have not previously
204 J. A. OBESO ET AL.
developed severe psychiatric complications (Vaa-
monde et al., 1991).
Overall, these results support the concept that repla-
cement of short-acting oral antiparkinsonian medication
with drugs capable of providing a more continuous
dopamine receptor stimulation may at least partially
avoid or reverse the sensitization process believed to
mediate the development of LID. In theory, therefore,
therapy with infusions capable of providing continuous
dopaminergic stimulation might be the pharmacological
treatment of choice for advanced PD patients.
Nevertheless, the degree of control of LID achieved
with infusions is not complete in many patients. Phar-
macological tolerance appears in a large proportion
after some time on treatment. It occurs more readily
the more severe the underlying disease is, leading to
off episodes or exacerbation of diphasic dyskinesias.
The latter may cause a very troublesome dyskinetic
status (Vaamonde et al., 1991). Thus, surgery may still
be the only and best therapeutic option for a proportion
of patients with severe LID.
40.5.2. Surgery
Early surgical procedures to treat hyperkinesias, such
as choreoathetosis or hemiballism, were aimed to
interrupt the peripheral and spinal motor pathways,
the cerebral peduncles and cerebral cortex with subpial
extirpations of motor areas. Subsequently, during the
early 1950s, the GPi became the target of choice for
the surgical treatment of any movement disorder,
whether bradykinetic or hyperkinetic.
The introduction of levodopa modified the need for
the surgical treatment of PD. For many years thalam-
otomy was the only surgical procedure performed in
patients with PD. Failure to control appropriately the
tremor or levodopa-induced side-effects were the prin-
cipal reasons for elective surgery during the 1970s and
up to the early 1990s. In the last decade, there has been
a revitalization of surgery for PD in the light of the
newer pathophysiological concepts (DeLong 1990;
Obeso et al., 1997), described in section 40.4 above.
40.5.2.1. Surgery of the globus pallidum
Unilateral pallidotomy induces a significant alleviation
of the cardinal motor features of PD in the side con-
tralateral to the surgery, reducing the severity of dis-
ability in the off motor state and the UPDRS motor
score. Alkhani and Lozano (2001) encountered 1735
pallidotomies in 85 papers published between1992 and
1999 from 40 different centers. The UPDRS motor
score improved by about 4045% at 6 and 12 months
after pallidotomy, the benefit being mainly contralateral
to the lesion (Alkhani and Lozano, 2001).
Motor function and UPDRS motor score are not
improved in the on medication condition following
pallidotomy (Bronstein et al., 1999; Alkhani and
Lozano, 2001). Pallidotomy conveys a marked and
permanent benefit against LID. The lesion practically
abolishes peak-dose dyskinesias, diphasic dyskinesias
and off-period dystonia on the contralateral side to
the lesion. This effect is permanent, in our experience
lasting 10 years postoperatively, and has been shown
to remain stable between 1 and 4 years after surgery
by controlled studies (Baron et al., 2000). A beneficial
effect in the ipsilateral side of the surgery has also
been reported but became not significant after 12
years (Lang et al., 1997; Baron et al., 2000). The
meta-analysis of Alkhani and Lozano (2001) found
71 patients properly assessed 1 year after pallidotomy.
In such a selected patient population, LID were
reduced by 73.5% and 86.4% at 6 months and 12
months respectively postsurgery. Bilateral pallidotomy
is, despite its potentially larger antiparkinsonian effect,
a procedure with high risk of speech (Favre et al.,
2000), gait and cognitive deterioration (Intemann
et al., 2001; Merello et al., 2001). Thus, it is not parti-
cularly indicated nowadays when deep brain stimula-
tion (DBS) is available throughout the world.
DBS of the GPi (GPi DBS) has a significant anti-
dyskinetic effect, about 7080% reduction, which is
associated with improvement in activities of daily liv-
ing (ADL) score. The effect of GPi DBS against LID
appears stable after several years in spite of maintain-
ing levodopa daily dosage unchanged. A recent study
showed a reduction in LID severity of 76% (P
< 0.0001) with no change in the levodopa dose equiva-
lents in 20 patients with severe PD followed by 34
years in the Cooperative Study of DBS for advanced
PD (Rodriguez-Oroz et al., 2005). Volkmann et al.
(2004) followed 11 patients for 5 years after bilateral
GPi DBS and reported that LID remained significantly
reduced (58% at 1 year, 63% at 3 and 64% at 5 years)
in parallel with a worsening in the degree of benefit in
the UPDRS motor scale (56% at 1 year, 43% at 3 and
24% improvement at 5 years). This study therefore
showed a differentiated response, being therapeutically
very positive against LID but showing no sustained
benefit against the parkinsonian condition, similar to
what occurs with pallidotomy (Volkmann et al., 2004).
Two studies described that GPi DBS may have both
a prodyskinetic and an antidyskinetic effect depending
upon electrode placement, suggesting two different
targets for parkinsonism and LID in the same anatomi-
cal structure (Bejjani et al., 1997; Krack et al., 1998).
The dorsal contacts of the GPi conveyed the prodyski-
netic effect whereas the antidyskinetic action was due
to activation of the ventral contacts. Yelnik et al.,
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
(2003) described that dyskinesias induced by stimula-
tion in the GPi may be correlated with the placement
of the dorsal contacts within or near the GPe. In mon-
keys, inactivation of the motor region of the GPe (by
local administration of bicuculline) is associated with
choreatic movements (Crossman et al., 1988; Grabli
et al., 2004). It is possible therefore that activation of
GABAergic fibers from the GPe or blockade of the
GPe itself from dorsal contacts is responsible for the
reported induction of dyskinesias. Interestingly, we
never encountered this problem with GPi DBS (Obeso
et al., 2001) and it has not been reported after long-
term follow-up of 20 patients from eight centers
(Rodriguez-Oroz et al., 2005).
40.5.2.2. Surgery of the subthalamic nucleus
Nowadays, bilateral stimulation of the STN (STN
DBS) is the surgical procedure most often used for
205
PD by its striking capacity to reduce off medica-
tion severity and disability and because it is usually
associated with a 3060% reduction of levodopa daily
dose, unlike pallidal surgery. The experience regarding
the effect of STN DBS on LID is relatively homoge-
neous in different studies. Most surgical groups have
reported a significant antidyskinetic effect, closely
correlated with reduction in daily levodopa dose
(Table 40.1) (Krack et al., 2003; Moro et al., 1999;
Molinuevo et al., 2000; Obeso et al., 2001; Simuni
et al., 2002). Subthalamic stimulation appears to
improve the whole spectrum of LID, namely peak
dose, diphasic dyskinesias and off-dystonia (Krack
et al., 1999). Two independent studies summing
together 98 patients reported a significant reduction of
LID severity after 45 years of follow-up (Krack
et al., 2003; Rodriguez-Oroz et al., 2005) (Table 40.1).
Levodopa was reduced from a mean of 1309 to 859

Table 40.1
Efficacy of bilateral deep brain stimulation (DBS) of the globus pallidum pars interna (GPi) and the subthalamic
nucleus (STN) against levodopa-induced dyskinesias in Parkinsons disease: summary of the literature

Levodopa
Reference Patients Surgery Dyskinesia reduction reduction Follow-up

Ghika et al. (1998) 6 GPi DBS P < 0.01 Unchanged 6 months

Houeto et al. (2000) 23 STN DBS 77% (P < 0.001) 61% (P < 0.001) 6 months
DBSPDSG 36 GPi DBS P < 0.01 Unchanged 6 months
96 STN DBS P < 0.001 (P < 0.001)
16 (6
Loher et al. (2002) unilateral) GPi DBS 71% Unchanged 12 months
Patel et al. (2003) 16 STN DBS Duration (P < 0.002) 48% (P < 0.002) 12 months
Disability (P < 0.01)
Simuni et al. (2002) 12 STN DBS 64% 55% 12 months
Hamel et al. (2003) 25 STN DBS 50% 50% 12 months
Ford et al. (2004) 30 STN DBS P < 0.001 22% 12 months
Burchiel et al. (1999) 6 STN DBS 67% (P < 0.003) 51% (P < 0.03) 12 months
Bejjani et al. (2000) 12 STN DBS 83% (P < 0.05) 70% (P < 0.05) 12 months
Kleiner-Fisman et al.
(2003) 25 STN DBS 46.4% (P < 0.007) 38% (P < 0.001) 24 months
Herzog et al. (2003) 48 STN DBS 85% 67.8% 24 months
Rodriguez-Oroz et al.
(2005) 11 STN DBS 53% (P < 0.01) 50% (P < 0.01) 4 years
Rodriguez-Oroz et al.
(2005) 20 GPi DBS 76% (P < 0.0001) Unchanged 4 years
49 STN DBS 59% (P < 0001) (P < 0.001)
Visser-Vanderwalle 75% (P < 0.001)3 4 years and
et al. (2003) 26 unilateral GPi DBS months 53% increased 3 months
28% (P < 0.03)15
months
Volkman et al. (2004) 11 GPi DBS 64% (P < 0.05) Unchanged 5 years
Krack et al. (2003) 49 STN DBS Duration (P < 0.001) 74% (P < 0.001) 5 years
Disability (P < 0.001)
206 J. A. OBESO ET AL.
mg/day (P < 0.001) and in 6 patients levodopa was
stopped altogether (Rodriguez-Oroz et al., 2005).
Hamani et al. (2005) in a recent survey encountered 38
studies from 34 neurosurgical centers with 737 patients
involved. They found reduction of LID (UPDRS dyskine-
sias scores) by 73% and 94% at 6 and 12 months in the
on-stimulation on medication compared with preopera-
tive on medication scores.
For a large majority of authors the LID response to
STN DBS is directly related to a reduction of dopami-
nergic drugs (Molinuevo et al., 2000; Moro et al.,
2002; Vingerhoets et al., 2002). Recently, a study
separated patients into two groups after STN DBS
according to the possibility of reducing levodopa.
The group that required medication after surgery had
a moderate alleviation in LID (47% reduction) and
the group that did not receive levodopa after surgery
had a dramatic reduction in LID (90%; P < 0.003)
(Vingerhoets et al., 2002). On the other hand, some
authors have suggested that the antidyskinetic
response after STN DBS could be due to a direct effect
of continuous high-frequency electrical stimulation in
the target (Krack et al., 1999). Another possible
mechanism could be that stimulation of fibers running
above the dorsal border of the STN (fasciculus lenticu-
laris and zona incerta) would block impulse trans-
mission in the GPi-thalamic projection. This would
be in agreement with the findings that the STN target
for stimulation is dorsal to the upper border of the
nucleus and therefore the electrical current may spread
to fibers in the fasciculus lenticularis passing through
the Forel field. In such instances, the mechanism
would be similar to a pallidotomy-like effect.
Lesion of the STN, i.e. subthalamotomy, as a sur-
gical approach for PD was first considered in the
early 1990s (Guridi et al., 1993). This relied on the
striking improvement induced in the MPTP monkey
model by unilateral ablation of the STN. However,
the fear of inducing hemiballism moved attention
towards pallidotomy, despite the fact that there was
no experimental basis, because of the important surgi-
cal experience accumulated in patients by Laitinen
et al. (1992). Currently, subthalamotomy is performed
by only a few teams, around the world. Probably, this is
due to the greater methodological difficulty, in com-
parison with DBS surgery, in establishing a lesion
large enough to have a permanent and marked benefit
without side-effects. The largest published experience
corresponds to the Centro Internacional Restauracion
Neurologica (CIREN) in La Habana (Cuba) as part of
an international collaborative effort (Alvarez et al.,
2001, 2005).
Subthalamotomy is associated with a significant
and maintained improvement in all cardinal features
of PD on the side contralateral to the surgery and on
axial features up to 7 years postoperatively (Alvarez
et al., 2001, 2005). Immediately after surgery, the
great majority of patients exhibit dyskinesias on the
operated side but these are transient and self-resolving
in most instances, mimicking what happened after pal-
lidotomy (Merello et al., 1997). The incidence of
symptomatic, i.e. severe, HCB secondary to lesion of
the STN is not as large as expected by classic neuro-
surgical concepts. A review of the literature looking
for HCB in PD secondary to mistargeting during thala-
motomy in the pre-levodopa era indicated a low inci-
dence of cases (Guridi and Obeso, 2001). In fact, we
have observed symptomatic HCB in 7% of 170 conse-
cutive patients with unilateral STN lesions operated in
the CIREN. In such instances, pharmacological man-
agement of the HCB is not simple. Stopping all anti-
parkinsonian drugs does not immediately abolish
the dyskinesias and may result in worsening of the
non-operated side (Su et al., 2002; Alvarez et al.,
2005). Amantandine is not useful either, even in
patients in whom this drug has been previously useful
for LID (Merello et al., 2005). Pallidotomy is higly
efficacious in eliminating the HCB in those few
patients in whom the dyskinesia persists and is dis-
abling. This corroborates the principle established in
the monkey by Carpenter et al. (1950) and recently
applied in patients with HCB of vascular origin (Vitek
et al., 1999). In our experience, pallidotomy abolishes
the HCB secondary to subthalamotomy without aggra-
vation of parkinsonian features or indeed any other
neurological complication.
Experience with bilateral, simultaneous subthala-
motomy is much more limited but it seems that HCB
may be more frequent with such an approach, which
requires further evaluation before being recommended
for routine application (Alvarez et al., 2005).
The factors governing the onset and persistence of
severe HCB after subthalamotomy are not yet well
defined. Extension of the lesion dorsally to interrupt
the fasciculus lenticularis, producing a pallidotomy-
like effect, has been suggested as an explanation of
the low incidence of HCB after a lesion of the STN
(Lozano, 2001; Guridi and Obeso, 2001; Chen et al.,
2002). However, almost all instances of severe HCB
have been associated with dorsal lesions, usually large
enough to extend well within the zona incerta, which
should have also lesioned the pallidothalamic projec-
tion. Guridi and Obeso (2001) suggested, based on their
experience with lesions of the STN in MPTP monkeys
and the organization of the BG, that the dyskinetic
threshold is increased in the parkinsonian state, thus
reducing the probability of developing severe HCB
after interrupting the STN efferent activity.
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
The striking antiparkinsonian effect of subthalamot-
omy per se or the presence of HCB has resulted in a
drastic reduction in levodopa daily dose in most
reported studies, making assessment of the impact on
LID almost impossible. However, Alvarez et al.
(2001) kept the levodopa dose unchanged up to a year
after unilateral subthalamotomy and found a signifi-
cant reduction in LID. Those patients nevertheless
were chosen for surgery precisely because of the
absence of severe LID preoperatively. Su et al.
(2002) also reported that LID were reduced by 75%
at 18 months postoperatively in 3 out of 4 patients
who suffered severe bilateral LID before surgery, even
though the levodopa dose was unchanged during the
initial 3 months. Recently, Alvarez et al. (2005)
reported the effects of bilateral subthalamotomy in
18 patients, 7 staged lesions and 11 simultaneous
surgery, followed for a minimum period of 3 years
and up to 7 years. In both groups, the reduction in
LID was significant after subthalamotomy together
with a reduction in daily levodopa dose.
40.5.2.3. Thalamic surgery
Hassler and Riechert in 1954 pioneered thalamotomy to
improve tremor control in PD. The optimal region within
the thalamus was later defined by Ohye et al. (1976) as
the ventralis intermedius (Vim) and became the estab-
lished surgical target for tremor up to the 1970s, when
levodopa was introduced as the treatment of choice for
PD. Subsequently, a few papers described a possible pre-
ventive effect on the development of LID in patients
with a prior thalamotomy (Narabayashi et al., 1984;
Derome et al., 1986; Tasker, 1990) or the successful
amelioration of LID after surgery (Kelly and Gilling-
ham, 1980; Fox et al., 1991; Jankovic et al., 1995). How-
ever, there is no consistent report in the literature truly
assessing the impact of Vim-thalamotomy against LID,
with the exception of the work of Narabayashi et al.
(1984). This report described that patients with surgical
lesions in Voa/Vop-thalamotomy (ventralis oralis ante-
rior and posterior, which are the pallidal receiving terri-
tory in the thalamus) prior to the introduction of
levodopa did not develop LID. On the other hand,
patients with Vim-thalamotomy for tremor developed
dyskinesias when levodopa was introduced for PD
(Narabayashi et al., 1984). They concluded that the
GPi-Voa/Vop pathway mediated LID, in agreement with
Hasslers previous concept about the origin of hyperki-
nesias (Hassler, 1978). Page et al. (1993) reported simi-
lar results in MPTP monkeys with LID in whom a lesion
in the pallidal territory of the thalamus abolished
dyskinesias but lesion of the nigral or cerebellar terminal
territories had no benefit.
207
Benabid in Grenoble introduced DBS for PD for the
treatment of tremor instead of thalamotomy (Benabid
et al., 1989, 1996). Generally, it is agreed that the
effect of Vim-DBS on LID is minor or nil. Limousin
et al. (1999) reported 73 patients enrolled in a multi-
center cooperative study for the treatment of tremor
and described that LID were slightly, but not signifi-
cantly decreased by DBS at 12 months postopera-
tively. Similarly, Tasker et al. (1997) found no
significant difference between Vim-thalamotomy and
Vim-DBS regarding LID. On the other hand, the Lille
group described in 12 parkinsonian patients LID aboli-
tion after Vim-DBS. They suggested that electrodes
placed near the centromedian-parafascicular nucleus
of the thalamus may have a more marked effect
against LID, but this has not been further substantiated
(Caparros-Lefebre et al., 1999).
40.5.2.4. Mechanism of action of surgery
against LID
Hassler in Freiburg and a few years later Cooper in
New York considered that hyperkinesias were asso-
ciated with uncontrolled discharges in the GPi, leading
to excessive impulses in the pallidal projection to the
Voa of the thalamus (Hassler et al., 1960; Cooper,
1969). Hassler reported that hyperkinesias of various
etiologies and in particular HCB following surgery
for PD could be abolished by a lesion placed in the
GPi, by coagulation of the Forel H2 field or by an
extensive lesion performed in the Voa/Vop of the tha-
lamus. This approach was supported by earlier work in
the monkey performed by Mettlers group (Whittier
and Mettler, 1949; Carpenter et al., 1950). They
described the induction of HCB by destruction of the
STN (at least 20% of its volume) and how a second
lesion placed in the globus pallidum or the lenticu-
lar fasciculus abolished the choreoballic movements
(Carpenter et al., 1950).
According to current pathophysiological concepts
of PD, surgical destruction or inactivation of pallidal
neuronal activity reduces excessive inhibitory output
to the thalamus (DeLong, 1990; Obeso et al., 1997).
Pallidotomy has been shown by PET, functional mag-
netic resonance imaging and physiological studies to
restore thalamocortical excitability functionally
(Bakay et al., 1992; Eidelberg et al., 1996; Samuel
et al., 1997). On the other hand, reduction of GPi out-
put activity is the essential physiological hallmark of
LID (Filion and Tremblay, 1991; Papa et al., 1999;
Boraud et al., 2001), which is superficially in contra-
diction with the profound antidyskinetic effect of palli-
dotomy. In other words, according to the classic
pathophysiological model of the BG, pallidotomy
208 J. A. OBESO ET AL.
should induce a worsening rather than amelioration of
LID. Recent findings may shed some light on this see-
mingly paradoxical finding.
In the rat with unilateral lesion of the nigrostriatal
pathway by 6-OHDA, LID are associated with a
reduction in neuronal firing rate in the SNpr, the main
BG output in rodents. Simultaneously, the same ani-
mals exhibited a peak in the theta/alpha band (410
Hz) recorded from the SNpr by LFPs. Thus, reduced
firing rate of single neuronal activity and oscillatory
activity in the theta band in the SNpr coincided with
excessive striatal dopamine release (Meissner et al.,
2006). Moreover, recording of LFP from the GPi and
STN of PD patients who were implanted with electro-
des for DBS have shown that LID are associated with
a specific oscillatory activity at around 48 Hz
(Brown, 2003; Foffani et al., 2005; Alonso-Frech
et al., 2006). These two complementary experimental
and clinical studies strongly suggest that LID coin-
cides with an abnormally slow synchronization of neu-
ronal activity in the output of the BG, which is the
code or signal conveyed to the cortex via the thalamus.
Indeed, neuroimaging studies using PET and SPECT
data showed increased activity and regional blood flow
in the supplementary motor area, premotor area and
ipsilateral and contralateral primary motor areas
(Rascol et al., 1998). Accordingly, pallidotomy and
Voa/Vop-thalamotomy would remove the effect
of slow oscillatory activity on the thalamocortical
motor projection, stopping the delivery of wrong
signals or noisy patterns to the cortex. Whether
GPi-DBS acts by a similar mechanism is unknown at
present. It seems likely that GPi-DBS will interfere
with the theta rhythm associated with LID, either by
blocking GPi neuronal activity or by driving it into a
different (i.e. non-prodyskinetic) oscillatory activity.
The improvement of LID in patients treated with
STN surgery may have a more complex interpretation.
Reduction of levodopa daily dose is not the sole expla-
nation, as a proportion of patients treated with STN
surgery clearly had an improvement in LID despite
maintaining levodopa dose unchanged. A pallidot-
omy-like effect, by dorsal extension of the lesion or
the electrical field, to block pallidothalamic transmis-
sion does not seem to account for all observations.
We may suggest here that blockade of STN activity
may have by itself an anti-LID effect. This could take
place through two principal mechanisms:
1. The abnormal rhythms and oscillation patterns
associated with LID represent neuronal firing syn-
chrony in various nuclei of the BG and possibly
elsewhere. The STN is the major driving force of
the BG through its dense glutamatergic innerva-
tion of the GPi, GPe and SNpr and, to a lesser
extent, of the substantia nigra pars compacta and
striatum. It could be that a given subregion of
the STN is required to maintain synchrony in the
BG at 48 Hz. Consequently, blockade of the
STN removes an essential component of the net-
work engaged in the generation of the abnormal
signals, leading to LID. In this regard, it is note-
worthy that LID in the MPTP monkey model is
associated with a significant increase in 2-deoxy-
glucose uptake in the ventromedial region of the
STN (Mitchell et al., 1992; Guigoni et al., 2005b).
2. STN blockade functionally restores the BG,
making it relatively insensible to the prodyskinetic
effects of levodopa. Reduction of STN effer-
ent activity, immediately after a lesion or at the
beginning of DBS treatment, may be associated
with dyskinesias because of drastic reduction in
excitatory drive on to the GPi. However, this gives
way over the following weeks to a functional
restoration of output (Hirsch et al., 2000). Thus,
molecular markers such as mRNA expression of
cytocrome oxidase and succinate dehydrogenase
(as an index of cellular activation) or mRNA
expression of GAD become reduced or even nor-
malized in the output BG after subthalamotomoty
in the rat and monkey (Guridi et al., 1996; Blan-
dini et al., 1997). Moreover, subthalamotomy
reverses the increase in corticostriatal glutamater-
gic activity and increased GAD mRNA expression
in entopeduncular nucleus (GPi equivalent in the
rat) associated with dopamine depletion, reverses
the abnormalities in striatal excitatory synaptic
transmission (Delfs et al., 1995; Touchon et al.,
2004; Centonze et al., 2005) and ameliorates the
wearing-off response (Marin et al., 2004). It
appears therefore that STN surgery leads to func-
tional normalization of the BG output nuclei. This
in turn could reduce the sensitivity of the BG net-
work to pulsatile dopaminergic stimulation with
standard levodopa (Obeso et al., 2004), thus
increasing the threshold for dyskinesias. We envi-
sage that STN blockade stabilizes the BG network,
removing the generation of abnormal signals in
the parkinsonian off state and in response to
levodopa.
40.6. Conclusions
The origin of LID in PD is mainly related to the impact
on striatal physiology of nigrostriatal dopaminergic
depletion and discontinuous levodopa replacement ther-
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
apy. These combine to induce abnormal expression of
dopamine-receptor signaling and neuropeptides, leading
to deranged corticostriatal plasticity. Avoiding pulsatile
dopaminergic stimulation (i.e. high dose of standard
levodopa administration) has already resulted in a reduc-
tion in the incidence and severity of LID in the general
PD population. Treatment of severe LID requires contin-
uous dopaminergic stimulation by means of infusions.
Nevertheless, it is worth trying simpler and more conven-
tional treatments as a first approach. Pallidotomy is radi-
cally useful against LID but nowadays rarely indicated
because of the limited unilateral effect. DBS of the GPi
or the STN is also highly efficacious in the treatment of
LID, perhaps through different mechanisms than simple
blockade of BG output. In patients with very severe and
complex LID, GPi-DBS may be a safer indication, even
when pallidal surgery is not associated with a significant
reduction in daily levodopa intake.
Advances in neuroprotection and better means of
replacing the dopaminergic striatal deficit should lead
to a gradual reduction of LID in PD in the near future.
Eventually, LID will become an obsolete neurological
complication.
References
Albin RL, Young AB, Penney JB (1989). The functional
anatomy of basal ganglia disorders. Trends Neurosci 12:
366375.
Alkhani A, Lozano AM (2001). Pallidotomy for Parkinsons
disease: a review of contemporary literature. J Neurosurg
94: 4349.
Alonso-Frech F, Zamarbide I, Alegre M et al. (2006). Slow
oscillatory activity and levodopa-induced dyskinesias in
Parkinsons disease. Brain 129: 17481757.
Alvarez L, Macias R, Guridi J et al. (2001). Dorsal subthala-
motomy for Parkinsons disease. Mov Disord 16: 7278.
Alvarez L, Macias R, Lopez G et al. (2005). Bilateral subtha-
lamotomy in Parkinsons disease: initial and long term
response. Brain 128: 570583.
Andersson M, Hilbertson A, Cenci MA (1999). Striatal fosB
expression is causally linked with L-Dopa-induced abnor-
mal involuntary movements and the associates upregula-
tion of striatal prodynorphin mRNA in a rat model of
Parkinsons disease. Neurobiol Dis 6: 461474.
Anglade P, Mouatt-Pringent A, Agid Y et al. (1996). Synaptic
plasticity in the caudate nucleus of patients with Parkin-
sons disease. Neurodegeneration 5: 121128.
Antonelli T, Fuxe K, Tomasini MC et al. (2005). Effects of
sarizotan on the corticostriatal glutamate pathways.
Synapse 58: 193199.
Asselin MC, Soghomonian JJ, Cote PY et al. (1994). Striatal
changes in preproenkephalin mRNA levels in parkinsonian
monkeys. Neuroreport 5: 21372140.
Aubert I, Guigoni C, Hakansson K et al. (2005). Increased
D1 dopamine receptor signaling in levodopa-induced
dyskinesia. Ann Neurol 57: 1726.
209
Augood SJ, Emson PC, Mitchell IJ et al. (1989). Cellular
localisation of enkephalin gene expression in MPTP-
treated cynomolgus monkeys. Brain Res Mol Brain Res
6: 8592.
Bakay RAE, DeLong MR, Vitek JL (1992). Posteroventral
pallidotomy for Parkinsons disease. Letter. J Neurosurg
77: 487488.
Bara-Jimenez W, Bibbiani F, Morris MJ et al. (2005). Effects
of serotonin 5-HT1A agonist in advanced Parkinsons
disease. Mov Disord 20: 932936.
Barbeau A (1976). Pathophysiology of the oscillations in
performance after long-term therapy with L-DOPA. In:
W Birkmayer, O Hornykiewicz (Eds.), Advances in Par-
kinsonism. Roche Editions, Basel. pp. 424428.
Baron MS, Vitek JL, Bakay RAE et al. (2000). Treatment of
advanced Parkinsons disease by unilateral posterior GPi
pallidotomy: 4 years results of a pilot study. Mov Disord
15: 230237.
Bartoszyk GD, van Amsterdam C, Greiner HE et al.
(2004). Sarizotan, a serotonin 5-HT1A receptor agonist
and dopamine receptor ligand 1. Neurochemical profile.
J Neural Transm 111: 113126.
Bejjani B, Damier P, Arnoulf I et al. (1997). Pallidal stimu-
lation for Parkinsons disease. Two targets? Neurology 49:
15641569.
Bejjani B, Gervais D, Arnulf I et al. (2000). Axial parkinso-
nian symptoms can be improved: the role of levodopa and
bilateral subthalamic stimulation. J Neurol Neurosurg
Psychiatry 68: 595600.
Belanger N, Gregoire L, Hadj Tahar A et al. (2003). Chronic
treatment with small doses of cabergoline prevents dopa-
induced dyskinesias in parkinsonian monkeys. Mov Disord
18: 14361441.
Bellforte JE, Pazo JH (2004). Turning behaviour induced by
stimulation of the 5-HT receptors in the subthalamic
nucleus. Eur J Neurosci 19: 346355.
Benabid AL, Pollak P, Hommel M et al. (1989). Traitement
du tremblement parkinsonien par stimulation chronique du
noyau ventral intermediere du thalamus. Rev Neurol 145:
320323.
Benabid AL, Pollak P, Gao JM et al. (1996). Chronic electri-
cal stimulation of the ventralis intermedius nucleus of the
thalamus as a treatment of movement disorders. J Neuro-
surg 84: 203214.
Bergman H, Wichmann T, Karmon B et al. (1994). The
primate subthalamic nucleus. II. Neuronal activity in the
MPTP model of parkinsonism. J Neurophysiol 72:
507520.
Betarbet R, Poisik O, Sherer TB et al. (2004). Differential
expression and ser897 phosphorylation of striatal N-
methyl-d-aspartate receptor subunit NR1 in animal models
of Parkinsons disease. Exp Neurol 187: 7685.
Bezard E, Brotchie JM, Gross CE (2001). Pathophysiology
of levodopa-induced dyskinesia: potential for new thera-
pies. Nat Rev Neurosci 2: 577588.
Bezard E, Ferry S, Mach U et al. (2003). Attenuation of
levodopa-induced dyskinesia by normalizing dopamine
D3 receptor function. Nat Med 9: 762767.
210 J. A. OBESO ET AL.
Bibbiani F, Oh JO, Chase TN (2001). Serotonin 5-HT1A
improves motor complications in rodent and primate par-
kinsonian models. Neurology 57: 18291834.
Blanchet PJ, Boucher R, Bedard PJ (1994). Excitotoxic lateral
pallidotomy does not relieve L-dopa-induced dyskinesia in
MPTP parkinsonian monkeys. Brain Res 65: 3239.
Blanchet PJ, Konitsiotis S, Whittemore ER et al. (1999). Diif-
fering effects of N-methyl-D-aspartate-receptor subtype
selective antagonists on dyskinesias in levodopa-treated
1-methyl-4-phenyl-tetrahydropyridine monkeys. J Phar-
macol Exp Ther 290: 10341040.
Blandini F, Garcia-Osuna M, Greenamyre JT (1997). Subthala-
mic ablation reverses changes in basal ganglio oxidative
metabolism and motor response to apomorphine induced by
nigrostriatal lesion in rats. Eur J Neurosci 9: 14071413.
Bonifati V, Fabrizio E, Cipriani R et al. (1994). Buspirone in
levodopa-induced dyskinesias. Clin Neuropharmacol 17:
7382.
Boraud T, Bezard E, Guehl D et al. (1998). Effects of L-
DOPA on neuronal activity of the globus pallidus externa-
lis (GPe) and globus pallidus internalis (GPi) in the
MPTP-treated monkey. Brain Res 787: 157160.
Boraud T, Bezard E, Bioulac B et al. (2001). Dopamine
agonist-induced dyskinesias are correlated to both firing
pattern and frequency alterations of pallidal neurones in
the MPTP-treated monkey. Brain 124: 546557.
Bordet R, Ridray S, Carboni S et al. (1997). Induction of
dopamine D3 receptor expression as a mechanism of beha-
vioral sensitization to levodopa. Proc Natl Acad Sci USA
94: 33633367.
Bordet R, Ridray S, Schwartz JC et al. (2000). Involvement
of the direct striatonigral pathway in levodopa-induced
sensitization in 6-hydroxydopamine-lesioned rats. Eur J
Neurosci 12: 21172123.
Bove J, Serrats J, Mengod G et al. (2005). Neuroprotection
induced by the adenosine A (2A) antagonist CSC in the
6-OHDA rat model of parkinsonism: effect on the activity
of striatal output pathways. Exp Brain Res 165: 362374.
Bracco F, Battaglia A, Chouza C et al. (2004). PKDS009
Study Group. The long-acting dopamine receptor agonist
cabergoline in early Parkinsons disease: final results of
a 5-year, double-blind, levodopa-controlled study. CNS
Drugs 18: 733746.
Braz CA, Borges V, Ferraz HB (2004). Effect of riluzole on
dyskinesia and duration of the on state in Parkinson dis-
ease patients: a double-blind, placebo-controlled pilot
study. Clin Neuropharmacol 27: 2529.
Bronstein JM, DeSalles A, DeLong MR (1999). for the
Workshop Participants. Stereotactic pallidotomy in the
treatment of Parkinsons disease. Arch Neurol 56:
10641069.
Brooks DJ, Ibanez V, Sawle GV et al. (1992). Striatal D-2
receptor status in patients with Parkinsons disease, stria-
tonigral degeneration, and progressive supranuclear palsy,
measured with 11C-raclopride and positron emission
tomography. Ann Neurol 31: 184192.
Brooks DJ, Piccini P, Turjanski N et al. (2000). Neuroima-
ging of dyskinesia. Ann Neurol 47 (Suppl 1): S154S158.
Brotchie JM, Lee J, Venderova K (2005). Levodopa-induced
dyskinesia in Parkinsons disease. J Neural Transm 112:
359391.
Brotchie P, Iansek R, Horne MK (1991). Motor function of
the monkey globus pallidus. 2. Cognitive aspects of move-
ment and phasic neuronal activity. Brain 114: 16851702.
Brown P (2003). Oscillatory nature of human basal ganglia
activity: relationship to the pathophysiology of Parkin-
sons disease. Mov Disord 18: 357363.
Burbaud P, Bonnet B, Guehl D et al. (1998). Movement dis-
orders induced by gamma-aminobutyric agonist and
antagonist injections into the internal globus pallidus and
substantia nigra pars reticulata of the monkey. Brain Res
780: 102107.
Burchiel K, Anderson V, Favre J et al. (1999). Comparison
of pallidal and subthalamic nucleus deep brain stimulation
for advanced Parkinsons disease: results of a randomized,
blinded pilot study. Neurosurgery 45: 13751384.
Calabresi P, Mercuri NB, Sancesario G et al. (1993). Elec-
trophysiology of dopamine-denervated striatal neurons.
Implications for Parkinsons disease. Brain 116: 433452.
Calabresi P, Pisani A, Mercuri NB et al. (1996). The corti-
costriatal projection: from synaptic plasticity to dysfunc-
tions of the basal ganglia. Trends Neurosci 19: 1924.
Calabresi P, Giacomini P, Centonze D et al. (2000). Levodopa-
induced dyskinesia: a pathological form of striatal synaptic
plasticity? Ann Neurol 47: S60S68.
Calon F, Di Paolo T (2002). Levodopa response motor
complications-GABA receptors and preproenkephalin
expression in human brain. Parkinsonism Relat Disord 8:
449454.
Calon F, Goulet M, Blanchet PJ et al. (1995). Levodopa or
D2 agonist induced dyskinesia in MPTP monkeys: corre-
lation with changes in dopamine and GABA-A receptors
in the striatopallidal complex. Brain Res 680: 4352.
Calon F, Morissette M, Goulet M et al. (1999). Chronic D1 and D2
dopaminomimetic treatment of MPTP-denervated monkeys:
effects on basal ganglia GABA(A)/benzodiazepine receptor
complex and GABA content. Neurochem Int 35: 8191.
Calon F, Hadj Tahar A, Blanchet PJ et al. (2000). Dopamine-
receptor stimulation: behavioral and biochemical conse-
quences. Trends Neurosci 23 (Suppl): S92S100.
Calon F, Morissette M, Ghribi O et al. (2002). .Alteration of
glutamate receptors in the striatum of dyskinetic 1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine-treated monkeys following
dopamine agonist treatment. Prog Neuropsychopharmacol
Biol Psychiatry 26: 127138.
Calon F, Rajput AH, Hornykiewicz O et al. (2003a). Levodopa-
induced motor complications are associated with alterations
of glutamate receptors in Parkinsons disease. Neurobiol
Dis 14: 404416.
Calon F, Morissette M, Rajput AH et al. (2003b). Changes of
GABA receptors and dopamine turnover in the postmor-
tem brains of parkinsonians with levodopa-induced motor
complications. Mov Disord 18: 241253.
Calon F, Dridi M, Hornykiewicz O et al. (2004). Increased
adenosine A2A receptors in the brain of Parkinsons
disease patients with dyskinesias. Brain 127: 10751084.
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
Caparros-Lefebre D, Blond S, Feltin M-P et al. (1999). Improve-
ment of levodopa induced dyskinesias by thalamic deep brain
stimulation is related to slight variation in electrode place-
ment: possible involvement of the center median and parafas-
cicular complex. J Neurol Neurosurg Psychiatry 67: 308314.
Carpenter MB, Witthier JR, Mettler FA (1950). Analysis of
choreoid hyperkinesias in the rhesus monkey. J Comp
Neurol 92: 293322.
Carpentier AF, Bonnet AM, Vidailhet M et al. (1996). Improve-
ment of levodopa-induced dyskinesia by propranolol in
Parkinsons disease. Neurology 46: 15481551.
Carroll CB, Bain PG, Teare L et al. (2004). Cannabis for
dyskinesia in Parkinson disease: a randomized double-
blind crossover study. Neurology 63: 12451250.
Carta AR, Pinna A, Cauli O et al. (2002). Differential regulation
of GAD67, enkephalin and dynorphin mRNAs by chronic-
intermittent L-dopa and A2A receptor blockade plus L-dopa
in dopamine-denervated rats. Synapse 44: 166174.
Carvalho AL, Duarte CB, Carvalho AP (2000). Regulation
of AMPA receptors by phosphorylation. Neurochem Res
25: 12451255.
Cenci MA (2002). Transcription factors involved in the
pathogenesis of L-DOPA-induced dyskinesia in a rat
model of Parkinsons disease. Amino Acids 23: 105109.
Cenci MA, Lee CS, Bjorklund A (1998). L-DOPA-induced
dyskinesia in the rat is associated with striatal overexpres-
sion of prodynorphin- and glutamic acid decarboxylase
mRNA. Eur J Neurosci 10: 26942706.
Centonze D, Calabresi P, Giacomini P et al. (1999). Neu-
rophysiology of Parkinsons disease: from basic research
to clinical correlates. Clin Neurophysiol 110: 20062013.
Centonze D, Gubellini P, Rossi S et al. (2005). Subthalamic
nucleus lesions reverses motor abnormalities and striatal
glutamatergic overactivity in experimental parkinsonism.
Neuroscience 133: 831840.
Chapuis S, Ouchchane L, Metz O et al. (2005). Impact of the
motor complications of Parkinsons disease on the quality
of life. Mov Disord 20: 224230.
Chase TN, Oh JD (2000). Striatal dopamine- and glutamate-
mediated dysregulation in experimental parkinsonism.
Trends Neurosci 23 (10 Suppl): S86S91.
Chase TN, Baronti F, Fabbrini G et al. (1989). Rationale for
continuous dopaminomimetic therapy of Parkinsons dis-
ease. Neurology 39 (Suppl 2): 710.
Chase TN, Oh JD, Konitsiotis S (2000). Antiparkinsonian and
antidyskinetic activity of drugs targeting central glutamatergic
mechanisms. J Neurol 247 (Suppl 2): 11361142.
Chen CC, Lee ST, Wu T et al. (2002). Hemiballism after sub-
thalamotomy in patients with Parkinsons disease: report of
2 cases. Mov Disord 17: 13671371.
Cooper IS (1969). Hemiballismus and hemichorea. In: IS
Cooper (Ed.), The Vital Probe: My life as a brain surgeon.
Morton and Company, New York, pp. 293315.
Cotzias GC, Papavasiliou PS, Gellene R (1969). Modification
of parkinsonism-chronic treatment with L-dopa. N Engl J
Med 280: 337345.
Crosby NJ, Deane KH, Clarke CE (2003). Amantadine for
dyskinesia in Parkinsons disease. Cochrane Database Syst
Rev CD003467.
211
Crossman AR (1987). Primate models of dyskinesia: the
experimental approach to the study of basal ganglia-
related involuntary movement disorders. Neuroscience
21: 140.
Crossman AR (1990). A hypothesis on the pathophysio-
logical mechanisms that underlie levodopa- or dopamine
agonist-induced dyskinesia in Parkinsons disease: impli-
cations for future strategies in treatment. Mov Disord 5:
100108.
Crossman AR, Mitchell IJ, Sambrook MA et al. (1988). Chorea
and myoclonus in the monkey induced by gamma-aminobu-
tyric acid antagonist in the lentiform complex: the site of
drug action and a hypothesis for the neural mechanism of
chorea. Brain 111: 12111233.
de la Fuente-Fernandez R, Sossi V, Huang Z et al. (2004).
Levodopa-induced changes in synaptic dopamine levels
increase with progression of Parkinsons disease: implica-
tions for dyskinesias. Brain 127: 27472754.
Del Dotto P, Pavese N, Gambaccini G et al. (2001). Intrave-
nous amantadine improves levadopa-induced dyskinesias:
an acute double-blind placebo-controlled study. Mov
Disord 16: 515520.
Delfs JM, Vivian M, Ciaramitaro M et al. (1995). Subthala-
mic nucleus lesions. Widespread effects on changes in
gene expression induced by nigrostriatal dopamine deple-
tion in rats. J Neurosci 15: 65626575.
DeLong MR (1990). Primate models of movement disorders
of basal ganglia origin. Trends Neurosci 13: 281285.
Denny-Brown D, Yanagisawa N (1976). The role of the
basal ganglia in the initiation of movement. Res Publ
Assoc Res Nerv Ment Dis 55: 115149.
Derome PJ, Jedynak CD, Visot A et al. (1986). Traitement
des mouvements anormaux par lesions thalamiques. Rev
Neurol 142: 391397.
Dingledine R, Borges K, Bowie D et al. (1999). The gluta-
mate receptor ion channels. Pharmacol Rev 51: 761.
Doucet JP, Nakabeppu Y, Bedard PJ et al. (1996). Chronic
alterations in dopaminergic neurotransmission produce a
persistent elevation of deltaFosB-like protein(s) in both
the rodent and primate striatum. Eur J Neurosci 8:
365381.
Dunah AW, Standaert DG (2001). Dopamine D1 receptor-
dependent trafficking of striatal NMDA glutamate receptors
to the postsynaptic membrane. J Neurosci 21: 55465558.
Dunah AW, Wang Y, Yasuda RP et al. (2000). Alterations in
subunit expression, composition, and phosphorylation of
striatal N-methyl-D-aspartate glutamate receptors in a rat
6-hydroxydopamine model of Parkinsons disease. Mol
Pharmacol 57: 342352.
Dunah AW, Sirianni AC, Fienberg AA et al. (2004). Dopa-
mine D1-dependent trafficking of striatal N-methyl-D-
aspartate glutamate receptors requires Fyn protein tyrosine
kinase but not DARPP-32. Mol Pharmacol 65: 121129.
Durif F, Vidailhet M, Bonnet AM et al. (1995). Levodopa-
induced dyskinesias are improved by fluoxetine. Neurology
45: 18551858.
Durif F, Debilly B, Galitzky M et al. (2004). Clozapine
improves dyskinesias in Parkinson disease: a double-blind,
placebo-controlled study. Neurology 62: 381388.
212 J. A. OBESO ET AL.
Eidelberg D, Moeller JR, Ishikawa T et al. (1996). Regional
metabolic correlates of surgical outcome following unilat-
eral pallidotomy for Parkinsons disease. Ann Neurol 39:
450459.
Fahn S (2000). The spectrum of levodopa-induced dyskine-
sias. Ann Neurol 47 (Suppl 1): 211.
Favre J, Burchiel KJ, Taha JM et al. (2000). Outcome of uni-
lateral and bilateral pallidotomy for Parkinsons disease:
patient assessment. Neurosurgery 46: 344355.
Filion M, Tremblay L (1991). Abnormal spontaneous activ-
ity of globus pallidus neurons in monkeys with MPTP-
induced parkinsonism. Brain Res 547: 142151.
Filion M, Treblay L, Bedard PJ (1991). Effects of dopamine
agonist on the spontaneous activity of the globus pallidus
neurons in monkeys with MPTP-induced parkinsonism.
Brain Res 547: 152161.
Foffani G, Ardolino G, Meda B et al. (2005). Altered
subthalamo-pallidal synchronisation in parkinsonian
dyskinesias. J Neurol Neurosurg Psychiatry 76: 426428.
Ford B, Winfield L, Pullman SL et al. (2004). Subthalamic
nucleus stimulation in advanced Parkinsons disease:
blinded assessment at one year follow up. J Neurol Neuro-
surg Psychiatry 75: 12551259.
Fox MW, Ahlskog JE, Kelly PJ (1991). Stereotactic ventro-
lateralis thalamotomy for medically refractory tremor in
post-levodopa era Parkinsons disease patients. J Neuro-
surg 75: 723730.
Francois C, Savy C, Jan C et al. (2000). Dopaminergic inner-
vation of the subthalamic nucleus in the normal state, in
MPTP-treated monkeys, and in Parkinsons disease
patients. J Comp Neurol 425: 121129.
Freed CR, Greene PE, Breeze RE et al. (2001). Transplanta-
tion of embryonic dopamine neurons for severe Parkin-
sons disease. N Engl J Med 344: 710719.
Genderman GL, Ronesi J, Lovinger DM (2002). Postsynaptic
endocannabinoid release is critical to long-term depression
in the striatum. Nat Neurosci 5: 445451.
Gerfen CR (1995). Molecular effects of dopamine on striatal
projections pathways. Trends Neurosci 23: S64S70.
Gerfen CR, Engber TM, Mahan LC et al. (1990). D1 and D2
dopamine receptor-regulated gene expression of striatoni-
gral and striatopallidal neurons. Science 250: 14291432.
Ghika J, Villemure J-G, Fankhauser H et al. (1998). Efficiency
and safety of bilateral contemporaneous pallidal stimula-
tion (deep brain stimulation) in levodopa-responsive
patients with Parkinsons disease with severe fluctuations:
a 2-year follow-up review. J Neurosurg 89: 713718.
Grabli D, McCairn K, Hirsch EC et al. (2004). Behavioural
disorders induced by external globus pallidus dysfunction
in primates: I. Behavioural study. Brain 127: 20392054.
Graham WC, Sambrook MA, Crossman AR (1993). Differen-
tial effect of chronic dopaminergic treatment on dopamine
D1 and D2 receptors in the monkey brain in MPTP-
induced parkinsonism. Brain Res 602: 290303.
Grondin R, Bedard PJ, Hadj Tahar A et al. (1999). Anti-
parkinsonian effect of a new selective adenosine A2A
receptor antagonist in MPTP-treated monkeys. Neurology
52: 16731677.
Grondin R, Hadj Tahar A, Doan VD et al. (2000). Noradreno-
ceptor antagonism with idazoxan improves L-dopa-
induced dyskinesias in MPTP monkeys. Naunyn Schmie-
debergs Arch Pharmacol 361: 181186.
Gubellini P, Pisani A, Centonze D et al. (2004). Metabotropic
glutamate receptors and striatal synaptic plasticity: implica-
tions for neurological diseases. Prog Neurobiol 74: 271300.
Guigoni C, Dovero S, Aubert I et al. (2005a). Levodopa-
induced dyskinesia in MPTP-treated macaques is not
dependent on the extent and pattern of nigrostriatal lesion-
ing. Eur J Neurosci 22: 283287.
Guigoni C, Li Q, Aubert I et al. (2005b). Involvement of sen-
sorimotor, limbic, and associative basal ganglia domains
in L-3,4-dihydroxyphenylalanine-induced dyskinesia.
J Neurosci 25: 21022107.
Guridi J, Obeso JA (2001). The subthalamic nucleus, hemi-
ballismus and Parkinsons disease: reappraisal of a surgi-
cal dogma. Brain 124: 519.
Guridi J, Luquin MR, Herrero MT et al. (1993). The subtha-
lamic nucleus: a possible target for stereotaxic surgery in
Parkinsons disease. Mov Disord 8: 421429.
Guridi J, Herrero MT, Luquin MR et al. (1996). Subthalamot-
omy in parkinsonian monkeys. Behavioural and biochem-
ical analysis. Brain 119: 17171727.
Hallett PJ, Dunah AW, Ravenscroft P et al. (2005). Altera-
tions of striatal NMDA receptor subunits associated with
the development of dyskinesia in the MPTP-lesioned pri-
mate model of Parkinsons disease. Neuropharmacology
48: 503516.
Hamada I, DeLong MR (1992). Excitotoxic acid lesions of
the primate subthalamic nucleus result in transient dyski-
nesias of the contralateral limbs. J Neurophysiol 68:
18501858.
Hamani C, Richter E, Schwalb J et al. (2005). Bilateral sub-
thalamic nucleus stimulation for Parkinsons disease: a
systematic review of the clinical literature. Neurosurgery
56: 13131324.
Hamel W, Fietzek U, Morsnowski A et al. (2003). Deep
brain stimulation of the subthalamic nucleus in Parkin-
sons disease: evaluation of active electrode contacts.
J Neurol Neurosurg Psychiatry 74: 10361046.
Hassler R (1978). Striatal control of locomotion, intentional
actions and of integrating and perceptive activity. J Neurol
Sci 36: 187224.
Hassler R, Riechert T (1954). Indikationen und lokalisations
methode der gezieten hirnoperationen. Nervenarzt 25:
441447.
Hassler R, Riechert T, Mundinger F et al. (1960). Physiologi-
cal observations in stereotaxic operations in extrapyramidal
motor disturbances. Brain 83: 337349.
Hedreen JC (1999). Tyrosine hydroxylase-immunoreactive
elements in the human globus pallidus and subthalamic
nucleus. J Comp Neurol 409: 400410.
Henry B, Crossman AR, Brotchie JM (1999). Effect of
repeated L-DOPA, bromocriptine, or lisuride administra-
tion on preproenkephalin-A and preproenkephalin-B
mRNA levels in the striatum of the 6-hydroxydopamine-
lesioned rat. Exp Neurol 155: 204220.
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
Henry B, Fox SH, Crossman AR et al. (2001). Mu- and
delta-opioid receptor antagonists reduce levodopa-induced
dyskinesia in the MPTP-lesioned primate model of Parkin-
sons disease. Exp Neurol 171: 139146.
Henry B, Duty S, Fox SH et al. (2003). Increased striatal pre-
proenkephalin B expression is associated with dyskinesia
in Parkinsons disease. Exp Neurol 183: 458468.
Herrero MT, Augood SJ, Hirsch EC et al. (1995). Effects of
L-DOPA on preproenkephalin and preprotachykinin gene
expression in the MPTP-treated monkey striatum. Neu-
roscience 68: 11891198.
Herrero MT, Augood SJ, Asensi H et al. (1996a). Effects of
L-dopa therapy on dopamine D-2 receptor mRNA expres-
sion in the striatum of MPTP-intoxicated parkinsonian
monkeys. Brain Res Mol Brain Res 42: 149155.
Herrero MT, Levy R, Ruberg M et al. (1996b). Consequence
of nigrostriatal denervation and L-dopa therapy on the
expression of glutamic acid decarboxylase messenger
RNA in the pallidum. Neurology 47: 219224.
Hershey T, Black KJ, Stambuk MK et al. (1998). Altered
thalamic response to levodopa in Parkinsons patients with
dopa-induced dyskinesias. Proc Natl Acad Sci USA 95:
1201612021.
Herzog J, Volkmann J, Krack P et al. (2003). Two-year
follow-up of subthalamic deep brain stimulation in Parkin-
sons disease. Mov Disord 18: 13321337.
Hikosaka O, Wurtz RH (1983). Visual and oculomotor func-
tions of monkey substantia nigra pars reticulata. I. Relation
of visual and auditory responses to saccades. J Neurophysiol
49: 12301253.
Hirsch E, Perier C, Orieux G et al. (2000). Metabolic effects
of nigrostriatal denervation in basal ganglia. Trends Neu-
rosci 23: (Suppl): 7885.
Hollmann M, Heinemann S (1994). Cloned glutamate recep-
tors. Annu Rev Neurosci 17: 31108.
Holloway RG, Shoulson I, Fahn S et al. (2004). Parkinson
Study Group Pramipexole vs levodopa as initial treatment
for Parkinson disease: a 4-year randomized controlled
trial. Arch Neurol 61: 10441053.
Horak FB, Anderson ME (1984). Influence of globus palli-
dus on arm movements in monkeys. I. Effects of kainic
acid-induced lesions. J Neurophysiol 52: 290304.
Horowski R, Marsden CD, Obeso JA (1988). Continuous dopa-
minergic stimulation for Parkinsons disease: state of the art
and outlook. J Neural Trans 27 (Suppl): 249252.
Houeto JL, Damier P, Bejjani PB et al. (2000). Suthalamic
stimulation in Parkinson disease. A multidisciplinary
approach. Arch Neurol 57: 461465.
Hoyer D, Hannon JP, Martin GR (2002). Molecular, pharma-
cological and functional diversity of 5-HT receptors. Phar-
macol Biochem Behav 71: 533554.
Hsu A, Togasaki DM, Bezard E et al. (2004). Effect of the
D3 dopamine receptor partial agonist BP897 [N-[4-
(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide]
on L-3,4-dihydroxyphenylalanine-induced dyskinesias
and parkinsonism in squirrel monkeys. J Pharmacol Exp
Ther 311: 770777.
Hurley MJ, Jolkkonen J, Stubbs CM et al. (1996a). Dopa-
mine D3 receptors in the basal ganglia of the common
213
marmoset and following MPTP and L-DOPA treatment.
Brain Res 709: 259264.
Hurley MJ, Stubbs CM, Jenner P et al. (1996b). D3 receptor
expression within the basal ganglia is not affected by
Parkinsons disease. Neurosci Lett 214: 7578.
Inase M, Buford JA, Anderson ME (1996). Changes in the
control of arm position, movement, and thalamic dis-
charge during local inactivation in the globus pallidus of
the monkey. J Neurophysiol 75: 10871104.
Intemann PM, Masterman D, Subamanian I et al. (2001).
Staged bilateral pallidotomy for treatment of Parkinson
disease. J Neurosurg 94: 437444.
Inzelberg R, Schechtman E, Nisipeanu P (2003). Cabergoline,
pramipexole and ropinirole used as monotherapy in early
Parkinsons disease: an evidence-based comparison. Drugs
Aging 20: 847855.
Jacobs BL, Fornal CA (1993). 5-HT and motor control: a
hypothesis. Trends Neurosci 16: 346352.
Jan C, Francois C, Tande D et al. (2000). Dopaminergic
innervation of the pallidum in the normal state, in
MPTP-treated monkeys and in parkinsonian patients. Eur
J Neurosci 12: 45254535.
Jankovic J, Cardoso F, Grossman RG et al. (1995). Outcome
after stereotactic thalamotomy for parkinsonism, essential,
and others types of tremor. Neurosurgery 37: 680687.
Kaelin-Lang A, Liniger P, Probst A et al. (2000). Adenosine
A2A receptor gene expression in the normal striatum and after
6-OH-dopamine lesion. J Neural Transm 107: 851859.
Kanda T, Jackson MJ, Smith LA et al. (1998). Adenosine
A2A antagonist: a novel antiparkinsonian agent that does
not provoke dyskinesia in parkinsonian monkeys. Ann
Neurol 43: 507513.
Kanda T, Jackson MJ, Smith LA et al. (2000). Combined use
of the adenosine A (2A) antagonist KW-6002 with L-
DOPA or with selective D1 or D2 dopamine agonists
increases antiparkinsonian activity but not dyskinesia in
MPTP-treated monkeys. Exp Neurol 162: 321327.
Kannari K, Yamato H, Shen H et al. (2001). Activation of 5-
HT1A, but not 5-HT1 B receptors attenuates an increase in
extracellular dopamine derived from exogenously admi-
nistered L-Dopa in the striatum with nigrostriatal denerva-
tion. J Neurochem 76: 13461353.
Kato M, Kimura M (1992). Effects of reversible blockade of
basal ganglia on a voluntary arm movement. J Neurophy-
siol 68: 15161534.
Katzenschlager R, Hughes A, Evans A et al. (2005). Contin-
uous subcutaneous apomorphine therapy improves dyski-
nesias in Parkinsons disease: a prospective study using
single-dose challenges. Mov Disord 20: 151157.
Kelly PJ, Gillingham FJ (1980). The long term of stereotaxic
surgery and L-Dopa therapy in patients with Parkinsons
disease. J Neurosurg 53: 332337.
Kim JS, Lee KS, Lee KH et al. (2002). Evidence of thalamic
disinhibition in patients with hemichorea: semiquantitative
analysis using SPECT. J Neurol Neurosurg Psychiatry 72:
329333.
Kleedorfer B, Lees AJ, Stern GM (1991). Buspirone in the
treatment of levodopa induced dyskinesias. J Neurol
Neurosurg Psychiatry 54: 376377.
214 J. A. OBESO ET AL.
Kleiner-Fisman, Fisman D, Sime E et al. (2003). Long-
term follow-up of bilateral deep brain stimulation of the
subthalamic nucleus in patients with advanced
Parkinsons disease. J Neurosurg 99: 489495.
Konitsiotis S, Blanchet PJ, Verhagen L et al. (2000). AMPA
receptor blockade improves levodopa-induced dyskinesia
in MPTP monkeys. Neurology 54: 15891595.
Krack P, Pollak P, Limousin P et al. (1998). Opposite motor
effects of pallidal stimulation in Parkinsons disease. Ann
Neurol 43: 180192.
Krack P, Pollak P, Limousin P et al. (1999). From off period
dystonia to peak dose chorea: the clinical spectrum of vary-
ing subthalamic nucleus activity. Brain 122: 11331146.
Krack P, Batir A, Van Blercom N et al. (2003). Five-year follow-
up of bilateral stimulation of the subthalamic nucleus in
advanced Parkinsons disease. N Eng J Med 349: 19251934.
Laitinen LV, Bergerheim T, Hariz MI (1992). Leksells pos-
teroventral pallidotomy in the treatment of Parkinsons
disease. J Neurosurg 76: 5361.
Lang AE, Lozano AM, Montgomery E et al. (1997). Postero-
ventral pallidotomy in advanced Parkinsons disease. N
Engl J Med 337: 10361042.
Lange KW, Kornhuber J, Riederer P (1997). Dopamine/
glutamate interactions in Parkinsons disease. Neurosci
Biobehav Rev 21: 393400.
Lee T, Seeman P, Rajput A et al. (1978). Receptor basis for
dopaminergic supersensitivity in Parkinsons disease.
Nature 273: 5961.
Levesque M, Parent A (2005). The striatofugal fiber system
in primates: a reevaluation of its organization based on
single-axon tracing studies. Proc Natl Acad Sci USA
102: 18881893.
Levesque D, Martres MP, Diaz J et al. (1995). A paradoxical
regulation of the dopamine D3 receptor expression sug-
gests the involvement of an anterograde factor from dopa-
mine neurons. Proc Natl Acad Sci USA 92: 17191723.
Levy R, Dostrovsky JO, Lang AE et al. (2001). Effects of
apomorphine on subthalamic nucleus and globus pallidus
internus neurons in patients with Parkinsons disease. J
Neurophysiol 86: 249260.
Levy R, Ashby P, Hutchison WD et al. (2002). Dependence
of subthalamic nucleus oscillations on movement and
dopamine in Parkinsons disease. Brain 125: 11961209.
Lieberman JA (2004). Dopamine partial agonists: a new
class of antipsychotic. CNS Drugs 18: 251267.
Limousin P, Speelman JD, Gielen F et al. (1999). study col-
laborators. Multicentre European study of thalamic stimu-
lation in parkinsonian and essential tremor. J Neurol
Neurosurg Psychiatry 66: 289296.
Lindefors N, Ungerstedt U (1990). Bilateral regulation of gluta-
mate tissue and extracellular levels in caudate-putamen by
midbrain dopamine neurons. Neurosci Lett 115: 248252.
Liu X, Ford-Dunn HL, Hayward GN et al. (2002). The oscil-
latory activity in the parkinsonian subthalamic nucleus
investigated using the macro-electrodes for deep brain
stimulation. Clin Neurophysiol 113: 16671672.
Loher T, Burgunder JM, Pohle T et al. (2002). Long-term pallidal
deep brain stimulation in patients with advanced Parkinsons
disease: 1-year follow-up study. J Neurosurg 96: 844853.
Lokk J (2004). Memantine can relieve certain symptoms in
Parkinson disease. Improvement achieved in two out of
three described cases with dyskinesia and cognitive fail-
ure. Lakartidningen 101: 20032006.
Lozano AM (2001). The subthalamic nucleus: myth and
opportunities. Mov Disord 16: 183184.
Lozano AM, Lang AE, Levy R et al. (2000). Neuronal
recordings in Parkinsons disease patients with dyskinesias
induced by apomorphine. Ann Neurol 47 (4 Suppl 1):
S141S146.
Luginger E, Wenning GK, Bosch S et al. (2000). Beneficial
effects of amantadine on L-dopa-induced dyskinesias in
Parkinsons disease. Mov Disord 15; 873878.
Lundblad M, Vaudano E, Cenci MA (2003). Cellular and
behavioural effects of the adenosine A2a receptor antago-
nist KW-6002 in a rat model of l-DOPA-induced dyskine-
sia. J Neurochem 84: 13981410.
Luquin MR, Laguna J, Obeso JA (1992a). Selective D2
receptor stimulation induces dyskinesia in parkinsonian
monkeys. Ann Neurol 31: 551554.
Luquin MR, Scipioni O, Vaamonde J et al. (1992b). Levodopa-
induced dyskinesias in Parkinsons disease. Clinical and
pharmacological classification. Mov Disord 7: 117124.
Ma Y, Feigin A, Dhawan V et al. (2002). Dyskinesia after
fetal cell transplantation for parkinsonism: a PET study.
Ann Neurol 52: 628634.
Manson AJ, Schrag A, Lees AJ (2000). Low-dose olanzapine
for levodopa induced dyskinesias. Neurology 55: 795799.
Manson AJ, Katzenschlager R, Hobart J et al. (2001). High
dose naltrexone for dyskinesias induced by levodopa.
J Neurol Neurosurg Psychiatry 70: 554556.
Manson AJ, Turner K, Lees AJ (2002). Apomorphine mono-
therapy in the treatment of refractory motor complications
of Parkinsons disease: long-term follow-up study of 64
patients. Mov Disord 17: 12351241.
Maratos EC, Jackson MJ, Pearce RK et al. (2001). Anti-
parkinsonian activity and dyskinesia risk of ropinirole
and L-DOPA combination therapy in drug naive MPTP-
lesioned common marmosets. Mov Disord 16: 631641.
Marin C, Jimenez A, Tolosa E et al. (2004). Bilateral subtha-
lamic nucleus lesion reverses L-dopa-induced motor
fluctuations and facilitates dyskinetic movements in hemi-
parkinsonian rats. Synapse 51: 140150.
Marek K, Jennings D, Seibyl J (2002). Do dopamine agonists
or levodopa modify Parkinsons disease progression? Eur
J Neurol 9 (Suppl 3): 1522.
Marsden CD (1982). The mysterious motor function of basal
ganglia. Neurology 32: 514539.
Marsden CD, Obeso JA (1994). The functions of the basal
ganglia and the paradox of stereotaxic surgery in Parkin-
sons disease. Brain 117: 877897.
Marsden CD, Parkes J (1977). Success and problems of long-
term levodopa therapy in Parkinsons disease. The Lancet
1: 345349.
Marsden CD, Parkes JS, Quinn NP (1981). Fluctuations of
disability in Parkinsons disease clinical aspects. In: CD
Marsden and S Fahn (Eds.), Neurology 2: Movement
Disorders. Butterworth Scientific, London-New York, pp.
96122.
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
Martinez-Mir MI, Probst A, Palacios JM (1991). Adenosine A2
receptors: selective localization in the human basal ganglia
and alterations with disease. Neurosci 42: 697706.
Massey PV, Johnson BE, Moult PR et al. (2004). Differential
roles of NR2A and NR2B-containing NMDA receptors in
cortical long-term potentiation and long-term depression. J
Neurosci 24: 78217828.
Meco G, Fabrizio E, Di Rezze S et al. (2003). Mirtazapine in
L-dopa-induced dyskinesias. Clin Neuropharmacol 26:
179181.
Meissner W, Ravenscroft P, Reese R et al. (2006). Increased
slow oscillatory activity in substantia nigra pars reticulata
triggers abnormal involuntary movements in the 6-OHDA-
lesioned rat in the presence of excessive extracellular
striatal dopamine. Neurobiol Dis 22: 586598.
Menegoz M, Lau LF, Herve D et al. (1995). Tyrosine phos-
phorylation of NMDA receptor in rat striatum: effects of
6-OH-dopamine lesions. Neuroreport 7: 125128.
Merello M, Cammarota A, Betti O et al. (1997). Involuntary
movements during thermolesion predict a better outcome
after microelectrode guided posteroventral pallidotomy.
J Neurol Neurosurg Psychiatry 63: 210213.
Merello M, Balej J, Delfino M et al. (1999a). Apomorphine
induces changes in GPi spontaneous outflow in patients
with Parkinsons disease. Mov Disord 14: 4549.
Merello M, Nouzeilles MI, Cammarota A et al. (1999b).
Effect of memantine (NMDA antagonist) on Parkinsons
disease: a double-blind crossover randomized study. Clin
Neuropharmacol 22: 273276.
Merello M, Starkstein S, Nouzeilles MI et al. (2001). Bilat-
eral pallidotomy for treatment of Parkinsons disease
induced corticobulbar syndrome and psychic akinesia
avoidable by globus pallidus lesion combined with con-
tralateral stimulation. J Neurol Neurosurg Psychiatry 71:
611614.
Merello M, Perez Lloret S, Antico J et al. (2006). Dyskinesias
induced by subthalamotomy in Parkinsons disease are
unresponsive to amantadine. J Neurol Neurosurg Psychiatry
77: 172174.
Meshul CK, Emre N, Nakamura CM et al. (1999). Time-
dependent changes in striatal glutamate synapses follow-
ing a 6-hydroxydopamine lesion. Neurosci 88: 116.
Miller DW, Abercrombie ED (1999). Role of high-affinity
dopamine uptake and impulse activity in the appearance
of extracellular dopamine in striatum after administration
of exogenous L-DOPA: studies in intact and 6-hydroxydo-
pamine-treated rats. J Neurochem 72: 15161522.
Mink JW (2003). The basal ganglia and involuntary move-
ments: impaired inhibition of competing motor patterns.
Arch Neurol 60: 13651368.
Mink JW, Thach WT (1991). Basal ganglia motor control III.
Pallidal ablation: normal reaction time, muscle contrac-
tion, and slow movement. J Neurophysiol 65: 330351.
Mitchell IJ, Jackson A, Sambrook MA et al. (1989). The role
of the subthalamic nucleus in experimental chorea.
Evidence from 2-deoxyglucose metabolic mapping and
horseradish peroxidase tracing studies. Brain 112:
15331548.
215
Mitchell IJ, Boyce S, Sambrook MA et al. (1992). A 2-deox-
yglucose study of the effects of dopamine agonists on the
parkinsonian primate brain. Implications for the neural
mechanisms that mediate dopamine agonist-induced dys-
kinesias. Brain 115: 808824.
Molinuevo J, Valldeoriola F, Tolosa E et al. (2000). Levodo-
pa withdrawal alter bilateral subthalamic nucleus stimula-
tion in advanced Parkinsons disease. Arch Neurol 57:
983988.
Monyer H, Sprengel R, Schoepfer R et al. (1992). Hetero-
meric NMDA receptors: molecular and functional distinc-
tion of subtypes. Science 256: 12171221.
Morissette M, Goulet M, Soghomonian JJ et al. (1997). Pre-
proenkephalin mRNA expression in the caudate-putamen
of MPTP monkeys after chronic treatment with the D2
agonist U91356A in continuous or intermittent mode of
administration: comparison with L-DOPA therapy. Brain
Res Mol Brain Res 49: 5562.
Morissette M, Goulet M, Grondin R et al. (1998). Associative
and limbic regions of monkey striatum express high levels of
dopamine D3 receptors: effects of MPTP and dopamine ago-
nist replacement therapies. Eur J Neurosci 10: 25652573.
Morissette M, Dridi M, Calon F et al. (2006). Prevention
of dyskinesia by an NMDA receptor antagonist in MPTP
monkeys: effect on adenosine A2A receptors. Synapse
60: 239250.
Moro E, Scerrati M, Romito LM et al. (1999). Chronic sub-
thalamic stimulation requirements in Parkinsons disease.
Neurology 53: 8590.
Moro E, Esselink R, Benabid AL et al. (2002). Response to
levodopa in parkinsonian patients with bilateral subthala-
mic nucleus stimulation. Brain 125: 24082417.
Mouradian MM, Heuser IJ, Baronti F et al. (1990). Modifica-
tion of central dopaminergic mechanisms by continuous
levodopa therapy for advanced Parkinsons disease. Ann
Neurol 27: 1823.
Muenter MD, Sharpless NS, Tyce GM et al. (1977). Patterns
of dystonia (I-D-I and D-I-D) in response to L-dopa
therapy of Parkinsons disease. Mayo Clinic Proc 52:
163174.
Murray TK, Messenger MJ, Ward MA et al. (2002). Evalua-
tion of the mGluR2/3 agonist LY379268 in rodent models
of Parkinsons disease. Pharmacol Biochem Behav 73:
455466.
Narabayashi H, Yokochi F, Nakajima Y (1984). Levodopa-
induced dyskinesia and thalamotomy. J Neurol Neurosurg
Psychiatry 47: 831839.
Nisbet AP, Foster OJ, Kingsbury A (1995). Preproenkephalin
and preprotachykinin messenger mRNA expression in nor-
mal human basal ganglia and in Parkinsons disease. Neu-
roscience 66: 361376.
Nyholm D, Nilsson Remahl AI, Dizdar N et al. (2005). Duo-
denal levodopa infusion monotherapy vs oral polyphar-
macy in advanced Parkinson disease. Neurology 64:
216223.
Obeso JA, Luquin MR, Martinez-Lage JM (1986). Lisuride
infusion pump: a device for the treatment of Parkinsons
disease. Lancet 1: 467470.
216 J. A. OBESO ET AL.
Obeso JA, Grandas F, Vaamonde J et al. (1989). Motor com-
plications associated with chronic levodopa therapy in
Parkinsons disease. Neurology 39 (Suppl 2): 1118.
Obeso JA, Grandas F, Herrero MT et al. (1994). The role of
pulsatile versus continous dopamine receptor stimulation
for functional recovery in Parkinsons disease. Eur J Neu-
rosci 6: 889897.
Obeso JA, Rodriguez MC, DeLong MR (1997). Basal ganglia
pathophysiology. A critical review. Adv Neurol 74: 318.
Obeso JA, Rodriguez-Oroz MC, Rodriguez M et al. (2000a).
Pathophysiology of the basal ganglia in Parkinsons dis-
ease. Trends Neurosci 23 (10 Suppl): S8S19.
Obeso JA, Rodrguez-Oroz MC, Rodrguez M et al. (2000b).
Current problems in understanding the basal ganglia
model for Parkinsons disease and levodopa-induced dys-
kinesias. Ann Neurol 47 (Suppl 1): 2232.
Obeso JA, Olanow CW, Rodriguez-Oroz MC et al. (2001).
Deep Brain Stimulation for Parkinsons Disease Study
Group. Deep brain stimulation of the subthalamic nucleus
or the pars interna of the globus pallidus in Parkinsons
disease. N Engl J Med 345: 956963.
Obeso JA, Rodriguez-Oroz M, Marin C et al. (2004). The
origin of motor fluctuations in Parkinsons disease: impor-
tance of dopaminergic innervation and basal ganglia
circuits. Neurology 62 (Suppl 1): S17S30.
Oh JD, Del Dotto P, Chase TN (1997). Protein kinase A inhi-
bitor attenuates levodopa-induced motor response altera-
tions in the hemi-parkinsonian rat. Neurosci Lett 228: 58.
Oh JD, Bibbiani F, Chase TN (2002). Quetiapine attenuates
levodopa-induced motor complications in rodent and pri-
mate parkinsonian models. Exp Neurol 177: 557564.
Ohye C, Maeda T, Narabayashi H (1976). Physiologically
defined Vim nucleus, its special reference to the control
of tremor. Appl Neurophysiol 39: 285295.
Olanow CW, Goetz CG, Kordower JH et al. (2003). A dou-
ble blind placebo-controlled trial of bilateral fetal nigral
transplantation in Parkinsons disease. Ann Neurol 54:
403414.
Page RD, Sambrook MA, Crossman AR (1993). Thalamot-
omy for the alleviation of levodopa-induced dyskinesia:
experimental studies in the 1-methyl-4-phenyl-1,2,3,6-tet-
rahydropyridine treated parkinsonian monkey. Neurosci
55: 147165.
Papa SM, Chase TN (1996). Levodopa-induced dyskinesias
improved by a glutamate antagonist in Parkinsonian mon-
keys. Ann Neurol 39: 574578.
Papa SM, Desimone R, Fiorani M et al. (1999). Internal glo-
bus pallidus discharge is nearly suppressed during levo-
dopa-induced dyskinesias. Ann Neurol 46: 732738.
Patel N, Plaha P, OSullivan K et al. (2003). MRI directed
bilateral stimulation of the subthalamic nucleus in patients
with Parkinsons disease. J Neurol Neurosurg Psychiatry
74: 16311637.
Piccini P, Weeks RA, Brooks DJ (1997). Alterations in opioid
receptor binding in Parkinsons disease patients with levo-
dopa-induced dyskinesias. Ann Neurol 42: 720726.
Picconi B, Pisani A, Centonze D et al. (2002). Striatal metabo-
tropic glutamate receptor function following experimental
parkinsonism and chronic levodopa treatment. Brain 125:
26352645.
Picconi B, Centonze D, Hakansson K et al. (2003). Loss of
bidirectional striatal synaptic plasticity in L-DOPA-
induced dyskinesia. Nat Neurosci 6: 501506.
Picconi B, Gardoni F, Centonze D et al. (2004). Abnormal
Ca2-calmodulin-dependent protein kinase II function
mediates synaptic and motor deficits in experimental par-
kinsonism. J Neurosci 24: 52835291.
Pinna A, Corsi C, Carta AR et al. (2002). Modification of
adenosine extracellular levels and adenosine A (2A)
receptor mRNA by dopamine denervation. Eur J Pharma-
col 446: 7582.
Pinna A, Wardas J, Simola N et al. (2005). New therapies for
the treatment of Parkinsons disease: Adenosine A (2A)
receptor antagonists. Life Sci 77: 32593267.
Pirtosek Z, Merello M, Carlsson A et al. (1993). Preclamol
and parkinsonian fluctuations. Clin Neuropharmacol 16:
550554.
Pisani A, Bonsi P, Catania MV et al. (2002). Metabotropic
glutamate 2 receptors modulate synaptic inputs and cal-
cium signals in striatal cholinergic interneurons. J Neu-
rosci 22: 61766185.
Pisani A, Centonze D, Bernardi G et al. (2005). Striatal
synaptic plasticity: implications for motor learning and
Parkinsons disease. Mov Disord 20: 395402.
Quik M, Police S, He L et al. (2000). Expression of D(3)
receptor messenger RNA and binding sites in monkey
striatum and substantia nigra after nigrostriatal degenera-
tion: effect of levodopa treatment. Neurosci 98: 263273.
Quik M, Police S, Langston JW et al. (2002). Increases
in striatal preproenkephalin gene expression are associa-
ted with nigrostriatal damage but not L-DOPA-induced
dyskinesias in the squirrel monkey. Neurosci 113:
213220.
Rabiner EA, Gunn RN, Wilkins MR et al. (2002). Evaluation
of EMD128130 occupancy of the 5HT1A and the D2
receptor: a human PET study with [11C]WAY-100365
and [11C]-raclopride. J Psychopharmacol 16: 195199.
Rascol O, Fabre N, Blin O et al. (1994). Naltrexone, an opi-
ate antagonist, fails to modify motor symptoms in patients
with Parkinsons disease. Mov Disord 9: 437440.
Rascol O, Sabatini U, Brefel C et al. (1998). Cortical motor
overactivation in parkinsonian patients with L-Dopa
induced peak-dose dyskinesia. Brain 121: 527533.
Rascol O, Brooks DJ, Korczyn AD et al. (2000). A five-year
study of the incidence of dyskinesia in patients with early
Parkinsons disease who were treated with ropinirole or
levodopa. 056 Study Group. N Engl J Med 342:
14841491.
Rascol O, Arnulf I, Peyro-Saint Paul H et al. (2001). Idazox-
an, an alpha-2 antagonist, and L-DOPA-induced dyskine-
sias in patients with Parkinsons disease. Mov Disord
16: 708713.
Robertson RG, Farmery SM, Sambrook MA et al. (1989).
Dyskinesia in the primate following injection of an excita-
tory amino acid antagonist into the medial segment of the
globus pallidus. Brain Res 476: 317322.
 LEVODOPA-INDUCED DYSKINESIAS IN PARKINSONS DISEASE
Rodriguez-Oroz MR, Obeso JA, Lang AE et al. (2005). Bilat-
eral deep brain stimulation in Parkinsons disease: a multi-
centre study with 4 years follow-up. Brain 128: 22402249.
Samadi P, Gregoire L, Bedard PJ (2004). The opioid agonist
morphine decreases the dyskinetic response to dopaminergic
agents in parkinsonian monkeys. Neurobiol Dis 16: 246253.
Samuel M, Ceballos Boumann AO, Turjanski N et al.
(1997). Pallidotomy in Parkinsons disease increases sup-
plementary motor area and prefrontal activation during
performance of volitional movements. An H2O PET
study. Brain 12: 13011313.
Sandyk R, Snider SN (1986). Naloxone treatment of
L-Dopa-induced dyskinesias in Parkinsons disease. Am
J Psychiatry 143: 118.
Santiago M, Matarredona ER, Machado A et al. (1998). Influ-
ence of serotoninergic drugs on in vivo dopamine extracel-
lular output in rat striatum. J Neurosci Res 52: 591598.
Shinotoh H, Hirayama K, Tateno Y (1993). Dopamine D1 and
D2 receptors in Parkinsons disease and striatonigral degen-
eration determined by PET. Adv Neurol 60: 488493.
Shoulson I (1998). DATATOP: a decade of neuroprotective
inquiry. Parkinson Study Group. Deprenyl And Tocopherol
Antioxidative Therapy Of Parkinsonism. Ann Neurol
44 (Suppl 1): S160S166.
Silberstein P, Kuhn AA, Kupsch A et al. (2003). Patterning
of globus pallidus local field potentials differs between
Parkinsons disease and dystonia. Brain 126: 25972608.
Silverdale MA, Crossman AR, Brotchie JM (2002). Striatal
AMPA receptor binding is unaltered in the MPTP-
lesioned macaque model of Parkinsons disease and dyski-
nesia. Exp Neurol 174: 2128.
Simuni T, Jaggi JL, Mulholland H et al. (2002). Bilateral
stimulation of the subthalamic nucleus in patients with
Parkinsons disease: a study of efficacy and safety.
J Neurosurg 96: 666672.
Smith Y, Charara A, Parent A (1996). Synaptic innervation of
midbrain dopaminergic neurons by glutamate-enriched term-
inals in the squirrel monkey. J Comp Neurol 364: 231253.
Snow BJ, Macdonald L, Mcauley D et al. (2000). The effect
of amantadine on levodopa-induced dyskinesias in Parkin-
sons disease: a double-blind, placebo-controlled study.
Clin Neuropharmacol 23: 8285.
Sokoloff P, Giros B, Martres MP et al. (1990). Molecular
cloning and characterization of a novel dopamine receptor
(D3) as a target for neuroleptics. Nature 347: 146151.
Standaert DG, Testa CM, Penney JB et al. (1994). Organization
of N-methyl-D-aspartate glutamate receptor gene expression
in the basal ganglia of the rat. J Comp Neurol 64: 1123.
Stanford IM, Kantaria MA, Chahal HS et al. (2005). 5-Hydro-
xytryptamine induced excitation and inhibition in the subtha-
lamic nucleus: action at 5-HT2c, 5-HTA4 and 5-HT1A
receptors. Neuropharmacology 49: 12281234.
Steiner H, Gerfen CR (1999). Enkephalin regulates acute D2
dopamine receptor antagonist-induced immediate early
gene expression in striatal neurons. Neurosci 88: 795810.
Stephens B, Mueller AJ, Shering AF et al. (2005). Evidence
of a breakdown of corticostriatal connections in Parkin-
sons disease. Neurosci 132: 741754.
217
Stocchi F, Ruggieri S, Vacca L et al. (2002). Prospective
randomized trial of lisuride infusion versus oral levo-
dopa in patients with Parkinsons disease. Brain 125:
20582066.
Su P, Tseng HM, Liu HM et al. (2002). Subthalamotomy for
advanced Parkinsons disease. J Neurosurg 97: 598606.
Sung KW, Choi S, Lovinger DM (2001). Activation of group
ImGluRs is necessary for long-term depression in striatal
synapses. J Neurophysiol 86: 24052412.
Svenningsson P, Le Moine C, Aubert I et al. (1998). Cellular
distribution of adenosine A2A receptor mRNA in the
primate striatum. J Comp Neurol 399: 299240.
Swope SL, Moss SJ, Raymond LA et al. (1999). Regulation
of ligand-gated ion channels by protein phosphorylation.
Adv Second Messenger Phosphoprotein Res 33: 4978.
Tanaka H, Kannari K, Maeda T et al. (1999). Role of serotoniner-
gic neurons in L-Dopa derived extracellular dopamine in the
striatum of 6-OHDA-lesioned rats. Neuroreport 10: 631634.
Tasker RR (1990). Thalamotomy. Neurosurg Clin N Am 1:
841864.
Tasker RR, Munz M, Junn FSCK et al. (1997). Deep brain
stimulation and thalamotomy for tremor compared. Acta
Neurochir Suppl 68: 4953.
Tekumalla PK, Calon F, Rahman Z et al. (2001). Elevated
levels of DeltaFosB and RGS9 in striatum in Parkinsons
disease. Biol Psychiatr 50: 813816.
Tel BC, Zeng BY, Cannizzaro C et al. (2002). Alterations in
striatal neuropeptide mRNA produced by repeated admin-
istration of L-Dopa, ropinirole or bromocriptine correlate
with dyskinesia induction on MPTP-treated common mar-
mosets. Neuroscience 115: 10471058.
Thomas A, Iacono D, Luciano AL et al. (2004). Duration of
amantadine benefit on dyskinesia of severe Parkinsons
disease. J Neurol Neurosurg Psychiatry 75: 141143.
Tomiyama M, Kimura T, Maeda T et al. (2005). A serotonin
5-HT1A receptor agonist prevents behavioral sensitization
to levodopa in a rodent model of Parkinsons disease.
Neurosci Res 52: 185194.
Touchon JC, Moore C, Frederickson C et al. (2004). Lesion
of subthalamic or motor thalamic nucleus in 6-hydroxydo-
pamine-treated rats: effects on striatal glutamate and apo-
morphine-induced contralateral rotations. Synapse 15:
287298.
Trabucchi M, Bassi S, Frattola L (1982). Effect of naloxone
on the on-off syndrome in patients receiving long-term
levodopa therapy. Arch Neurol 39: 120121.
Ulas J, Weihmuller FB, Brunner LC et al. (1994). Selective
increase of NMDA-sensitive glutamate binding in the
striatum of Parkinsons disease, Alzheimers disease, and
mixed Parkinsons disease/Alzheimers disease patients:
an autoradiographic study. J Neurosci 14: 63176324.
Vaamonde J, Luquin MR, Obeso JA (1991). Subcutaneous
lisuride infusion in Parkinsons disease: response to chronic
administration in 34 patients. Brain 114: 601614.
Verhagen Metman L, Del Dotto P, Blanchet PJ et al. (1998a).
Blockade of glutamatergic transmission as treatment for
dyskinesias and motor fluctuations in Parkinsons disease.
Amino Acids 14: 7582.
218 J. A. OBESO ET AL.
Verhagen Metman L, Del Dotto P, Natte R et al. (1998b).
Dextromethorphan improves levodopa-induced dyskine-
sias in Parkinsons disease. Neurology 51: 203206.
Vila M, Levy R, Herrero MT et al. (1997). Consequences of
nigrostriatal denervation on the functioning of the basal
ganglia in human and nonhuman primates: an in situ
hybridization study of cytochrome oxidase subunit I
mRNA. J Neurosci 17: 765773.
Vingerhoets FJG, Villemure JG, Temperli P et al. (2002).
Subthalamic DBS replace levodopa in Parkinsons dis-
ease: two year follow-up. Neurology 58: 396401.
Visser-Vanderwalle V, Van der Linden C, Temel Y et al.
(2003). Long term motor effect of unilateral pallidal sti-
mulation in 26 patients with advanced Parkinson disease.
J Neurosurg 99: 701707.
Vitek JL, Giroux M (2000). Physiology of hypokinetic and
hyperkinetic movement disorders: model for dyskinesia.
Ann Neurol 47 (Suppl 1): S131S140.
Vitek JL, Chockkan V, Zhang IY et al. (1999). Neuronal
activity in the basal ganglia in patients with generalized
dystonia and hemiballismus. Ann Neurol 46: 2235.
Volkmann J, Allert N, Voges J et al. (2004). Long term
results of bilateral pallidal stimulation in Parkinsons
disease. Ann Neurol 55: 871875.
Whittier JR, Mettler FA (1949). Studies of the subthalamus in
rhesus monkey. II. Hyperkinesia and other physiological
effects of the subthalamic lesion, with special reference to
the subthalamic nucleus of Luys. J Comp Neurol 90: 319372.
Whone AL, Watts RL, Stoessl AJ et al. (2003), REAL-PET
Study Group. Slower progression of Parkinsons disease
with ropinirole versus levodopa: the REAL-PET study.
Ann Neurol 54: 93101.
Yelnik J, Damier P, Demeret S et al. (2003). Localization of
stimulation electrodes in patients with Parkinson disease
by using a three-dimensional atlas-magnetic resonance
coregistration method. J Neurosurg 99: 8999.
Zeng BY, Pearce RK, MacKenzie GM et al. (2000). Alterations
in preproenkephalin and adenosine-2a receptor mRNA,
but not preprotachykinin mRNA correlate with occurrence
of dyskinesia in normal monkeys chronically treated with
L-DOPA. Eur J Neurosci 12: 10961104.
Further Reading
Bonifati V, Fabrizio E, Cipriani R et al. (1992). Buspirone
in levodopa-induced dyskinesias. Clin Neuropharmacol
17: 7382.
Hadj Tahar A, Gregoire L, Darre A et al. (2004). Effect of a
selective glutamate antagonist on L-dopa-induced dyski-
nesias in drug-naive parkinsonian monkeys. Neurobiol
Dis 15: 171176.
Katzenschlager R, Manson AJ, Evans A et al. (2004).
Low dose quetiapine for drug induced dyskinesias in Par-
kinsons disease: a double blind cross over study. J Neurol
Neurosurg Psychiatry 75: 295297.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 41

Treatment-induced mental changes in Parkinsons disease

KELVIN L. CHOU AND JOSEPH H. FRIEDMAN*

Department of Clinical Neurosciences, Brown University Medical School and NeuroHealth Parkinsons Disease and
Movement Disorders Center, Warwick, RI, USA

41.1. Introduction This chapter provides an overview of the various

Although Parkinsons disease (PD) is defined by the
presence of its motor features alone, it has become
increasingly clear that PD is not just a neurological
disorder, but a neurobehavioral syndrome with well-
documented mood, cognitive and behavioral symptoms.
Unfortunately, many of the behavioral abnormalities
associated with PD are due to or exacerbated by the med-
ications used to treat the myriad symptoms of
the disease. In addition, evidence is accumulating to
show that surgical therapies may worsen or even cause
behavioral or cognitive decline in patients with PD.
Because these mental changes may occur late in the
course of the illness, long after antiparkinsonian
medications have been started, it can be difficult to
determine whether these changes are treatment-induced,
treatment-exacerbated or intrinsic to the disease process.
Further complicating the problem is the issue of
dementia with Lewy bodies (DLB) and our limited
understanding of the dementia syndrome that often
occurs in PD (see Ch. 60). Whereas the presence of visual
hallucinations in an untreated state is one of the clinical
hallmarks of DLB, visual hallucinations in DLB are
indistinguishable from drug-induced hallucinosis in PD.
Moreover, DLB is diagnosed clinically when the demen-
tia occurs before or soon after the onset of parkinsonism
(McKeith et al., 1996), yet it has become clear that the
dementing aspect may develop years later (Apaydin
et al., 2002). Finally, all of the dementing disorders,
including the dementia of PD and DLB, are associated
with a variety of psychotic and other behavioral symp-
toms (Cahn-Weiner et al., 2002). These overlapping
clinical symptoms make it challenging to distinguish
between the different disorders.
adverse behavioral and cognitive changes seen as a
result of the pharmacological and surgical treatment
of PD. The phenomenology and treatment of drug-
induced psychosis will be discussed in detail, and
mood fluctuations, as well as repetitive and compul-
sive behaviors due to dopaminergic medications, will
be reviewed. Recent literature highlighting the nega-
tive behavioral and cognitive changes from ablative
surgeries and deep brain stimulation (DBS) for PD will
also be covered.
41.2. Mental changes due to pharmacologic
treatment of Parkinsons disease
41.2.1. Drug-induced psychosis
Although psychosis used to be defined as a major
mental disorder in which reality testing is impaired,
the current definition describes psychosis as a disorder
characterized by hallucinations, delusions or disorga-
nized thinking (American Psychiatric Association,
1994). Hallucinations are perceptions without any
basis in reality, i.e. seeing, hearing, smelling, tasting
or feeling things that are not present. These need to
be distinguished from illusions, which are distorted
perceptions, such as seeing an animal in a shadow,
mistaking a distant tree for a person, seeing faces in
flowers or misperceiving a motor sound for a voice.
A delusion is a false and irrational belief that has no
foundation. Common examples include believing that
strangers are living in or moving objects around the
house, thinking that family members have been
replaced by imposters and believing that one is being
investigated by the Federal Bureau of Investigation.

*Correspondence to: Joseph H. Friedman, NeuroHealth Parkinsons Disease and Movement Disorders Center, 227 Centerville
Road, Warwick, RI 02886, USA. E-mail: Joseph_Friedman@brown.edu, Tel: 1-401-732-3332, Fax: 1-401-737-3623.
220 K. L. CHOU AND J. H. FRIEDMAN
Psychosis is not a feature of untreated PD. Whereas
visual hallucinations are typical of untreated DLB and
delusions may occur in demented PD patients who are
not taking medication, the vast majority of PD patients
who develop psychotic symptoms do so on PD
medications and return to their non-psychotic baseline
if the PD medications are discontinued (Kofman,
1984; Friedman, 1985).
Psychosis affects 510% of drug-treated PD
patients (Dewey and OSuilleabhain, 2000). There
are three explanations for the occurrence of psychosis
in this population. Most commonly, the medications
themselves are responsible. However, many psychoses
also undoubtedly occur because of the presence of
dementia, whether due to PD dementia, DLB or some
other pathology (see Ch. 60). Additionally, a tiny per-
centage of patients have a premorbid primary psycho-
sis, such as schizophrenia, and later develop PD. The
importance of recognizing and treating psychosis in
PD is illustrated by studies which have shown that
psychosis, not motor dysfunction, is the single greatest
precipitant for nursing-home placement in PD patients
(Goetz and Stebbins, 1993; Aarsland et al., 2000).
As might be deduced from this observation, the single
greatest stress for care-takers is also psychosis
(Aarsland et al., 1999). In addition, the appearance of
psychosis markedly increases the risk of mortality
(Goetz and Stebbins, 1995; Factor et al., 2003). In
one double-blind, placebo-controlled treatment trial
of psychosis in PD, 10% of the subjects died during
or shortly after completing a 3-month trial (Parkinson
Study Group, 1999). In another, 5% of the subjects
died (Pollak et al., 2004).
The clinical scenario for psychosis in PD is fairly
stereotypic and can be divided into two major cate-
gories: psychosis with a clear sensorium and psychosis
with a clouded sensorium. In both conditions patients
typically develop hallucinations. The latter condition
is often termed an encephalopathy by neurologists
and a delirium by psychiatrists.
41.2.1.1. Psychosis with a clear sensorium
These patients are much more like the primary
psychiatric patient in that they will have a normal
attention span, memory and cognition. The psychosis
is manifest primarily by hallucinations and, to a lesser
extent, by delusions, which are generally of a paranoid
nature. The most common delusion in a descriptive
analysis of two double-blind, placebo-controlled anti-
psychotic trials (Table 41.1) was stealing (Friedman
et al., 2002). However, not all patients have delusions.
When the hallucinations are so severe that they are
believed to be real, then the patient is considered
psychotic. At this point, food may be set out for the
Table 41.1
Types of delusions in 160 Parkinsons disease patients
with drug-induced psychosis
Type of delusion Number of patients
Stealing 53
Not my house 46
Abandonment 41
Spouse imposter 32
Infidelity 26
Other 38 paranoid 21 non-paranoid
imagined guests and water and food bowls are placed
for dog and cat visitors. The police may be called to
catch burglars. The phenomenology of the delusions
overlaps with those seen in other dementing illnesses
(Cahn-Weiner et al., 2002), as assessed in the Neuropsy-
chiatric Inventory (Cummings, 1997). Family members
or other people may be stealing money or discussing
things about the patient, strangers may be living in the
house, patients may accuse the spouse of being an
imposter, trips are supposedly being taken without the
patient and nursing-home placement is planned none
of which is true. Another common delusion is the
accusation of spousal infidelity, which affects both men
and women and is even more difficult to manage.
41.2.1.2. Psychosis with an impaired sensorium or
dementia
Unlike psychosis in patients with a clear sensorium,
these patients are delirious or demented and, as a
result, manifest psychotic features. Delirious and
demented patients with psychosis do less well, in all
respects. They are less responsive to and less tolerant
of antipsychotic drugs. The common antipsychotics
used in managing PD patients with psychosis,
clozapine and quetiapine, are sedating. Whereas this
side-effect is beneficial in helping the patient sleep at
night, it may increase the confusion that occurs when
the patient awakens during the night, as well as pro-
duce a hangover state in the morning. In a demented
or delirious patient, this increased daytime somnolence
contributes to the delirium. In some cases, we believe
this worsened sleepiness may also blunt the response
to the anti-PD medications, resulting in worsened
motor function. Since both drugs may also cause or
worsen orthostatic hypotension, precautions to prevent
fainting, especially after lying supine at night, must be
maintained.
41.2.1.3. Hallucinations
Hallucinations are not part of the untreated state of
idiopathic PD but were described with postencephalitic
 TREATMENT-INDUCED MENTAL CHANGES IN PARKINSONS DISEASE
parkinsonism (de Ajuriaguerra, 1972) and constitute a
cardinal feature of untreated DLB (McKeith et al.,
1996). In terms of frequency, visual hallucinations
are most commonly reported (Fenelon et al., 2000;
Holroyd et al., 2001). We analyzed baseline data
regarding hallucinations (Table 41.2) on 160 subjects
from two identical antipsychotic studies performed
simultaneously in Europe and the USA (Friedman
et al., 2002). DLB patients were excluded, but 58
patients were demented (defined as Mini-Mental State
Examination (MMSE) < 24). Visual hallucinations were
the most prevalent, followed by auditory, olfactory
and then tactile hallucinations. These data were from
subjects enrolled in double-blind placebo-controlled
trials and are therefore not representative of the general
PD population, but are probably representative of mild
to moderately psychotic PD patients with drug-induced
psychosis.
There are marked differences between the halluci-
nations encountered in treated PD and those reported
with primary psychiatric disorders such as schizophre-
nia (Table 41.3). Primary psychiatric hallucinations
are usually auditory and ego-syntonic, whereas drug-
induced hallucinations in PD are generally visual and
without emotional content. This is true even when
the hallucinated image should have some emotional
content, such as a deceased spouse, a deceased pet or
a long-unseen loved one. In PD, most patients recog-
nize that the hallucinations are not real, but in primary
Table 41.2
Types of hallucinations in 160 Parkinsons disease
patients with drug-induced psychosis
Type of hallucination No. of patients
Visual 155
Auditory 76
Olfactory 25
Table 41.3
Differences in the hallucinations of schizophrenia and
Parkinsons disease
Schizophrenia Drug-induced Parkinsons disease
Auditory Visual
Poor insight Preserved insight
Demeaning/nasty Benign
Present for long periods Usually under 5 minutes
Ego-syntonic Unrelated to emotional state
Interact with patient Ignore patient
221
psychotic conditions, they are perceived as real.
Auditory hallucinations frequently make demeaning
comments in schizophrenia whereas the drug-induced
PD hallucinations are not bothersome and may even
be entertaining.
Visual hallucinations occur in 944% of drug-
treated patients, depending on the survey (Meco
et al., 1990; Haeske-Derwick, 1995; Sanchez-Ramos
et al., 1996; Graham et al., 1997; McDowell and
Harris, 1997; Fenelon et al., 2000; Barnes and David,
2001; Holroyd et al., 2001). The hallucinations may
occur at any time and with any type of lighting.
Fenelon and colleagues (2000) included the term
presence hallucinations to denote the vivid sensation
of the presence of somebody either somewhere in the
room or . . . behind him. This presence was usually
that of a person, but occasionally was an animal
and, in one case, the patient felt a guardian angel.
They also described passage hallucinations, which
were brief visions that were seen in the periphery of
the visual field. These so-called minor hallucinations
occurred slightly more frequently than formed visual
hallucinations, which were usually of non-threatening
people, animals or objects. The hallucinations usually
last under 5 minutes and many last for seconds only.
They usually occur a few times a week, but are rarely
omnipresent. The hallucinations may look clear and
real or hazy and out of focus. Occasional patients will
report using their spectacles to see the hallucinations
more clearly. They may be in color or black and white.
Sometimes the hallucinations are in the house, but
frequently are outdoors, i.e. workers digging up the
garden, checking the telephone lines or playing in
the street. One of the most interesting aspects of the
hallucinations is their consistency. A patient who
hallucinates children wearing funny clothes tends to
see the same children wearing the same clothing each
time, often sitting in the same chairs in the house
doing the same things. This type of stereotyped
hallucination is therefore quite different from a dream.
The hallucinated figures typically ignore the patient
but may talk or gesture among themselves without
sound. The hallucinations may get up and walk out
of the door, but the closing door makes no noise. Less
frequently, the hallucination may be inanimate, like a
statue or plant.
Visual hallucinations are more frequent in the
evening but may occur during the day as well. Some
patients only see hallucinations in the light. The hal-
lucinations may be Lilliputian (i.e. small people
living in a houseplant) or of normal size. Giant peo-
ple are generally not part of the phenomenology,
although enlarged animals, like large rats or cats,
may be.
222 K. L. CHOU AND J. H. FRIEDMAN
Auditory hallucinations, on the other hand, are
usually quite different from the visual. Auditory
hallucinations occur primarily in people who already
have visual hallucinations (Inzelberg et al., 1998).
In these cases, the visual hallucinations may talk to
the patient and carry on interactive conversations.
When auditory hallucinations occur without visual hal-
lucinations, the sounds tend to be indistinct, such as
party noises coming from another room or voices talk-
ing outside, but without individual words being heard.
The hallucinations almost always occur when the
patient is otherwise unstimulated. The patient is
usually alone, either reading or watching television,
when he/she notices the hallucinated people watching
him/her.
Major risk factors for visual hallucinations include
impaired vision, disease duration, dementia, depres-
sion, sleep disorders and recent medication changes
(Nausieda et al., 1982; Comella et al., 1993; Pappert
et al., 1999; Arnulf et al., 2000; Barnes and David,
2001), but many patients have no risk factors. Most
hallucinating patients have no premorbid psychiatric
history. A common misconception is that the halluci-
nations only arise when medications have been
increased. Although this is frequently true, it is not
always the case. Patients commonly develop hallucina-
tions on doses of drugs that have not been changed in
several years. The association of diminished vision
with visual hallucinations brings to mind Bonnets
syndrome, in which elderly people with severe visual
dysfunction but normal cognition develop visual hallu-
cinations. Since PD patients may have impaired vision
that is unrelated to their PD, they are subject to Bon-
nets hallucinations (Matsui et al., 2004). However,
the statistical association between visual dysfunction
and hallucinations is loose, with hallucinators
performing only slightly worse on eyechart testing
(mean visual acuity 20/44.6) than non-hallucinators
(20/32.8) (Holroyd et al., 2001). Dementia has been
clearly documented as a risk factor, which brings up
the possible alternative diagnosis of DLB. A promi-
nent expert has opined that most cases of drug-induced
hallucinations represent the premature unmasking of
DLB by use of dopaminergic drugs (McKeith, perso-
nal communication), but no data exist to support this
claim.
It is interesting that all of the PD medications
(anticholinergics, dopaminergics and amantadine)
have been found to induce very similar hallucinations
(Goetz et al., 1982b) despite their different mechan-
isms of action. Yet certain drugs are more likely than
others to induce these problems. For example, the
dopaminomimetics, such as pramipexole, ropinirole
and pergolide (Parkinson Study Group, 2000; Rascol
et al., 2000), are more likely to induce visual halluci-
nations than levodopa. Drug doses are also important
risk factors. The higher the dose, the higher the risk.
Yet the occurrence of hallucinations is only partly
related to the serum or brain level of the drug. One
study infused high-dose levodopa intravenously into
PD patients who suffered from visual hallucinations
at home (Goetz et al., 1998a). Despite receiving much
higher levels of drug than they did at home, none of
them hallucinated in the hospital research setting, indi-
cating that there is a combined effect of the drug and
the patients mental state at the time. It is believed,
but without supportive data, that polypharmacy also
increases risk. Some experts believe that there is more
risk from low levels of multiple psychoactive drugs
than higher levels of a single or few numbers of other
drugs.
Tactile, olfactory and gustatory hallucinations tend
to be considerably less common in PD patients with
drug-induced psychosis, but occur more than rarely
(Friedman et al., 2002). One report described tactile
hallucinations as affecting about 7% of hallucinators
(Goetz et al., 1998b). As with auditory hallucinations,
these non-visual hallucinations occur almost exclu-
sively in people who already suffer from visual ones
(Fenelon et al., 2002; Tousi and Frankel, 2004). The
tactile hallucinations tend to be animals, worms, bugs
and other generally unpleasant things that are also seen
(Fenelon et al., 2002).
The recognition of hallucinations is usually quite
simple. Nevertheless, when the patient is too demented
to produce a reliable history or when the hallucinations
take place around sleep, it can be challenging. It is
unknown whether PD patients experience an increase
in hypnagogic or hypnopompic hallucinations. A var-
iant of these conditions, the rapid-eye movement
(REM) intrusion, occurs when a patient may experi-
ence a dream intruding into consciousness while
sleepy but not actually asleep. It has become clear in
recent years that patients frequently do not recognize
their sleepiness and may suffer from sleep attacks
(Olanow et al., 2000), suggesting that a patient suffer-
ing a REM intrusion may not recognize it as a dream,
but rather remember it later as a hallucination. How-
ever, the most likely confusion arises in distinguishing
nocturnal hallucinations from vivid dreams and REM
sleep behavior disorder. In the former the patient
experiences realistic dreams whereas in the latter the
dream is acted out, typically of fighting or running
away from a threat.
41.2.1.4. Treatment
The management of the psychotic PD patient is similar
in delirious and non-delirious patients. Most importantly,
 TREATMENT-INDUCED MENTAL CHANGES IN PARKINSONS DISEASE
the possibility of triggering factors should be considered.
The most likely triggers are infection or drug toxicity.
Although infections generally produce fever and other
systemic symptoms, this is not always the case. There-
fore, urinary tract infections and pneumonias should
always be considered as possible underlying explanations
for the onset of psychosis. PD drug overdoses may
produce psychotic symptoms with or without delirium.
Of all the PD medications, only amantadine is cleared
by the kidney, so that a degree of renal failure which
would produce no encephalopathic features in a typical
PD patient may produce a toxic delirium in one taking
amantadine. Other common drugs taken by PD patients
that may cause or exacerbate psychosis include pain or
sleeping medications. However, digitalis toxicity as well
as other drug toxicities may be contributory. Occasionally
other metabolic explanations are found, such as isolated
renal or hepatic impairment or hypoxia.
Structural brain lesions are virtually never explana-
tions. Although a patient may have fallen and sustained
a subdural hematoma or intraparenchymal hemorrhage,
these are exceedingly uncommon and, when found, are
usually the result, not the cause, of the psychiatric
decline.
When possible, the patient is best managed at
home, in a secure, comforting, familiar environment.
It is common for PD patients who had no psychotic
or delirious behavior at home to decompensate simply
upon moving into the hospital environment. We
strongly recommend that, whenever possible, the neu-
rologist develop a working relationship with a limited
number of psychiatric inpatient units, so that their
PD patients can be referred to these units. This allows
the clinical staff in such units to gain more experience
with management of psychosis in this population,
which ultimately results in better care for the patient.
The approach to treatment in patients with PD is dif-
ferent than in other conditions where the drug causing
the side-effect is discontinued. First of all, all
antiparkinsonian medications can produce mental dis-
turbances, making it difficult to know which drug is
responsible or contributing to the psychosis. Secondly,
reductions in these PD medications may cause intoler-
able motor decline. We therefore recommend the
following approach. First, we suggest discontinuing
medications used to treat other conditions, such as pain
and insomnia, before reducing the anti-PD medications.
We would then discontinue, in the following order,
anticholinergics, selegiline and amantadine, because
these medications have such mild antiparkinsonian
effects that they can usually be discontinued without
difficulty. If the patient remains psychotic, the next step
is to reduce or stop the dopamine agonists, since studies
comparing the benefits of levodopa to dopamine
223
agonists in previously untreated PD patients have
demonstrated that the agonists are more likely than
levodopa to induce psychotic symptoms (Parkinson
Study Group, 2000; Rascol et al., 2000). We would
reduce COMT inhibitors and levodopa last. If psychosis
persists despite the fact that anti-PD medications have
been reduced to their lowest level consistent with toler-
able motor function, then an antipsychotic medication
should be started.
Other approaches to reducing the psychosis have
included drug holidays (Friedman, 1991) and electro-
convulsive therapy (ECT) (Hurwitz et al., 1988; Factor
et al., 1995). The data on drug holidays are scanty
and were accumulated primarily as a treatment of
clinical fluctuations, not psychosis or delirium (Goetz
et al., 1982a). These data suggest that it is not helpful
and often harmful. The use of ECT is supported by
isolated case reports and appears to work even in cases
not diagnosed with psychotic depressions. We consider
ECT a treatment of last resort, although psychiatrists
with an interest in ECT think this is a major and biased
oversight.
The atypical antipsychotic drugs (AA) represent the
newest generation of antipsychotic drugs used primar-
ily in the treatment of schizophrenia but also the other
psychotic disorders (primarily schizoaffective, bipolar
and psychotic depressive disorders). Clozapine was
the first such drug, followed shortly thereafter by ris-
peridone, olanzapine, quetiapine, ziprasidone and most
recently aripiprazole. Unfortunately there is no con-
sensus definition of atypicality. Although several
different suggestions have been entertained, the most
commonly accepted definition is relative freedom
from extrapyramidal side-effects at the usual antipsy-
chotic doses. What relative means however has never
been addressed and for patients with PD or DLB, who
are the most sensitive populations to the extrapyrami-
dal effects of these drugs, the issue is of great
importance. Data now exist on the effects of each of
the AAs, with the exception of ziprasidone. Although
ziprasidone is not the most recently released AA, it
alone carries a warning about a prolonged QT interval
on the electrocardiogram, making it an unpopular drug
to try on the elderly frail. There are double-blind pla-
cebo-controlled data on clozapine and olanzapine in
the treatment of drug-induced psychosis in PD
(Parkinson Study Group, 1999; Breier et al., 2002;
Pollak et al., 2004). Prior to the first randomized trial
of clozapine there was a wealth of open-label data
indicating that the drug, at very low doses in compar-
ison to the doses used in schizophrenia, was extremely
effective in treating the psychosis without worsening
of motor function (Friedman and Factor, 2000).
In fact, several reports have demonstrated that clozapine
224 K. L. CHOU AND J. H. FRIEDMAN
has antitremor efficacy that rivals that of levodopa
and benztropine (Friedman and Lannon, 1990; Jansen,
1994; Friedman et al., 1997). In schizophrenia,
clozapine was started at 25 mg/day and increased by
25 mg each day on a t.i.d. regimen to a dose total of
300900 mg/day (Kane et al., 1988). For schizophrenics
with fixed delusions, that is, delusions that had
been present and unchanged for several months, the
improvement was generally only partial and usually
took several weeks or months. In PD patients, fixed
delusions sometimes resolved overnight even when
the delusions had been present for many months.
In addition, the dose required was often as low as
6.25 mg/day. Before this was recognized, a double-
blind placebo-controlled trial was instituted using
the schizophrenia titration schedule, resulting in the
only negative study ever reported on the efficacy of
clozapine in PD (Wolters et al., 1990). In 1999 the
only two randomized, double-blind placebo-controlled
trials of low-dose clozapine were published (Parkinson
Study Group, 1999; French Clozapine Parkinson Study
Group, 1999). Both designs were almost identical and
the results were very close. Both showed that low-dose
clozapine, with doses held between 6.25 and 50 mg/
day, resulted in clinically and statistically significant
benefit in all measures of psychosis employed and
that motor function did not decline. In fact there
was a non-statistically significant motor benefit of
clozapine due to its antitremor effect. (The tremor
benefit was statistically significant.) In the American
study, the most commonly used dose, chosen in a
double-blinded fashion, was only 6.25 mg/day and
the mean dose required was 25 mg/day (Parkinson
Study Group, 1999). In the French study, the mean
dose was 35 mg/day (Pollak et al., 2004). Interest-
ingly, the schizophrenic dosing is t.i.d. whereas the
PD dosing is generally limited to a single dose, given
at bedtime. These different responses again under-
score the major differences between schizophrenic
psychosis and drug-induced psychosis in PD. The
clozapine data from the double-blinded trials support
the way clozapine was used prior to the two trials.
Generally clozapine is started at 6.25 mg at bedtime
and increased, based on response and tolerance, by
6.25 mg to 12.5 mg each night, as needed. We
recommend increasing the dose daily until the patient
sleeps through the night, at which point the dose
should be increased more slowly, based on whether
the patient is oversedated in the morning. Despite
the low dosing, weekly white blood cell counts must
be monitored as the agranulocytosis side-effect is not
dose-dependent and appears to be mildly more
common in the elderly (Alvir et al., 1993), affecting
between 1 and 2% within the first 3 months. It becomes
increasingly less likely thereafter but, in the USA,
biweekly monitoring is required as long as the patient
takes the clozapine. The Food and Drug Administra-
tion, in order to secure the blood count monitoring,
has required the blood count result before dispensing
the clozapine. Only enough pills are dispensed to last
until the next blood draw, thus guaranteeing compli-
ance while on the clozapine. In Europe the monitoring
is reduced to monthly after the first 6 months. There
have been no deaths attributed to clozapine among
PD patients in the USA.
The monitoring requirement has made alternatives
to clozapine very attractive. The second AA, risperi-
done, unfortunately failed to preserve motor function.
Risperidone has all the side-effects of a low-potency
neuroleptic. It causes dose-dependent parkinsonism,
acute dystonic reactions, akathisia and increases in
prolactin secretion. It also induces tardive dyskinesia,
but at a considerably lower rate than the historical
controls to which it has been compared (Jeste, 2004).
The data on risperidone in PD are actually quite
mixed, with some reports describing the complete
absence of motor side-effects (Meco et al., 1994; Allen
et al., 1995; Workman et al., 1997) whereas others
reported severe motor worsening in each patient who
took the drug (Ford et al., 1994; McKeith et al.,
1995). No double-blinded trial has been published
and it is unlikely that any will be performed, given
the mixed results.
Olanzapine was the subject of four double-blinded
trials, three of which were placebo-controlled and
one actively controlled, comparing the risperidone to
clozapine (Goetz et al., 2000; Breier et al., 2002; Ondo
et al., 2002). The clozapine trial was halted prema-
turely due to intervention by the Safety Monitoring
Board on behalf of the olanzapine-treated patients.
The Safety Monitoring Board declared that olanzapine
was unsafe for use in PD because of worsened motor
function, despite mean dosages of about 5 mg/day.
The three other trials used placebo controls and all
were completed. All three had similar results. Olanza-
pine was ineffective as an antipsychotic and worsened
motor function. This was in direct contrast to the first
prospective study, in which PD patients had dramatic
improvement in their psychosis without any decline
in motor function (Wolters et al., 1996). Two of these
negative studies were identical and performed in the
USA and Europe simultaneously (Breier et al., 2002).
Each of the studies involved 80 subjects, the most ever
in any study of a treatment for a behavioral abnormal-
ity in PD. Thus 160 subjects were enrolled. Both stu-
dies had very similar negative outcomes. Since
olanzapine does not increase prolactin levels and does
not cause acute dystonic reactions, the sensitivity of
 TREATMENT-INDUCED MENTAL CHANGES IN PARKINSONS DISEASE
PD patients is surprising. It is also surprising that the
drug did not improve the psychosis. The mean doses
in these studies were about one-third to one-half of
the doses used in primary psychoses, in contrast to
the relatively much smaller doses of clozapine and
risperidone, which were effective in drug-induced psy-
chosis in PD. These discrepancies remain unexplained.
The third drug, quetiapine, has been subject only to
a single double-blinded placebo-controlled trial (Ondo
et al., 2005). This trial was powered to determine
whether the drug interfered with motor function, not
to prove that it was an effective treatment. The study
confirmed the safety of the drug and did not worsen
motor function, but there was no statistically signifi-
cant improvement in psychosis. In addition, a double-
blinded comparison trial found no differences between
clozapine and quetiapine, but the number of subjects
was small (Morgante et al., 2004). The open-label
reports, involving over 400 patients, indicate that
quetiapine, although somewhat less potent and less
effective than clozapine and without the benefit on
tremor, is nevertheless an effective drug for treating
the psychosis. The mean dose of quetiapine for treat-
ing this condition is about 65 mg/day, in contrast to
the 2535 mg/day of clozapine. Like clozapine, que-
tiapine is sedating and may contribute to orthostatic
hypotension.
The most recent AA is aripiprazole. This drug has
partial dopamine agonist properties despite being an
effective antipsychotic. There was hope that aripipra-
zole may improve both the psychosis and the motor
dysfunction, but early reports suggest that this is not
the case (Fernandez et al., 2004b; Friedman et al.,
2005). At very low doses, even under 5 mg, aripipra-
zole worsened motor function in some PD patients.
Since the smallest commercially available dose is
5 mg and since the lower doses were not effective in
treating the psychosis, it is unlikely that this drug will
prove helpful.
41.2.1.5. Long-term outcome
Little data exist on this topic. The first report
described a small nursing-home cohort of PD patients
with hallucinations, all of whom died within 2 years
(Goetz and Stebbins, 1995). This was in the era before
treatment with AAs was initiated. After clozapine
found widespread use, a study of the long-term out-
come of patients who had participated in the American
double-blind trial of clozapine (all of whom partici-
pated in an open-label safety extension) found that
25% of completers were dead, that 42% were in
nursing homes, 68% were demented and 69% were
still psychotic (Factor et al., 2003). Another study,
225
reflecting a retrospective outcome analysis of 39 par-
kinsonian, not necessarily PD, patients who had been
treated with clozapine for psychosis found that 15%
had died by 5 years and 33% had been admitted to nur-
sing homes (Fernandez et al., 2004a). Few were off
antipsychotic treatment, although an Israeli group
(Klein et al., 2003) reported that 9 of 32 clozapine-
treated patients no longer required the clozapine. In
contrast, another report on only 6 patients who had
been on either quetiapine or clozapine for a mean
duration of 20 months had their antipsychotic slowly
tapered and discontinued (Fernandez et al., 2004c).
Five of the 6 suffered worsened psychosis and 3 of
these had a more severe psychosis than at baseline,
suggesting the possibility of a rebound psychosis.
Compared to the one historical report involving a
small number of patients (Goetz and Stebbins, 1995),
these data suggest a somber but marked improved
outcome with quetiapine and clozapine.
It is likely that most psychotic patients will require
their antipsychotic for life if the medications responsi-
ble are not dramatically altered. However, it is always
appropriate to consider the possibility of tapering and
stopping an antipsychotic to determine if it is still
required. Since the recurrent psychosis can be treated
very early, it is unlikely to become severe and hard
to control, even if the concept of a rebound psychosis
turns out to be true.
41.2.2. Mood and anxiety fluctuations associated
with motor fluctuations
It is well known that some patients who exhibit motor
fluctuations also experience associated mood fluctua-
tions. In general, off periods are associated with
depressed mood and increased anxiety, whereas on
periods are associated with normal or elevated moods
(Hardie et al., 1984; Cantello et al., 1986; Friedenberg
and Cummings, 1989). In addition, some patients
experience off states as relatively pure sensory or
mood experiences and others report mood swings pre-
ceding the changes in motor function. These observa-
tions imply that mood changes in fluctuating patients
are not simply a reaction to the motor changes. It
may be that mood is directly affected by changing
drug levels, with anxiety and depression having
somewhat different temporal relationships to serum
drug levels than motor responses (Maricle et al.,
1995b). In one study, two-thirds of patients with motor
fluctuations also suffered from mood fluctuations
(Nissenbaum et al., 1987); however, these data were
obtained by post hoc questioning of patients. Overall,
only a small number of PD patients have actually been
226 K. L. CHOU AND J. H. FRIEDMAN
studied during their motor fluctuations to determine
mood and anxiety changes (Menza et al., 1990;
Maricle et al., 1995a, b). The results so far have been
difficult to interpret due to the small numbers of sub-
jects as well as different techniques for assessment
and, perhaps most importantly, possibly different
patient populations.
In a double-blind placebo-controlled trial of 2-hour
levodopa infusions in the off state in 8 PD patients
with clinical fluctuations, Maricle et al. (1995b)
demonstrated that mean depression and anxiety scores
improved in a dose-related manner to levodopa infu-
sions, although finger-tapping rate, the sole measure
of motor function, did not differ much with the two
different infusion rates. Six of the 8 subjects noted an
improvement in mood and anxiety with high-dose
levodopa. Four had a response to low-dose infusion
and 2 responded to placebo. Anxiety scores appeared
to have a different time response to the infusions
than either the depression or the motor score, but the
numbers of subjects were too small for statistical
significance.
Menza and colleagues (1990) reported that, in 10
consecutive, non-demented, non-depressed PD patients
with on, off and on with dyskinesia periods, mood cognitive slowing, racing thoughts, sweating, belching,
and anxiety fluctuated with the onoff status, but,
interestingly, and in contrast to the report by Maricle
et al. (1995b), worsened when the patients suffered
from their dyskinesias. These authors described
improvement of mood and anxiety as the patient went
from off to on, then worsening from on to on sensations, producing the usual conundrum of whether
with dyskinesias. This important observation suggests
that the mood change is not a function of dopamine
brain release, since that hypothesis would predict
either stability of mood or further enhancement of
mood as dopamine responsiveness increased. It is
commonly observed that PD patients do, in fact, some-
times become hypomanic when they become dyski-
netic (Giovannoni et al., 2000); however that did not
occur in this report. The decline in mood and worsen-
ing anxiety in this case may simply have been due to
the fact that dyskinesias were bothersome, which
would suggest that mood is a reflection of changes in
motor responses rather than biochemical changes
in the brain or serum.
One study of 16 PD patients with motor fluctua-
tions found that the correlation between motor state
and either mood or anxiety was not very strong over
a 1-week period (Richard et al., 2001). In this study,
7 patients experienced daily mood fluctuations and 7
patients reported daily anxiety fluctuations. However,
these were not necessarily the same patients. Some
patients had mood fluctuations without anxiety fluc-
tuations, whereas in others, the opposite was true.
Only one subject had positive correlations between
mood and motor function each day. The investigators
concluded that a consistent relationship between
anxiety and motor states is not the rule. Furthermore,
the study failed to confirm a consistent temporal
relationship between mood and motor states. Perhaps
most surprising was this studys observation that mood
was sometimes negatively correlated with motor
function.
Another study reported that 22 out of 47 PD patients
experienced non-motor symptoms associated with
their motor fluctuations whereas only 16 had purely
motor changes (Raudino, 2001). The non-motor
symptoms reported in this study were autonomic symp-
toms, pain, mood changes and anxiety. Other reports
have described patients with mood or other non-motor
fluctuations during the day that are independent of
motor changes (Nissenbaum et al., 1987).
The fact that some patients become hypomanic in
the on with dyskinesia state, whereas others are
euthymic, remains difficult to explain (Nissenbaum
et al., 1987), but no more so than the wide phenomen-
ological spectrum of non-motor fluctuations that have
been reported, which include pain, irritability,
constipation, respiratory dysfunction, akathisia,
restless legs, cough, hunger, limb edema, nausea and
temperature (Hillen and Sage, 1996; Quinn, 1998). It
must be noted that mood and anxiety may fluctuate
in response to many of these very uncomfortable
certain symptoms are causal, related or merely
coincidental.
Clearly, more research needs to be performed in
order to understand better the phenomenology of mood
and anxiety fluctuations in patients with PD. Although
the general impression is that in fluctuators mood and
motor function go hand in hand, some studies indicate
that this is frequently not the case. Simple explanations
for mood and anxiety changes will probably never be
adequate.
41.2.3. Repetitive or compulsive behaviors
Although there is a relationship between abnormal repe-
titive or obsessive-compulsive behaviors and PD, its
nature is far from clear (Evans et al., 2004; Kurlan,
2004; Voon, 2004). Even the terminology is somewhat
confusing. Obsessive-compulsive disorder (OCD) is
described as intrusive cognitive events (obsessions),
which result in intentional repetitive behaviors (compul-
sions) designed to neutralize both the cognitive intrusions
and associated anxiety (Voon, 2004). This is in contrast
to the obsessive-compulsive spectrum disorders (OCSD),
 TREATMENT-INDUCED MENTAL CHANGES IN PARKINSONS DISEASE
which are intrusive events with associated repetitive
behaviors (Voon, 2004), the difference being that
cognitive intrusions are absent from OCSD. These
two categories are thought to have different underlying
mechanisms, but overlapping phenomenologies, sow-
ing confusion in our clinical understanding. Tics and
behaviors such as hair-pulling, nail-biting and foot-
tapping fall into the OCSD category, whereas ritual
behaviors and checking are considered OCD. In addi-
tion, OCD is classified as an anxiety disorder, which
the OCSD syndrome is not. There are also non-patho-
logical obsessive-compulsive personality traits that
have sometimes been considered to be part of the
PD character, such as inflexibility, neatness, punc-
tuality, obeying rules, following commands and a
decrease in novelty-seeking behavior (Menza et al.,
1993). Studies of such character attributes have been
contradictory, leading to the conclusion that such
associations are still highly speculative. Although
the possibility of an obsessive-compulsive personal-
ity being part of PD has been hypothesized for a
long time, the occurrence of abnormal repetitive
behaviors in the setting of PD has been recognized
only recently (Friedman, 1994; Fernandez and Fried-
man, 1999) and its relationship to the drug treatment
of PD versus being intrinsic to the disease itself is
unclear (Evans et al., 2004; Kurlan, 2004; Voon,
2004; Friedman, 2005).
Although certain pathological non-psychotic
behaviors have been attributed to levodopa, such as
hypersexuality, other compulsive behaviors such as
punding (see below), pathological gambling, com-
pulsive shopping and levodopa drug abuse (or the
dopamine dysregulation syndrome) also occur in
PD patients. Furthermore, the absence of studies
looking at control populations makes interpretation
of these reports somewhat tenuous in arguing the
connection between either disease state or drug
treatment. The main observations concerning these
behaviors are that they developed while on dopami-
nergic therapy and thus likely result from alterations
of either dopamine or serotonin. However, the small
number of patients involved and the variability of
responses to interventions make it quite difficult to
infer much from these reports.
41.2.3.1. Dopamine dysregulation syndrome
It has become increasingly apparent that a small num-
ber of PD patients, mostly treated with levodopa,
begin to take increasing amounts of their medication,
despite the fact that their motor symptoms are well
controlled with lower doses. This compulsive drug
use pattern has been variably described in the litera-
227
ture as levodopa dependence or abuse, hedonistic
homeostatic dysregulation and, most commonly, the
dopamine dysregulation syndrome (Priebe, 1984; Nau-
sieda, 1985; Giovannoni et al., 2000; Lawrence et al.,
2003; Evans et al., 2004). The patients who develop this
syndrome tend to be male with a young onset of their
PD. Past drug abuse, heavy alcohol use or a history of
mood disorders may be predisposing factors (Giovan-
noni et al., 2000; Lawrence et al., 2003). The rapid titra-
tion to high levels of levodopa use occurs relatively
early in the disease, often in excess of 2000 mg/day.
Consequently, these patients often have severe, violent
dyskinesias and display aggressive and devious tenden-
cies when physicians attempt to curb their levodopa
use. The extra levodopa results in enhanced mood,
vigor and productivity and patients often base their
increase in medications not on the control of motor
symptoms, but on somatic cues (Evans et al., 2004).
Apomorphine, a short-acting dopamine agonist, may
exacerbate or even initiate the symptoms of this
disorder (Giovannoni et al., 2000).
It may be debated whether dopamine dysregulation
syndrome represents a true addiction to levodopa, but
many physicians acknowledge that patients become
psychologically dependent on levodopa. Such a defini-
tion requires a pattern of excessive and inappropriate
use that results in impairment of social functioning
and causes withdrawal when the drug is discontinued.
In the PD population, it may be difficult to tell whether
there is excessive use of levodopa, particularly
because the medication alleviates motor symptoms.
Yet a case report of a PD patient who needed his
levodopa dose despite being quadriplegic from
GuillainBarre syndrome suggests that patients can
develop a pattern of excessive and inappropriate use
(Merims et al., 2000). There is no doubt that patients
with dopamine dysregulation syndrome display beha-
viors that are detrimental to normal social functioning
and, when limiting levodopa use, develop dysphoria
and other symptoms consistent with withdrawal.
Additionally, central dopaminergic pathways, specifi-
cally the mesolimbic dopaminergic projections to the
nucleus accumbens, have been implicated in models
of drug abuse and dependence (Koob and Le Moal,
1997; Sanchez-Ramos, 2002), so it is no surprise that
patients have the potential to develop dependence on
levodopa.
Other abnormal behaviors can be seen with this syn-
drome, including mania, psychosis, aggression, drug
hoarding, punding (see below), hypersexuality, compul-
sive shopping and pathological gambling. Management
of this disorder can be difficult, but it is essential to
decrease and ration dopaminergic medications. Atypical
antipsychotics such as quetiapine or clozapine can
228 K. L. CHOU AND J. H. FRIEDMAN
be used to treat the behavioral manifestations (Giovan-
noni et al., 2000).
41.2.3.2. Punding
Punding refers to a repetitive behavior first described
in amphetamine addicts who developed an endless
fascination with taking objects such as flashlights and
small electrical gadgets apart, then trying, usually
unsuccessfully, to put them back together (Rylander,
1972). This type of repetitive behavior was calming
to the patient and considered pleasurable. Several PD
patients have been described with similar behavior,
all developing while under dopaminergic drug treat-
ment, although in 2 patients, the punding appeared
after the initiation of quetiapine and decreased or
resolved when the quetiapine dose was reduced (Miwa
et al., 2004). The different punding behaviors that have
been described include cataloging a small, inexpensive
jewelry collection, repetitively adding tables of sums,
endlessly rearranging a collection of buttons, taking
apart and putting together flashlights, examining
television and other electrical cords and repeatedly
reading the labels on cans in a supermarket (Friedman,
1994; Fernandez and Friedman, 1999; Evans et al.,
2004; Miwa et al., 2004). These behaviors are often
connected to the patients occupation and the patients
themselves realize that the time spent on their punding
tasks is excessive (Friedman, 1994; Evans et al.,
2004). In contrast to the punding of amphetamine
users, PD patients often feel irritable or anxious when
distracted from or stopping their behaviors, although
most report no compulsion to pund (Fernandez and
Friedman, 1999; Evans et al., 2004).
Although punding is hypothesized to be due to
excessive dopaminergic stimulation (Ridley and Baker,
1982) and some patients have improved with decreased
doses of dopaminergic medications (Fernandez and
Friedman, 1999), one report describes similar stereo-
typed behaviors in PD patients that were unresponsive
to reductions in antiparkinsonian therapy (Kurlan,
2004). As mentioned before, 2 other PD patients have
been reported where punding began after the adminis-
tration of quetiapine (Miwa et al., 2004). These reports
suggest that a simple hyperdopaminergic state is not
enough to account for these stereotyped behaviors.
Hypomanic symptoms have occurred in conjunction
with repetitive behaviors in some cases, implying that
the underlying pathophysiology is complex and may
involve a combination of dopaminergic, serotonergic
and other neurotransmitter systems (Kurlan, 2004).
Other repetitive behaviors have been reported,
including 1 patient who made annoying sucking sounds
which bothered his friends. This developed after many
years of PD and was unrelated to medications or his
clinical condition. Another patient hummed, but only
as an off phenomenon (Friedman, 2005).
41.2.3.3. Pathological gambling
Although pathological gambling can be seen as part of
the dopamine dysregulation syndrome or mania, it has
been reported in patients with PD without other symp-
toms of the above disorders. Pathological gambling is
characterized by a failure to resist the impulse to gam-
ble despite severe consequences, whether personal,
financial or vocational. It is considered an impulse
control disorder in the Diagnostic and Statistical
Manual of Mental Disorders, 4th edition (DSM-IV)
(American Psychiatric Association, 1994). This phe-
nomenon was first reported in 12 patients with PD, 9
of whom began gambling after initiating levodopa
therapy (Molina et al., 2000). One patient, who
gambled prior to levodopa therapy, reported that his
gambling behavior worsened after starting treatment.
The authors of this paper noted that their patients were
relatively young and 5 of them had alcohol use or
dependence. Since this initial report, pathologic gam-
bling has been observed in other patients on levodopa
therapy (Gschwandtner et al., 2001; Avanzi et al.,
2004) and in patients on dopamine agonist therapy
alone (Seedat et al., 2000; Driver-Dunckley et al.,
2003). The patients on dopamine agonists alone were
on pramipexole or pergolide and, for many, their gam-
bling behavior resolved when switched to ropinirole.
Others noted improvement with reductions in total
dopaminergic medication, the addition of antipsycho-
tic therapy, antidepressant therapy, family control or
DBS (Molina et al., 2000; Seedat et al., 2000; Avanzi
et al., 2004). Most did not respond to standard thera-
pies for pathological gambling, such as behavioral or
cognitive therapy (Molina et al., 2000; Avanzi et al.,
2004). Although these reports suggest that pathologic
gambling is linked to dopaminergic medications in
PD, it should be noted that no report has specifically
assessed the prevalence of pathologic gambling in the
general population and compared it to the prevalence
in patients with PD.
41.3. Mental changes due to surgical
treatments for Parkinsons disease
41.3.1. Overview of surgical treatments for
Parkinsons disease
The surgical approach to PD has evolved dramatically
since the pre-levodopa era. Early attempts at treating
PD surgically were highly variable, partly due to an
 TREATMENT-INDUCED MENTAL CHANGES IN PARKINSONS DISEASE
incomplete understanding of basal ganglia pathophy-
siology, but mostly because of poor techniques for tar-
geting brain structures. Target localization improved
dramatically with the advent of stereotactic techniques
(Spiegel et al., 1947), but unfortunately, surgical treat-
ments for PD were abandoned after the introduction of
levodopa in the 1960s. It wasnt until the medical
community realized that long-term levodopa therapy
severely restricted PD patients daily functioning due
to the development of motor fluctuations and dyskine-
sias that there was a resurgence of interest in surgical
therapies for PD. Over the last two decades, major
progress has been made in the field of movement
disorders surgery, from the refinement of ablative
techniques to the development of new alternatives,
such as DBS (Benabid et al., 1991), and surgery is
now an accepted form of therapy for advanced PD.
The thalamus was originally the preferred target for
PD. However, because thalamic lesions improve only
the tremor in PD and because bilateral lesions were
associated with a high incidence of speech problems
(Kelly and Gillingham, 1980), the thalamus has fallen
out of favor as a target. The internal segment of the
globus pallidus (GPi) and the subthalamic nucleus
(STN) are much more commonly targeted now
because a lesion in either structure reduces all three
of the cardinal motor manifestations in PD, but
because no double-blind, randomized, head-to-head
trials have been conducted between the two sites, it
is unclear which target is better. There are also
minimal data comparing the two different surgical
techniques in use for PD surgery today: ablation and
DBS. Nevertheless, most surgical centers are now
performing DBS. This is largely because DBS offers
several advantages over ablative therapy, including:
(1) reversibility, meaning there is no permanent
destructive lesion made in the brain and likely will
not hamper future PD therapies; (2) DBS can be
performed bilaterally with relatively few adverse
effects; and (3) stimulation parameters can adjusted
to decrease adverse effects and increase clinical effect
as the disease progresses.
Despite the controversy regarding which surgical
target or technique is clinically superior in PD, it is
abundantly clear that both ablation and stimulation of
either target can provide significant relief of many
parkinsonian motor symptoms and reduce the severity
of long-term motor complications from levodopa ther-
apy. Unfortunately, as neurologists and neurosurgeons
have slowly accumulated more experience with these
procedures, especially DBS, it has been recognized
that patients sometimes experience declines in mood
and cognition. Despite the fact that most movement
disorders surgical centers actively screen potential
229
candidates for psychiatric and cognitive disorders, we
still have limited knowledge of who is subject to these
adverse effects. Possible explanations include interrup-
tion of fibers controlling mood and cognition, natural
progression of the neurobehavioral features of PD,
dopaminergic medication withdrawal or a combination
of the above. Hopefully, as the cognitive and psychia-
tric morbidities associated with ablation and DBS
are studied more systematically, we will be able to
understand the underlying etiologies better.
41.3.2. Adverse psychiatric effects of surgical
treatments for Parkinsons disease
Although cognitive side-effects have been reported
with thalamotomy in PD, this section will focus on
adverse psychiatric and cognitive effects from the
most common surgical procedures currently performed
for advanced PD: pallidotomy, GPi DBS and STN
DBS. Table 41.4 shows the common psychiatric
changes seen with surgery. It is important to keep in
mind that most surgical studies of PD patients have
not used psychiatric scales to assess behavior. Thus,
most of the data on adverse psychiatric effects of PD
surgery consist of descriptive case reports or case ser-
ies. The cognitive consequences of PD surgery have
been better studied, but are also limited because of
small sample sizes and short-term follow-up.
41.3.2.1. Psychosis
Despite being the most common neuropsychiatric
complication of pharmacologic therapy in PD, psycho-
sis is a relatively rare occurrence after ablation
or DBS surgery and, in fact, has only been reported
after STN DBS. In one study, 4 out of 77 PD patients
Table 41.4
Adverse psychiatric effects reported with surgical
treatments in Parkinsons disease
Pallidotomy
Depression
Hypomania
Globus pallidus internal segment stimulation
Mania
Subthalamic nucleus stimulation
Apathy
Anxiety
Depression
Hypomania
Mania
Mirthful laughter
Psychosis
230 K. L. CHOU AND J. H. FRIEDMAN
undergoing STN DBS surgery and evaluated up to 3
years postoperatively suffered from psychosis (Funkie-
wiez et al., 2004). One of these patients reportedly had
a transient psychosis that occurred 6 weeks after
electrode implantation. The other 3 had permanent
psychoses, although 2 were demented. In another
study examining 48 PD patients following bilateral
STN DBS surgery, 2 had psychotic syndromes that
resolved without any specific therapy (Herzog et al.,
2003b). The Grenoble group (Krack et al., 2003)
reported 1 case of transient psychosis in a 5-year fol-
low-up study of 49 STN DBS patients. Unfortunately
none of these studies reported the specifics of the
psychotic episodes, so it is unknown whether they
had hallucinations, delusions or both. Furthermore, it
is unclear if these patients had psychosis prior to
surgery, a factor that could predispose them to develop
psychosis after implantation. In another study of 24
DBS patients (Houeto et al., 2002), 1 patient with
drug-induced psychosis prior to surgery developed a
florid psychosis with mystic delusions a few weeks
postoperatively. However, another patient with drug-
induced psychosis prior to surgery did not manifest
psychotic symptoms afterwards.
One patient has been reported as having developed
delusions subsequent to STN DBS surgery (Herzog
et al., 2003a). This patient had no psychiatric history.
Her delusions occurred concurrently with manic
symptoms, including euphoria, loosened associations,
flight of ideas and hyperactivity. The mania and the
delusions eventually needed to be controlled with a
combination of carbamazepine and clozapine.
A few patients have experienced isolated visual hal-
lucinations after DBS surgery of the STN. One patient,
off all dopaminergic medications after bilateral STN
DBS surgery, experienced formed visual hallucina-
tions only when the stimulators were turned on
(Diederich et al., 2000). Because the visual hallucina-
tions responded to clozapine therapy, the authors
concluded that electrical stimulation physiologically
mimicked drug-induced visual hallucinations and
suggested that there may be a connection between
the STN and limbic pathways. However, not all cases
of visual hallucinations after surgery are induced by
stimulation. Some are related to the development of
dementia (Krack et al., 2003; Rodriguez-Oroz et al.,
2004), whereas in others, the etiology is less clear
(Varma et al., 2003).
41.3.2.2. Mania
Although manic symptoms have been known to occur
with pallidal lesions (Turecki et al., 1993), mania or
hypomania hardly ever occurs after pallidotomy.
This is largely because most neurosurgeons specifi-
cally target the posterior ventral pallidum in PD, which
contains purely sensorimotor fibers, making it the
most effective target for ameliorating parkinsonian
symptoms (Bakay et al., 1997). Lesions restricted to
this area do not result in mood disorders, whereas
lesions outside this area may affect the non-motor
basal ganglia circuits responsible for cognitive and
mood changes (Lombardi et al., 2000). Two patients
were recently reported to have transient hypomania
subsequent to pallidotomy (Okun et al., 2003). It was
discovered that both of these patients had lesions
involving the anteromedial (non-motor) portion of the
GPi, which was believed to be responsible for their
mood changes. Mania has also been reported as a
result of pallidal stimulation (Miyawaki et al., 2000).
In this case report, the patient had recurrent mania
which always occurred temporally after his stimulators
were turned on. When the stimulators were off, he
never went into a manic state. His mood eventually
stabilized in the on stimulation state with the reduc-
tion of dopaminergic therapy, leading the authors to
suspect that stimulation altered his sensitivity level
to the mood-altering effects of levodopa.
In contrast to pallidotomy or pallidal stimulation,
mania has frequently been observed with STN stimula-
tion. As mentioned above, 1 patient experienced mania
with delusions after STN DBS surgery (Herzog et al.,
2003a). Another study reported manic symptoms
occurring in 3 out of 15 STN stimulation patients
(Kulisevsky et al., 2002), including elation, inflated
self-esteem, overactivity and sexual indiscretion. None
had previous psychiatric episodes and in all 3 patients,
manic symptoms began shortly after stimulation was
turned on. Interestingly enough, stimulation was
switched from the lowest contacts to higher ones in
all 3 patients a week after surgery because of better
motor responses and the symptoms resolved. In 1
patient, restimulating the lowest contact on the right
side caused the mania to recur. Because the lowest
contacts were located caudally to the substantia nigra
in all 3 patients, the authors speculated that stimulation
may have affected limbic projections from the mid-
brain. Romito and colleagues (2002), among their first
30 STN DBS patients, described 2 who met DSM-IV
diagnostic criteria for mania postoperatively. One
developed manic symptoms prior to the initial pro-
gramming session, whereas the other developed
symptoms a few hours after the stimulators were
turned on. The mania persisted even after discontinua-
tion of all antiparkinsonian medications. Similar to the
patients reported by Kulisevsky et al. (2002), the lower
contacts were stimulated in both of these patients.
However, in contrast, Romito and colleagues (2002)
did not change the contacts in their patients and the
 TREATMENT-INDUCED MENTAL CHANGES IN PARKINSONS DISEASE
mania resolved spontaneously over the ensuing months
without therapy.
In addition to mania, hypomania has also been
commonly described after placement of bilateral STN
electrodes (Houeto et al., 2002; Herzog et al., 2003b;
Krack et al., 2003; Funkiewiez et al., 2004). Nearly
all of the episodes reported occurred within the first
3 months of surgery and resolved spontaneously.
Moreover, 2 cases of mirthful laughter due to STN
stimulation have been described (Krack et al., 2001).
The laughter seen in these patients was acutely
induced by stimulation increases in voltage or pulse
width. It remains unclear, however, whether the STN
itself is involved in regulating affect and behavior or
whether diffusion of the stimulation to limbic-related
structures adjacent to the STN is responsible for these
changes in mood.
41.3.2.3. Depression
Although the strong association between depression
and PD had been recognized for some time, investiga-
tors did not pay close attention to depression following
surgical interventions in PD until 1999, when a case
report of stimulation-induced depression following
bilateral STN electrode implantation was published
(Bejjani et al., 1999). In this patient, electrical
stimulation through the lowest contact (0) of the left
STN electrode elicited symptoms of depression that
disappeared immediately when stimulation was turned
off. Although this particular contact was estimated to
lie in the left substantia nigra rather than the STN, this
observation shattered the concept that depression in PD
was mainly a reaction to the parkinsonian symptoms
experienced by the patient and suggested that depres-
sion could be hard-wired in the brain. A number of
reports from different surgical centers have since
reported the development of depression following
STN DBS surgery in patients with PD (Krack et al.,
1997; Volkmann et al., 2001; Berney et al., 2002;
Doshi et al., 2002; Thobois et al., 2002; Herzog et al.,
2003b; Kleiner-Fisman et al., 2003; Funkiewiez et al.,
2004), with a frequency ranging from 10% to 30%,
but none has been so clearly induced by stimulation.
Although PD patients undergoing STN DBS seem to
show mild improvement overall when evaluated with
depression rating scales at baseline and postoperatively
(Ardouin et al., 1999; Daniele et al., 2003; Troster
et al., 2003), certain individuals seem to be susceptible
to severe mood changes after surgery, with some
even attempting suicide (Krack et al., 1997; Berney
et al., 2002; Doshi et al., 2002; Houeto et al., 2002;
Kleiner-Fisman et al., 2003). It is still difficult at this
time, however, to predict which patients are at the
greatest risk.
231
It may be that targeting the STN itself predisposes
patients to the development of postoperative depres-
sion. It is of particular interest that depressive sympto-
matology has been reported more often after bilateral
STN DBS surgery than after pallidotomy or GPi sti-
mulation. In fact, most studies report that severity of
depression is either unchanged (Vingerhoets et al.,
1999; Baron et al., 2000; Favre et al., 2000) or mildly
improved (Troster et al., 1997; Masterman et al., 1998;
Martinez-Martin et al., 2000; Straits-Troster et al.,
2000) after pallidotomy or GPi stimulation, whereas
only a few have reported otherwise. One group noted
that 12% of their pallidotomy patients developed
depression after surgery (Bezerra et al., 1999).
Interestingly, all of them had undergone left-sided
unilateral ablation. Another group conducted a rando-
mized trial of bilateral pallidotomy versus a combina-
tion of unilateral pallidotomy plus contralateral GPi
stimulation, but had to discontinue the study early
when the 3 patients undergoing bilateral pallidotomy
displayed a significant deterioration on the Hamilton
depression and apathy scores (Merello et al., 2001).
A third study reported that 2 out of 4 bilateral pallidot-
omy patients experienced postoperative depression
(Ghika et al., 1999).
The reasons for a greater incidence of depression
after STN DBS remain unclear. Several possibilities
exist, however. More attention has recently been
focused on non-motor symptoms in PD, such as
depression and dementia, than in the past. It may be
that this spotlight on cognitive and behavioral issues
has caused investigators to recognize psychiatric
side-effects more readily. The discrepancy between a
patients expectations from surgery and the actual
result may be a contributing factor. Furthermore, the
STN is a small target, making it more likely for the
electrode to be misplaced. It is also probable that elec-
trical stimulation in this area may activate limbic
fibers traveling from the STN through the striatum to
the prefrontal cortex, pathways that have been impli-
cated in the neurobiology of depression (Groenewegen
and Berendse, 1990; Drevets, 2003). Finally, because
STN stimulation allows patients to reduce their medi-
cations, generally by approximately 50% (Thobois
et al., 2002; Kleiner-Fisman et al., 2003; Krack et al.,
2003), patients may experience a depressed mood
because of the withdrawal of levodopa or other PD
medication.
The existing literature suggests that those who
develop a depressed mood postoperatively often have
a prior psychiatric history. Of the 5 patients with
depression after STN surgery in the group reported by
Houeto and colleagues (2002), 4 had a previous
history of depression, whereas 2 of 6 patients with
232 K. L. CHOU AND J. H. FRIEDMAN
postoperative depression in a separate series had
depression preoperatively (Berney et al., 2002). How-
ever, 15 other patients in these two studies had
depressive symptomatology prior to DBS, yet did not
experience a depressed mood afterwards. Therefore,
although a past psychiatric history may predispose
patients to postsurgical depression, it is clearly not the
only factor. Fortunately, it seems that most postopera-
tive depressive episodes are transient. If treatment is
necessary, an increase in dopaminergic medication or
the addition of an antidepressant, such as a serotonin
uptake inhibitor, is usually sufficient (Doshi et al.,
2002; Thobois et al., 2002; Krack et al., 2003;
Funkiewiez et al., 2004).
41.3.2.4. Apathy
Apathy as a sequela of surgical procedures in PD has
been reported specifically with bilateral STN DBS
(Trepanier et al., 2000; Daniele et al., 2003; Krack
et al., 2003; Funkiewiez et al., 2004). These patients
are generally not depressed or demented and typically
sit in a chair for most of the day (Funkiewiez et al.,
2004). The pathophysiology is unknown. Although
an increase in dopaminergic agents or antidepressant
therapy may help apathy in PD, most of the patients
with post-DBS apathy did not respond to dopaminer-
gic therapy. Nevertheless, signs of apathy should be
sought in patients following STN stimulation surgery
and treatment should be attempted.
41.3.2.5. Anxiety
Anxiety disorders are commonly seen in patients with
PD. However, they do not seem to develop after surgi-
cal procedures for PD. In fact, symptoms of anxiety
generally improve in PD patients after pallidotomy,
pallidal stimulation and STN stimulation (Fields et al.,
1999; Straits-Troster et al., 2000; Higginson et al.,
2001; Martinez-Martin et al., 2002; Daniele et al.,
2003). Only one study reported a decompensation of
anxiety symptoms after surgery in PD patients (Houeto
et al., 2002). In this study, 24 PD patients undergoing
STN DBS were evaluated for behavioral disorders
before and after surgery. Seventeen (71%) were diag-
nosed with generalized anxiety and 4 (17%) were diag-
nosed with agoraphobia before the DBS procedure.
Unfortunately, in all 17 of the anxiety patients and 2
of the agoraphobic patients, symptoms worsened after
surgery. One patient without psychiatric symptoms prior
to surgery was discovered to have anxiety postopera-
tively, but the reasons for this decompensation remain
unclear. Given such sparse data, it is obvious that more
studies need to be conducted in order to determine how
anxiety symptoms respond to surgery in PD.
41.3.3. Adverse cognitive effects of surgical
treatments for Parkinsons disease
As with psychiatric symptoms, STN DBS procedures
are generally associated with more declines in
cognitive function than with procedures involving
GPi, although long-term postoperative assessments in
these patients remain limited. Although most patients
remain cognitively stable after surgery overall, there
are reports of PD patients with dementia or borderline
cognitive function who worsen irreversibly postopera-
tively (Limousin et al., 1998; Hariz et al., 2000).
Furthermore, patients of advanced age and increased
PD severity may have worse cognitive outcomes after
surgery for PD (Vingerhoets et al., 1999; Baron et al.,
2000; Kubu et al., 2000; Saint-Cyr et al., 2000). As a
result, it is essential to screen potential surgical candi-
dates for the presence of a dementing illness with
preoperative neuropsychological testing. Such testing
ensures that only the most optimal candidates are
selected and also provides a baseline for comparison
of postsurgical changes in cognition.
41.3.3.1. Neuropsychological assessment
Preoperative neuropsychological testing involves the
assessment of multiple cognitive domains. These are
generally grouped into five categories: (1) general cog-
nitive or intellectual ability; (2) language; (3) learning
and memory; (4) executive function; and (5) visuospa-
tial function. Common neuropsychological tests used
to evaluate these different domains are listed in
Table 41.5.
Loss of general intellectual ability is one of the
hallmarks of a dementing illness (Saint-Cyr and
Trepanier, 2000). Because the main purpose of neu-
ropsychological testing prior to surgery is to rule out
dementia, evaluation of intellectual ability is essential.
The common neuropsychological tests that are utilized
(Table 41.5) can estimate current intellectual ability
and premorbid intellectual level and provide a global
cognitive screen. PD patients with evidence of border-
line or impaired cognitive function based on these tests
are not considered good surgical candidates. Evalua-
tion of the domain of language involves examining
the ability to comprehend and produce verbal language
easily and fluently. Future long-term follow-up studies
assessing language ability after surgery for PD will be
important because decreased verbal fluency has been
the most consistent change reported postoperatively
(see section 41.3.3.3 below). Memory disturbance
can be another sign of dementia. In PD, free recall is
typically impaired, whereas cued recall is preserved
(Pillon et al., 1994). This is in contrast to other
 TREATMENT-INDUCED MENTAL CHANGES IN PARKINSONS DISEASE
Table 41.5
Common neuropsychological tests used in the evaluation
of Parkinsons disease patients before and after surgery
General cognitive/intellectual ability

Wechsler Adult Intelligence Scale-III (WAIS-III)

American New Adult Reading Test (ANART)

Mattis Dementia Rating Scale (DRS)

Mini-Mental State Examination (MMSE)
Language

Subsets of the WAIS-III

Boston Naming Test

Category Fluency (Animals trial)

Controlled Oral Word Association Test
Learning and memory

Wechsler Memory Scale-III (WMS-III)

Hopkins Verbal Learning Test

California Verbal Learning Test
Executive function

Digit span and digit span backwards

Wisconsin Card Sorting Test (WCST)

Trail Making Test

Stroop Color-Word Test
Visuospatial function

Construction subscore of the DRS

Hooper Visual Organization Test

Benton Judgment of Line Orientation
dementing illnesses such as Alzheimers disease where
both free and cued recall is disrupted. Thus, a deficit in
cued recall in a PD patient prior to surgery may imply
a memory disorder more severe than what would
be expected. The domain of executive function
allows patients to formulate, plan and execute actions.
Problems in this domain generally suggest frontal lobe
dysfunction (Lezak, 1995), a finding commonly seen
in PD and thus important to evaluate. The presence
and extent of visuospatial deficits in PD remain deba-
table (Pillon et al., 2001). Because of this, visuospatial
function has not been consistently assessed pre- and
postsurgery in PD patients.
41.3.3.2. Global cognitive and intellectual ability
It is important to make sure that PD patients are not
demented prior to surgery. Therefore, testing for intel-
lectual function and global cognitive ability is always
performed preoperatively. However, most centers do
not routinely test intellectual function after surgery.
The Mattis Dementia Rating Scale (DRS) has emerged
as a popular test of global cognitive ability, but only a
few studies have examined changes in the DRS before
and after surgery.
Most of the early pallidotomy literature did not
routinely employ neuropsychological tests to assess
233
cognitive decline (Laitinen, 2000) and among the early
pioneers of pallidotomy, only Leksells group reported
general postoperative cognitive decline (Svennilson
et al., 1960). This decline was a permanent deficit
that occurred in 4 of 81 patients. More recently, Baron
and colleagues reported that, of 9 patients undergoing
pallidotomy, 3 showed significant declines in DRS
scores over 4 years (Baron et al., 2000). However,
these 3 patients were older at the time of surgery and
it is unclear if the cognitive decline was due to the pal-
lidotomy or because their older age put them at greater
risk of developing dementia. In contrast, a study of
43 patients undergoing unilateral pallidotomy showed
no significant changes in the DRS scores at 3 and
12 months, respectively (Obwegeser et al., 2000).
In general, DRS scales show no significant dete-
rioration with either GPi (Troster et al., 1997; Ardouin
et al., 1999; Fields et al., 1999) or STN DBS (Ardouin
et al., 1999; Pillon et al., 2000; Funkiewiez et al.,
2004). However, one small study found a small but
statistically significant improvement (6.7%) in the
MMSE after 12 months of STN stimulation (Daniele
et al., 2003).
41.3.3.3. Language
No studies have reported an improvement in language
function postoperatively. On the contrary, declines in
language function have been consistently reported after
surgical procedures for PD. Specifically, reductions in
verbal fluency have been observed after pallidotomy
(Uitti et al., 1997; Ghika et al., 1999; Kubu et al.,
2000; Lacritz et al., 2000; Obwegeser et al., 2000;
Trepanier et al., 2000), pallidal stimulation (Troster
et al., 1997; Ghika et al., 1998) and STN stimulation
(Ardouin et al., 1999; Pillon et al., 2000; Saint-Cyr
et al., 2000; Trepanier et al., 2000; Alegret et al.,
2001; Gironell et al., 2003; Funkiewiez et al., 2004).
Although there are studies that have reported no
change in verbal fluency after pallidotomy (Soukup
et al., 1997; Turner et al., 2002; Gironell et al.,
2003), these are clearly in the minority. Even more
interesting is the fact that this decrease in fluency
seems to occur with left-sided pallidotomy, but not
right pallidotomy (Uitti et al., 1997; Kubu et al.,
2000; Lacritz et al., 2000; Obwegeser et al., 2000;
Trepanier et al., 2000). These differential findings are
not found with unilateral GPi stimulation (Troster
et al., 1997; Vingerhoets et al., 1999), although the
number of patients studied so far has been small.
Ghika and colleagues (1998) reported that 2 of 6
patients undergoing bilateral GPi DBS had decreased
verbal fluency postoperatively, but most others have
reported no significant change (Ardouin et al., 1999;
Fields et al., 1999; Trepanier et al., 2000).
234 K. L. CHOU AND J. H. FRIEDMAN
A recent review of neuropsychological conse-
quences following STN DBS found that 69% of the
studies reported significant declines in measures of
phonemic fluency, category fluency or both (Woods
et al., 2002). These deficits continue to be present in
long-term studies of STN DBS that have followed
patients anywhere from 12 to 36 months postopera-
tively (Saint-Cyr et al., 2000; Daniele et al., 2003;
Funkiewiez et al., 2004). It is unclear why these reduc-
tions in verbal fluency tests occur. It does not seem to
be related to the stimulation itself, given that, in one
study, verbal fluency deficits were present at 3 and
12 months after STN surgery, regardless of stimulation
status (Pillon et al., 2000).
41.3.3.4. Learning and memory
Changes in learning and memory have been variable
following pallidotomy. Whereas many studies showed
either no change or an improvement on memory testing
postpallidotomy (Uitti et al., 1997; Lacritz et al., 2000;
Obwegeser et al., 2000; Turner et al., 2002; Gironell
et al., 2003), others have shown a decline in memory
(Ghika et al., 1999; Trepanier et al., 2000). In one of
these studies, free recall worsened in patients with a
left-sided pallidotomy as opposed to patients who
underwent right-sided pallidotomy (Trepanier et al.,
2000), a pattern similar to that observed with verbal
fluency. Interestingly enough, another study observed
an improvement in memory in patients who had a
pallidotomy on the right side (Obwegeser et al.,
2000). However, the data remain too limited to draw
any conclusions.
Thus far pallidal DBS has not been shown to
worsen performance on learning and memory testing.
A few studies examining both unilateral (Troster
et al., 1997; Vingerhoets et al., 1999) and bilateral
GPi stimulation (Ardouin et al., 1999; Burchiel et al.,
1999) reported no change in learning or memory,
whereas a separate study showed that bilateral GPi
stimulation actually improved free recall, as assessed
by the California Verbal Learning Test in 6 patients
(Fields et al., 1999).
Most studies following STN electrode implantation
have demonstrated no change on measures of learning
and memory (Ardouin et al., 1999; Burchiel et al.,
1999; Moro et al., 1999; Alegret et al., 2001; Perozzo
et al., 2001; Gironell et al., 2003). One study observed
a decline in immediate and delayed recall on Reys
auditory verbal learning test 3 months postoperatively,
but this decline returned to baseline at both the 6- and
12-month follow-up visit (Daniele et al., 2003). In con-
trast, another study found significant declines in long-
delay free recall and long-delay cued recall at both
the 3- and 6-month postoperative visits (Trepanier
et al., 2000).
41.3.3.5. Executive function
Executive function is generally unchanged after
pallidotomy and GPi stimulation (Troster et al., 1997;
Ardouin et al., 1999; Burchiel et al., 1999; Fields
et al., 1999; Ghika et al., 1999; Vingerhoets et al.,
1999; Trepanier et al., 2000; Gironell et al., 2003).
However, one group demonstrated greater persevera-
tion on the Wisconsin Card Sorting Test in PD patients
tested 3 months after a right pallidotomy (Lacritz
et al., 2000), whereas another found that performance
declined after pallidotomy on the Tower of London
Test, a finding that suggests reduced planning ability
(Turner et al., 2002).
Similarly, most groups have found no significant
changes in attention or executive function after STN
DBS surgery (Ardouin et al., 1999; Burchiel et al.,
1999; Pillon et al., 2000; Trepanier et al., 2000;
Perozzo et al., 2001; Daniele et al., 2003; Gironell
et al., 2003), with only a couple of studies showing
improvement (Alegret et al., 2001; Daniele et al.,
2003). Although the surgery itself does not seem to
have much of an effect on this domain overall, some
recent studies have suggested that stimulation itself
may have a positive effect on frontal lobe function.
One study reported the results of both STN and GPi
stimulation on neuropsychological measures in the sti-
mulator on and off states and discovered that, when
stimulation was on, both STN and GPi groups
improved on various measures of executive function,
including the Trail Making Test (parts A and B) and
the interference task on the Stroop test (Jahanshahi
et al., 2000). Pillon and colleagues (2000) reported
similar findings on the Stroop and Trail Making Tests
with stimulators turned on and off in a group of 48
STN DBS patients.
41.3.3.6. Visuospatial function
Only a few studies have looked at measures of visuos-
patial function. One pallidotomy study showed no
significant changes in this domain, as assessed by the
Wechsler Adult Intelligence Scale-Revised Block
Design and the Benton Judgment of Line Orientation
(Obwegeser et al., 2000). Another pallidotomy study
showed a transient decrease in visuoconstructional abil-
ity, as assessed by copying the Rey-Osterrieth Complex
Figure, although the effects were transient and had dis-
appeared by 1 year (Trepanier et al., 1998). It was also
unclear whether the difficulty in copying the figure was
due solely to a visuospatial deficit, as reduced planning
ability may also cause patients to have problems with
 TREATMENT-INDUCED MENTAL CHANGES IN PARKINSONS DISEASE
this test. Pallidal DBS overall seems to have no effect on
visuospatial function (Troster et al., 1997; Ardouin et al.,
1999; Vingerhoets et al., 1999), but one study reported
that bilateral GPi DBS caused a decline in the construc-
tion subscore on the DRS (Fields et al., 1999). Likewise,
STN stimulation appears not to affect significantly cog-
nitive function in this domain, with only one study
reporting a negative effect (assessed with the Judgment
of Line Orientation test) (Alegret et al., 2001).
41.4. Conclusions
In order to provide quality care to the PD patient, we
can no longer be content with just treating the motor
symptoms because the cognitive and behavioral mani-
festations that result from PD treatment are just as dis-
abling, if not more so. This is true not only of the
pharmacologic treatments currently available, but also
of the various surgical options. Future research focus-
ing on understanding the underlying mechanisms of
drug-induced psychosis and its relation to PD and
DLB should enable us to develop better treatments
and perhaps alter the long-term outcome of PD
patients with psychosis. Elucidating why dopaminer-
gic treatment causes abnormal behaviors in certain
patients and not others should help us in that regard,
but discovering how DBS can induce or exacerbate
these symptoms may be the key to unlocking how
cognition and behavior are hard-wired in the brain.
References
Aarsland D, Larsen JP, Karlsen K et al. (1999). Mental
symptoms in Parkinsons disease are important contribu-
tors to caregiver distress. Int J Geriatr Psychiatry 14:
866874.
Aarsland D, Larsen JP, Tandberg E et al. (2000). Predictors
of nursing home placement in Parkinsons disease: A
population-based, prospective study. J Am Geriatr Soc
48: 938942.
Alegret M, Junque C, Valldeoriola F et al. (2001). Effects of
bilateral subthalamic stimulation on cognitive function in
Parkinson disease. Arch Neurol 58: 12231227.
Allen RL, Walker Z, DAth PJ et al. (1995). Risperidone for
psychotic and behavioural symptoms in Lewy body
dementia. Lancet 346: 185.
Alvir JM, Lieberman JA, Safferman AZ et al. (1993). Cloza-
pine-induced agranulocytosis. Incidence and risk factors in
the United States. N Engl J Med 329: 162167.
American Psychiatric Association (1994). Diagnostic and Sta-
tistical Manual of Mental Disorders, 4th edn. (DSM-IV).
American Psychiatric Association, Washington, DC.
Apaydin H, Ahlskog JE, Parisi JE et al. (2002). Parkinson
disease neuropathology: Later-developing dementia and
loss of the levodopa response. Arch Neurol 59: 102112.
235
Ardouin C, Pillon B, Peiffer E et al. (1999). Bilateral
subthalamic or pallidal stimulation for Parkinsons
disease affects neither memory nor executive functions:
A consecutive series of 62 patients. Ann Neurol 46:
217223.
Arnulf I, Bonnet AM, Damier P et al. (2000). Hallucinations,
REM sleep, and Parkinsons disease: A medical hypoth-
esis. Neurology 55: 281288.
Avanzi M, Uber E, Bonfa F (2004). Pathological gambling
in two patients on dopamine replacement therapy for
Parkinsons disease. Neurol Sci 25: 98101.
Bakay RA, Starr PA, Vitek JL et al. (1997). Posterior ventral
pallidotomy: Techniques and theoretical considerations.
Clin Neurosurg 44: 197210.
Barnes J, David AS (2001). Visual hallucinations in Parkin-
sons disease: A review and phenomenological survey.
J Neurol Neurosurg Psychiatry 70: 727733.
Baron MS, Vitek JL, Bakay RA et al. (2000). Treatment of
advanced Parkinsons disease by unilateral posterior GPi
pallidotomy: 4-year results of a pilot study. Mov Disord
15: 230237.
Bejjani BP, Damier P, Arnulf I et al. (1999). Transient
acute depression induced by high-frequency deep-brain
stimulation. N Engl J Med 340: 14761480.
Benabid AL, Pollak P, Gervason C et al. (1991). Long-term
suppression of tremor by chronic stimulation of the ventral
intermediate thalamic nucleus. Lancet 337: 403406.
Berney A, Vingerhoets F, Perrin A et al. (2002). Effect on
mood of subthalamic DBS for Parkinsons disease: A con-
secutive series of 24 patients. Neurology 59: 14271429.
Bezerra ML, Martinez JV, Nasser JA (1999). Transient acute
depression induced by high-frequency deep-brain stimula-
tion. N Engl J Med 341: 1003.
Breier A, Sutton VK, Feldman PD et al. (2002). Olanzapine
in the treatment of dopamimetic-induced psychosis in
patients with Parkinsons disease. Biol Psychiatry 52:
438445.
Burchiel KJ, Anderson VC, Favre J et al. (1999). Comparison
of pallidal and subthalamic nucleus deep brain stimulation
for advanced Parkinsons disease: Results of a rando-
mized, blinded pilot study. Neurosurgery 45: 13751382.
Cahn-Weiner DA, Grace J, Ott BR et al. (2002). Cognitive
and behavioral features discriminate between Alzheimers
and Parkinsons disease. Neuropsychiatry Neuropsychol
Behav Neurol 15: 7987.
Cantello R, Gilli M, Riccio A et al. (1986). Mood changes asso-
ciated with end-of-dose deterioration in Parkinsons dis-
ease: A controlled study. J Neurol Neurosurg Psychiatry
49: 11821190.
Comella CL, Tanner CM, Ristanovic RK (1993). Polysomno-
graphic sleep measures in Parkinsons disease patients
with treatment-induced hallucinations. Ann Neurol 34:
710714.
Cummings JL (1997). The Neuropsychiatric Inventory:
Assessing psychopathology in dementia patients.
Neurology 48: S10S16.
Daniele A, Albanese A, Contarino MF et al. (2003). Cogni-
tive and behavioural effects of chronic stimulation of the
236 K. L. CHOU AND J. H. FRIEDMAN
subthalamic nucleus in patients with Parkinsons disease. J
Neurol Neurosurg Psychiatry 74: 175182.
de Ajuriaguerra J (1972). Etude psychopathologique des par-
kinsoniens. In: J de Ajuriaguerra, G Gauthier (Eds.),
Monoamines, Noyaux Gris Centraux et Syndrome de
Parkinson. Masson, Geneve, pp. 327355.
Dewey RB Jr, OSuilleabhain PE (2000). Treatment of
drug-induced psychosis with quetiapine and clozapine in
Parkinsons disease. Neurology 55: 17531754.
Diederich NJ, Alesch F, Goetz CG (2000). Visual hallucina-
tions induced by deep brain stimulation in Parkinsons
disease. Clin Neuropharmacol 23: 287289.
Doshi PK, Chhaya N, Bhatt MH (2002). Depression leading
to attempted suicide after bilateral subthalamic nucleus
stimulation for Parkinsons disease. Mov Disord 17:
10841085.
Drevets WC (2003). Neuroimaging abnormalities in the
amygdala in mood disorders. Ann NY Acad Sci 985:
420444.
Driver-Dunckley E, Samanta J, Stacy M (2003). Pathological
gambling associated with dopamine agonist therapy in
Parkinsons disease. Neurology 61: 422423.
Evans AH, Katzenschlager R, Paviour D et al. (2004). Pund-
ing in Parkinsons disease: Its relation to the dopamine
dysregulation syndrome. Mov Disord 19: 397405.
Factor SA, Molho ES, Brown DL (1995). Combined
clozapine and electroconvulsive therapy for the treatment
of drug-induced psychosis in Parkinsons disease.
J Neuropsychiatry Clin Neurosci 7: 304307.
Factor SA, Feustel PJ, Friedman JH et al. (2003). Longitudi-
nal outcome of Parkinsons disease patients with psychosis.
Neurology 60: 17561761.
Favre J, Burchiel KJ, Taha JM et al. (2000). Outcome of uni-
lateral and bilateral pallidotomy for Parkinsons disease:
Patient assessment. Neurosurgery 46: 344353.
Fenelon G, Mahieux F, Huon R et al. (2000). Hallucinations
in Parkinsons disease: Prevalence, phenomenology and
risk factors. Brain 123 (Pt 4), 733745.
Fenelon G, Thobois S, Bonnet AM et al. (2002). Tactile hallu-
cinations in Parkinsons disease. J Neurol 249: 16991703.
Fernandez HH, Friedman JH (1999). Punding on L-dopa.
Mov Disord 14: 836838.
Fernandez HH, Donnelly EM, Friedman JH (2004a). Long-
term outcome of clozapine use for psychosis in
parkinsonian patients. Mov Disord 19: 831833.
Fernandez HH, Trieschmann ME, Friedman JH (2004b). Ari-
piprazole for drug-induced psychosis in Parkinson disease:
Preliminary experience. Clin Neuropharmacol 27: 45.
Fernandez HH, Trieschmann ME, Okun MS (2004c). Rebound
psychosis: Effect of discontinuation of antipsychotics in
Parkinsons disease. Mov Disord 20 (1), 104105.
Fields JA, Troster AI, Wilkinson SB et al. (1999). Cognitive
outcome following staged bilateral pallidal stimulation for
the treatment of Parkinsons disease. Clin Neurol Neuro-
surg 101: 182188.
Ford B, Lynch T, Greene P (1994). Risperidone in Parkinsons
disease. Lancet 344: 681.
French Clozapine Parkinson Study Group (1999). Clozapine
drug-induced psychosis in Parkinsons disease. Lancet
353: 20412042.
Friedenberg DL, Cummings JL (1989). Parkinsons disease,
depression, and the on-off phenomenon. Psychosomatics
30: 9499.
Friedman JH (1985). Drug holidays in the treatment of Par-
kinsons disease. A brief review. Arch Intern Med 145:
913915.
Friedman JH (1991). The management of the levodopa
psychoses. Clin Neuropharmacol 14: 283295.
Friedman JH (1994). Punding on levodopa. Biol Psychiatry
36: 350351.
Friedman JH (2005). More on repetitive behaviors in Parkin-
sons disease. Mov Disord 20, 509510.
Friedman JH, Factor SA (2000). Atypical antipsychotics in
the treatment of drug-induced psychosis in Parkinsons
disease. Mov Disord 15: 201211.
Friedman JH, Lannon MC (1990). Clozapine-responsive tre-
mor in Parkinsons disease. Mov Disord 5: 225229.
Friedman JH, Koller WC, Lannon MC et al. (1997). Benztro-
pine versus clozapine for the treatment of tremor in
Parkinsons disease. Neurology 48: 10771081.
Friedman JH, Messing S, Oakes D et al. (2002). Parkinson
Study Group. A descriptive and comparative analysis of
psychotic symptoms in three placebo-controlled, double-
blinded trials of atypical antipsychotic drugs in the treat-
ment of drug-induced psychosis in Parkinsons disease.
Mov Disord 17: 1105.
Friedman JH, Berman R, Carson W et al. (2005). Low dose
aripiprazole for the treatment of drug induced psychosis
in Parkinsons disease. Ninth International Congress of
Parkinsons Disease and Movement Disorders, New
Orleans, MS.
Funkiewiez A, Ardouin C, Caputo E et al. (2004). Long term
effects of bilateral subthalamic nucleus stimulation on
cognitive function, mood, and behaviour in Parkinsons
disease. J Neurol Neurosurg Psychiatry 75: 834839.
Ghika J, Villemure JG, Fankhauser H et al. (1998). Efficiency
and safety of bilateral contemporaneous pallidal stimu-
lation (deep brain stimulation) in levodopa-responsive
patients with Parkinsons disease with severe motor
fluctuations: A 2-year follow-up review. J Neurosurg 89:
713718.
Ghika J, Ghika-Schmid F, Fankhauser H et al. (1999). Bilat-
eral contemporaneous posteroventral pallidotomy for the
treatment of Parkinsons disease: Neuropsychological
and neurological side effects. Report of four cases and
review of the literature. J Neurosurg 91: 313321.
Giovannoni G, OSullivan JD, Turner K et al. (2000). Hedonis-
tic homeostatic dysregulation in patients with Parkinsons
disease on dopamine replacement therapies. J Neurol
Neurosurg Psychiatry 68: 423428.
Gironell A, Kulisevsky J, Rami L et al. (2003). Effects of
pallidotomy and bilateral subthalamic stimulation on
cognitive function in Parkinson disease. A controlled
comparative study. J Neurol 250: 917923.
 TREATMENT-INDUCED MENTAL CHANGES IN PARKINSONS DISEASE
Goetz CG, Stebbins GT (1993). Risk factors for nursing
home placement in advanced Parkinsons disease. Neurol-
ogy 43: 22272229.
Goetz CG, Stebbins GT (1995). Mortality and hallucinations
in nursing home patients with advanced Parkinsons dis-
ease. Neurology 45: 669671.
Goetz CG, Tanner CM, Klawans HL (1982a). Drug holiday
in the management of Parkinson disease. Clin Neurophar-
macol 5: 351364.
Goetz CG, Tanner CM, Klawans HL (1982b). Pharmacology
of hallucinations induced by long-term drug therapy. Am J
Psychiatry 139: 494497.
Goetz CG, Pappert EJ, Blasucci LM et al. (1998a). Intrave-
nous levodopa in hallucinating Parkinsons disease
patients: High-dose challenge does not precipitate halluci-
nations. Neurology 50: 515517.
Goetz CG, Vogel C, Tanner CM et al. (1998b). Early dopami-
nergic drug-induced hallucinations in parkinsonian patients.
Neurology 51: 811814.
Goetz CG, Blasucci LM, Leurgans S et al. (2000). Olanzapine
and clozapine: Comparative effects on motor function in
hallucinating PD patients. Neurology 55: 789794.
Graham JM, Grunewald RA, Sagar HJ (1997). Hallucinosis
in idiopathic Parkinsons disease. J Neurol Neurosurg
Psychiatry 63: 434440.
Groenewegen HJ, Berendse HW (1990). Connections of the
subthalamic nucleus with ventral striatopallidal parts of
the basal ganglia in the rat. J Comp Neurol 294: 607622.
Gschwandtner U, Aston J, Renaud S et al. (2001). Pathologic
gambling in patients with Parkinsons disease. Clin
Neuropharmacol 24: 170172.
Haeske-Derwick HC (1995). Hallucinations in Parkinsons
disease: Characteristics and associated clinical features.
Int J Geriatr Psychiatry 10: 487495.
Hardie RJ, Lees AJ, Stern GM (1984). On-off fluctuations in
Parkinsons disease. A clinical and neuropharmacological
study. Brain 107 (Pt 2), 487506.
Hariz MI, Johansson F, Shamsgovara P et al. (2000). Bilateral
subthalamic nucleus stimulation in a parkinsonian patient
with preoperative deficits in speech and cognition: Persis-
tent improvement in mobility but increased dependency:
A case study. Mov Disord 15: 136139.
Herzog J, Reiff J, Krack P et al. (2003a). Manic episode with
psychotic symptoms induced by subthalamic nucleus
stimulation in a patient with Parkinsons disease. Mov
Disord 18: 13821384.
Herzog J, Volkmann J, Krack P et al. (2003b). Two-year
follow-up of subthalamic deep brain stimulation in
Parkinsons disease. Mov Disord 18: 13321337.
Higginson CI, Fields JA, Troster AI (2001). Which symp-
toms of anxiety diminish after surgical interventions for
Parkinson disease? Neuropsychiatry Neuropsychol Behav
Neurol 14: 117121.
Hillen ME, Sage JI (1996). Nonmotor fluctuations in patients
with Parkinsons disease. Neurology 47: 11801183.
Holroyd S, Currie L, Wooten GF (2001). Prospective study
of hallucinations and delusions in Parkinsons disease.
J Neurol Neurosurg Psychiatry 70: 734738.
237
Houeto JL, Mesnage V, Mallet L et al. (2002). Behavioural
disorders, Parkinsons disease and subthalamic stimula-
tion. J Neurol Neurosurg Psychiatry 72: 701707.
Hurwitz TA, Calne DB, Waterman K (1988). Treatment of
dopaminomimetic psychosis in Parkinsons disease with
electroconvulsive therapy. Can J Neurol Sci 15: 3234.
Inzelberg R, Kipervasser S, Korczyn AD (1998). Auditory
hallucinations in Parkinsons disease. J Neurol Neurosurg
Psychiatry 64: 533535.
Jahanshahi M, Ardouin CM, Brown RG et al. (2000). The
impact of deep brain stimulation on executive function
in Parkinsons disease. Brain 123 (Pt 6), 11421154.
Jansen EN (1994). Clozapine in the treatment of tremor in
Parkinsons disease. Acta Neurol Scand 89: 262265.
Jeste DV (2004). Tardive dyskinesia rates with atypical anti-
psychotics in older adults. J Clin Psychiatry 65 (Suppl 9),
2124.
Kane J, Honigfeld G, Singer J et al. (1988). Clozapine for the
treatment-resistant schizophrenic. A double-blind compar-
ison with chlorpromazine. Arch Gen Psychiatry 45:
789796.
Kelly PJ, Gillingham FJ (1980). The long-term results of
stereotaxic surgery and L-dopa therapy in patients with
Parkinsons disease. A 10-year follow-up study. J Neuro-
surg 53: 332337.
Klein C, Gordon J, Pollak L et al. (2003). Clozapine in
Parkinsons disease psychosis: 5-year follow-up review.
Clin Neuropharmacol 26: 811.
Kleiner-Fisman G, Fisman DN, Sime E et al. (2003). Long-
term follow up of bilateral deep brain stimulation of the
subthalamic nucleus in patients with advanced Parkinson
disease. J Neurosurg 99: 489495.
Kofman OS (1984). Are levodopa drug holidays justified?
Can J Neurol Sci 11: 206209.
Koob GF, Le Moal M (1997). Drug abuse: Hedonic homeo-
static dysregulation. Science 278: 5258.
Krack P, Limousin P, Benabid AL et al. (1997). Chronic stimu-
lation of subthalamic nucleus improves levodopa-induced
dyskinesias in Parkinsons disease. Lancet 350: 1676.
Krack P, Kumar R, Ardouin C et al. (2001). Mirthful laugh-
ter induced by subthalamic nucleus stimulation. Mov Dis-
ord 16: 867875.
Krack P, Batir A, Van Blercom N et al. (2003). Five-year
follow-up of bilateral stimulation of the subthalamic
nucleus in advanced Parkinsons disease. N Engl J Med
349: 19251934.
Kubu CS, Grace GM, Parrent AG (2000). Cognitive outcome
following pallidotomy: The influence of side of surgery and
age of patient at disease onset. J Neurosurg 92: 384389.
Kulisevsky J, Berthier ML, Gironell A et al. (2002). Mania
following deep brain stimulation for Parkinsons disease.
Neurology 59: 14211424.
Kurlan R (2004). Disabling repetitive behaviors in Parkin-
sons disease. Mov Disord 19: 433437.
Lacritz LH, Cullum CM, Frol AB et al. (2000). Neuropsycho-
logical outcome following unilateral stereotactic pallidot-
omy in intractable Parkinsons disease. Brain Cogn 42:
364378.
238 K. L. CHOU AND J. H. FRIEDMAN
Laitinen LV (2000). Behavioral complications of early
pallidotomy. Brain Cogn 42: 313323.
Lawrence AD, Evans AH, Lees AJ (2003). Compulsive use
of dopamine replacement therapy in Parkinsons disease:
Reward systems gone awry? Lancet Neurol 2: 595604.
Lezak MD (1995). Executive function. In: MD Lezak, (Ed.),
Neuropsychological Assessment. Oxford University Press,
Oxford.
Limousin P, Krack P, Pollak P et al. (1998). Electrical stimu-
lation of the subthalamic nucleus in advanced Parkinsons
disease. N Engl J Med 339: 11051111.
Lombardi WJ, Gross RE, Trepanier LL et al. (2000). Rela-
tionship of lesion location to cognitive outcome following
microelectrode-guided pallidotomy for Parkinsons dis-
ease: Support for the existence of cognitive circuits in
the human pallidum. Brain 123 (Pt 4), 746758.
Maricle RA, Nutt JG, Carter JH (1995a). Mood and anxiety
fluctuation in Parkinsons disease associated with levo-
dopa infusion: Preliminary findings. Mov Disord 10:
329332.
Maricle RA, Nutt JG, Valentine RJ et al. (1995b). Dose-
response relationship of levodopa with mood and anxiety
in fluctuating Parkinsons disease: A double-blind,
placebo-controlled study. Neurology 45: 17571760.
Martinez-Martin P, Valldeoriola F, Molinuevo JL et al.
(2000). Pallidotomy and quality of life in patients with Par-
kinsons disease: An early study. Mov Disord 15: 6570.
Martinez-Martin P, Valldeoriola F, Tolosa E et al. (2002).
Bilateral subthalamic nucleus stimulation and quality of
life in advanced Parkinsons disease. Mov Disord 17:
372377.
Masterman D, DeSalles A, Baloh RW et al. (1998). Motor,
cognitive, and behavioral performance following unilat-
eral ventroposterior pallidotomy for Parkinson disease.
Arch Neurol 55: 12011208.
Matsui H, Udaka F, Oda M et al. (2004). [Two cases of Par-
kinsons disease in which visual hallucinations disappeared
after cataract surgery.] No To Shinkei 56: 351354.
McDowell SA, Harris JP (1997). Visual problems in Parkin-
sons disease: A questionnaire survey. Behav Neurol 10:
7781.
McKeith IG, Ballard CG, Harrison RW (1995). Neuroleptic
sensitivity to risperidone in Lewy body dementia. Lancet
346: 699.
McKeith IG, Galasko D, Kosaka K et al. (1996). Consensus
guidelines for the clinical and pathologic diagnosis of
dementia with Lewy bodies (DLB): Report of the
consortium on DLB international workshop. Neurology
47: 11131124.
Meco G, Bonifati V, Cusimano G et al. (1990). Hallucina-
tions in Parkinson disease: Neuropsychological study. Ital
J Neurol Sci 11: 373379.
Meco G, Alessandria A, Bonifati V et al. (1994). Risperidone
for hallucinations in levodopa-treated Parkinsons disease
patients. Lancet 343: 13701371.
Menza MA, Sage J, Marshall E et al. (1990). Mood changes
and on-off phenomena in Parkinsons disease. Mov
Disord 5: 148151.
Menza MA, Golbe LI, Cody RA et al. (1993). Dopamine-
related personality traits in Parkinsons disease. Neurology
43: 505508.
Merello M, Starkstein S, Nouzeilles MI et al. (2001). Bilat-
eral pallidotomy for treatment of Parkinsons disease
induced corticobulbar syndrome and psychic akinesia
avoidable by globus pallidus lesion combined with con-
tralateral stimulation. J Neurol Neurosurg Psychiatry 71:
611614.
Merims D, Galili-Mosberg R, Melamed E (2000). Is there
addiction to levodopa in patients with Parkinsons disease?
Mov Disord 15: 10141016.
Miwa H, Morita S, Nakanishi I et al. (2004). Stereotyped
behaviors or punding after quetiapine administration in
Parkinsons disease. Parkinsonism Relat Disord 10:
177180.
Miyawaki E, Perlmutter JS, Troster AI et al. (2000). The
behavioral complications of pallidal stimulation: A case
report. Brain Cogn 42: 417434.
Molina JA, Sainz-Artiga MJ, Fraile A et al. (2000). Patholo-
gic gambling in Parkinsons disease: A behavioral mani-
festation of pharmacologic treatment? Mov Disord 15:
869872.
Morgante L, Epifanio A, Spina E et al. (2004). Quetiapine
and clozapine in parkinsonian patients with dopaminergic
psychosis. Clin Neuropharmacol 27: 153156.
Moro E, Scerrati M, Romito LM et al. (1999). Chronic
subthalamic nucleus stimulation reduces medication
requirements in Parkinsons disease. Neurology 53: 8590.
Nausieda PA (1985). Sinemet abusers. Clin Neuropharma-
col 8: 318327.
Nausieda PA, Weiner WJ, Kaplan LR et al. (1982). Sleep
disruption in the course of chronic levodopa therapy: An
early feature of the levodopa psychosis. Clin Neurophar-
macol 5: 183194.
Nissenbaum H, Quinn NP, Brown RG et al. (1987). Mood
swings associated with the on-off phenomenon in
Parkinsons disease. Psychol Med 17: 899904.
Obwegeser AA, Uitti RJ, Lucas JA et al. (2000). Predictors
of neuropsychological outcome in patients following
microelectrode-guided pallidotomy for Parkinsons dis-
ease. J Neurosurg 93: 410420.
Okun MS, Bakay RA, DeLong MR et al. (2003). Transient
manic behavior after pallidotomy. Brain Cogn 52: 281283.
Olanow CW, Schapira AH, Roth T (2000). Waking up to
sleep episodes in Parkinsons disease. Mov Disord 15:
212215.
Ondo WG, Levy JK, Vuong KD et al. (2002). Olanzapine
treatment for dopaminergic-induced hallucinations. Mov
Disord 17: 10311035.
Ondo WG, Tintner R, Vuong KD et al. (2005). Double-blind,
placebo-controlled, unforced titration parallel trial of
quetiapine for dopaminergic-induced hallucinations in
Parkinsons disease. Mov Disord 20, 958963.
Pappert EJ, Goetz CG, Niederman FG et al. (1999). Hallucina-
tions, sleep fragmentation, and altered dream phenomena in
Parkinsons disease. Mov Disord 14: 117121.
 TREATMENT-INDUCED MENTAL CHANGES IN PARKINSONS DISEASE
Parkinson Study Group (1999). Low-dose clozapine for the
treatment of drug-induced psychosis in Parkinsons dis-
ease. N Engl J Med 340: 757763.
Parkinson Study Group (2000). Pramipexole vs levodopa as
initial treatment for Parkinson disease: A randomized con-
trolled trial. JAMA 284: 19311938.
Perozzo P, Rizzone M, Bergamasco B et al. (2001). Deep
brain stimulation of the subthalamic nucleus in Parkinsons
disease: Comparison of pre- and postoperative neuropsy-
chological evaluation. J Neurol Sci 192: 915.
Pillon B, Deweer B, Michon A et al. (1994). Are explicit
memory disorders of progressive supranuclear palsy
related to damage to striatofrontal circuits? Comparison
with Alzheimers, Parkinsons, and Huntingtons diseases.
Neurology 44: 12641270.
Pillon B, Ardouin C, Damier P et al. (2000). Neuropsycholo-
gical changes between off and on STN or GPi stimu- Spiegel EA, Wycis HT, Marks M et al. (1947). Stereotaxic
lation in Parkinsons disease. Neurology 55: 411418.
Pillon B, Boller F, Levy R et al. (2001). Cognitive deficits
and dementia in Parkinsons disease. In: F Boller, S
Cappa (Eds.), Vol. 6, Elsevier Science BV, Amsterdam,
pp. 311371.
Pollak P, Tison F, Rascol O et al. (2004). Clozapine in drug
induced psychosis in Parkinsons disease: A randomised,
placebo controlled study with open follow up. J Neurol
Neurosurg Psychiatry 75: 689695.
Priebe S (1984). Levodopa dependence: A case report. Phar-
macopsychiatry 17: 109110.
Quinn NP (1998). Classification of fluctuations in patients
with Parkinsons disease. Neurology 51: S25S29.
Rascol O, Brooks DJ, Korczyn AD et al. (2000). A five-year
study of the incidence of dyskinesia in patients with early
Parkinsons disease who were treated with ropinirole
or levodopa. 056 Study Group. N Engl J Med 342:
14841491.
Raudino F (2001). Non motor off in Parkinsons disease.
Acta Neurol Scand 104: 312315.
Richard IH, Justus AW, Kurlan R (2001). Relationship
between mood and motor fluctuations in Parkinsons
disease. J Neuropsychiatry Clin Neurosci 13: 3541.
Ridley RM, Baker HF (1982). Stereotypy in monkeys and
humans. Psychol Med 12: 6172.
Rodriguez-Oroz MC, Zamarbide I, Guridi J et al. (2004).
Efficacy of deep brain stimulation of the subthalamic
nucleus in Parkinsons disease 4 years after surgery: Dou-
ble blind and open label evaluation. J Neurol Neurosurg
Psychiatry 75: 13821385.
Romito LM, Raja M, Daniele A et al. (2002). Transient
mania with hypersexuality after surgery for high frequency
stimulation of the subthalamic nucleus in Parkinsons
disease. Mov Disord 17: 13711374.
Rylander G (1972). Psychoses and the punding and chorei-
form syndromes in addiction to central stimulant drugs.
Psychiatr Neurol Neurochir 75: 203212.
Saint-Cyr JA, Trepanier LL (2000). Neuropsychologic
assessment of patients for movement disorder surgery.
Mov Disord 15: 771783.
239
Saint-Cyr JA, Trepanier LL, Kumar R et al. (2000). Neurop-
sychological consequences of chronic bilateral stimulation
of the subthalamic nucleus in Parkinsons disease. Brain
123 (Pt 10), 20912108.
Sanchez-Ramos J (2002). The straight dope on addiction to
dopamimetic drugs. Mov Disord 17: 223225.
Sanchez-Ramos JR, Ortoll R, Paulson GW (1996). Visual
hallucinations associated with Parkinson disease. Arch
Neurol 53: 12651268.
Seedat S, Kesler S, Niehaus DJ et al. (2000). Pathological
gambling behaviour: Emergence secondary to treatment
of Parkinsons disease with dopaminergic agents. Depress
Anxiety 11: 185186.
Soukup VM, Ingram F, Schiess MC et al. (1997). Cognitive
sequelae of unilateral posteroventral pallidotomy. Arch
Neurol 54: 947950.
apparatus for operations on the human brain. Science
106: 349350.
Straits-Troster K, Fields JA, Wilkinson SB et al. (2000).
Health-related quality of life in Parkinsons disease after
pallidotomy and deep brain stimulation. Brain Cogn 42:
399416.
Svennilson E, Torvik A, Lowe R et al. (1960). Treatment of
parkinsonism by stereotatic thermolesions in the pallidal
region. A clinical evaluation of 81 cases. Acta Psychiatr
Scand 35: 358377.
Thobois S, Mertens P, Guenot M et al. (2002). Subthalamic
nucleus stimulation in Parkinsons disease: Clinical
evaluation of 18 patients. J Neurol 249: 529534.
Tousi B, Frankel M (2004). Olfactory and visual hallucina-
tions in Parkinsons disease. Parkinsonism Relat Disord
10: 253254.
Trepanier LL, Saint-Cyr JA, Lozano AM et al. (1998). Neu-
ropsychological consequences of posteroventral pallidot-
omy for the treatment of Parkinsons disease. Neurology
51: 207215.
Trepanier LL, Kumar R, Lozano AM et al. (2000). Neurop-
sychological outcome of GPi pallidotomy and GPi or
STN deep brain stimulation in Parkinsons disease. Brain
Cogn 42: 324347.
Troster AI, Fields JA, Wilkinson SB et al. (1997). Unilateral
pallidal stimulation for Parkinsons disease: Neurobeha-
vioral functioning before and 3 months after electrode
implantation. Neurology 49: 10781083.
Troster AI, Fields JA, Wilkinson S et al. (2003). Effect of
motor improvement on quality of life following subthala-
mic stimulation is mediated by changes in depressive
symptomatology. Stereotact Funct Neurosurg 80: 4347.
Turecki G, Mari Jde J, Del Porto JA (1993). Bipolar disorder
following a left basal-ganglia stroke. Br J Psychiatry 163: 690.
Turner KR, Reid WG, Homewood J et al. (2002). Neurop-
sychological sequelae of bilateral posteroventral pallidot-
omy. J Neurol Neurosurg Psychiatry 73: 444446.
Uitti RJ, Wharen REJr, Turk MF et al. (1997). Unilateral pal-
lidotomy for Parkinsons disease: Comparison of outcome in
younger versus elderly patients. Neurology 49: 10721077.
240 K. L. CHOU AND J. H. FRIEDMAN
Varma TR, Fox SH, Eldridge PR et al. (2003). Deep brain sti-
mulation of the subthalamic nucleus: Effectiveness in
advanced Parkinsons disease patients previously reliant on
apomorphine. J Neurol Neurosurg Psychiatry 74: 170174.
Vingerhoets G, van der Linden C, Lannoo E et al. (1999).
Cognitive outcome after unilateral pallidal stimulation in
Parkinsons disease. J Neurol Neurosurg Psychiatry 66:
297304.
Volkmann J, Allert N, Voges J et al. (2001). Safety and effi-
cacy of pallidal or subthalamic nucleus stimulation in
advanced PD. Neurology 56: 548551.
Voon V (2004). Repetition, repetition, and repetition: Compul-
sive and punding behaviors in Parkinsons disease. Mov
Disord 19: 367370.
Wolters EC, Hurwitz TA, Mak E et al. (1990). Clozapine in
the treatment of parkinsonian patients w ith dopaminomi-
metic psychosis. Neurology 40: 832834.
Wolters EC, Jansen EN, Tuynman-Qua HG et al. (1996). Olan-
zapine in the treatment of dopaminomimetic psychosis in
patients with Parkinsons disease. Neurology 47: 10851087.
Woods SP, Fields JA, Troster AI (2002). Neuropsychological
sequelae of subthalamic nucleus deep brain stimulation in
Parkinsons disease: A critical review. Neuropsychol Rev
12: 111126.
Workman RH Jr, Orengo CA, Bakey AA et al. (1997). The
use of risperidone for psychosis and agitation in demented
patients with Parkinsons disease. J Neuropsychiatry Clin
Neurosci 9: 594597.
 Section 7

Surgical treatment
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 42

Ablative surgery for the treatment of Parkinsons disease

FREDERICK A. LENZ*

Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA

42.1. Introduction 42.2. Mechanisms of parkinsonian

Spiegel and Wycis (1954; Cooper, 1954; Spiegel et al.,
1958) pioneered stereotactic surgery for the treatment
of Parkinsons disease (PD) by introducing coagula-
tion of the globus pallidus stereotactic pallidotomy.
(Hassler et al., 1979), introduced ablation of the ventral
oral nucleus of thalamus (Vo, consisting of Voa and
Vop, anterior and posterior subnuclei), the terminus
for pallidal afferents to the thalamus. Microelectrode
recordings demonstrated that the area posterior to
Vop, i.e. the terminus of cerebellar afferents (ventral
intermediate: Vim), was later found to have rhythmic
bursting activity close to the frequency of tremor (Guiot
et al., 1962). Vim then became the target of choice for
tremor of all types.
The introduction of levodopa in the early 1970s led
to a dramatic decrease in the number of stereotactic
surgeries for movement disorders (Levy, 1992). Two
decades later, drug-related complications of medical
treatment, including dyskinesias and fluctuations, had
proven intractable (Marsden and Parkes, 1977; Marsden
and Fahn, 1987). Neurophysiologic studies in the
realistic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) model of PD had demonstrated increased activ-
ity in the subthalamic nucleus (STN) and the internal
segment of the globus pallidus (GPi) (Bergmam et al.,
1990). Finally, the demonstration that posteroventral
GPi pallidotomy was effective for advanced PD
(Laitinen et al., 1992) led to a resurgence in ablative
approaches for the treatment of PD. The introduction
of stimulation techniques led to decreased frequency
of ablative approaches to the movement disorders
(Siegfried and Lippitz, 1994; Benabid et al., 1996;
Clatterbuck et al., 2000).
motor symptoms
PD affects approximately 1% of the population over 65
years (Adams et al., 1996). The three cardinal signs of
PD are resting tremor, cogwheel rigidity and bradykine-
sia (Paulson and Stern, 1997). After years of treatment
with levodopa, patients with PD often develop intract-
able complications of this therapy, including dyskinesias
and fluctuations (Marsden and Parkes, 1977; Marsden
and Fahn, 1987). The forebrain mechanisms of some
of these symptoms have recently been clarified, lead-
ing to a rationale for effective targets for treatment
of PD.
42.2.1. Bradykinesia
The motor circuit of the basal ganglia includes a
direct inhibitory pathway from the putamen to the
internal segment of the GPi and an indirect, excita-
tory pathway from the putamen to GPi via the
STN (see Ch. 1). In monkeys, GPi-inhibitory
(GABAergic) efferents in the motor loop project to
neurons of the monkey thalamic nucleus ventral lat-
eral pars oralis (VLo) (Penney and Young, 1981;
Young and Penney, 1984), corresponding to human
Vop. Cortical projections activate these pathways,
with a resultant reduction in inhibitory GPi activity
via the direct pathway and an increase in inhibitory
GPi activity via the indirect pathway.
The motor manifestations of parkinsonism are
seen with dysfunction of the nigrostriatal dopaminergic
pathway (Hornykiewicz, 1974). Dopaminergic projections
from the substantia nigra tend to activate the direct path-
way (D1 dopamine receptor-mediated) and decrease the

*Correspondence to: Professor F. A. Lenz, Department of Neurosurgery, Meyer Building 8-181, Johns Hopkins Hospital,
600 North Wolfe Street, Baltimore, MD 21287-7713, USA. E-mail: flenz1@jhmi.edu, Tel: 1-410-955-2257, Fax:1- 410-
614-9877.
244 F. A. LENZ
activity of the indirect pathway (D2-receptor-mediated).
Therefore, in PD there is decreased inhibition of
GPi through the direct pathway and increased excita-
tion though the indirect pathway. As a result of these
effects of dopamine deficiency there is increased GPi
activity leading to inhibition of Vop (Vitek et al.,
1993). Thus thalamocortical and corticothalamic
motor circuits might be inhibited, leading to slowing
of movement initiation and of movement itself, i.e.
bradykinesia (Penney and Young, 1981; Young and
Penney, 1984; DeLong, 1990).
42.2.2. Tremor
In the case of Parkinsons tremor the most current
hypothesis is a thalamic oscillator activated by hyperpo-
larization of the thalamocortical cells in VLo/Vop due
to increased inhibitory input from the pallidum in PD
(Bergman et al., 1990; Pare et al., 1990; see also
Lamarre and Joffroy, 1979; Marsden, 1984; Elble and
Koller, 1990). When inhibited, these cells generate a
somatic calcium spike which produces an action poten-
tial burst (LTS bursts, low-threshold spike bursts) with
a following inhibition, leading to recurrent oscillations
(Filion et al., 1988; Buzsaki et al., 1990; Pare et al.,
1990). However such bursts are rarely found in recordings
from Vim and Vop of parkinsonian patients undergoing
thalamotomy (Zirh et al., 1998; Magnin et al., 2000).
Another proposed central generator is GPi, specifi-
cally neurons that project to and inhibit Vop neurons.
This hypothesis is inconsistent with higher rates of tre-
mor-related activity in a cerebellar relay (Vim: 25%)
than a pallidal relay of patients with PD (Vop: 21%)
(Lenz et al., 1994; Hua et al., 1998). Furthermore,
GPi activity at tremor frequency is rarely correlated
with tremor in PD (Hutchison et al., 1997b; Lemstra
et al., 1999) or in monkey models of parkinsonism
(Raz et al., 2000). Therefore, the activity of cells in
thalamus and pallidum is not consistent with a pallidal
generator for parkinsonian tremor.
Another proposed mechanism of parkinsonian
tremor is the peripheral-feedback hypothesis. This
hypothesis proposes that tremor is the oscillation of
unstable stretch reflex arcs (long-loop reflex arc)
which may traverse motor cortex in much the same way
tendon tap reflexes traverse the spinal cord (Desmedt,
1978; Lenz et al., 1983a, b). The increased gain of these
reflexes may cause parkinsonian rigidity and tremor, in
much the same way as increased spinal reflexes cause
spasticity and clonus (Stein and Lee, 1981). This
hypothesis has been supported by the finding that thala-
mic neuronal activity precedes tremor in the case of
thalamic neurons with sensory inputs, but not those
without (Strick, 1976; Lenz et al., 1990, 1994; Vitek
et al., 1994). Therefore sensory cells participating in a
reflex or feedback loop might cause tremor. Finally, a
transfer function analysis has demonstrated a feedback
loop in > 90% of cells in the Vim and Vop (Schnider
et al., 1989).
42.2.3. Dyskinesias
The current model of hyperkinetic disorders (DeLong,
1990) suggests that a decrease in pallidal activity dis-
inhibits the pallidal relays, VLo/Vop, by decreased
inhibitory input to the thalamus from the pallidum
(Penney and Young, 1981). In hemiballism the activity
of neurons in GPi is characterized by firing rates
which are lower and more irregular than parkinonsian
patients off or on medications (intravenous apo-
morphine) (Suarez et al., 1997; Vitek et al., 1999),
consistent with studies in monkeys (Nini et al., 1995).
The pauses and grouped discharges of GPi neurons
may be related to the random bursts of electromyo-
gram (EMG) activity hemiballistic movements (Vitek
et al., 1999). The importance of patterned GPi activity
in hemiballismus is consistent with the efficacy of pal-
lidotomy since pallidotomy will interrupt activity but
not decreased pallidal firing (DeLong, 1990). A simi-
lar mechanism seems to be involved in drug (apomor-
phine)-related dyskinesias (Hutchison et al., 1997a;
Merello et al., 1999).
42.2.4. Dystonia
Dystonia is a common feature of PD. During dystonia
of multiple etiologies, firing rates of cells in GPi are
patterned and are intermediate between those in hemi-
ballismus and normal monkeys (Vitek et al., 1995,
1998b; Suarez et al., 1997). However, normal firing
rates can occur with mild dystonia whereas decreased
firing rates develop with repeated active movements
which also exacerbate dystonia (Lenz et al., 1998). Thus
the inverse relationship between GPi cellular firing and
dystonia may be the result of cortically mediated, activ-
ity-dependent changes in striatal activity transmitted to
GPi and then to Vop through the direct pathway (Albin
et al., 1989; Carlson and Carlson, 1990).
Decreased patterned firing of GPi neurons in
patients with dystonia should produce an increased
patterned firing in the monkey/human thalamic palli-
dal relay VLo/Vop. However, decreased, patterned
firing was reported in Vop more than Vim during dys-
tonia (Lenz et al., 1999), perhaps related to the
dystonia-related plasticity of firing in GPi (Lenz
et al., 1998). Thalamic dystonia frequency activity
correlated with and leading dystonia is significantly
more common in Vop than Vim. Lesions of GPi
 ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSONS DISEASE
(Vitek and Lenz, 1998) and presumed Vop (Andrew
et al., 1983; Tasker et al., 1988; Cardoso et al., 1995;
Lenz et al., 1999) can relieve dystonia, which suggests
that, for neurons in Vop, patterned activity is more
important than decreased firing rates in the mechanism
of dystonia (Lenz et al., 1999). Therefore, there is
reasonable rationale for lesions of the pallidum and
Vop as treatment for the dystonia of PD.
42.3. Stereotactic surgical technique
Radiologic and physiologic landmarks are usually used
to localize accurately the target for ablative procedures
(Bakay et al., 1992; Lozano et al., 1996; Garonzik et al.,
2002; Patel et al., 2003). Many surgeons employ radi-
ologic localization of the anterior (AC) and posterior
commissure (PC) and of the border between the capsule
and thalamus using computed tomography (CT) or
magnetic resonance imaging (MRI) scans. The radiolo-
gic estimate of location is refined physiologically
by microelectrode recording before radiofrequency
lesioning (Mandir et al., 1997; Garonzik et al., 2002;
Hua et al., 2004). Alternative approaches are to loca-
lize radiologically using ventriculography or CT/MR
fusion techniques (Carlson and Iacono, 1999) and to
localize physiologically using semimicroelectrode
recording or macrostimulation (Burchiel, 1995) and
to lesion using radiosurgery (Friedman et al., 1996;
Kondziolka, 2002). The relative efficacy and safety
of these different techniques have not been examined
systematically.
42.4. Radiologic localization
Ventriculography can still be used as a means of
locating the ACPC line (Diederich et al., 1992;
Schuurman et al., 2000), although it has largely been
replaced by CT and MRI scanning. Computerized
imaging is as accurate as ventriculography (Tasker
et al., 1991) and does not carry the risks of ventricular
puncture and instillation of contrast media into the
ventricles. MRI scanning is slightly less accurate than
CT scanning, with errors of approximately 2 mm on
average and 4 mm at maximum (Kondziolka et al.,
1992; Gerdes et al., 1994; Holtzheimer et al., 1999).
This error is due to artifacts related to inhomogeneities
and non-linearities in the gradient field the position-
dependent strength in the magnetic field (Hardy and
Barnett, 1998). Artifacts can be induced by metal or
magnetic suseptibility artifacts, produced at the
interface between materials (e.g. air and bone) which
have different tendencies to affect the magnetic field
in a region.
245
Attempts to decrease errors in MRI scan due to
these artifacts include software modifications and
overlapping (fusion) of the three-dimensional MRI
database with the CT database which is not prone to
these types of artifacts (Alexander et al., 1995). These
databases can then be merged with atlas maps of anat-
omy to estimate the location of nuclei relative to the
radiologic anatomy. These atlas maps may be trans-
formed either to match the ACPC line in isolation or
to match the ACPC line and other structures, such as
the margins of the third ventricle or the internal
capsule (Kelly et al., 1987; Dostrovsky, 1998).
Another approach is to estimate the target directly
from the ACPC line as determined radiologically.
The target for Vim is 3 mm anterior and 14 mm lateral
to PC and 2 mm above the ACPC line. Alternatively,
the target in Vim can be estimated in the lateral plane
midway between the internal capsule and the lateral
edge of the T2 intense medial dorsal nucleus of the
thalamus (Hua et al., 2004).
GPi can be estimated 3 mm anterior, 3 mm inferior
and 2022 mm lateral to the mid commissural point.
Direct targeting can be carried out on axial and coro-
nal inversion recovery series. On an axial cut through
the ACPC line at the anterior posterior coordinate is
the mid commissural point and the medial lateral
coordinate is 4 mm medial to the external lamina
separating the internal from the external pallidal seg-
ment. The vertical axis was targeted from the location
of the optic tract and GPi on the coronal cut through
the mid commissural point (Starr et al., 1999).
The location of STN can be estimated at 4 mm
posterior, 4 mm inferior and 12 mm lateral to the
midpoint of ACPC (Guridi et al., 1999; Patel et al.,
2003). STN can be directly localized using 2 mm,
T2-weighted spin-echo sequence axial and coronal
scans through the thalamus and midbrain. On such a
series STN can also be localized 7 mm lateral and
4 mm anterior to the center of the red nucleus (Starr
et al., 2002). Fusion of other MR series, such as gradi-
ent echo T2 and fast spin-echo series or CT can be used
to localize STN and target the dorsal part of the poster-
ior third of STN (Patel et al., 2003). Physiological
confirmation of the radiologic estimate is carried out
by stimulation or recording at and around the target.
42.5. Physiologic localization
Radiologic targeting should be verified by identifying
the different nuclei (GPi, STN and Vim) on the basis
of properties such as spontaneous activity and neuro-
nal firing related to the movement disorders and to
passive and active movements. Nuclear properties are
also defined by microstimulation (< 100 mA)-evoked
246
sensations and motor effects such as alteration in the
movement disorder, e.g. decreased tone or tremor.
Physiologic localization can be carried out by stimula-
tion using a macroelectrode (impedance < 1000 ohms)
or by stimulation and recording using a semimicroelec-
trode (impedance < 100 kohms) or a microelectrode
(impedance > 500 kohms).
In our institution a map of physiologic results is
made to the same scale as a set of transparent atlas
maps from the sagittal sections of the Schaltenbrand
and Bailey atlas (1959) parasagittal sections for
different targets as follows: 13.5 mm lateral atlas
map for Vim, 21 mm for GPi and 11 mm for the
STN. The fusion and fitting of the imaging studies to
the physiologic and atlas maps can also be accom-
plished through a number of commercially available
surgical navigation systems.
42.5.1. Microelectrode localization
F. A. LENZ
stimulation determines the amount of local current
spread (Ranck, 1975).
Semimicroelectode recordings are carried out using
low-impedance microelectrodes with an impedance of
less than 100 kohms. The semimicroelectrode signal is
often amplified against a concentric ring electrode
which is located on a radius of 0.4 mm around the
microelectrode (Taren et al., 1968; Burchiel, 1995;
Ohye, 1998). Recordings through a semimicroelec-
trode will yield recordings of local field potentials
(slow waves) or multiunit activity. Bipolar stimulation
through a concentric ring electrode can be used alone or
in combination with recording through a semimicroelec-
trode (Ojemann and Ward, 1982; Tasker et al., 1982;
Laitinen and Hariz, 1996).
42.6. Stereotactic lesioning technique
42.6.1. Radiofrequency

Microelectrodes for physiologic monitoring and
recording are designed to isolate single action poten-
tials (Hubel, 1957; Jasper and Bertrand, 1966; Lenz
et al., 1988a) and to withstand microstimulation which
degrades the electrode. Typically these characteristics are
achieved by constructing electrodes from a platinum-iri-
dium alloy or from tungsten, producing a tapered tip and
insulating with glass (Hubel, 1957; Wolbarsht et al.,
1960; Umbach and Ehrhardt, 1965; Albe-Fessard, 1973;
Ohye, 1982; Lenz et al., 1988a). The electrode impedance
is usually (Lozano et al., 1996) greater than 500 kohms
(Jasper and Bertrand, 1966; Lenz et al., 1988a). A high-
impedance microelectrode is required to isolate single
units (Lenz et al., 1988a).
The assembled electrode is attached to a hydraulic
or piezoelectric microdrive and mounted on the
stereotaxic frame. Some microdrive systems incorpo-
rate a coarse drive so that overlying structures can be
traversed quickly. The tip is then retracted into a
protective cylindrical housing while the whole assem-
bly is advanced to a new depth (Vitek et al., 1998a).
The microdrive may then be employed from this new
depth for detailed exploration of deeper structures.
Another option is to use the microdrive throughout
the trajectory by advancing it each time it reaches
the end of its traverse (Lenz et al., 1988a).
The signal from the microelectrode is amplified and
filtered. Multiple neuronal discharges of varying sizes
may be seen on an oscilloscope and heard by use of an
audio monitor. In addition to recording, microstimula-
tion of subcortical structures may be delivered.
We employ biphasic, square-wave pulse trains of
0.10.3 ms pulses for up to 10 seconds at a frequency
of 300 Hz (Lenz et al., 1993). The current used in
One or two lesions are then made at the target defined
by the above techniques. Lesions are made by the
technique of radiofrequency coagulation using an
electrode with a 1.1 mm outer diameter and a 3 mm
exposed tip and a thermister at the tip of the electrode
(TM electrode: Radionics, Burlington, MA). Tempera-
ture is held constant at 60
C over a 1-minute interval.
The temperature is increased in 510
C steps during
subsequent 1-minute intervals to a level of approxi-
mately 80
C. Since temperature is increased in steps
of about 10
C, the average length of time to make
the lesion is 4 minutes. Neurologic examination stres-
ses the function of structures adjacent to the target so
that during GPi coagulation motor strength and visual
fields are stressed. In the case of Vim, the examination
stresses cutaneous sensory, pyramidal and cerebellar
function, plus speech. These abbreviated exams should
be carried out before, during and after each stage of
lesion-making. The coagulum of each such separate
lesion made by this technique is approximated to a
cylinder with a diameter of 3 mm and a length of
5 mm (Cosman and Cosman, 1985; Lenz et al., 1995).
42.6.2. Localization of Vim
Sensory cells responding to sensory stimulation in small,
well-defined, receptive fields are found in the ventral
caudal thalamic nucleus (Vc), posterior to Vim (Lenz
et al., 1988c). There is a well-described mediolateral
somatotopy within Vc (Jasper and Bertrand, 1966; Lenz
et al., 1988c) proceeding from representation of oral
structures medially to leg laterally. In anterior Vc and
further anterior in Vim, neuronal firing is related to pas-
sive joint movement (deep sensory cells) or to active
 ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSONS DISEASE
movement (voluntary cells) (Raeva, 1986; Lenz et al.,
1990). Some neurons respond to both active movement
and to sensory stimulation such as joint movement
(combined cells) (Lenz et al., 1990, 1994). Deep
sensory, combined and voluntary cells have activity
correlated with EMG activity during tremor (Lenz
et al., 1985, 1988b; Hua et al., 1998a) and have a soma-
totopy parallel to that in Vc. Stimulation in Vc will
evoke somatic sensations (Lenz et al., 1993). Stimula-
tion in Vim may produce brief movements or alter
ongoing tremor or dystonia (Lenz et al., 1999).
Thalamic semimicroelectrode recordings (Ohye,
1982, 1998; Burchiel, 1995) reveal patterns of neuronal
activity parallel to those of microelectrode recordings.
Macrostimulation through a low-impedance electrode
(impedance often less than 1000 kohms) can reliably
identify Vim by alterations in the movement disorder
(Tasker et al., 1982) and capsule by stimulation-evoked
tetanic contraction of skeletal muscle at low threshold
(Ojemann and Ward, 1982; Tasker et al., 1982).
Stimulation of intralaminar nuclei medial to Vc or
Vim may evoke the recruiting response long-latency,
high-voltage, negative waves occurring over much of
the cortex at the frequency of stimulation (usually less
than 10 Hz) (Jones, 1985; Fisher et al., 1996).
An analysis of the locations of tremor cells suggests
that the optimal target for thalamotomy is located 2
mm anterior to Vc and 3 mm above the ACPC line
(Lenz et al., 1995). Alternatively, targets in thalamot-
omy have been placed anterior to the site at which
evoked potentials can be recorded in response to cuta-
neous stimulation of the fingers (Guiot et al., 1973;
Kelly et al., 1978; Fox et al., 1991). Lesions have been
made in the region where electrical stimulation
produces effects on tremor and anterior to the region
where electrical stimulation evokes sensations (Tasker
et al., 1982). Lesions have also been made in the
region where cells respond to somatosensory stimula-
tion of muscle, joint and tendon and where electrical
stimulation affects tremor (Ohye and Narabayashi,
1979).
42.6.3. Localization of target within the internal
segment of the globus pallidus
During pallidotomy, microelectrode penetrations
toward the radiologic target are made from a coronal
burrhole about 25 mm from the midline. Striatum,
globus pallidus external segment (GPe) and GPi each
have a characteristic pattern of neural activity (DeLong,
1971; Lozano et al., 1996; Mandir et al., 1997; Vitek
et al., 1998a). Striatal cells are characterized by
broad action potentials and a slow firing rate
(approximately 1 Hz), often with long silent periods.
247
Cells in GPe have narrower action potentials and fire
either at high frequency (approximately 50 Hz) with
intermittent pauses (pause cells) or at lower fre-
quency (approximately 20 Hz) with intermittent
bursts (burst cells). Cells in GPi fire tonically at high
rates (6080 Hz). Cellular activity is also recorded
during passive movements of upper and lower extre-
mities both ipsilateral and contralateral to the record-
ing site to identify the cellular receptive field. Cells
in GPi of PD patients often respond to movement
of multiple joints.
At the target the optic tract is about 1 mm below
the lower border of GPi. The optic tract can be iden-
tified by the hissing sound resulting from the firing of
multiple myelinated axons which increases in
response to a flashing light (visual-evoked poten-
tials). Microstimulation in the optic tract evokes mul-
tiple colored sparkles of light. The internal capsule
behind GPi can be identified by the same hissing
sound plus microstimulation-evoked muscle twitches.
These data are used to generate a functional map of the
target zone in sagittal section. Two lesions are made
within the part of GPi where cells respond to move-
ments of the extremities (Lozano et al., 1996; Mandir
et al., 1997; Vitek et al., 1998a). Each lesion is made
to 70
with the tip of the electrode 2 mm above the
optic tract and to 80
with the tip 34 mm above
the optic tract and in front of the internal capsule.
Alternately, the lateral extend to the target may be
estimated by lateral microelectrode trajectories and
multiple small lesions (13 per trajectory) can be used
to fit the lesion to the contours of GPi (Bakay et al.,
1992; Vitek et al., 1998a).
The value of microelectrode-guided lesion location in
pallidotomy has often been debated. In one report micro-
electrode recording led to a change in final location for
lesion placement in 14/20 (70%) cases (Hiner et al.,
1997) with an average change of 3.5 mm. In another,
75% of cases were within 3  1 mm of the final lesion
site, whereas 25% (4/10) were > 5 mm away (Azizi
et al., 1996). Another study reported an incidence of
correction of the radiologic target by microelectrode
recording which was too high to justify pallidotomy
without microelectrode recording (Taha et al., 1996).
Although these results suggest that microelectrode
recording increases the accuracy of pallidotomy, this
position has not been proven (Hariz, 2002).
42.6.4. Localization of the subthalamic
nucleus lesions
During the subthalamic explorations, trajectories are
made from a coronal burrhole about 25 mm from
the midline. Striatum and Voa thalamus each have a
248 F. A. LENZ
characteristic pattern of neural activity (Hutchison For each procedure this review considered the
et al., 1998). As the electrode approaches the STN following subjects: (1) indications prior to the TTA-
from anterior and dorsal directions, striatal cells are AAN/MDS position papers; (2) randomized controlled
often encountered and are characterized by broad studies of the procedures; (3) studies included in the
action potentials and a slow firing rate (approximately position papers and then the final ATT-AAN/MDS
1 Hz), often with long silent periods. When the thala- recommendation.
mus is entered the action potentials become narrower
and often occur in bursts of the LTS type (see above).
42.7.1. General comments on all procedures
LTS bursts are preceded by a silent period of 20100
ms and consist of a interspike interval of less than
Across all procedures the TTA-AAN/MDS position
6 ms followed by interspike intervals of less than
papers made a number of general comments, as follows.
16 ms (Zirh et al., 1998; Ramcharan et al., 2000).
The publications included in these position papers were
A relatively acellular gap of 16 mm is observed
carried out by groups having neurosurgeons and neuro-
below the thalamus and above the STN, depending
physiologists with particular expertise in functional
upon the anteriorposterior location of the trajectory.
stereotactic procedures, as well as neurologists with
The STN is characterized by multiple spike trains
expertise in movement disorders. Inexperienced centers
recorded from closely packed neurons, each with a
had less success and more complications in all surgical
mean rate of about 20 ms. Microstimulation evokes
procedures. Cognitive impairment was a predictor of
paresthesias posterior to STN, muscle contractions
poor outcome and patients with advanced age derived
lateral to STN and decreases in tremor or tone within
less benefit. Contraindications were medical or psychia-
STN. The single lesion may be made dorsolateral to
tric conditions and abnormal imaging studies, including
STN (Patel et al., 2003) or two lesions may be made
focal lesions or atrophy greater than expected for age
within STN but located 3 mm apart in the medial
(Hallett and Litvan, 1999).
lateral plane (Lopez-Flores et al., 2003), with much
Many of the complications of ablative stereotactic
different results (see below).
surgery are common to all procedures. Complications
from lesion-making can arise from infection or intracra-
42.7. Results
nial hemorrhage. Hemorrhages comprise a significant
percentage of operative mortalities in stereotactic sur-
In this section we will consider the indications,
gery, occurring in 16% of procedures (Louw and
efficacy, complications/safety for pallidotomy, thala-
Burchiel, 1998). Hemorrhages may occur at the lesion
motomy and subthalamotomy. The analysis of efficacy
site or at cortical sites, resulting in intracerebral or sub-
and safety was based on the comprehensive assess-
dural hematomas. The risk of radiologically defined
ment of lesioning procedures for the treatment of PD.
hemorrhage during functional stereotactic procedures
This assessment by the Therapeutics and Technology
employing coagulation is 9/57 overall (16%; Vim 5/
Assessment Committee of the American Academy of
23: 22%; GPi 4/34: 12%) and the risk of symptomatic
Neurology (TTA-AAN) led to a position paper on
bleeding is 4/57 (7%) (Terao et al., 2003). This is
surgery for PD based on a systematic evaluation of
greater than the risk of deep brain stimulation (DBS)
the literature (Hallett and Litvan, 1999). This paper
surgery (3%: 2/59). Following stereotactic biopsy, radi-
was subsequently updated and endorsed in a scientific
ologically defined bleeds occurred in 40/500 (8%);
position paper by the Movement Disorder Society
delayed hemorrhages as defined by CT and symptoms
(MDS) (Hallett and Litvan, 2000).
occurred rarely, but always occurred within 48 hours
The literature searches were based on papers identi-
of the procedure (0.4%, 2/500) (Kondziolka et al.,
fied in four databases for the medical literature which
1998). Overall 12 patients were symptomatic (1.2%)
were searched for terms related to surgical treatment
and 1 died (0.2%). In that study platelet counts of less
of PD. All papers included in the analysis had to meet
than 150 000 were identified as a risk of bleeding in
the minimum standard of class III evidence as follows:
comparison with higher counts.
non-randomized, retrospective studies with historical
controls which were peer-reviewed, used validated
methods of assessment and provided consistent, clini- 42.7.2. Pallidotomy for Parkinsons disease
cal (rather than technical) data. Although most studies
considered were prospective, a few included a concur- At the time of rebirth of surgical approaches to the
rent control group, a requirement necessary to meet treatment of PD, pallidotomy was considered an
class II evidence, and fewer still were randomized, option for treatment of patients with advanced PD who
controlled studies. have motor drug-related complications, particularly
 ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSONS DISEASE
dyskinesias and fluctuations (Laitinen et al., 1992; Krack
et al., 2000). These symptoms should be disabling and
unresponsive to optimal medical therapy if they are to
be considered as indications for pallidotomy. Patients
with relatively less advanced disease but who are dis-
abled by tremor or dystonia are also candidates for these
procedures.
42.7.2.1. Randomized, controlled studies
of pallidotomy
There are two randomized, controlled studies of
pallidotomy for the treatment of PD (de Bie et al.,
1999; Vitek et al., 2003). In the most recent study 18
patients were randomized each to best medical therapy
and to unilateral pallidotomy (Vitek et al., 2003).
The change in the Unified Parkinsons Disease Rating
Scale (UPDRS) scale at 6 months demonstrated that
the pallidotomy group had significant improvement
whereas the medical arm was slightly worse (overall
35% versus 5%, off motor 32% versus 3%). In the
surgical patients improvements were most significant
in the symptoms of contralateral tremor, rigidity and
dyskinesia. Improvements in postural stability, gait and
bradykinesia were less significant (Vitek et al., 2003).
Improvements during the off periods were always
larger than those in the on periods, which were often
insignificant.
Patients in the medical arm were given the option
of surgery at 6-month follow-up and all patients opted
for surgery. Follow-up in 20 of the 36 patients was
obtained at 2 years postoperative and showed highly
significant (P < 0.00001) improvements in the UPDRS
overall (21%), in the off motor subscale (26%) and in
the drug-related complications subscale (fluctuations
and dyskinesias, 58%). Sustained improvements in tre-
mor, rigidity, bradykinesia, percentage on time and
drug-related dyskinesias were also observed. There
was a highly significant relationship between UPDRS
score at 2 years and age. Patients who were aged 50
or less had twice the reduction in the UPDRS score
of those greater than 60 years of age. There were some
significant complications (6/36: 17%). Two patients
had seizures intraoperatively, delaying the completion
of the procedure by weeks. Four patients had hemor-
rhages, 1 of whom had worsening of speech, which
resolved by 6 months postoperatively.
Similar results were obtained in an earlier
randomized, controlled, single-blind, multicenter trial
of pallidotomy versus best medical therapy (de Bie
et al., 1999). At 6 months the off condition of the
UPDRS motor subscale improved (44%) significantly
in the surgical group whereas it decreased in medical
controls (7%). The on-phase motor UPDRS
improved by 50% in the surgical group but was
249
unchanged in the medical group. The UPDRS-2
activities of daily living subscale improved by 23%
in the surgical group and diminished by 16% in the
medical group. All but 2 of the patients in the medical
arm crossed over but results were not reported. In
the surgical group of 19 there were 6 patients (32%)
with persistent complications, including: psychosis
and dysarthria/imbalance (one each) and 4 with minor
complications including dysarthria, facial weakness,
urinary incontinence and mental status change.
Therefore, controlled randomized trials have shown
consistent benefit for motor function as measured
by the UPDRS motor scale. Complications in pallidot-
omy ranged from 17% to 57%, suggesting technical
differences between centers.
42.7.2.2. Prospective uncontrolled studies
A review combining results of unilateral pallidotomy
examined all original studies of surgical outcome with
or without validated measures of clinical PD status or
a control group (Alkhani and Lozano, 2001). Those
studied using the validated UPDRS scores at 1 year
reported 45% improvement in off UPDRS motor sub-
scale and 35% improvement in the combined motor and
activities of daily living subscales. In addition, there
was a 41% improvement in the Schwab and England
activities of daily living scale (Alkhani and Lozano,
2001). Contralateral on-period dyskinesias improved
by 86%.
The beneficial effect on ipsilateral dyskinesias was
lost by 1 year whereas the effect on gait and balance
was lost by 36 months. Greater than 50% improve-
ments at 1 year were observed in tremor and rigidity
scales. This is consistent with another review of
studies of unilateral pallidotomy which showed a
30% improvement in the UPDRS motor subscale and
in the UPDRS overall (Okun and Vitek, 2004).
Levodopa-equivalent dose was not decreased post-
operatively (Alkhani and Lozano, 2001; Okun and
Vitek, 2004). Continued benefit has been documented
up to 2 years postoperatively (Lang et al., 1997).
Complications were common. Overall there was a
hemorrhage rate of 1.7%, resulting in a mortality rate
of 0.4% (Alkhani and Lozano, 2001). The incidence
of visual field defects was variable, as a function of
institution, with permanent deficits in 1.5%. Persistent
facial and limb weakness was observed in 1.3% and
0.9%, respectively. Persistent dysarthria, hypophonia
and dysphagia were reported in 1.6%, 1.3% and 0.5%,
respectively. Postoperative confusion, which was
usually transient, occurred in about 10% of patients.
Overall, the morbidity rate was 23%, of which 14% were
permanent, as assessed by summing all complications
across and within patients and dividing by the total
250 F. A. LENZ
number of patients. Older patients were more likely to
have cognitive problems and left-sided lesions were
associated with persistent verbal deficits (Saint-Cyr
et al., 1996).
42.7.2.3. Bilateral pallidotomy
A small, multicenter prospective study of staged
bilateral pallidotomy controlled the second side
against the first and found significant differences
between the two pallidotomies (Parkin et al., 2002).
Three months after the first pallidotomy there was a
significant decrease in the off UPDRS motor score
(mean 27%, P < 0.05) and dyskinesias were comple-
tely abolished in 40%. After the second side these
figures were 31% and 63%. At 1 year after the second
side the improvement in the motor scales diminished
but the effect on activities of daily living scales and
dyskinesias was maintained. Persistent complications
were reported in 4%, much less than the average for
unilateral pallidotomies (Saint-Cyr et al., 1996).
An earlier retrospective study of 25 patients reported
efficacy for simultaneous, bilateral pallidotomy in the
treatment of bilateral symptoms and dyskinesias
without surgical complications (Iacono et al., 1997).
A prospective study compared the efficacy of the
second staged side of a bilateral pallidotomy with
the first side (de Bie et al., 2002). Clinical ratings after
the first surgery were significantly improved for the
off UPDRS motor and activities of daily living scales
and the Schwab and England scales. There was a trend
toward improvement in the first two of these scales
for the second as compared to the first procedure.
Three out of 10 patients had persistent complications
following the first pallidotomy whereas 8/10 had such
complications after the second, including dysarthria
(n 7), hypothonia (n 1), hemiplegia (n 1) and
visual field defect (n 1). Thus, the pallidotomy is
associated with an incremental improvement of
more than the improvement after the first side with a
variable rate of complications.
42.7.2.4. TTA-AAN/MDS recommendation
regarding pallidotomy
Forty studies of pallidotomy were found in the position
papers, of which approximately one-half met the cri-
teria listed above (Laitinen et al., 1992; Dogali et al.,
1995; Lozano et al., 1995; Baron et al., 1996; Fazzini
et al., 1997; Hariz and De Salles, 1997; Kazumata
et al., 1997; Kishore et al., 1997; Krauss et al., 1997;
Lang et al., 1997; Soukup et al., 1997; Uitti et al.,
1997; Biousse et al., 1998; Cahn et al., 1998; Giller
et al., 1998; Lozano et al., 1998; Masterman et al.,
1998; Ondo et al., 1998; Shannon et al., 1998; Samuel
et al., 1998; Scott et al., 1998; Trepanier et al., 1998).
Unilateral pallidotomy was recommended as effective
and safe based on class III evidence. Unilateral pallidot-
omy was thought to be indicated for patients with PD
with fluctuations, bradykinesia, tremor and rigidity and
particularly for those with dyskinesias. The benefit for
gait and postural disturbances was judged to be less pro-
nounced. Based on the unreliable, contradictory data
and reports of speech complications, bilateral pallidot-
omy was given a type D negative recommendation.
42.7.3. Thalamotomy for Parkinsons disease
Studies published prior to the mid-1980s established
thalamotomy as an option for patients with PD who
are disabled by tremor and who have not responded
to medication, including levodopa-carbidopa and antic-
holinergics (Narabayashi, 1982; Nagaseki et al., 1986).
Contraindications to thalamotomy include patients
who have dementia, significant medical illness or Par-
kinsons plus syndromes (e.g. ShyDrager, multisystem
atrophy).
42.7.3.1. Randomized, controlled trial of Vim
thalamotomy versus Vim-DBS
A recent trial compared Vim thalamotomy versus DBS
in 68 patients with PT (n 45), as well as patients
with essential tremor (n 13) and intention tremor
(n 10) (Schuurman et al., 2000). Among patients
with parkinsonian tremor, abolition or slight residual
tremor was seen post-Vim-DBS 21/21 (100%) and in
21/23 (93%) of patients postthalamotomy. Overall,
types of tremor functional scales (Schuling et al.,
1993) demonstrated a significantly greater increase in
functional ability for Vim-DBS (16%) versus thala-
motomy (2%). Functional status was improved in sig-
nificantly more patients following Vim-DBS (54%,
18/33) than thalamotomy (24%, 8/34). Overall, tremor
was abolished or minimal residual in 30/33 (90%) of
patients treated with Vim-DBS and 27/34 (79%)
of patients treated with thalamotomy (Schuurman
et al., 2000).
The only death, secondary to intracerebral hema-
toma, occurred in the Vim-DBS group. Nevertheless,
complications overall were more common in the thala-
motomy group. In PT patients at 6 months postopera-
tively cognitive deterioration was found in 1 patient
postthalamotomy versus none post-Vim-DBS, mild
dysarthria in 3 versus 1, severe dysarthria in 3 versus
1, gait and balance disturbance was mild in 3 versus 0
and severe in 4 versus 0 and there was arm ataxia in
1 versus 0. Overall, significantly more patients (16/
34) had complications postthalamotomy than patients
following Vim-DBS stimulation (6/33).
 ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSONS DISEASE
42.7.3.2. Prospective, uncontrolled studies
of thalamotomy for Parkinsons disease
Vim thalamotomies have been performed for PT over
five decades and advances in technology during this
period have improved the accuracy and safety of
this operation. CT or MR imaging as well as micro-
electrode recording has advanced the technical
standards of thalamotomy. Tasker (1990) reported that
good results from thalamotomy increased from 45%
for surgeries performed before 1967 to 8696% for
surgeries carried out during the 1970s. Reports of
thalamotomies performed from 1980 to 1990 reveal
good results in 8694% of cases (Fox et al., 1991;
Jankovic et al., 1995).
One such study reported the results of Vim
thalamotomy performed between 1982 and 1994 in
42 patients with severe, asymmetric, medically intract-
able parkinsonian tremor (Jankovic et al., 1995). Thala-
motomies were guided by CT or ventriculographic
localization and microelectrode recording. Treating
physicians performed outcome assessments using the
UPDRS and a global tremor-rating scale. Tremor was
completely abolished in 72% (31/42) of cases, whereas
an additional 14% (6/42) showed significant improve-
ment in tremor and functional ability. None of the
patients who were tremor-free after surgery experienced
a recurrence of the tremor at long-term follow-up
(60158 months).
Similar efficacy rates were reported in another study,
in which 37 Vim thalamotomies were performed between
1984 and 1989 for medically refractory parkinsonian
tremor (Fox et al., 1991). CT localization and micro-
electrode guidance were used. At the time of discharge,
complete abolition of contralateral tremor was seen
in 94% (34/36), which was maintained in 81% (13/16)
at 3 years. All recurrences occurred within 3 months
of surgery.
In a third study ventriculography and macrostimula-
tion were used to localize the lesion site, which was
thought to be in Vop, a thalamic pallidal relay nucleus
(Wester and Hauglie-Hanssen, 1990), unlike the Vim
target chosen in other studies reviewed here. Good to
moderate improvement was achieved in 82% (27/33)
of patients with Parkinsons tremor, as assessed by
the referring neurologists.
One blinded, long-term assessment of the efficacy
of thalamotomy compared tremor in the arm contralat-
eral to thalamotomy versus the ipsilateral arm
(Diederich et al., 1992). The potentially confounding
effect of asymmetry in tremor was not considered.
Thalamotomies were performed between 1976 and
1985 and patients were followed for a mean of 10
years. A significant concordance for UPDRS score
251
was demonstrated between blinded raters and tremor
severity scores were consistently better contralateral
to surgery. This study suggests that thalamotomy can
abolish tremor.
Tasker (1998) has reported that tremor which was
completely abolished contralateral to a thalamic lesion
for 3 months never recurred. Such results have
prompted some to propose that thalamotomy may
actually alter the course of PD (Matsumoto et al.,
1984). An investigation into this issue has revealed
three subgroups of PD in which the disease progresses
so slowly that elimination of the major symptoms may
appear to have altered the progression of the disease.
PD of the young-onset, postencephalitis type and a
subset of patients with idiopathic parkinsonism all
seem to have very slow progression of their parkinso-
nian symptoms (Tasker, 1998). Thus elimination of
tremor in these patients might give the appearance
of a long-term cure.
42.7.3.3. Thalamotomy for dyskinesias
in Parkinsons disease
In addition to the reduction of tremor symptoms,
several studies have shown that patients require less
or no levodopa after thalamotomy (Fox et al., 1991;
Jankovic et al., 1995). This decreased requirement
for levodopa helps to reduce the drug-related compli-
cations of PD (e.g. dyskinesias). Independent of this
reduction of levodopa, thalamotomy has been shown
to reduce levodopa-induced dyskinesias (Jankovic
et al., 1995). Narabayashi et al. (1984) reported that,
although levodopa dyskinesias are ameliorated by
Vim thalamotomy, the optimal site for a lesion to
relieve dyskinesias may be Vop, just anterior to Vim.
Such reduction in dyskinesia and increased tolerance
of levodopa is important for patients who have other
parkinsonian symptoms in addition to tremor, such as
bradykinesia and rigidity (Poewe and Granata, 1997).
42.7.3.4. Complications of thalamotomy
Neurological complications specific to thalamotomy
can be explained by lesion-induced disruption of the
cerebellothalamocortical pathway or damage to thala-
mic and nearby structures. In a series of 60 patients
with essential, parkinsonian or cerebellar tremor,
functional deficits in the immediate postoperative
period were reported in 58% of patients (Jankovic
et al., 1995). These transient deficits included weak-
ness (34%), dysarthria (29%), ataxia (8%), dystonia
(5%) and sensory deficits (3%). Cognitive deficits
were seen, including disorientation and somnolence,
as well as speech and language deficits, including
252 F. A. LENZ
hypophonia. Functional deficits persisted in 23% but
were generally mild and did not increase disability
(Jankovic et al., 1995).
In a series of 34 patients operated on for parkinso-
nian tremor, there were permanent complications in
14% (5), including apraxia (1), dysarthria (2), dyspha-
sia (1) and abulia (1) (Fox et al., 1991). Transient
complications in 61% included cognitive decline (5),
central facial (10) or hand weakness (7) and hand
numbness (2). Half of the transient deficits resolved
by 1 week and most deficits, including transient and
permanent, had resolved at the 3-month follow-up
visit.
Parkinsonian patients in the study of Wester and
Hauglie-Hassen (1990) had mild complications, not
yielding invalidity, in 36% (12/33), including: mild
mental status changes in 4, mild contralateral weak-
ness in 3, dysphasia in 4 and dysarthia in 1. Significant
complications occurred in 18% (6/33), including: men-
tal status change in 3, dysphasia in 1 and dysarthia in
2. Thus, significant or permanent side-effects were
often observed in patients with PD, as in essential
and intention tremor. Therefore, the best available
evidence supports a rate of transient complications in
approximately 60% of patients and persistent compli-
cations in the range of 1520%.
42.7.3.5 TTA-AAN/MDS recommendation
regarding thalamotomy
For thalamotomy, 18 articles were found in the TTA-
AAN study, but only the four studies cited above met
the TTAS-AAN criteria (Wester and Hauglie-Hanssen,
1990; Fox et al., 1991; Diederich et al., 1992; Jankovic
et al., 1995). Thalamotomy was recommended as
effective and safe for asymmetric, severe, medically
intractable tremor, particularly for the tremor variant
of PD. This was a positive recommendation based on
results of prospective studies with historical controls.
It was judged to be possibly effective for the treatment
of dyskinesias and rigidity. Thalamotomy was not
thought to be effective for micrographia, bradykinesia
or difficulties of gait or speech. Thalamotomy on the
second side was felt to be effective for the treatment
of tremor but to be associated with a high incidence
of speech and swallowing difficulty. Therefore a class
D negative recommendation was made for bilateral
thalamotomy; Vim-DBS was recommended on the
second side.
42.7.4. Subthalamotomy
There are no historical studies of subthalamotomy for
the treatment of PD so that indications for surgery
were based upon general principles. The first study
of subthalmotomy included patients with relatively
early PD characterized by hemiparkinsonism (off
Hoehn and Yahr scale 3.1) (Patel et al., 2003). In this
study many patients were disabled by tremor but not
other parkinsonian symptoms, i.e. the tremor variant
of PD. In the other study subthalamotomy was carried
out in patients (n 18) with bilateral involvement
indicating more advanced disease, as reflected in the
off Hoehn and Yahr grade of III in 22% and of IV
in 78% (Alvarez et al., 2005).
These two studies of subthalamotomy for PD were
also much different with respect to techniques and
results. In the first, unilateral single lesions of the dor-
solateral STN were made to 80
C for 60 seconds with
an electrode having a 2 mm exposed tip. Postoperative
MRIs demonstrated extension of the lesions dorsal to
STN, i.e. zona incerta, in 19 of 21 cases.
At 6 months there was an improvement in total
UPDRS of 22% off and 24% on, both of which
were maintained at 24 months, 18% and 11% respec-
tively. There was a significant improvement in off
UPDRS activities of daily living scale at 6 (19%) but
not 24 months. UPDRS III (motor) off was signifi-
cantly improved at 6 months contralateral to the lesion
(36%) and overall (19%) and at 24 months (16% con-
tralateral and 38% overall). There were also significant
improvements in tremor, rigidity and bradykinesia in
all patients followed for 12 and 24 months. Levodopa-
equivalent doses were approximately halved post-
operatively. Neuropsychological tests revealed mild
cognitive deficits of verbal function observed on tests
such as the Rey auditory verbal learning test. Intract-
able dyskinesias occurred in 1 patient but responded
to implantation of a DBS electrode into the zona
incerta.
The technique and results of the second study of
subthalamotomy for PD (Alvarez et al., 2005) were
much different from the first. Lesions were made to
a temperature of 70
C for 60 seconds with an electrode
having a 2 mm exposed tip. Two of these lesions were
made centered in the STN and located 3 mm apart in
the mediallateral plane. UPDRS motor scores were
improved by 50% in the off state and 38% in the
on state, measured at the time of last assessment, a
minimum of 3 years postoperatively. Tremor, rigidity,
bradykinesia, activities of daily living and dyskinesias
were all significantly improved at the time of the last
assessment.
Three patients had severe postoperative dyskinesias
which resolved over 36 months. Two of these
patients developed severe persistent gait instability.
Two of these and 1 other patient had severe persistent
postoperative dysharthria. These 4 patients had lesion
temperatures of 80
C for 1 minute and had large
 ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSONS DISEASE
lesions that were 3040% larger than the average for
the rest of the population. Two of the patients with
severe dyskinesias and 1 other developed severe ataxia
and broad-based gait which improved substantially
by 1 year. Severe ataxia occurred in a third patient
who also had a larger than expected lesion. Thus there
were significant, persistent complications in 26% of
patients in this study.
Therefore, both studies demonstrated significant
long-term improvements at 2 years postoperatively.
The first had relatively limited morbidity, whereas
the second had significant, persistent morbidity, per-
haps related to inclusion of patients with more
advanced PD or to the bilateral, large lesions. Subtha-
lamotomy was not included in the TTC-AAC/MDS
review. The results reviewed here suggest that both
unilateral and bilateral subthalamotomy may be
effective procedures. The safety of these procedures
is in doubt because of inconsistent reports of signifi-
cant persistent complications, possibly related to
surgical technique and the extent of the lesions. Since
there is only one report each for unilateral and bilateral
subthalamotomy, it is not possible at present to assess
the consistency of these results or to make a recom-
mendation.
42.7.5. Radiosurgery for the treatment
of movement disorders
The use of MRI to provide radiologic localization has
led to the development of stereotactic radiosurgical
ablation. The majority of stereotactic gamma-knife
procedures are carried out with an 50% isodose plan
(Kondziolka, 2002) using 4 mm collimators, some-
times located on a secondary collimator helmet
(Young et al., 1998) and sometimes on the standard 201
cobalt source helmet. Maximal doses of 120160 Gy
are usually used (Niranjan et al., 1999), although doses
of approximately 180 Gy (Friedman et al., 1996; Pan
et al., 1996) or 200 Gy have also been reported (Friehs
et al., 1997). Lesions with a volume of approximately
250 mm3 are created (Duma et al., 1998; Young et al.,
1998). The lesion placement is estimated from the
usual location of Vim in relation to the AC and PC and
the internal capsule (Duma et al., 1998; Young et al.,
1998).
In the largest of these series, MRI-guided gamma-
knife procedures (4 mm collimator, 110165 Gy, 50%
isodose line at the medial edge of the internal capsule)
were carried out in 34 patients with Parkinsons
tremor at high risk for standard stereotactic procedures
(Duma et al., 1998). Patients and their physicians rated
the outcome using the UPDRS tremor scale. Retrospec-
tively, the groups were stratified by radiation dose into
253
110135 Gy and 140165 Gy groups. A good to
excellent result (increase of 23 UPDRS grades at three
evaluations) was significantly more common in the
high- (78%) than the low-dose group (56%), which
was less than their success with standard stereotactic
procedures. No complications were reported at mini-
mum follow-up of 5 months (median 28 months).
Another series of MRI-guided gamma-knife radiosur-
gery reported complete to nearly complete relief of
tremor in 88% of cases (n 27) (Young et al., 1998).
An older series of patients with intention, parkinsonian
and undefined tremor reported good outcome of MRI-
guided gamma-knife thalamotomy in 66% of cases
(n 9) (Rand et al., 1992). No complications were
reported to occur in these latter two series.
Linear accelerator thalamotomy targeting the cen-
tral median and parafascicular nuclei for the treatment
of neuropathic and central pain has been reported in
3 cases (Frighetto et al., 2004). The lesion (75100 Gy)
was made 4 mm anterior to PC and 10 mm lateral
to the ACPC line using a 5 mm collimator along 58
non-coplanar arcs separated by 20
. Postoperatively
immediate pain relief was reported in all 3 cases based
on the assessment of the treating physician. Post-MRIs
showed lesions 7  8 mm in the posterior ventral medial
thalamus and 3.5  5 mm in the posterior ventral thala-
mus. No complications were reported.
In contrast to these series is a report of 9 complica-
tions encountered at Emory University Altanta, GA,
from a series of gamma-knife ablations for movement
disorders carried out at a nearby medical center (Okun
et al., 2001, 2002). These complications occurred
among an estimated total of 118 patients, including
PD in 96: 7 had the tremor-predominant variant and
there was essential tremor in 22 (Okun et al., 2001,
2002). In this series, patients were found to have onset
of benefit from the radiation never to 6 months and
onset of complications from 5 to 10 months. Compli-
cations included weakness or paresis (n 3), visual
loss, speech/bulbar symptoms (n 3), dysphagia/
aspiration pneumonia/death (n 1).
This report resulted in a debate centered on techni-
que (Kondziolka, 2002), interpretation of the accuracy
of these lesions (De Salles et al., 2003) and the com-
plications of gamma-knife versus open procedures
(Kondziolka, 2002). The conservative interpretation
of this debate is that gamma-knife (4 mm collimator,
12040 Gy, targeting with a 50% isodose line) is
indicated for thalamotomy, but not pallidotomy, in
patients whose high surgical risk precludes a microelec-
trode-guided, radiofrequency procedure (Kondziolka,
2002). The need for a consensus and for prospective
or controlled studies of gamma-knife movement
disorder surgery is clear (Okun et al., 2002).
254 F. A. LENZ
42.7.6. Lesions versus stimulation for treatment
of Parkinsons disease
42.7.6.1. Pallidotomy
As a way of evaluating ablative versus stimulation pro-
cedures we now compare the best data for ablative
procedures with that for stimulation of the same ana-
tomic locus. In the two randomized, controlled trials
of pallidotomy for the treatment of PD there was a
significant improvement in off motor UPDRS score
of 3544% versus slight deterioration in the medical
group (5% and 7%) at 6 months (de Bie et al.,
1999; Vitek et al., 2003). Results of the surgical group
at 6 months were preserved at 2 years in the whole
cohort following cross-over (Vitek et al., 2003). Two
patients had seizures intraoperatively which delayed
the pallidotomy. There were 4 hemorrhages, 1 with
temporary worsening of speech, which resolved by 6
months postoperatively (17%).
Similar results were obtained in an earlier rando-
mized, controlled, single-blind, multicenter trial of
pallidotomy versus best medical therapy (de Bie
et al., 1999). At 6 months the off condition of the
UPDRS motor subscale improved (44%) significantly
in the surgical group whereas it decreased in medical
controls (7%). The on motor UPDRS and activities
of daily living subscale were both improved in com-
parison with the medical group. In the surgical group
of 19 there were 2 patients with major complications
and 4 patients with minor but persistent side-effects
(32%).
Pallidal stimulation in patients with advanced PD
(n 38) in a prospective trial with a non-randomized
control group of patients with subthalamic stimulators
showed a UPDRS motor score improvement of 49%
and an increase in on time without dyskinesias from
24 to 64% of the day at 3 months. In the total study
(n 140) there were 7 hemorrhages (5%), 6 with
neurologic deficits, of which 4 were persistent (3%).
Thus the results of a controlled prospective study for
GPi-DBS are similar to those of the randomized
controlled study of pallidotomy with higher rates of
surgical complications in the pallidotomy group.
A small randomized, controlled, multicenter trial of
unilateral pallidotomy versus bilateral STN stimula-
tion has been reported; the latter is often considered
to be the best surgical treatment for advanced PD.
Patients had advanced PD (n 34, Hoehn and Yahr
> 4 in 20/34) (Esselink et al., 2004) and both surgical
groups were improved by off UPDRS motor scale; the
primary outcome was variable. The improvement
was less in the pallidotomy group (15%) than in the
subthalamic stimulation group (37%). Dyskinesias
improved in both groups; the duration but not severity
of dyskinesias was significantly better in the subthala-
mic stimulation group. Pallidotomy patients had
persistent complications in 9/14 (64%) whereas the
stimulation patients had complications in 8/20 (40%).
This study demonstrated significantly greater benefit
for bilateral subthalamic stimulation than unilateral
pallidotomy with numerous significant complications
of both procedures.
42.7.6.2. Thalamotomy
The primary alternative to Vim thalamotomy for tremor
has been implantation of DBS electrodes into the VIM.
The two have recently been compared in a recent trial
of surgery for parkinsonian, essential and intention
tremor (Schuurman et al., 2000). Among patients with
parkinsonian tremor (PT), abolition or slight residual
tremor was seen post-Vim-DBS in 21/21 (100%) and
21/23 (93%) of patients postthalamotomy. Functional
status was reported to be improved in significantly
more patients following Vim-DBS (18/33, 54%) than
in patients with thalamotomy (24%, 8/34). Although
the only death occurred in the DBS group, there were
significantly more complications in the group under-
going thalamotomy (16/34, P < 0.05) than in those
undergoing Vim-DBS (6/33). Thus Vim-DBS was safer
and more effective than thalamotomy in PD.
42.7.6.3. Subthalamotomy
The subthalamotomy study with bilateral surgery in
patients with more advanced disease is more compar-
able to a study of STN-DBS (Alvarez et al., 2005).
UPDRS motor scores were improved by 50% in the
off state at a minimum of 3 years postoperatively.
Tremor, rigidity, bradykinesia activities of daily living
and dyskinesias were all significantly decreased at the
time of the last assessment. Severe persistent complica-
tions, including imbalance, dyskinesias and ataxia,
occurred in 28% of these patients. On the contrary, no
severe persistent complications were encountered in a
study of subthalamotomy in patients with less advanced
PD, with unilateral lesions (Patel et al., 2003).
A prospective, uncontrolled study of bilateral
STN-DBS in patients with advanced PD with 5-year
follow-up (n 42) had UPDRS motor scale (54%)
and activities of daily living (49%) improvements in
comparison with preoperative baseline (Krack et al.,
2003). All subscales except speech were improved
with respect to baseline. Levodopa equivalents were
decreased in comparison with baseline, as was the
amount of drug-related dyskinesia. Surgical complica-
tions were limited to death secondary to an intracereb-
ral hematoma and suicide (1 each). Thus the efficacy
is similar for STN-DBS and subthalamotomy.
 ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSONS DISEASE
However, the risks are higher for bilateral, but not uni-
lateral, subthalamotomy.
Therefore, the efficacy is similar for ablative and
stimulation procedures in the subthalamus and palli-
dum. The efficacy of Vim-thalamotomy is less than
that for Vim-DBS. The rate of complications, both
transient and permanent, is much higher for ablative
procedures. Thus, lesions of the subthalamus, thalamus
and pallidum are indicated when stimulation is
contraindicated by the particular circumstances of an
individual patient.
Acknowledgments
Some of the studies described in this chapter were
supported by grants to FAL from the National
Institutes of Health (RO1:NS38493, RO1:NS40059).
References
Adams RD, Victor M, Ropper AH (1996). Principles of Neu-
rology. McGraw-Hill, New York.
Albe-Fessard D (1973). Electrophysiological methods for the
identification of thalamic nuclei. Z Neurol 205: 1528.
Albin RL, Young AB, Penney JB (1989). The functional
anatomy of basal ganglia disorders. Trends Neurosci 12:
366375.
Alexander E 3rd, Kooy HM, van Herk M et al. (1995). Mag-
netic resonance image-directed stereotactic neurosurgery:
use of image fusion with computerized tomography to
enhance spatial accuracy. J Neurosurg 83: 271276.
Alkhani A, Lozano AM (2001). Pallidotomy for Parkinson
disease: a review of contemporary literature. J Neurosurg
94: 4349.
Alvarez L, Macias R, Lopez G et al. (2005). Bilateral subtha-
lamotomy in Parkinsons disease: initial and long-term
response. Brain 128: 570583.
Andrew J, Fowler CJ, Harrison MJ (1983). Stereotaxic thala-
motomy in 55 cases of dystonia. Brain 106: 9811000.
Azizi A, Goldman WH, Moreledge D (1996). Posteroventral
pallidotomy: comparison of the accuracy of anatomical
targets defined by MR and CT imaging with physiological
targets defined by microelectrode recording. Neurology
46 (Suppl): A199.
Bakay RA, DeLong MR, Vitek JL (1992). Posteroventral palli-
dotomy for Parkinsons disease. J Neurosurg 77: 487488.
Baron MS, Vitek JL, Bakay RA et al. (1996). Treatment of
advanced Parkinsons disease by posterior GPi pallidotomy:
1-year results of a pilot study. Ann Neurol 40: 355366.
Benabid AL, Pollak P, Gao D et al. (1996). Chronic electrical
stimulation of the ventralis intermedius nucleus of the tha-
lamus as a treatment of movement disorders. J Neurosurg
84: 203214.
Bergman H, Wichmann T, DeLong MR (1990). Reversal of
experimental parkinsonism by lesions of the subthalamic
nucleus. Science 249: 14361438.
255
Biousse V, Newman NJ, Carroll C et al. (1998). Visual fields
in patients with posterior GPi pallidotomy. Neurology 50:
258265.
Burchiel KJ (1995). Thalamotomy for movement disorders.
In: PL Gildenberg, (Ed.), Neurosurgery Clinics of North
America. WB Saunders Company, Philadelphia, pp. 5571.
Buzsaki G, Smith A, Berger S et al. (1990). Petit mal epilepsy
and parkinsonian tremor: hypothesis of a common pace-
maker. Neuroscience 36: 114.
Cahn DA, Sullivan EV, Shear PK et al. (1998). Neuropsycho-
logical and motor functioning after unilateral anatomically
guided posterior ventral pallidotomy. Preoperative
performance and three-month follow-up. Neuropsychiatry
Neuropsychol Behav Neurol 11: 136145.
Cardoso F, Jankovic J, Grossman RG et al. (1995). Outcome
after stereotactic thalamotomy for dystonia and hemibal-
lismus. Neurosurgery 36: 501507.
Carlson JD, Iacono RP (1999). Electrophysiological versus
image-based targeting in the posteroventral pallidotomy.
Comput Aided Surg 4: 93100.
Carlson M, Carlson A (1990). Interactions between glutami-
nergic and monoaminergic systems within the basal
ganglia. Trends Neurosci 13: 272276.
Clatterbuck R, Lee J-I, Lenz FA (2000). Movement disorder
surgery: lesions or stimulation. Prog Neurol Surg 15:
227235.
Cooper IS (1954). Intracerebral injection of procaine into the
globus pallidus in hyperkinetic disorders. Science 119:
417418.
Cosman ER, Cosman BJ (1985). Methods of making nervous
system lesions. In: RH Wilkins, SS Rengachary (Eds.),
Neurosurgery. McGraw-Hill, New York, pp. 24902499.
de Bie RM, de Haan RJ, Nijssen PC et al. (1999). Unilateral
pallidotomy in Parkinsons disease: a randomised, single-
blind, multicentre trial. Lancet 354: 16651669.
de Bie RM, Schuurman PR, Esselink RA et al. (2002). Bilat-
eral pallidotomy in Parkinsons disease: a retrospective
study. Mov Disord 17: 533538.
De Salles AA, Frighetto L, Lacan G et al. (2003). Radiosur-
gery can achieve precision needed for functional neurosur-
gery. Arch Neurol 60: 14941496.
DeLong MR (1971). Activity of pallidal neurons during
movement. J Neurophysiol 34: 414427.
DeLong MR (1990). Primate models of movement disorders
of basal ganglia origin. Trends Neurosci 13: 281285.
Desmedt JE (1978). Progress in Clinical Neurophysiology.
Cerebral Motor Control in Man: Long Loop Mechanisms
Karger, Basel.
Diederich N, Goetz CG, Stebbins GT et al. (1992). Blinded
evaluation confirms long-term assymmetric effect of
unilateral thalamotomy or subthalamotomy on tremor in
Parkinsons disease. Neurology 42: 13111314.
Dogali M, Fazzini E, Kolodny E et al. (1995). Stereotactic
ventral pallidotomy for Parkinsons disease. Neurology
45: 753761.
Dostrovsky JO (1998). The use of inexpensive personal
computers for map generation and data analysis. In: PL
Gildenberg, RR Tasker (Eds.), Textbook of Stereotactic
256 F. A. LENZ
and Functional Neurosurgery. McGraw-Hill, New York,
pp. 20312036.
Duma CM, Jacques DB, Kopyov OV et al. (1998). Gamma
knife radiosurgery for thalamotomy in parkinsonian tre-
mor: a five year experience. J Neurosurg 88: 10441049.
Elble RJ, Koller W (1990). Tremor Johns Hopkins Univer-
sity Press, Baltimore.
Esselink RA, de Bie RM, de Haan RJ et al. (2004). Unilateral
pallidotomy versus bilateral subthalamic nucleus stimula-
tion in PD: a randomized trial. Neurology 62: 201207.
Fazzini E, Dogali M, Sterio D et al. (1997). Stereotactic pal-
lidotomy for Parkinsons disease: a long-term follow-up of
unilateral pallidotomy. Neurology 48: 12731277.
Filion M, Tremblay L, Bedard PJ (1988). Abnormal influences
of passive limb movement on the activity of globus pallidus
neurons in parkinsonian monkeys. Brain Res 444: 165176.
Fisher RS, Uematsu S, Krauss GL et al. (1996). Placebo-
controlled pilot study of centromedian thalamic stimula-
tion in treatment of intractable seizures. Epilepsia 33 (5):
841851.
Fox MW, Ahlskog EJ, Kelly PJ (1991). Stereotactic ventro-
lateralis thalamotomy for medically refactory tremor in
post-levodopa era Parkinsons disease patients. J Neuro-
surg 75: 723730.
Friedman JH, Epstein M, Sanes JN et al. (1996). Gamma
knife pallidotomy in advanced Parkinsons disease. Ann
Neurol 39: 535538.
Friehs GM, Ojakangas CL, Schrottner O et al. (1997).
Radiosurgical lesioning of the caudate nucleus as a treat-
ment for parkinsonism: a preliminary report. Neurol Res
19: 97103.
Frighetto L, De Salles A, Wallace R et al. (2004). Linear
accelerator thalamotomy. Surg Neurol 62: 106113.
Garonzik IM, Hua SE, Ohara S et al. (2002). Intraoperative
microelectrode and semi-microelectrode recording during
the physiological localization of the thalamic nucleus ven-
tral intermediate. Mov Disord 17 (Suppl 3): S135S144.
Gerdes JS, Hitchon PW, Neerangun W et al. (1994). Com-
puted tomography versus magnetic resonance imaging in
stereotactic localization. Stereotact Funct Neurosurg 63:
124129.
Giller CA, Dewey RB, Ginsburg MI et al. (1998). Stereotactic
pallidotomy and thalamotomy using individual variations of
anatomic landmarks for localization. Neurosurgery 42:
5662.
Guiot G, Hardy J, Albe-Fessard D (1962). Delimitation pre-
cis des structures sous-corticales et identification de
noyaux thalamiques chez lhomme par lelectrophyiologie
stereotactic. Neurochirurgia 5: 118.
Guiot G, Derome P, Arfel G et al. (1973). Electrophysiological
recordings in stereotaxic thalamotomy for parkinsonism.
In: H Krayenbuhl, PE Maspes, WH Sweet (Eds.), Progress
in Neurological Surgery. Karger, Basel, pp. 189221.
Guridi J, Gorospe A, Ramos E et al. (1999). Stereotactic
targeting of the globus pallidus internus in Parkinsons
disease: imaging versus electrophysiological mapping.
Neurosurgery 45: 278287.
Hallett M, Litvan I (1999). Evaluation of surgery for Parkin-
sons disease: a report of the Therapeutics and Technology
Assessment Subcommittee of the American Academy of
Neurology. The Task Force on Surgery for Parkinsons
Disease. Neurology 53: 19101921.
Hallett M, Litvan I (2000). Scientific position paper of the
Movement Disorder Society evaluation of surgery for
Parkinsons disease. Task Force on Surgery for Parkin-
sons Disease of the American Academy of Neurology
Therapeutic and Technology Assessment Committee.
Mov Disord 15: 436438.
Hardy PA, Barnett GH (1998). Spatial distortion in magnetic
resonance imaging: impact on stereotactic localization.
In: PL Gildenberg, RR Tasker (Eds.), Textbook of Stereo-
tactic and Functional Neurosurgery. McGraw-Hill, New
York, pp. 271280.
Hariz MI (2002). Safety and risk of microelectrode recording
in surgery for movement disorders. Stereotact Funct
Neurosurg 78: 146157.
Hariz MI, De Salles AA (1997). The side-effects and compli-
cations of posteroventral pallidotomy. Acta Neurochir
Suppl (Wien) 68: 4248.
Hassler R, Mundinger F, Reichert T (1979). Stereotaxis in
the Parkinson Syndrome. Springer Verlag, Berlin.
Hiner B, Madden K, Neal J (1997). Effect of microelectrode
recording on final lesion placement in pallidotomy. Neu-
rology 48 (Suppl 2): A251.
Holtzheimer PE 3rd, Roberts DW, Darcey TM (1999). Mag-
netic resonance imaging versus computed tomography for
target localization in functional stereotactic neurosurgery.
Neurosurgery 45: 290297.
Hornykiewicz D (1974). The mechanisms of action of
L-dopa in Parkinsons disease. Life Sci 15 (7): 12491259.
Hua SE, Lenz FA, Zirh TA et al. (1998a). Thalamic neuronal
activity correlated with essential tremor. J Neurol Neuro-
surg Psychiatry 64: 273276.
Hua S, Reich SG, Zirh AT et al. (1998b). The role of the tha-
lamus and basal ganglia in parkinsonian tremor. Mov
Disord 13 (Suppl 3): 4042.
Hua SE, Garonzik IM, Lee J-I et al. (2004). Thalamotomy
for tremor. In: RH Winn (Ed.), Youmans Neurological
Surgery. Saunders, Philadelphia, pp. 27692784.
Hubel DH (1957). Tungsten microelectrode for recording
from single units. Science 125: 549550.
Hutchison WD, Levy R, Dostrovsky JO et al. (1997a). Effects
of apomorphine on globus pallidus neurons in parkinsonian
patients. Ann Neurol 42: 767775.
Hutchison WD, Lozano AM, Tasker RR et al. (1997b).
Identification and characterization of neurons with
tremor-frequency activity in human globus pallidus. Exp
Brain Res 113: 557563.
Hutchison WD, Allan RJ, Opitz H et al. (1998). Neuro-
physiological identification of the subthalamic nucleus
in surgery for Parkinsons disease. Ann Neurol 44:
622628.
Iacono RP, Carlson JD, Kuniyoshi S et al. (1997). Contem-
poraneous bilateral pallidotomy. Neurosurg Focus 2: e5.
 ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSONS DISEASE
Jankovic J, Cardoso F, Grossman RG et al. (1995). Outcome
after stereotactic thalamotomy for parkinsonian, essential
and other types of tremor. Neurosurgery 37: 680686.
Jasper HH, Bertrand G (1966). Thalamic units involved in
somatic sensation and voluntary and involuntary move-
ments in man. In: DP Purpura, MD Yahr (Eds.), The Thala-
mus. Columbia University Press, New York, pp. 365390.
Jones EG (1985). The Thalamus. Plenum, New York.
Kazumata K, Antonini A, Dhawan V et al. (1997). Preopera-
tive indicators of clinical outcome following stereotaxic
pallidotomy. Neurology 49: 10831090.
Kelly PJ, Derome P, Guiot G (1978). Thalamic spatial varia-
bility and the surgical results of lesions placed with neuro-
physiologic control. Surg Neurol 9: 307315.
Kelly PJ, Ahlskog JE, Goerss SJ et al. (1987). Computer-
assisted stereotactic ventralis lateralis thalamotomy with
microelectrode recording control in patients with Parkin-
sons disease. Mayo Clin Proc 62: 655664.
Kishore A, Turnbull IM, Snow BJ et al. (1997). Efficacy,
stability and predictors of outcome of pallidotomy for
Parkinsons disease. Six-month follow-up with additional
1-year observations. Brain 120 (Pt 5): 729737.
Kondziolka D (2002). Gamma knife thalamotomy for
disabling tremor. Arch Neurol 59: 16601664.
Kondziolka D, Dempsey PK, Lunsford LD et al. (1992).
A comparison between magnetic resonance imaging and
computed tomography for stereotactic coordinate determi-
nation. Neurosurgery 30: 402407.
Kondziolka D, Firlik AD, Lunsford LD (1998). Complica-
tions of stereotactic brain surgery. Neurol Clin 16: 3554.
Krack P, Poepping M, Weinert D et al. (2000). Thalamic,
pallidal, or subthalamic surgery for Parkinsons disease?
J Neurol 247 (Suppl 2): II122II134.
Krack P, Batir A, Van Blercom N et al. (2003). Five-year
follow-up of bilateral stimulation of the subthalamic
nucleus in advanced Parkinsons disease. N Engl J Med
349: 19251934.
Krauss JK, Desaloms JM, Lai EC et al. (1997). Microelec-
trode-guided posteroventral pallidotomy for treatment of
Parkinsons disease: postoperative magnetic resonance
imaging analysis. J Neurosurg 87: 358367.
Laitinen LV, Hariz MI (1996). Movement disorders. In:
JR Youmans (Ed.), Neurological Surgery. WB Saunders
Company, Philadelphia, pp. 35753609.
Laitinen LV, Bergenheim AT, Hariz MI (1992). Leksells
posteroventral pallidotomy in the treatment of Parkinsons
disease. J Neurosurg 76: 5361.
Lamarre Y, Joffroy A (1970). Thalamic unit activity in monkey
with experimental tremor. In: A Barbeau, FH McDowell
(Eds.), L-Dopa and Parkinsonism. Davis, Philadelphia, pp.
163170.
Lamarre Y, Joffroy AJ (1979). Experimental tremor in mon-
key: activity of thalamic and precentral cortical neurons in
the absence of peripheral feedback. Adv Neurol 24:
109122.
Lang AE, Lozano AM, Montgomery E et al. (1997). Postero-
ventral medial pallidotomy in advanced Parkinsons
disease. N Engl J Med 337: 10361042.
257
Lemstra AW, Verhagen ML, Lee JI et al. (1999). Tremor-
frequency (36 Hz) activity in the sensorimotor arm repre-
sentation of the internal segment of the globus pallidus in
patients with Parkinsons disease. Neurosci Lett 267:
129132.
Lenz FA, Tatton WG, Tasker RR (1983a). Electromyographic
response to displacement of different forelimb joints in the
squirrel monkey. J Neurosci 3: 783794.
Lenz FA, Tatton WG, Tasker RR (1983b). The effect of cor-
tical lesions on the electromyographic response to joint
displacement in the squirrel monkey forelimb. J Neurosci
3: 795805.
Lenz FA, Tasker RR, Kwan HC et al. (1985). Cross-correla-
tion analysis of thalamic neurons and EMG activity in
parkinsonian tremor. Appl Neurophysiol 48: 305308.
Lenz FA, Dostrovsky JO, Kwan HC et al. (1988a). Methods
for microstimulation and recording of single neurons and
evoked potentials in the human central nervous system.
J Neurosurg 68: 630634.
Lenz FA, Tasker RR, Kwan HC et al. (1988b). Single unit
analysis of the human ventral thalamic nuclear group: corre-
lation of thalamic tremor cells with the 36 Hz component
of parkinsonian tremor. J Neurosci 8: 754764.
Lenz FA, Dostrovsky JO, Tasker RR et al. (1988c). Single-
unit analysis of the human ventral thalamic nuclear group:
somatosensory responses. J Neurophysiol 59: 299316.
Lenz FA, Kwan H, Dostrovsky JO et al. (1990). Single unit
analysis of the human ventral thalamic nuclear group.
Activity correlated with movement. Brain 113: 17951821.
Lenz FA, Seike M, Richardson RT et al. (1993). Thermal
and pain sensations evoked by microstimulation in the
area of human ventrocaudal nucleus. J Neurophysiol 70:
200212.
Lenz FA, Kwan HC, Martin RL et al. (1994). Single unit
analysis of the human ventral thalamic nuclear group. Tre-
mor-related activity in functionally identified cells. Brain
117: 531543.
Lenz FA, Normand SL, Kwan HC et al. (1995). Statistical
prediction of the optimal site for thalamotomy in parkinso-
nian tremor. Mov Disord 10: 318328.
Lenz FA, Suarez JL, Verhagen Metman L et al. (1998). Palli-
dal activity during dystonia: somatosensory reorganization
and changes with severity. J Neurol Neurosurg Psychiatry
65: 767770.
Lenz FA, Jaeger CJ, Seike MS et al. (1999). Thalamic single
neuron activity in patients with dystonia: dystonia-related
activity and somatic sensory reorganization. J Neurophy-
siol 82: 23722392.
Levy R (1992). A Short History of Stereotactic Neurosurgery.
American Association of Neurological Surgeons. Park
Ridge, IL. Ref Type: Serial (Book, Monograph).
Lopez-Flores G, Miguel-Morales J, Teijeiro-Amador J et al.
(2003). Anatomic and neurophysiological methods for
the targeting and lesioning of the subthalamic nucleus:
cuban experience and review. Neurosurgery 52: 817830.
Louw DF, Burchiel KJ (1998). Ablative therapy for movement
disorders. Complications in the treatment of movement dis-
orders. Neurosurg Clin N Am 9: 367373.
258 F. A. LENZ
Lozano AM, Lang AE, Galvez-Jimenez N et al. (1995).
Effect of GPi pallidotomy on motor function in Parkin-
sons disease. Lancet 346: 13831387.
Lozano AM, Hutchison W, Kiss Z et al. (1996). Methods for
microelectrode guided posteroventral pallidotomy. J Neuro-
surg 84: 194202.
Lozano AM, Lang AE, Hutchison WD (1998). Pallidotomy
for tremor. Mov Disord 13 (13 Suppl 3): 107110.
Magnin M, Morel A, Jeanmonod D (2000). Single-unit ana-
lysis of the pallidum, thalamus and subthalamic nucleus in
parkinsonian patients. Neuroscience 96: 549564.
Mandir AS, Rowland LH, Dougherty PM et al. (1997).
Microelectrode recording and stimulation techniques during
stereotactic procedures in the thalamus and pallidum. Adv
Neurol 74: 159165.
Marsden CD (1984). Origins of normal and pathological tre-
mor. In: LJ Findley, R Capildeo (Eds.), Movement Disor-
ders: Tremor. Macmillan Press Ltd., London, pp. 3785.
Marsden CD, Fahn S (1987). Problems in the Dyskinesias.
In: CD Marsden, S Fahn (Eds.), Movement Disorders II.
Butterworths, London.
Marsden CD, Parkes JD (1977). Success and problems of
long-term levodopa therapy in Parkinsons disease. Lancet
1: 345349.
Masterman D, DeSalles A, Baloh RW et al. (1998). Motor,
cognitive, and behavioral performance following unilat-
eral ventroposterior pallidotomy for Parkinson disease.
Arch Neurol 55: 12011208.
Matsumoto K, Shichijo F, Fukami T (1984). Long-term
follow-up review of cases of Parkinsons disease after uni-
lateral or bilateral thalamotomy. J Neurosurg 53: 332337.
Merello M, Balej J, Delfino M et al. (1999). Apomorphine
induces changes in GPi spontaneous outflow in patients
with Parkinsons disease. Mov Disord 14: 4549.
Nagaseki Y, Shibazaki T, Hirai T et al. (1986). Long-term
follow-up results of selective VIM-thalamotomy. J Neuro-
surg 65: 296302.
Narabayashi H (1982). Surgical approach to tremor. In:
CD Marsden, S Fahn (Eds.), Movement Disorders. Butter-
worth Scientific, London, Boston, Sydney, Wellington,
Durban, Toronto, pp. 292299.
Narabayashi H, Yokochi F, Nakajima Y (1984). Levodopa-
induced dyskinesia and thalamotomy. J Neurol Neurosurg
Psychiatry 47: 831839.
Nini A, Feingold A, Slovin H et al. (1995). Neurons in the glo-
bus pallidus do not show correlated activity in the normal
monkey, but phase-locked oscillations appear in the MPTP
model of parkinsonism. J Neurophysiol 74: 18001805.
Niranjan A, Jawahar A, Kondziolka D et al. (1999). A compar-
ison of surgical approaches for the management of tremor:
radiofrequency thalamotomy, gamma knife thalamotomy
and thalamic stimulation. Stereotact Funct Neurosurg 72:
178184.
Ohye C (1982). Depth microelectrode studies. In: G Schal-
tenbrand, AE Walker (Eds.), Stereotaxy of the Human
Brain. Anatomical, Physiological and Clinical Applica-
tions. Georg Thieme, Stuttgart, pp. 372389.
Ohye C (1998). Neural noise recording in functional neurosur-
gery. In: PL Gildenberg, RR Tasker (Eds.), Textbook of
Stereotactic and Functional Neurosurgery. McGraw-Hill,
New York, pp. 941948.
Ohye C, Narabayashi H (1979). Physiological study of
presumed ventralis intermedius neurons in the human
thalamus. J Neurosurg 50: 290297.
Ojemann GA, Ward AA Jr (1982). Abnormal movement
disorders. In: JR Youmans, (Ed.), Neurological Surgery.
WB Saunders Company, Philadelphia, pp. 38213857.
Okun MS, Vitek JL (2004). Lesion therapy for Parkinsons
disease and other movement disorders: update and contro-
versies. Mov Disord 19: 375389.
Okun MS, Stover NP, Subramanian T et al. (2001). Compli-
cations of gamma knife surgery for Parkinson disease.
Arch Neurol 58: 19952002.
Okun MS, Vitek JL, DeLong MR (2002). Not our knife:
gamma knife surgery for Parkinson disease. Arch Neurol
59: 13341335.
Ondo WG, Jankovic J, Lai EC et al. (1998). Assessment of
motor function after stereotactic pallidotomy. Neurology
50: 266270.
Pan L, Dai JZ, Wang BJ et al. (1996). Stereotactic Gamma
thalamotomy for the treatment of parkinsonism. Stereotact
Funct Neurosurg 66 (Suppl 1): 329332.
Pare D, Curro Dossi R, Steriade M (1990). Neuronal basis
of the parkinsonian resting tremor: a hypothesis and its
implications for treatment. Neuroscience 35: 217226.
Parkin SG, Gregory RP, Scott R et al. (2002). Unilateral and
bilateral pallidotomy for idiopathic Parkinsons disease: a
case series of 115 patients. Mov Disord 17: 682692.
Patel NK, Heywood P, OSullivan K et al. (2003). Unilateral
subthalamotomy in the treatment of Parkinsons disease.
Brain 126: 11361145.
Paulson HL, Stern MB (1997). Clinical manifestations of Par-
kinsons disease. In: RL Watts, WC Koller (Eds.), Move-
ment Disorders. McGraw Hill, New York, pp. 183199.
Penney JB Jr, Young AB (1981). GABA as the Pallidothala-
mic neurotransmitter: implications for basal ganglia func-
tion. Brain Res 207: 195199.
Poewe W, Granata R (1997). Pharmacologic treatment of Par-
kinsons disease. In: RL Watts, WC Koller (Eds.), Move-
ment Disorders. McGraw-Hill, New York, pp. 201220.
Raeva S (1986). Localization in human thalamus of units
triggered during verbal commands, voluntary move-
ments and tremor. Electroencephalogr Clin Neurophysiol
63: 160173.
Ramcharan EJ, Gnadt JW, Sherman SM (2000). Burst and
tonic firing in thalamic cells of unanesthetized, behaving
monkeys. Vis Neurosci 17: 5562.
Ranck JB (1975). Which elements are excited in electrical
stimulation of mammalian central nervous system: a
review. Brain Res 98: 417440.
Rand RW, Jacques DB, Melbye RW et al. (1992). Gamma
knife thalamotomy and pallidotomy in patients with move-
ment disorders: preliminary results. Stereotact Funct Neu-
rosurg 61 (Suppl 1): 6592.
 ABLATIVE SURGERY FOR THE TREATMENT OF PARKINSONS DISEASE
Raz A, Vaadia E, Bergaman H (2000). Firing patterns and
correlations of spontaneous discharge of pallidal neurons
in the normal and the tremulous 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine vervet model of parkinsonism.
J Neurosci 20: 85598571.
Saint-Cyr J, Trepanier L, Lang A (1996). Neuropsychological
outcome of posteroventral pallidotomy in parkinsonian
patients. Mov Disord 11: 161.
Samuel M, Caputo E, Brooks DJ et al. (1998). A study of
medial pallidotomy for Parkinsons disease: clinical out-
come, MRI location and complications. Brain 121 (Pt 1):
5975.
Schaltenbrand G, Bailey P (1959). Introduction to Stereotaxis
with an Atlas of the Human Brain. Thieme, Stuttgart.
Schnider SM, Kwong RH, Lenz FA et al. (1989). Detection
of feedback in the central nervous system using system
identification techniques. Biol Cybern 60: 203212.
Schuling J, de Haan R, Limburg M et al. (1993). The
Frenchay Activities Index. Assessment of functional status
in stroke patients. Stroke 24: 11731177.
Schuurman PR, Bosch DA, Bossuyt PM et al. (2000).
A comparison of continuous thalamic stimulation and
thalamotomy for suppression of severe tremor. N Engl J
Med 342: 461468.
Scott R, Gregory R, Hines N et al. (1998). Neuropsychological,
neurological and functional outcome following pallidotomy
for Parkinsons disease. A consecutive series of eight simul-
taneous bilateral and twelve unilateral procedures. Brain
121 (Pt 4): 659675.
Shannon KM, Penn RD, Kroin JS et al. (1998). Stereotactic
pallidotomy for the treatment of Parkinsons disease.
Efficacy and adverse effects at 6 months in 26 patients.
Neurology 50: 434438.
Siegfried J, Lippitz B (1994). Chronic electrical stimulation
of the VL-VPL complex and of the pallidum in the treat-
ment of movement disorders: personal experience since
1982. Stereotact Funct Neurosurg 62: 7175.
Soukup VM, Ingram F, Schiess MC et al. (1997). Cognitive
sequelae of unilateral posteroventral pallidotomy. Arch
Neurol 54: 947950.
Spiegel EA, Wycis HT (1954). Ansotomy in paralysis agi-
tans. AMA Arch Neurol Psychiatry 71: 598614.
Spiegel EA, Wycis HT, Baird HW 3rd (1958). Long-range
effects of electropallidoansotomy in extrapyramidal and
convulsive disorders. Neurology 8: 734740.
Starr PA, Vitek JL, DeLong M et al. (1999). Magnetic reso-
nance imaging-based stereotactic localization of the glo-
bus pallidus and subthalamic nucleus. Neurosurgery 44:
303313.
Starr PA, Christine CW, Theodosopoulos PV et al. (2002).
Implantation of deep brain stimulators into the sub-
thalamic nucleus: technical approach and magnetic reso-
nance imaging-verified lead locations. J Neurosurg 97:
370387.
Stein RB, Lee RG (1981). Tremor and clonus. In: VB
Brooks (Ed.), Handbook of Physiology. Section I: Ner-
vous System. Volume II: Motor Control Part II. American
Physiological Society, Bethesda, pp. 325343.
259
Strick PL (1976). Activity of ventrolateral thalamic neurons
during arm movement. J Neurophysiol 39: 10321044.
Suarez JL, Verhagen Metman L, Reich SG et al. (1997). Pal-
lidotomy for hemiballismus: efficacy and characteristics of
neuronal activity. Ann Neurol 42: 807811.
Taha JM, Favre J, Burchiel KJ (1996). The value of macro-
stimulation in patients who underwent microrecording
during pallidotomy. Congress of Neurological Surgeons
Abstract at 46th Annual meeting, Chicago, IL, October
5, 1994, pp. 264265. Ref Type: Abstract.
Taren J, Guiot G, Derome P et al. (1968). Hazards of stereo-
taxic thalamectomy. Added safety factor in corroborating
X-ray target localization with neurophysiological methods.
J Neurosurg 29: 173182.
Tasker RR (1990). Thalamotomy. Neurosurg Clin N Am 1:
841864.
Tasker RR (1998). Ablative therapy for movement disorders.
Does thalamotomy alter the course of Parkinsons disease.
Neurosurg Clin N Am 9: 375380.
Tasker RR, Organ LW, Hawrylyshyn P (1982). The Thala-
mus and Midbrain in Man: a Physiologic Atlas Using
Electrical Stimulation. Thomas, Springfield, Illinous.
Tasker RR, Doorly T, Yamashiro K (1988). Thalamotomy in
generalized dystonia. Adv Neurol 50: 615631.
Tasker RR, Dostovsky JO, Dolan EJ (1991). Computerized
tomography (CT) is just as accurate as ventriculography
for functional stereotactic thalamotomy. Stereotact Funct
Neurosurg 57: 157166.
Terao T, Takahashi H, Yokochi F et al. (2003). Hemorrhagic
complication of stereotactic surgery in patients with
movement disorders. J Neurosurg 98: 12411246.
Trepanier LL, Saint-Cyr JA, Lozano AM et al. (1998).
Neuropsychological consequences of posteroventral
pallidotomy for the treatment of Parkinsons disease.
Neurology 51: 207215.
Uitti RJ, Wharen RE Jr, Turk MF et al. (1997). Unilateral
pallidotomy for Parkinsons disease: comparison of outcome
in younger versus elderly patients. Neurology 49: 10721077.
Umbach W, Ehrhardt KJ (1965). Micro-electrode recording
in the basal ganglia during stereotaxic operations. Confin
Neurol 26: 315317.
Vitek JL, Lenz FA (1998). Contemporary pallidotomy for
treatment of dystonia and other movement disorders. In:
J Jankovic, RG Grossman, G Krauss (Eds.), Pallidotomy
for Treatment of Parkinsons Disease and Other Movement
Disorders. Lippincott-Raven, New York, pp. 267274.
Vitek JL, Kaneoke Y, Turner R et al. (1993). Neuronal activ-
ity in the internal (GPi) and external (GPe) segments of
the globus pallidus (GP) of parkinsonian patients is similar
to that in the MPTP-treated primate model of parkinson-
ism. Society for Neuroscience Abstract 19: 1584. Ref
Type: Abstract.
Vitek JL, Ashe J, DeLong MR et al. (1994). Physiologic
properties and somatotopic organization of the primate
motor thalamus. J Neurophysiol 71: 14981513.
Vitek JL, Kaneoke Y, Hashimoto T et al. (1995). Neuronal
activity in the pallidum of a patient with hemiballismus.
Neurology 38: 296. Ref Type: Abstract.
260 F. A. LENZ
Vitek JL, Bakay RA, Hashimoto T et al. (1998a). Microelectrode-
guided pallidotomy: technical approach and its application in
medically intractable Parkinsons disease. J Neurosurg 88:
10271043.
Vitek JL, Zhang J, Evatt M et al. (1998b). GPi pallidotomy
for dystonia: clinical outcome and neuronal activity, Adv
Neurol 78: 211219.
Vitek JL, Chockkan V, Zhang J-Y et al. (1999). Neuronal
activity in the basal ganglia in patients with generalized
dystonia and hemiballismus. Ann Neurol 46: 2235.
Vitek JL, Bakay RA, Freeman A et al. (2003). Randomized
trial of pallidotomy versus medical therapy for Parkinsons
disease. Ann Neurol 53: 558569.
Wester K, Hauglie-Hanssen E (1990). Stereotaxic thalamot-
omy experiences from the levodopa era. J Neurol Neuro-
surg Psychiatry 53: 427430.
Wolbarsht ML, MacNichol EF Jr, Wagner HG (1960). Glass
insulated platinum microelectrode. Science 132: 13091310.
Young AB, Penney JB (1984). Neurochemical anatomy of
movement disorders. Neurol Clin 2: 417433.
Young RF, Shumway-Cook A, Vermeulen SS et al. (1998).
Gamma knife radiosurgery as a lesioning technique in
movement disorder surgery. J Neurosurg 89: 183193.
Zirh AT, Lenz FA, Reich SG et al. (1998). Patterns of
bursting occurring in thalamic cells during parkinsonian
tremor. Neuroscience 83: 107121.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 43

Deep brain stimulation

J. VOLKMANN* AND G. DEUSCHL

Department of Neurology, Christian-Albrechts-University, Kiel, Germany

43.1. Introduction
Deep brain stimulation (DBS) is an alternative to abla-
tive stereotaxy, which was first introduced in the
1970s but has not been routinely used for the treatment
of movement disorders until the pioneering work of
Benabid and colleagues in Grenoble became public
in the late 1980s. The subthalamic nucleus (STN),
which was introduced as a target for DBS in 1993,
quickly changed the scope of DBS from a sympto-
matic treatment of tremor to a highly effective therapy
for all cardinal symptoms of Parkinsons disease (PD)
and levodopa-induced motor complications.
DBS is based on the empirical observation that
high-frequency electrical stimulation of specific brain
targets can mimic the effect of a lesion without the
need for destroying brain tissue. DBS is accomplished
by permanently implanting an electrode into the target
area and connecting it to an internal pulse generator.
The stimulator settings can be adjusted telemetrically
with respect to electrode configuration, current ampli-
tude, pulse width and pulse frequency. DBS has rapidly
replaced ablative stereotactic surgery in movement
disorders with several advantages: (1) DBS does not
require a destructive lesion to be made in the brain;
(2) it can be performed bilaterally with relative safety,
in contrast to most lesioning procedures; (3) stimulation
parameters can be adjusted postoperatively to improve
efficacy, to reduce adverse effects and to adapt DBS
to the course of disease; and (4) DBS is in principle
reversible and does not preclude the use of possible
future therapies in PD requiring integrity of the basal
ganglia circuitry.
The number of DBS procedures for PD has been stea-
dily increasing over the past decade and has reached
a cumulative number of approximately 22 000 patients
worldwide in the year 2005, which may underline the
importance of this therapy in the treatment algorithm of
PD. In 2004 sufficient scientific evidence had accumu-
lated for the Movement Disorder Society to conclude
in its evidence-based medical review update that DBS
of the STN was efficacious for the symptomatic control
of parkinsonism. Although the status of DBS has chan-
ged from an investigational therapy to an evidence-based
routine treatment, a number of issues still need to be
addressed in controlled clinical trials, such as the target
selection and the safety in subgroups of patients or the
timing of DBS within the course of disease.
43.2. Physiological mechanisms
Despite the clinical success of DBS and the rapidly
expanding application for different neuropsychiatric
disorders, its mechanism of action is still poorly under-
stood. DBS mimics the clinical effects of lesioning in all
three target structures currently used for the treatment of
PD (ventrolateral thalamus, internal pallidum and STN),
when high-frequency (> 100 Hz) stimulation (HFS) is
applied. Stimulation at lower frequencies (< 50 Hz) results
in little or no clinical benefit or may even aggravate par-
kinsonian symptoms (Moro et al., 2000; Fogelson et al.,
2005).
When stimulating the central nervous tissue, the
electrode is placed within a complex volume conductor
containing three main elements, which could be
affected by stimulation: (1) local cells, that have their
cell body close to the stimulating electrode; (2) afferent
fibers making synaptic contact to the local cells; and
(3) fibers of passage, where both the cell body and axon
terminal are far from the stimulating electrode. Given
the stimulation parameters and electrode configurations
presently used, it is likely that DBS directly affects all

*Correspondence to: Dr Jens Volkmann, Department of Neurology, Christian-Albrechts-University, Schittenhelmstr. 10, 24105
Kiel, Germany. E-mail: j.volkmann@neurologie.uni-kiel.de, Tel: 49-431-597-8509, Fax: 49-431-597-8506.
262 J. VOLKMANN AND G. DEUSCHL
three elements. The inability to stimulate a single
element selectively complicates our ability to under-
stand the contribution of each of these elements to the
final behavioral effect of DBS.
Electrical stimulation of nervous tissue, in general, is
more likely to activate large myelinated fibers before
small axons or cell bodies, axons near the cathode before
those near the anode and axons oriented parallel to the
electrode before axons oriented transversely (Ranck,
1975). Presently, there exist five principal hypotheses
to explain the therapeutic mechanism of DBS, that have
derived from in vitro and in vivo experiments in animals
or intraoperative recordings in humans: (1) non-synaptic
blocking of neural output through inactivation of vol-
tage-dependent ion channels near the stimulating elec-
trode (Benazzouz et al., 1995; Beurrier et al., 2001);
(2) antidromic stimulation of inhibitory afferents to the
target nucleus and local release of gamma-aminobutyric
acid (GABA) (Dostrovsky et al., 2000); (3) driving of
efferents and masking (or jamming) of pathological net-
work activity (Montgomery and Baker, 2000; Hashimoto
et al., 2003); (4) modulation of afferent input to the target
nucleus (Strafella et al., 1997; Anderson et al., 2006); and
(5) synaptic transmission failure of the efferent output of
stimulated neurons as a result of synaptic depletion
(synaptic depression) (Brock et al., 1952; Urbano et al.,
2002). Which of these mechanisms alone or in combina-
tion is involved in the behavioral effect of DBS is
unknown and may depend on the anatomy of the target
structure (e.g. the thalamic target contains a local inhibi-
tory circuitry of interneurons and projections from reticu-
lar thalamic nuclei, which does not exist in the pallidal
and subthalamic target) and the exact location of the sti-
mulating electrode. First clinical evidence in line with
the mechanisms proposed above suggests that the opti-
mal target point for DBS may not be within the target
nuclei themselves but rather at entry or exit sites of fiber
tracts or adjacent crossings of large fiber bundles
(Velasco et al., 2001; Saint-Cyr et al., 2002; Voges
et al., 2002; Hamel et al., 2003; Murata et al., 2003;
Herzog et al., 2004; Plaha et al., 2004; Kitagawa et al.,
2005). These preliminary results, however, await further
confirmation in larger series and for other target sites.
For this reason, the exact documentation of the final
electrode location postoperatively and the corresponding
clinical effects not only serves for internal quality control
but is also essential to create a sufficiently large database
to address the important controversy about DBS mechan-
isms and the optimal electrode location.
43.2.1. Systemic effects of thalamic DBS
Two studies using positron emission tomography (PET)
to reveal the cerebral activity changes associated with
thalamic DBS in parkinsonian tremor have revealed
conflicting results. Parker et al. (1992) could demon-
strate that suppression of parkinsonian tremor by thala-
mic DBS was associated with significant reduction of
regional cerebral blood flow (rCBF) in the ipsilateral
putamen, sensorimotor cortex, supplementary motor
area (SMA) and contralateral cerebellum. They argued
that DBS could inactivate the involuntary running of a
central motor program for alternating movements
involving the basal gangliathalamocortical loop and
that cerebellar deactivation might be secondary to
reduced proprioceptive input. In contrast, Deiber
et al. (1993) found reduced cerebellar activity exclu-
sively during thalamic DBS and therefore assumed
a tremor generator within the cerebellothalamic
network.
Tremor-locked neuronal discharges have been
found in the internal pallidum and STN (Rodriguez-
Oroz et al., 2001) during stereotactic surgery, but most
prominently in areas of the ventrolateral thalamus
receiving cerebellar input (Lenz et al., 1994). Tremor
in PD, however, is unlikely to originate from the olivo-
cerebellar loop, because cerebellectomy does not
abolish resting tremor, but rather transforms it into a
slow resting, postural and intention tremor (Deuschl
et al., 1999). Nevertheless, most neurosurgeons believe
that the cerebellar relay nucleus, ventrointermediate
nucleus (VIM), represents the optimal site for thalamic
lesioning or stimulation in various types of tremor,
including parkinsonian tremor. The regional anatomy,
however, is complex and pallidothalamic afferents to
the adjacent nucleus ventrooralis anterior (Voa)
receiving pallidal input cross at the base of the VIM
or even pass through (Krack et al., 2002), such that
this site may rather reflect a strategic anatomical bot-
tleneck where interventions may affect either loop of
the extrapyramidal motor system. Because postmortem
studies are rare and inconclusive, it is difficult to dis-
cern currently whether thalamotomy or DBS effects
in the various types of tremors are mediated by inhibi-
tion of abnormal activity originating from the basal
ganglia, cerebellum or both.
43.2.2. Systemic effects of pallidal
or subthalamic DBS
The pathophysiological hallmarks of the parkinsonian
state in animal models of PD are abnormally increased
neuronal discharge rates in the STN and globus palli-
dus internal segment (GPi). Lesioning or HFS of
these structures reverses the symptoms of 1-methyl-
4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced
parkinsonism, thus supporting the functional signifi-
cance of these changes. The increased output activity
 DEEP BRAIN STIMULATION 263
of the basal ganglia results from opposite effects of
the striatal dopaminergic depletion on the direct and
indirect basal ganglia pathway according to the cur-
rent model of basal ganglia circuitry: The activity of
the direct basal ganglia pathway is reduced, resulting
in decreased inhibition of the GPi. Along the indirect
basal ganglia pathway excitatory afferents from STN
are driving GPi neurons to be overactive as a result of
decreased inhibitory input to the STN from globus
pallidus external segment (GPe) (DeLong, 1990).
The hyperactive inhibitory influence of the GPi on
thalamic nuclei and via this path on cortical motor
areas linked with the corresponding thalamic areas
is thought to cause bradykinesia and other PD
symptoms.
Pallidotomy can restore a normal level of activity in
the thalamocortical motor pathways by decreasing the
excessive inhibitory drive from the GPi to the ventro-
lateral thalamus. PET studies after successful pallidot-
omy showed increased rCBF and metabolism in
ipsilateral SMA and dorsolateral prefrontal cortex of Fig. 43.1. Axial (A) and coronal section (B) of a T2-weighted
parkinsonian patients (Eidelberg et al., 1996; Samuel magnetic resonance imaging scan at the level of the subthala-
mic nucleus (STN). On the upper images the STN is visible
et al., 1997; Ceballos Baumann et al., 1999). Similar
preoperatively in relation to the red nucleus (RN) and substan-
reversible changes of rCBF in SMA and dorsolateral
tia nigra (SN). The lower rows depict the artifact caused by
prefrontal cortex were described after HFS of the the deep brain stimulation electrode implanted bilaterally
internal pallidum (Davis et al., 1997) or STN within the STN.
(Ceballos Baumann et al., 1999).
Although these observations may explain the alle-
viation of akinesia, they provide little insight into the
43.3. Methods
mechanisms by which tremor, rigidity or dyskinesias
might be improved. The simple rate model of abnor- 43.3.1. Surgical procedure
mal neuronal activity in PD would predict reduced pal-
lidal discharge rates in hyperkinetic states and thus a Accurate electrode placement requires the use of a
further worsening with pallidal lesioning or DBS stereotactic head frame. Imaging is one of the most
(Marsden and Obeso, 1994). Clinically, however, the critical aspects of the stereotactic procedure and gener-
most consistent effect of pallidal surgery is a marked ally includes ventriculography, computed tomography
reduction of contralateral hyperkinesias (Volkmann (CT) and/or magnetic resonance imaging (MRI). His-
et al., 2004). It has therefore been suggested that palli- torically, ventriculography had been the radiological
dal or STN surgery in more general terms is effective gold standard for a reliable identification of the ante-
by removing the disturbing influence of a noisy basal rior and posterior commissure (AC, PC) and landmark-
ganglia operator on to thalamocortical motor areas based, indirect stereotactic targeting, but today it has
(Marsden and Obeso, 1994). Noisy or unphysiologi- largely been replaced by CT and MRI. The advantage
cal basal ganglia activity could result not only from of MRI lies in the direct visualization of the target
changes in discharge rate but also from abnormal pat- (STN, GPi) and neighboring structures (Fig. 43.1).
terning, oscillation or synchronization of neuronal fir- Moreover, three-dimensional reconstructions from
ing (Bergman and Deuschl, 2002; McIntyre et al., MRI or CT allow coronal, axial and sagittal determina-
2004b; Brown and Williams, 2005). Furthermore, des- tion of the AC and PC, planning of the entry point and
cending projections from the basal ganglia to the a control of the entire trajectory for possible conflicts
brainstem nuclei and spinal cord are often neglected with deep and superficial vessels. The radiologically
and may also play an important role in the pathophy- derived target is further refined intraoperatively by
siology of rigidity, postural instability and gait disor- neurophysiological techniques. Intraoperative stimula-
der of PD (Delwaide et al., 2000; Pahapill and tion predicts the effect of chronic stimulation and
Lozano, 2000; Nandi et al., 2002a, b; Potter et al., is crucial to determine the final site of electrode
2004). implantation. To allow for clinical evaluation of the
264 J. VOLKMANN AND G. DEUSCHL
stimulation response, the implantation is usually per-
formed under local anesthesia in awake patients.
Microelectrode recordings may provide additional
information on the nuclear boundaries and allow map-
ping of the target area along several passes (Fig. 43.2).
Microelectrode mapping is particularly useful when
clinical testing is difficult or inconclusive due to a
microlesioning effect or in uncooperative patients.
There is some debate on whether microelectrode map-
ping increases the surgical bleeding risk (Hariz and
Fodstad, 1999). However, leading centers in the field
routinely explore multiple microelectrode trajectories
and have reported low complication rates along with
excellent clinical results in DBS (Krack et al., 2003;
Lyons et al., 2004; Mehdorn et al., 2005; Schupbach
et al., 2005; Goodman et al., 2006). After insertion of
the permanent DBS electrode and attachment of the
extension cable, the system is connected to the internal
pulse generator. This is either done immediately or in
a staged fashion.
43.3.2. Target location
Optimal targeting is the prerequisite for clinical suc-
cess in DBS. Clinically effective stimulation is most
commonly directed at the anterior segment of the
dorsolateral STN (Saint-Cyr et al., 2002; Voges
et al., 2002; Herzog et al., 2004; Zonenshayn et al.,
2004). This target corresponds to the sensorimotor
territory of the nucleus, which may be identified by
the presence of movement-responsive cells in micro-
electrode recordings (Rodriguez-Oroz et al., 2001).
In this location the electrode also passes Forelss field
H and the zona incerta, which are dorsally adjacent to
the STN. Whether current spread into the subthalamic
white matter is necessary for optimal clinical success
is a matter of debate. However, exclusive stimulation
of subthalamic white matter by placing the electrode
dorsal to the STN boundary results in an unfavorable
relation between clinical improvement and current
consumption (Herzog et al., 2004).
The usual coordinates for pallidotomy are 2021 mm
lateral to the intercommissural line (ACPC line), 56
mm below and 3 mm anterior to the mid commissural
point (Laitinen et al., 1992). This corresponds to the
ventrolateral aspect of the GPi, where microelectrode
recordings demonstrate movement-related cells
(Iacono et al., 1997; Lozano et al., 1997). To what
extent the topography of pallidal stimulation effects
is related to the anatomical subdivision of GPi or the
anatomy of pallidal fiber tracts remains a matter of
speculation. Neither is it known whether the optimal

Zona Incerta (4.3 mm)

White matter (3.7 mm)

VLp
d STN (3.5 mm)
CL
VA
R
MDpl

VLp STN (2 mm)

PuA v
VLa
CM
VM
VPM
ZI STN (0.7 mm)
Po pc
STN
Anatomical
target
point SNr (0.3 mm)
SN

0.1 sec
Fig. 43.2. Typical traces of microelectrode recordings along a trajectory to the subthalamic nucleus (STN) are displayed in
relation to the recording site. Proximal to the STN sparse neuronal activity can be found in the zona incerta alternating with
traces of white-matter noise, when the electrode passes fiber tracts. STN is identified by a marked increase in background noise
and large-amplitude, burst-like spike discharges. This pattern changes to tonic, high-frequency discharges when the microelec-
trode enters substantia nigra (SNr). The characteristic difference in neuronal discharge patterns of STN and SNr may help to
refine the anatomical target, because the ventral border of STN is difficult to delineate on magnetic resonance images, as it
was in this case, where the anatomical target was chosen too deep.
 DEEP BRAIN STIMULATION
sites for pallidal lesioning and stimulation are identi-
cal. Two independent studies on the acute effects of
pallidal stimulation have found a better reduction of
parkinsonian symptoms by stimulating the distal con-
tacts of the quadrupolar stimulating electrode (Bejjani
et al., 1997; Krack et al., 1998b), which were located in
the dorsolateral aspect of GPi, closely neighboring
GPe. Stimulation of the ventromedial GPi, in contrast,
was antidyskinetic but also blocked the beneficial effect
of levodopa on akinesia. In our own experience, the posi-
tion of the most beneficial electrode pole used for
chronic pallidal stimulation was on average slightly
more lateral and dorsal than the standard pallidotomy
target (Volkmann et al., 1998). This corresponds to a
location lateral and dorsal to the optic tract in postopera-
tive MRI controls. Given a current spread of approxi-
mately 3 mm around the cathode, based on average
electrical parameters for pallidal stimulation (Ranck,
1975; McIntyre et al., 2004a), it is likely that stimulation
at these coordinates will not remain restricted to the sen-
sorimotor region of GPi, but may spread to the efferent
fiber tracts of GPi and medial regions of GPe.
A reduction of parkinsonian tremor may be achieved
by stimulation within a rather larger volume encom-
passing the ventrolateral thalamus and subthalamic
areas. There is no consensus in the literature regarding
the clinically most effective site. Most neurosurgeons
favor the thalamic VIM as the optimal site for thalamic
lesioning or stimulation in various types of tremor,
including parkinsonian tremor. Others have reported
excellent outcome with DBS of the subthalamic white
matter, including the prelemniscal radiation and zona
incerta (Velasco et al., 2001; Plaha et al., 2004;
Kitagawa et al., 2005). These clinical observations are
complemented by recent physiological data suggesting
that DBS might be effective for tremor by blocking
afferent synaptic input to thalamic tremor cells, thereby
stopping propagation of abnormal oscillations beyond
the thalamus (Anderson et al., 2006). Finally, DBS of
the STN is considered an alternative to thalamic surgery
and reduces the tremor score by approximately 80%
even in PD patients with severe high-amplitude tremor
(Krack et al., 1998a; Rodriguez et al., 1998). Because
no comparative trials exist, it is difficult to conclude
on a better efficacy of either target.
43.3.3. Safety
Adverse events associated with DBS must be divided
into those related to the surgical procedure, to the
implanted device, to stimulation and to medication
changes necessitated by DBS. In this section the safety
of the operative procedure and hardware-associated
problems are discussed. Therapy-related adverse
265
events (induced by stimulation or medication changes)
depend on the stimulated area and will be discussed
with the clinical results of each target.
43.3.3.1. Surgery-related adverse events
DBS requires a craniotomy and one or several needle
passes through the brain, carrying with it the risks of
intracranial hemorrhage and damage to adjacent brain
structures. The risk of unintended injury to adjacent
brain structures, however, is much smaller than in abla-
tive procedures, where the exact size of the final thera-
peutic lesion may be difficult to predict. In the only
prospective controlled study randomizing patients to
either thalamic stimulation or lesioning for the treatment
of tremor, the cumulative rate of neurological adverse
events was 47% in the thalamotomy group and 16% in
the DBS group. All adverse events in the DBS group
were reversible when stimulation was turned off. One
death related to an intracranial hemorrhage in the DBS
group, however, cautions about the inherent risk of any
stereotactic intervention (Schuurman et al., 2001).
In the literature intracranial hemorrhages are reported
in 14% of patients undergoing functional stereotactic
procedures (Favre et al., 2002; Binder et al., 2003; Terao
et al., 2003). The proportion of asymptomatic and symp-
tomatic bleedings within this percentage is unclear, but
the prevalence of persistent neurological deficits seems
to be considerably lower compared with the total sum
of hemorrhagic complications. Transient postoperative
confusion is present in up to 20% of the patients after
implantation of STN leads. This proportion is higher
than the rate of confusion previously reported for other
targets and may be related to the usual STN trajectory,
which passes the head of the caudate on both sides
(Woods et al., 2002). An additional source of surgery-
related morbidity is infection with an incidence of
34% (Lyons et al., 2004; Goodman et al., 2006).
43.3.3.2. Device-related adverse events
The reported rate of hardware-related problems (e.g.
lead dislocation, lead breakage, internal pulse generator
dysfunction, skin erosion) varies between different cen-
ters in the range of 530% (Hariz et al., 1999; Oh et al.,
2001; Lyons et al., 2004; Goodman et al., 2006) and
must not be underestimated. Most hardware-related
problems, however, occurred in the first patients of a
series and were less frequent afterwards. This sheds
light on the sophisticated nature of the procedure, which
requires extensive neurosurgical skill learning before
getting into a routine with DBS surgery. Device-related
complications are usually manageable, but often require
an additional surgical intervention. The permanent
morbidity associated with these problems is low.
266 J. VOLKMANN AND G. DEUSCHL
43.3.3.3. Summary
The risk of permanent neurological deficits associated
with DBS is lower than in lesional stereotaxy. Most lar-
ger controlled series report permanent neurological
morbidity in the region of 23%. Mortality is extremely
rare. Therefore, the benefit-to-risk ratio of the DBS pro-
cedure seems favorable, at least in severely disabled
patients. A careful selection of candidates for increased
neurosurgical risks should help to maintain a relatively
low level of morbidity.
43.4. Clinical efficacy
43.4.1. Thalamic deep brain stimulation
Experience with DBS in the thalamus for the treatment
of parkinsonian tremor has been generally safe and
effective. Clinical success is usually defined as a com-
plete abolition or a reduction of contralateral tremor to
grade 1 on the tremor-rating scale (mild and intermittent
tremor) with chronic stimulation. The success rates of
DBS in the following paragraph relate to this definition.
For tremor in PD, Benabid et al. (1991) reported a suc-
cess rate of 88% in 26 patients and very low morbidity
even after bilateral surgery. These findings were con-
firmed in a European multicenter study with 74 patients
and a follow-up of 1 year (Limousin et al., 1999). The
tremor reduction is sustained in the long term for up
to 7 years, but thalamic DBS does not improve other
symptoms of PD, nor does it alleviate long-term com-
plications of levodopa treatment. Akinesia, rigidity, gait
and postural problems may progress despite successful
treatment of tremor and can cause new therapeutic
difficulties (Rehncrona et al., 2003).
In a double-blind randomized study comparison of
thalamotomy and thalamic DBS Schuurman et al.
(2000, 2001) demonstrated after 2 years of follow-up
that both procedures resulted in about equal sympto-
matic relief of tremor, but that functional outcome
according to the Frenchay activity index was signifi-
cantly better in the DBS group. The authors related
this difference to permanent mild neurological seque-
lae of thalamotomy such as impairment of fine motor
skills due to lesions encroaching upon the internal
capsule.
43.4.2. Pallidal deep brain stimulation
The consistent effect of pallidal stimulation in all current
reports is a marked reduction of contralateral levodopa-
induced dyskinesias. Improvement of off-period symp-
toms of parkinsonism is more variable but significant in
most studies. Figure 43.3. summarizes the results of 15
studies in the literature, including a total of 276 patients
(Gross et al., 1997; Pahwa et al., 1997; Tronnier et al.,
1997; Ghika et al., 1998; Krack et al., 1998c; Kumar
et al., 1998; Burchiel et al., 1999; Merello et al., 1999;
The Deep-Brain Stimulation for Parkinsons Disease
Study Group, 2001; Volkmann et al., 2001; Durif et al.,
2002; Loher et al., 2002; Ogura et al., 2004; Peppe
et al., 2004; Anderson et al., 2005). In these studies the
median improvement of off-period motor symptoms
induced by pallidal stimulation was 36% (lower quartile
31%, upper quartile 43.1%) and the median reduction of
dyskinesias in the on-state 71% (lower quartile 52.5%,
upper quartile 78.5%). These data leave little doubt
about the clinical efficacy of palllidal DBS.
In our own experience bilateral GPi stimulation
(n 11) led to a 54
33.1% improvement of the
off-period Unified Parkinsons Disease Rating Scale
(UPDRS) motor score at 1-year follow-up (Volkmann
et al., 1998, 2001). In UPDRS subscores we found

Fig. 43.3. Summary of results of pallidal deep brain stimulation (DBS) in the literature: 15 publications from 1997 to 2005:
276 patients, 54 unilateral. For each study the average reduction of off-period motor symptoms by levodopa before surgery
(levodopa response in %), by DBS at the final visit, the reduction of dyskinesias and the reduction of the levodopa-equivalent
daily dose (LEDD) are represented by a symbol. Horizontal lines denote the median of all studies. STIM, stimulation.
 DEEP BRAIN STIMULATION
significant improvements for bradykinesia, tremor and
posture and gait and a tendency towards improvement
of rigidity. On-period motor symptoms did not sig-
nificantly change after surgery except for dyskinesias,
which were reduced by 83% at 1-year follow-up. The
alleviation of dyskinesias and the reduction of off-
period motor symptoms in combination led to a signif-
icant reduction of self-perceived motor fluctuations in
our patients. Unfortunately, the initial benefit on off-
period symptoms of PD tended to decrease in the long
term, whereas the antidyskinetic effect remained stable
for up to 5 years. The worsening of akinetic-rigid
symptoms of PD had to be compensated for by
increases in dopaminergic medication (Volkmann
et al., 2004), which kept the total duration of off-time
after surgery at a stable level. As a result, both hyper-
and hypokinetic motor fluctuations were still reduced
after 5 years but the increases in dopaminergic medi-
cation caused additional problems in some patients,
such as delusions or gambling.
Interestingly, one group reported, in contrast to all
other available studies, a reduction of dyskinesias but
a worsening of motor function during the medication
on period (Tronnier et al., 1997) after bilateral palli-
dal stimulation. Because the exact position of the sti-
mulating electrodes is uncertain in this and most
other studies, it is difficult to discern how much of
the variable effect of pallidal stimulation results from
different target locations within GPi. Two studies
(Bejjani et al., 1997; Krack et al., 1998b) claim, based
on the observation of acute stimulation effects, that
DBS of the ventral GPi may block dyskinesias but
aggravate akinesia, whereas dorsal GPi stimulation
ameliorates akinesia on account of being prodyski-
netic. The importance of these experimental observa-
267
tions for therapeutic long-term stimulation can only
be determined in future studies carefully relating the
efficacy of chronic pallidal stimulation to the exact tar-
get location within GPi determined by neuroimaging
techniques and microelectrode recordings.
Despite the common assumption that DBS is equally
effective but safer than lesioning techniques, there is
only one clinical trial currently available addressing this
issue. In a group of 13 patients randomized to either
unilateral pallidal DBS or radiofrequency lesioning of
the GPi, Merello and colleagues (1999) found about
equal improvement of the UPDRS motor score after
3-month follow-up. There was greater reduction of
contralateral dyskinesias after pallidotomy, whereas
bilateral hand-tapping scores improved more with DBS.
43.4.3. Subthalamic nucleus deep brain stimulation
DBS of the STN has replaced pallidal DBS in most
centers for the treatment of advanced PD. This prefer-
ence for the subthalamic target is rarely based on own
comparative experience. Centers that started a surgical
program for advanced PD with STN DBS have little
incentive to explore another target, if they obtain good
results in the STN. For this reason, there is a reporting
bias in the literature in favor of STN DBS in recent years.
Figure 43.4. summarizes 39 clinical studies of STN DBS
in advanced PD, reporting on a total of 1129 patients
(Moro et al., 1999; Pinter et al., 1999; Houeto et al.,
2000; Molinuevo et al., 2000; Broggi et al., 2001;
Katayama et al., 2001; Krause et al., 2001; Lopiano
et al., 2001; The Deep-Brain Stimulation for Parkinsons
Disease Study Group, 2001; Volkmann et al., 2001;
Doshi et al., 2002; Figueiras-Mendez et al., 2002; Iansek
et al., 2002; Kleiner-Fisman et al., 2002; Lanotte et al.,

Fig. 43.4. Summary of results of subthalamic nucleus deep brain stimulation (DBS) in the literature: 39 publications, from
2000 to 2005: 1129 patients. For each study, the average reduction of off-period motor symptoms by levodopa before surgery
(levodopa response in %), by DBS at the final visit, the reduction of dyskinesias and the reduction of the levodopa-equivalent
dose (LEED) are represented by a symbol. Horizontal lines denote the median of all studies. STIM, stimulation.
268 J. VOLKMANN AND G. DEUSCHL
2002; Martinez-Martin et al., 2002; Ostergaard et al.,
2002; Romito et al., 2002b; Simuni et al., 2002; Tavella
et al., 2002; Thobois et al., 2002; Valldeoriola et al.,
2002; Vesper et al., 2002; Vingerhoets et al., 2002;
Herzog et al., 2003b; Krack et al., 2003; Landi et al.,
2003; Pahwa et al., 2003; Tamma et al., 2003; Varma
et al., 2003; Esselink et al., 2004; Ford et al., 2004; Jaggi
et al., 2004; Peppe et al., 2004; Capecci et al., 2005;
Lyons and Pahwa, 2005; Minguez-Castellanos et al.,
2005; Rodriguez-Oroz et al., 2005; Visser-Vandewalle
et al., 2005). The median improvement in the UPDRS
motor score in the off-period was 50.2% (lower quartile
42%, upper quartile 60.8%) More specifically, improve-
ment is seen in off-phase akinesia, rigidity, tremor
(Krack et al., 1998c; Rodriguez et al., 1998), gait (Allert
et al., 2001; Faist et al., 2001; Stolze et al., 2001) and bal-
ance. Bilateral STN stimulation improves most axial fea-
tures of PD that responded to levodopa before surgery
(Bejjani et al., 2000b). Hypokinetic motor fluctuations
tend to disappear and patients show marked improve-
ment in the activities of daily living (median improve-
ment 37.5%). Off-period dystonia is immediately
alleviated, synchronously with stimulation (Krack
et al., 1999). The on-period dyskinesias are reduced in
parallel with a marked reduction of the equivalent daily
levodopa dose (LEED). The median reduction of dyski-
nesias was 73% (lower quartile 64%, upper quartile
91%) in our survey and the median reduction of the
LEED 54% (lower quartile 40%, upper quartile 66%).
In the long term, the antidyskinetic effect of STN stimu-
lation may be equivalent to or superior to that of GPi sti-
mulation if the levodopa dose remains reduced. Whereas
STN stimulation has a direct effect on off-period dysto-
nia, on-period dyskinesias are decreased by a more com-
plex mechanism, involving the decrease in levodopa
dosage and possibly adaptive neuronal changes induced
by continuous HFS. Bejjani et al. (2000a) demonstrated
that the sensitization phenomenon resulting from long-
term intermittent levodopa administration presumably
causing dyskinesias is partially reversible with STN
DBS. His group used a challenging dose to induce dys-
kinesias before surgery and, after 6 months of continu-
ous STN DBS, found that in the stimulation off-
condition, the severity of levodopa-induced dyskinesias
was greatly reduced compared to baseline.
The motor changes after STN DBS can have a signifi-
cant impact on patients quality of life (Just and Oster-
gaard, 2002; Lagrange et al., 2002; Martinez-Martin
et al., 2002; Spottke et al., 2002; Tamma et al., 2003;
Troster et al., 2003; Esselink et al., 2004; Lezcano et al.,
2004; Drapier et al., 2005; Lyons and Pahwa, 2005). In
studies using the Parkinsons Disease Questionnaire
PDQ-39, an average improvement of the summary index
of approximately 35% was reported. PDQ-39 dimensions
that significantly improved were stigma (54.4
18.1%),
activities of daily living (51.6
18.2%), mobility (38.5

18.2%), bodily discomfort (35.8
15.4%) and emotional
well-being (32.1
18.1%). Dimensions with modest
benefit included social support (17.0
19.1%), cognition
(16.5
15.0%) and communication (13.0
26.9%).
43.4.4. Comparison of the different targets
Few studies have compared the effect of STN and GPi
DBS. Most of them are parallel-group comparisons,
except for one randomized but underpowered clinical
trial (Burchiel et al., 1999; Anderson et al., 2005).
Krack et al. (1998c) reported a 71% improvement of
the off-period UPDRS motor score with STN stimu-
lation but only 39% with GPi stimulation in a group of
13 patients with young-onset PD. This significant dif-
ference resulted from a greater reduction of akinesia
in the STN-stimulated group, whereas other parkinso-
nian symptoms showed about equal improvement.
In contrast, Burchiel and colleagues (Burchiel et al.,
1999; Anderson et al., 2005) found no difference in
reduction of akinetic-rigid symptoms of PD or dyski-
nesias between STN- and GPi-stimulated patients in
a well-designed, randomized prospective trial. In our
own retrospective analysis of the initial 11 patients
implanted within GPi and 16 patients implanted within
STN, the main finding was a 54
33.1% improve-
ment of off-period motor symptoms in the first and
67
22.6% improvement in the later group after
1 year of follow-up (Volkmann et al., 2001). The 10
15% difference between both groups was not signifi-
cant and power analysis suggested that, based on the
group variances, a much larger trial including a mini-
mum of 135 patients in each arm would have been
needed to prove significance of this possible small dif-
ference in favor of STN stimulation. A non-rando-
mized multicenter study enrolled 96 patients with
STN DBS and 38 with GPi DBS (The Deep-Brain Sti-
mulation for Parkinsons Disease Study Group, 2001).
Except for levodopa-induced dyskinesias, which were
greatly alleviated in both groups, all other outcome
variables favored the STN group, although some of
the differences were small. At 3-month follow-up,
double-blind, cross-over evaluations demonstrated that
STN stimulation was associated with a median
improvement in the motor score (as compared with no
stimulation) of 49% and GPi stimulation with a median
improvement of 37%. Between the preoperative and
6-month visits, the percentage of time during the day
that patients had good mobility without involuntary
movements increased from 27 to 74% with STN sti-
mulation and from 28 to 64% with GPi stimulation.
Interestingly, these differences in the severity of
 DEEP BRAIN STIMULATION
off-period symptoms did not affect the total on-time
after surgery, which was still significantly increased
34 years after surgery to an identical extent after
DBS of the STN or GPi (Rodriguez-Oroz et al., 2005).
In a small group of PD patients that had simultaneous
bilateral electrode implants in the STN and the GPi,
Peppe et al. (2004) recently confirmed the slightly better
efficacy of STN DBS in reducing off-period symptoms.
They found a larger decrease in off-period UPDRS
III scores with DBS of the STN (54.5%) than during
DBS in the GPi (43.1%), when either target was stimu-
lated separately. The additive effect of stimulation in
both targets was small (54.5%) and not significant.
The available data, therefore, suggest a better effi-
cacy of STN DBS in reducing off-period motor symp-
toms, but formal confirmation in a larger prospective
randomized trial has to be awaited (Follett et al.,
2005). Other consistent differences between pallidal
and STN stimulation concern medication requirements
and stimulation parameters. Patients with pallidal sti-
mulation continue to require preoperative anti-PD
medication doses and in some cases even higher doses
are introduced postoperatively. In contrast, STN
stimulation allows an average reduction of dopaminergic
medication in the range of 5060% and approximately
10% of patients are able to discontinue all dopaminergic
drugs (Moro et al., 1999). This gives STN DBS a favor-
able benefit-to-cost ratio, but these advantages contrast
with a need for more intensive postoperative monitoring
and a higher incidence of adverse events (Volkmann
et al., 2001; Rodriguez-Oroz et al., 2005).
In summary, no general advice can be given yet
about the optimal target for the treatment of advanced
PD. The STN will be the preferred choice for younger
patients in most centers based on the expected
levodopa savings and the lower energy expenditure.
Pallidal stimulation, however, is an effective proce-
dure and may still be considered in older patients,
who may not tolerate levodopa withdrawal or time-
consuming programming of STN-DBS. Mild cognitive
impairment or a history of depression (as outlined in
section 43.3.3.1) could also be arguments in favor of
GPi DBS.
43.4.5. Therapy-related adverse effects
Optimal surgical positioning of the stimulating elec-
trode helps to reduce the risk of stimulation-induced
side-effects which mostly result from unintended cur-
rent spread to adjacent fiber tracts or nuclei. Stimula-
tion-induced side-effects are fully reversible when
stimulation is stopped and can be improved in most
cases by changing stimulation parameters or electrode
configuration. If sufficient control of motor symptoms
269
is not achieved without side-effects, patient and physician
may deliberately accept a certain degree of stimulation-
induced adverse effects.
In thalamic DBS, paresthesias and dysarthria are
among the most common stimulation-induced side-
effects. Especially with bilateral DBS some dysarthria
will have to be accepted in up to 10% of cases if opti-
mal tremor control is desired. Less frequent are real
dystonia or pseudodystonia resulting from costimula-
tion of the pyramidal tract (Limousin et al., 1999;
Schuurman et al., 2000, 2001; Rehncrona et al., 2003).
Stimulation-induced side-effects in pallidal DBS
are rare and mostly transient during the immediate
postoperative adaptation of stimulation parameters.
They include visual field disturbances from current
spread to the optic tract, tetanic muscle contractions
(pseudodystonia) from costimulation of the pyramidal
tract and nausea or dizziness.
Possible therapeutic problems with DBS of the STN
result from the complex interactions of medical ther-
apy and electrical stimulation. One of the challenges
in follow-up treatment is to distinguish between gen-
uine stimulation-induced side-effects and pre-existing
symptoms of the disease that are uncovered by a com-
bination of reduced dopaminergic therapy and inade-
quate stimulation effects. Postoperative speech, gait
and balance problems fall within this particular cate-
gory. Stimulation-induced dyskinesias are one of the
most frequent and important specific side-effects of
STN stimulation. The appearance of dyskinesias indi-
cates correct lead placement and an additive effect
has been observed in bilateral stimulation. Stimula-
tion-induced dyskinesias are worsened by levodopa.
Therefore initial programming should always be done
early in the morning when the patient is off medica-
tion. Stimulation is continuously increased over a per-
iod of days or weeks until a satisfactory effect on
bradykinesia in the off-phase is achieved and at the
same time the levodopa dosage is lowered (Volkmann
et al., 2000).
Either current diffusion due to excessive stimula-
tion parameters or incorrect lead placement may result
in reversible stimulation-induced side-effects, such as
tonic muscle contractions, dysarthria, eyelid-opening
apraxia, ocular deviation, ipsilateral mydriasis, flush-
ing, unilateral (ipsilateral) perspiration (contralateral)
paresthesias, worsening of akinesia and a reversal of
the levodopa effect. These reversible side-effects may
help to define the optimal target intraoperatively or
to track the deviation of a misplaced electrode after
surgery (Volkmann et al., 2000).
Despite the theoretical concern that pallidal or STN
stimulation could interfere with the functioning of
cognitive basal ganglia loops, most studies found no
270 J. VOLKMANN AND G. DEUSCHL
or clinically insignificant changes in neuropsychologi-
cal functioning after DBS (Ardouin et al., 1999;
Jahanshahi et al., 2000; Pillon et al., 2000; Trepanier
et al., 2000; Alegret et al., 2001). Some reports, how-
ever, have warned that STN DBS has a risk of inducing
cognitive decline with a frontal executive dysfunction
similar to progressive supranuclear palsy in older
patients (above 70 years) or those with minimal cogni-
tive dysfunction prior to surgery (Saint-Cyr et al.,
2000; Dujardin et al., 2001).
Mood disorders are among the most frequently
observed postoperative side-effects in STN stimulation
(Limousin et al., 1998; Volkmann et al., 2001;
Rodriguez-Oroz et al., 2005) but the true prevalence is
still difficult to estimate due to small sample sizes and
possible biases in reporting on adverse events. The
incidence of depression in the first postoperative
months has been up to 25% in some reports (Volkmann
et al., 2001; Berney et al., 2002), but there may be a
considerable overlap with apathy, that can present after
surgery as reduced drive without sadness. Depression
was associated with suicidal ideation in some patients
(Berney et al., 2002; Doshi et al., 2002). One center
described a suicide rate of 4% following DBS for PD,
which is probably not representative for the therapy in
general. More recently, Foncke et al. (2006) reported
on 2 suicides out of 16 patients that were included in a
clinical trial for pallidal DBS for dystonia. This observa-
tion indicates that suicide risk after DBS may not be
associated with specific targets or indications, but rather
with more general characteristics of the patient group
suffering from long-standing and severe motor disability
and often regarding DBS as a last-resort treatment.
Manic disorders are less frequent, somewhere
around 25% (Kulisevsky et al., 2002; Romito et al.,
2002a; Daniele et al., 2003; Herzog et al., 2003a) after
STN DBS. Other reports about behavioral abnormal-
ities after DBS of the STN include hypersexuality,
gambling or aggressiveimpulsive behavior in indivi-
dual patients (Houeto et al., 2002). Many of the
patients with behavioral abnormalities after surgery
had a pre-existing psychiatric condition (Houeto
et al., 2002). Therefore, careful preoperative psychia-
tric assessment is indicated to identify patients at risk
and to follow these patients closely after DBS.
The high incidence of psychiatric problems after STN
DBS is most likely multifactorial, but the relevance of
the individual factors still needs to be determined:
1. PD is a neuropsychiatric disease most frequently
associated with depression and anxiety. Mood
and behavioral abnormalities after surgery often
reflect a reactivation of a pre-existing psychiatric
condition (Houeto et al., 2002).
2. Levodopa has psychotropic effects in addition to
the well-known motor effects. Patients describe
the action of levodopa as pleasantly euphoria-
and drive-enhancing. In extreme cases, mania
and hypersexuality may be affective and beha-
vioral side-effects of dopaminergic therapy. The
medication reduction after STN stimulation may,
therefore, cause withdrawal phenomena with an
impact on mood and drive.
3. The basal ganglia are integrated into associative-
cognitive and limbic regulatory systems, so that
psychiatric symptoms could also result as a direct
side-effect of stimulation. However, the acute
emotional effect of STN DBS is mood-enhancing
(Funkiewiez et al., 2003; Schneider et al., 2003)
and high stimulation amplitudes may cause laughing
spells (Krack et al., 2001; Funkiewiez et al., 2003;
Schneider et al., 2003). There is currently no
evidence for other emotional or behavioral effects
of HFS within STN. The two spectacular cases
of stimulation-induced depression and aggressive
behavior resulted from misplaced electrodes
(Bejjani et al., 1999, 2002) within the substantia
nigra pars reticulata and the triangle of Sano.
4. Successful surgery reduces disability and may
enable the patient to regain independence. This
may affect partnership, social bonds and profes-
sional life and, at the same time, cause a loss of
primary and secondary gains from the illness
(Perozzo et al., 2001). The psychological and beha-
vioral consequences of social readaptation have
been extensively studied in patients undergoing
epilepsy surgery. The term burden of normality
describes a syndrome of social maladjustment caus-
ing most of the psychiatric problems after successful
treatment (Wilson et al., 2001). Whether a similar
concept applies to movement disorder surgery
remains to be determined.
43.5. Patient selection
DBS has not been evaluated for other forms of par-
kinsonism than idiopathic PD. From the experience
in few patients with progressive supranuclear palsy,
multiple system atrophy or other atypical parkinso-
nian syndroms who underwent DBS, one can con-
clude that the overall progression of these disorders
rapidly counteracts a possible transient benefit from
surgery. Up to 10% of the therapeutic failures after
DBS may result from an inappropriate diagnosis of
PD (Okun et al., 2005), which underlines the impor-
tance of involving movement disorder specialists in
the selection process.
 DEEP BRAIN STIMULATION
The objective of the selection process in general is to
identify those individuals in whom the expected benefit
will outlast the inherent risks of the surgical procedure.
Functional stereotactic surgery strives to improve
motor function and to reduce disability by alleviating
symptoms of a movement disorder. Benefit in the
context of movement disorder surgery is therefore a
complex variable, addressing the multidimensional
components of health and health-related well-being
in an individual. In the World Health Organization
(2005) WHO International Classification of Function-
ing, Disability and Health (ICF), these health-related
domains are described from the perspective of the
body, the individual and society. Disability is used
as an umbrella term for impairments of body struc-
ture or function, resulting activity limitations and par-
ticipation restrictions (social handicap). The degree of
activity limitations and social handicap a patient may
experience from a physical impairment is influenced
by individual factors (such as profession and family
status) within this framework.
The challenge that any neurologist or neurosurgeon
is facing in the selection process for movement disor-
der surgery is:
1. to determine whether the target symptom for sur-
gery is the predominant source of disability in this
patient,
2. to identify other potential sources of disability,
3. to estimate the likelihood of improving the target
symptom by surgery,
4. to estimate the individual risk of suffering from
complications,
5. to formulate realistic goals for the rehabilitation of
the patient on the different levels of functioning,
6. to relate the patients own expectation from sur-
gery to these goals and to correct unrealistic
expectations.
Patients need to be informed about their individual
risk/benefit analysis and possible alternative treatments.
43.5.1. Tremor
Tremor is seldom the most incapacitating symptom in
PD. Social embarrassment may be the driving force for
patients seeking surgical treatment rather than func-
tional impairment. In our view, the involved risks do
not justify surgery in these cases unless the patient is
experiencing relevant disability from the social restric-
tions implied by tremor. Before advising surgery, the
following medical therapies should have been tried:
levodopa with a sufficiently high daily dose (1000
1500 mg/day) for a period of at least 4 weeks to
observe the long-term levodopa effect, a dopamine
271
agonist, clozapine up to 75 mg/day and propanolol or
primidone in cases of predominant action tremor
(Deuschl and Volkmann, 2002).
Thalamic DBS is effective in reducing tremor, but
does not improve other symptoms of PD. As an alter-
native, STN DBS should be advised in younger
patients who are at risk of developing akinesia and
levodopa-related motor complications in the further
course of disease or in patients already suffering from
these symptoms. Older patients (> 70 years) with tre-
mor-dominant PD are less likely to progress and may
undergo thalamic DBS with good benefit. The advan-
tage of thalamic DBS in these cases lies in a more
rapid and predictable therapeutic response and the less
complicated adjustment of stimulation and medication
compared to STN DBS.
43.5.2. Advanced Parkinsons disease
Pallidal or subthalamic DBS are symptomatic treat-
ments for motor fluctuations and dyskinesias in
advanced PD. Levodopa-resistant symptoms of PD
do not respond to DBS either. Hence, ideal candi-
dates should suffer from idiopathic PD with an excel-
lent levodopa response but side-effects of long-term
medical treatment. Dementia, acute psychosis and
major depression are usually exclusion criteria.
The general health condition of the patient needs to
be good enough to withstand the operation and to
maintain cooperation during prolonged awake-sur-
gery. The presurgical levodopa test helps to predict
the individual response profile of a patient to bilateral
STN or GPi stimulation (Welter et al., 2002). Symp-
toms other than dyskinesias or tremor which persist
during best on after taking a challenging dose of
levodopa (11.5 times the equivalent of the regular
antiparkinsonian morning medication in the form of
short-acting, soluble levodopa) are less likely to bene-
fit from DBS. Most centers have operated primarily on
patients suffering from young-onset PD, because they
fulfill these criteria best. Older patients may also ben-
efit from surgery, but levodopa-resistant symptoms are
more often encountered in this group; axial symptoms
may respond less to DBS than in younger patients
(Russmann et al., 2004), surgical adverse events are
more frequent, motor rehabilitation is slower and
comorbidities (such as orthopedic problems secondary
to a parkinsonian postural or gait disorder) may limit
the degree of functional restitution.
The treating physician should be informed about the
patients personal expectations about surgery and cor-
rect unrealistic perspectives. Finally, the patient needs
to understand that the therapeutic benefits of DBS for
advanced PD are not immediately obtained after
272 J. VOLKMANN AND G. DEUSCHL
surgery. Programming the device and adjusting medica-
tion may be time-consuming and tedious and the patient
must be ready to cooperate during this process.
43.6. Conclusion
DBS is one of the most promising new therapies for
the treatment of PD. There is sufficient evidence in
the literature that DBS of the STN is an effective and
relatively safe therapy for all cardinal symptoms of
PD and levodopa-induced motor complications. The
improvements in motor symptoms are so profound that
quality of life is significantly improved by STN DBS.
With respect to possible side-effects of DBS, especially
behavioral and psychiatric adverse events, larger regis-
tries or multicenter trials are needed, because single
centers would take several years to recruit sufficient data
for a safety evaluation. Finally, future trials have to clar-
ify the differential indications for the three targets in
which DBS can be applied for treating PD (Follett
et al., 2005).
References
Alegret M, Junque C, Valldeoriola F et al. (2001). Effects of
bilateral subthalamic stimulation on cognitive function in
Parkinson disease. Arch Neurol 58 (8): 12231227.
Allert N, Volkmann J, Dotse S et al. (2001). Effects of bilat-
eral pallidal or subthalamic stimulation on gait in advanced
Parkinsons disease. Mov Disord 16 (6): 10761085.
Anderson TR, Hu B, Iremonger K et al. (2006). Selective
attenuation of afferent synaptic transmission as a mechan-
ism of thalamic deep brain stimulation-induced tremor
arrest. J Neurosci 26 (3): 841850.
Anderson VC, Burchiel KJ, Hogarth P et al. (2005). Pallidal
vs subthalamic nucleus deep brain stimulation in Parkin-
son disease. Arch Neurol 62 (4): 554560.
Ardouin C, Klinger H, Limousin P et al. (1999). The effect
of bilateral subthalamic nucleus stimulation on cognitive
functions [abstract]. Neurology 52 (Suppl 2): A514.
Bejjani B, Damier P, Arnulf I et al. (1997). Pallidal stimula-
tion for Parkinsons disease. Two targets? [see comments].
Neurology 49 (6): 15641569.
Bejjani BP, Damier P, Arnulf I et al. (1999). Transient acute
depression induced by high-frequency deep-brain stimula-
tion. N Engl J Med 340 (19): 14761480.
Bejjani BP, Arnulf I, Demeret S et al. (2000a). Levodopa-
induced dyskinesias in Parkinsons disease: is sensitization
reversible? Ann Neurol 47 (5): 655658.
Bejjani BP, Gervais D, Arnulf I et al. (2000b). Axial parkin-
sonian symptoms can be improved: the role of levodopa
and bilateral subthalamic stimulation. J Neurol Neurosurg
Psychiatry 68 (5): 595600.
Bejjani BP, Houeto JL, Hariz M et al. (2002). Aggressive
behavior induced by intraoperative stimulation in the tri-
angle of Sano. Neurology 59 (9): 14251427.
Benabid AL, Pollak P, Gervason C et al. (1991). Long-term
suppression of tremor by chronic stimulation of the ventral
intermediate thalamic nucleus. Lancet 337 (8738): 403406.
Benazzouz A, Piallat B, Pollak P et al. (1995). Responses of
substantia nigra pars reticulata and globus pallidus com-
plex to high frequency stimulation of the subthalamic
nucleus in rats: electrophysiological data. Neurosci Lett
189 (2): 7780.
Bergman H, Deuschl G (2002). Pathophysiology of Parkinsons
disease: from clinical Neurology to basic neuroscience and
back. Mov Disord 17 (Suppl 3): S28S40.
Berney A, Vingerhoets F, Perrin A et al. (2002). Effect on
mood of subthalamic DBS for Parkinsons disease: a conse-
cutive series of 24 patients. Neurology 59 (9): 14271429.
Beurrier C, Bioulac B, Audin J et al. (2001). High-frequency
stimulation produces a transient blockade of voltage-gated
currents in subthalamic neurons. J Neurophysiol 85 (4):
13511356.
Binder DK, Rau G, Starr PA (2003). Hemorrhagic complica-
tions of microelectrode-guided deep brain stimulation.
Stereotact Funct Neurosurg 80 (14): 2831.
Brock LG, Coombs JS, Eccles JC (1952). The recording of
potentials from motoneurons with intracellular electrode.
J Physiol 117: 431460.
Broggi G, Franzini A, Ferroli P et al. (2001). Effect of
bilateral subthalamic electrical stimulation in Parkinsons
disease. Surg Neurol 56 (2): 8994; discussion 9496.
Brown P, Williams D (2005). Basal ganglia local field poten-
tial activity: character and functional significance in the
human. Clin Neurophysiol 116 (11): 25102519.
Burchiel KJ, Anderson VC, Favre J et al. (1999). Comparison
of pallidal and subthalamic nucleus deep brain stimulation
for advanced Parkinsons disease: results of a randomized,
blinded pilot study. Neurosurgery 45 (6): 13751382.
Capecci M, Ricciuti RA, Burini D et al. (2005). Functional
improvement after subthalamic stimulation in Parkinsons
disease: a non-equivalent controlled study with 1224
month follow up. J Neurol Neurosurg Psychiatry 76 (6):
769774.
Ceballos Baumann AO, Boecker H, Bartenstein P et al.
(1999). A positron emission tomographic study of subtha-
lamic nucleus stimulation in Parkinson disease: enhanced
movement-related activity of motor-association cortex
and decreased motor cortex resting activity. Arch Neurol
56 (8): 9971003.
Daniele A, Albanese A, Contarino MF et al. (2003). Cogni-
tive and behavioural effects of chronic stimulation of the
subthalamic nucleus in patients with Parkinsons disease.
J Neurol Neurosurg Psychiatry 74 (2): 175182.
Davis KD, Taub E, Houle S et al. (1997). Globus pallidus sti-
mulation activates the cortical motor system during allevia-
tion of parkinsonian symptoms. Nat Med 3 (6): 671674.
Deiber MP, Pollak P, Passingham R et al. (1993). Thalamic
stimulation and suppression of parkinsonian tremor. Evi-
dence of a cerebellar deactivation using positron emission
tomography. Brain 116 (Pt 1): 267279.
DeLong MR (1990). Primate models of movement disorders
of basal ganglia origin. Trends Neurosci 13: 281285.
 DEEP BRAIN STIMULATION
Delwaide PJ, Pepin JL, De Pasqua V et al. (2000). Projections
from basal ganglia to tegmentum: a subcortical route for
explaining the pathophysiology of Parkinsons disease
signs? J Neurol 247 (Suppl 2): 7581.
Deuschl G, Volkmann J (2002). Tremors: differential diagno-
sis, physiology and pharmacology. In: J Jankovic, E Tolosa
(Eds.), Parkinsons Disease and Movement Disorders.
4th edn., Lippincott Williams and Wilkins, Baltimore,
pp. 270290.
Deuschl G, Wilms H, Krack P et al. (1999). Function of the
cerebellum in Parkinsonian rest tremor and Holmes tremor.
Ann Neurol 46 (1): 126128.
Doshi PK, Chhaya N, Bhatt MH (2002). Depression leading
to attempted suicide after bilateral subthalamic nucleus
stimulation for Parkinsons disease. Mov Disord 17 (5):
10841085.
Dostrovsky JO, Levy R, Wu JP et al. (2000). Microstimula-
tion-induced inhibition of neuronal firing in human globus
pallidus. J Neurophysiol 84 (1): 570574.
Drapier S, Raoul S, Drapier D et al. (2005). Only physical
aspects of quality of life are significantly improved by
bilateral subthalamic stimulation in Parkinsons disease.
J Neurol 252 (5): 583588.
Dujardin K, Defebvre L, Krystkowiak P et al. (2001). Influ-
ence of chronic bilateral stimulation of the subthalamic
nucleus on cognitive function in Parkinsons disease.
J Neurol 248 (7): 603611.
Durif F, Lemaire JJ, Debilly B et al. (2002). Long-term fol-
low-up of globus pallidus chronic stimulation in advanced
Parkinsons disease. Mov Disord 17 (4): 803807.
Eidelberg D, Moeller JR, Ishikawa T et al. (1996). Regional
metabolic correlates of surgical outcome following unilat-
eral pallidotomy for Parkinsons disease. Ann Neurol
39 (4): 450459.
Esselink RA, de Bie RM, de Haan RJ et al. (2004). Unilateral
pallidotomy versus bilateral subthalamic nucleus stimula-
tion in PD: a randomized trial. Neurology 62 (2): 201207.
Faist M, Xie J, Kurz D et al. (2001). Effect of bilateral sub-
thalamic nucleus stimulation on gait in Parkinsons
disease. Brain 124 (Pt 8): 15901600.
Favre J, Taha JM, Burchiel KJ (2002). An analysis of the
respective risks of hematoma formation in 361 consecu-
tive morphological and functional stereotactic procedures.
Neurosurgery 50 (1): 4856; discussion 5657.
Figueiras-Mendez R, Regidor I, Riva-Meana C et al. (2002).
Further supporting evidence of beneficial subthalamic stimu-
lation in Parkinsons patients. Neurology 58 (3): 469470.
Fogelson N, Kuhn AA, Silberstein P et al. (2005). Frequency
dependent effects of subthalamic nucleus stimulation in
Parkinsons disease. J Neurophysiol 382 (12): 59.
Follett K, Weaver F, Stern M et al. (2005). Multisite rando-
mized trial of deep brain stimulation. Arch Neurol 62 (10):
16431644.
Foncke EM, Schuurman PR, Speelman JD (2006). Suicide
after deep brain stimulation of the internal globus pallidus
for dystonia. Neurology 66 (1): 142143.
Ford B, Winfield L, Pullman SL et al. (2004). Subthalamic
nucleus stimulation in advanced Parkinsons disease:
273
blinded assessments at one year follow up. J Neurol Neu-
rosurg Psychiatry 75 (9): 12551259.
Funkiewiez A, Ardouin C, Krack P et al. (2003). Acute psycho-
tropic effects of bilateral subthalamic nucleus stimulation
and levodopa in Parkinsons disease. Mov Disord 18 (5):
524530.
Ghika J, Villemure JG, Fankhauser H et al. (1998). Efficiency
and safety of bilateral contemporaneous pallidal stimulation
(deep brain stimulation) in levodopa-responsive patients
with Parkinsons disease with severe motor fluctuations:
a 2-year follow-up review. J Neurosurg 89 (5): 713718.
Goodman RR, Kim B, McClelland S 3rd et al. (2006). Opera-
tive techniques and morbidity with subthalamic nucleus
deep brain stimulation in 100 consecutive patients with
advanced Parkinsons disease. J Neurol Neurosurg Psychia-
try 77 (1): 1217.
Gross C, Rougier A, Guehl D et al. (1997). High-frequency
stimulation of the globus pallidus internalis in Parkinsons
disease: a study of seven cases. J Neurosurg 87 (4): 491498.
Hamel W, Fietzek U, Morsnowski A et al. (2003). Deep brain
stimulation of the subthalamic nucleus in Parkinsons
disease: evaluation of active electrode contacts. J Neurol
Neurosurg Psychiatry 74: 10361046.
Hariz MI, Fodstad H (1999). Do microelectrode techniques
increase accuracy or decrease risks in pallidotomy and
deep brain stimulation? A critical review of the literature.
Stereotact Funct Neurosurg 72 (24): 157169.
Hariz MI, Shamsgovara P, Johansson F et al. (1999). Toler-
ance and tremor rebound following long-term chronic tha-
lamic stimulation for Parkinsonian and essential tremor.
Stereotact Funct Neurosurg 72 (24): 208218.
Hashimoto T, Elder CM, Okun MS et al. (2003). Stimulation
of the subthalamic nucleus changes the firing pattern of
pallidal neurons. J Neurosci 23 (5): 19161923.
Herzog J, Reiff J, Krack P et al. (2003a). Manic episode with
psychotic symptoms induced by subthalamic nucleus
stimulation in a patient with Parkinsons disease. Mov
Disord 18 (11): 13821384.
Herzog J, Volkmann J, Krack P et al. (2003b). Two year
follow up of subthalamic deep brain stimulation in Parkin-
sons disease. Mov Disord 18 (11): 13321337.
Herzog J, Fietzek U, Hamel W et al. (2004). Most effective
stimulation site in subthalamic deep brain stimulation for
Parkinsons disease. Mov Disord 19 (9): 10501054.
Houeto JL, Damier P, Bejjani PB et al. (2000). Subthalamic
stimulation in Parkinson disease: a multidisciplinary
approach. Arch Neurol 57 (4): 461465.
Houeto JL, Mesnage V, Mallet L et al. (2002). Behavioural
disorders, Parkinsons disease and subthalamic stimula-
tion. J Neurol Neurosurg Psychiatry 72 (6): 701707.
Iacono RP, Carlson JD, Kuniyoshi SM et al. (1997). Electro-
physiologic target localization in posteroventral pallidot-
omy. Acta Neurochir (Wien) 139 (5): 433441.
Iansek R, Rosenfeld JV, Huxham FE (2002). Deep brain
stimulation of the subthalamic nucleus in Parkinsons
disease. Med J Aust 177 (3): 142146.
Jaggi JL, Umemura A, Hurtig HI et al. (2004). Bilateral stimu-
lation of the subthalamic nucleus in Parkinsons disease:
274 J. VOLKMANN AND G. DEUSCHL
surgical efficacy and prediction of outcome. Stereotact
Funct Neurosurg 82 (23): 104114.
Jahanshahi M, Ardouin CM, Brown RG et al. (2000). The
impact of deep brain stimulation on executive function
in Parkinsons disease. Brain 123 (Pt 6): 11421154.
Just H, Ostergaard K (2002). Health-related quality of life in
patients with advanced Parkinsons disease treated with
deep brain stimulation of the subthalamic nuclei. Mov
Disord 17 (3): 539545.
Katayama Y, Kasai M, Oshima H et al. (2001). Subthalamic
nucleus stimulation for Parkinson disease: benefits
observed in levodopa-intolerant patients. J Neurosurg
95 (2): 213221.
Kitagawa M, Murata J, Uesugi H et al. (2005). Two-year fol-
low-up of chronic stimulation of the posterior subthalamic
white matter for tremor-dominant Parkinsons disease.
Neurosurgery 56 (2): 281289; discussion 281289.
Kleiner-Fisman G, Saint-Cyr JA, Miyasaki J et al. (2002).
Subthalamic DBS replaces levodopa in Parkinsons dis-
ease. Neurology 59 (8): 12931294.
Krack P, Benazzouz A, Pollak P et al. (1998a). Treatment of
tremor in Parkinsons disease by subthalamic nucleus
stimulation. Mov Disord 13 (6): 907914.
Krack P, Pollak P, Limousin P et al. (1998b). Opposite motor
effects of pallidal stimulation in Parkinsons disease. Ann
Neurol 43 (2): 180192.
Krack P, Pollak P, Limousin P et al. (1998c). Subthalamic
nucleus or internal pallidum stimulation in young onset
Parkinsons disease. Brain 121: 451457.
Krack P, Pollak P, Limousin P et al. (1999). From off-period
dystonia to peak-dose chorea. The clinical spectrum of
varying subthalamic nucleus activity. Brain 122 (Pt 6):
11331146.
Krack P, Kumar R, Ardouin C et al. (2001). Mirthful laugh-
ter induced by subthalamic nucleus stimulation. Mov Dis-
ord 16 (5): 867875.
Krack P, Dostrovsky J, Ilinsky I et al. (2002). Surgery of the
motor thalamus: problems with the present nomenclatures.
Mov Disord 17 (Suppl 3): S2S8.
Krack P, Batir A, Van Blercom N et al. (2003). Five-year
follow-up of bilateral stimulation of the subthalamic
nucleus in advanced Parkinsons disease. N Engl J Med
349 (20): 19251934.
Krause M, Fogel W, Heck A et al. (2001). Deep brain stimu-
lation for the treatment of Parkinsons disease: subthala-
mic nucleus versus globus pallidus internus. J Neurol
Neurosurg Psychiatry 70 (4): 464470.
Kulisevsky J, Berthier ML, Gironell A et al. (2002). Mania
following deep brain stimulation for Parkinsons disease.
Neurology 59 (9): 14211424.
Kumar R, Lozano AM, Montgomery E et al. (1998). Pallidot-
omy and deep brain stimulation of the pallidum and sub-
thalamic nucleus in advanced Parkinsons disease. Mov
Disord 13 (Suppl 1): 7382.
Lagrange E, Krack P, Moro E et al. (2002). Bilateral subtha-
lamic nucleus stimulation improves health-related quality
of life in PD. Neurology 59 (12): 19761978.
Laitinen LV, Bergenheim AT, Hariz MI (1992). Leksells
posteroventral pallidotomy in the treatment of Parkinsons
disease. J Neurosurg 76 (1): 5361.
Landi A, Antonini A, Parolin M et al. (2003). [Chronic sub-
thalamus stimulation for the treatment of Parkinsons dis-
ease. Analysis of results by classes of symptoms and
adverse effects]. J Neurosurg Sci 47 (1 Suppl 1): 2427.
Lanotte MM, Rizzone M, Bergamasco B et al. (2002). Deep
brain stimulation of the subthalamic nucleus: anatomical,
neurophysiological, and outcome correlations with the
effects of stimulation. J Neurol Neurosurg Psychiatry
72 (1): 5358.
Lenz FA, Kwan HC, Martin RL et al. (1994). Single unit
analysis of the human ventral thalamic nuclear group. Tre-
mor-related activity in functionally identified cells. Brain
117 (Pt 3): 531543.
Lezcano E, Gomez-Esteban JC, Zarranz JJ et al. (2004).
Improvement in quality of life in patients with advanced
Parkinsons disease following bilateral deep-brain stimula-
tion in subthalamic nucleus. Eur J Neurol 11 (7): 451454.
Limousin P, Krack P, Pollak P et al. (1998). Electrical stimu-
lation of the subthalamic nucleus in advanced Parkinsons
disease. N Engl J Med 339: 11051111.
Limousin P, Speelman JD, Gielen F et al. (1999). Multicentre
European study of thalamic stimulation in parkinsonian
and essential tremor. J Neurol Neurosurg Psychiatry
66 (3): 289296.
Loher TJ, Burgunder JM, Pohle T et al. (2002). Long-term
pallidal deep brain stimulation in patients with advanced
Parkinson disease: 1-year follow-up study. J Neurosurg
96 (5): 844853.
Lopiano L, Rizzone M, Bergamasco B et al. (2001). Deep
brain stimulation of the subthalamic nucleus: clinical
effectiveness and safety. Neurology 56 (4): 552554.
Lozano AM, Lang AE, Hutchison WD et al. (1997). Micro-
electrode recording-guided posteroventral pallidotomy in
patients with Parkinsons disease. Adv Neurol 74: 167174.
Lyons KE, Pahwa R (2005). Long-term benefits in quality of
life provided by bilateral subthalamic stimulation in patients
with Parkinson disease. J Neurosurg 103 (2): 252255.
Lyons KE, Wilkinson SB, Overman J et al. (2004). Surgical
and hardware complications of subthalamic stimulation:
a series of 160 procedures. Neurology 63 (4): 612616.
Marsden CD, Obeso JA (1994). The functions of the basal
ganglia and the paradox of stereotaxic surgery in Parkinsons
disease. Brain 117 (Pt 4): 877897.
Martinez-Martin P, Valldeoriola F, Tolosa E et al. (2002).
Bilateral subthalamic nucleus stimulation and quality of
life in advanced Parkinsons disease. Mov Disord 17 (2):
372377.
McIntyre CC, Mori S, Sherman DL et al. (2004a). Electric
field and stimulating influence generated by deep brain
stimulation of the subthalamic nucleus. Clin Neurophysiol
115 (3): 589595.
McIntyre CC, Savasta M, Walter BL et al. (2004b). How
does deep brain stimulation work? Present understanding
and future questions. J Clin Neurophysiol 21 (1): 4050.
 DEEP BRAIN STIMULATION
Mehdorn HM, Pinsker MO, Volkmann J et al. (2005). Deep
brain stimulation for idiopathic or secondary movement
disorders. Acta Neurochir Suppl 93 (Suppl): 105111.
Merello M, Nouzeilles MI, Kuzis G et al. (1999). Unilateral
radiofrequency lesion versus electrostimulation of postero-
ventral pallidum: a prospective randomized comparison.
Mov Disord 14 (1): 5056.
Minguez-Castellanos A, Escamilla-Sevilla F, Katati MJ et al.
(2005). Different patterns of medication change after sub-
thalamic or pallidal stimulation for Parkinsons disease:
target related effect or selection bias? J Neurol Neurosurg
Psychiatry 76 (1): 3439.
Molinuevo JL, Valldeoriola F, Tolosa E et al. (2000). Levo-
dopa withdrawal after bilateral subthalamic nucleus stimu-
lation in advanced Parkinson disease. Arch Neurol 57 (7):
983988.
Montgomery EB Jr, Baker KB (2000). Mechanisms of deep
brain stimulation and future technical developments.
Neurol Res 22 (3): 259266.
Moro E, Scerrati M, Romito LM et al. (1999). Chronic subtha-
lamic nucleus stimulation reduces medication requirements
in Parkinsons disease. Neurology 53 (1): 8590.
Moro E, Esselink RA, Van Blercom N et al. (2000). Bilateral
subthalamic nucleus stimulation in a parkinsonian patient
with previous unilateral pallidotomy and thalamotomy.
Mov Disord 15 (4): 753755.
Murata J, Kitagawa M, Uesugi H et al. (2003). Electrical
stimulation of the posterior subthalamic area for the treat-
ment of intractable proximal tremor. J Neurosurg 99 (4):
708715.
Nandi D, Aziz TZ, Giladi N et al. (2002a). Reversal of aki-
nesia in experimental parkinsonism by GABA antagonist
microinjections in the pedunculopontine nucleus. Brain
125 (Pt 11): 24182430.
Nandi D, Liu X, Winter JL et al. (2002b). Deep brain stimula-
tion of the pedunculopontine region in the normal non-human
primate. J Clin Neurosci 9 (2): 170174.
Ogura M, Nakao N, Nakai E et al. (2004). The mechanism
and effect of chronic electrical stimulation of the globus
pallidus for treatment of Parkinson disease. J Neurosurg
100 (6): 9971001.
Oh MY, Kim SH, Abosch A et al. (2001). Hardware related
complications of deep brain stimulaiton in 100 consecutive
electrodes. J Neurosurg 94: (Proceedings of the AANS
meeting) 412A.
Okun MS, Tagliati M, Pourfar M et al. (2005). Management
of referred deep brain stimulation failures: a retrospective
analysis from 2 movement disorders centers. Arch Neurol
62 (8): 12501255.
Ostergaard K, Sunde N, Dupont E (2002). Effects of bilateral
stimulation of the subthalamic nucleus in patients with
severe Parkinsons disease and motor fluctuations. Mov
Disord 17 (4): 693700.
Pahapill PA, Lozano AM (2000). The pedunculopontine nuc-
leus and Parkinsons disease. Brain 123 (Pt 9): 17671783.
Pahwa R, Wilkinson S, Smith D et al. (1997). High-fre-
quency stimulation of the globus pallidus for the treatment
of Parkinsons disease. Neurology 49 (1): 249253.
275
Pahwa R, Wilkinson SB, Overman J et al. (2003). Bilateral
subthalamic stimulation in patients with Parkinson dis-
ease: long-term follow up. J Neurosurg 99 (1): 7177.
Pahwa R, Wilkinson SB, Overman J et al. (2005). Preopera-
tive clinical predictors of response to bilateral subthalamic
stimulation in patients with Parkinsons disease. Stereotact
Funct Neurosurg 83 (23): 8083.
Parker F, Tzourio N, Blond S et al. (1992). Evidence for a
common network of brain structures involved in parkinso-
nian tremor and voluntary repetitive movement. Brain Res
584 (12): 1117.
Peppe A, Pierantozzi M, Bassi A et al. (2004). Stimulation of
the subthalamic nucleus compared with the globus palli-
dus internus in patients with Parkinson disease. J Neuro-
surg 101 (2): 195200.
Perozzo P, Rizzone M, Bergamasco B et al. (2001). Deep
brain stimulation of subthalamic nucleus: behavioural
modifications and familiar relations. Neurol Sci 22 (1):
8182.
Pillon B, Ardouin C, Damier P et al. (2000). Neuropsy-
chological changes between off and on STN or GPi
stimulation in Parkinsons disease. Neurology 55 (3):
411418.
Pinter MM, Alesch F, Murg M et al. (1999). Deep brain sti-
mulation of the subthalamic nucleus for control of extra-
pyramidal features in advanced idiopathic Parkinsons
disease: one year follow-up. J Neural Transm 106 (78):
693709.
Plaha P, Patel NK, Gill SS (2004). Stimulation of the subtha-
lamic region for essential tremor. J Neurosurg 101 (1):
4854.
Potter M, Illert M, Wenzelburger R et al. (2004). The effect
of subthalamic nucleus stimulation on autogenic inhibition
in Parkinson disease. Neurology 63 (7): 12341239.
Ranck JB (1975). Which elements are excited in electrical
stimulation of mammalian central nervous system?
A review. Brain Res 98: 417440.
Rehncrona S, Johnels B, Widner H et al. (2003). Long-term
efficacy of thalamic deep brain stimulation for tremor:
double-blind assessments. Mov Disord 18 (2): 163170.
Rodriguez MC, Guridi OJ, Alvarez L et al. (1998). The
subthalamic nucleus and tremor in Parkinsons disease.
Mov Disord 13 (Suppl 3): 111118.
Rodriguez-Oroz MC, Rodriguez M, Guridi J et al. (2001).
The subthalamic nucleus in Parkinsons disease: somatoto-
pic organization and physiological characteristics. Brain
124 (Pt 9): 17771790.
Rodriguez-Oroz MC, Obeso JA, Lang AE et al. (2005).
Bilateral deep brain stimulation in Parkinsons disease:
a multicentre study with 4 years follow-up. Brain
128 (Pt 10): 22402249.
Romito LM, Raja M, Daniele A et al. (2002a). Transient
mania with hypersexuality after surgery for high frequency
stimulation of the subthalamic nucleus in Parkinsons
disease. Mov Disord 17 (6): 13711374.
Romito LM, Scerrati M, Contarino MF et al. (2002b). Long-
term follow up of subthalamic nucleus stimulation in
Parkinsons disease. Neurology 58 (10): 15461550.
276 J. VOLKMANN AND G. DEUSCHL
Russmann H, Ghika J, Villemure JG et al. (2004). Sub-
thalamic nucleus deep brain stimulation in Parkinson dis-
ease patients over age 70 years. Neurology 63 (10):
19521954.
Saint-Cyr JA, Trepanier LL, Kumar R et al. (2000). Neurop-
sychological consequences of chronic bilateral stimulation
of the subthalamic nucleus in Parkinsons disease. Brain
123 (Pt 10): 20912108.
Saint-Cyr JA, Hoque T, Pereira LC et al. (2002). Localization
of clinically effective stimulating electrodes in the human
subthalamic nucleus on magnetic resonance imaging.
J Neurosurg 97 (5): 11521166.
Samuel M, Ceballos-Baumann AO, Turjanski N et al. (1997).
Pallidotomy in Parkinsons disease increases supplementary
motor area and prefrontal activation during performance of
volitional movements an H2(15)O PET study. Brain
120 (Pt 8): 13011313.
Schneider F, Habel U, Volkmann J et al. (2003). Deep brain
stimulation of the subthalamic nucleus enhances emo-
tional processing in Parkinson disease. Arch Gen Psychia-
try 60 (3): 296302.
Schupbach WM, Chastan N, Welter ML et al. (2005). Stimu-
lation of the subthalamic nucleus in Parkinsons disease:
a 5 year follow up. J Neurol Neurosurg Psychiatry
76 (12): 16401644.
Schuurman PR, Bosch DA, Bossuyt PM et al. (2000).
A comparison of continuous thalamic stimulation and
thalamotomy for suppression of severe tremor. N Engl J
Med 342 (7): 461468.
Schuurman P, Bosch D, Speelman J (2001). Thalamic stimu-
lation versus thalamotomy: long-term follow-up. Parkin-
sonism Relat Disord 7 (Suppl): S85(Abstract).
Simuni T, Jaggi JL, Mulholland H et al. (2002). Bilateral stimu-
lation of the subthalamic nucleus in patients with Parkinson
disease: a study of efficacy and safety. J Neurosurg 96 (4):
666672.
Spottke EA, Volkmann J, Lorenz D et al. (2002). Evaluation
of healthcare utilization and health status of patients with
Parkinsons disease treated with deep brain stimulation
of the subthalamic nucleus. J Neurol 249 (6): 759766.
Stolze H, Klebe S, Poepping M et al. (2001). Effects of bilat-
eral subthalamic nucleus stimulation on parkinsonian gait.
Neurology 57 (1): 144146.
Strafella A, Ashby P, Munz M et al. (1997). Inhibition of
voluntary activity by thalamic stimulation in humans:
relevance for the control of tremor. Mov Disord 12 (5):
727737.
Tamma F, Rampini P, Egidi M et al. (2003). Deep brain
stimulation for Parkinsons disease: the experience of the
Policlinico-San Paolo Group in Milan. Neurol Sci
24 (Suppl 1): S41S42.
Tavella A, Bergamasco B, Bosticco E et al. (2002). Deep
brain stimulation of the subthalamic nucleus in Parkinsons
disease: long-term follow-up. Neurol Sci 23 (Suppl 2):
S111S112.
Terao T, Takahashi H, Yokochi F et al. (2003). Hemorrhagic
complication of stereotactic surgery in patients with move-
ment disorders. J Neurosurg 98 (6): 12411246.
The Deep-Brain Stimulation for Parkinsons Disease Study
Group (2001). Deep-brain stimulation of the subthalamic
nucleus or the pars interna of the globus pallidus in
Parkinsons disease. N Engl J Med 345 (13): 956963.
Thobois S, Mertens P, Guenot M et al. (2002). Subthalamic
nucleus stimulation in Parkinsons disease: clinical eva-
luation of 18 patients. J Neurol 249 (5): 529534.
Trepanier LL, Kumar R, Lozano AM et al. (2000). Neurop-
sychological outcome of GPi pallidotomy and GPi or
STN deep brain stimulation in Parkinsons disease. Brain
Cogn 42 (3): 324347.
Tronnier VM, Fogel W, Kronenbuerger M et al. (1997). Pal-
lidal stimulation: an alternative to pallidotomy? J Neuro-
surg 87: 700705.
Troster AI, Fields JA, Wilkinson S et al. (2003). Effect of
motor improvement on quality of life following subthala-
mic stimulation is mediated by changes in depressive
symptomatology. Stereotact Funct Neurosurg 80 (14):
4347.
Urbano FJ, Leznki E, Linas RR (2002). Cortical activation
patterns evoked by afferent axons stimuli at different fre-
quencies: an in vitro voltage-sensitive dye imaging study.
Thalamus Rel Syst 1: 371378.
Valldeoriola F, Pilleri M, Tolosa E et al. (2002). Bilateral
subthalamic stimulation monotherapy in advanced Parkin-
sons disease: long-term follow-up of patients. Mov Dis-
ord 17 (1): 125132.
Varma TR, Fox SH, Eldridge PR et al. (2003). Deep brain
stimulation of the subthalamic nucleus: effectiveness in
advanced Parkinsons disease patients previously reliant
on apomorphine. J Neurol Neurosurg Psychiatry 74 (2):
170174.
Velasco F, Jimenez F, Perez ML et al. (2001). Electrical sti-
mulation of the prelemniscal radiation in the treatment of
Parkinsons disease: an old target revised with new techni-
ques. Neurosurgery 49 (2): 293306; discussion 306308.
Vesper J, Klostermann F, Stockhammer F et al. (2002).
Results of chronic subthalamic nucleus stimulation for
Parkinsons disease: a 1-year follow-up study. Surg Neu-
rol 57 (5): 306311; discussion 311313.
Vingerhoets FJ, Villemure JG, Temperli P et al. (2002).
Subthalamic DBS replaces levodopa in Parkinsons dis-
ease: two-year follow-up. Neurology 58 (3): 396401.
Visser-Vandewalle V, van der Linden C, Temel Y et al.
(2005). Long-term effects of bilateral subthalamic nucleus
stimulation in advanced Parkinson disease: a four year fol-
low-up study. Parkinsonism Relat Disord 11 (3): 157165.
Voges J, Volkmann J, Allert N et al. (2002). Bilateral high-
frequency stimulation in the subthalamic nucleus for the
treatment of Parkinson disease: correlation of therapeutic
effect with anatomical electrode position. J Neurosurg
96 (2): 269279.
Volkmann J, Sturm V, Weiss P et al. (1998). Bilateral high-
frequency stimulation of the internal globus pallidus in
advanced Parkinsons disease. Ann Neurol 44: 953961.
Volkmann J, Fogel W, Krack P (2000). Postoperatives
neurologisches Management bei Stimulation des Nucleus
subthalamicus. Aktuelle Neurolog 27 (Suppl 1): 2339.
 DEEP BRAIN STIMULATION
Volkmann J, Allert N, Voges J et al. (2001). Safety and effi-
cacy of pallidal or subthalamic nucleus stimulation in
advanced PD. Neurology 56 (4): 548551.
Volkmann J, Allert N, Voges J et al. (2004). Long-term
results of bilateral pallidal deep brain stimulation in
Parkinsons disease. Ann Neurol 55: 871875.
Welter ML, Houeto JL, Tezenas du Montcel S et al. (2002).
Clinical predictive factors of subthalamic stimulation in
Parkinsons disease. Brain 125 (Pt 3): 575583.
Wilson S, Bladin P, Saling M (2001). The burden of nor-
mality: concepts of adjustment after surgery for seizures.
J Neurol Neurosurg Psychiatry 70 (5): 649656.
277
Woods SP, Fields JA, Troster AI (2002). Neuropsychological
sequelae of subthalamic nucleus deep brain stimulation in
Parkinsons disease: a critical review. Neuropsychol Rev
12 (2): 111126.
World Health Organization (2005). The International Classi-
fication of Functioning, Disability and HealthICF.
WHO, Geneva.
Zonenshayn M, Sterio D, Kelly PJ et al. (2004). Location of
the active contact within the subthalamic nucleus (STN) in
the treatment of idiopathic Parkinsons disease. Surg Neu-
rol 62 (3): 216225; discussion 225226.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 44

Transplantation

CURT R. FREED*, W. MICHAEL ZAWADA, MAUREEN LEEHEY,

WENBO ZHOU AND ROBERT E. BREEZE

University of Colorado School of Medicine, Denver, CO, USA

44.1. Introduction to survive in large numbers because of the insurmoun-

Neurotransplantation offers a novel treatment strategy
for Parkinsons disease (PD), replacing lost dopamine
neurons with new cells. The fact that there are so many
successful therapies for PD is extraordinary. This book
has summarized both pharmacologic and neurosurgical
procedures, including lesions and deep brain stimula-
tion. Neurotransplantation is fundamentally different
from these strategies, because only neurotransplanta-
tion repairs a primary defect of PD, the loss of
dopamine neurons.
Transplantation of dopamine neurons into humans
has developed from a comprehensive series of experi-
ments in animal models of PD, particularly rats. Most
principles established in the rat have proven applicable
to humans. In the rat, embryonic dopamine neurons from
a narrow window of development, 1315 days after
conception, are suitable for transplantation. For human
transplantation, the equivalent stage of embryonic devel-
opment is 68 weeks after conception. All successful
allografts of human embryonic tissue into patients with
PD have come from tissue in this developmental window
(for reviews, see Clarkson and Freed, 1999; Bjorklund
et al., 2003; Lang and Obeso, 2004).
Tissues other than fetal dopamine neurons have
been transplanted into PD patients. Autotransplants
of adrenal chromaffin cells were pursued intensively
in the late 1980s, without success. Because the supply
of human fetal tissue is limited and variable in quality,
some researchers looked to other species as a source of
fetal dopamine neurons. Ventral mesencephalon from
fetal pig was transplanted into patients who were
immunosuppressed with ciclosporin and prednisone.
Despite efforts to prevent rejection, porcine cells failed
table problem of xenograft rejection.
In the USA, during the presidency of Bill Clinton,
there was a window of federal funding to test systema-
tically the value of embryonic dopamine cell trans-
plants. Two double-blind studies were performed
(Freed et al., 2001; Olanow et al., 2003). Although
neither study achieved significance in primary outcome
variables, both showed long-term survival of embryo-
nic dopamine cells. In the first of these, we found that
transplants significantly improved Unified Parkinsons
Disease Rating Scale (UPDRS) and Schwab and
England off scores in patients under age 60 (Freed
et al., 2001). A proportion of patients in our study as
well as the later study by Olanow et al. (2003) devel-
oped persistent dyskinesias in a pattern similar to that
seen after levodopa therapy in the same patients. Thus,
transplants replicated the effects of levodopa, including
the tendency to produce dyskinesias in patients with an
earlier history of drug-induced dyskinesias.
To explore the value of dopamine cell transplanta-
tion for PD comprehensively, a more reliable tissue
source must be found. Efforts to produce dopamine
neurons from human embryonic stem cells are promis-
ing (Buytaert-Hoefen et al., 2004; Perrier et al., 2004;
Yan et al., 2005). If a homogeneous supply of dopamine
neurons can be generated, cell replacement can be
systematically studied in large groups of patients, better
defining the potential of this therapeutic strategy.
44.2. Experimental basis for
neurotransplantation
Developing a good rodent model of PD was critical to
the development of neurotransplantation. Ungerstedt

*Correspondence to: Curt R. Freed, University of Colorado Health Sciences Center, Box C237, 4200 E. Ninth Avenue, Denver,
CO 80262, USA. E-mail: curt.freed@uchsc.edu, Tel: 1-303-315-8455, Fax: 1-303-315-3272.
280 C. R. FREED ET AL.
and Arbuthnott (1970) demonstrated that unilateral
injection of the neurotoxin 6-hydroxydopamine
(6-OHDA) into the medial forebrain bundle of rat brain
can destroy dopamine neurons in the substantia nigra
pars compacta with loss of dopamine nerve terminals
in the striatum. Nearly complete destruction of dopa-
mine neurons can be achieved on one side of the brain
without damaging other neural systems or dopamine
neurons on the contralateral side. Animals maintain
nearly normal eating, drinking and grooming behaviors.
When doses of methamphetamine are administered that
ordinarily produce stereotypic behavior (5 mg/kg
subcutaneously), the unilaterally lesioned animals will
begin circling toward their lesioned side at rates as high
as 10 rpm. Dopamine released asymmetrically from the
intact side of striatum drives the circling behavior. Only
rats with >95% unilateral dopamine depletion will
circle at these high rates. By contrast, the dopamine
agonist apomorphine stimulates the supersensitive
dopamine receptors in the denervated striatum and
leads to circling in the direction contralateral to the
lesion.
This rat model made it possible to explore cell
replacement therapies for PD. Cells from a wide devel-
opmental range from early embryonic to adult tissue
were tested for their ability to survive in brain. Critical
experiments by Bjorklund and Stenevi (1979) and
Perlow et al. (1979) were the first to show that rat
mesencephalic dopamine cells transplanted into the
denervated striatum could survive, extend neurites
and stop the circling response to amphetamine as
dopamine concentrations were restored.
These early experiments were followed by others
that showed that dopamine neurite outgrowth occurred
in response to factors produced by the dopamine
denervated striatum. Only mesencephalic dopamine
neurons will reinnervate the striatum and transplant
growth occurs only after striatum has been denervated.
The behavioral effects of transplantation in rats are
specific to mesencephalic dopamine cells. Rats trans-
planted with serotonergic neurons from mesencephalic
raphe or dopamine neurons from hypothalamus have
no improvement in behavior (Dunnett et al., 1988;
Hudson et al., 1994). These experiments showed that
innervation of the target is a specific interaction
between the appropriate dopamine neuron and factors
released from the denervated striatum.
This important principle provides an argument for
the safety of dopamine cell transplants, suggesting that
a wide range of tissue doses could produce an accepta-
ble behavioral response since the host striatum would
secrete neurotrophic factors until appropriate dopami-
nergic input was achieved. Because this response is
likely to be very local, even confined to individual or
small groups of striatal neurons, the model does not
assure homogeneous reinnervation by dopamine neu-
rons. Since the grafted dopamine neurons are ectopi-
cally placed in the striatum and do not have normal
afferents, the dopamine neurons do not receive normal
inputs regulating their own firing rates. If those inputs
are needed for fully normal control of movement,
dopamine cell transplants will be limited in value.
Based on current results in humans, as described
below, fetal cell transplants into putamen appear to
mimic all of the effects of levodopa. At the present
time, transplants can be viewed as equivalent to a
continuous infusion of levodopa. This outcome is quite
remarkable, given the fact that dopamine is being
made available only to putamen.
Ultrastructural studies have shown that fetal grafts
reinnervate denervated striatum with both host-to-graft
and graft-to-host synapses (Mahalik et al., 1985).
Dopaminergic nerve terminals synapse on dendritic
spines of medium spiny neurons. Transplanted cells
synthesize and release dopamine (Schmidt et al.,
1982). Grafted dopamine neurons exhibit electrical fir-
ing patterns and pharmacologic responses to dopamine
agonists similar to the intrinsic dopamine cells of the
substantia nigra pars compacta of adult animals
(Wuerthele et al., 1981).
Prior to transplanting human embryonic dopamine
neurons into patients, human cells were transplanted
into the rat model of PD. In ciclosporin-immunosup-
pressed rats, human fetal dopamine neurons were
shown to survive and produce behavioral effects
equivalent to rat dopamine cells, albeit with a time
course delayed to 820 weeks compared to the 46
weeks seen with the faster-developing rat neurites
(Brundin et al., 1986; Stromberg et al., 1986).
Xenograft transplants of human to rat predicted the
future difficulty of xenograft transplants in humans.
Although allografts of human embryonic dopamine
neurons are not rejected following transplant, even
with no immunosuppression (Freed et al., 2001), xeno-
graft transplants of human into rat require continuous
treatment with ciclosporin.
In the search for alternatives to mesencephalic
dopamine neurons, cells from the adrenal medulla
were harvested and transplanted into the rat model of
PD (Freed et al., 1981; Freed, 1983; Stromberg et al.,
1985). Ordinarily, these cells produce norepinephrine
and epinephrine, not dopamine. Separated from
adrenal cortex, adrenal medullary tissue generates a
substantial amount of dopamine. Although these cells
usually secrete neurotransmitters directly into the cir-
culation and do not resemble neurons, isolated adrenal
medulla cells adopt a neuronal morphology, particu-
larly when exposed to a source of nerve growth factor
 TRANSPLANTATION
(NGF) (Freed, 1983; Stromberg et al., 1985). Survival
of cells in striatum was much better with a source of
NGF or equivalent neurotrophic factor. Behavioral
effects were not as robust as seen with mesencephalic
dopamine neurons (Freed, 1983).
Humans and monkeys were shown to be at risk for
chemically induced PD after catastrophic incidents in
drug addicts. Initially, a young man who tried to pro-
duce synthetic narcotics inadvertently injected himself
with a mixture that was subsequently shown to include
the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahy-
dropyridine (MPTP) (Davis et al., 1979). Shortly
thereafter, he developed bradykinetic signs that were
initially diagnosed as catatonic schizophrenia but later
rediagnosed as parkinsonism. Because he was a single
case and the phenomenon could not be reproduced in
rats, the report gained little attention. Had the investi-
gators picked any other mammal, such as mouse, cat,
dog or monkey, they would have seen a parkinsonian
syndrome. Instead, this critical observation had to be
rediscovered after a group of drug addicts obtained
MPTP from a single dealer (Langston et al., 1983).
From these unfortunate events came a non-human
primate model of PD (Burns et al., 1983). Monkeys
lesioned by MPTP showed signs of bradykinesia,
rigidity and tremor with dopamine depletion in the
caudate and putamen. Levodopa improved these signs.
Although the systemically lesioned monkey closely
resembled idiopathic PD, the condition was highly
variable. Some animals recovered to normal, making
it difficult to distinguish a therapeutic intervention
from spontaneous improvement. Others, unable to feed
themselves or maintain an upright posture, died of the
complications of immobility. A more predictable
lesioning method was developed by Bankiewicz et al.
(1986). By unilaterally infusing MPTP into the inter-
nal carotid artery, dopamine neurons on one side of
the brain could be destroyed, leading to contralateral
signs of parkinsonism. As with the 6-OHDA-lesioned
rat, these animals could care for themselves.
Transplanting fetal dopamine neurons into dener-
vated striatum reduced the parkinsonian signs in both
systemically and unilaterally lesioned monkeys, if the
embryonic dopamine cells were obtained from early
in embryogenesis at a developmental stage equivalent
to days 1316 in the embryonic rat (Bakay et al.,
1985; Freed et al., 1988; Annett et al., 1994, 1997).
By contrast, if mesencephalic tissue from later fetal
stages was transplanted, cells failed to survive and ani-
mals did not improve (Redmond et al., 1986; Freed
et al., 1988). Monkey experiments were valuable for
showing that the principles established in rats also
applied to primates. Because embryonic monkey tissue
of the appropriate early gestational stage is even more
281
difficult to obtain than human fetal tissue, the number
of monkey transplants reported in the literature has
been relatively small.
The question of targeting transplants to putamen,
caudate or both is based on electrophysiological and
transplant studies in monkeys. Alexander and DeLong
(1985) used microstimulation of the caudate and puta-
men to show that the putamen had motor responses
specific to parts of the body with a homonculus that
resembled that of motor and sensorimotor cortex.
Leg and trunk movements were dorsolateral, arm
movements intermediate and orofacial movements
ventromedial. By contrast, microstimulation of
caudate produced no limb movements. Hikosaka and
colleagues (1989a) performed a series of experiments
in monkeys showing that caudate controls saccadic
eye movements. They also showed that caudate has a
role in more complex behavioral responses to reward,
perhaps reflecting its connections with prefrontal
cortex (Hikosaka et al., 1989b). The same group has
found that monkeys with dopamine depletion of cau-
date show impaired eye movements, similar to
PD patients, but no abnormalities of limb movement
(Kori et al., 1995). Only one study in monkeys has
directly compared transplants into caudate versus
putamen. In the marmoset, dopamine neurons placed
in caudate reversed amphetamine-induced circling,
whereas transplants introduced into putamen improved
motor function of the contralateral limb (Annett et al.,
1995). Taken together, these experiments in monkeys
indicate that dopamine replacement in the putamen
will directly improve movement of the limbs,
whereas dopamine cell transplants into the caudate
may have effects on eye movements and complex
motor behaviors.
44.3. Clinical experience with adrenal
medulla transplantation
In 1987, an article by Madrazo et al. described a remark-
able improvement in 2 patients after transplantation of
adrenal medulla fragments recovered from the patients
own adrenals and placed into the head of the caudate on
one side of the brain. Although the clinical improvement
was confounded by also initiating levodopa treatment,
the fact that the report appeared in the New England
Journal of Medicine brought a great deal of attention.
Immediately, many groups began performing trans-
plants of adrenal medulla, with more than 200 patients
receiving surgery over the next 2 years. Although these
open clinical trials reported some improvement for up to
6 months, there were no sustained effects of transplant.
The morbidity of the surgery was significant. During
recovery from the abdominal surgery on the adrenal
282 C. R. FREED ET AL.
gland, patients were often unable to take their oral
antiparkinsonian medications. Typically, patients spent
10 days in the intensive care unit and up to 30 days in
hospital. One-year mortality was 10% and 2-year mor-
tality was 20%. In a registry of 61 patients, only 19%
were judged improved 2 years after transplant (Goetz
et al., 1991). Autopsy revealed few surviving adrenal
chromaffin cells (Hurtig et al., 1989). Since no source
of NGF had been provided, significant cell survival
was improbable.
Adrenal medulla transplants using cografts of
peripheral nerve as a source of trophic factors have
been conducted with reportedly better cell survival
and longer duration of clinical effects (Date et al.,
1996; Watts et al., 1997). Nonetheless, enthusiasm
based on flawed case reports turned to disappointment.
Grafting of cells from the adrenal medulla was
abandoned because of the lack of efficacy and the
significant morbidity associated with the surgical
procedure itself.
44.4. Clinical experience with human fetal
dopamine cell transplantation
Since transplantation of human fetal tissue was first
undertaken in the late 1980s, several groups have
reported results using a variety of methods (Freed
et al., 1990, 1992, 1995, 2001; Langston et al., 1992;
Spencer et al., 1992; Widner et al., 1992; Peschanski
et al., 1994; Freeman et al., 1995a; Kordower et al.,
1995; Kopyov et al., 1996; Lindvall et al., 2001;
Olanow et al., 2003). Comparisons among studies have
been difficult because technical strategies and clinical
evaluations have differed so widely. Tissue has been
placed in putamen as well as caudate and unilaterally
as well as bilaterally. It has been transplanted as solid
tissue fragments as well as suspensions. Because trans-
plants of allografts in outbred rats and in monkeys are
not rejected even without immunosuppression, the need
for immunosuppressants was uncertain. Therefore,
some groups used immunosuppression, some did not
and others compromised with short-term antirejection
regimens. Patients with parkinsonism provide addi-
tional variability. Age is an important variable, as is
the specific disease in the individual patient. To define
patients as having idiopathic PD, most investigators
have chosen patients who were responsive to levodopa.
Some investigators have used fluorodopa positron
emission tomography (FDOPA PET) to image the char-
acteristic pattern of dopamine depletion in putamen
with relative sparing in the caudate nucleus. No single
clinical rating scale has been used, though there was
an effort to define an evaluation strategy using a combi-
nation of the UPDRS scale and timed tests called Core
Assessment Program for Intracerebral Transplantations
(Langston et al., 1992).
Kordower and colleagues (1995), who did bilateral
transplants of fragments of embryonic mesencephalon
into postcommissural putamen, were the first to
demonstrate surviving dopamine cells postmortem.
The patient was immunosuppressed with ciclosporin
for 6 months and died 18 months after transplant.
Large numbers of surviving dopamine neurons were
seen in the transplant tracks.
The biggest problems with most clinical efforts
were that patient numbers were small and trials uncon-
trolled. Therefore, statistically valid group compari-
sons could not be made. Results were anecdotal
assertions rather than statistically valid evaluations.
Only the two clinical trials sponsored by the National
Institutes of Health have had experimental designs
with enough patients, consistent methodology and
control groups to make it possible to draw conclusions.
Our double-blind, placebo-controlled trial trans-
planted dopamine neurons from ventral mesencephalon
recovered from four embryos 78 weeks postconception
and transplanted into four sites in the putamen, bilater-
ally under stereotaxic control. Tissue had been kept as
strands in culture for up to 4 weeks prior to transplant.
A 34-cm-long column of cells was placed in a dorsal
and a ventral site in putamen on each side of the brain
via twist drill holes in the forehead under local anesthe-
sia. Sham surgery patients received the identical proce-
dure except there was no needle penetration of the brain
and no tissue was deposited. All patients gave informed
consent to receive either tissue transplants or sham sur-
gery. All recovery of embryonic tissue from elective
abortions was done only after women had consented to
the abortion and after they had given a second consent
to donate fetal tissue per federal law and Institutional
Review Board (IRB) requirements. There were no surgi-
cal complications that led to breaking the blind. There
were no infections.
We found that, 12 months after surgery, transplant
subjects showed improvements in UPDRS motor
off scores for the group as a whole and for the
subgroup under age 60 compared to the sham surgery
controls (Fig. 44.1) (Freed et al., 2001). As shown in
Figure 44.2, transplants were detectable in 85% of
patients by blind scoring of FDOPA PET scans and
grew equally well in younger and older patients
(Nakamura et al., 2001). Patients under the age of 60
were most likely to benefit and changes in the UPDRS
correlated with changes in PET signal. The signs that
improved were bradykinesia and rigidity. Although
tremor showed a trend for improvement, statistical
significance was not reached. For each patient, the
best on state was carefully determined after the first
 TRANSPLANTATION 283

All subjects Age 60 Age > 60

50 50 50
= Sham
45 = Real 45 45
Motor UPDRS "OFF"

40 40 40

35 35 35

30 30 30

25 25 25
p = 0.015 p = 0.0003 p = 0.989
20 20 20
b12 p04 p08 p12 b12 p04 p08 p12 b12 p04 p08 p12
Visit
Fig. 44.1. Changes in Unified Parkinsons Disease Rating Scale motor off scores in the first 12 months after transplant dur-
ing the double-blind phase. Results show significant improvement for the transplant group as a whole and for the younger
transplant patients, compared to the sham surgery group.

Fetal mesencephalic cell implant

FDOPA PET

Preop. Postop.

Sham surgery

Normal

Preop. Postop.
Fig. 44.2. For full color figure, see plate section. Fluorodopa positron emission tomography (FDOPA PET) scans before and after
transplantation. The left-hand panel shows the FDOPA PET signal of a normal person scanned in a horizontal plane that includes
caudate and putamen. Stored F-dopamine is shown in false color red. The two right upper panels show PET scans in a patient
before and 12 months after implantation with embryonic dopamine neurons. The preoperative panel demonstrates the profound
depletion of putamenal signal. Caudate signal is relatively higher. Twelve months after transplant, the FDOPA PET signal in puta-
men has increased toward the normal range. The two right lower panels show PET signals in a sham-surgery patient before and
12 months after transplant. As shown, there is no improvement in putamenal dopamine. The caudate dopamine is further depleted.
Reproduced from Freed et al. (2001), by permission of the New England Journal of Medicine. Copyright # 2001 Massachusetts
Medical Society. All rights reserved.

morning dose of levodopa. After transplant, there was
no change in the best on state. The sham surgery
group had no changes in UPDRS or Schwab and
England scores after surgery (Freed et al., 2001).
In patients with the best clinical responses, trans-
plants could equal but not exceed the best effect of
levodopa seen preoperatively. Therefore, transplants
generate a purely dopaminergic effect. Just as with deep
brain stimulation, parkinsonian signs not improved by
levodopa cannot be altered with transplants. Because
transplants were placed only into putamen, we can say
with some confidence that the motor effects of levo-
dopa are mediated through actions on the putamen.
The primary outcome variable in our study, a global
rating scale, proved to be an unreliable measure of
patient outcome. While still blinded at 12 months post-
transplant, patients were asked to pick terms that
described their current state compared to 1 year before.
284 C. R. FREED ET AL.
Those descriptors were then assigned whole-number
values and averaged as though they were continuous
variables. Scores were recorded. Patients were then
shown videos of themselves 1 year before and all
groups changed their ratings to more positive values.
Our study demonstrated that a global rating scale can-
not provide reliable assessments of long-term outcome
in PD patients.
Because some subjects are now more than 10 years
posttransplant, long-term analysis is possible. As noted
above, the most important predictor of response to
transplant was the magnitude of the preoperative
response to levodopa. Patients who had less than 50%
improvement after the first morning dose of levodopa
were unlikely to respond to transplant. In our group of
subjects, levodopa had a much broader range of effects
in those over age 60 compared to younger. Some older
patients had only the minimal 30% improvement in
UPDRS scores required to enter the study whereas
others had up to 90% improvement. All subjects under
age 60 had greater than 50% improvement after levo-
dopa. Transplant results showed that only patients with
greater than 50% levodopa response had improvement
after surgery. When corrected for levodopa responsive-
ness, the older and younger patients had similar trans-
plant outcomes. By 2 or 3 years after transplantation,
UPDRS motor off scores showed an average improve-
ment of 50% of the best response to levodopa seen
before transplant, regardless of age.
At the current stage of development, the average
response to transplant is equivalent to about half of
the levodopa effect. These long-term changes are
similar to what we first described in 1992 (Freed
et al., 1992) and they are similar to what other groups
have subsequently reported. One could argue that a
transplant which produces at least 50% of the best levo-
dopa effect is an appropriate target response. This effect
is large enough to prevent severe off symptoms while
still not leading to dyskinetic movements (Freed et al.,
2001). With the transplant producing 50% of the
needed dopamine, the optimum clinical response in
the individual patient can be achieved by administra-
tion of levodopa and other dopamine agonists.
Individual variability of transplants has been a pro-
blem. Using tissue obtained from elective abortion,
transplant outcome has varied from no effect to com-
plete replacement of the need for levodopa. If stem
cell research leads to a source of authentic midbrain
dopamine neurons with more predictable growth and
survival characteristics, then outcome might become
more uniform. If cell transplantation could reliably
replace 5080% of the levodopa requirement in the
individual patient, then transplantation could become
an important component of the management of PD.
Dyskinesias have appeared in some transplant
recipients who had levodopa-induced dyskinesias prior
to transplant (Freed et al., 1990, 1992, 2001; Hagell
et al., 2002; Olanow et al., 2003). In nearly all patients
who respond to transplants, there is an initial period of
increased dyskinesias which resolve as drug doses are
reduced. In some patients, dyskinetic responses per-
sisted even after substantial reduction or even elimina-
tion of levodopa and other dopamine agonist therapy.
In our double-blind study, all patients who developed
persistent off dyskinesias were from the younger
transplant group and all had had levodopa-induced
dyskinesias prior to transplantation. It appears that
the transplantation of tissue from four embryos pro-
vided enough dopamine to trigger dyskinesias. In the
first year after transplant, these patients had had
remarkable resolution of their parkinsonian signs.
FDOPA PET scans showed some asymmetry of dopa-
mine fiber outgrowth in these patients, with greater
signal in left ventral putamen than was seen in other
patients who did not develop dyskinesias (Ma et al.,
2002). Patients did not show supranormal concentra-
tions of dopamine. Although asymmetric transplant
growth may be an explanation for dyskinesias, it is
also possible that the dyskinetic response has its origin
in other brain structures such as the subthalamic
nucleus, the pallidum or the pars reticulata of the sub-
stantia nigra. An imbalance between the restored dopa-
mine innervation of putamen and the persistent
denervation of other brain regions may be responsible
for the dyskinetic responses. We reported a tendency
toward dyskinetic movements in our first transplant
recipient in 1990 (Freed et al., 1990), as well as in
6 of 7 patients described in 1992 (Freed et al., 1992).
In most of these patients, dyskinesias were controlled
by reductions in drug doses.
Neurophysiologic and cognitive effects of transplant
were evaluated during the double-blind phase. Results
showed significant improvement in reaction plus
movement times (Gordon et al., 2004). This benefit
was seen in both younger and older subjects. Cognitive
performance showed no change in any measure 1 year
after transplant (Trott et al., 2003).
In the second double-blind clinical trial, the goal of
the study was to compare placebo surgery with two
doses of tissue, a low dose of cells from two embryos
and a high dose of tissue from up to eight embryos
transplanted into putamen, bilaterally (Olanow et al.,
2003). The primary outcome variable was the UPDRS
motor off score, which had shown significant
changes in our earlier study. Surprisingly, at the 2-year
endpoint, there were no differences in the transplant
groups compared to the placebo surgery controls.
FDOPA PET scans showed greater reinnervation of
 TRANSPLANTATION
the putamen with the higher tissue dose at 1 year after
transplant but similar reinnervation at 2 years after
transplant. This result is compatible with animal
studies which indicate that transplant growth occurs
in response to signals generated by denervated stria-
tum (Dunnett et al., 1988). Presumably, the transplants
from the low-dose group continued to have axon
arborization between year 1 and year 2 in order to sup-
ply portions of putamen inadequately innervated in the
first year. By this mechanism, the FDOPA PET scans
of the low-dose group caught up with the high-dose
group by the second year.
The authors could not account for the failure of the
transplants to have effects on UPDRS scores. Because
immunosuppression was instituted for only 6 months,
they speculated that transplants might have been
rejected after drugs were stopped. This conjecture is
unlikely, since this same group has shown transplant
survival at 18 months after transplant (Kordower
et al., 1995) and FDOPA PET scan signals did not fall
as they would if transplant rejection had occurred.
They did find that patients with more severe baseline
signs (higher UPDRS off scores) failed to improve
after transplant (Olanow et al., 2003).
Olanow et al. did note dyskinesias present in the
off state in a large proportion of their transplant sub-
jects and in none of the sham-surgery patients.
Although the dyskinesias were of minor significance
in most, some patients required the placement of deep
brain stimulating electrodes in the subthalamic nucleus
to control excess movements.
44.4.1. Unilateral versus bilateral transplantation
Unilateral transplantation of fetal tissue was used in
the first clinical PD transplant trials (Lindvall et al.,
1989, 1990; Freed et al., 1990). Typically, implants
were made into the side of the brain contralateral to
the side of the body with the worse parkinsonian
symptoms. In an attempt to provide more symmetric
innervation and with the goal of improving axial func-
tions such as walking, we and others began transplant-
ing fetal tissue bilaterally in the early 1990s (Freed
et al., 1992).
44.4.2. Solid versus suspension graft
Fetal mesencephalic tissue can be transplanted either
as a suspension of dissociated mesencephalon or as a
solid graft. In some studies, human fetal tissue trans-
planted into immunosuppressed 6-OHDA-lesioned
rats showed comparable survival of both solid and
suspension grafts (Freeman et al., 1995b). However,
our studies showed that rat mesencephalon transplanted
285
in the form of a strand (made by extruding mesencepha-
lic tissue through a tapered glass cannula with a 0.2-mm
bore) into 6-OHDA-lesioned rats produced greater
behavioral improvement and better dopamine neuron
survival than transplants of dissociated mesencephalon
(Clarkson et al., 1998b).
44.4.3. Age as a predictor of transplant outcome
Although PD is primarily a disease of elderly people,
some researchers have been hesitant to perform trans-
plantation in older patients. In our 1999 review, we
noted that the average age at the time of transplanta-
tion was 54 years, with average disease duration of
about 13 years (Clarkson and Freed, 1999). Because
in PD, the average age of onset is 55 years and the
average patient with PD is estimated to be 67, clinical
trials have been biased toward younger patients.
Our double-blind study specifically addressed the
issue of age with half of recruited patients 60 or over
and half younger than 60. As noted above, it was not
age per se but the preoperative response to levodopa
that correlated with transplant outcome. In the aging
brain, the symptoms of PD are likely to be one mani-
festation of a more global neuropathologic process.
44.4.4. Number of donors
The number of surviving dopaminergic neurons needed
to improve motor function significantly in a patient
with PD is unknown. The normal adult human
substantia nigra contains approximately 500 000
dopamine-producing neurons (Pakkenberg et al.,
1991). Unfortunately, about 95% of dopamine neurons
die after transplantation of rat or human tissue. In
human patients, no more than 20 00025 000 dopamine
cells survive from each embryo transplanted (Kordower
et al., 1995; Freed et al., 2001). Some investigators
have argued that such a high rate of cell death requires
that tissue from six or more donors be transplanted into
each putamen to restore a complete complement of
dopamine-producing neurons. Studies examining the
ideal volume of grafted tissue in patients with PD are
limited (Kopyov et al., 1997; Olanow et al., 2003) and
the issue is still widely debated. Because PD symptoms
only develop after a 50% loss of nigral neurons and a
6080% reduction in striatal dopamine (Bernheimer
et al., 1973; Kish et al., 1988), complete replacement
of dopamine-producing neurons may not be required
to improve motor skills and to reduce the need for
levodopa.
We have counted the dopamine neurons that have
survived in transplant tracks in postmortem brain. In
patients with bilateral putamenal implants who had
286 C. R. FREED ET AL.
clinical improvement sufficient to discontinue all levo-
dopa, the total number of surviving dopamine neurons
was 30 00040 000 (Freed et al., 2005). The two
individuals had received tissue from two and four
embryos, respectively. Figure 44.3 shows transplanted
dopamine neurons in a subject who received cells from
two embryos via the frontal surgery approach. He
discontinued all levodopa 15 months after transplant.
He was never immunosuppressed. He died 10 years
after surgery. These data provide experimental rather
than hypothetical evidence for the amount of embryo-
nic tissue and the number of surviving cells needed to
have maximum clinical effect.
44.5. Alternative tissue sources
In addition to the scientific controversies about techni-
ques for transplantation of human fetal tissue, ethical
concerns remain about the use of fetal tissue. There
are logistical problems to recovering tissue after elec-
tive abortion. With the demonstration that a few fetal
pig neural cells can survive transplantation into a
patient with PD (Deacon et al., 1997), xenografts
have been proposed as an alternative to human cell
transplants, although the immunologic hurdles are
enormous and unresolved. We reported that cloned
transgenic cow embryos could survive transplantation
in immunosuppressed rat and improve circling beha-
vior (Zawada et al., 1998a). Immortalized dopaminer-
gic cell lines that do not generate tumors can reduce
behavioral deficits and may offer an additional alter-
native to human fetal tissue (Clarkson et al., 1998a).
Because xenograft rejection remains an unsolved pro-
blem, aggressive immunosuppression is required for
transplantation of all non-human tissue. Efforts to
blunt the immune response by methods such as using
fragments of a monoclonal antibody to major histo-
compatibility complex class I (Palzaban et al., 1995)
or class II antigens may reduce xenograft rejection.
Encapsulating dopamine-producing xenografts may
also prevent rejection, although such anatomically
isolated grafts have no capacity to reinnervate the
host brain (Emerich et al., 1992). Xenografts carry
the potential risk of animal virus transmission to
humans. With the concern about CreutzfeldtJakob
disease, special efforts to monitor and control this
risk are required.
Non-neuronal dopamine cells from retinal pigment
epithelium have been proposed and are under clinical
evaluation (Stover et al., 2005). This biotechnology
approach has expanded dopamine-producing retinal
pigment epithelial cells and made them adhere to micro-
spheres which have then been transplanted into PD
patient striatum. An open clinical trial has suggested
some clinical benefits from this approach and a double-
blind study is underway.

Dopamine neurons-10 yrs after transplant

Fig. 44.3. Surviving dopamine neurons in a putamenal transplant track of a patient who died 10 years after implant.
This patient received dopamine neurons from two embryos via four needle passes in the putamen using a frontal surgical
approach. He received no immunosuppression. The left-hand panel shows a low-power view of one of the transplant tracks
with large numbers of dopamine neurons in the field (35
). The right-hand panel shows a high-power view of the same trans-
plant with profiles of individual tyrosine hydroxylase-positive dopamine neurons evident (400
). Cell counts revealed nearly
40 000 surviving dopamine neurons from the two embryos. Cells and processes are immunostained with antibody to tyrosine
hydroxylase (Pel Freez) followed by a secondary antibody with peroxidase diaminobenzidine visualization.
 TRANSPLANTATION
The most promising source of an unlimited supply of
dopamine neurons is from differentiated human embryo-
nic stem cells. Since 2000, mouse and non-human pri-
mate embryonic stem cells have been successfully
converted to neurons with some dopaminergic charac-
teristics and transplanted into experimental animals
(Kawasaki et al., 2000; Lee et al., 2000; Kim et al.,
2002; Shim et al., 2004; Takagi et al., 2005). Although
strategies have differed in details, the basic concept has
been to differentiate embryonic stem cells from neuro-
progenitor cells, then expand that cell population and
finally guide differentiation to dopamine neurons using
known differentiation factors such as sonic hedgehog
and fibroblast growth factor 8 (FGF8). The same prin-
ciples have been applied to human embryonic stem
cells with similar results, although with a slower time-
line because of the longer cell cycle of human cells
(Buytaert-Hoefen et al., 2004; Perrier et al., 2004; Yan
et al., 2005).
For reasons that remain uncertain, transplant survi-
val of dopamine neurons derived from embryonic stem
cells has been even worse than from fetal mesencepha-
lon. Some success has been achieved by transplanting
small numbers of mouse embryonic stem cells into
immunosuppressed rat models of PD, though teratomas
inevitably form in a proportion of the animals (Bjork-
lund et al., 2002). Selecting only neural progenitors at
an earlier stage of differentiation may eliminate the ter-
atoma risk (Chung et al., 2006).
Interest has also focused on the delivery of neuro-
trophic factors to help reduce the number of dopamine
neurons that die after transplantation. Cotransplantation
of fibroblasts infected to produce basic fibroblast
growth factor with mesencephalic grafts increased the
number of dopamine neurons in these transplants
(Takayama et al., 1995). Other survival factors, includ-
ing insulin-like growth factor I and glial cell line-
derived neurotrophic factor and caspase inhibitors, can
protect transplanted cells from apoptotic cell death
(Clarkson et al., 1995; Zawada et al., 1996, 1998b;
Schierle et al., 1999). Inhibitors of lipid peroxidation
have been tested in humans and may promote improved
dopamine cell survival (Brundin et al., 2000).
44.6. Summary
Since 1988, neurotransplantation with embryonic
mesencephalic dopamine neurons has been tried as a
treatment for patients with advanced PD. Although
transplant methods have differed substantially among
centers, most reports have found some value to
implants made into putamen.
Open clinical trials of small numbers of patients have
shown benefit from transplantation in most patients
reported. Reduction of levodopa dose is frequently
287
reported. Several principles have emerged. Mesencepha-
lic tissue must be from early in embryonic development,
typically 78 weeks after conception. Bilateral transplan-
tation into putamen can be done safely during a single
operation. Unilateral transplantation leads to asymmetric
transplant effects. Immunosuppression is not required.
Two double-blind studies have shown that trans-
plants can survive and improve FDOPA PET scans in
most subjects. One has shown that UPDRS motor
scores (bradykinesia and rigidity) can significantly
improve in transplant patients compared to placebo
controls (Freed et al., 2001). Well-controlled double-
blind studies must be used to compare the outcome of
the transplant strategies yet to be tested.
Although the clinical benefit in individual patients
has made drug elimination possible, there is substantial
variability in outcome. Contributing to this variability
are differences in pathologic processes in individual
patients and in dopamine neuron survival and out-
growth. The best predictor of transplant outcome is
the preoperative response to levodopa (Freed et al.,
2004). Transplantation can duplicate but cannot exceed
the best preoperative response to levodopa. Some
patients with a prior history of levodopa-induced dys-
kinesias may have persistent dyskinesias even after
the reduction or elimination of levodopa. These dyski-
nesias respond to inhibitors of dopamine synthesis such
as metyrosine or to deep brain stimulation of pallidum
or subthalamic nucleus.
44.7. Future prospects for neural
transplantation
Where shall human transplant research go from here? To
evaluate fully the effectiveness of dopamine cell trans-
plants for PD, a uniform source of dopamine neurons
must be developed. Differentiation of embryonic stem
cells from dopamine neurons may produce an unlimited
number of dopamine neurons for transplant. Unlike most
somatic tissue transplants, allografts of human fetal
neural tissue are not rejected. Therefore, donor-specific
embryonic stem cells will probably not be required.
Although less likely, some of the other cell sources
described in this chapter may prove useful. Because
of immunologic barriers, successful xenografts are
improbable.
Results of the double-blind studies indicate that
transplants only into the putamen can produce benefi-
cial motor effects. On the other hand, clinical benefits
have been incomplete in most patients. Many PD
patients have cognitive deterioration either early or late
in their disease. In an effort to improve the outcome of
neurotransplantation, we are obliged to consider new
targets for transplantation. Because the region of dopa-
mine cell loss, the substantia nigra pars compacta, has
288 C. R. FREED ET AL.
important regional connections with the pars reticulata,
the subthalamic nucleus and the pallidum, dual tran-
plants into putamen and substantia nigra should be con-
sidered. Because the caudate nucleus has a role in
cognitive function and eye movements, comparison of
dual transplants into caudate and putamen could be com-
pared to putamen alone. Since dyskinesias in both
experimental animals and in humans are most often seen
after priming with levodopa, a clinical trial of transplan-
tation early in PD may show that transplantation pre-
vents the development of levodopa-induced dyskinesias.
Although restoring uniform anatomic integrity of the
nigrostriatal dopamine system is a daunting challenge,
transplantation has already demonstrated successful
repair of the human PD brain. Nonetheless, transplant
effects are limited to the replacement of dopamine.
There is no treatment for the progressive, non-dopami-
nergic signs of PD. The ideal treatment for PD would
stop the loss of dopamine neurons and other affected
cell types at the earliest stage of the disease.
References
Alexander GE, DeLong MR (1985). Microstimulation of the
primate neostriatum. II. Somatotopic organization of stria-
tal microexcitable zones and their relation to neuronal
response properties. J Neurophysiol 53: 14171430.
Annett LE, Martel FL, Rogers DC et al. (1994). Behavioral
assessment of the effects of embryonic nigral grafts in
marmosets with unilateral 6-OHDA lesions of the nigros-
triatal pathway. Exp Neurol 125: 228246.
Annett LE, Torres EM, Ridley RM et al. (1995). A comparison
of the behavioural effects of embryonic nigral grafts in the
caudate nucleus and in the putamen of marmosets with uni-
lateral 6-OHDA lesions. Exp Brain Res 103: 355371.
Annett LE, Torres EM, Clarke DJ et al. (1997). Survival of
nigral grafts within the striatum of marmosets with 6-
OHDA lesions depends critically on donor embryo age.
Cell Transplant 6: 557569.
Bakay RAE, Fiandaca MS, Barrow DL et al. (1985). Preli-
minary report of the use of fetal tissue transplantation to
correct MPTP-induced Parkinson-like symptoms in
primates. Appl Neurophysiol 48: 358361.
Bankiewicz KS, Oldfield EH, Chiueh CC et al. (1986). Hemi-
parkinsonism in monkeys after unilateral internal carotid
artery infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydro-
pyridine (MPTP). Life Sci 39: 716.
Bernheimer H, Birkmayer W, Hornykiewicz O et al. (1973).
Brain dopamine and the syndromes of Parkinson and
Huntingtons: clinical, morphological and neurochemical
correlations. J Neurol Sci 20: 415455.
Bjorklund A, Steveni U (1979). Reconstruction of the
nigrostriatal dopamine pathway by intracerebral nigral
transplants. Brain Res 177: 555560.
Bjorklund A, Dunnett S, Brundin P et al. (2003). Neural
transplantation for the treatment of Parkinsons disease.
Lancet Neurol 2: 437445.
Bjorklund LM, Sanchez-Pernaute R, Chung S et al. (2002).
Embryonic stem cells develop into functional dopaminer-
gic neurons after transplantation in a Parkinson rat model.
Proc Natl Acad Sci USA 99: 23442349.
Brundin P, Nilsson OG, Strecker RE et al. (1986). Behavioral
effects of human fetal dopamine neurons grafted in a rat
model of Parkinsons disease. Exp Brain Res 65: 235240.
Brundin P, Pogarell O, Hagell P et al. (2000). Bilateral cau-
date and putamen grafts of embryonic mesencephalic tis-
sue treated with lazaroids in Parkinsons disease. Brain
123: 13801390.
Burns RS, Chiueh CC, Markey SP et al. (1983). A primate
model of parkinsonism: selective destruction of dopami-
nergic neurons in the pars compacta of the substantia nigra
by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc
Natl Acad Sci USA 80: 45464550.
Buytaert-Hoefen KA, Alvarez E, Freed CR (2004). Genera-
tion of tyrosine hydroxylase positive neurons from human
embryonic stem cells after coculture with cellular sub-
strates and exposure to GDNF. Stem Cells 22: 669674.
Chung S, Shin BS, Hedlund E et al. (2006). Genetic selection
of sox1GFP-expressing neural precursors removes residual
tumorigenic pluripotent stem cells and attenuates tumor
formation after transplantation. J Neurochem 97:
14671480.
Clarkson ED, Freed CR (1999). Minireview: development of
fetal neural transplantation as a treatment for Parkinsons
disease. Life Sci 65: 24272437.
Clarkson ED, Zawada WM, Freed CR (1995). GDNF
reduces apoptosis in dopaminergic neurons in vitro. Neu-
roreport 7: 145149.
Clarkson ED, La Rosa FC, Edwards-Prasad J et al. (1998a).
Improvement of neurological deficits in 6-hydroxydopamine-
lesioned rats after transplantation with allogeneic simian virus
40 large tumor antigen gene-induced immortalized dopamine
cells. Proc Natl Acad Sci USA 95: 12561270.
Clarkson ED, Zawada WM, Adams FS et al. (1998b). Strands
of embryonic mesencephalic tissue show greater dopamine
neuron survival and better behavioral improvement than
cell suspensions after transplantation in parkinsonian rats.
Brain Res 806: 6068.
Date I, Imaoka T, Miyoshi Y et al. (1996). Chromaffin cell
survival and host dopaminergic fiber recovery in a patient
with Parkinsons disease treated by cografts of adrenal
medulla and pretransected peripheral nerve. Case report.
J Neurosurg 84: 685689.
Davis GC, Williams AC, Markey SP et al. (1979). Chronic
Parkinsonism secondary to intravenous injection of meper-
idine analogues. Psychiatry Res 1: 249254.
Deacon T, Schumacher J, Dinsmore J et al. (1997). Histological
evidence of fetal pig neural cell survival after transplantation
into a patient with Parkinsons disease. Nat Med 3: 350353.
Dunnett SB, Hernandez TO, Summerfield A et al. (1988).
Graft-derived recovery from 6-OHDA lesions: specificity
of ventral mesencephalic graft tissues. Exp Brain Res 71:
411424.
Emerich DF, Winn SR, Christenson L et al. (1992). A novel
approach to neural transplantation in Parkinsons disease:
 TRANSPLANTATION
use of polymer-encapsulated cell therapy. Neurosci
Biobehav Rev 16: 437447.
Freed CR, Richards JB, Sabol KE et al. (1988). Fetal substan-
tia nigra transplants lead to dopamine cell replacement and
behavioral improvement in Bonnet monkeys with MPTP
induced Parkinsonism. In: PM Beart, G Woodruff, DM
Jackson (Eds.), Pharmacology and Functional Regulation
of Dopaminergic Neurons. Macmillan Press, London, pp.
353360.
Freed CR, Breeze RE, Rosenberg NL et al. (1990). Trans-
plantation of human fetal dopamine cells for Parkinsons
disease. Results at 1 year. Arch Neurol 47: 505512.
Freed CR, Breeze RE, Rosenberg NL et al. (1992). Survival
of implanted fetal dopamine cells and neurologic improve-
ment 12 to 46 months after transplantation for Parkinsons
disease. N Engl J Med 327: 15491555.
Freed CR, Breeze RE, Schneck SA et al. (1995). Fetal neural
transplantation for Parkinsons disease. In: RR Rich,
(Ed.), Clinical Immunology; Principles and Practice.
Mosby-Year Book, St. Louis, pp. 16771687.
Freed CR, Greene PE, Breeze RE et al. (2001). Transplanta-
tion of embryonic dnpamine neurons for severe Parkin-
sons disease. N Engl J Med 344: 710719.
Freed CR, Breeze RE, Fahn S et al. (2004). Preoperative
response to levodopa is the best predictor of transplant
outcome. Ann Neurol 55: 896.
Freed CR, Zawada M, DeMasters BK et al. (2005). Human
embryonic dopamine neurons transplanted into Parkinson
patients survive and improve motor function for at least
10 years without immunosuppression. Program No.
329.6. 2005 Abstract Viewer/Itinerary Planner. Society
for Neuroscience, Washington, DC [Online].
Freed WJ (1983). Functional brain tissue transplantation:
reversal of lesion-induced rotation by intraventricular
substantia nigra and adrenal medulla grafts, with a
note on intracranial retinal grafts. Biol Psychiatry 18:
12051267.
Freed WJ, Morihisa JM, Spoor E et al. (1981). Transplanted
adrenal chromaffin cells in rat brain reduce lesion-induced
rotational behaviour. Nature 292: 351352.
Freeman TB, Olanow CW, Hauser BA et al. (1995a). Bilat-
eral fetal nigral transplantation into the postcommissural
putamen in Parkinsons disease. Ann Neurol 38:
379388.
Freeman TB, Sanberg PR, Nauert CM et al. (1995b). The
influence of donor age on the survival of solid and suspen-
sion inrraparenchymal human embryonic nigral cells. Cell
Transplant 4: 141154.
Goetz CG, Stebbins GT 3rd, Klawans HL et al. (1991). United
Parkinson Foundation Neurotransplantation Registry on
adrenal medullary transplants: presurgical, and 1- and 2-year
follow-up. Neurology 41: 17191722.
Gordon PH, Yu Q, Qualls C et al. (2004). Reaction time and
movement time after embryonic cell implantation in Par-
kinson disease. Arch Neurol 61: 858861.
Hagell P, Piccini P, Bjorklund A et al. (2002). Dyskinesias
following neural transplantation in Parkinsons disease.
Nat Neurosci 5: 627628.
289
Hikosaka O, Sakamoto M, Usui S (1989a). Functional
properties of monkey caudate neurons. I. Activities
related to saccadic eye movements. J Neurophysiol 61:
780798.
Hikosaka O, Sakamoto M, Usui S (1989b). Functional prop-
erties of monkey caudate neurons. III. Activities related to
expectation of target and reward. J Neurophysiol 61:
814832.
Hudson JL, Bickford P, Johansson M et al. (1994). Target
and neurotransmitter specificity of fetal central nervous
system transplants: importance for functional reinnerva-
tion. J Neurosci 14: 283290.
Hurtig H, Joyce J, Sladek JR Jr et al. (1989). Postmortem ana-
lysis of adrenal-medulla-to-caudate autograft in a patient
with Parkinsons disease. Ann Neurol 25: 607614.
Kawasaki H, Mizuseki K, Nishikawa S et al. (2000). Induction
of midbrain dopaminergic neurons from ES cells by stromal
cell-derived inducing activity. Neuron 28: 3140.
Kim JH, Auerbach JM, Rodriguez-Gomez JA et al. (2002).
Dopamine neurons derived from embryonic stem cells
function in an animal model of Parkinsons disease.
Nature 418: 5056.
Kish SJ, Shannak K, Hornykiewicz O (1988). Uneven pat-
tern of dopamine loss in the striatum of patients with idio-
pathic Parkinsons disease. N Engl J Med 318: 876880.
Kopyov OV, Jacques O, Lieberman A et al. (1996). Clinical
study of fetal mesencephalic intracerebral transplants
for the treatment of Parkinsons disease. Cell Transplant
5: 327337.
Kopyov OV, Jacques DS, Lieberman A et al. (1997). Out-
come following intrastriatal fetal mesencephalic grafts
for Parkinsons patients is directly related to the volume
of grafted tissue. Exp Neurol 146: 536545.
Kordower JH, Freeman TB, Snow BJ et al. (1995). Neuro-
pathological evidence of graft survival and striatal reinner-
vation after the transplantation of fetal mesencephalic
tissue in a patient with Parkinsons disease. N Engl J
Med 332: 11181124.
Kori A, Miyashita N, Kato M et al. (1995). Eye movements
in monkeys with local dopamine depletion in the caudate
nucleus. II. Deficits in voluntary saccades. J Neurosci
15: 928941.
Lang A, Obeso O (2004). Challenges in Parkinsons disease:
restoration of the nigrostriatal dopamine system is not
enough. Lancet Neurology 3: 309316.
Langston JW, Ballard P, Tetrud JW et al. (1983). Chronic
Parkinsonism in humans due to a product of meperidine-
analog synthesis. Science 219: 979980.
Langston JW, Widner H, Goetz CG et al. (1992). Core
assessment program for intracerebral transplantations
(CAPIT). Mov Disord 7: 213.
Lee SH, Lumelsky N, Studer L et al. (2000). Efficient gen-
eration of mid-brain and hindbrain neurons from mouse
embryonic stem cells. Nat Biotechnol 18: 675679.
Lindvall O, Rehncrona S, Brundin P et al. (1989). Human
fetal dopamine neurons grafted into the striatum in two
patients with severe Parkinsons disease. Arch Neurol 46:
615631.
290 C. R. FREED ET AL.
Lindvall O, Brundin P, Widner H et al. (1990). Grafts of
fetal dopamine neurons survive and improve motor func-
tion in Parkinsons disease. Science 247: 574577.
Ma Y, Feigin A, Dhawan V et al. (2002). Dyskinesia after
fetal cell transplantation for parkinsonism: a PET study.
Ann Neurol 52: 628634.
Madrazo I, Drucker-Colin T, Daiz V et al. (1987). Open micro-
surgical autograft of adrenal medulla to the right caudate
nucleus in two patients with intractable Parkinsons disease.
N Eng J Med 316: 831833.
Mahalik TJ, Finger TE, Stromberg I et al. (1985). Subsranria
nigra transplants into denervated srriatum of the rat ultra-
strucrure of graft and host interconnections. J Comp Neu-
rol 240: 6070.
Nakamura T, Dhawan V, Chaly T et al. (2001). Blinded
positron emission tomography study of dopamine cell
implantation for Parkinsons disease. Ann Neurol 50:
181187.
Olanow CW, Goetz CG, Kordower JH et al. (2003). A double-
blind controlled trial of bilateral fetal nigral transplantation
in Parkinsons disease. Ann Neurol 54: 403414.
Pakkenberg B, Moller A, Cundersen HJ et al. (1991). The
absolute number of nerve cells in substantia nigra in normal
subjects and in patients with Parkinsons disease estimated
with unbi-based stereological method. J Neurol Neurosurg
Psychiatry 54: 3033.
Palzaban P, Deacon TW, Burns LH et al. (1995). A novel
mode of immunoprotection of neural xenotransplants:
masking of donor major histocompatibility complex class
I enhances transplant survival in the central nervous
system. Neuroscience 65: 983996.
Perlow MJ, Freed WJ, Hoffer BJ et al. (1979). Brain grafts
reduce motor abnormalities produced by destruction of
nigrosttiatal dopamine system. Science 204: 555560.
Perrier AL, Tabar V, Barberi T et al. (2004). Derivation of
midbrain dopamine neurons from human embryonic stem
cells. Proc Natl Acad Sci USA 101: 1254312548.
Peschanski M, Defer C, NGuyen JP et al. (1994). Bilateral
motor improvement and lateralization of L-dopa effect in
two patients with Parkinsons disease following intrastria-
tal transplantation of foetal ventral mesencephalon. Brain
117: 487499.
Redmond DE, Sladek JR Jr, Roth RH et al. (1986). Fetal
neuronal grafts in monkeys given methylphenyltetrahydro-
pyridine. Lancet 8490: 11251127.
Schierle GS, Hansson O, Leist M et al. (1999). Caspase inhi-
bition reduces apoptosis and increases survival of nigral
transplants. Nat Med 5: 97100.
Schmidt RH, Ingvar M, Lindvall O et al. (1982). Functional
activity of substantia nigra grafts reinnervating the stria-
tum: neurotransmitter metabolism and (14C)-2-deoxy-D-
glucose autoradiography. J Neurochem 38: 737748.
Shim JW, Koh HC, Chang MY et al. (2004). Enhanced
in vitro midbrain dopamine neuron differentiation, dopa-
minergic function, neurite outgrowth, and 1-methyl-4-phe-
nylpyridium resistance in mouse embryonic stem cells
overexpressing Bcl-XL. J Neurosci 24: 843852.
Spencer DD, Robbins RJ, Naftojin F et al. (1992). Unilateral
transplantation of human fetal mesencephalic tissue into
the caudate nucleus of patients with Parkinsons disease.
N Engl J Med 327: 15411548.
Stover NP, Bakay RA, Subramanian T et al. (2005). Intras-
triatal implantation of human retinal pigment epithelial
cells attached to microcarriers in advanced Parkinson
disease. Arch Neurol 62: 18331837.
Stromberg I, Herrera-Marschitz M, Ungerstedt U et al.
(1985). Chronic implants of chromaffin tissue into the
dopamine-denervated striatum. Effects of NGF on graft
survival, fiber growth and rotational behavior. Exp Brain
Res 60: 335349.
Stromberg I, Bygdeman M, Goldstein M et al. (1986). Human
fetal substantia nigra grafted to the dopamine-denervated
striatum of immunosuppressed rats: evidence for func-
tional reinnervation. Neurosci Lett 71: 271276.
Takagi Y, Takahashi J, Saiki H et al. (2005). Dopaminergic neu-
rons generated from monkey embryonic stem cells function in
a Parkinson primate model. J Clin Invest 115: 102109.
Takayama H, Ray J, Raymon HK et al. (1995). Basic fibro-
blasts growth factor increases dopaminergic graft survival
and function in a rat model of Parkinsons disease. Nat
Med 1: 5358.
Trott CT, Fahn S, Greene P et al. (2003). Cognition follow-
ing bilateral implants of embryonic dopamine neurons in
PD: a double blind study. Neurology 60: 19381943.
Ungerstedt U, Arbuthoott CW (1970). Quantitative recording
of rotational behavior in rats after 6-hydroxy-dopamine
lesions of the nigrostriatal dopamine system. Brain Res
24: 485493.
Watts RL, Subramanian T, Freeman A et al. (1997). Effect
of stereotaxic intrastriatal cografts of autologous adrenal
medulla and peripheral nerve in Parkinsons disease:
two-year follow-up study. Exp Neurol 147: 510517.
Widner H, Tetrud J, Rehncrona S et al. (1992). Bilateral fetal
mesencephalic grafting in two patients with Parkinsonism
induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP). N Engl J Med 327: 15561563.
Wuerthele SM, Freed WJ, Olson L et al. (1981). Effect of
dopamine agonists and antagonists on the electrical activ-
ity of substantia nigra neurons transplanted into the lateral
ventricle of the rat. Exp Brain Res 44: 110.
Yan Y, Yang D, Zarnowska ED et al. (2005). Directed dif-
ferentiation of dopaminergic neuronal subtypes from
human embryonic stem cells. Stem Cells 23: 781790.
Zawada WM, Kirschman DL, Cohen JJ et al. (1996). Growth
factors rescue embryonic dopamine neurons from
programmed cell death. Exp Neurol 140: 6067.
Zawada WM, Cibelli JB, Choi PK et al. (1998a). Somatic
cell cloned transgenic bovine neurons for transplantation
in parkinsonian rats. Nat Med 4: 569574.
Zawada WM, Zastrow DJ, Clarkson ED et al. (1998b).
Growth factors improve immediate survival of embryonic
dopamine neurons after transplantation into rats. Brain
Res 786: 96103.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 45

Gene therapy approaches for the treatment

of Parkinsons disease

BIPLOB DASS AND JEFFREY H. KORDOWER*

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

Parkinsons disease (PD) is the second most common
neurodegenerative disease, with over 1 million Ameri-
cans suffering from this disorder. The cardinal symptoms
of PD are rigidity of the cogwheel type, resting tremor,
bradykinesia and postural instability (Marsden, (1990)).
These symptoms result from striatal dopamine insuffi-
ciency secondary to degeneration of dopaminergic
neurons in the substantia nigra (SN) pars compacta
(Ehringer and Hornykiewicz, 1960). Although it has been
over 50 years since its discovery, levodopa remains the
gold-standard treatment by which all other therapies
are compared. Despite being an outstanding therapy,
levodopa ultimately loses its usefulness, not because it
can no longer provide benefit, but because benefit is
accompanied by debilitating side-effects that limit its uti-
lity (Marsden and Parkes, 1977; Curtis et al., 1984).
Therefore novel therapeutic strategies are needed for
the long-term treatment of PD patients. Towards this
end, a myriad of pharmacological therapies have com-
prised the armament of treatment strategies for PD. These
have been reviewed elsewhere in this volume. Further-
more, a variety of surgical treatments have been tested
clinically, such as adrenal cell transplants, adrenal cell/per-
ipheral nerve cografts, human fetal nigral transplantation
and porcine fetal transplantation (Madrazo et al., 1987;
Lindvall et al., 1989; Quinn, (1990); Kordower et al.,
1995; Date et al., 1996; Deacon et al., 1997; Wenning
et al., 1997; Schumacher et al., 2000; Freed et al., 2001).
Out of all the surgical interventions tested to date, only
deep brain stimulation has emerged as a genuinely useful
treatment strategy (Figueiras-Mendez et al., 1999).
Recently, preclinical studies delivering therapeutic
genes have shown such promise that three strategies have
already begun clinical trials (Neurologix: adeno-associated
virus-glutamic acid decarboxylase (AAV-GAD), Avigen:
AAV-aromatic acid decarboxylase (AADC) and Cere-
gene: adeno-associated virus-neurturin (AAV-NTN)).
There are a number of reasons to suspect that delivery
of therapeutic genes would be superior to the delivery of
pharmacological agents. The first reason is site specificity.
When delivering therapeutic drugs peripherally, you are
often dose-limited because the drug usually acts in a non-
specific manner and activates unintended systems. For
example, administration of levodopa in high enough doses
can lead to hallucinations due to increasing dopaminergic
neurotransmission in the mesolimbic system. The meso-
limbic system emanates from the ventral tegmental area,
a region adjacent to the SN. Axons from the ventral teg-
mental area do not terminate in the striatum but rather in
the nucleus accumbens and medial prefrontal cortex.
When this occurs, the dose of levodopa needs to be low-
ered, thereby minimizing the therapeutic efficacy of this
powerful compound. In contrast, novel therapeutic strate-
gies such as gene therapy can drive the dose of the thera-
peutic molecule by placing the vectors in site-specific
loci and, with care, this delivery method should not affect
unintended brain regions.
For prodopaminergic gene therapy approaches (see
below), it is thought that the postcommissural putamen
is the most critical site. This choice has been based
upon a number of factors. First, the loss of dopamine
in PD is greatest in the postcommissural putamen. Sec-
ond, this region of the striatum is intimately connected
with motor cortex. In contrast, the caudate nucleus and
anterior putamen are similar embryologically, have
dense interconnections with association cortices and
are linked to higher-order functions such as cognition
rather than motor function. Based upon this logic and

*Corresponding author: Jeffrey H. Kordower, Department of Neurological Sciences, Cohn Building, Rush University Medical
Center Chicago, IL 60612, USA. E-mail: jkordowe@rush.edu, Tel: 312-563-3570, Fax: 312-563-3571.
292 B. DASS AND J. H. KORDOWER
due to the limited availability of donor material, double-
blinded clinical trials testing human and porcine fetal
transplantation strategies have grafted cells exclusively
to the postcommissural putamen that were based upon
successful open-label studies (Lindvall et al., 1989;
Kordower et al., 1995; Deacon et al., 1997; Wenning
et al., 1997; Schumacher et al., 2000; Freed et al.,
2001). Similarly, Amgen sponsored a double-blind trial
in which catheters were placed in the postcommissural
putamen to deliver the trophic factor glial-derived
neurotrophic factor that were also based upon success-
ful open-label studies (GDNF, Gill et al., 2003; Slevin
et al., 2005). It is notable that all of these double-blind
trials have failed to meet their primary endpoints. There
are a number of explanations for the failure of these
trials, for instance, cells not surviving in the porcine
transplantation study, immune issues may have influ-
enced the human embryonic transplantation experi-
ments and dose and catheter design issues may have
influenced the outcome of the GDNF trial. However, it
remains troubling that this dogmatic view that the
postcommissural putamen is the essential region for
dopaminergic reinnervation has yet to be sustained in
any double-blinded clinical trial in PD.
45.1. Drug development strategy
Because PD is a long-term degenerative disorder and
the gene delivery itself will require neurosurgery, a
single surgical procedure that results in long-term or
permanent therapy will be required to make this thera-
peutic option practical. This means that the gene trans-
fer should lead to very long-term or permanent gene
expression. The issue of which vector would be ideal
for use in the treatment was initially a problem, since
each virus has strengths and drawbacks. Adenovirus
and herpes simplex virus (HSV) administrations were
initially shown to induce strong immunogenic res-
ponses and be short-acting and were therefore non-
starters for clinical application in PD. AAV has a low
level of transgene expression and lentivirus has a fairly
small capacity and the stigma of being associated with
human immunodeficiency virus (HIV). However there
has been remarkable improvement in the safety and ex-
pression of many of these vectors. The use of gutless
adenovirus has minimized its immunogenicity. The
creation and characterization of novel AAV serotypes
have resulted in robust long-term gene expression in rats
and monkeys. For a while, empirical evidence favored
lentivirus as the vector of choice as studies progressed
towards clinical trials. However, AAV now appears
equal to lentivirus with regard to many of the character-
istics deemed important for gene delivery, such as long-
term expression, infectivity of neurons and the absence
of immunogenicity and inflammation. In fact, the one
clear empirical difference between AAV and lentivirus
is that the former is retrogradely transported whereas
the latter is not. The functional relevance of this differ-
ence, if any, is unclear. Given their safety profile and
scientific advantages, only AAVs have currently been
approved for clinical trials in PD.
45.2. Gene therapy for Parkinsons disease:
delivery of therapeutic enzymes
The first strategy proposed as a gene therapeutic treat-
ment for PD was striatal levodopa delivery by ex vivo
expression of tyrosine hydroxylase (TH) (Wolff et al.,
1989). The initial basis for the ex vivo delivery of
TH was the known efficacy of peripheral levodopa
treatment combined with the neurosurgical safety
demonstrated by fetal ventral mesencephalic dopamine
grafting in rodents and humans (Brundin et al., 1986;
Lindvall et al., 1989). These studies failed due to the
inability of ex vivo gene therapy approaches at that
time to provide high-titer long-term gene expression,
as well as having issues with inflammation. Indeed,
shutdown of the transgene and only transient and
low-level functional recovery was seen using this
approach. Although the rationale for proceeding with
enzyme gene delivery was logical, the tools at that
time to elicit long-term high-titer gene expression
were unavailable. To expand upon this initial study,
a serotype 2 AAV encoding TH was utilized in 6-
hydroxydopamine (6-OHDA)-lesioned rats. The use
of stably lesioned animals facilitated the investigation
of the reversal of deficits induced by neurotoxin treat-
ment. TH immunoreactivity was detectable in the
striata up to 4 months after vector administration and
resulted in a persistent reduction of apomorphine-
induced rotational behavior for the duration of the
experiment (Kaplitt et al., 1994). Following this, vec-
tors encoding for combinations of genes involved in
the synthesis of levodopa were injected into the dener-
vated striata of rats using separate AAVs. Thus, double
or triple transfections of TH, AADC and guanosine tri-
phosphate-cyclohydrolase-1 (GCH-1) were shown to
be effective at producing levodopa in the 6-OHDA-
lesioned striatum, as measured by microdialysis
(Mandel et al., 1998; Shen et al., 2000; Kirik et al.,
2002). The success of this approach was also deter-
mined by the PD model that was employed. In fully
lesioned animals, gene delivery of TH and GCH-1
did not alter apomorphine-induced rotational behavior,
but rotational deficits were attenuated in rats with a
partial lesion of the nigrostriatal pathway (Kirik
et al., 2002). When three genes were delivered (TH,
GTPCH1 and AADC), behavioral recovery, as mea-
sured by apomorphine-induced rotational behavior,
could be observed in rats with complete nigrostriatal
 GENE THERAPY APPROACHES FOR THE TREATMENT OF PARKINSONS DISEASE
lesions. The increase in striatal dopamine content was
modest in these animals, although the effects of the
gene delivery could be demonstrated for 12 months
(Kirik et al., 2002). Using a lentivirus gene delivery
system based on equine infectious anemia virus,
Azzouz and coworkers (2002) performed similar
experiments. A non-human lentivirus was employed
as a safety measure as it is less likely to recombine
and form HIV if used clinically. It is critical to note,
however, that there is currently no empirical evidence
that lentivirus could recombine to form a pathogenic
HIV particle and there is also no proof that non-human
forms of HIV would pose a lesser risk. Rotational
behavior induced by apomorphine administration was
partially reversed by treatment with the tricistronic
(TH, GTPCH1 and AADC) vector, although turning
behavior was still greater than 5 per minute in these
rats. Striatal dopamine content was also partially ele-
vated by the gene delivery, but levels were still less
than 10% of the intact hemisphere.
Since the symptoms of PD only arise after a thresh-
old of approximately 70% striatal dopamine depletion
occurs, a small increase in dopamine levels could result
in significant improvements in motor function. Thus,
these strategies were investigated in primates with stable
lesions. When administered to 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP)-treated primates,
AAV-mediated gene delivery of TH and AADC was
successful up to 10 weeks (During et al. (1998)). No
inflammation or other adverse effects were noted after
AAV administration. However, no behavioral recovery
was observed in these monkeys and postmortem
Table 45.1
Characteristics and uses of viral vectors in animal models of Parkinsons disease
Neuronal Maximum Strength of
Vector preference insert expression
Adenovirus 7.5 kb
Adeno 4 kb (type 2)
associated (type 2) (type 5)
virus (type 5)
Herpes simplex 30150 kb
virus
Lentivirus 9 kb
TH, tyrosine hydroxylase; GDNF, glial-derived neurotrophic factor; XIAP, X chromosome-linked inhibitor of apoptosis; JBD, JNK binding
domain; SOD, superoxide dismutase; AADC, aromatic acid decarboxylase; GTP, guanosine triphosphate; NTN, neurturin; SHH, sonic hedge-
hog; GAD, glutamic acid decarboxylase.
293
dopamine concentrations were only modestly raised in
the lesioned striata. In contrast, triple transfection in the
putamen of TH, AADC and GCH-1 did result in beha-
vioral recovery of 4060% in 4 MPTP-treated primates
(Muramatsu et al., 2002). Dopamine synthesis in the
striatum was also increased approximately fivefold,
although this increase was still very low. Long-term
studies examining bi- and tricistronic delivery of thera-
peutic enzymes are still needed prior to the initiation of
clinical trials.
As an alternative to expressing the enzymes
required for the production of levodopa and dopamine,
the Bankiewicz group has used viral vectors (see
Table 45.1) to express solely AADC in the striatum
to enhance the production of dopamine following the
administration of levodopa. This approach is hoped
to reduce levodopa requirements and provide a more
stable level of conversion to dopamine in the striatum
and therefore help avoid the incidences of levodopa-
induced dyskinesias. In their initial experiments, they
injected AAV-AADC into the striata of MPTP-
lesioned monkeys and were able to observe increased
AADC activity in vivo, coupled with increased dopa-
mine metabolite production (Bankiewicz et al.,
2000). Convection-enhanced delivery was used as the
infusion method and resulted in a high density of
AADC immunoreactive cells throughout the striatum.
Most transfected cells had a NeuN-positive, medium
spiny neuron-type morphology and there were very
few glial fibrillary acid protein and AADC co-positive
cells. In a subsequent experiment in 6-OHDA-lesioned
rats, the gene transfer of AADC also resulted in
Duration of Immunogenic Current uses in
expression response models of PD
Weeks TH, GDNF, XIAP, JBD,
Calpastatin, Cu/Zn
SOD,
>2 years TH, AADC, GTP-
cyclohydrolase,
BDNF, GDNF, NTN,
SHH, GAD
Weeks TH, Bcl-2, GDNF
>1 year GDNF, TH, AADC,
GTPcyclohydrolase
294 B. DASS AND J. H. KORDOWER
enhanced conversion of levodopa to dopamine, but the
dopamine was not stored within the neurons and
seemed to be released continuously (Sanchez-Pernaute
et al., 2001). Theoretically, uncontrolled and increased
dopamine release in the striatum might exacerbate
levodopa-induced dyskinesias. However, a reduction
in the required dose of levodopa might lead to fewer
treatment-related side-effects. Interestingly, when
AAV-AADC was delivered without using convection-
enhanced delivery at three focal points in the striatum of
MPTP-lesioned monkeys, dyskinesias were observed,
suggesting that the creation of a hotspot of dopamine
activity is key to the generation of levodopa-related
side-effects (Bankiewicz et al., 2006). This corroborates
previous work with cell grafts, suggesting that focal
hotspots rather than widespread grafts can cause
dyskinesias (Steece-Collier et al., 2003). In further
studies with MPTP-lesioned monkeys infused with
AAV-AADC throughout the striatum using convec-
tion-enhanced delivery, no dyskinesia was observed
over a 5-year time period, although behavior in response
to levodopa treatment was improved in these animals
(personal communications from Dr. Bankiewicz).
As a result of the preclinical work performed in the
Bankiewicz laboratory using MPTP-lesioned monkeys
and 6-OHDA-lesioned rats, a clinical trial was
initiated by Avigen in December of 2004 using an
AAV to deliver the DNA for AADC into the human
putamen. At the time of writing, the trial is still under
way and no peer review data are available for ass-
essment. However, a press release suggested that
AAV-AADC was well tolerated and resulted in the
production of AADC (Avigen press release, 18 July
2005).
Currently, a phase I clinical trial utilizing an AAV
expressing GAD in PD patients is under way in New
York (During et al., 2001). The rationale behind this
study is that the overactivity of the excitatory subthala-
mic nucleus (STN) in PD patients might be reduced by
the transfer of the GAD gene into this nucleus and so
provide relief from thalamic inhibition. Previously,
this group had shown that AAV-GAD transfection into
the STN of fully 6-OHDA-lesioned rats could induce a
phenotypic change in these nuclei, causing them to
release gamma-aminobutyric acid (GABA) in addition
to glutamate (Luo et al., 2002). Injection of an AAV-
GAD65 vector 3 weeks before a nigrostriatal lesion
resulted in a 35% protection of nigral TH-positive
cells and decreased rotational behavior and behavioral
asymmetries. As with other studies utilizing AAVs, no
inflammation was found 45 months after administra-
tion and no antibodies against the viral capsid were
detected in the sera of these animals (Luo et al., 2002).
Thus, the basis for further studies utilizing AAV-GAD
has been set and currently patients enrolled in the phase
I trial that have received unilateral AAV-GAD into the
STN are reported to have improved 27% on the Unified
Parkinsons Disease Rating Scale and have significant
decreases in fluorodeoxyglucose utilization on the side
contralateral to the injection (Neurologix press release,
25 September 2005).
45.3. Delivery of trophic molecules
Although the striatal delivery of genes encoding for
dopaminergic enzymes or STN delivery of inhibitory
enzymes might provide substantial therapeutic benefit,
none of these approaches has a compelling basis for
altering the underlying disease. An alternative ap-
proach, which theoretically could alter the natural his-
tory of PD, is the delivery of genes encoding for
neuron-saving trophic factors. In addition to providing
neuroprotection, gene delivery of trophic factors has
the added advantage of enhancing the function of cells
and inducing cells to produce greater amounts of rele-
vant neurotransmitters (i.e. dopamine). A wealth of data
has been amassed on the efficacy of many dopaminergic
trophic molecules, such as epidermal growth factor,
basic fibroblast growth factor, brain-derived neuro-
trophic factor (BDNF), sonic hedgehog and GDNF to
prevent degeneration following bolus administrations
in models of nigrostriatal degeneration (Gash et al.,
1996; Pearce et al., 1996, 1999; Svendsen et al., 1996;
Dass et al., 2002; for review, see Collier and Sortwell,
1999). In particular, GDNF is a particularly promising
candidate for clinical use, based on a series of studies
in animal models of PD. Initial open-label and double-
blind studies examining the safety and efficacy of
monthly intraventricular injections GDNF failed. No
efficacy was seen and serious side-effects were
observed (Kordower et al., 1999; Nutt et al., 2003).
However this result was to be expected, since vulner-
able neurons are not exposed to GDNF via this delivery
method. Indeed, even chronic intraventricular infusions
of GDNF demonstrated trivial immunoreactivity to
GDNF protein beyond the ventricular ependyma. These
initial studies demonstrated that, even if GDNF is the
correct protein, it would be unsuccessful if delivered
in an ineffective manner. In an attempt to improve
delivery parameters, two open-label trials delivered
GDNF chronically into the postcommissural putamen
of PD patients (Gill et al., 2003; Amgen press releases,
June 2004, February 2005; Slevin et al., 2005). Both stu-
dies reported sustained functional benefit. One trial
(Gill et al., 2003) also reported increases in fluoro-
dopa uptake on positron emission tomography (PET)
scan, an effect that increased from 6 months to 1 year.
Disappointingly, the 1 patient who has currently come
 GENE THERAPY APPROACHES FOR THE TREATMENT OF PARKINSONS DISEASE
to autopsy showed only marginal changes in TH, an
effect that was dwarfed by other procedures such as
fetal transplants that have yet to be proved efficacious.
As a follow-up to these open-label studies, Amgen
sponsored a multicenter double-blind trial examining
the safety and efficacy of bilateral intraputamenal
GDNF in patients with PD. This trial failed to dem-
onstrate efficacy. At first glance, one has to consider
strongly that placebo effects and experimenter bias,
phenomena that are inherent to all open-label trials
and particularly those in PD (de la Fuente-Fernandez
et al., 2001), resulted in the positive clinical effects seen
in the Bristol and Kentucky studies and when they were
controlled for by the enhanced rigor associated with a
double-blind trial, these reported effects could not be
substantiated. However, equally strongly, it needs to
be noted that there were substantial and potentially
critical differences in technique between the open-label
trials and the double-blind trial. These differences
included dosage (higher dosages ultimately used in the
open-label trials), catheter design (a thicker catheter
(Bristol) and multiport catheter (Kentucky) in the
open-label studies) and rate of trophic factor delivery
(convection-enhanced delivery in the open-label trials
and non-convection enhanced delivery in the double-
blind trial). Therefore it is very possible that delivery
methods in the double-blind procedure were inferior to
those in the open-label trial and this critical aspect of
the study prevented the induction of functional benefit.
In addition to the absence of clinical benefit, the Amgen
trial was stopped prematurely due to the presence of
side-effects. Neutralizing antibodies against GDNF
were observed in approximately 10% of patients and
some monkeys treated with high-dose GDNF displayed
profound cerebellar degeneration. The origin of the
antibody response is unclear and has been seen in all
infusion trials. It could be due to leakage of protein into
the abdomen during refilling of the pump. It also could
be due to the use of glycosylated, rather than native,
GDNF. It is unclear what side-effects antibodies
to GDNF might cause in adult humans and, to date, no
side-effects have been reported in patients who received
GDNF. With regard to the cerebellar damage, it is pos-
sible that, due to the thin catheter and non-convection
delivery method, the GDNF backed up the catheter
and GDNF flowed over the brain convexities to the cer-
ebellum. Two aspects of this phenomenon are notable.
It never happens when GDNF or GDNF family mem-
bers are delivered via viral vectors to monkeys directly
to the striatum. Second, no patients who have received
intraputamenal GDNF have been reported to have signs
of cerebellar degeneration. The only thing at this point
that is perfectly clear is that nothing is perfectly clear.
The safety and delivery issues surrounding intraputame-
295
nal infusions of GDNF need to be addressed and once
further information is gathered, a new double-blind trial
using more optimal dosing and delivery parameters
should be initiated.
45.4. Gene delivery of glial-derived
neurotrophic factor in rodents before lesioning
A superior approach to trophic factor infusion may be
gene therapy. Gene therapy does not have the hardware
issues associated with the implantation of catheters and
pumps, nor does it have the issue of numerous pump
refills over long periods of time. In this regard, numer-
ous studies have created a body of evidence indicating
that gene delivery of GDNF and GDNF-like molecules
may be a powerful therapeutic tool to provide neuropro-
tection and neuroaugmentation for degenerating SN
neurons. Martha Bohn and colleagues deserve credit
for performing the first experiments examining gene
delivery of GDNF in animal models of PD. Initial
studies used an adenovirus to deliver GDNF before
6-OHDA lesioning in rats and so examined the neuro-
protective potential of this therapeutic strategy
(Bilang-Bleuel et al., 1997; Choi-Lundberg et al.,
1997; Lapchak et al., 1997). In Choi-Lundbergs study,
supranigral administration of Ad-GDNF (AD, adeno-
virus) 7 days before the initiation of a striatal 6-OHDA
lesion in rats resulted in a 75% protection of nigral fluor-
ogold-positive dopaminergic neurons, but the size of the
striatal lesion was unchanged in these animals, com-
pared to controls. Horellous group injected Ad-GDNF
into the rat striatum 6 days before the initiation of a stria-
tal 6-OHDA partial lesion (Bilang-Bleuel et al., 1997).
The number of TH-IR (IR, immunoreactivity) cells in
the SN was significantly greater than in control animals,
although again complete protection of the SN was not
achieved. In the striatum, TH immunoreactivity was
increased following striatal Ad-GDNF administration
and amphetamine-induced rotational asymmetry was
attenuated. Thus, the site of administration of GDNF is
critical to the protection of the nigrostriatal pathway fol-
lowing a neurotoxic insult. Using GDNF protein, simi-
lar results have been obtained when comparing the
protective effects of intrastriatal, intranigral and intra-
ventricular administration (Kirik et al., 2000a). Accord-
ingly, GDNF was only able to protect the anatomy and
function of the nigrostriatal pathway following an
intrastriatal injection of Ad-GDNF and, if a viral vector
encoding a trophic molecule was considered for use
in PD patients, it is more likely to be efficacious to
administer the vector into the caudate and putamen.
Choi-Lundberg and colleagues (1998) repeated the
administration of Ad-GDNF, but injected the vector
intrastriatally before creating a partial 6-OHDA lesion.
296 B. DASS AND J. H. KORDOWER
No improvement in the density of TH-IR fibers in the
striatum was observed, but behavioral asymmetry was
reduced and nigral TH-IR cell numbers were pro-
tected. This result might be mediated by the retrograde
transport of GDNF itself or Ad-GDNF into the SN and
the subsequent trophic support that GDNF could pro-
vide to the functionality of the cell body. GDNF was
detectable at nanogram levels in the striatum and pico-
gram levels in the nigra. Since GDNF can undergo ret-
rograde transportation along the nigrostriatal tract, it
was unclear if this finding was as a result of the
actions on GDNF or a function of the adenovirus
(Tomac et al., 1995; Lapchak et al., 1997; Mufson
et al., 1999). Following this study, the same group pre-
treated aged rats with Ad-GDNF before initiating a
striatal 6-OHDA lesion (Connor et al., 1999). GDNF
increased TH-IR optical density in the striatum, indi-
cating the potent phenotypic upregulation GDNF can
provide in addition to its neuroprotective properties.
It is likely that the actions of GDNF transfected by
an adenovirus not only protects cells from 6-OHDA-
mediated cell death but also from the toxicity induced
by the virus itself, highlighting the reason to use less
immunogenic vectors such as AAV or lentivirus in
the brain. As an example of this, in the studies by
Choi-Lundberg et al. (1997) and Bilang-Bleuel et al.
(1997), both groups reported adverse cellular reactions
to the administration of first-generation adenovirus,
regardless of the particular gene sequence transfected
by the vector. Choi-Lundberg et al. reported that 12 out
of 14 rats injected with adenovirus possessed a mild to
moderate reaction in the SN, whereas Bilang-Bleuel
and colleagues found that the size of the striatum was
reduced and that Ad-b-Gal (Gal, galactosidase) adminis-
tration alone reduced the number of TH-IR cells by 37%.
To circumvent the adenovirus-mediated immuno-
genic response, the use of AAVs has markedly
increased in the last few years. GDNF, when expressed
following transfection by an AAV, has been very suc-
cessful at preventing dopaminergic cell death in the
SN pars compacta and reducing behavioral deficits in
6-OHDA-lesioned rats (Mandel et al., 1997; Kirik
et al., 2000b; Wang et al., 2002). In the study by Man-
del et al., the authors injected AAV-GDNF 3 weeks
before initiating a partial 6-OHDA lesion, resulting
in protection of fluorogold-labeled neurons in the
SN. Kirik and colleagues (2000b) found that the
expression of GDNF was stable for over 6 months
when AAV-GDNF was injected into the SN, but no
protection of the striatal dopaminergic immunoreac-
tive terminals was observed and behavioral recovery
did not occur following striatal 6-OHDA treatment
(Kirik et al., 2000b). In contrast, when AAV-GDNF
was administered into the striatum of rats prior to a
6-OHDA lesion, the dopaminergic nigrostriatal path-
way was completely protected and this was accompa-
nied by a reduction in ()-amphetamine-induced
asymmetry (Kirik et al., 2000b). This landmark study
indicates that the site of GDNF delivery and the rein-
statement of striatal dopamine are critical if functional
effects are to be observed.
Another alternative vector to adenovirus that
induces little inflammation is lentivirus and this has
also been used in the rat 6-OHDA model of nigrostriatal
degeneration. Georgievska and coworkers (2002a)
demonstrated that GDNF administered 3 weeks before
a striatal injection of 6-OHDA can preserve nigral neu-
rons relative to rats receiving a control vector in a dose-
dependent manner. In this regard, animals treated with
a lower titer of vector preserved 65% of TH-IR neurons
whereas animals administered with a higher concentra-
tion of lenti-GDNF preserved 77% of TH-positive cells.
Interestingly, intense sprouting of fibers was observed
in the medial parts of the striatum, globus pallidus and
entopeduncular nucleus and this corresponded to the
presence of GDNF immunoreactivity, indicating that
GDNF was transported and had effects away from the
injection site. The same group repeated this experiment
with a single titer of lenti-GDNF administered into the
striatum (Georgievska et al., 2002b). As before, TH-
positive cell numbers in the nigra were preserved by
lenti-GDNF treatment and deficits in amphetamine-
induced rotational behavior were prevented. Tracing
the nigrostriatal pathway using fluorogold retrograde
labeling from the striatum or AAV-GFP (GFP, green
fluorescent protein) anterograde marking from the nigra
showed that lenti-GDNF administration also protected
the axonal projections of the SN pars compacta into
the striatum. However TH fiber immunoreactivity was
downregulated in the striatum: the authors speculated
that this was due to a downregulation of TH follow-
ing high levels of GDNF expression. Also, non-
drug-induced motor asymmetry was unchanged by
lenti-GDNF administration and this was attributed
to the aberrant sprouting of TH-positive fibers from
the striatum projecting to the globus pallidus, ento-
penduncular nucleus and the SN.
GDNF gene therapy has been successful at protect-
ing dopamine neurons in other models of PD, includ-
ing mice receiving MPTP. MPTP, after metabolism
to 1-methyl-4-phenylpyridinium ion (MPP), selec-
tively kills dopaminergic neurons by inhibiting com-
plex I in the electron transport chain and thereby
stopping cellular respiration. GDNF delivered into
the striatum using an adenovirus, 2 days prior to the
administration of MPTP in mice, elevated striatal
dopamine levels in comparison to lesioned control
mice, although the dopamine content was still severely
 GENE THERAPY APPROACHES FOR THE TREATMENT OF PARKINSONS DISEASE
reduced compared to naive animals (Kojima et al.,
1997). In another interesting study, Ad-GDNF was
concurrently administered into the striatum with an
adenovirus encoding the protein caspase inhibitor, X-
chromosome-linked inhibitor of apoptosis (XIAP)
(Eberhardt et al., 2000). Treatment of the mice with
Ad-GDNF alone, followed by a chronic lesioning
paradigm with MPTP injections over 5 days, resulted
in no protection of TH-IR neurons in the SN and no ele-
vation of striatal dopamine, or dopamine metabolites
levels. However, when Ad-XIAP and Ad-GDNF treat-
ments were administered in combination, a synergistic
elevation in both nigral TH-IR cell numbers and
protection of the catecholamine content of the striatum
from MPTP treatment occurred.
GDNF has also been transfected in combination
with the antiapoptotic molecule Bcl-2, using HSV vec-
tors (Natsume et al., 2001). When administered to 6-
OHDA-lesioned rats amphetamine-induced rotational
behavior was significantly reduced by the administra-
tion of either HSV-GDNF or HSV-Bcl-2 or an injec-
tion of both combined. Cell survival was enhanced
by either vector and there was an additive effect of
the two when co-administered. It is unclear however
if this effect would be replicated in parkinsonian
patients, since so little is known about the etiology of
the disease and this approach is primarily oriented
towards neuroprotection. Also, in a previous experi-
ment, the administration of either HSV-Bcl-2 or a
control virus resulted in a 40% reduction in fluorogold
and TH-positive cells, in the absence of 6-OHDA
lesioning, and so the use of HSV as a vector for gene
transfer in humans is unlikely (Yamada et al., 1999).
It is important to note that gene delivery of GDNF
is not effective in all models of PD. Lo Bianco et al.
(2004) administered lenti-GDNF to the supranigral
region of rats 2 weeks prior to an intranigral lentiviral
injection of the A30P mutant human a-synuclein.
Although excellent expression of GDNF was obser-
ved, gene delivery of this trophic factor was unable
to prevent the loss of nigrostriatal neurons.
Two other trophic molecules have been tested in
animal models of PD. BDNF has been delivered into
the SN pars compacta of rats using a recombinant
AAV, which also encoded green fluorescent protein
(Klein et al., 1999). Expression of the green fluores-
cent protein was observed at 9 months after the admin-
istration of the viral vector. Six months after gene
transfection, the animals were partially lesioned with
6-OHDA and rotational behavior in response to
amphetamine was reduced in the AAV-BDNF-treated
animals in comparison to controls. However, no pro-
tection from 6-OHDA-induced dopaminergic cell
death in the SNpc was found and so this neurotrophin
297
has not been considered further (Klein et al., 1999).
Sonic hedgehog has also been shown by two groups to
protect cells in vivo from 6-OHDA lesioning. Using an
adenoviral construct, Hurtado-Lorenzo and colleagues
(2004) protected dopaminergic cells at the nigral level
from 6-OHDA lesioning, but could not protect the stria-
tal axonal terminals. In an alternative study, the admin-
istration of sonic hedgehog delivered using an AAV 3
weeks before striatal 6-OHDA treatment reduced
amphetamine-induced rotational behavior and pro-
tected striatal dopamine levels and nigral TH-positive
cell counts (Dass et al., 2005b).
45.5. Neuroprotection in a primate model
of Parkinsons disease
Primate studies are essential prerequisites for deter-
mining whether novel therapies for PD are ready for
clinical trials. Primarily, primate studies employ
MPTP to induce a lesion and often repeated adminis-
trations are required to induce a stable lesion. Using
this method, the extent of the MPTP-induced lesion
cannot be predicted before degeneration, making neu-
roprotective effects difficult to interpret. Thus, some
investigators have used sterotaxic administrations of
6-OHDA in smaller primates, such as marmosets, to
guarantee destruction of the nigrostriatal pathway.
AAV-GDNF administered into the striatum and SN
of marmosets, before an injection of 6-OHDA into
the medial forebrain bundle (MFB), only provided a
modest protection of dopaminergic cells in the SN.
However, motor function assessed by a modified clin-
ical rating scale was reversed to pre-lesion levels 5
weeks after 6-OHDA (Eslamboli et al., 2003). Also
()-amphetamine induced rotational behavior and
head positional bias were attenuated at all time points
after lesioning, indicating that AAV-transfected GDNF
protected motor function in the primates.
45.6. Neurorestoration following
6-hydroxydopamine lesioning
Of equal importance to the protection of the nigrostria-
tal system from the unknown degenerative processes
of PD is the ability to restore dopaminergic transmis-
sion using trophic factors. Lapchak and colleagues
(1997) attempted to use Ad-GDNF to restore the dopa-
minergic function of the nigrostriatal pathway of rats
with an established 6-OHDA lesion. Their 6-OHDA
administration paradigm resulted in a 73% loss of
dopamine in the SN and a 99% reduction in the stria-
tum. In animals injected with Ad-GDNF into the SN,
the nigral dopamine content was elevated to 44% of
the levels on the intact side, whereas dopamine levels
298 B. DASS AND J. H. KORDOWER
in the striatum were increased to 4% of the contralat-
eral side. These neurochemical improvements in the
nigrostriatal system were reflected in a moderate
reduction in apomorphine-induced asymmetry and an
improvement in locomotor activity. In a recent similar
study, the administration of Ad-GDNF, 7 days after
the initiation of a striatal 6-OHDA lesion, protected
basal, potassium chloride and amphetamine-evoked
extracellular dopamine levels in the striatum measured
by mcirodialysis, such that the basal level of dopamine
was 65% of intact animal levels and the drug-induced
levels were 3540% (Smith et al., 2005).
Another group investigated the effect of administra-
tion of AAV-GDNF after the initiation of a striatal 6-
OHDA partial lesion in rats and examined effects of
gene therapy over a longer term. Delayed delivery of
AAV-GDNF prevented nigral cell death, when admi-
nistered 4 weeks following the initiation of a 6-OHDA
lesion. Behavioral recovery, assessed by apomorphine-
induced rotations and contralateral limb use, was also
improved following AAV-GDNF treatment and these
changes were maintained for 20 weeks (Wang et al.,
2002). Thus, the use of AAV offers a mechanism for
the expression of molecules in the striatum over a long
period of time, whilst inducing minimal side-effects,
such as inflammation, and so could be used to achieve
a long-term administration of trophic factors.
45.7. Neurorestoration following MPTP
treatment
Our group generated a GDNF-expressing lentivirus and
injected it into the striatum and nigra of young adult rhe-
sus monkeys 1 week after MPTP lesioning, or unlesioned
aged monkeys (Kordower et al., 2000). In all monkeys,
strong GDNF immunoreactivity was observed and
this was coupled with increased striatal fluorodopa
uptake, TH immunoreactivity, dopamine and HVA con-
tent. Interestingly, GDNF immunoreactivity was also
observed in the globus pallidus and SN pars reticulata,
indicating anterograde transport of the transgene.
MPTP-lesioned animals displayed clear motor dis-
ability, as measured by a clinical rating scale, but the
administration of lenti-GDNF resulted in a reduction
over the following 3 months. Dexterity, as measured
by a hand-reach task, was also improved in lenti-
GDNF-administered monkeys compared to the lenti-b-
Gal-treated animals. Lenti-GDNF-treated animals had
a 300% increase in fluorodopa uptake seen in PET
scans taken at 3 months postvector injection compared
to control monkeys, although this was limited to the
putamen only.
Striatal TH immunoreactivity was enhanced by
lenti-GDNF treatment in a manner that correlated with
the individual dexterity levels of MPTP-lesioned mon-
keys. Overall, TH immunoreactivity in the striatum
was significantly greater in lenti-GDNF-treated mon-
keys compared to control animals. In the SN, an
increase in TH-positive cell numbers and cell density
compared to the untreated hemisphere was observed
following lenti-GDNF administration, whereas lenti-
b-Gal-treated animals had large decreases in cell
counts and density on the MPTP-lesioned side. Immu-
nohistochemistry for CD45, CD3 and CD8 resulted in
negligible levels of positive cells, indicating that the
lentivirus caused no immunogenicity.
Two young unlesioned rhesus monkeys were also
administered with lenti-GDNF into the right caudate
and putamen and left SN pars compacta and examined
8 months later for gene expression. Enzyme-linked
immunosorbent assay analysis found 2.53.5ng/mg tis-
sue of GDNF in the caudate and putamen, whereas in
the SN there were many GDNF immunoreactive cells,
proving long-term transgene expression. In a subse-
quent study, the effect of lenti-GDNF was examined
stereologically in the striatum of aged monkeys and
unilaterally MPTP-lesioned monkeys (Palfi et al.,
2002). MPTP treatment alone increased the numbers
of intrinsic dopamine neurons in the striatum and
lenti-GDNF administration further increased the stria-
tal TH immunoreactive cell counts sevenfold. In aged
monkeys, there was also a large increase in TH and
dopamine transporter immunoreactivity in the striatum
and this correlated with GDNF expression, indicating
an autotrophic effect. The coupling of the two res-
ults suggests that lenti-GDNF is effective, regardless
of the level of downregulation of the dopaminergic
phenotype (Figs. 45.1 and 45.2).
45.8. Effect of glial-derived neurotrophic
factor in an intact system
Following 6-OHDA lesioning in rats, it was noticed by
Georgievska and colleagues (2002b) that in areas of
strong lentivirally mediated overexpression of GNDF
in the striatum, the expression of TH was reduced.
The authors then checked to see if this phenomenon
was replicated in naive rats and observed that treat-
ment with lenti-GDNF into either the striatum or nigra
resulted in 6070% decreases in TH expression and
TH mRNA levels. Levodopa production remained at
normal levels, indicating that GDNF increased the
activity of TH (Georgievska et al., 2004). However,
when GDNF is delivered using a viral vector in primates,
TH expression has only been observed to increase in
naive animals, indicating that the phenotypic downregu-
lation only occurs in rodents (Kordower et al., 2000;
Eslamboli et al., 2005).
 GENE THERAPY APPROACHES FOR THE TREATMENT OF PARKINSONS DISEASE 299

GDNF
Immunoreactivity

TH
Immunoreactivity

Fig 45.1. Bilateral lentiviral delivery of glial-derived neurotrophic factor (GDNF) into the caudate and putamen improves
(TH-IR) in aged rhesus monkeys.

45.9. Neurturin: An alternative to glial-derived
neurotrophic factor
Neurturin is a protein that was discovered by Milbrandt
and coworkers (Kotzbauer et al., 1996) and is the second
trophic factor identified in the GDNF family of ligands.
The amino acid sequence of neurturin has a high
sequence homology to GDNF. Although both GDNF
and neurturin signal through the RET receptor, they phy-
siologically bind to two separate receptors; GDNF uses
GFRa1 whereas neurturin prefers GFRa2. There are no
GFRa2 receptors in the striatum, suggesting that the
delivery of neurturin would not be effective. However,
at the levels achieved following gene delivery, neurturin
can bind to GFRa1 and, like GDNF, provide potent neu-
roprotection for degenerating nigrostriatal neurons.
In this regard, neurturin has recently been delivered
to four sites in the rat striatum via a lentivirus, 2 weeks
before a 6-OHDA lesion. Lenti-neurturin was shown to
protect over 90% of the nigral TH immunoreactive
cells. Unfortunately, striatal innervation was not
spared and amphetamine-induced rotational behavior
was not ameliorated (Fjord-Larsen et al., 2005). Our
lab, in collaboration with Ceregene Inc., has per-
formed a series of experiments in rats and monkeys
that indicate that neurturin can provide structural and
functional protection of nigrostriatal neurons (Dass
et al., 2004, 2005a; Bartus et al., 2005; Herzog et al.,
2005). These studies have led to the initiation of a
phase I clinical trial.
45.10. Conclusions
When considering a gene therapy strategy to treat any
human disease, there are two major unknowns that
must be conquered. These are: (1) the safety of the
gene transfer itself; and (2) the efficacy of the trans-
gene product. In addition, any new treatment, espe-
cially a highly experimental strategy such as gene
therapy, must be shown to be superior to the current
gold-standard therapy of levodopa.
The most important issue to be addressed, if gene
therapy is to be utilized clinically, is safety. Previously,
in 2002, a gene therapy trial involving patients with
severe combined immune deficiency using a retrovirus
was halted after 1 out of the 11 trial subjects developed
leukemia (Hacein-Bey-Abina et al., 2003). Analysis of
this patient revealed that the retrovirus had integrated
into the host genome at 40 different sites, including
one, LMO-2, which was related to oncogenesis and
300 B. DASS AND J. H. KORDOWER

GDNF
Immunoreactivity

TH
Immunoreactivity

Fig. 45.2. Unilateral lentiviral delivery of GDNF into the caudate and putamen increases (TH-IR) in 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP)-lesioned rhesus monkeys. No GDNF-IR or increases in TH-IR are observed in the untreated
hemisphere (left side).

this contributed to the abnormal growth of a T cell.
Insertational mutagenesis is therefore a concern with
the use of integrating viral vectors, especially those
such as serotype 5 AAV or lentivirus, which are capable
of infecting glial cells. Also, Nakai and colleagues
(2003) showed in mice that AAV serotype 2 integrates
its DNA more frequently into active genes rather than
quiescent ones.
More seriously, a patient suffering from ornithine
transcarbamylase (OTC) deficiency was infused into
the right hepatic artery with an adenovirus encoding
the human OTC gene, as part of a phase I trial (Raper
et al., 2003). Unfortunately, the patient suffered from a
severe immune reaction to the adenovirus and died 5
days after treatment. The reason for this may have
been that the patient was previously exposed to adeno-
virus and this may have contributed towards an
increased autoimmune response to the vector. Most
of the other patients in this trial, who all received
lower titers of adenovirus, also rapidly developed
fever, supporting the theory that previous exposure to
adenovirus followed by a second administration of
the virus could cause greater inflammation. Therefore
rigorous screening of patients must be conducted
before the commencement of gene therapy.
To gain the greatest efficacy when treating PD, the
best site for administration of a viral vector must be
ascertained. AAV, but not lentivirus, has shown a cap-
ability for retrograde transport. Anterograde transport
can also occur with trophic factors such as GDNF.
This could cause problems of unwanted expression of
transgenes in other areas of the brain if the site of
administration was the striatum. Currently this is just
a theoretical concept as no adverse reactions have been
demonstrated as a result of such transport. Thus,
although it would be favorable to have transport of a
trophic factor or dopamine-synthesizing enzyme into
the SN pars compacta, it is unclear whether transport
to the pallidum, thalamus or the neocortex would be
beneficial, harmful or inconsequential. Diffusion, fol-
lowing an injection of a vector into the nigral region,
equally could result in major problems with alterations
in the firing of ventral tegmental area neurons. Thus,
the preferential site of injection and the expression
level of transgenes away from the administration loca-
tion need to be fully investigated. One possibility to
 GENE THERAPY APPROACHES FOR THE TREATMENT OF PARKINSONS DISEASE
limit the expression of a transgene is to infect cells
with a viral vector and then transplant them into the
brain, but currently this strategy has had mixed results
in promoting behavioral recovery in 6-OHDA-lesioned
rats (Ostenfeld et al., 2002; Park et al., 2003).
The ideal candidate for gene therapy in PD is another
question that needs more study. Trophic factors, dopa-
mine-synthesizing enzymes and basal ganglia modula-
tion therapies have been outlined here. The transfection
of trophic factors promises the greatest benefit, in that
it could prevent the progressive degeneration of the
dopaminergic nigrostriatal system, whilst enhancing the
function of surviving neurons. The problems encoun-
tered following the administration of GDNF protein
should not discourage the site-specific gene delivery of
trophic molecules. Consideration must be made about
whether the gene therapy treatments in development
today for PD are truly being tested in conditions and
models that reflect the clinical scenario in which they
would actually be employed. The etiology of the disease
remains unknown and therefore the neuroprotective ele-
ments of trophic factor therapy may become ineffectual,
but the well-characterized restorative effects should still
provide benefit. Other strategies for the treatment of PD
may also provide benefit for patients, by reducing their
levodopa requirements and so ameliorate the develop-
ment of levodopa-induced side-effects. Site-specific
intrastriatal delivery of the enzymes involved in the pro-
duction of levodopa is expected to obviate side-effects
resulting from global decarboxylation of levodopa in
non-therapeutic brain compartments, as occurs with
Sinemet treatment. Thus, future research into gene ther-
apy is promising with regard to the development of pro-
spective treatments for PD.
References
Amgen Press Release 28th June 2004. Amgens Phase 2
Study of GDNF for Advanced Parkinsons Disease Fails
to Meet Primary Endpoint; Six Months of Treatment
Showed Biological Effect But No Clinical Improvement.
http://wwwext.amgen.com/media/media_pr_detail.jsp?
year2004&releaseID585632
Amgen Press Release 11th Feb 2005. Following Complete
Review of Phase 2 Trial Data Amgen Confirms Decision to
Halt GDNF Study; Comprehensive Review of Scientific Find-
ings, Patient Safety, Drove Decision. http://wwwext. amgen.
com/media/media_pr_detail.jsp?year2005&releaseID
673490
Avigen Press Release 18th July 2005. Avigen Announces
Encouraging Early Data from Parkinsons Disease Clinical
Trial. Evidence for First Successful Gene Transfer of
AADC Gene in Humans. http://www.avigen.com/non_
financial_release/2005/2005_Avigen_EarlyData_PDClini-
calTrial_071805.htm
301
Azzouz M, Martin-Rendon E, Barber RD et al. (2002).
Multicistronic lentiviral vector-mediated striatal gene
transfer of aromatic L-amino acid decarboxylase, tyrosine
hydroxylase, and GTP cyclohydrolase I induces sustained
transgene expression, dopamine production, and func-
tional improvement in a rat model of Parkinsons disease.
J Neurosci 22 (23): 1030210312.
Bankiewicz KS, Eberling JL, Kohutnicka M et al. (2000).
Convection-enhanced delivery of AAV vector in parkinso-
nian monkeys; in vivo detection of gene expression and
restoration of dopaminergic function using pro-drug
approach. Exp Neurol 164 (1): 214.
Bankiewicz KS, Daadi M, Pivirotto P et al. (2006). Focal stria-
tal dopamine may potentiate dyskinesias in parkinsonian
monkeys. Exp Neurol 197 (2): 363372. [Epub 2005 Dec 9].
Bartus RT, Herzog CD, Cunningham JJ et al. (2005). Biolo-
gical activity of CERE-120, an AAV2 vector encoding
human neurturin, in the rat 6-hydroxydopamine model of
nigrostriatal degeneration and in the young intact and aged
rat. J Neurosci #545.1.
Bilang-Bleuel A, Revah F, Colin P et al. (1997). Intrastriatal
injection of an adenoviral vector expressing glial-cell-line-
derived neurotrophic factor prevents dopaminergic neuron
degeneration and behavioral impairment in a rat model of
Parkinson disease. Proc Natl Acad Sci USA 94 (16):
88188823.
Brundin P, Nilsson OG, Strecker RE et al. (1986). Beha-
vioural effects of human fetal dopamine neurons grafted
in a rat model of Parkinsons disease. Exp Brain Res
65 (1): 235240.
Choi-Lundberg DL, Lin Q, Chang YN et al. (1997). Dopami-
nergic neurons protected from degeneration by GDNF
gene therapy. Science 275 (5301): 838841.
Choi-Lundberg DL, Lin Q, Schallert T et al. (1998). Beha-
vioral and cellular protection of rat dopaminergic neurons
by an adenoviral vector encoding glial cell line-derived
neurotrophic factor. Exp Neurol 154 (2): 261275.
Collier TJ, Sortwell CE (1999). Therapeutic potential of
nerve growth factors in Parkinsons disease. Drugs Aging
14 (4): 261287 Review.
Connor B, Kozlowski DA, Schallert T et al. (1999). Differ-
ential effects of glial cell line-derived neurotrophic factor
(GDNF) in the striatum and substantia nigra of the aged
Parkinsonian rat. Gene Ther 6 (12): 19361951.
Curtis L, Lees AJ, Stern GM et al. (1984). Effect of L-DOPA
on course of Parkinsons disease. Lancet 2 (8396):
211212.
Date I, Imaoka T, Miyoshi Y et al. (1996). Chromaffin cell
survival and host dopaminergic fiber recovery in a patient
with Parkinsons disease treated by cografts of adrenal
medulla and pretransected peripheral nerve. Case report.
J Neurosurg 84 (4): 685689.
Deacon T, Schumacher J, Dinsmore J et al. (1997). Histolo-
gical evidence of fetal pig neural cell survival after trans-
plantation into a patient with Parkinsons disease. Nat
Med 3 (3): 350353.
Dass B, Iravani MM, Jackson MJ et al. (2002). Behavioural
and immunohistochemical changes following supranigral
302 B. DASS AND J. H. KORDOWER
administration of sonic hedgehog in 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine-treated common marmosets.
Neuroscience 114 (1): 99109.
Dass B, Herzog CD, Gasmi M et al. (2004). Adeno-asso-
ciated virus mediated gene delivery of neurturin (CERE-
120) in non-human primates. J Neurosci #790.19.
Dass B, Herzog CD, Gasmi M et al. (2005a). Adeno-associated
virus mediated gene delivery of neurturin (CERE-120)
prevents MPTP-induced motor disability following injec-
tion into the striatum of non-human primates. J Neurosci
#545.6.
Dass B, Iravani MM, Huang C et al. (2005b). Sonic hedge-
hog delivered by an adeno-associated virus protects dopa-
minergic neurones against 6-OHDA toxicity in the rat.
J Neural Transm 112 (6): 763778. [Epub 2004 Dec 10].
de la Fuente-Fernandez R, Ruth TJ, Sossi V et al. (2001). Expec-
tation and dopamine release: mechanism of the placebo effect
in Parkinsons disease. Science 293 (5532): 11641166.
During MJ, Samulski RJ, Elsworth JD et al. (1998). In vivo
expression of therapeutic human genes for dopamine pro-
duction in the caudates of MPTP-treated monkeys using
an AAV vector. Gene Ther 5 (6): 820827.
During MJ, Kaplitt MG, Stern MB et al. (2001). Subthalamic
GAD gene transfer in Parkinson disease patients who are
candidates for deep brain stimulation. Hum Gene Ther
12 (12): 15891591.
Eberhardt O, Coelln RV, Kugler S et al. (2000). Protection by
synergistic effects of adenovirus-mediated X-chromosome-
linked inhibitor of apoptosis and glial cell line-derived
neurotrophic factor gene transfer in the 1-methyl-
4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinsons
disease. J Neurosci 20 (24): 91269134.
Ehringer H, Hornykiewicz O (1960). Verteilung von nora-
drenalin und dopamin (3-hydroxytyramine) im gerhin des
menschen und ihr verhalten bei erkrantungen des extrapyr-
amidalen systems. Kiln Wschr 38: 12361239.
Eslamboli A, Cummings RM, Ridley RM et al. (2003).
Recombinant adeno-associated viral vector (rAAV) deliv-
ery of GDNF provides protection against 6-OHDA lesion
in the common marmoset monkey (Callithrix jacchus).
Exp Neurol 184 (1): 536548.
Eslamboli A, Georgievska B, Ridley RM et al. (2005). Con-
tinuous low-level glial cell line-derived neurotrophic fac-
tor delivery using recombinant adeno-associated viral
vectors provides neuroprotection and induces behavioral
recovery in a primate model of Parkinsons disease. J Neu-
rosci 25 (4): 769777.
Figueiras-Mendez R, Marin-Zarza F, Antonio, Molina J et al.
(1999). Subthalamic nucleus stimulation improves directly
levodopa induced dyskinesias in Parkinsons disease.
J Neurol Neurosurg Psychiatry 66 (4): 549550.
Fjord-Larsen L, Johansen JL, Kusk P et al. (2005). Efficient
in vivo protection of nigral dopaminergic neurons by len-
tiviral gene transfer of a modified Neurturin construct.
Exp Neurol 195 (1): 4960.
Freed CR, Greene PE, Breeze RE et al. (2001). Transplanta-
tion of embryonic dopamine neurons for severe Parkinsons
disease. N Engl J Med 344 (10): 710719.
Gash DM, Zhang Z, Ovadia A et al. (1996). Functional
recovery in parkinsonian monkeys treated with GDNF.
Nature 380 (6571): 252255.
Georgievska B, Kirik D, Rosenblad C et al. (2002a). Neuropro-
tection in the rat Parkinson model by intrastriatal GDNF gene
transfer using a lentiviral vector. Neuroreport 13 (1): 7582.
Georgievska B, Kirik D, Bjorklund A (2002b). Aberrant
sprouting and downregulation of tyrosine hydroxylase in
lesioned nigrostriatal dopamine neurons induced by long-
lasting overexpression of glial cell line derived neuro-
trophic factor in the striatum by lentiviral gene transfer.
Exp Neurol 177 (2): 461474.
Georgievska B, Kirik D, Bjorklund A (2004). Overexpression
of glial cell line-derived neurotrophic factor using a lenti-
viral vector induces time- and dose-dependent downregu-
lation of tyrosine hydroxylase in the intact nigrostriatal
dopamine system. J Neurosci 24 (29): 64376445.
Gill SS, Patel NK, Hotton GR et al. (2003). Direct brain
infusion of glial cell line-derived neurotrophic factor in
Parkinson disease. Nat Med 9 (5): 589595.
Hacein-Bey-Abina S, von Kalle C, Schmidt M et al.
(2003). A serious adverse event after successful gene ther-
apy for X-linked severe combined immunodeficiency.
N Engl J Med 348 (3): 255256.
Herzog CD, Holden JE, Bakay RA et al. (2005). Enhanced
18Fdopa uptake in the striatum of aged rhesus monkeys
following striatal delivery of CERE120, an AAV2 vector
encoding human neurturin. J Neurosci #545.7.
Hurtado-Lorenzo A, Millan E, Gonzalez-Nicolini V et al.
(2004). Differentiation and transcription factor gene ther-
apy in experimental Parkinsons disease: Sonic Hedgehog
and Gli-1, but not Nurr-1, protect nigrostriatal cell bodies
from 6-OHDA-induced neurodegeneration. Mol Ther
10 (3): 507524.
Kaplitt MG, Leone P, Samulski RJ et al. (1994). Long-term
gene expression and phenotypic correction using adeno-
associated virus vectors in the mammalian brain. Nat
Genet 8 (2): 148154.
Kirik D, Rosenblad C, Bjorklund A (2000a). Preservation of
a functional nigrostriatal dopamine pathway by GDNF in
the intrastriatal 6-OHDA lesion model depends on the site
of administration of the trophic factor. Eur J Neurosci
12 (11): 38713882.
Kirik D, Rosenblad C, Bjorklund A et al. (2000b). Long-
term rAAV-mediated gene transfer of GDNF in the rat
Parkinsons model: intrastriatal but not intranigral trans-
duction promotes functional regeneration in the lesioned
nigrostriatal system. J Neurosci 20 (12): 46864700.
Kirik D, Georgievska B, Burger C et al. (2002). Reversal of
motor impairments in parkinsonian rats by continuous
intrastriatal delivery of L-DOPA using rAAV-mediated
gene transfer. Proc Natl Acad Sci USA 99 (7):
47084713. [Epub 2002 Mar 26].
Klein RL, Lewis MH, Muzyczka N et al. (1999). Prevention
of 6-hydroxydopamine-induced rotational behavior by
BDNF somatic gene transfer. Brain Res 847 (2): 314320.
Kojima H, Abiru Y, Sakajiri K et al. (1997). Adenovirus-
mediated transduction with human glial cell line-derived
 GENE THERAPY APPROACHES FOR THE TREATMENT OF PARKINSONS DISEASE
neurotrophic factor gene prevents 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine-induced dopamine depletion in
striatum of mouse brain. Biochem Biophys Res Commun
238 (2): 569573.
Kordower JH, Freeman TB, Snow BJ et al. (1995). Neuro-
pathological evidence of graft survival and striatal reinner-
vation after the transplantation of fetal mesencephalic
tissue in a patient with Parkinsons disease. N Engl J
Med 332 (17): 11181124.
Kordower JH, Palfi S, Chen EY et al. (1999). Clinicopatholo-
gical findings following intraventricular glial-derived neu-
rotrophic factor treatment in a patient with Parkinsons
disease. Ann Neurol 46 (3): 419424.
Kordower JH, Emborg ME, Bloch J et al. (2000). Neuro-
degeneration prevented by lentiviral vector delivery of
GDNF in primate models of Parkinsons disease. Science
290 (5492): 767773.
Kotzbauer PT, Lampe BA, Heuckeroth RO et al. (1996).
Neurturin, a relative of glial-cell-line-derived neurotrophic
factor. Nature 384: 467470.
Lapchak PA, Araujo DM, Hilt DC et al. (1997). Adenoviral
vector-mediated GDNF gene therapy in a rodent lesion
model of late stage Parkinsons disease. Brain Res
777 (1-2): 153160.
Lindvall O, Rehncrona S, Brundin P et al. (1989). Human
fetal dopamine neurons grafted into the striatum in two
patients with severe Parkinsons disease. A detailed
account of methodology and a 6-month follow-up. Arch
Neurol 46 (6): 615631.
Lo Bianco C, Deglon N, Pralong W et al. (2004). Lentiviral
nigral delivery of GDNF does not prevent neurodegenera-
tion in a genetic rat model of Parkinsons disease. Neuro-
biol Dis 17 (2): 283289.
Luo J, Kaplitt MG, Fitzsimons HL et al. (2002). Subthalamic
GAD gene therapy in a Parkinsons disease rat model.
Science 298 (5592): 425429.
Madrazo I, Drucker-Colin R, Diaz V et al. (1987). Open
microsurgical autograft of adrenal medulla to the right
caudate nucleus in two patients with intractable Parkin-
sons disease. N Engl J Med 316 (14): 831834.
Mandel RJ, Spratt SK, Snyder RO et al. (1997). Midbrain
injection of recombinant adeno-associated virus encoding
rat glial cell line-derived neurotrophic factor protects
nigral neurons in a progressive 6-hydroxydopamine-
induced degeneration model of Parkinsons disease in rats.
Proc Natl Acad Sci USA 94 (25): 1408314088.
Mandel RJ, Rendahl KG, Spratt SK et al. (1998). Characteri-
zation of intrastriatal recombinant adeno-associated virus-
mediated gene transfer of human tyrosine hydroxylase and
human GTP-cyclohydrolase I in a rat model of Parkin-
sons disease. J Neurosci 18 (11): 42714284.
Marsden CD (1990). Parkinsons disease. Lancet 335 (8695):
948952.
Marsden CD, Parkes JD (1977). Success and problems of
long-term levodopa therapy in Parkinsons disease. Lancet
1 (8007): 345349.
Mufson EJ, Kroin JS, Sendera TJ et al. (1999). Distribution
and retrograde transport of trophic factors in the central
nervous system: functional implications for the treatment
303
of neurodegenerative diseases. Prog Neurobiol 57 (4):
451484 Review.
Muramatsu S, Fujimoto K, Ikeguchi K et al. (2002). Beha-
vioral recovery in a primate model of Parkinsons disease
by triple transduction of striatal cells with adeno-asso-
ciated viral vectors expressing dopamine-synthesizing
enzymes. Hum Gene Ther 13 (3): 345354.
Nakai H, Montini E, Fuess S et al. (2003). AAV serotype 2
vectors preferentially integrate into active genes in mice.
Nat Genet 34 (3): 297302.
Natsume A, Mata M, Goss J et al. (2001). Bcl-2 and GDNF
delivered by HSV-mediated gene transfer act additively to
protect dopaminergic neurons from 6-OHDA-induced
degeneration. Exp Neurol 169 (2): 231238.
Neurologix Press Release 25th September 2005. Neurologix
Announces PositiveInterim Results of Landmark Gene
Therapy Clinical Trial for Patients with Parkinsons Disease.
http://phx.corporate-ir.net/phoenix.zhtml?c106413p
irol-newsArticleID760701highlight
Nutt JG, Burchiel KJ, Comella CL et al. (2003). ICV GDNF
Study Group. Implanted intracerebroventricular. Glial cell
line-derived neurotrophic factor. Randomized, double-
blind trial of glial cell line-derived neurotrophic factor
(GDNF) in PD. Neurology 60 (1): 6973.
Ostenfeld T, Tai YT, Martin P et al. (2002). Neurospheres
modified to produce glial cell line-derived neurotrophic
factor increase the survival of transplanted dopamine neu-
rons. J Neurosci Res 69 (6): 955965.
Palfi S, Leventhal L, Chu Y et al. (2002). Lentivirally deliv-
ered glial cell line-derived neurotrophic factor increases
the number of striatal dopaminergic neurons in primate
models of nigrostriatal degeneration. J Neurosci 22 (12):
49424954.
Park S, Kim EY, Ghil GS et al. (2003). Genetically modified
human embryonic stem cells relieve symptomatic motor
behavior in a rat model of Parkinsons disease. Neurosci
Lett 353 (2): 9194.
Pearce RKB, Collins P, Jenner P et al. (1996). Intraventricular
infusion of basic fibroblast growth factor (bFGF) in the
MPTP treated common marmoset. Synapse 23: 192200.
Pearce RKB, Costa S, Jenner P et al. (1999). Chronic supra-
nigral infusion of BDNF in normal and MPTP treated
common marmosets. J Neural Transm 106: 663683.
Quinn NP (1990). The clinical application of cell grafting
techniques in patients with Parkinsons disease. Prog
Brain Res 82: 619625.
Raper SE, Chirmule N, Lee FS et al. (2003). Fatal systemic
inflammatory response syndrome in a ornithine transcar-
bamylase deficient patient following adenoviral gene
transfer. Mol Genet Metab 80 (1-2): 148158.
Sanchez-Pernaute R, Harvey-White J, Cunningham J et al.
(2001). Functional effect of adeno-associated virus mediated
gene transfer of aromatic L-amino acid decarboxylase into
the striatum of 6-OHDA-lesioned rats. Mol Ther 4 (4):
324330.
Schumacher JM, Ellias SA, Palmer EP et al. (2000). Trans-
plantation of embryonic porcine mesencephalic tissue in
patients with PD. Neurology 54 (5): 10421050.
304 B. DASS AND J. H. KORDOWER
Shen Y, Muramatsu SI, Ikeguchi K et al. (2000). Triple
transduction with adeno-associated virus vectors expres-
sing tyrosine hydroxylase, aromatic-L-amino-acid decar-
boxylase, and GTP cyclohydrolase I for gene therapy
of Parkinsons disease. Hum Gene Ther 11 (11):
15091519.
Slevin JT, Gerhardt GA, Smith CD et al. (2005). Improve-
ment of bilateral motor functions in patients with Parkin-
son disease through the unilateral intraputaminal infusion
of glial cell line-derived neurotrophic factor. J Neurosurg
102 (2): 216222.
Smith AD, Kozlowski DA, Bohn MC et al. (2005). Effect of
AdGDNF on dopaminergic neurotransmission in the stria-
tum of 6-OHDA-treated rats. Exp Neurol 193 (2):
420426.
Steece-Collier K, Collier TJ, Danielson PD et al. (2003).
Embryonic mesencephalic grafts increase levodopa-
induced forelimb hyperkinesia in parkinsonian rats. Mov
Disord 18: 14421454.
Svendsen CN, Clarke DJ, Rosser AE et al. (1996). Survival
and differentiation of rat and human epidermal growth
factor-responsive precursor cells following grafting into
the lesioned adult central nervous system. Exp Neurol
137 (2): 376388.
Tomac A, Widenfalk J, Lin LF et al. (1995). Retrograde
axonal transport of glial cell line-derived neurotrophic
factor in the adult nigrostriatal system suggests a trophic
role in the adult. Proc Natl Acad Sci USA 92 (18):
82748278.
Wang L, Muramatsu S, Lu Y et al. (2002). Delayed delivery
of AAV-GDNF prevents nigral neurodegeneration and
promotes functional recovery in a rat model of Parkinsons
disease. Gene Ther 9 (6): 381389.
Wenning GK, Odin P, Morrish P et al. (1997). Short- and
long-term survival and function of unilateral intrastriatal
dopaminergic grafts in Parkinsons disease. Ann Neurol
42 (1): 95107.
Wolff JA, Fisher LJ, Xu L et al. (1989). Grafting fibroblasts
genetically modified to produce L-DOPA in a rat model of
Parkinson disease. Proc Natl Acad Sci USA 86 (22):
90119014.
Yamada M, Oligino T, Mata M et al. (1999). Herpes simplex
virus vector-mediated expression of Bcl-2 prevents 6-
hydroxydopamine-induced degeneration of neurons in the
substantia nigra in vivo. Proc Natl Acad Sci USA 96 (7):
40784083.
Further Reading
Maries E, Kordower JH, Chu Y et al. (2006). Focal not wide-
spread grafts induce novel dyskinetic behavior in parkinsonian
rats. Neurobiol Dis 21 (1): 165180. [Epub 2005 Aug 10].
 Section 8

Other parkinsonian syndromes

Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 46

Multiple system atrophy

RONALD F. PFEIFFER*

University of Tennessee Health Science Center, Memphis, TN, USA

46.1. Introduction
The nosological history of what is now known as mul-
tiple system atrophy (MSA) brings to mind the well-
known ancient Buddhist parable of the blind men
examining an elephant. In the parable, each of the
blind men feels a different part of the elephant and
then, unable to visualize the entire beast, describes
the elephant in strikingly different terms. MSA might
be considered the movement disorders elephant.
Descriptions of the three parts of the MSA elephant
date back to the end of the 19th century, when Dejer-
ine and Thomas (1900) described two individuals
with a sporadic, adult-onset syndrome characterized
primarily by ataxia, but also displaying parkinsonism,
brisk reflexes and incontinence. The autopsy findings
of atrophy in the inferior olives, pons, middle cerebel-
lar peduncles and cerebellum led them to apply the
label of olivopontocerebellar atrophy (OPCA) to the
condition. Wenning and colleagues (1997) in their
review of 203 cases of pathologically proven cases of
MSA document even earlier descriptions by Schultze
(1887) and Arndt (1894) of individuals with cerebellar
syndromes that would now be called MSA. In 1960,
two additional conditions that would later be rec-
ognized as MSA were described. Shy and Drager
(1960) reported two individuals with progressive auto-
nomic failure accompanied by parkinsonism, dysar-
thria, ataxia, pyramidal signs, distal muscle wasting
and extraocular muscle weakness. Autopsy in one of
the cases demonstrated degenerative changes in the
caudate, substantia nigra, cerebellum, inferior olives,
locus ceruleus and intermediolateral cell columns. In
the same year, van der Eecken and colleagues (1960)
detailed unique pathological findings in 3 patients with
predominantly rigid-akinetic parkinsonism. Atrophy
with neuronal loss and gliosis in the putamen and cau-
date and loss of pigmented neurons in the substantia
nigra were evident, but Lewy bodies were conspicuously
absent. Described in more detail 1 year later (Adams
et al., 1961), cerebellar dysfunction, pyramidal tract
abnormalities and autonomic impairment were also pre-
sent in these individuals. Although the original authors
applied the appellation striopallidonigral degeneration
to the condition, the abbreviated label of striatonigral
degeneration (SND) was subsequently employed. Thus,
it came to be that three syndromes sporadic OPCA with
predominantly cerebellar dysfunction, ShyDrager syn-
drome (SDS) with striking autonomic impairment and
SND with rigid-akinetic parkinsonism existed side by
side in the neurological nomenclature as three distinct
entities.
The conceptual synthesis of these three entities into a
single pathological process was initiated by Graham and
Oppenheimer in 1969, when they described an indivi-
dual with progressive autonomic failure and ataxia.
In discussing the case, they noted the clinical and patho-
logical similarities between OPCA, SDS and SND and
suggested that the term multiple system atrophy be
used for them all. This suggestion did not meet with
immediate or universal acceptance and employment of
the older three terms in publications continued for many
years. However, the discovery of a distinctive patholo-
gical marker, glial cytoplasmic inclusions (GCI), by
Papp and colleagues in 1989 finally provided a firm
basis for the designation of MSA as a distinct disease
process with a complex combination of clinical presen-
tations (Papp et al., 1989). The subsequent identifica-
tion of a-synuclein as a major component of GCI has
established MSA as a member of the family of synuclei-
nopathies (Gai et al., 1998; Wakabayashi et al., 1998;
Dickson et al., 1999a).

*Correspondence to: Ronald F. Pfeiffer, Department of Neurology, University of Tennessee Health Science Center, 855
Monroe Avenue, Memphis TN 38163, USA. E-mail: rpfeiffer@utmem.edu, Tel: 1-901-448-5209, Fax: 1-901-448-7440.
308 R. F. PFEIFFER
The confusing clinical picture of MSA, with its
diversity of clinical presentations and the absence of
any unequivocally diagnostic clinical feature or defini-
tive laboratory test, has prompted formation of clinical
diagnostic criteria to aid in diagnosis. The first effort
was undertaken by Quinn in 1989 (Quinn, 1989a), fol-
lowed a decade later by the development of the
currently employed Consensus Criteria assembled by
Gilman and colleagues (1998, 1999).
This chapter will address the epidemiology, clini-
cal features, pathological characteristics, diagnostic
evaluation and treatment approaches for MSA.
46.2. Epidemiology
46.2.1. Descriptive epidemiology
MSA is a rare disease and relatively few formal stu-
dies of its prevalence have been completed. In two stu-
dies reported by the same group of investigators, the
prevalence rate of MSA was approximately 1.9 per
100 000 (Tison et al., 2000; Chrysostome et al.,
2004). In a report by another group of investigators,
the crude prevalence (including probable and possible
cases) was 3.3 per 100 000 and the age-adjusted preva-
lence 4.4 per 100 000 (Schrag et al., 1999). Schrag and
colleagues (1999) also extrapolated MSA prevalence
rates of 2.3 per 100 000 (Wermuth et al., 1997) and
4.9 per 100 000 (Chio et al., 1998) from two studies
that were primarily investigating the prevalence of
Parkinsons disease in the Faroe Islands and in north-
west Italy respectively. Not all studies have arrived
at rates this low. Trenkwalder and colleagues (1995)
investigated the prevalence of different types of par-
kinsonism in individuals over age 65 by performing a
door-to-door survey in two Bavarian villages and
found a markedly higher prevalence of MSA, with a
rate over 300 per 100 000. Whether this difference is
due to the age limitation employed in this study, its
door-to-door design leading to improved ascertain-
ment, or simple chance is unclear.
Studies of annual incidence of MSA are equally
scarce. Bower and colleagues (1997) employed the
medical records linkage system of the Rochester Epi-
demiology Project to estimate an overall annual in-
cidence rate of 0.6 per 100 000; in their study no
patient developed MSA prior to age 50, whereas
between ages 50 and 99 incidence was 3.0 per 100
000. Schrag and colleagues (1999) obtained a similar
figure (approximately 0.5 per 100 000) when they
indirectly measured MSA annual incidence.
Although MSA affects both sexes, studies seem to
indicate that men are at somewhat higher risk than
women. Wenning and colleagues (1997) reported a
male-to-female ratio of 1.3:1 in their 203 cases of
MSA; Bower and colleagues (1997) a ratio of 2:1 in
9 patients. The mean age of onset of symptoms of
MSA is somewhat younger than that of Parkinsons
disease. In most studies, the mean age of onset of
symptoms has hovered between 53 and 56, with a
range of 3178 years (Saito et al., 1994; Wenning
et al., 1994, 1997; Ben-Shlomo et al., 1997; Testa
et al., 2001; Watanabe et al., 2002). Quinn (2005)
has made the point that there has never been a case
of pathologically proven MSA with onset of symptoms
before age 30. Although there is a case report of an
individual with very slowly progressive probable
MSA who experienced the onset of symptoms at age
18 (Schatz, (2003)), the accuracy of the clinical diag-
nosis is thrown into some doubt by the unusually pro-
longed survival (40 years) of that patient. The report
of Bower and colleagues (1997) stands somewhat
apart from the other studies, with a more advanced
median age of symptom onset of 66, with a range of
5182 years.
In addition to earlier age of onset, individuals with
MSA possess a considerably poorer prognosis than per-
sons with Parkinsons disease, with more rapid dete-
rioration in neurological function. The mean survival
time for someone with MSA is only 67 years (Ben-
Shlomo et al., 1997; Wenning et al., 1997; Kurisaki,
1999). Viewed from another standpoint, survival rates
of 90% at 3 years, 83.5% at 5 years, 54% at 6 years
and 2939.9% at 10 years have been documented (Saito
et al., 1994; Testa et al., 2001; Watanabe et al., 2002).
Watanabe and colleagues (2002) also reported median
intervals from disease onset until requiring aids for
walking to be 3 years, to wheelchair requirement 5 years
and to being bed-ridden 8 years.
46.2.2. Analytical epidemiology
MSA is generally considered a sporadic disease.
According to the Consensus Criteria formulated for
the diagnosis of MSA (Gilman et al., 1998, 1999;
Quinn, 2005), a family history of a similar disorder is
considered an exclusion criterion. Nevertheless, some
reports have suggested the possibility of a genetic
component to MSA. Nee and colleagues (1991) com-
pleted a case-control study of 60 patients with MSA
and 60 control subjects and noted that first-degree
relatives of persons with MSA were more likely to
report clinical symptoms of MSA than were relatives
of the control subjects.
There have also been several descriptions of
families with possible autosomal-dominant MSA.
Lewis (1964) reported a kindred with familial ortho-
static hypotension (the term multiple system atrophy
 MULTIPLE SYSTEM ATROPHY
had not yet been created) involving six family mem-
bers over three generations. However, the accuracy
of the portrayal of this family as having MSA has
recently been questioned (Berciano and Wenning,
2005). More recently, another family with an autoso-
mal-dominant disorder possessing the clinical phenotype
of MSA has been reported (Wullner et al., 2004).
Although no pathological confirmation of the diagnosis
of MSA is yet available in this family, extensive clinical
testing that has included autonomic function testing,
magnetic resonance imaging (MRI) and even single-
photon emission computed tomography (SPECT) in sev-
eral affected individuals has been consistent with a diag-
nosis of MSA.
The possibility that genetic polymorphisms might
play a role in the development of MSA has received
considerable attention in recent years but the search
thus far has been largely fruitless. Multiple studies,
looking at multiple genes (cytochrome P4502D6,
cytochrome P4501A1, N-acetyltransferase 2, dopa-
mine transporter, glutathione S-transferase M1, ciliary
neurotrophic factor, insulin-like growth factor-1,
hiGIRK2, HLA-A32, a-synuclein, apolipoprotein E,
synphilin, tau, alcohol dehydrogenase 7, UCHL-1)
have not demonstrated any association with the dev-
elopment of MSA (Plante-Bordeneuve et al., 1995;
Bandmann et al., 1997; Cairns et al., 1997; Nicholl
et al., 1999; Morris et al., 2000; Kim and Lee, 2003;
Healy et al., 2005). However, Combarros and collea-
gues (2003) have reported that individuals homo-
zygous for interleukin-1A (IL-1A) allele 2 in the
regulatory region of the IL-1A gene have a fivefold
(odds ratio (OR) 5.1) increased risk of developing
MSA; persons with only one copy of the allele also
have an increased risk (OR 1.6), but considerably
less than those with two copies. Even more recently,
the same group of investigators has provided evidence
that the IL-8 and intercellular adhesion molecule-1
(ICAM-1) genes may also be susceptibility genes for
MSA (Infante et al., 2005). The presence of two
copies of the IL-8 T allele increased the risk of
MSA over threefold (OR 3.89). Polymorphism of
the ICAM-1 gene did not independently affect the risk
of MSA, but individuals carrying two copies of the
ICAM-1 K allele and two copies of the IL-8 T allele
had an even higher risk of MSA (OR 11.0). Since
both studies involved relatively small numbers of
MSA patients (30 and 41 respectively), the authors
point out that further studies, both to confirm their
findings and to investigate the potential mechanisms
by which these polymorphisms might act to increase
risk of MSA, need to be undertaken.
Possible environmental risk factors for MSA have
also received some attention. Nee and colleagues
309
(1991) performed a case-control study of 60 indivi-
duals with MSA and 60 controls, using a self-adminis-
tered questionnaire and found statistically significant
increased exposure to metal dusts and fumes (OR
14.75), pesticides (OR 5.8), plastic monomers and
additives (OR 5.25) and organic solvents (OR
2.41) in the MSA group. A more recent case-control
study, using the Consensus Criteria for the diagnosis
of MSA, has been carried out by the European Study
Group for Atypical Parkinsonism (Vanacore et al.,
2001, 2005). A total of 73 patients with MSA, 73
population controls and 146 hospital controls with
non-neurodegenerative neurological diseases were
enrolled. A statistically significant difference between
the MSA group and both the population and hospital
control groups was uncovered for an occupational his-
tory of farming (adjusted OR 2.52 versus hospital
controls; adjusted OR 4.53 versus population
controls). Additionally, a doseresponse effect was
demonstrable with regard to duration of farming
exposure. The specific component(s) of farming
exposure responsible for the increased risk could not
be determined from this study, but the authors nomi-
nated pesticides, solvents and mycotoxins as candi-
date risk factors for MSA. In the same study,
increased but not statistically significant ORs for
several other occupational categories (iron and steel,
textile and clothing, leather and shoe) were also
documented. In another investigation in which medi-
cal records of 100 patients with MSA were reviewed,
significant environmental toxin exposure was docu-
mented in 11 individuals (Hanna et al., 1999). No
single suspect toxin was again identified, but a his-
tory of significant exposure to pesticides was docu-
mented in 6 of the 11 individuals, and exposure to a
variety of other chemicals in the other 5. Prolonged
occupational exposure to carbon disulfide in a person
with MSA has also been reported (Frumkin, 1998).
In contrast, Chrysostome and colleagues (2004) did
not find any relationship between occupational expo-
sure to pesticides and MSA in their study of 50 MSA
patients, 50 Parkinsons disease patients and 50
healthy controls.
As has been reported with Parkinsons disease, an
inverse association between MSA and smoking has
been identified by several groups of investigators
(Vanacore et al., 2000; Chrysostome et al., 2004).
The mechanism by which smoking might reduce the
risk of MSA is not known. One patient has been
reported in whom the symptoms of MSA were exacer-
bated by cigarette smoking (Johnsen and Miller,
1986), but this phenomenon could not account for the
higher numbers of never-smokers in the ranks of
MSA patients.
310 R. F. PFEIFFER
46.3. Primary clinical features
The pleomorphic propensity of MSA produces a
potentially confusing picture for the clinician, who
can be faced with a bewildering array of symptoms
and signs in the patient with MSA. The difficulty in
diagnosing MSA was amply illustrated in a study
carried out by Litvan and colleagues (1997), in which
the diagnostic accuracy of the treating neurologist in
16 patients with autopsy-proven MSA had been only
25% at the first clinic visit and 50% at the final visit.
In this and another series, however, the diagnostic
accuracy of movement disorders specialists was
considerably higher (Hughes et al., 2002).
The clinical features of MSA generally fall into
four categories: extrapyramidal, cerebellar, autonomic
and pyramidal. Individuals may display any combina-
tion of these features and do not necessarily develop
all of them during the course of their illness. In a study
of 203 cases of autopsy-proven MSA drawn from pub-
lished literature, Wenning and colleagues (1997) found
that parkinsonism was present in 87% of patients dur-
ing the course of their illness, autonomic failure in
74%, cerebellar signs in 54% and pyramidal signs in
49%. In the same study, parkinsonism was the initial
motor disturbance in 58% of the patients, cerebellar
ataxia in 29% and a mixture of the two in 9%; pyrami-
dal signs were the initial motor feature in only 3% of
individuals. In an earlier analysis of 100 MSA cases,
autonomic symptoms were the initial clinical feature
in 41% of patients, parkinsonism in 46% and cerebel-
lar symptoms or signs in only 5% (Wenning et al.,
1994). Gilman (2002) observes, however, that the pre-
dominance of parkinsonism in the latter series may
have reflected sampling bias since the patients were
derived from a movement disorders clinic.
The proclivity of MSA to present with predomi-
nantly parkinsonian or predominantly cerebellar motor
features has led to the convention of classifying MSA
as being of either the MSA-P or MSA-C type (Quinn,
1989a, 2005). The distinction is somewhat artificial,
however, since most patients eventually acquire both
extrapyramidal and cerebellar dysfunction. Autonomic
features eventually develop in both groups.
46.3.1. Extrapyramidal features
46.3.1.1. Parkinsonism
Parkinsonism is by far the most common extrapyra-
midal feature of MSA. Most frequently, it is character-
ized by rigidity and bradykinesia/akinesia. In the
literature series of Wenning and colleagues (1997),
akinesia was noted to be present in 83% of patients
and rigidity in 63%. It is a common misconception that
tremor does not occur in MSA. It does. In fact, tremor
of some type develops in the majority of patients; even
rest tremor is seen in 2940% of cases, although a
classic pill-rolling tremor is evident in only 79%
(Colosimo et al., 2005a). What has been branded tre-
mor in MSA, however, may not always actually be
so. The term jerky tremor is sometimes used to
describe postural tremor in MSA (Gouider-Khouja
et al., 1995; Bower, 2000), but accelerometric and
electromyographic recordings of such small-ampli-
tude, non-rhythmic movements of the fingers that
occur when holding a posture or initiating movement
demonstrate that they are actually a form of postu-
ral and action myoclonus (labeled minipolymyocl-
onus by the authors) rather than tremor (Salazar
et al., 2000).
Several other misconceptions have crept into the
neurological mindset regarding the parkinsonian fea-
tures of MSA. Recognition that asymmetric onset of
symptoms or signs is more common in Parkinsons
disease than in the atypical parkinsonian disorders
(Hughes et al., 1992a) has sometimes been miscon-
strued to mean that the atypical syndromes, such as
MSA, never present asymmetrically. In fact, bilateral
symmetric onset of motor dysfunction actually occurs
in only a minority of MSA patients (Colosimo et al.,
1995, 2005a). The idea that MSA is invariably levo-
dopa-unresponsive is also incorrect. Response to levo-
dopa, occasionally good or even excellent, but often
suboptimal and fleeting, is evident in approximately
3060% of patients (Parati et al., 1993; Boesch et al.,
2002; Wenning et al., 2003a; Christine and Aminoff,
2004). The experience of Tison and colleagues
(2002), however, stands in some contrast in that they
noted a subjective impression of greater than 50%
improvement in motor function in fewer than 10% of
their MSA subjects.
Balance impairment with postural instability and fre-
quent falling occur earlier and with greater frequency in
MSA than in Parkinsons disease. Tison and colleagues
(2002) elicited a history of falling at symptom onset in
20% of the 50 MSA patients they studied, compared
with 2% of the 50 individuals with Parkinsons disease;
postural instability was present on testing in 10% of the
MSA patients at the initial exam, but in only 2% of the
Parkinsons disease subjects. With disease progression
over 70% of MSA patients develop postural instability
(Tison et al., 2002).
46.3.1.2. Dystonia
Dystonia is another facet of extrapyramidal dysfunc-
tion that surfaces in MSA. Although reported to be
present relatively infrequently by some investigators
 MULTIPLE SYSTEM ATROPHY
(Rivest et al., 1990; Wenning et al., 1997) and not at
all by others (Adams and Salam-Adams, 1986),
Boesch and colleagues (2002), in a prospective study
of 24 individuals with MSA followed for up to 10
years, documented the development of dystonia prior
to any levodopa exposure in 46%. In individuals with
MSA who responded to levodopa, the emergence of
levodopa-induced dystonic dyskinesia was also fre-
quent. In an accompanying editorial, Riley (2002)
made the point that, if actively sought, dystonia
may actually be one of the most common features of
MSA. Head and neck are the most common sites for
dystonia development in MSA, in both levodopa-naive
and levodopa-induced settings, but limb involvement
also occurs. Several patterns of dystonia are particu-
larly notable in MSA. Dystonia involving orofacial
and platysma muscles may produce a tetanus-like
facial distortion that has been christened the risus sar-
donicus of MSA (Wenning et al., 2003b). Two addi-
tional phenomena have generated some controversy
as to whether they represent dystonic phenomena or
not: stridor and disproportionate antecollis.
Inspiratory stridor, typically occurring at night,
develops in 1334% of patients with MSA (Wenning
et al., 1994, 1997). Although most often considered a
later manifestation, one group of investigators noted
stridor to be the initial clinical feature in 4% of 200
consecutive patients with probable MSA (Uzawa
et al., 2005) and in another study 69% of individuals
who developed stridor did so within the first 4 years
of disease diagnosis (Yamaguchi et al., 2003). Con-
flicting opinions exist regarding the genesis of stridor
in MSA. Some investigators attribute it to laryngeal
abductor paralysis (Bannister et al., 1981; Iranzo
et al., 2000, 2004; Uzawa et al., 2005), whereas others
maintain, and provide electromyographic documenta-
tion, that stridor is a dystonic phenomenon, with sus-
tained contraction of vocal cord adductors (Simpson
et al., 1992; Merlo et al., 2002). Regardless of its etiol-
ogy, the presence of stridor in an individual with MSA
should be interpreted as a danger signal. Persons with
stridor have an increased mortality risk, which has
led to the suggestion that tracheostomy be considered
in all individuals in whom stridor develops (Silber
and Levine, 2000).
Unusually prominent neck flexion resulting in a
dropped-head syndrome, or disproportionate antecol-
lis, has been widely recognized as a feature suggestive
of, though not unique to, MSA (Quinn, 1989b,
2005). Disproportionate antecollis is uncomfortable
for patients; it may also interfere with eating and speak-
ing and even effectively impair vision (Colosimo et al.,
2005a). As with stridor, the etiology of disproportionate
antecollis in MSA has been the source of controversy.
311
Although most often considered a dystonic phenom-
enon, some have suggested that antecollis in MSA
may sometimes be a manifestation of neck extensor
myopathy (Askmark et al., 2001). Extreme forward
flexion of the spine that appears or increases when the
individual is walking and disappears when supine
(camptocormia) and laterally oriented trunk flexion
(Pisa syndrome) may also develop in the setting
of MSA (Slawek et al., 2006). It is also unsettled
whether these phenomena represent axial dystonia or
axial myopathy.
46.3.2. Autonomic dysfunction
Impairment of autonomic function eventually develops
in the vast majority of individuals with MSA. As noted
earlier, autonomic symptoms were the presenting clin-
ical feature in 41% of 100 patients with clinically
probable MSA and they ultimately developed in 97%
(Wenning et al., 1994). Similarly, in an analysis of
35 subjects with pathologically proven MSA, auto-
nomic failure had been present in 97% (Wenning
et al., 1995a). Among 75 persons with MSA followed
at the Mayo Clinic, severe autonomic dysfunction
developed in 97% also (Sandroni et al., 1991). Geni-
tourinary, cardiovascular, gastrointestinal (GI) and
thermoregulatory autonomic dysfunction may all
appear in the setting of MSA.
46.3.2.1. Genital dysfunction
Erectile dysfunction is almost universal in men with
MSA. It ultimately develops in 96% and is the initial
clinical feature in 37% (Beck et al., 1994). It typically
precedes the development of both urinary dysfunction
and orthostatic hypotension (Kirchhof et al., 2003).
Oertel and colleagues (2003) studied genital sensation
(as a possible equivalent of erectile dysfunction) in 17
women with MSA and found reduced genital sensitiv-
ity in 47%, compared with only 4% of 27 women with
Parkinsons disease and 4% of 26 normal controls. In
most of the women with MSA, the reduced genital
sensitivity had preceded the onset of motor dysfunc-
tion and in many it had developed subacutely over a
period of several months.
46.3.2.2. Urinary dysfunction
Disordered bladder function is also common in MSA. It
may be the initial clinical feature (Sakakibara et al.,
1993) and routinely is one of the earliest autonomic fea-
tures to emerge (Mabuchi et al., 2005). Over 90% of
individuals with MSA develop micturition disturbances
during the course of the disease (Sakakibara et al.,
1993, 2000). Both urinary retention and incontinence
312 R. F. PFEIFFER
may occur. The most frequent urinary symptom in per-
sons with MSA is difficulty voiding, which Sakakibara
and colleagues (2000) catalogued in 79% of the 121
patients they studied. In the same study, nocturnal urin-
ary frequency was present in 74%, urgency in 63%,
urge incontinence in 63% and urinary retention in 8%.
Others have described urinary incontinence in 5571%
and urinary retention in 1827% of individuals with
MSA (Wenning et al., 1994, 1997). Urodynamic and
neurophysiological testing also presents a diverse pic-
ture; both hyperactive and hypoactive bladder dys-
function occur. Sakakibara and colleagues (2000)
documented detrusor hyperreflexia in 56% of the
MSA patients they studied. In contrast, some other
investigators have found detrusor hyporeflexia to be
more frequent (Bonnet et al., 1997). Sakakibara and
colleagues (2000, 2001) also reported the presence of
a low-compliance bladder in 31%, an atonic curve in
5% and detrusor-sphincter dyssynergia in 45% of the
persons with MSA they studied. Increased postmicturi-
tion residual urine (>30 ml) was evident in 74% of
patients and residual urine of over 100 ml was noted
in 52%. In MSA, urinary disturbances typically deve-
lop earlier and are more severe than those seen in
Parkinsons disease.
46.3.2.3. Cardiovascular dysfunction
Cardiovascular dysfunction in the form of orthostatic
hypotension is the autonomic feature that has attracted
the most attention in MSA, but it actually occurs less
frequently than urogenital dysfunction. Symptoms of
orthostatic hypotension develop in 4368% of in-
dividuals with MSA (Wenning et al., 1994, 1997;
Sakakibara et al., 2000). Postural lightheadedness is
the most frequently experienced symptom of ortho-
static hypotension, but individuals may instead experi-
ence blurred vision, clouded cognition, head and neck
pain in a coat-hanger distribution, lower back or but-
tock pain, a sense of weakness or fatigue, tremulous-
ness, or simply an ill-defined feeling of dizziness
(Mathias et al., 1999; Bower, 2000; Mathias,
2005). Syncope occurs in 1519% of MSA patients
with orthostatic hypotension (Wenning et al., 1994,
1997; Sakakibara et al., 2000). Orthostatic hypotension
may be present and become symptomatic early in the
course of MSA, a characteristic that provides some
contrast with Parkinsons disease (Wenning et al.,
1999). A variety of factors can accentuate and magnify
orthostatic hypotension. Symptoms upon first arising
in the morning can be prominent, consequent to pro-
longed recumbency. Postprandial hypotension, espe-
cially following a large, carbohydrate-heavy meal,
may also occur, due to impairment of compensatory
autonomic responses normally triggered by increased
superior mesenteric artery blood flow (Mathias, 2005)
and is more prominent in MSA than in Parkinsons
disease (Thomaides et al., 1993).
46.3.2.4. Gastrointestinal dysfunction
Although considerable ink has flowed concerning
electromyographic abnormalities of the anal sphincter
in MSA (discussed below), relatively little has been
written about clinical GI dysfunction. Nevertheless,
both upper and lower GI disturbances occur frequently
in MSA. Dysphagia is common in MSA and tends to
develop earlier than in Parkinsons disease. In one
study, the median latency to the onset of dysphagia
in 15 patients with MSA was 24 months (Muller
et al., 2001). Higo and colleagues (2003) documented
reduced oropharyngeal and hypopharyngeal swallow-
ing pressures in 29 persons with MSA and incomplete
relaxation of the upper esophageal sphincter was pre-
sent in 23%. Gastric emptying may also be delayed
in individuals with MSA, comparable to that seen in
Parkinsons disease (Thomaides et al., 2005).
Bowel dysfunction, including both decreased bowel
movement frequency and difficulty with the act of
defecation itself, is another aspect of GI dysfunction
in MSA. In one study, decreased bowel movement fre-
quency (fewer than 3/week) was present in 60% of
participating MSA patients, and 67% experienced dif-
ficulty with defecation (Sakakibara et al., 2004a). In
another study of 16 persons with MSA experiencing
GI symptoms, 87% were having fewer than 3 bowel
movements per week and 69% were experiencing
difficulty with defecation (Stocchi et al., 2000).
Decreased bowel movement frequency in MSA is
due to slowed colon transit time. Sakakibara and
colleagues (2004a) documented a mean total colon
transit time of 71.8 hours in 15 individuals with
MSA, compared with 39 hours in 10 age-matched con-
trols. Disturbances in anorectal function, leading to
increased straining and incomplete evacuation during
defecation, are also present in many patients with
MSA. Manometric and electromyographic recordings
of anorectal function demonstrate a plethora of abnor-
malities that suggests these disturbances are due to
either paradoxical contraction or insufficient inhibition
of the anal musculature during straining, along with
weakness of associated abdominal muscle contraction
(Stocchi et al., 2000; Sakakibara et al., 2004a). Fecal
incontinence, especially following laxative ingestion,
may also occur in 1231% of patients with MSA
(Wenning et al., 1997; Stocchi et al., 2000; Sakakibara
et al., 2004a). Denervation, with consequent weakness
of the external anal sphincter, is probably responsible.
 MULTIPLE SYSTEM ATROPHY
46.3.2.5. Thermoregulatory dysfunction
A number of features indicative of thermoregulatory
and sudomotor dysfunction have been identified in
MSA. Reduced sweating is common and may be severe
(Cohen et al., 1987; Kumazawa et al., 1989). Indivi-
duals with MSA demonstrate impaired heat tolerance
(Colosimo et al., 2005a) and may be at risk for
increased morbidity due to worsened orthostatic hypo-
tension during heat exposure (Pathak et al., 2005).
Reduced skin temperature may also be present in per-
sons with MSA, along with a more profound reduction
in skin temperature when exposed to cold (Klein
et al., 1997). These abnormalities may, in turn, account
for the presence of cold, blue or purple hands (and feet)
that has been christened as one of the red flags of
MSA (Klein et al., 1997). Raynauds phenomenon, with
painful, pale fingers and hands due to vasospasm,
induced by cold or by ergot drugs, may also afflict indi-
viduals with MSA (Kaufmann and Biaggioni, 2003;
Geser and Wenning, 2005). One further reflection of
impaired thermoregulatory control in MSA is the blunt-
ing of the physiological fall in body temperature that
normally occurs at night (Pierangeli et al., 2001).
46.3.3. Cerebellar dysfunction
In patients evaluated in movement disorders clinics, cer-
ebellar dysfunction is only rarely the presenting clinical
feature of MSA, accounting for only 5% in one study
(Wenning et al., 1994). Gilman (2002) points out, how-
ever, that this may reflect a sampling bias and implies
that the percentage might be greater in a general neurol-
ogy clinic. With disease progression, the percentage of
individuals displaying cerebellar dysfunction expands
considerably. Gait ataxia eventually becomes evident in
almost 50% of individuals and dysarthria in almost
everyone (Wenning et al., 1997; Shulman et al., 2004).
A quintet of abnormalities characterizes cerebellar dys-
function in MSA: gait ataxia, limb ataxia, kinetic tremor,
oculomotor dysfunction and dysarthria (Wenning et al.,
1997, 2004; Shulman et al., 2004; Colosimo et al.,
2005a). Not all of the features develop in each individual
and any combination of them may occur. In one study,
gait ataxia eventually became evident in 49% of subjects,
limb ataxia in 47%, intention tremor in 24% and nystag-
mus in 23% (Wenning et al., 1997). In addition to ny-
stagmus, other oculomotor abnormalities seen in MSA
include ocular dysmetria, impaired smooth pursuit and
square-wave jerks (Bower, 2000).
46.3.4. Pyramidal signs
Clinically apparent pyramidal tract dysfunction, such
as spastic paraparesis, is unusual in MSA. Signs of
313
pyramidal tract dysfunction on neurological examina-
tion, in contrast, are quite frequently present. In the
series of 203 MSA patients assembled from the litera-
ture by Wenning and colleagues (1997), hyperreflexia
was present in 46% and Babinski responses in 41%,
but spasticity in only 10%. Although the clinical con-
sequences of pyramidal tract dysfunction in MSA are
not striking, the presence of unequivocal pyramidal
tract signs in an individual with parkinsonism and
autonomic dysfunction is of diagnostic utility in that
it points toward a diagnosis of MSA rather than
Parkinsons disease.
46.4. Other clinical features
46.4.1. Disordered sleep
Recognition is growing that a variety of sleep disor-
ders may emerge during the course of MSA. In a ques-
tionnaire study involving 57 patients with MSA, 70%
voiced complaints of sleep impairment (Ghorayeb
et al., 2002). In the study, 60% were aware of night-
time vocalizations, 52.5% experienced sleep fragmen-
tation, 47.5% described symptoms of rapid-eye
movement (REM) sleep behavior disorder, 32.5%
were troubled by early awakening, 20% by insomnia,
19% experienced stridor and 12.5% were kept awake
by symptoms of restless-legs syndrome. Snoring was
also acknowledged by 72.5%. Persons with MSA are
also more likely to experience excessive daytime slee-
piness than individuals with Parkinsons disease
(Ghorayeb et al., 2002). Video-polysomnographic
recordings confirm and expand the information gath-
ered from questionnaire studies. In a study of 19
MSA patients who were not selected on the basis of
any sleep or respiratory problems, inspiratory noise
was documented in every participant, with stridor in
42% and snoring in 100% (Vetrugno et al., 2004). In
fact, subjects in this study spent 50% of their sleep
time either snoring or with stridor. Abnormal sleep
structure, with reduced non-REM deep sleep and
decreased sleep efficiency but normal amounts of
REM sleep, were also evident.
REM sleep behavior disorder is now recognized as
a feature of a-synucleinopathies such as MSA, Parkin-
sons disease and dementia with Lewy bodies (Boeve
et al., 2001), but it appears to develop earlier and with
greater severity in individuals with MSA (Iranzo et al.,
2005). Manifestations of REM sleep behavior disorder
can be present early in the course of MSA, prior to
institution of any antiparkinson medication (Wetter
et al., 2000) and may even antedate the appearance
of motor and autonomic features (Tison et al., 1995;
Boeve et al., 2001). In one study, 44% of the MSA
314 R. F. PFEIFFER
patients experienced the symptoms of REM sleep
behavior disorder more than 1 year before the onset
of motor features (Plazzi et al., 1997). Polysomno-
graphic recordings can be very useful in establishing
the presence of REM sleep behavior disorder in
MSA patients and have revealed a considerably higher
frequency of the abnormality than subjective question-
naire studies. In a study of 39 consecutive MSA
patients reported by Plazzi and colleagues (1997),
polysomnographic evidence of REM sleep behavior
disorder was present in 90%. It has been suggested that
increased or excessive sleep talking may be an early
manifestation of REM sleep behavior disorder in
MSA (Tachibana et al., 1997).
46.4.2. Behavioral disorders
Frank dementia is not a feature of MSA and, in fact, is
one of the exclusionary criteria for the diagnosis
(Gilman et al., 1998, 1999). However, behavioral
changes do occur in the setting of MSA and may actu-
ally be quite common. Executive dysfunction, similar
to but more severe than that seen in Parkinsons dis-
ease, has been documented in MSA (Dujardin et al.,
2003; Lange et al., 2003). Persons with MSA fre-
quently suffer from depression. In a study of 99 indivi-
duals with MSA, Benrud-Larson and colleagues
(2005) documented symptoms of at least mild depres-
sion in 80%, with moderate to severe depression in
39%. Emotional blunting or apathy has also been
described in persons with MSA. In one small study,
this was evident in 92% of 12 individuals evaluated
(Fetoni et al., 1999).
46.4.3. Other features
A number of other clinical features have been
described in persons with MSA, although they have
not received extensive scrutiny. Although impairment
of olfaction is often present in patients with MSA, it
is typically mild compared with the deficits character-
istic of Parkinsons disease (Nee et al., 1993; Wenning
et al., 1995b; Muller et al., 2001). Pramstaller and
colleagues (1995) documented electromyographic
abnormalities consistent with peripheral neuropathy
in 40% of the 74 patients with MSA they studied. In
a single case report, sensory polyneuropathy was the
initial neurological abnormality in an individual who
later developed MSA (Wu et al., 2004). Pain has been
reported to be the initial clinical manifestation of MSA
in 6% of patients (Pezzoli et al., 2004). Anisocoria was
present in 8% of the 203 cases of MSA described by
Wenning and colleagues (1997); in 5%, it was asso-
ciated with Horners syndrome. Dizziness or vertigo
with head turning, distinct from orthostatic light-
headedness, has been described in individuals with
the cerebellar form of MSA (Sakakibara et al., 2004b).
46.5. Consensus criteria
The diversity of clinical features of MSA, their vari-
able mode of presentation and the absence of any
unequivocal diagnostic test for MSA combine to make
the clinical diagnosis of MSA a difficult, even trea-
cherous exercise. In response to this diagnostic quick-
sand, a conference was convened in 1998, in which
guidelines for the diagnosis were developed (Gilman
et al., 1998, 1999). The Consensus Criteria are detailed
in Tables 46.146.3. Three diagnostic categories are
employed: possible MSA, probable MSA and definite
MSA (Table 46.1). Pathological confirmation is
required for a diagnosis of definite MSA. Therefore,
in the clinical setting the only possible diagnoses are
possible or probable MSA and determination between
these two categories is dependent upon the number
of features within the four clinical domains that are
met (Table 46.2). The third component of the consen-
sus criteria is a list of exclusion criteria; the presence
of any feature listed therein prohibits a diagnosis of
MSA (Table 46.3).
46.6. Neuropathology
46.6.1. Macroscopic pathology
Involvement of both basal ganglia and cerebellum may
be evident on gross examination of the brain in MSA.
Table 46.1
Diagnostic categories of multiple system atrophy (MSA)
I. Possible MSA
One criterion plus two features from separate other
domains
When the criterion is parkinsonism, a poor levodopa
response qualifies as one feature (hence only one
additional feature is required)
II. Probable MSA
Criterion for autonomic failure/urinary dysfunction plus
poorly levodopa-responsive parkinsonism or cerebellar
dysfunction
III. Definite MSA
Pathologically confirmed by the presence of a high density
of glial cytoplasmic inclusions in association with a
combination of degenerative changes in the nigrostriatal
and olivopontocerebellar pathways
Adapted from Gilman et al. (1999) with permission.
 MULTIPLE SYSTEM ATROPHY
Table 46.2
Clinical domains, features and criteria used in the
diagnosis of multiple system atrophy
Domain I: Autonomic and urinary dysfunction
A. Features:
1. Orthostatic hypotension (20 mmHg systolic or 10 mmHg
diastolic)
2. Urinary incontinence or incomplete bladder emptying
B. Criterion:
Orthostatic fall in blood pressure (30 mmHg systolic or 15
mmHg diastolic)
or
Urinary incontinence (persistent, involuntary partial
or total bladder emptying, accompanied by erectile
dysfunction in men)
or
Both
Domain II: Parkinsonism
A. Features:
1. Bradykinesia (slowness of voluntary movement with
progressive reduction in speed and amplitude during
repetitive actions)
2. Rigidity
3. Postural instability (not caused by primary visual,
vestibular, cerebellar or proprioceptive dysfunction)
4. Tremor (postural, resting or both)
B. Criterion:
Bradykinesia plus at least one of items 2 through 4
Domain III: Cerebellar dysfunction
A. Features:
1. Gait ataxia (wide-based stance with steps of irregular
length and direction)
2. Ataxic dysarthria
3. Limb ataxia
4. Sustained gaze-evoked nystagmus
B. Criterion:
Gait ataxia plus at least one of items 2 through 4
Domain IV: Corticospinal tract dysfunction
A. Features:
1. Extensor plantar responses with hyperreflexia
B. Criterion:
No corticospinal features are used
Adapted from Gilman et al. (1999) with permission.
The putamen may be shrunken and display grayish
discoloration due to iron deposition, whereas involve-
ment of the caudate and globus pallidus is less notice-
able (Dickson et al., 1999b; Colosimo et al., 2005a;
Jellinger et al., 2005). Loss of pigmentation of the sub-
stantia nigra pars compacta and locus ceruleus is also
characteristic. Cerebellar atrophy, along with atrophy
of pons, inferior olives and the inferior and middle
cerebellar peduncles may also be present (Burn and
Jaros, 2001; Jellinger et al., 2005).
315
Table 46.3
Exclusion criteria for the diagnosis of multiple system
atrophy
I. History
A. Symptomatic onset under 30 years of age
B. Family history of a similar disorder
C. Systemic diseases or other identifiable causes for
features listed in Table 2
D. Hallucinations unrelated to medication
II. Physical examination
A. DSM criteria for dementia
B. Prominent slowing of vertical saccades or vertical
supranuclear gaze palsy
C. Evidence of focal cortical dysfunction: aphasia,
alien-limb syndrome, parietal dysfunction
III. Laboratory investigation
A. Metabolic, molecular genetic and imaging evidence
of an alternative cause of features listed in Table 46.2
Adapted from Gilman et al. (1999) with permission.
DSM, Diagnostic and Statistical Manual of Mental Disorders.
46.6.2. Microscopic pathology
On a microscopic level, MSA is characterized by neu-
ronal loss and gliosis involving multiple areas of the
brain, brainstem and spinal cord. The most prominent
neurodegenerative changes occur in putamen, globus
pallidus, substantia nigra, locus ceruleus, cerebellar
cortex, inferior olive, pontine nuclei, dorsal motor
nucleus of the vagus and in the intermediolateral col-
umns and Onufs nucleus in the spinal cord (Lantos
and Papp, 1994; Wenning et al., 1997; Burn and Jaros,
2001; Gilman, 2002). Neuronal loss may also
involve catecholaminergic neurons in the ventrolateral
medulla (Benarroch et al., 1998), neurons in the
EdingerWestphal nucleus and in the hypothalamus
(Shy and Drager, 1960). White-matter pathology, with
myelin degeneration, is also present in MSA (Matsuo
et al., 1998).
As noted earlier, the discovery by Papp et al.,
(1989) of argyrophilic inclusions within the cytoplasm
of oligodendroglia in the brains of MSA patients has
provided the pathological hallmark of MSA
(Fig. 46.1). In fact, MSA is the only neurodegenerative
disease in which oligodendroglial pathology is predo-
minant (Jellinger et al., 2005). These inclusions, now
labeled GCI, are composed of loosely aggregated,
multilayered, tubular filaments that are immunoreac-
tive for ubiquitin and a-synuclein, along with a num-
ber of additional cytoskeletal proteins (Wakabayashi
et al., 1998; Dickson et al., 1999a; Gai et al., 1999,
2003; Burn and Jaros, 2001). a-Synuclein is normally
expressed in only low levels in oligodendrocytes and
316
Fig. 46.1. Glial cytoplasmic inclusions. a-Synuclein staining.
Courtesy of Dr. Dennis Dickson, Mayo Clinic-Jacksonville.
it is uncertain whether in MSA there is impaired abil-
ity to degrade a-synuclein or whether increased
amounts are being formed (Wenning et al., 2003a).
Pountney and colleagues (2005a) have recently identi-
fied aB-crystallin, a chaperone protein that binds to
unfolded proteins and inhibits aggregation, in GCIs
in MSA and have suggested that it may play an impor-
tant role in the development of the GCIs. They have
also demonstrated the presence of SUMO-1, a small
ubiquitin-like modifier protein, within 1030% of
GCIs and speculate that SUMO-1 may be playing a
role in the formation of GCIs and reflect dysfunc-
tion of the proteasomal machinery (Pountney et al.,
2005b). GCIs primarily reside in what has been termed
a system-bound distribution within the suprasegmen-
tal motor systems (primary and supplementary motor
cortex, basal ganglia, corticocerebellar system) and
supraspinal autonomic systems and their targets (Papp
and Lantos, 1994; Burn and Jaros, 2001). In addition
to GCIs, oligodendroglial nuclear inclusions have been
identified in MSA, as have neuronal cytoplasmic and
nuclear inclusions (Papp and Lantos, 1992).
46.7. Diagnostic evaluation
Although no single diagnostic study is capable of pro-
viding incontrovertible proof of the diagnosis of MSA,
useful information that may help to include or exclude
the diagnosis can sometimes be derived from a variety
of examinations.
46.7.1. Structural neuroimaging
Although MRI has uncovered no features that are
pathognomonic for MSA, several abnormalities have
been identified that, if present, increase the probability
R. F. PFEIFFER
of the diagnosis. A band-like rim of hyperintense sig-
nal may be present at the lateral putamenal border on
T2-weighted images. Konagaya and colleagues
(1994) identified this abnormality in 17 of 28 patients
with clinically diagnosed MSA. Some investigators
have suggested that the hyperintensity is due to reac-
tive microgliosis or iron deposition (Schwarz et al.,
1996), whereas others have attributed it to widened
intertissue space produced by putamenal shrinkage
(Konagaya et al., 1998). Hypointensity within the
putamen itself on T2-weighted images may also be
seen in MSA. Hypointensity of the dorsolateral puta-
men coupled with hyperintensity of the putamenal
rim on T2-weighted images is highly specific for
MSA, but its absence does not exclude the diagnosis
(Schrag et al., 1998; Kraft et al., 1999). Increased signal
involving the pyramidal tracts from the cortex down
to the cerebral peduncles has recently been described
on T2-weighted fluid-attenuated inversion recovery
(FLAIR) images, but is not specific for MSA (Limberg
et al., 2005). MRI abnormalities within the posterior
fossa may also be evident in MSA. Atrophy of the cer-
ebellar vermis, pons, middle cerebellar peduncles and
the cerebellar hemispheres is often present, primarily
in patients presenting with predominantly cerebellar
clinical findings (MSA-C). Degeneration of ponto-
cerebellar fibers in the pons and middle cerebellar ped-
uncles sometimes produces hyperintensity within the
pons on T2-weighted images in a cross-like pattern that
has been labeled the hot-cross bun sign (Schrag et al.,
1998). More sophisticated MRI techniques, such as dif-
fusion-weighted imaging, proton magnetic resonance
spectroscopy, magnetization transfer imaging and mag-
netic resonance volumetry may prove to be of value in
the diagnosis of MSA, but are not used in routine
clinical care at this time (Seppi et al., 2005).
46.7.2. Functional neuroimaging
Functional neuroimaging procedures, such as positron
emission tomography (PET) and SPECT, have been
extensively evaluated for potential utility in the diag-
nosis of MSA. However, neither ligands that are presy-
naptic dopaminergic markers nor dopamine receptor
ligands can consistently and reliably differentiate
MSA from other parkinsonian disorders in individual
patients (Quinn, 2005). PET imaging with 18F-de-
oxyglucose may do somewhat better, especially if
computer-assisted interpretation using statistical para-
metric mapping is employed (Eckert et al., 2005;
Juh et al., 2005), but is also still not fully adequate
(Quinn, 2005). Moreover, since neither PET nor
SPECT imaging with these ligands is widely available,
 MULTIPLE SYSTEM ATROPHY
use of functional imaging in the diagnosis of MSA is
currently confined to the research setting.
Multiple studies employing either 6-[18F]fluorodo-
pamine PET or 123I-metaiodobenzylguanidine (MIBG)
scintigraphy to image the sympathetic innervation of
the heart have demonstrated marked denervation in
Parkinsons disease, in contrast to intact innervation
in MSA (Goldstein, 2005; Mathias, 2005). A
meta-analysis of studies involving 245 patients with
Parkinsons disease and 45 with MSA who underwent
cardiac MIBG scintigraphy demonstrated a specificity
of 94.6% in discriminating between the two conditions
(Braune, 2001). The commercial availability of
MIBG and scintigraphy may encourage more extensive
use of this technique in the future in differentiating
MSA from Parkinsons disease.
46.7.3. Autonomic function tests
Autonomic function testing can be valuable both in the
diagnosis of MSA and in the formulation of treatment
plans. Virtually all aspects of autonomic function are
amenable to testing that can illuminate both the char-
acter and severity of any autonomic deficit. Tests of
cardiovascular and urinary function are most fre-
quently employed in evaluation of the MSA patient,
but examination of GI and thermoregulatory function
is also available and can be very useful. The mere pre-
sence of abnormalities on autonomic function testing,
however, does not clinch a diagnosis of MSA; similar,
though typically less severe, abnormalities can also
be present in other conditions, especially Parkinsons
disease.
Tilt-table testing, in which heart rate and blood
pressure are continuously monitored, is a sensitive
and non-invasive method by which the presence of
orthostatic hypotension can be documented. Ortho-
static hypotension has been defined as a drop of 20
mmHg or greater in systolic pressure or a drop of 10
mmHg or greater in diastolic pressure within 3 min-
utes of standing or head-up tilt (Consensus statement
on the definition of orthostatic hypotension, pure auto-
nomic failure and multiple system atrophy, 1996;
Goldstein et al., 2002). An array of additional tests of
cardiovascular function is available and may be part
of the testing battery in the autonomic function labora-
tory. Plasma norepinephrine levels are often normal or
near normal when measured in the supine position in
persons with MSA, but levels do not rise appropriately
with standing (Mathias, 2005). Reversal of the circa-
dian change in blood pressure, assessed by 24-hour
blood pressure and heart rate monitoring, may also
be present in MSA (Mathias, 2005). Tests assessing
parasympathetic cardiovascular function, such as the
317
heart rate response to deep breathing and the Valsalva
maneuver, are also abnormal in MSA (Khurana,
1994).
Assessment of bladder function, with measurement
of postvoid residual urine volume, can be performed
by either bladder sonography or catheterization. Cathe-
terization is simple and requires no special equipment,
but sonography is non-invasive and can even be per-
formed at bedside (Hahn and Ebersbach, 2005).
Videourodynamic testing is a more elegant procedure
that provides a more expansive picture of bladder
function (Sakakibara et al., 2001). Erectile function is
most often evaluated simply by questionnaire; specia-
lized objective testing, such as nocturnal penile tumes-
cence and rigidity assessment, is not usually necessary
(Montorsi, 2005).
A variety of tests is available for assessment of GI
dysfunction in MSA. The modified barium swallow
test is widely employed for evaluation of dysphagia.
Gastric emptying time can be measured by sciniti-
graphic means (Thomaides et al., 2005). In eva-
luating bowel function, colon transit time is most
often assessed by the repetitive ingestion method
(Sakakibara et al., 2004a), and anorectal manometry
can be used to examine anorectal function (Stocchi
et al., 2000).
Tests of thermoregulatory function that have been
employed in MSA include the thermoregulatory sweat
test and the quantitative sudomotor axon reflex test
(Kihara et al., 1991). However, these tests are not
always readily available and have not been extensively
employed in patients with MSA.
46.7.4. Neurophysiological testing
The ability of external anal and urethral sphincter elec-
tromyography (EMG) to distinguish MSA from
Parkinsons disease and other parkinsonian disorders
has been the subject of considerable controversy.
Electromyographic evidence of denervation, due to
anterior horn cell loss in the nucleus of Onufrowicz
(Onufs nucleus) in the sacral spinal cord, is present
in over 80% of individuals with MSA (Wenning
et al., 2004). However, similar abnormalities may be
present in persons with other parkinsonian disorders,
such as Parkinsons disease and progressive supranuc-
lear palsy (Valldeoriola et al., 1995; Colosimo et al.,
2000). In light of this, the idea has emerged that a
normal sphincter EMG renders a diagnosis of MSA
very unlikely, especially if disease symptoms have
been present for more than 5 years, whereas an abnor-
mal EMG cannot be considered as confirmation of a
diagnosis of MSA (Nahm and Freeman, 2003; Paviour
et al., 2005).
318 R. F. PFEIFFER
A number of other neurophysiologic studies may
demonstrate abnormalities in patients with MSA.
Various varieties of evoked potentials somatosen-
sory, visual and auditory may be abnormal in a min-
ority of persons (Abele et al., 2000b), but these are not
of any genuine diagnostic utility. Evidence of periph-
eral neuropathy on nerve conduction velocity testing
has been noted in 24% of 42 subjects with MSA
(Abele et al., 2000a), but this is also a non-specific
finding that has no diagnostic usefulness.
46.7.5. Other examinations
Kimber and colleagues (1997) reported that patients with
MSA do not display a rise in serum growth hormone in
response to administration of the a2-adrenoreceptor
agonist clonidine, whereas individuals with Parkinsons
disease do. However, other investigators have found that
the test does not reliably distinguish the two disease
processes (Tranchant et al., 2000; Pellecchia et al.,
2001; Strijks et al., 2002).
The use of brain parenchyma sonography (transcra-
nial ultrasound) to differentiate Parkinsons disease
from MSA and other atypical parkinsonian disorders
has also been advocated (Benecke, 2002; Walter
et al., 2003). In preliminary studies, hyperechogenicity
of the substantia nigra was present in 96% of in-
dividuals with Parkinsons disease but in only 9% of
patients with atypical parkinsonian syndromes,
whereas lentiform nucleus hyperechogenicity was
evident in 77% of persons with atypical parkinsonism
and in only 23% of those with Parkinsons disease
(Walter et al., 2003). Investigations that are more
recent have reinforced these findings (Behnke et al.,
2005). Although the non-invasive nature of sono-
graphy is appealing, the practical utility of this proce-
dure in individual patients, especially those with
suspected MSA, remains to be determined.
46.8. Treatment
There has been a general perception that MSA is
rapidly and relentlessly progressive and completely
refractory to any treatment measures. Although it is
certainly correct that no treatment modality has
demonstrated an ability to alter the progression of the
underlying disease process itself, it is incorrect to con-
clude that there are no useful symptomatic treatment
measures that may be marshaled in the management
of MSA. In fact, it is often possible to ameliorate the
non-motor features of MSA and even the motor fea-
tures may at least transiently demonstrate some
response to treatment. However, the relative rarity of
MSA has rendered it exceedingly difficult to mount
controlled trials of targeted treatment modalities. Thus,
the available evidence of efficacy for various agents is
largely empiric.
46.8.1. Motor features
The parkinsonian features of MSA are treated with the
same medications that are invoked in the treatment of
Parkinsons disease. A clinically meaningful, though
typically suboptimal, response to levodopa is evident
in 3365% of patients with MSA (Rajput et al.,
1990; Hughes et al., 1992b; Parati et al., 1993; Wen-
ning et al., 1994; Colosimo and Pezzella, 2002; Colo-
simo et al., 2005b; Gilman et al., 2005). Individuals
with MSA may require larger levodopa doses than
individuals with Parkinsons disease to generate a
recognizable response. Therefore, a therapeutic trial
of levodopa should not be abandoned until a levodopa
dose of at least 1000 mg/day is reached (Gilman et al.,
1998, 1999), although adverse effects such as ortho-
static hypotension may prohibit titration to such levels.
Wenning and colleagues (2005a) recently reported that
41% of 337 patients with MSA experienced a benefi-
cial response to levodopa at a mean daily dose of
686 mg, with the response lasting for an average of 4
years. Although the initial improvement diminishes
with the passage of time in most individuals, Hughes
and colleagues (1992b) reported that over 50% of the
MSA patients they studied who initially experienced
improvement with levodopa remained partially respon-
sive until death. Levodopa-induced dyskinesia devel-
ops in approximately 50% of responders and, in
contrast to Parkinsons disease, is often dystonic in
character, preferentially involving the face and neck
(Boesch et al., 2002).
The experience with other antiparkinsonian agents
has been more discouraging. Although an occasional
patient will derive some benefit from a dopamine
agonist, most do not and tolerance of these agents is
generally poor. Conflicting reports regarding the effec-
tiveness of amantadine have been published. Rajput
and colleagues (1998) noted improvement on amanta-
dine in over 60% of the 13 MSA patients they studied,
but in a recent double-blind, placebo-controlled,
cross-over trial involving 8 subjects, no statistically
significant improvement with amantadine could be
documented (Wenning, 2005). However, the investiga-
tors did note a trend toward improvement with aman-
tadine and commented that the small sample size
may have obscured mild amantadine-related benefit.
Anticholinergic drugs are generally ineffective in
alleviating parkinsonism in individuals with MSA,
but an occasional patient may benefit (Polinsky,
1984; Wenning et al., 2005). Botulinum toxin A
 MULTIPLE SYSTEM ATROPHY
injections may be effective in reducing blepharospasm
and limb dystonia, but some investigators caution
against using it to treat cervical dystonia or antecollis
because of the risk of inducing severe dysphagia (Tho-
bois et al., 2001; Wenning et al., 2005). Stereotactic and
deep brain stimulation surgery has generally been consid-
ered ineffective in the treatment of MSA. However,
investigators have described sustained improvement in
4 individuals who underwent bilateral high-frequency
stimulation of the subthalamic nuclei and recommended
a larger prospective study (Visser-Vandewalle et al.,
2003). In contrast, the same procedure has been reported
to aggravate dysarthria, dysphagia and gait impairment in
MSA (Tarsy et al., 2003).
There is no proven effective treatment for the
cerebellar dysfunction that develops in MSA.
46.8.2. Autonomic features
46.8.2.1. Genital dysfunction
Although erectile dysfunction in MSA responds to
cyclic guanosine monophosphate phosphodiesterase
inhibitors such as sildenafil and its relatives, these
drugs have also demonstrated a predilection to produce
plummeting blood pressure with severe symptoms
of orthostatic hypotension, especially in men with
pre-existent orthostatic hypotension (Hussain et al.,
2001). It thus seems wise to avoid these drugs in
men with MSA. Other treatment modalities for erectile
dysfunction are available. Intracavernosal injections of
alprostadil are effective, but the necessity for and
discomfort with the injections deters many from this
treatment modality. Priapism and the formation of
fibrotic nodules within the corpora are other potential
complications (Hatzichristou, 1999). Alprostadil
can also be administered by intraurethral instillation.
Vacuum devices, used in conjunction with constrictor
bands, are also effective, but patient acceptance of
the devices is low.
46.8.2.2. Urinary dysfunction
Appropriate treatment of bladder dysfunction depends
on the specific type of impairment present. The
approach to treatment of an overactive bladder is very
different from that toward an underactive or areflexic
bladder. Because both types of bladder dysfunction
may occur in MSA, use of appropriate urodynamic
and neurophysiologic testing is of immense value in
setting the treatment course. For detrusor overactivity
with urinary frequency and urgency, peripherally
acting anticholinergic drugs are the treatment of
choice. Oxybutynin has been the standard-bearer for
many years, but the recent introduction of several
newer, more selective anticholinergic drugs (trospium,
319
solifenacin, darifenacin) with a better therapeutic
index holds the promise of reduced toxicity. For indi-
viduals who cannot tolerate anticholinergic drugs,
other treatment approaches are available. Gabapentin
has been reported to improve symptoms of overactive
bladder (Kim et al., 2004), although it has not been
specifically tested in MSA. Desmopressin, admin-
istered at bedtime, can be used to reduce nocturia
(Dasgupta and Haslam, 1999; Fowler, 1999). For
individuals with an underactive or hypotonic bladder,
anticholinergic drugs are contraindicated. Instead,
methods to promote bladder emptying are needed.
Unfortunately, the treatment choices for this dysfunc-
tion are more limited. If an element of prostatic hyper-
trophy is present, a-blocking agents such as tamsulosin
are appropriate, but if the problem is strictly due to a
hypocontractile detrusor muscle, intermittent catheter-
ization is the best treatment option (Fowler, 1999).
For those individuals with detrusor-sphincter dys-
synergia, anticholinergic drugs will diminish detrusor
overactivity but intermittent catheterization may be
necessary to deal with the failure of the urethral
sphincter to relax. Botulinum toxin A injections
into the urethral sphincter have also been used suc-
cessfully on an experimental basis in this regard,
though not in individuals with MSA (Smith et al.,
2005).
46.8.2.3. Cardiovascular dysfunction
Management of orthostatic hypotension in persons
with MSA can be very challenging. Both pharmacolo-
gic and non-pharmacologic treatment approaches may
be necessary. Non-pharmacologic measures are often
overlooked by physicians, but are simple, inexpensive
and often effective. Avoidance of high environmental
temperature, large meals, alcohol, prolonged recum-
bency, straining during voiding or defecation, exces-
sive exercise and sudden changes in position can
reduce the risk of serious postural hypotension
(Mathias, 2003, 2005). Sleeping with the head of
the bed elevated will reduce the supine hypertension
that often occurs in MSA (Mathias, (2005)). The
mechanism for this nocturnal blood pressure increase
is not entirely clear, but may involve baroreflex
abnormalities or shifting of fluid into the central vas-
cular compartment, producing an effective increase in
blood volume (Goldstein et al., 2003; Mathias,
2005). Elevating the head of the bed may also dimin-
ish orthostatic hypotension upon getting out of bed in
the morning, possibly by reducing nocturnal sodium
loss that occurs because of increased renal glomerular
filtration prompted by the effective increase in blood
volume (Pechere-Bertschi et al., 1998). Increased salt
320 R. F. PFEIFFER
intake can also diminish orthostatic symptoms by
increasing intravascular volume. The most effective
non-pharmacologic measure for reducing orthostatic
symptoms, however, may be the use of individually
measured and fitted waist-high support stockings.
Unfortunately, the stockings are difficult to don and
very uncomfortable to wear, thus patients often resist
wearing them. An abdominal binder also reduces
venous pooling and is often better tolerated than the
stockings (Mathias, 2003). The initial step in medical
management of orthostatic hypotension is usually
administration of the mineralocorticoid fludrocortisone
(Mathias, 2005; Wenning et al., 2005). If this is
insufficiently effective, midodrine can be added to
the treatment regimen. In a double-blind study of 171
patients (40 with MSA), Low and colleagues (1997)
reported that midodrine, an a-adrenergic agonist, was
both effective and safe in reducing symptomatic ortho-
static hypotension. The authors cautioned that mido-
drine should be avoided after 6 p.m. in order to reduce
the risk of inducing nocturnal supine hypertension.
Other drugs that may be directly helpful in alleviating
orthostatic hypotension include ephedrine, indometa-
cin, yohimbine and L-threo-dihidroxy-phenylserine.
Octreotide, a somatostatin analog, ameliorates post-
prandial hypotension by inhibiting release of vasodila-
tory GI peptides (Mathias, 2003). Desmopressin can
diminish orthostatic hypotension in the morning by
reducing nocturnal diuresis (Mathias, 2003). Increas-
ing red cell mass by means of erythropoietin administra-
tion has also been reported to improve orthostatic
hypotension (Winkler et al., 2002).
46.8.2.4. Gastrointestinal dysfunction
Very little has been written specifically to address
treatment of GI dysfunction in MSA. However, mea-
sures that have been successfully employed in the
management of GI problems in Parkinsons disease
(Pfeiffer, 2005a) are likely to be useful in MSA also.
Anticholinergic drugs have traditionally been used to
alleviate drooling, but adverse effects are sometimes
problematic. An approach that may limit the potential
for toxicity while still reducing saliva production is
the employment of one drop of 1% atropine ophthal-
mic solution sublingually twice daily (Hyson et al.,
2002). Salivary gland injections of both botulinum
toxin A and B have also been successfully employed
to reduce saliva production in persons with parkinson-
ism, including some individuals with MSA (Mancini
et al., 2003; Racette et al., 2003). Although anti-
parkinson medications sometimes improve dysphagia
in Parkinsons disease, no similar information exists
regarding MSA. Swallowing therapy techniques may
be helpful if patients are experiencing dysphagia with
aspiration, but percutaneous endoscopic gastrostomy
tube placement is sometimes necessary. Domperidone,
where available, is effective in accelerating gastric
emptying in persons with Parkinsons disease and,
presumably, would also do so in the setting of MSA,
although no specific information is available. Tega-
serod has been reported to improve gastric emptying
in normal volunteers and in critically ill patients in
intensive care units (Degen et al., 2001; Banh et al.,
2005). Whether it might do so in individuals with
MSA or Parkinsons disease is unknown. Management
of constipation due to slowed colonic transit in MSA
can be patterned after that practiced for Parkinsons
disease (Pfeiffer, 2005a, b). Increased fiber and fluid
should be the first step, along with a stool softener if
necessary. If that does not suffice, lactulose can be
added to the treatment regimen. The next rung up the
treatment ladder is the use of polyethylene glycol elec-
trolyte balanced solutions, which have specifically
been studied in patients with MSA and found to be
effective (Eichhorn and Oertel, 2001). Finally, enemas
are available, if needed. The value of prokinetic agents
in treating colonic dysmotility is uncertain. The other
component of bowel dysfunction in MSA, defecatory
dysfunction due to disturbed function of the anorectal
musculature, presents a much more difficult manage-
ment problem. In patients with Parkinsons disease,
subcutaneous apomorphine injections and botulinum
toxin A injections into the external anal sphincter have
been employed with benefit (Mathers et al., 1989;
Edwards et al., 1993), but there is no experience with
these treatment modalities in MSA.
46.9. Conclusion
In the almost four decades since Graham and Oppen-
heimer first recognized MSA as a distinct disease pro-
cess, awareness and knowledge concerning the clinical
features and pathophysiology of MSA have soared.
However, progress in discovering effective treatment
has languished behind the scientific advances. Strides
have been made, but there is still a tremendously long
way to travel. Our blindness has been cured and we
recognize the elephant. The daunting task that still
faces us is taming the beast.
References
Abele M, Schulz JB, Burk K et al. (2000a). Nerve conduc-
tion studies in multiple system atrophy. Eur Neurol 43:
221223.
Abele M, Schulz JB, Burk K et al. (2000b). Evoked poten-
tials in multiple system atrophy (MSA). Acta Neurol
Scand 101: 111115.
 MULTIPLE SYSTEM ATROPHY
Adams RD, Salam-Adams M (1986). Striatonigral degeneration.
In: PJ Vinken, GW Bruyn, HL Klawans (Eds.), Extrapyr-
amidal Disorders. Handbook of Clinical Neurology, Vol. 5
(49). Elsevier, Amsterdam, pp. 205212.
Adams RD, van Bogaert L, van der Eecken H (1961).
Degenerescence nigro-striees et cerebello-nigro-striee. (1997). Incidence of progressive supranuclear palsy and
Psychiatry Neurol 142: 219259 (Article in French).
Arndt M (1894). Zur Pathologie des Kleinhirns. Arch
Psychiatr Nervenkr 26: 404429 (Article in German).
Askmark H, Eeg-Olofsson KE, Johansson A et al.
(2001). Parkinsonism and neck extensor myopathy. A
new syndrome or coincidental findings? Arch Neurol 58:
232237.
Bandmann O, Sweeney MG, Daniel SE et al. (1997). Multiple-
system atrophy is genetically distinct from identified inher-
ited causes of spinocerebellar degeneration. Neurology 49:
15981604.
Banh HL, MacLean C, Topp T et al. (2005). The use of tega-
serod in critically ill patients with impaired gastric moti-
lity. Clin Pharmacol Ther 77: 583586.
Bannister R, Gibson W, Michaels L et al. (1981). Laryngeal
abductor paralysis in multiple system atrophy. A report on
three necropsied cases, with observations on the laryngeal
muscles and the nuclei ambigui. Brain 104: 351368.
Beck RO, Betts CD, Fowler CJ (1994). Genitourinary dys-
function in multiple system atrophy: clinical features and
treatment in 62 cases. J Urol 151: 13361341.
Behnke S, Berg D, Naumann M et al. (2005). Differentiation
of Parkinsons disease and atypical parkinsonian syn-
dromes by transcranial ultrasound. J Neurol Neurosurg
Psychiatry 76: 423425.
Benarroch EE, Smithson IL, Low PA et al. (1998). Depletion
of catecholaminergic neurons of the rostral ventrolateral
medulla in multiple systems atrophy with autonomic
failure. Ann Neurol 43: 156163.
Benecke R (2002). Clinical features and laboratory findings
for differentiating parkinsonian syndromes. J Neurol
249 (Suppl 3): III/6III14.
Benrud-Larson LM, Sandroni P, Schrag A et al. (2005). Depres-
sive symptoms and life satisfaction in patients with multiple
system atrophy. Mov Disord 20: 951957.
Ben-Shlomo Y, Wenning GK, Tison F et al. (1997). Survival
of patients with pathologically proven multiple system
atrophy: a meta-analysis. Neurology 48: 384393.
Berciano J, Wenning GK (2005). The Lewis family revisited:
no evidence for autosomal dominant multiple system atro-
phy. Parkinsonism Relat Disord 11: 363365.
Boesch SM, Wenning GK, Ransmayr G et al. (2002). Dysto-
nia in multiple system atrophy. J Neurol Neurosurg Psy-
chiatry 72: 300303.
Boeve BF, Silber MH, Ferman TJ et al. (2001). Association
of REM sleep behavior disorder and neurodegenerative
disease may reflect an underlying synucleinopathy. Mov
Disord 16: 622630.
Bonnet AM, Pichon J, Vidailhet M et al. (1997). Urinary dis-
turbances in striatonigral degeneration and Parkinsons
disease: clinical and urodynamic aspects. Mov Disord
12: 509513.
321
Bower JH (2000). Multiple system atrophy. In: CH Adler, JE
Ahlskog (Eds.), Parkinsons Disease and Movement Disor-
ders: Diagnosis and Treatment Guidelines for the Practi-
cing Physician. Humana Press, Totowa, NJ, pp. 235242.
Bower JH, Maraganore DM, McDonnell SK et al.
multiple system atrophy in Olmsted County, Minnesota,
19761990. Neurology 49: 12841288.
Braune S (2001). The role of cardiac metaiodobenzylguani-
dine uptake in the differential diagnosis of parkinsonian
syndromes. Clin Auton Res 11: 351355.
Burn DJ, Jaros E (2001). Multiple system atrophy: cellular
and molecular pathology. Mol Pathol 54: 419426.
Cairns NJ, Atkinson PF, Kovacs T et al. (1997). Apolipopro-
tein E e4 allele frequency in patients with multiple system
atrophy. Neurosci Lett 221: 161164.
Chio A, Magnani C, Schiffer D (1998). Prevalence of Par-
kinsons disease in Northwestern Italy: comparison of tra-
cer methodology and clinical ascertainment of cases. Mov
Disord 13: 400405.
Christine CW, Aminoff MJ (2004). Clinical differentiation
of parkinsonian syndromes: prognostic and therapeutic
relevance. Am J Med 117: 412419.
Chrysostome V, Tison F, Yekhlef F et al. (2004). Epidemiol-
ogy of multiple system atrophy: a prevalence and pilot risk
factor study in Aquitaine, France. Neuroepidemiology 23:
201208.
Cohen J, Low P, Fealey R et al. (1987). Somatic and auto-
nomic function in progressive autonomic failure and
multiple system atrophy. Ann Neurol 22: 692699.
Colosimo C, Pezzella FR (2002). The symptomatic treatment
of multiple system atrophy. Eur J Neurol 9: 195199.
Colosimo C, Albanese A, Hughes AJ et al. (1995). Some
specific clinical features differentiate multiple system
atrophy (striatonigral variety) from Parkinsons disease.
Arch Neurol 52: 294298.
Colosimo C, Inghilleri M, Chaudhuri KR (2000). Parkinsons
disease misdiagnosed as multiple system atrophy by
sphincter electro-myography. J Neurol 247: 559561.
Colosimo C, Geser F, Wenning GK (2005a). Clinical spec-
trum and pathological features of multiple system atrophy.
In: M LeDoux, (Ed.), Animal Models of Movement
Disorders. Elsevier, Amsterdam, pp. 541570.
Colosimo C, Tiple D, Wenning GK (2005b). Management of
multiple system atrophy: state of the art. J Neural Transm
112: 16951704.
Combarros O, Infante J, Llorca J et al. (2003). Interleukin-
1A (-889) genetic polymorphism increases the risk of mul-
tiple system atrophy. Mov Disord 18: 13851386.
Consensus statement on the definition of orthostatic hypoten-
sion, pure autonomic failure, and multiple system atrophy
(1996). J Neurol Sci 144: 218219.
Dasgupta P, Haslam C (1999). Treatment of neurogenic
bladder dysfunction. In: CJ Fowler, (Ed.), Neurology of
Bladder, Bowel, and Sexual Dysfunction. Butterworth
Heinemann, Boston, pp. 163183.
Degen L, Matzinger D, Merz M et al. (2001). Tegaserod, a 5-
HT4 receptor partial agonist, accelerates gastric emptying
322 R. F. PFEIFFER
and gastrointestinal transit in healthy male subjects.
Aliment Pharmacol Ther 15: 17451751.
Dejerine J, Thomas AA (1900). Latrophie olivo-ponto-cere-
belleuse. Nouvelle Iconographie de la Salpetriere 13:
330370 (Article in French).
Dickson DW, Liu WK, Hardy J et al. (1999a). Widespread
alterations of asynuclein in multiple system atrophy. Am
J Pathol 155: 12411251.
Dickson DW, Lin W, Liu WK et al. (1999b). Multiple system
atrophy: a sporadic synucleinopathy. Brain Pathol 9:
721732.
Dujardin K, Defebvre L, Krystkowiak P et al. (2003). Exe-
cutive function differences in multiple system atrophy
and Parkinsons disease. Parkinsonism Relat Disord 9:
205211.
Eckert T, Barnes A, Dhawan V et al. (2005). FDG PET in
the differential diagnosis of parkinsonian disorders. Neu-
roimage 26: 912921.
Edwards LL, Quigley EM, Harned RK et al. (1993). Defeca-
tory function in Parkinsons disease: response to apomor-
phine. Ann Neurol 33: 490493.
Eichhorn TE, Oertel WH (2001). Macrogol 3350/electrolyte
improves constipation in Parkinsons disease and multiple
system atrophy. Mov Disord 16: 11761177.
Fetoni V, Soliveri P, Monza D et al. (1999). Affective symp-
toms in multiple system atrophy and Parkinsons disease:
response to levodopa therapy. J Neurol Neurosurg Psy-
chiatry 66: 541544.
Fowler CJ (1999). Neurological disorders of micturition and
their treatment. Brain 122: 12131231.
Frumkin H (1998). Multiple system atrophy following
chronic carbon disulfide exposure. Environ Health Per-
spect 106: 611613.
Gai WP, Power JH, Blumbergs PC et al. (1998). Multiple
system atrophy: a new alpha-synuclein disease? Lancet
352: 547548.
Gai WP, Power JH, Blumbergs PC et al. (1999). Alpha-synu-
clein immunoisolation of glial inclusions from multiple
system atrophy brain tissue reveals multiprotein compo-
nents. J Neurochem 73: 20932100.
Gai WP, Pountney DL, Power JH et al. (2003). alpha-Synu-
clein fibrils constitute the central core of oligodendroglial
inclusion filaments in multiple system atrophy. Exp Neu-
rol 181: 6878.
Geser F, Wenning GK (2005). Multiple system atrophy. In: I
Litvan, (Ed.), Atypical Parkinsonian Disorders. Humana
Press, Totowa, NJ, pp. 335360.
Ghorayeb I, Yekhlef F, Chrysostome V et al. (2002). Sleep
disorders and their determinants in multiple system atro-
phy. J Neurol Neurosurg Psychiatry 72: 798800.
Gilman S (2002). Multiple system atrophy. In: JJ Jankovic, E
Tolosa (Eds.), Parkinsons Disease and Movement Disorders.
Lippincott Williams & Wilkins, Philadelphia, pp. 170184.
Gilman S, Low P, Quinn N et al. (1998). Consensus state-
ment on the diagnosis of multiple system atrophy. Ameri-
can Autonomic Society and American Academy of
Neurology. Clin Auton Res 8: 359362.
Gilman S, Low PA, Quinn N et al. (1999). Consensus
statement on the diagnosis of multiple system atrophy.
J Neurol Sci 163: 9498.
Gilman S, May SJ, Shults CW et al. (2005). The North
American Multiple System Atrophy Study Group.
J Neural Transm 112: 16871694.
Goldstein DS (2005). Cardiovascular autonomic dysfunction.
In: RF Pfeiffer, I BodisWollner (Eds.), Parkinsons Dis-
ease and Nonmotor Dysfunction. Humana Press, Totowa,
NJ, pp. 149157.
Goldstein DS, Robertson D, Esler M et al. (2002). Dysauto-
nomias: clinical disorders of the autonomic nervous
system. Ann Intern Med 137: 753763.
Goldstein DS, Pechnik S, Holmes C et al. (2003). Association
between supine hypertension and orthostatic hypotension
in autonomic failure. Hypertension 42: 136142.
Gouider-Khouja N, Vidailhet M, Bonner AM et al.
(1995). Pure striatonigral degeneration and Parkinsons
disease: a comparative clinical study. Mov Disord 10:
288294.
Graham JG, Oppenheimer DR (1969). Orthostatic hypoten-
sion and nicotine sensitivity in a case of multiple system
atrophy. J Neurol Neurosurg Psychiatry 32: 2834.
Hahn K, Ebersbach G (2005). Sonographic assessment of
urinary retention in multiple system atrophy and idiopathic
Parkinsons disease. Mov Disord 20: 14991502.
Hanna PA, Jankovic J, Kirkpatrick JB (1999). Multiple sys-
tem atrophy: the putative causative role of environmental
toxins. Arch Neurol 56: 9094.
Hatzichristou DG (1999). Treatment of sexual dysfunction
and infertility in patients with neurologic diseases. In:
CJ Fowler, (Ed.), Neurology of Bladder, Bowel, and Sex-
ual Dysfunction. Butterworth Heinemann, Boston, pp.
209225.
Healy DG, Abou-Sleiman PM, Quinn N et al. (2005).
European MSA Study Group. UCHL-1 gene in multiple
system atrophy: a haplotype tagging approach. Mov Disord
20 (10): 13381343.
Higo R, Tayama N, Watanabe T et al. (2003). Videofluoro-
scopic and manometric evaluation of swallowing function
in patients with multiple system atrophy. Ann Otol Rhinol
Laryngol 112: 630636.
Hughes AJ, Ben-Shlomo Y, Daniel SE et al. (1992a). What
features improve the accuracy of clinical diagnosis in Par-
kinsons disease: a clinicopathologic study. Neurology 42:
11421146.
Hughes AJ, Colosimo C, Kleedorfer B et al. (1992b). The
dopaminergic response in multiple system atrophy. J Neu-
rol Neurosurg Psychiatry 55: 10091013.
Hughes AJ, Daniel SE, BenShlomo Y et al. (2002). The
accuracy of diagnosis of parkinsonian syndromes in a spe-
cialist movement disorder service. Brain 125: 861870.
Hussain IF, Brady CM, Swinn MJ et al. (2001). Treatment of
erectile dysfunction with sildenafil citrate (Viagra) in
parkinsonism due to Parkinsons disease or multiple sys-
tem atrophy with observations on orthostatic hypotension.
J Neurol Neurosurg Psychiatry 71: 371374.
 MULTIPLE SYSTEM ATROPHY
Hyson HC, Johnson AM, Jog MS (2002). Sublingual
atropine for sialorrhea secondary to parkinsonism: a pilot
study. Mov Disord 17: 13181320.
Infante J, Llorca J, Berciano J et al. (2005). Interleukin-8,
intercellular adhesion molecule-1 and tumor necrosis
factor-a gene polymorphisms and the risk for multiple
system atrophy. J Neurol Sci 228: 1113.
Iranzo A, Santamaria J, Tolosa E (2000). Continuous posi-
tive air pressure eliminates nocturnal stridor in multiple
system atrophy. Barcelona Multiple System Atrophy
Study Group. Lancet 356: 13291330.
Iranzo A, Santamaria J, Tolosa E et al. (2004). Long-term
effect of CPAP in the treatment of nocturnal stridor in
multiple system atrophy. Neurology 63: 930932.
Iranzo A, Santamaria J, Rye DB et al. (2005). Characteristics
of idiopathic REM sleep behavior disorder and that asso-
ciated with MSA and PD. Neurology 65: 247252.
Jellinger KA, Seppi K, Wenning GK (2005). Grading of neu-
ropathology in multiple system atrophy: proposal for a
novel scale. Mov Disord 20 (Suppl 12): S29S36.
Johnsen JA, Miller VT (1986). Tobacco intolerance in multi-
ple system atrophy. Neurology 36: 986988.
Juh R, Pae CU, Lee CU et al. (2005). Voxel based com-
parison of glucose metabolism in the differential diagnosis
of the multiple system atrophy using statistical parametric
mapping. Neurosci Res 52: 211219.
Kaufmann H, Biaggioni I (2003). Autonomic failure in neu-
rodegenerative disorders. Semin Neurol 23: 351363.
Khurana RK (1994). Cholinergic dysfunction in Shy-Drager
syndrome: effect of the parasympathomimetic agent,
bethanechol. Clin Auton Res 4: 513.
Kihara M, Sugenoya J, Takahashi A (1991). The assessment
of sudomotor dysfunction in multiple system atrophy. Clin
Auton Res 1: 297302.
Kim HS, Lee MS (2003). Frequencies of single nucleotide
polymorphism in alcohol dehydrogenase7 gene in patients
with multiple system atrophy and controls. Mov Disord
18: 10651067.
Kim YT, Kwon DD, Kim J et al. (2004). Gabapentin for
overactive bladder and nocturia after anticholinergic fail-
ure. Int Braz J Urol 30: 275278.
Kimber JR, Watson L, Mathias CJ (1997). Distinction of
idiopathic Parkinsons disease from multiple-system atro-
phy by stimulation of growth-hormone release with cloni-
dine. Lancet 349: 18771881.
Kirchhof K, Apostolidis AN, Mathias CJ et al. (2003). Erec-
tile and urinary dysfunction may be the presenting features
in patients with multiple system atrophy: a retrospective
study. Int J Impot Res 15: 293298.
Klein C, Brown R, Wenning G et al. (1997). The cold hands
sign in multiple system atrophy. Mov Disord 12: 514518.
Konagaya M, Konagaya Y, Iida M (1994). Clinical and
magnetic resonance imaging study of extrapyramidal
symptoms in multiple system atrophy. J Neurol Neurosurg
Psychiatry 57: 15281531.
Konagaya M, Sakai M, Matsuoka Y et al. (1998). Patho-MR
imaging study in the putaminal margin in multiple system
atrophy. No To Shinkei 50: 383385 (Article in Japanese).
323
Kraft E, Schwarz A, Trenkwalder C et al. (1999). The
combination of hypointense and hyperintense signal
changes on T2-weighted magnetic resonance imaging
sequences: a specific marker of multiple system atrophy?
Arch Neurol 56: 225228.
Kumazawa K, Sobue G, Nakao N et al. (1989). Postganglio-
nic sudomotor function in multiple system atrophy. Rinsho
Shinkeigaku 29: 13571363 (Article in Japanese).
Kurisaki H (1999). Prognosis of multiple system atrophy
survival time with or without tracheostomy. Rinsho
Shinkeigaku 39: 503507 (Article in Japanese).
Lange KW, Tucha O, Alders GL et al. (2003). Differentiation
of parkinsonian syndromes according to differences in
executive functions. J Neural Transm 110: 983995.
Lantos PL, Papp MI (1994). Cellular pathology of multiple
system atrophy: a review. J Neurol Neurosurg Psychiatry
57: 129133.
Lewis P (1964). Familial orthostatic hypotension. Brain 87:
719728.
Limberg N, Jeavons S, Robertson T et al. (2005). Pyramidal
tract imaging in multiple-system atrophy. Mov Disord 20:
15271528.
Litvan I, Goetz CG, Jankovic J et al. (1997). What is the
accuracy of the clinical diagnosis of multiple system
atrophy? A clinicopathologic study. Arch Neurol 54:
937944.
Low PA, Gilden JL, Freeman R et al. (1997), for the Mido-
drine Study Group. Efficacy of midodrine vs. placebo in
neurogenic orthostatic hypotension: a randomized, dou-
ble-blind multicenter study. JAMA 277: 10461051.
Mabuchi N, Hirayama M, Koike Y et al. (2005). Progression
and prognosis in pure autonomic failure (PAF): compari-
son with multiple system atrophy. J Neurol Neurosurg
Psychiatry 76: 947952.
Mancini F, Zangaglia R, Cristina S et al. (2003). Double-
blind, placebo-controlled study to evaluate the efficacy
and safety of botulinum toxin type A in the treatment of
drooling in parkinsonism. Mov Disord 18: 685688.
Mathers SE, Kempster PA, Law PJ et al. (1989). Anal
sphincter dysfunction in Parkinsons disease. Arch Neurol
46: 10611064.
Mathias CJ (2003). Autonomic diseases: management.
J Neurol Neurosurg Psychiatry 74 (Suppl 3): iii42iii47.
Mathias CJ (2005). Cardiovascular autonomic dysfunction
in Parkinsons disease and parkinsonian syndromes. In:
M Ebadi, RF Pfeiffer (Eds.), Parkinsons Disease. CRC
Press, Boca Raton, pp. 295317.
Mathias CJ, Mallipeddi R, Bleasdale-Barr K (1999). Symp-
toms associated with orthostatic hypotension in pure auto-
nomic failure and multiple system atrophy. J Neurol 246:
893898.
Matsuo A, Akiguchi I, Lee GC et al. (1998). Myelin degen-
eration in multiple system atrophy detected by unique
antibodies. Am J Pathol 153: 735744.
Merlo IM, Occhini A, Pacchetti C et al. (2002). Not paraly-
sis, but dystonia causes stridor in multiple system atrophy.
Neurology 58: 649652.
324 R. F. PFEIFFER
Montorsi F (2005). Assessment, diagnosis, and investigation
of erectile dysfunction. Clin Cornerstone 7: 2935.
Morris HR, Vaughan JR, Datta SR et al. (2000). Multiple sys-
tem atrophy/progressive supranuclear palsy: a-synuclein,
synphilin, tau, and APOE. Neurology 55: 19181920.
Muller J, Wenning GK, Verny M et al. (2001). Progression
of dysarthria and dysphagia in postmortem-confirmed
parkinsonian disorders. Arch Neurol 58: 259264.
Nahm F, Freeman R (2003). Sphincter electromyography
and multiple system atrophy. Muscle Nerve 28: 1826.
Nee LE, Gomez MR, Dambrosia J et al. (1991). Environmen-
tal-occupational risk factors and familial associations in
multiple system atrophy: a preliminary investigation. Clin
Auton Res 1: 913.
Nee LE, Scott J, Polinsky RJ (1993). Olfactory dysfunction
in the Shy-Drager syndrome. Clin Auton Res 3: 281282.
Nicholl DJ, Bennett P, Hiller L et al. (1999), for the Eur-
opean Study Group on Atypical Parkinsonism. A study
of five candidate genes in Parkinsons disease and related
neurodegenerative disorders. Neurology 53: 14151421.
Oertel WH, Wachter T, Quinn NP et al. (2003). Redu-
ced genital sensitivity in female patients with multiple sys-
tem atrophy of parkinsonian type. Mov Disord 18: 430432.
Papp MI, Lantos PL (1992). Accumulation of tubular struc-
tures in oligodendroglial and neuronal cells as the basic
alteration in multiple system atrophy. J Neurol Sci 107:
172182.
Papp MI, Lantos PL (1994). The distribution of oligodendro-
glial inclusions in multiple system atrophy and its rele-
vance to clinical symptomatology. Brain 117: 235243.
Papp MI, Kahn JE, Lantos PL (1989). Glial cytoplasmic
inclusions in the CNS of patients with multiple system atro-
phy (striatonigral degeneration, olivopontocerebellar atro-
phy and Shy-Drager syndrome). J Neurol Sci 94: 79100.
Parati EA, Fetoni V, Geminiani GC et al. (1993). Response
to L-DOPA in multiple system atrophy. Clin Neurophar-
macol 16: 139144.
Pathak A, Lapeyre-Mestre M, Montastruc JL et al.
(2005). Heat-related morbidity in patients with orthostatic
hypotension and primary autonomic failure. Mov Disord
20: 12131219.
Paviour DC, Williams D, Fowler CJ et al. (2005). Is sphinc-
ter electromyography a helpful investigation in the diagno-
sis of multiple system atrophy? A retrospective study with
pathological diagnosis. Mov Disord 20: 14251430.
Pellecchia MT, Salvatore E, Pivonello R et al. (2001). Stimu-
lation of growth hormone release in multiple system atro-
phy, Parkinsons disease, and idiopathic cerebellar ataxia.
Neurol Sci 22: 7980.
Pechere-Bertschi A, Nussberger J, Biollaz J et al. (1998). Cir-
cadian variations of renal sodium handling in patients with
orthostatic hypotension. Kidney Int 54: 12761282.
Pezzoli G, Canesi M, Galli C (2004). An overview of parkin-
sonian syndromes: data from the literature and from an
italian data-base. Sleep Med 5: 181187.
Pfeiffer RF (2005a). Gastrointestinal dysfunction in Parkinsons
disease. In: M Ebadi, RF Pfeiffer (Eds.), Parkinsons Disease.
CRC Press, Boca Raton, pp. 259273.
Pfeiffer RF (2005b). Intestinal dysfunction. In: RF Pfeiffer, I
Bodis-Wollner (Eds.), Parkinsons Disease and Nonmotor
Dysfunction. Humana Press, Totowa, NJ, pp. 115125.
Pierangeli G, Provini F, Maltoni P et al. (2001). Nocturnal
body core temperature falls in Parkinsons disease but
not in multiple-system atrophy. Mov Disord 16: 226232.
Plante-Bordeneuve V, Bandmann O, Wenning G et al.
(1995). CYP2D6-debrisoquine hydroxylase gene poly-
morphism in multiple system atrophy. Mov Disord 10:
277278.
Plazzi G, Corsini R, Provini F et al. (1997). REM sleep beha-
vior disorders in multiple system atrophy. Neurology 48:
10941097.
Polinsky RJ (1984). Multiple system atrophy. Clinical
aspects, pathophysiology, and treatment. Neurol Clin 2:
487498.
Pramstaller PP, Wenning GK, Smith SJ et al. (1995). Nerve
conduction studies, skeletal muscle EMG, and sphincter
EMG in multiple system atrophy. J Neurol Neurosurg Psy-
chiatry 58: 618621.
Pountney DL, Treweek TM, Chataway T et al. (2005a).
Alpha B-crystallin is a major component of glial cytoplas-
mic inclusions in multiple system atrophy. Neurotox Res
7: 7785.
Pountney DL, Chegini F, Shen X et al. (2005b). SUMO-1
marks subdomains within glial cytoplasmic inclusions of
multiple system atrophy. Neurosci Lett 381: 7479.
Quinn N (1989a). Multiple system atrophythe nature of
the beast. J Neurol Neurosurg Psychiatry 52 (Suppl): 7889.
Quinn N (1989b). Disproportionate antecollis in multiple
system atrophy. Lancet 1: 844.
Quinn NP (2005). How to diagnose multiple system atrophy.
Mov Disord 20 (Suppl 12): S5S10.
Racette BA, Good L, Sagitto S et al. (2003). Botulinum toxin
B reduces sialorrhea in parkinsonism. Mov Disord 18:
10591061.
Rajput AH, Rozdilsky B, Rajput A et al. (1990). Levodopa
efficacy and pathological basis of Parkinson syndrome.
Clin Neuropharmacol 13: 553558.
Rajput AH, Uitti RJ, Fenton ME et al. (1998). Amantadine
effectiveness in multiple system atrophy and progressive
supranuclear palsy. Parkinsonism Relat Disord 3:
211214.
Riley DE (2002). Dystonia in multiple system atrophy.
J Neurol Neurosurg Psychiatry 72: 286.
Rivest J, Quinn N, Marsden CD (1990). Dystonia in Parkin-
sons disease, multiple system atrophy, and progressive
supranuclear palsy. Neurology 40: 15711578.
Saito Y, Matsuoka Y, Takahashi A et al. (1994). Survival of
patients with multiple system atrophy. Intern Med 33:
321325.
Sakakibara R, Hattori T, Tojo M et al. (1993). Micturitional
disturbance in multiple system atrophy. Jpn J Psychiatry
Neurol 47: 591598.
Sakakibara R, Hattori T, Uchiyama T et al. (2000). Urinary
dysfunction and orthostatic hypotension in multiple system
atrophy: which is the more common and earlier manifesta-
tion? J Neurol Neurosurg Psychiatry 68: 6569.
 MULTIPLE SYSTEM ATROPHY
Sakakibara R, Hattori T, Uchiyama T et al. (2001). Videouro-
dynamic and sphincter motor unit potential analyses in
Parkinsons disease and multiple system atrophy. J Neurol
Neurosurg Psychiatry 71: 600606.
Sakakibara R, Odaka T, Uchiyama T et al. (2004a). Colonic
transit time, sphincter EMG, and rectoanal videomanome-
try in multiple system atrophy. Mov Disord 19: 924929.
Sakakibara R, Hiruma K, Arai K et al. (2004b). Head-turning
dizziness in multiple system atrophy. Parkinsonism Relat
Disord 10: 255256.
Salazar G, Valls-Sole J, Marti MJ et al. (2000). Postural and
action myoclonus in patients with parkinsonian type multi-
ple system atrophy. Mov Disord 15: 7783.
Schatz IJ (2003). A remarkable patient40 years with prob-
able multiple system atrophy (MSA). Clin Auton Res 13:
221223.
Schultze V (1887). Uber einen Fall von Kleinhirnschwund mit
Degenerationen im verlangerten Marke und im Rucken-
marke (wahrscheinlich in Folge von Alkoholismus). Virch-
ows Arch Pathol Anat 108: 331343 (Article in German).
Schrag A, Kingsley D, Phatouros C et al. (1998). Clinical
usefulness of magnetic resonance imaging in multiple sys-
tem atrophy. J Neurol Neurosurg Psychiatry 65: 6571.
Schrag A, Ben-Shlomo Y, Quinn NP (1999). Prevalence of
progressive supranuclear palsy and multiple system atro-
phy: a cross-sectional study. Lancet 354: 17711775.
Schwarz J, Weis S, Kraft E et al. (1996). Signal changes on
MRI and increases in reactive microgliosis, astrogliosis,
and iron in the putamen of two patients with multiple sys-
tem atrophy. J Neurol Neurosurg Psychiatry 60: 98101.
Seppi K, Schocke MF, Wenning GK et al. (2005). How to
diagnose MSA early: round table magnetic resonance ima-
ging. J Neural Transm 112: 16251634.
Shulman LM, Minagar A, Weiner WJ (2004). Multiple-sys-
tem atrophy. In: RL Watts, WC Koller (Eds.), Movement
Disorders: Neurologic Principles and Practice, second
edn., McGraw-Hill, New York, pp. 359369.
Shy GM, Drager GA (1960). A neurological syndrome asso-
ciated with orthostatic hypotension. Arch Neurol 2: 511527.
Silber MH, Levine S (2000). Stridor and death in multiple
system atrophy. Mov Disord 15: 699704.
Simpson DM, Kaufmann H, Sanders I et al. (1992). Laryn-
geal dystonia in multiple system atrophy. Muscle Nerve
15: 12131215.
Slawek J, Derejko M, Lass P et al. (2006). Camptocormia or
Pisa syndrome in multiple system atrophy. Clin Neurol
Neurosurg 108: 699704.
Smith CP, Nishiguchi J, OLeary M et al. (2005). Single-
institution experience in 110 patients with botulinum toxin
A injection into bladder or urethra. Urology 65: 3741.
Stocchi F, Badiali D, Vacca L et al. (2000). Anorectal func-
tion in multiple system atrophy and Parkinsons disease.
Mov Disord 15: 7176.
Strijks E, vant Hof M, Sweep F et al. (2002). Stimulation of
growth-hormone release with clonidine does not distinguish
individual cases of idiopathic Parkinsons disease from those
with striatonigral degeneration. J Neurol 249: 12061210.
Tachibana N, Kimura K, Kitajima K et al. (1997). REM
sleep motor dysfunction in multiple system atrophy: with
325
special emphasis on sleep talk as its early clinical manifes-
tation. J Neurol Neurosurg Psychiatry 63: 678681.
Tarsy D, Apetauerova D, Ryan P et al. (2003). Adverse
effects of subthalamic nucleus DBS in a patient with mul-
tiple system atrophy. Neurology 61: 247249.
Testa D, Monza D, Ferrarini M et al. (2001). Comparison of
natural histories of progressive supranuclear palsy and
multiple system atrophy. Neurol Sci 22: 247251.
Thobois S, Broussole E, Toureille L et al. (2001). Severe dys-
phagia after botulinum toxin injection for cervical dystonia
in multiple system atrophy. Mov Disord 16: 764765.
Thomaides T, Bleasdale-Barr K, Chaudhuri KR et al. (1993).
Cardiovascular and hormonal responses to liquid food chal-
lenge in idiopathic Parkinsons disease, multiple system atro-
phy, and pure autonomic failure. Neurology 43: 900904.
Thomaides T, Karapanayiotides T, Zoukos Y et al. (2005).
Gastric emptying after semi-solid food in multiple system
atrophy and Parkinson disease. J Neurol 252: 10551059.
Tison F, Wenning GK, Quinn NP et al. (1995). REM sleep
behaviour disorder as the presenting symptom of multiple
system atrophy. J Neurol Neurosurg Psychiatry 58: 379380.
Tison F, Yekhlef F, Chrysostome V et al. (2000). Prevalence
of multiple system atrophy. Lancet 355: 495496.
Tison F, Yekhlef F, Chrysostome V et al. (2002). Parkinson-
ism in multiple system atrophy: natural history, severity
(UPDRS-III), and disability assessment compared with
Parkinsons disease. Mov Disord 17: 701709.
Tranchant C, Guiraud-Chaumeil C, EchanizLaguna A et al.
(2000). Is clonidine growth hormone stimulation a good
test to differentiate multiple system atrophy from Parkin-
sons disease? J Neurol 247: 853856.
Trenkwalder C, Schwarz J, Gebhard J et al. (1995). Starnberg
trial on epidemiology of Parkinsonism and hypertension in
the elderly. Prevalence of Parkinsons disease and related
disorders assessed by a door-to-door survey of inhabitants
older than 65 years. Arch Neurol 52: 10171022.
Uzawa A, Sakakibara R, Tamura N et al. (2005). Laryngeal
abductor paralysis can be a solitary manifestation of multi-
ple system atrophy. J Neurol Neurosurg Psychiatry
76 (12): 17391741.
Valldeoriola F, Valls-Sole J, Tolosa ES et al. (1995). Striated
anal sphincter denervation in patients with progressive
supranuclear palsy. Mov Disord 10: 550555.
van der Eecken H, Adams RD, van Bogaert L (1960). Strio-
pallidal-nigral degeneration: a hitherto undescribed lesion
in paralysis agitans. J Neuropathol Exp Neurol 19: 159161.
Vanacore N, Bonifati V, Fabbrini G et al. (2000). Smoking
habits in multiple system atrophy and progressive supra-
nuclear palsy. European Study Group on Atypical Parkin-
sonisms. Neurology 54: 114119.
Vanacore N, Bonifati V, Fabbrini G et al. for the ESGAP
Consortium (2001). Epidemiology of multiple system
atrophy. Neurol Sci 22: 9799.
Vanacore N, Bonifati V, Fabbrini G et al. (2005), the ESGAP
Consortium. Casecontrol study of multiple system atro-
phy. Mov Disord 20: 158163.
Vetrugno R, Provini F, Cortelli P et al. (2004). Sleep
disorders in multiple system atrophy: a correlative video-
polysomnographic study. Sleep Med 5: 2130.
326 R. F. PFEIFFER
Visser-Vandewalle V, Temel Y, Colle H et al. (2003). Bilat-
eral high-frequency stimulation of the subthalamic nucleus
in patients with multiple system atrophyparkinsonism.
Report of four cases. J Neurosurg 98: 882887.
Wakabayashi K, Yoshimoto M, Tsuji S et al. (1998). Alpha-
synuclein immunoreactivity in glial cytoplasmic inclusions
in multiple system atrophy. Neurosci Lett 249: 180182.
Walter U, Niehaus L, Probst T et al. (2003). Brain paren-
chyma sonography discriminates Parkinsons disease and
atypical parkinsonian syndromes. Neurology 60: 7477.
Watanabe H, Saito Y, Terao S et al. (2002). Progression and
prognosis in multiple system atrophy. An analysis of 230
Japanese patients. Brain 125: 10701083.
Wenning GK (2005), on behalf of the Working Group on
Atypical Parkinsonism of the Austrian Parkinsons Society.
Placebo-controlled trial of amantadine in multiple system
atrophy. Clin Neuropharmacol 28: 225227.
Wenning GK, Ben-Shlomo Y, Magalhaes M et al. (1994).
Clinical features and natural history of multiple system
atrophy. An analysis of 100 cases. Brain 117: 835845.
Wenning GK, Ben-Shlomo Y, Magalhaes M et al. (1995a).
Clinicopathological study of 35 cases of multiple system
atrophy. J Neurol Neurosurg Psychiatry 58: 160166.
Wenning GK, Shephard B, Hawkes C et al. (1995b). Olfactory
function in atypical parkinsonian syndromes. Acta Neurol
Scand 91: 247250.
Wenning GK, Tison F, Ben Shlomo Y et al. (1997). Multiple
system atrophy: a review of 203 pathologically proven
cases. Mov Disord 12: 133147.
Wenning GK, Scherfler C, Granata R et al. (1999). Time
course of symptomatic orthostatic hypotension and urinary
incontinence in patients with postmortem confirmed
parkinsonian syndromes: a clinicopathological study.
J Neurol Neurosurg Psychiatry 67: 620623.
Wenning GK, Geser F, StampferKountchev M et al. (2003a).
Multiple system atrophy: an update. Mov Disord 18 (Suppl
6): S34S42.
Wenning GK, Geser F, Poewe W (2003b). The risus sardo-
nicus of multiple system atrophy. Mov Disord 18: 1211.
Wenning GK, Colosimo C, Geser F et al. (2004). Multiple
system atrophy. Lancet Neurol 3: 93103.
Wenning GK, Geser F, Poewe W (2005). Therapeutic
strategies in multiple system atrophy. Mov Disord
20 (Suppl 12): S67S76.
Wermuth L, Joensen P, Bunger N et al. (1997). High preva-
lence of Parkinsons disease in the Faroe Islands. Neurol-
ogy 49: 426432.
Wetter TC, Collado-Seidel V, Pollmacher T et al. (2000).
Sleep and periodic leg movement patterns in drug-free
patients with Parkinsons disease and multiple system
atrophy. Sleep 23: 361367.
Winkler AS, Landau S, Watkins P et al. (2002). Observations
on haematological and cardiovascular effects of erythro-
poietin treatment in multiple system atrophy with sympa-
thetic failure. Clin Auton Res 12: 203206.
Wu YR, Chen CM, Ro LS et al. (2004). Sensory neuropathy
as the initial manifestation of multiple system atrophy.
J Formos Med Assoc 103: 727730.
Wullner U, Abele M, SchmitzHuebsch T et al. (2004). Prob-
able multiple system atrophy in a German family. J Neurol
Neurosurg Psychiatry 75: 924925.
Yamaguchi M, Arai K, Asahina M et al. (2003). Laryngeal
stridor in multiple system atrophy. Eur Neurol 49:
154159.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 47

Progressive supranuclear palsy

DAVID J. BURN1* AND ANDREW J. LEES2

1
Institute of Ageing and Health, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
2
Reta Lila Weston Institute of Neurological Studies, University College London, London, UK

47.1. Introduction . . . chilled, slow, earthy, fixed old man. A cada-

In its full-blown form, the clinical picture of progres-
sive supranuclear palsy (PSP, or SteeleRichardson
Olszewski syndrome) is both arresting and highly
characteristic. The patient has a fixed Mona Lisa
stare, with a markedly reduced blink frequency (04
blinks/minute). The head is retracted and the voice is
reduced to a distinctive slurred growl. The sufferer
walks clumsily and unsteadily (like a drunken sailor),
with a notable tendency to topple backwards. Motor
recklessness is a common early feature, leading to
the highly distinctive rocket sign on rising from a
chair. Clothes are soiled with spilled food, due an
inability to look down at the plate and difficulties
swallowing (the messy-tie sign). The time taken to
respond to a question is prolonged, because of slow
cognitive processing (bradyphrenia).
Recent clinical and molecular genetic studies suggest
that PSP should be considered a relatively common,
discrete neurodegenerative disorder with a number of
different clinical presentations but a distinctive neuro-
pathological signature. This chapter will include im-
portant recent developments in PSP, including the
association of the disease with an H1 haplotype, an altered
tau isoform ratio, evidence for mitochondrial dysfunction
and oxidative stress in the pathogenesis and the discovery
of a cluster of a PSP-like syndrome on Guadeloupe.
47.2. Historical perspective
The intriguing suggestion has been made that Charles
Dickens may have been first to describe a subject with
classical PSP in 1857 in his novel The Lazy Tour of
Two Idle Apprentices (Larner, 2002):
verous man of measured speech. An old man
who seemed as unable to wink, as if his eyelids
had been nailed to his forehead. An old man
whose eyes two spots of fire had no more
motion that [sic] if they had been connected with
the back of his skull by screws driven through
it and riveted and bolted outside, among his
grey hair.
He had come in and shut the door and he now
sat down. He did not bend himself to sit, as other
people do, but seemed to sink bolt upright, as if
in water, until the chair stopped him.
The late 19th century was a productive time for semi-
nal descriptions of neurological disorders. Charcot
encouraged the use of medical photography and draw-
ings to document the physical signs of the patients under
his care and from two daguerreotypes published in 1889
in the Nouvelle Iconographie de la Salpetrie`re by Dutil,
one of his interns, a case of PSP may have been
described as a hemiplegic paralysis agitans with unu-
sual postures of the trunk and head (Goetz, 1996). Ret-
rocollis and an eye movement disorder were prominent
components of the clinical picture. Charcots celebrated
case history and sketches of Bachere, reported as a case
of Parkinsons in extension, may be another missed
early example.
A recent review of 2000 studies on Parkinsons dis-
ease (PD) between 1861 and 1963 found 9 cases with
possible PSP in the pre-encephalitis lethargica (von
Economos disease) era (18611920) (Brusa et al.,
2004). The authors felt it could therefore be assumed
that PSP is neither a new disease, nor a variant of
postencephalitic parkinsonism (PEP).

*Correspondence to: Prof. David J. Burn, Regional Neurosciences Centre, Newcastle General Hospital, Westgate Road, Newcas-
tle upon Tyne NE4 6BE, UK. E-mail: d.j.burn@ncl.ac.uk, Tel: 44-(0)-191-256-3425, Fax: 44-(0)-191-256-3534.
328 D. J. BURN AND A. J. LEES
It is of note that, although motor neuron disease
and PSP were described within 20 years of each
other, the former condition, with its accompanying
distinctive pathology, was rapidly accepted by neu-
rologists as a discrete morbid entity, whereas a full
clinicopathological description of PSP had to wait
almost another century. Misdiagnosis of many cases
of PSP as PEP or inappropriate lumping with other
atypical causes of parkinsonism such as arteriosclero-
tic Parkinsons syndrome may be a partial explana-
tion for this paradox.
In 1963, Dr. J. Clifford Richardson described 8
patients with a common syndrome of ocular, motor
and mental symptoms at the American Neurological
Association in Atlantic City. Richardson drew an ana-
logy between this seemingly new condition and Von
Economos disease and Asao Hirano, one of the dis-
cussants, was struck by its similarity to a new disorder
being found amongst the indigenous Chamorros on the
Mariana Islands (lytico-bodig).
the likeliest explanation for the apparent variation. For
instance, the incidence of 0.4 per 100 000 per year from
the study of Mastaglia et al. is derived from 8 cases
seen in Perth, Western Australia over a 2-year period,
population approximately one million. Their study
was primarily clinical and electrophysiological, not
epidemiological in nature (Mastaglia et al., 1973). In
contrast, Bower and colleagues (1997) studied the inci-
dence of PSP over a 14-year period in Olmsted County,
Minnesota. Sixteen incident cases were identified and
none had an age of onset before 50 years of age. The
average annual incidence rate for ages 5099 years
was 5.3 per 100 000. This study was specifically desig-
ned to measure incidence and utilized the records link-
age system of the Rochester Epidemiology Project.
The authors suggested that increased awareness of
PSP by physicians could have contributed toward the
higher incidence figure.
47.3.2. Prevalence

47.3. Epidemiology PSP comprises 26% of parkinsonian patients seen in

movement disorder clinics in Europe and the USA
47.3.1. Incidence
(Jackson et al., 1983; Katzenschlager et al., 2003).
Extrapolation of population prevalence from such data
Table 47.1 summarizes available incidence data for
is, however, misleading as atypical cases or patients
PSP (Mastaglia et al., 1973; Rajput et al., 1984;
responding poorly to treatment are more likely to be
Radhakrishnan et al., 1988; Bower et al., 1997). The
referred to these clinics. Similarly, the use of so-called
figure from the study of Golbe et al. (1988) was
necroepidemiological data may also be skewed towards
obtained indirectly, using prevalence and survival data.
more atypical parkinsonian cases, including PSP, as
The incidence of PSP ranges from 0.3 to 1.1 per
these patients are more likely to undergo postmortem
100 000 per year, with differences in study design being
(Maraganore et al., 1998).
Only four studies have directly addressed the pre-
Table 47.1
valence of PSP (Golbe et al., 1988; Schrag et al.,
Incidence studies for progressive supranuclear palsy 1999; Nath et al., 2001; Kawashima et al., 2004).
Table 47.2 summarizes these studies, together with
Year Incidence (cases other estimates of the prevalence of PSP. In the latter,
of Geographical per 100 000 per standard diagnostic criteria were not used and the pri-
Author report area covered year)
mary aim of the work was to determine the preva-
Mastaglia 1973 Perth, 0.4* lence of PD.
et al. Australia Golbe et al. (1988), based in New Jersey, USA, first
Rajput et al. 1984 Minnesota, 0.3 addressed the population prevalence of PSP. Neuro-
USA logists were the only physicians approached, so under-
Radhakrishnan 1988 Benghazi, 0.3 ascertainment would have occurred if PSP cases were
et al. Libya being managed by other specialists. The authors had to
Golbe et al. 1988 New Jersey, 0.5y use their own definition of PSP, since standardized
USA
criteria were unavailable at the time. Despite potential
Bower et al. 1997 Minnesota, 1.1
USA
criticisms, this study established that PSP was not as rare
as had previously been supposed. Golbe (1992) later
*Figure derived from number of cases seen in 2 years with ill- suggested that the true prevalence of symptomatic cases
defined population denominator. could be at least twice that of diagnosed cases, since
y
Figure estimated from prevalence and survival data. the average delay from symptom onset to diagnosis is
Modified from Nath and Burn (2000). approximately 50% of the disease course.
 PROGRESSIVE SUPRANUCLEAR PALSY 329
Table 47.2
Prevalence studies for progressive supranuclear palsy (PSP)

Year of PSP prevalence Geographical Population Crude prevalence

Author report primary area studied denominator (per 100 000)

Golbe et al. 1988 Yes New Jersey, USA 799 022 1.39
De Rijk 1995 No Rotterdam, Netherlands 6969 14.3*
Wermuth 1997 No Faroe Islands 43 709 4.6
Chio 1998 No North-west Italy 61 830 3.2
Schrag et al. 1999 Yes London and Kent, UK 121 608 4.9
Nath et al. 2001 Yes Newcastle, UK 259 998 6.5
Kawashima et al. 2004 Yes Yonago, Japan 137 420 5.82

*Only persons aged 55 years of age or older were included.

Modified from Nath and Burn (2000).

Seventeen cases of PSP were identified within an improbably early age and incompatible with PSP
the community study (population 259 998) of Nath according to current diagnostic criteria (Kristensen,
et al., yielding an age-adjusted prevalence figure 1985).
of 5.0 (95% confidence interval (CI) 2.57.5) per There is a remarkably consistent median age of dis-
100 000, standardized to the hypothetical European ease onset in the different series, between 60 and 66
population. When the Schrag data are standardized to years. With the exception of Kristensens review, no
the same population, an identical prevalence figure of case has been reported with a disease onset below
5.0 is obtained. The most recent study, undertaken in the age of 40. The upper limit of the age range for
Japan, also found a similar crude prevalence for PSP
of 5.82 (95% CI 1.789.86) per 100 000 (Kawashima Table 47.3
et al., 2004).
Sex ratio and age at disease onset of progressive
There is a high prevalence of PSP in the French
supranuclear palsy from published series
Antilles, with a minimum prevalence of 14 per 100 000
on the island of Guadeloupe (Caparros-Lefebvre Median age at
et al., 2002). Of 220 consecutive patients with Year of No. of Sex ratio disease onset
Parkinsons syndrome examined, 58 had probable Author report cases (M:F) (range) years
PSP, a further 96 had undetermined parkinsonism
(many of whom closely resembled the incomplete Kristensen* 1985 325y 1.5:1 60.0 (1280)
or a typical bradykinetic presentation of PSP), 50 Maher and 1986 52 0.7:1 63.5 (5077)
Lees
had PD and 15 had an amyotrophic lateral sclero-
Golbe et al. 1988 50 1.4:1 62.9 (4475)
sisparkinsonian syndrome. Pathological confirma-
Frasca et al. 1991 26 1:1 63.1 (4376)
tion of PSP, with a major doublet of pathological De Bruin 1994 90{ 1.5:1 62.0 (4778)
tau at 64 and 69 kDa in brain tissue homogenates and
(see below), has been found in all three of the prob- Lees*
able PSP cases coming to postmortem. Collins 1995 12{ 3:1 66.0 (4877)
et al.
Litvan et al. 1996c 24{ 1.6:1 63.0 (4573)
47.3.3. Age of onset and sex ratio Verny et al. 1996 21{ 0.4:1 62.0 (4370)
Santacruz 1998 437} 1.1:1 66.0 (4187)
Table 47.3 summarizes the sex ratio and age of onset et al.
of PSP in published series to date (Kristensen, 1985;
Frasca et al., 1991; De Bruin and Lees, 1994; Collins *Review of published cases.
y
et al., 1995; Litvan et al., 1996c; Verny et al., 1996; Sex and disease onset specified in 302 and 202 cases, respectively.
{
All cases pathologically confirmed.
Santacruz et al., 1998). One must be cautious in the }
Admixture of living and deceased patients, surveyed by postal ques-
interpretation of cases where no pathological confir- tionnaire. Median age at disease onset is approximated from data
mation is available. In one review, the lower end of given in paper.
the range for age at onset was reported as 12 years Modified from Nath and Burn (2000).
330 D. J. BURN AND A. J. LEES
PSP must also be viewed cautiously, as clinicopatho-
logical series are prone to bias and older cases are
less likely to undergo postmortem (Maraganore et al.,
1998).
Men may be diagnosed later than women follow-
ing symptom onset (33.4 versus 24.1 months), but
die earlier following the diagnosis (37.0 versus 47.6
months) (Santacruz et al., 1998). Regarding the sex
ratio of PSP, six series have found a male predomi-
nance, two a female predominance and one an even
ratio (Table 47.3). The most parsimonious explana-
tion is that there is no significant difference in the
sex ratio.
47.4. Classical progressive supranuclear palsy
(Richardsons syndrome)
47.4.1. Clinical features
Poor mobility and slowness of movement are the most
commonly occurring symptoms at disease onset,
occurring in nearly 70% of cases, followed by cogni-
tive problems (15%) and bulbar dysfunction (14%)
(Nath et al., 2003). Falls occur in the majority of
patients and are typically backwards (Maher and Lees,
1986). In the National Institute of Neurological Dis-
orders (NINDS) study, 83% of 24 PSP patients had a
history of falls (Litvan et al., 1996c), whereas 88%
reported this problem out of 187 cases studied by Nath
and coworkers (2003).
The supranuclear gaze paresis characteristic of PSP
is in the vertical plane, with non-targeted sac-
cadic movements first affected. As the clinical picture
evolves, slow pursuit eye movements are involved
and eventually there may be complete vertical and hor-
izontal gaze ophthalmoparesis. Electro-oculographic
studies confirm early and persistent saccadic slowing
in PSP compared to other parkinsonian syndromes
whereas, unlike corticobasal degeneration (CBD), sac-
cadic latency is normal (Vidailhet et al., 1994; Rottach
et al., 1996; Rivaud-Pechoux et al., 2000). The per-
centage of errors in an antisaccade task, an index of
prefrontal dysfunction, is markedly increased in PSP
(Vidailhet et al., 1994). Square-wave jerks are com-
mon in PSP. Vertical optokinetic nystagmus in PSP
has an impaired slow-phase response and slowed quick
phases, combined with frequent small, paired, hori-
zontal saccadic intrusions (Garbutt et al., 2004). Eyelid
and corneal problems are common, including vague grit-
tiness, corneal ulceration, photophobia and apraxia of
eyelid opening. The latter, occurring in 43% of 49 PSP
patients undergoing a standardized clinical assessment,
may be severe enough to cause functional blindness
(Nath et al., 2003).
Bradykinesia affects nearly half the patients by the
time of diagnosis and up to 95% of PSP patients
during the course of their illness (Maher and Lees,
1986; Verny et al., 1996). Bilateral bradykinesia was
reported in 88% of the NINDS series (Litvan et al.,
1996c). Axial and nuchal rigidity, in particular, may
also be marked but disproportionate retrocollis, al-
though thought to be characteristic of PSP, is usually
a late and relatively infrequent sign (Litvan, 2001).
Generalized hyperreflexia is common, but of limited
diagnostic help. Tremor may be reported in up to
20% of cases; this is usually postural in type (Nath
et al., 2003). A classic pill-rolling tremor is atypical
for PSP (Quinn, 1997). The profoundly reduced blink
frequency, facial dystonia and gaze abnormalities
produce an unnervingly impassive face (so-called rep-
tilian stare). Dystonic vertical wrinkles in the glabel-
lar region and bridge of the nose have been termed
the procerus sign (Romano and Colosimo, 2001),
although the use of this term has been questioned by
others (Lepore and Moudgil, 2002). Glabellar and pal-
momental reflexes are present in 92% and 25% of
PSP, respectively, but do not correlate with cognition,
as assessed using the Mini-Mental State Examination
(MMSE) (Brodsky et al., 2004).
Early bulbar dysfunction is notable, with a peculiar
growling dysarthrophonia (Litvan et al., 1996c).
Swallowing difficulties, reported in 60% of patients,
may be severe enough to warrant insertion of a per-
cutaneous endoscopic gastrostomy feeding system in
up to 10% (Nath et al., 2003).
Vague changes in personality may be amongst the
earliest signs of PSP, at a time when the diagnosis can-
not be made with any degree of certainty. These
changes include forgetfulness, anhedonia, irritability,
depressed mood and impaired concentration. The cog-
nitive problems may worsen with disease progression
and ultimately conform to a pattern of subcorticofron-
tal dementia, characterized by a slowing of thought
processes and impaired executive functions with recall
deficit improved by cueing, recognition and preserva-
tion of instrumental activities (Grafman et al., 1995;
Aarsland et al., 2003).
Patients with PSP may also show behavioral
changes, exhibiting apathy and disinhibition, together
with prehension, initiation and utilization behaviors
(Pillon et al., 1991). These behavioral and cognitive
problems are a source of considerable distress to the
patients and their carers. Depression has not been well
studied in PSP but may occur in up to 20% of patients
(Aarsland et al., 2003). Sometimes it may be difficult
to discriminate mood disorder from apathy. Rapid-eye
movement (REM) sleep behavior disorder is rare in
PSP, when compared with synucleinopathic disorders
 PROGRESSIVE SUPRANUCLEAR PALSY
(PD, multiple system atrophy (MSA) and dementia with
Lewy bodies) (Boeve et al., 2003).
The MMSE is relatively insensitive to frontal
dysfunction and either the Dementia Rating Scale or
the Addenbrookes Cognitive Examination-Revised
(ACE-R) may be more useful for assessing global
cognition in PSP (Aarsland et al., 2003). The Frontal
Assessment Battery (FAB) is a short bedside cognitive
and behavioral battery, comprising six subtests explor-
ing the following: conceptualization, mental flexibil-
ity, motor programming, sensitivity to interference,
inhibitory control and environmental autonomy
(Dubois et al., 2000). The FAB is sensitive to the fron-
tal lobe dysfunction of PSP, takes about 10 minutes to
administer and has good discriminant validity. Motor
perseveration is also detected by showing, then asking,
the patient to clap three times only. PSP sufferers com-
monly continue to clap in excess of three times (the
signe dapplause). (1999) and the methodologically similar community-
The combination of subcorticofrontal disturbance
and postural instability may lead to the so-called
rocket sign, whereby the patient jumps up impulsively
from a seated position, only to fall back immediately
into the chair. Sitting en bloc is also a common sign,
with both feet coming up off the floor as the patient
falls backwards into their chair when asked to sit down
(Litvan, 2001).
47.4.2. Natural history
Classic PSP is a rapidly progressive neurodegenerative
illness. The median duration from disease onset to
death is 5.85.9 years (Maher and Lees, 1986). Mean
interval from symptom onset to diagnosis ranges from
3.6 to 4.9 years, indicating that many patients with
PSP may remain misdiagnosed for much of their dis-
ease course (Golbe et al., 1988). Onset of falls (hazard
ratio (HR) 3.28, 95% CI 1.179.13), speech problems
(HR 4.74, 95% CI 1.1020.4) or diplopia (HR 4.23,
95% CI 1.2314.6) within 1 year and swallowing pro-
blems within 2 years (HR 3.91, 95% CI 1.3911.0)
were associated with a worse prognosis in one study
of 187 PSP cases (Nath et al., 2003). Goetz and collea-
gues (2003) approached the natural history in a differ-
ent way, defining key motor impairments in PSP as
unintelligible speech, no independent walking, inabil-
ity to stand unassisted, wheelchair-bound or recom-
mendation for feeding tube placement. Median time
from disease onset to the first key motor impairment
in a sample of 50 subjects was 48 months, 24 months
after the first consultation. The three gait items
occurred temporally closely together and, when con-
sidered as a single milestone, occurred at a median
disease duration of only 57 months.
331
An analysis of International Classification of Dis-
eases, version 9 (ICD-9)-coded deaths obtained through
the UK Office of National Statistics over an 8-year per-
iod yielded a crude annual mortality rate for PSP of 1.77
(95% CI 1.641.90) cases per million (Nath et al.,
2005). In this study, the annual mortality rate increased
over time, possibly as a result of increased incidence or
increased awareness of the disorder. The commonest
proximate cause of death in PSP is pneumonia, as cited
in 4565% of death certificates (Maher and Lees, 1986;
Nath et al., 2005).
47.5. Misdiagnosis and diagnostic criteria
Primary care diagnoses on hospital referral are protean
and include PD (30%), balance disorders (20%),
stroke (10%) and depression (7%) (Nath et al., 2003).
Combining the prevalence studies of Schrag et al.
based component of the Nath et al. (2001) study, a
total of 23 PSP cases were identified. Of these, 10
patients (43%) carried a primary referral diagnosis of
PSP. In the remainder, PD and cerebrovascular disease
accounted for all but one of the misdiagnosed cases.
In a clinicopathological study, based in a specialist
movement disorders service, 19 of 143 cases of parkin-
sonism were pathologically confirmed as PSP (Hughes
et al., 2002). Antemortem clinical diagnosis was correct
in 16 of these 19 cases: MSA, PD and parkinsonism
undetermined constituted the three misdiagnoses
(Hughes et al., 2002). Utilizing the Society for PSP brain
bank, Josephs and Dickson (2003) found that, of 180
cases referred with a clinical diagnosis of PSP, 137 had
this diagnosis confirmed pathologically. CBD, MSA
and dementia with Lewy bodies accounted for 70% of
the 43 misdiagnosed cases. A history of tremor, psycho-
sis, dementia and asymmetric findings was more frequent
in misdiagnosed cases. Using the Queen Square Brain
Bank for Neurological Disorders, Osaki and colleagues
(2003) found that the clinical diagnosis of PSP was con-
firmed pathologically in 78% of 60 cases, a remarkably
similar positive predictive value to that obtained by
Josephs and Dickson. False-positive diagnoses inclu-
ded PD with significant cortical Lewy body (n 3) or
Alzheimer (n 1) pathology and MSA (n 4). At the
first consultation, only 17% of the 47 true PSP cases,
6 of which had been seen by consultant neurologists,
were diagnosed as PSP.
Postural instability, leading to falls (typically back-
wards) within the first year of disease onset, coupled
with a vertical supranuclear gaze paresis have good
discriminatory diagnostic value when PSP is com-
pared with other degenerative parkinsonian syndromes
(Litvan et al., 1997).
332 D. J. BURN AND A. J. LEES
47.5.1. Diagnostic criteria
Seven different sets of diagnostic criteria have been
proposed for PSP (Table 47.4) (Lees, 1987; Blin et al.,
1990; Duvoisin, 1992; Golbe, 1993; Tolosa et al., 1994;
Collins et al., 1995; Litvan et al., 1996a). In the majority,
the criteria were not derived in a systematic fashion, but
were mainly compiled from the extensive clinical experi-
ence of the authors. There is considerable overlap between
the different sets of criteria, with disease onset over the age
of 40 or 45 and supranuclear gaze palsy common to all.
The most rigorous approach to date led to the
formulation of the National Institute of Neurologi-
Table 47.4
Published diagnostic criteria for progressive supranuclear
palsy
Author (year) Derivation and use
Lees (1987) Not explicitly stated; defined as progressive
non-familial disorder beginning in
middle or old age with SNO and
2 of 5
further cardinal features
Blin et al. Not explicitly stated; defined as probable
(1990) if all of 9 criteria met or possible if 7
out of 9 criteria fulfilled
Duvoisin Not explicitly stated; criteria divided into
(1992) four sections essential for diagnosis,
confirmatory manifestations,
manifestations consistent with but not
diagnostic of PSP and features
inconsistent with PSP
Golbe (1993) Not explicitly stated; defined as onset after
age 40, progressive course bradykinesia
and SNO, plus
3 of 6 further features,
plus absence of 3 inconsistent clinical
features
Tolosa et al. Not explicitly stated; defined as a non-
(1994) familial disorder of onset after age 40,
progressive course and SNO, plus
3 of
5 further features for probable and 2 of
5 for possible, plus absence of 5
inconsistent clinical features
Collins et al. Retrospectively from review of 12
(1995) pathologically confirmed cases;
algorithm-based, including prerequisites
and exclusionary criteria; SNO and/or
prominent postural instability, plus a
number of other specified signs
Litvan et al. Systematic literature review, logistic
(1996a) regression and CART analysis; validated
using data from postmortem confirmed
cases; definite, probable and
possible categories described
(see Table 47.5 and text)
SNO, supranuclear ophthalmoparesis; CART, classification and
regression tree analysis.
cal Disorders and Stroke and Society for Progressive
Supranuclear Palsy (NINDS-SPSP) diagnostic criteria
(Table 47.5) (Litvan et al., 1996a, 2003). When applied
retrospectively to a case mix comprising various parkin-
sonian syndromes, the NINDS-SPSP criteria have high
diagnostic sensitivity and specificity (Litvan et al.,
2003). These parameters have not, however, yet been
determined for prospective series with pathological cor-
relation, nor have they been applied retrospectively to
an independent clinicopathological series. The accuracy
of the NINDS-SPSP clinical diagnostic criteria has also
been evaluated along with existing criteria for three
other dementing disorders by a different group of raters
in an independent sample of pathologically confirmed
cases (Lopez et al., 1999). This study confirmed that
both probable and possible NINDS-SPSP diagnostic
categories for PSP had excellent specificity.
One area where the NINDS-SPSP criteria would be
predicted to have lower sensitivity is when the devel-
opment of core diagnostic features is delayed. Appli-
cation of the NINDS-SPSP criteria marginally
improved the accuracy of initial clinical diagnosis in
one retrospective clinicopathological series (Osaki
et al., 2003), but did not improve accuracy of the final
clinical diagnosis. Diagnostic sensitivity, using the
possible PSP category of these criteria, was still only
21%, compared with 17% for initial clinical diagnosis.
47.6. Clinical heterogeneity
Atypical phenotypic variants of PSP add to the
difficulty of accurate diagnosis. Pathologically
confirmed cases of PSP have been reported in which
there was pure akinesia, whereas others have
documented early and severe dementia (Davis et al.,
1985; Matsuo et al., 1991). Additional reports have
described features that would conventionally be
considered unusual for PSP, including unilateral limb
dystonia or apraxia, prominent tremor, palatal myoclo-
nus and cricopharyngeal dysfunction (Schleider and
Nagurney, 1977; Masucci and Kurtzke, 1989; Barclay
and Lang, 1997; Pharr et al., 1999). Conversely, cases
of frontotemporal lobar degeneration with ubiquitin-
only-immunoreactive neuronal changes (including
the frontotemporal lobar degeneration with motor
neuron disease (FTLD-MND) variant) (Paviour et al.,
2004), frontotemporal dementia linked to chromosome
17 (tau exon 10 16 mutation) (Morris et al., 2003),
Whipples disease (Averbuch-Heller et al., 1999),
neurosyphilis (Murialdo et al., 2000), cerebral
autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) (Van
Gerpen et al., 2003), primary antiphospholipid anti-
body syndrome (Reitblat et al., 2003), Creutzfeldt
Jakob disease (Josephs et al., 2004), clebopride
 PROGRESSIVE SUPRANUCLEAR PALSY 333
Table 47.5
NINDS-SPSP diagnostic criteria for progressive supranuclear palsy (PSP)

Mandatory exclusion
PSP Mandatory inclusion criteria criteria Supportive criteria

Possible Gradually progressive disorder Recent history of Symmetric akinesia or rigidity, proximal
encephalitis more than distal
Onset age 40 or later Alien-limb syndrome, Abnormal neck posture, especially
cortical sensory deficits, retrocollis. Poor or absent response of
focal frontal or parkinsonism to levodopa. Early
temporoparietal atrophy dysphagia and dysarthria. Early onset
Either vertical supranuclear palsy or Hallucinations or delusions of cognitive impairment including
both slowing of vertical saccades unrelated to > 2 of: apathy, impairment in abstract
and postural instability with falls dopaminergic therapy thought, decreased verbal fluency,
< 1 year after disease onset utilization or imitation behavior or
No evidence of other diseases that Cortical dementia of frontal release signs
could explain the foregoing features, Alzheimer type
as indicated by exclusion criteria Prominent, early cerebellar
symptoms or unexplained
autonomic dysautonomia
Probable Gradually progressive disorder
Onset age 40 or later
Vertical supranuclear palsy and
prominent postural instability with
falls < 1 year after disease onset
No evidence of other diseases that
could explain the foregoing features,
as indicated by exclusion criteria
Definite Clinically probable or possible PSP
and histopathological evidence
of typical PSP

NINDS-SPSP, National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy.
Modified from Litvan et al. (1996a).

exposure (Campdelacreu et al., 2004) and postsurgical
repair of ascending aortic dissection or aneurysm (Mokri
et al., 2004) have been reported with a PSP phenotype.
Morris and colleagues (2002a) have drawn attention
to a clinically atypical form of PSP, in which a classi-
cal distribution of PSP pathology occurs, but with the
deposition of Alzheimer disease-type tau protein rather
than PSP-type tau (see below). Four of these 15 atypi-
cal cases had PD-like presentations with an asymme-
trical onset and good levodopa response and 3 of the
4 were documented to have normal eye movements.
Another case had asymmetrical dystonia and apraxia,
suggestive of CBD.
Using factor analysis, Williams and colleagues
(2004) identified two distinct groups amongst 107
consecutive cases of pathologically confirmed PSP.
Fifty-three percent of cases had features compatible
with the classic clinical description outlined above.
A second group of 32% cases, however, were charac-
terized by asymmetric onset, tremor and response to
levodopa. Mean disease duration in this group
was, at 9.2 years, significantly longer than the classic
cases (5.9 years). It was suggested that the first group
of cases might be named Richardsons syndrome
and the second group PSP-parkinsonism (PSP-P)
(Williams et al., 2004).
47.7. Investigations
The diagnosis of PSP still rests on the clinical history
and examination. Attempts have been made, however,
to improve diagnostic accuracy through cerebrospinal
fluid (CSF) analysis and protein biomarkers, structu-
ral and functional imaging and neurophysiological
techniques.
47.7.1. Neuropsychological assessment
Neuropsychological assessment in the early stages may
assist the accurate clinical diagnosis of a parkinsonian dis-
order, as may the time course and pattern of progression of
cognitive and behavioral decline (Soliveri et al., 2000).
334 D. J. BURN AND A. J. LEES
Patients with PSP show a greater decline in attention,
set-shifting and categorization abilities, compared with
PD and MSA. Patients with PSP also show greater
impairment in both phonemic and semantic fluency
than patients with MSA or PD. Using discriminant
function analysis, variables derived from four verbal
fluency tasks (simple and alternate semantic and phone-
mic fluency) were able to classify correctly over 90%
of PSP patients (Lange et al., 2003). The Katz Adjust-
ment Scale-Relatives (KAS-R) may be sensitive to
changes in apathy, social withdrawal and independence
in PSP (Millar et al., 2006). Comparative studies are
required, however, to assess the sensitivity and
specificity of this profile in differentiating PSP from
other parkinsonian conditions.
47.7.2. Cerebrospinal fluid analysis
Studies have attempted to identify biomarkers in the
CSF to achieve early and accurate diagnosis, as well
as monitoring response to treatment. CSF amyloid
A-b42 levels are normal in PSP and do not discrimi-
nate this condition from PD (Holmberg et al., 2003).
Tau has potential as a candidate protein, although it
may lack specificity unless isoform analysis can also
be performed (see below). Significantly higher tau
protein levels in CSF have been reported in CBD,
compared with PSP, yielding sensitivities and speci-
ficities of 100% and 87.5%, respectively (Urakami
et al., 2001). Other proteins in the CSF, including
neurofilament protein (NFL) and glial fibrillary acidic
protein (GFAP), have also been studied. Whereas no
difference was found in CSF GFAP levels between
PD, MSA and PSP, high NFL concentrations seemed
to differentiate typical from atypical parkinsonian dis-
orders (Holmberg et al., 1998). The overlap in ranges,
however, limits the sensitivity of this technique and it
was not possible to differentiate MSA from PSP cases.
More recently, Holmberg and colleagues (2001) sug-
gested that the concomitant use of a levodopa test in
combination with CSF NFL assay could improve diag-
nostic accuracy for atypical parkinsonism to 90%.
Major products of lipid peroxidation are selectively
increased in PSP midbrain tissue, suggesting that a
CSF assay for these products could provide a specific
biomarker.
Since the clinical phenotype of Whipples disease
may resemble PSP, investigators have examined CSF
from PSP patients for Tropheryma whippelii DNA
(Pezzella et al., 2004). Polymerase chain reaction
for T. whippelii was negative in all samples tested,
indicating that this pathogen is not involved in the
etiopathogenesis of PSP, nor is it a useful biomarker
for the disease.
47.7.3. Magnetic resonance imaging (MRI)
Over 70% of patients with clinically diagnosed PSP
may be correctly classified on the basis of 0.5 T
or 1.5 T MRI brain scanning (Schrag et al., 2000).
Criteria used for the diagnosis of PSP include midbrain
diameter on axial scans of less than 17 mm, signal
increase in the midbrain, atrophy or signal increase
of the red nucleus and signal increase in the globus
pallidus. Other studies have also suggested that
reduced midbrain diameter on routine MRI may be
of value in discriminating PSP from PD and MSA-P,
although values may overlap and do not clearly corre-
late with disease duration or severity (Warmuth-Metz
et al., 2001; Righini et al., 2004). Atrophy or abnormal
signal of the superior cerebellar peduncle on proton
density-weighted MRI, postulated to represent demye-
lination and gliosis, may also be of help in differentiat-
ing PSP from PD (Oka et al., 2001). Pathological data
indicate that atrophy of this structure is a relatively
early feature of PSP and correlates with disease dura-
tion (Tsuboi et al., 2003). Tegmental T2 hyperintensity
has poor sensitivity for the diagnosis of PSP (Righini
et al., 2004). In all radiological studies, clinically
typical PSP cases were selected, rendering the discri-
minatory value of MRI something of a tautology. The
value of routine MRI scanning in longitudinal clinico-
pathological studies, particularly of early indeterminate
cases, has not been investigated.
MRI-based volumetry (MRV) has also been used to
differentiate PSP from other parkinsonian syndromes,
by examining atrophy of the caudate nucleus, puta-
men, brainstem and cerebellum (Schulz et al., 1999).
Although significant group differences were found in
mean striatal and brainstem volumes, on an individual
patient basis this technique could still not reliably
separate PSP from MSA-P. Voxel-based morphome-
try, an observer-independent MRV technique, has
demonstrated atrophy in PSP, predominantly involving
mesiofrontal targets of striatal projections (Brenneis
et al., 2004). This study did not compare PSP with
other parkinsonian syndromes, however, so the diag-
nostic value of these observations is unknown. More
elaborate mathematical modeling has also been
applied in an attempt to discriminate PSP from CBD
using MRV (Groschel et al., 2004). As for MRI, the
potential utility of MRV remains to be established in
prospective studies, including subjects with early
indeterminate parkinsonism.
Proton magnetic resonance spectroscopy may pro-
vide an indirect measure of neuronal loss in vivo.
There have been a number of reports of the use of
this technique in PSP, concentrating mainly upon
spectral changes in the lentiform nucleus. In general,
 PROGRESSIVE SUPRANUCLEAR PALSY
although lentiform N-acetylaspartate/choline and/or N-
acetylaspartate/creatine ratios may be reduced in PSP,
the discriminatory value of this technique on an indi-
vidual basis remains questionable. A systematic
review of proton magnetic resonance spectroscopy in
parkinsonian syndromes concluded that the heteroge-
neity of the results to date precludes the use of any
of these findings in differential diagnosis at the
present time (Clarke and Lowry, 2001).
Apparent diffusion coefficient measurements using
diffusion-weighted MRI (DWI) may discriminate
PSP from PD with a sensitivity of 90% and a positive
predictive value of 100%; significant increases in
regional apparent diffusion coefficients have been
noted in striatum and globus pallidus in PSP cases
(Seppi et al., 2003). Importantly, however, DWI could
not discriminate PSP from MSA-C in this study. Mag-
netization transfer imaging, a measure that correlates
with myelination and axonal density, has revealed
changes in magnetization transfer ratios corresponding
with known sites of pathological predilection in PSP,
MSA and PD (Eckert et al., 2004). The same study
showed fairly good discrimination of PD from
control subjects and of MSA from PSP.
47.7.4. Brain parenchyma sonography (BPS)
BPS is a new ultrasound technique capable of display-
ing tissue echogenicity of the brain through an intact
skull. Information may be obtained from key brain
structures that may be of value in differentiating PSP
from other parkinsonian syndromes. BPS can be useful
in discriminating typical from atypical parkinsonism
(MSA and PSP) (Walter et al., 2003). Marked hypere-
chogenicity of the substantia nigra has been reported
in CBD but not in PSP, whereas dilatation of the third
ventricle is common in PSP, but not in CBD. The pre-
sence of at least one of the BPS findings, marked
nigral hyperechogenicity and third ventricle width
<10 mm, indicated CBD with sensitivity of 100%, a
specificity of 83% and a positive predictive value of
80% in one small cross-sectional study (Walter et al.,
2004).
47.7.5. Functional imaging
Blood flow and oxygen or glucose metabolism positron
emission tomography (PET) studies in PSP subjects
have demonstrated relative frontal lobe hypometa-
bolism, although bifrontal hypoperfusion using
more widely available 99mTc-HMPAO (99mTc-hexa-
methylpropylene amine oxime) single-photon emission
computed tomography technique (SPECT) is not a
robust finding in PSP. [18F]-Fluorodeoxyglucose PET
335
and statistical parametric mapping highlights hypome-
tabolism in cingulate gyrus, caudate nucleus, thalamus
and midbrain in PSP (Juh et al., 2004), compared to nor-
mal controls, PD and MSA patients, whereas midbrain
hypometabolism may be an early diagnostic marker
for PSP (Mishina et al., 2004). Both findings require
validation in independent, prospective series.
Evaluation of the nigrostriatal dopaminergic system
using cocaine analogs and functional imaging (PET or
SPECT) reliably shows presynaptic dopaminergic
degeneration in PSP and can also demonstrate pro-
gression of this degeneration. The pattern of abnormal-
ity is, however, non-specific and cannot differentiate
PSP from other parkinsonian syndromes (Pirker
et al., 2002), even when used in combination with
a dopamine D2-receptor ligand (Kim et al., 2002;
Plotkin et al., 2005). A newly developed PET ligand,
the dopamine D2-receptor antagonist, [18F]-desmethoxy-
fallypride, can discriminate between typical and atypi-
cal parkinsonism with high specificity (100%) and
sensitivity (76%), but cannot reliably differentiate
PSP from MSA, limiting its use in clinical practice
(Schreckenberger et al., 2004).
The lack of specificity in functional imaging of the
dopaminergic system has led to the study of other neu-
rotransmitter systems in PSP. Thus, significant reduc-
tions in both caudate and putamen opioid receptor
binding were seen in PSP using [11C]-diprenorphine
PET, compared with PD, MSA and controls (Burn
et al., 1995). [11C]-flumazenil and PET, used to image
benzodiazepine receptors, demonstrated a modest
reduction in binding in the anterior cingulate gyrus
when compared with normal controls, but no other
regional abnormality (Foster et al., 2000). Although
benzodiazepine binding is reduced in the globus palli-
dus of autopsy tissue from PSP patients and preserved
in the striatum, the low level of the receptors in the
pallidum and the proximity of the putamen indicate
functional imaging of the benzodiazepine receptor is
too insensitive to detect these differences.
Ligands for the cholinergic system may offer more
hope in improving diagnostic accuracy for PSP. Ana-
logs of vesamicol, an inhibitor of the acetylcholine vesi-
cular transporter, demonstrate loss of intrinsic striatal
cholinergic neurons (Eidelberg and Dhawan, 2002).
N-methyl-4-[11C]piperidyl acetate and PET reflect ace-
tylcholinesterase activity and indicate preferential loss
of cholinergic innervation to the thalamus in PSP,
compared with PD and controls (Shinotoh et al., 1999).
In vivo imaging of activated microglia, using [11C]
PK11195 and PET, revealed increased binding in the
lentiform nucleus and pons, in particular, although dor-
solateral prefrontal cortex, caudate, substantia nigra
and thalamus were also involved (Gerhard et al., 2001).
336 D. J. BURN AND A. J. LEES
The significance of this preliminary finding (in only 2
PSP patients) is uncertain.
47.7.6. Neurophysiological techniques
A variety of neurophysiological techniques have been
used to study PSP, both with the aim of improving diag-
nostic accuracy and also improving understanding of
the underlying pathophysiological process. A longitud-
inal oculomotor study of patients with PSP and other
parkinsonian syndromes has suggested that electro-
oculography may help diagnose PSP earlier. PSP
patients are characterized by decreased saccadic velo-
city throughout their disease course, as well as having
less specific findings of frequent square-wave jerks
and increased error rate on antisaccade tasks (Rivaud-
Pechoux et al., 2000). Significant orthostatic hypoten-
sion is rare in PSP, in contrast to MSA, with only minor
and inconsistent abnormalities on formal assessment of
sympathetic and parasympathetic functions. Further-
more, there is a normal rise in growth hormone follow-
ing clonidine administration in PSP patients (Kimber
et al., 2000). Sphincter electromyography may differ-
entiate atypical akinetic-rigid syndromes from PD, but
fails to discriminate reliably between PSP and MSA
(Vodusek, 2001). Neuronal loss in Onufs nucleus of
the sacral spinal cord in PSP could explain this lack of
specificity (Scaravilli et al., 2000). The auditory startle
response is delayed or absent in PSP and without habi-
tuation, although there is overlap with values obtained
from other akinetic-rigid syndromes. A combination of
abnormalities on acoustic blink reflex, acoustic startle
reflex and electro-oculography may have high specifi-
city (95%) and sensitivity (100%) for an early diagnosis
of PSP, according to one prospective study of 41 atypi-
cal parkinsonian patients with mean 26-month clinical
follow-up (Gironell et al., 2003). Abnormalities in
visual event-related potentials (P300 amplitude and
reaction times to rare target stimuli), somatosensory
evoked potentials (enlarged cortical somatosen-
sory evoked potentials) and pattern of facial reflexes
(electromyogram activity in mentalis but not orbicularis
oculi muscles following electrical stimulation of the
median nerve at the wrist) have all been reported in
PSP patients. Transcranial magnetic stimulation reveals
disinhibition of the motor cortex in PSP, with enlarged
response amplitudes at rest, reduced intracortical inhibi-
tion and prolonged ipsi- and contralateral silent periods
(Kuhn et al., 2004; Wolters et al., 2004). The clinical
utility of these investigations remains uncertain, as does
their pathophysiological significance. Computerized
posturography testing may differentiate early PSP from
early PD and age-matched controls (Ondo et al., 2000).
Seventy-five percent of the 20 PSP patients met all
optimal criteria for PSP, according to the NINDS-SPSP
criteria, implying early postural instability and falls
within the first year of disease onset. The sensitivity
and specificity of this and several of the other tech-
niques described above in prospectively followed
indeterminate parkinsonian cases would be of interest.
Sleep architecture studies in PSP patients are char-
acterized by almost complete absence of REM sleep,
reduction of total sleep time and sleep spindles, atonic
slow-wave sleep and fragmentation with disrup-
ted sleep pattern (Montplaisir et al., 1997; Brotini
and Gigli, 2004). Cell loss in the pedunculopontine
tegmentum may be the pathophysiological basis for
the absence of REM sleep.
47.8. Pathology
The majority of PSP cases have little or no visible atro-
phy macroscopically, distinguishing it from other tauo-
pathies (Schofield et al., 2004). PSP is characterized by
the destruction of a number of subcortical structures,
including the substantia nigra, globus pallidus, sub-
thalamic nucleus and midbrain and pontine reticular
formation (Jellinger and Blancher, 1992). Deeper corti-
cal layers, especially around the precentral gyrus, may
also be affected to a lesser degree. Large numbers of
neurofibrillary tangles (NFTs, made up of ultramicro-
scopic straight filaments), neuropil threads and tufted
astrocytes are also found in these brain regions. These
distinctive histopathological inclusions are made up of
insoluble aggregates of tau phosphoprotein. Coiled
bodies are small round cells of oligodendrocytic origin
found in white matter, underlining the widespread nat-
ure of the pathology in PSP. Tau-positive glial inclu-
sions are also positively stained with antibodies
against ubiquitin, DJ-1 (Neumann et al., 2004) and heat
shock protein (HSP) ab-crystallin (but not HSP70)
(Richter-Landsberg and Bauer, 2004). In contrast to
CBD, ballooned neurons are sparse in PSP and limited
to the limbic system (Wakabayashi and Takahashi,
2004).
47.8.1. Neuropathological diagnostic criteria and
differential diagnosis
There are a number of clinical and pathological similari-
ties between PSP, PEP and the parkinsonismdementia
complex of Guam (PDCG) (Geddes et al., 1993).
When no clinical information is given, the neuro-
pathologist may have difficulty in differentiating PSP
from PEP and PDCG. The sensitivity and reliability
of the diagnosis of PEP improve significantly when
clinical data are available (Litvan et al., 1996b). NFTs
in subcortical and cortical areas are found in all three
 PROGRESSIVE SUPRANUCLEAR PALSY 337
conditions. PSP may also be difficult to discriminate fibrillar aggregates that are resistant to proteolysis.
from CBD, where NFTs also occur and where the A number of posttranslational processes may be in-
basophilic inclusions of CBD are not always readily volved in the aggregation of tau in PSP, but hyperpho-
distinguished from the tangle pathology. sphorylation, glycation and transglutamination have
Standardized neuropathological criteria have been been principally implicated. Glycation leads to the for-
developed for PSP. An early version divided the neu- mation of advanced glycation end-products (AGEs),
ropathology of PSP into typical, atypical and com- detected histochemically in NFTs (Sasaki et al.,
bined types, although the value of the atypical 1998). The tau in these aggregates is abnormally
category was controversial (Hauw et al., 1994). hyperphosphorylated and in turn this may lead to
Revised criteria subsequently omitted this category, tau release from microtubules. Tissue transglut-
leaving typical and combined PSP, with the latter asso- aminase (TGase) is a calcium-activated enzyme which
ciated with infarcts in the brainstem, basal ganglia, or cross-links substrate proteins into insoluble, protease-
both sites (Table 47.6) (Litvan et al., 1996b). A clini- resistant complexes, potentially initiating NFT forma-
cal history compatible with PSP is mandatory when tion. By altering the conformation of tau, TGase may
defining typical PSP, according to these criteria. render digestion sites inaccessible to proteases. In sup-
port of a pathogenic role for TGase, high levels of
47.8.2. Tau aggregation and cell death epsilon-(gamma-glutamyl) lysine cross-linked tau,
together with increased TGase and mRNA levels for
Tau is critically important for the dynamic behavior TGase 1 and 2 have been found in the pallidum and
and stabilization of microtubules in the cytoskeleton. pons in PSP (Zemaitaitis et al., 2003). Antibodies cap-
In normal neurons, tau is soluble, unfolded and binds able of detecting nitrated tau have also shown labeling
reversibly to microtubules, enhanced by chaperone in the glial and neuronal tau of PSP, in addition to
activity of HSPs. In PSP the protein loses its affinity other tauopathies, implying that nitrative injury might
for microtubules and excess free tau accumulates into also be involved (Horiguchi et al., 2003). In addition
to pathogenic mechanisms leading to tau hyperpho-
Table 47.6
sphorylation, proteasomal inhibition may also be
necessary to produce the stable fibrillary deposits of
NINDS-SPSP neuropathological criteria for the diagnosis tau found in PSP, as indicated by results from an
of typical progressive supranuclear palsy (PSP) in vitro oligodendroglial cell model (OLN-t40) (Gold-
baum et al., 2003). Indirect evidence for proteasome
Inclusion criteria Exclusion criteria
inhibition in PSP is derived from immunohistochem-
Typical A high density of Large or numerous ical and immunoblotting studies, demonstrating an
PSP neurofibrillary infarcts; marked aberrant ubiquitin protein (UBB1) in human pons tis-
tangles and neuropil diffuse or focal sue (Hope et al., 2004). UBB1 is regarded as a repor-
threads in > 3 of: atrophy; Lewy ter for proteasomal dysfunction. Interestingly, the
pallidum, bodies; changes presence of UBB1 was not associated with an HSP
subthalamic nucleus, diagnostic of response. Since HSPs are linked to normal tau func-
substantia nigra or Alzheimers disease;
tion and also act as a rescue response to UBB1
pons and a low-to- oligodendroglial
expression, this could explain both tau dysfunction
high density of argyrophilic
neurofibrillary inclusions, Pick and tau accumulation in PSP (Hope et al., 2004).
tangles or neuropil bodies; diffuse The mechanism leading to cell death in PSP is
threads in > 3 of: spongiosis; prion unknown but is likely to be multifactorial, with both
striatum, oculomotor P-positive amyloid environmental (toxic) and genetic influences playing
complex, medulla, or plaques a role. Microglial activation is greater in PSP than in
dentate nucleus* and control brains and correlates with tau burden in most
clinical history areas. There is also accumulating evidence for oxida-
compatible with PSP tive stress and mitochondrial dysfunction in PSP
(Albers and Augood, 2001). Complex I activity is sig-
*Tau-positive astrocyte processes or astrocyte cell bodies in the nificantly reduced compared with controls in transmi-
areas of neurofibrillary tangles and neuropil threads confirm the
tochondrial cytoplasmic hybrid (cybrid) cell lines,
diagnosis; other lesions include various degrees of neuronal loss
and gliosis in affected areas. expressing mitochondrial genes from subjects with
NINDS-SPSP, National Institute of Neurological Disorders and PSP. The mitochondrial dysfunction may be of toxic
Stroke and Society for Progressive Supranuclear Palsy. or genetic origin. In addition, tau-positive astrocytes
Modified from Litvan et al. (1996b). may exert neurotoxicity through the overproduction
338 D. J. BURN AND A. J. LEES
of nitric oxide, in excess of the detoxification capacity
of superoxide dismutase. The formation of AGE-tau,
detectable in NFTs, is also associated with the genera-
tion of oxygen free radicals and the induction of oxida-
tive stress. Phosphorylation of tau in PSP and Picks
disease may be a direct consequence of the oxidative
stress-induced activation of mitogen-activated protein
kinases, including the p38 pathway (phosphor-MKK6
and phosph-p38) (Hartzler et al., 2002).
The consumption of tropical plants and herbal teas
has been linked with an abnormally high frequency of
a levodopa-resistant form of parkinsonism, clinically
and pathologically resembling PSP, in Guadeloupe
(French West Indies) (Caparros-Lefebvre et al., 1999).
Stabilization or even improvement in some symp-
toms has been reported after cessation of consumption
of these fruits and infusions. Moreover, when mesence-
phalic dopaminergic neurons are exposed in culture to
corexime and reticuline, the most abundant subfractions
of Annona muricata (corossol, soursop), apoptotic cell
death occurs (Lannuzel et al., 2002). Cell death in these
cultures seems independent of excitotoxic mechanisms,
although energy depletion has been implicated. Low-
molecular weight benzylisoquinoline derives of the Ann-
onaceae family (reticuline and N-methylcoculaurine)
are toxic to SH-SY5Y neuroblastoma cells and can
inhibit mitochondrial complex I in vitro (Kotake et al.,
2004).
47.8.3. Familial progressive supranuclear palsy
Although PSP is considered to be a late-onset, sporadic
neurodegenerative disease, a number of families with
sometimes heterogeneous clinical presentation have
been described. Postmortem confirmation of diagnosis
in one or more cases has been obtained in many of
these reports. In a report of 12 pedigrees, the presence
of affected members in at least two generations in
eight of the families and the absence of consangui-
nity suggested autosomal-dominant transmission with
incomplete penetrance (Rojo et al., 1999).
A clinical study yielded the intriguing observation
that 39% of 23 asymptomatic first-degree relatives of
patients with PSP scored abnormally on a PD test bat-
tery, compared with none of 23 age-matched normal
controls (Baker and Montgomery, 2001). The authors
suggested that the test battery could have detected an
asymptomatic carrier state or risk for PSP, or a sub-
clinical effect of a shared environmental exposure.
Further evidence for subclinical cases comes from
PET studies using 18F-dopa and 18fluorodeoxyglu-
cose (Piccini et al., 2001). Four of 15 asymptomatic
relatives scanned from two families with PSP had
abnormal striatal 18F-dopa uptake and a fifth subject
showed significant reduction in cortical and striatal
glucose metabolism.
The relative rarity of familial PSP cases may be due
to a failure to recognize atypical cases, other dia-
gnostic problems or death of the carriers before the
appearance of clinical symptoms. The use of neuro-
physiological and/or imaging techniques to detect pre-
symptomatic cases could assist in linkage analysis of
potential PSP families, with a view to identifying cau-
sative genes. Conversely, families with phenotypically
characteristic PSP may have been reported where
molecular pathology would be indicative of another
neurodegenerative condition. Frontotemporal dementia-
parkinsonism (FTDP-17), for example, is clearly linked
to mutations in the tau gene (see below) and may mimic
PSP clinically.
47.8.4. Molecular pathology
The human tau gene (MAPT) is located on chro-
mosome 17q21 and contains 16 exons. Six different
isoforms of tau are found in the human brain, gener-
ated by alternate splicing of exons 2, 3 and 10. These
isoforms can be divided into two groups of three, differ-
ing in the presence of three or four repeated microtubule-
binding domains (three-repeat or four-repeat tau). The
isoform is determined by whether the exon 10 coding
for one of the four microtubule-binding repeat domains,
a 31-amino-acid repeat located in the C-terminal part, is
spliced in or out of the final tau protein product. In
normal brain, there is a slight preponderance of three-
repeat tau, whereas in PSP the ratio is at least 3:1 in favor
of four-repeat tau. This isoform ratio contrasts with
Alzheimers disease, in which the paired helical fila-
ments contain both three- and four-repeat tau, and also
with Picks disease where three-repeat tau is the major
component (van Slegtenhorst et al., 2000). Bodig
(PDCG) has tau inclusions with an isoform composition
similar to Alzheimers disease but very few studies have
been reported so far. Tau isoform composition varies
markedly within PSP, without a simple relationship
between isoform composition and the pattern of insolu-
ble tau before dephosphorylation (Gibb et al., 2004).
Some of the clinically atypical PSP cases reported by
Morris and colleagues (2002a) were also found to have
a triplet band, raising the possibility that bodig may not
be a disorder restricted to a few geographic isolates.
These differences may help the neuropathologist to cate-
gorize and distinguish the tauopathies, since electrophor-
esis reveals two main protein bands of 64 and 68kDa in
PSP and CBD, whereas Picks disease has two lighter
bands of 55 and 64 kDa. Furthermore, PSP and CBD may
be distinguishable on immunoblots of sarkosyl-insoluble
brain extracts by different patterns of amino-terminally
 PROGRESSIVE SUPRANUCLEAR PALSY
cleaved tau fragments, with a 33-kDa band predo-
minating in PSP, compared with two closely related
bands of approximately 37 kDa in CBD (Arai et al.,
2004).
The discovery of mutations in MAPT in some
families with FTDP-17 confirmed that tau dysfunction
can lead to neurodegeneration. In some of these
families, the three- to four-repeat tau ratio is similar
to that found in PSP. A number of different MAPT
mutations have now been found in FTDP-17 families,
in and near the 50 splice site, downstream of exon 10
(Hutton, 2000). Through disruption of a stem-loop
structure formed in pre-mRNA, 50 splice site mutations
increase recognition of exon 10 by U1 snRNP splicing
factor, increasing the proportion of exon 10 mRNA
and thus four-repeat tau. Analysis of FTDP-17 families
would support this stem-loop hypothesis and its
pathogenicity, in that mutations with the greatest effect
on splicing in vitro cause an earlier age of disease
onset. Disruption of the stem-loop structure need not,
of course be only genetic in origin and toxic causes
could also be involved.
There is some evidence from analysis of tau mRNA
in affected brain regions in PSP that selective four-
repeat tau deposition in PSP may also involve disrup-
tion of exon 10 alternative splicing. Furthermore, there
have now been two reported families with a clinical
syndrome resembling PSP where mutations in MAPT
have been detected (Stanford et al., 2000; Pastor
et al., 2001). In the first, Australian kindred, a silent
mutation (S305S) was identified in the stem-loop
structure. Although not producing an amino acid sub-
stitution (hence silent), functional exon-trapping ex-
periments suggested that the mutation caused up to
a fivefold increase in splicing of exon 10, resulting
in overexpression of four-repeat tau. In the second,
Spanish kindred, two brothers born from a third-degree
consanguineous marriage were both affected by clini-
cally atypical PSP. Both cases had an age of disease
onset below the age of 40, a history of cocaine-abuse
asymmetric parkinsonism and reduced saccadic speed,
whereas neither had an ophthalmoparesis. In 1 of the 2
cases, a homozygous deletion at codon 296 (delN296)
was identified, lying within the sequence corresponding
to the second tubulin repeat of tau protein. The clinical
phenotype of these siblings closely resembled that
described in a familial tauopathy with a N279K muta-
tion, where cases developed parkinsonism, supranuc-
lear gaze paresis and dementia in their fifth decade
(Delisle et al., 1999). The nosology of these familial
PSP mutations remains a matter of debate and at this
point it may be better to classify them as familial tauo-
pathies. It is likely that further sporadic cases clinically
resembling young-onset PSP will be found to have tau
339
mutations. However, a sequence analysis of MAPT
exons 913 in two small families with PSP and 7 clini-
cally typical and atypical sporadic PSP cases with
pathological confirmation of diagnosis has not identi-
fied coding or splice site mutations, suggesting that
PSP or typical PSP-like syndromes are not due to muta-
tions in MAPT (Morris et al., 2002b). A recent study
concluded that screening for MAPT gene mutations in
sporadic cases is unlikely to identify pathogenic muta-
tions (Stanford et al., 2004). However, based on asso-
ciation studies, it is possible that pathogenic variation
in non-coding regions (e.g. introns and promoter and
30 or 50 UTR) could be involved in influencing expres-
sion levels of mRNA.
Conrad and colleagues (1997) first reported a poly-
morphic dinucleotide repeat sequence in intron 9
(between exons 9 and 10) of MAPT in which the A0
allele (TG repeat number of 11) and in particular the
A0/A0 genotype were overrepresented in PSP cases
compared with controls in the white population. These
data were later extended to a haplotype, H1, including
several polymorphisms in linkage disequilibrium with
A0, spanning MAPT (Baker et al., 1999). During evo-
lution of the two human tau haplotypes, H1 and H2,
almost no recombination has occurred between the
two alleles. Although the H1 allele has a frequency
approaching 100% in pathologically confirmed
patients with PSP, it is also found in about 70% of
controls. It is not known at the present time whether
there is a rarer mutation on the H1 haplotype predis-
posing to PSP, or whether it is the haplotype itself.
The presence of an H1 haplotype or H1/H1 genotype
may therefore be regarded as no more than a modest
genetic predisposition towards developing PSP.
Furthermore, almost all normal Japanese people carry
the H1/H1 genotype. The H1 haplotype seems to have
no effect upon the tau or amyloid burden in the lenti-
form nucleus of PSP cases. Furthermore, the H1/H1
genotype does not influence age at disease onset,
severity or survival of patients with PSP. Recently,
the Saitohin gene (STH) Q7R polymorphism, nested
within intron 9 of MAPT, has been shown to be in com-
plete linkage disequilibrium with the extended H1/H2
haplotype (de Silva et al., 2003; Ezquerra et al., 2004).
This implicates the Q allele of this non-silent STH poly-
morphism as a potentially important candidate patho-
genic variant in PSP. STH codes for a protein of
unknown homologies and function that may play an
important role in tau regulation.
Further studies using 19 single nucleotide poly-
morphisms (SNPs) have identified specific subha-
plotypes in 17q21 that modify risk for PSP and CBD
(Pastor et al., 2004). A subhaplotype, H10 A, was
present in 16% of PSP patients but not observed in
340 D. J. BURN AND A. J. LEES
controls, whereas the H2E0 A subhaplotype was rarely walking aids, such as weighted walkers and exercises
present in the disease group, suggesting that it might (Sosner et al., 1993). Severe postural instability, coupled
have a protective role. Again, using SNPs, linkage dis- with the inability of the patient to recognize the balance
equilibrium in the regions flanking MAPT was mapped problem because of frontal lobe dysfunction, may mean
to establish the maximum extent of the haplotype that a wheelchair is the safest option when falling
block on chromosome 17q21.31 as a region covering becomes a frequent occurrence. Expert nursing support
approximately 2 Mb (Pittman et al., 2004). The entire and lay associations are invaluable for carers and
fully extended H1 haplotype was associated with PSP, families. Such support can also provide important advice
implicating several other genes in addition to MAPT as with regard to future care planning, legal options of
candidate pathogenic loci. power of attorney, trusteeship, advance directives and
Additional intriguing findings are of significant asso- consideration for brain donation (Rohs, 1996).
ciations between the A0 polymorphism of tau and both Table 47.7, modified from a review by Litvan
PD and CBD and between the extended tau gene haplo- (2001), summarizes palliative treatments that may be
type H1 and CBD and clinically defined non-demented considered for PSP.
PD cases (Houlden et al., 2001; Maraganore et al.,
2001). For PD, it has been postulated that the H1 haplo-
47.9.2. Neurotransmitter replacement strategies
type might interact with a-synuclein, thereby influencing
the propensity of a-synuclein to aggregate. This would
No drug tested to date has had a major symptomatic ben-
imply potential pathogenic synergism between synuclei-
efit in PSP. Minor benefits could have been missed, since
nopathies and tauopathies. A study of pathologically
small trial sizes may have introduced a type II error.
confirmed PD cases did not, however, confirm any asso-
ciation with the H1 haplotype (de Silva et al., 2002).
However, in the genetically more homogeneous Norwe-
gian population, Farrer and colleagues (2002) showed a Table 47.7
significant association of tau with sporadic PD. At present,
the association of MAPT with PD therefore remains Palliative treatments for progressive supranuclear palsy
controversial and requires further study. (PSP)
To date, no linkage has been found between PSP and
Feature Palliative approach
the candidate genes for PD synuclein, synphilin or par-
kin, nor the ApoE4 allele, a risk factor for late-onset Alz- Gait instability Weighted walkers; physiotherapy
heimers disease. In addition, no association with Dysphagia Thickeners; dietician, speech and
polymorphisms in the CYP2D6 (which encodes for deb- language input; percutaneous
risoquine 4-hydroxylase cytochrome P450), CYP1A1, endoscopic gastrostomy
N-acetyltransferase 2, dopamine transporter and glu- Dysarthria Speech therapy; communication
tathione S-transferase M1 genes has been found for PSP. aids
Decreased rate of eye Artificial tears (to avoid
blink exposure keratitis); dark
47.9. Management glasses (to reduce photophobia)
Vertical Prism glasses; talking books
47.9.1. General considerations ophthalmoplegia
Blepharospasm and Eyelid crutches; botulinum toxin
A multidisciplinary approach is essential for the man- apraxia of eyelid
agement of PSP. Speech and language therapists and opening
dieticians can advise to improve dysphagia and com- Depression Antidepressants; supportive
munication difficulties, although severe dysphagia therapy
may warrant insertion of a percutaneous gastrostomy Emotional incontinence Tricyclic antidepressants
feeding system. Mirror prism spectacles can make it Drooling Anticholinergics (topical or oral)
use cautiously
possible for patients with severe down-gaze limitation
Patient and family Social services; two lay
to read and feed themselves. Eyelid crutches, sometimes support associations:
combined with botulinum toxin therapy, may be useful PSP (Europe) Association
for apraxia of eyelid opening (Krack and Marion, (http://www.pspeur.org)
1994). Botulinum toxin injections may also be helpful Society for PSP
in improving blepharospasm, retrocollis and orofacial (http://www.psp.org)
dystonia (Polo and Jabbari, 1994; Piccione et al., 1997;
Muller et al., 2002). A physiotherapist can advise on Modified from Litvan (2001).
 PROGRESSIVE SUPRANUCLEAR PALSY
The response to a variety of medications, usually admi-
nistered in a non-systematic and unblinded fashion and
without the use of standardized assessment scales has
been documented (Jackson et al., 1983; Jankovic, 1984;
Maher and Lees, 1986; Nieforth and Golbe, 1993;
Kompoliti et al., 1998; Birdi et al., 2002).
47.9.2.1. Dopaminergic agents
Intravenous levodopa fails to elicit the increases in
cerebral blood flow in PSP observed in PD (Kobari
et al., 1992), whereas PSP patients rarely show a clini-
cally significant response to apomorphine testing
(DCosta et al., 1991; Bonuccelli et al., 1992). Thera-
peutic trials of levodopa noted benefit in 51%
(Jankovic, 1984), 54% (Golbe et al., 1990) and 38%
(Nieforth and Golbe, 1993) of patients. In a more
recent study, only 4 out of 12 postmortem confirmed
PSP cases showed a modest improvement whilst
receiving levodopa that was not sustained (Kompoliti
et al., 1998). Adverse effects occurred in over half of
the patients. Birdi and colleagues (2002) reported that
in 15 of their postmortem-confirmed patients receiving
levodopa either alone or in combination with an anti-
cholinergic, dopamine agonist, selegiline or amanta-
dine, 9 had shown some benefit. Consistent with
the recent observations by Williams and colleagues
(2004), none of the 7 cases with supranuclear ophthal-
moplegia responded to levodopa, whereas 5 of 8
patients without ophthalmoplegia improved (although
the magnitude and duration of the improvement were
not documented).
Bromocriptine is generally ineffective in doses up
to 70 mg/day (Williams et al., 1979). A controlled
study of lisuride, a relatively selective dopamine D2-
receptor agonist, in daily doses of up to 5 mg in 7
patients did not yield any positive results whereas 3
patients developed hallucinations (Neophytides et al.,
1982). Pergolide at a daily dose of 4 mg improved par-
kinsonian and/or pseudobulbar signs in 2 out of 3 PSP
patients (Jackson et al., 1983). Pramipexole, a non-
ergot dopamine agonist with high affinity for the dopa-
mine D3-receptor, failed to show any benefit in 6 PSP
patients, in a daily dose of up to 4.5 mg (Weiner et al.,
1999). Two patients reported visual hallucinations and
1 a worsening of motor symptoms.
Selegiline, a monoamine oxidase type B inhibitor,
has not shown any significant therapeutic effect in
PSP (Golbe et al., 1990). Amantadine, a drug with
multiple actions, including increasing the synthesis,
release and reuptake of dopamine, as well as potent
N-methyl-D-aspartate antagonist properties, can pro-
vide a transient therapeutic benefit in up to 15% of
cases (Litvan and Chase, 1992).
341
47.9.2.2. Cholinergic agents
PSP is characterized by a loss of cholinergic neurons,
particularly in the striatum, thalamus, pedunculopon-
tine nucleus and nucleus basalis of Meynert. Choliner-
gic blockade using scopolamine worsens memory and
gait in PSP (Litvan et al., 1994). Cholinomimetic
drugs have thus been explored for their therapeutic
potential in PSP.
Physostigmine, a centrally acting cholinesterase
inhibitor, improved long-term memory and visuo-
spatial function in 8 PSP patients in a double-blind,
placebo-controlled cross-over study, but no benefits
were reported for extraocular, parkinsonian or pseudo-
bulbar features (Litvan et al., 1989; Kertzman et al.,
1990). The same drug had no effect upon swallow-
ing or oral motor function in a 10-day cross-over
placebo-controlled double-blind trial (Frattali et al.,
1999). Direct stimulation of postsynaptic cholinergic
receptors with the non-selective M1 and M2 muscari-
nic agonist, RS-86, did not produce any beneficial
effects in motor function, eye movements or cognitive
performance in 10 PSP patients in a 9-week double-
blind, placebo-controlled cross-over trial, despite elec-
troencephalographic evidence of enhanced central
cholinergic activity upon sleep architecture (Foster
et al., 1989).
The effects of the cholinesterase inhibitor donepezil
upon cognitive function, motor skills and activities of
daily living (ADL) were assessed in 6 PSP patients
at baseline and after 3 months of treatment. There
was no change from baseline in any of the parameters
measured (Fabbrini et al., 2001). Litvan used the same
dose of donepezil (10 mg) in 21 patients in a double-
blind, placebo-controlled, randomized, cross-over trial
(Litvan et al., 2001). There was a modest improvement
in one of the memory tests but a significant worsening
in motor and ADL scores.
47.9.2.3. Adrenergic agents
A placebo-controlled, double-blind, cross-over study
of idazoxan in 9 PSP patients showed a significant
decrease in the Unified Parkinsons Disease Rating
Scale (UPDRS), corresponding to an improvement in
mobility, balance and dexterity (Ghika et al., 1991).
In contrast, the potent a2-antagonist efaroxan did not
significantly improve motor impairments in 14 PSP
patients using a double-blind, placebo-controlled,
cross-over study design (Rascol et al., 1998).
47.9.2.4. Other drugs
Nortriptyline may be useful for the management of
depression in PSP (Tamai and Almeida, 1997). Ami-
triptyline has been produced with variable results.
342 D. J. BURN AND A. J. LEES
Three of 4 patients showed moderate to definite
improvement in one study, whereas postural instability
worsened in the fourth (Newman, 1985). A retrospec-
tive analysis of 28 PSP patients, treated with doses of
amitriptyline ranging from 50 to 200 mg, indicated
an improvement in gait or dysphagia in 9 patients,
but moderate to severe side-effects, particularly antic-
holinergic-related, occurred in 14. Other case reports
have demonstrated moderate improvement in motor
scores at low doses (2080 mg/day), with cognitive
and behavioral problems only emerging at higher
doses (Engel, 1996).
A double-blind, placebo-controlled, cross-over
study of the GABAergic drug zolpidem in 10 PSP
patients revealed significant improvements in motor
function and saccadic eye movements (Daniele et al.,
1999). Adverse effects were drowsiness and increased
postural instability. A further case report highlighted a
non-sustained improvement in gaze palsy and parkin-
sonism in a patient taking 5 mg zolpidem at night, with
benefit lasting 4 weeks (Mayr et al., 2002).
Methysergide was associated with clinical impro-
vement in 1 of 3 PSP patients and with deterioration
of symptoms in another (Kompoliti et al., 1998). One
of 2 patients experienced modest improvement with
5-hydroxytryptophan. Fluoxetine, mianserin and biper-
iden hydrochloride have all been used in single
patients with no observed improvement (Kompoliti
et al., 1998).
47.9.3. Non-pharmacological interventions
Barclay et al. (1996) reported 5 patients with PSP who
each received 9 electroconvulsive therapy (ECT) treat-
ments, over 3 weeks. One patient showed a dramatic
improvement in mobility, although no long-term data
were available, whereas 2 experienced a mild benefit
and a further 2 did not change. There were transient
side-effects in all patients, including confusion and
bulbar dysfunction. An apomorphine challenge carried
out pre- and post-ECT did not show any change in
motor improvement, suggesting that ECT did not
induce dopamine receptor sensitization. ECT may
improve severe depression in PSP without beneficial
or deleterious effects on motor function (Netzel and
Sutor, 2001), although adverse effects of ECT on
motor function have also been reported (Hauser and
Trehan, 1994).
Other non-drug treatments include transcranial
alternate current pulsed electromagnetic fields, which
apparently reduced the frequency of freezing by 50%
and falls by 90% in 1 patient (Sandyk, 1998). Auto-
logous adrenal medullary transplantation into the cau-
date nucleus of 3 PSP patients had limited efficacy and
was associated with a number of transient postopera-
tive complications (Koller et al., 1989; Ward-Smith
and Berry, 1990). A small number of PSP patients
have also undergone pallidotomy without significant
benefit (Litvan, 2001).
47.9.4. Future directions
More radical advances in PSP therapeutics will come
from a greater understanding of the pathophysiology
of the condition and the development of animal mod-
els in which to test new disease-modifying treatments
(Golbe, 2000). Regarding the latter, transgenic mice,
Drosophila and zebrafish models have biological simi-
larities with a number of tauopathies, including PSP
(Lewis et al., 2000; Wittman et al., 2001; Tomasiewicz
et al., 2002). One example of the use of such models
comes from a report of the inhibition of glycogen
synthase 3 kinase (GSK-3b), an enzyme believed to
be important in tau phosphorylation, leading to func-
tional improvement in transgenic Drosophila (Mudher
et al., 2004). Lithium is an inhibitor of GSK-3b and
trials are already planned for Alzheimers disease
(Mudher et al., 2004), although preliminary studies
using human tissue have suggested that GSK-3b levels
are unchanged in PSP, compared with age-matched
controls (Borghi et al., 2004).
Other approaches to disease modification in PSP
could involve the manipulation of splicing regulation
by RNA stem-loops, with the aim of reducing four-
repeat tau production (Golbe, 2000). This could be
achieved, for example, by the use of RNA interference
to inhibit the translation of E10 messenger RNA
(Litvan, 2001; Davidson and Paulson, 2004).
A number of posttranslational processes may be
involved in the aggregation of tau in PSP, but glyca-
tion and transglutamination have been principally
implicated (see above). Targeted inhibition of TGase
might be capable of reducing tau aggregation. The for-
mation of AGE-tau is also associated with the genera-
tion of oxygen free radicals and the induction of
oxidative stress. Phosphorylation of tau in PSP may
be a direct consequence of oxidative stress-induced
activation of mitogen-activated protein kinases,
including the p38 pathway, thus opening up further
therapeutic potential through manipulation of this
pathway (Hartzler et al., 2002).
Microglial activation is greater in PSP than in con-
trol brains and microglial activation correlates with tau
burden in most areas. The use of anti-inflammatory
agents could therefore be considered, although from
trials of these drugs in Alzheimers disease and the
size of effect, the feasibility of similar studies for
PSP must be questionable. Finally, the use of trophic
 PROGRESSIVE SUPRANUCLEAR PALSY
factors could be a promising therapeutic approach for
PSP, although there would be considerable technical
issues to overcome (Litvan, 2001).
47.10. Conclusions
Despite greater awareness in recent years, many patients
with PSP remain undiagnosed or misdiagnosed for much
of their disease duration. The role of tau protein in the
pathophysiological process, together with the establish-
ment of a modest genetic predisposition has stimul-
ated research. At the same time, studies on a cluster of
a PSP-like condition in Guadeloupe have produced new
clues for potential environmental toxins. If the funda-
mental pathophysiological process in PSP turns out to
be an overproduction of four-repeat tau, it will be crucial
to determine how the function of the RNA stem-loop
structure, a key regulator in the alternate splicing process,
may be affected by various genetic influences and toxins.
As disease-modifying therapies emerge it will be
vital to intervene as early in the pathological process
as possible. There is therefore a need for a greater
awareness of PSP and the development of robust diag-
nostic clinical and investigational markers that predict
whether an individual with suspicious, but not typical
classical features, will go on to develop PSP. Physi-
cians should consider PSP when rigidity and bradyki-
nesia coexist with early falls. The patient should be
examined carefully for slowing of downward saccadic
eye movements and the presence of square-wave jerks.
The presence of frank vertical ophthalmoparesis is of
significant diagnostic help but it should also be borne
in mind that this physical sign might take several years
to develop in some patients.
References
Aarsland D, Litvan I, Salmon D et al. (2003). Performance
on the dementia rating scale in Parkinsons disease with
dementia and dementia with Lewy bodies: comparison
with progressive supranuclear palsy and Alzheimers dis-
ease. J Neurol Neurosurg Psychiatry 74: 12151220.
Albers DS, Augood SJ (2001). New insights into progressive
supranuclear palsy. Trends Neurosci 24: 347353.
Arai T, Ikeda K, Akiyama H et al. (2004). Identification of
amino-terminally cleaved tau fragments that distinguish
progressive supranuclear palsy from corticobasal degen-
eration. Ann Neurol 55: 7279.
Averbuch-Heller L, Paulson GW, Daroff RB et al.
(1999). Whipples disease mimicking progressive supra-
nuclear palsy: the diagnostic value of eye movement
recording. J Neurol Neurosurg Psychiatry 66: 532535.
Baker KB, Montgomery EB (2001). Performance on the
PD test battery by relatives of patients with progressive
supranuclear palsy. Neurology 56: 2530.
343
Baker M, Litvan I, Houlden H et al. (1999). Association of
an extended haplotype in the tau gene with progressive
supranuclear palsy. Hum Mol Genet 8: 711715.
Barclay CL, Lang AE (1997). Dystonia in progressive supra-
nuclear palsy. J Neurol Neurosurg Psychiatry 62:
352356.
Barclay CL, Duff J, Sandor P et al. (1996). Limited useful-
ness of electroconvulsive therapy in progressive supranuc-
lear palsy. Neurology 46: 12841286.
Birdi S, Rajput AH, Fenton M et al. (2002). Progressive
supranuclear palsy diagnosis and confounding features:
report on 16 autopsied cases. Mov Disord 17: 12551264.
Blin J, Baron JC, Dubois B et al. (1990). Positron emission
tomography study in progressive supranuclear palsy: brain
hypometabolic pattern and clinicometabolic correlations.
Arch Neurol 47: 747752.
Boeve BF, Silber MH, Parisi JE et al. (2003). Synucleinopa-
thy pathology and REM sleep behavior disorder plus
dementia or parkinsonism. Neurology 61: 4045.
Bonuccelli U, Piccini P, Del Dotto P et al. (1992). Apomor-
phine test in de novo Parkinsons disease. Funct Neurol 7:
295298.
Borghi R, Piccini A, Delacourte A et al. (2004). Protein
levels of glycogen synthase 3 kinase are normal in pro-
gressive supranuclear palsy. Neurosci Lett 366: 6770.
Bower JH, Maraganore DM, McDonnell SK et al.
(1997). Incidence of progressive supranuclear palsy and
multiple system atrophy in Olmsted County, Minnesota,
1976 to 1990. Neurology 49: 12841288.
Brenneis C, Seppi K, Schocke M et al. (2004). Voxel based
morphometry reveals a distinct pattern of frontal atrophy
in progressive supranuclear palsy. J Neurol Neurosurg
Psychiatry 75: 246249.
Brodsky H, Dat Vuong K, Thomas M et al. (2004). Glabellar
and palmomental reflexes in Parkinsonian disorders. Neu-
rology 63: 10961098.
Brotini S, Gigli GL (2004). Epidemiology and clinical fea-
tures of sleep disorders in extrapyramidal disease. Sleep
Med 5: 169179.
Brusa A, Stoehr R, Pramstaller PP (2004). Progressive supra-
nuclear palsy: new disease or variant of postencephalitic
parkinsonism? Mov Disord 19: 247252.
Burn DJ, Rinne JO, Quinn NP et al. (1995). Striatal opioid
receptor binding in Parkinsons disease, striatonigral
degeneration and Steele-Richardson-Olszewski syndrome.
A [11C]diprenorphine PET study. Brain 118: 951958.
Campdelacreu J, Kumru H, Tolosa E et al. (2004). Progres-
sive supranuclear palsy syndrome induced by clebopride.
Mov Disord 19: 482484.
Caparros-Lefebvre D, Elbaz A (1999). Caribbean Parkinson-
ism Study Group. Possible relation of atypical parkinson-
ism in the French West Indies with consumption of
tropical plants: a case-control study. Lancet 354:
281286.
Caparros-Lefebvre D, Sargent N, Lees AJ et al.
(2002). Guadeloupean parkinsonism: a cluster of progres-
sive supranuclear palsy-like tauopathy. Brain 125:
801811.
344 D. J. BURN AND A. J. LEES
Chio A, Magnani C, Schiffer D (1998). Prevalence of
Parkinsons disease in Northwestern Italy: comparison of
tracer methodology and clinical ascertainment of cases.
Mov Disord 13: 400405.
Clarke CE, Lowry M (2001). Systematic review of proton
magnetic resonance spectroscopy of the striatum in par-
kinsonian syndromes. Eur J Neurol 8: 573577.
Collins SJ, Ahlskog JE, Parisi JE et al. (1995). Progressive
supranuclear palsy: neuropathologically based diagnostic
clinical criteria. J Neurol Neurosurg Psychiatry 58:
167173.
Conrad C, Andreadis A, Trojanowski JQ et al. (1997). Gene-
tic evidence for the involvement of tau in progressive
supranuclear palsy. Ann Neurol 41: 277281.
Daniele A, Moro E, Bentivoglio AR (1999). Zolpidem in
progressive supranuclear palsy. N Engl J Med 341:
543544.
Davidson BL, Paulson HL (2004). Molecular medicine for
the brain: silencing of disease genes with RNA interfer-
ence. Lancet Neurol 3: 145149.
Davis PH, Bergeron C, McLachlan DR (1985). Atypical pre-
sentation of progressive supranuclear palsy. Ann Neurol
17: 337343.
DCosta DF, Abbott RJ, Pye IF et al. (1991). The apomor-
phine test in Parkinsonian syndromes. J Neurol Neurosurg
Psychiatry 54: 870872.
De Bruin VM, Lees AJ (1994). Subcortical neurofibrillary
degeneration presenting as Steele-Richardson-Olszewski
and other related syndromes: a review of 90 pathologically
verified cases. Mov Disord 9: 381389.
de Rijk MC, Breteler MMB, Graveland GA et al. (1995).
Prevalence of Parkinsons disease in the elderly: the
Rotterdam study. Neurology 45: 21432146.
de Silva R, Hardy J, Crook J et al. (2002). The tau locus
is not significantly associated with pathologically con-
firmed sporadic Parkinsons disease. Neurosci Lett 330:
201203.
de Silva R, Hope A, Pittman A et al. (2003). Strong associa-
tion of the Saitohin gene Q7 variant with progressive
supranuclear palsy. Neurology 61: 407409.
Delisle MB, Murrell JR, Richardson R et al. (1999). A muta-
tion at codon 279 (N279K) in exon 10 of the Tau gene
causes a tauopathy with dementia and supranuclear palsy.
Acta Neuropathol (Berl) 98: 6277.
Dubois B, Slachevsky A, Litvan I et al. (2000). The FAB:
a frontal assessment battery. Neurology 55: 16211626.
Duvoisin RC (1992). Clinical diagnosis. In: I Litvan,
Y Agid (Eds.), Progressive Supranuclear Palsy: Clin-
ical and Research Approaches.Oxford University
Press, New York, pp. 1533.
Eckert T, Sailer M, Kaufmann J et al. (2004). Differentiation
of idiopathic Parkinsons disease, multiple system atrophy,
progressive supranuclear palsy, and healthy controls using
magnetization transfer imaging. Neuroimage 21: 229235.
Eidelberg D, Dhawan V (2002). Can imaging distinguish
PSP from other neurodegenerative disorders? Neurology
58: 997998.
Engel PA (1996). Treatment of progressive supranuclear
palsy with amitriptyline: therapeutic and toxic effects.
J Am Geriatr Soc 44: 10721074.
Ezquerra M, Campdelacreu J, Munoz E, Oliva R et al.
(2004). Sequence analysis of tau 30 untranslated region
and saitohin gene in sporadic progressive supranuclear
palsy. J Neurol Neurosurg Psychiatry 75: 155157.
Fabbrini G, Barbanti P, Bonifati V et al. (2001). Donepezil in
the treatment of progressive supranuclear palsy. Acta Neu-
rol Scand 103: 123125.
Farrer M, Skipper L, Berg M et al. (2002). The tau H1 hap-
lotype is associated with Parkinsons disease in the Nor-
wegian population. Neurosci Lett 322: 8386.
Foster NL, Aldrich MS, Bluemlein L et al. (1989). Failure of
cholinergic agonist RS-86 to improve cognition and move-
ment in PSP despite effects on sleep. Neurology 39:
257261.
Foster NL, Minoshima S, Johanns J et al. (2000). PET mea-
sures of benzodiazepine receptors in progressive supranuc-
lear palsy. Neurology 54: 17681773.
Frasca J, Blumbergs PC, Henschke P et al. (1991). A clinical
and pathological study of progressive supranuclear palsy.
Clin Exp Neurol 28: 7989.
Frattali CM, Sonies BC, Chi-Fishman G et al. (1999). Effects
of physostigmine on swallowing and oral motor functions
in patients with progressive supranuclear palsy: a pilot
study. Dysphagia 14: 165168.
Garbutt S, Riley DE, Kumar AN et al. (2004). Abnormalities
of optokinetic nystagmus in progressive supranuclear
palsy. J Neurol Neurosurg Psychiatry 75: 13861394.
Geddes JF, Hughes AJ, Lees AJ et al. (1993). Pathological
overlap in cases of parkinsonism associated with neurofi-
brillary tangles. A study of recent cases of postencephalitic
parkinsonism and comparison with progressive supra-
nuclear palsy and Guamanian parkinsonismdementia
complex. Brain 116: 281302.
Gerhard A, Banati RB, Cagnin A et al. (2001). In vivo ima-
ging of activated microglia with [11C] PK11195 positron
emission tomography (PET) in idiopathic and atypical
Parkinsons disease. Neurology 56: A270.
Ghika J, Tennis M, Hoffman E et al. (1991). Idazoxan treat-
ment in progressive supranuclear palsy. Neurology 41:
986991.
Gibb GM, de Silva R, Revesz T et al. (2004). Differential
involvement and heterogeneous phosphorylation of tau
isoforms in progressive supranuclear palsy. Brain Res
Mol Brain Res 121: 95101.
Gironell A, Kulisevsky J, Roig C et al. (2003). Diagnostic
potential of acoustic startle reflex, acoustic blink reflex,
and electro-oculography in progressive supranuclear
palsy: a prospective study. Mov Disord 18: 12731279.
Goetz CG (1996). An early photographic case of prob-
able progressive supranuclear palsy. Mov Disord 11:
617618.
Goetz CG, Leurgans S, Lang AE et al. (2003). Progression of
gait, speech and swallowing deficits in progressive supra-
nuclear palsy. Neurology 60: 917922.
 PROGRESSIVE SUPRANUCLEAR PALSY
Golbe LI (1992). Epidemiology. In: I Litvan, Y Agid (Eds.),
Progressive Supranuclear Palsy: Clinical and Research
Approaches.Oxford University Press, Oxford, pp. 3443.
Golbe LI (1993). Progressive supranuclear palsy. In: J Jankovic,
E Tolosa (Eds.), Parkinsons Disease and Move-
ment Disorders.Williams & Wilkins, Baltimore, pp.
145161.
Golbe LI (2000). Progressive supranuclear palsy in the mole-
cular age. Lancet 356: 870871.
Golbe LI, Davis PH, Schoenberg BS et al. (1988). Prevalence
and natural history of progressive supranuclear palsy.
Neurology 38: 10311034.
Golbe LI, Sage JI, Duvoisin RC (1990). Drug treatment of 83
patients with progressive supranuclear palsy. Neurology
40: 438.
Goldbaum O, Oppermann M, Handschuh M et al. (2003).
Proteasome inhibition stabilizes tau inclusions in oligo-
dendroglial cells that occur after treatment with okadaic
acid. J Neurosci 23: 88728880.
Grafman J, Litvan I, Stark M (1995). Neuropsychological
features of progressive supranuclear palsy. Brain Cogn
28: 311320.
Groschel K, Hauser TK, Luft A et al. (2004). Magnetic reso-
nance imaging-based volumetry differentiates progressive
supranuclear palsy from corticobasal degeneration. Neuro-
image 21: 714724.
Hartzler AW, Zhu X, Siedlak SL et al. (2002). The p38 pathway
is activated in Pick disease and progressive supranuclear
palsy: a mechanistic link between mitogenic pathways, oxi-
dative stress, and tau. Neurobiol Aging 23: 855859.
Hauser RA, Trehan R (1994). Initial experience with electro-
convulsive therapy for progressive supranuclear palsy.
Mov Disord 9: 467469.
Hauw JJ, Daniel SE, Dickson D et al. (1994). Preliminary
NINDS neuropathologic criteria for Steele-Richardson-
Olszewski syndrome (progressive supranuclear palsy).
Neurology 44: 20152019.
Holmberg B, Rosengren L, Karlsson JE et al. (1998).
Increased cerebrospinal fluid levels of neurofilament pro-
tein in progressive supranuclear palsy and multiple-system
atrophy compared with Parkinsons disease. Mov Disord
13: 7077.
Holmberg B, Johnels B, Ingvarsson P et al. (2001). CSF-
neurofilament and levodopa tests combined with discrimi-
nant analysis may contribute to the differential diagnosis
of Parkinsonian syndromes. Parkinsonism Relat Disord
8: 2331.
Holmberg B, Johnels B, Blennow K et al. (2003). Cerebrosp-
inal fluid Abeta42 is reduced in multiple system atrophy
but normal in Parkinsons disease and progressive supra-
nuclear palsy. Mov Disord 18: 186190.
Hope AD, Lashley T, Lees AJ et al. (2004). Failure in heat-
shock protein expression in response to UBB1 protein in
progressive supranuclear palsy in humans. Neurosci Lett
359: 9498.
Horiguchi T, Uryu K, Giasson BI et al. (2003). Nitration of
tau protein is linked to degeneration in tauopathies. Am
J Pathol 163: 10211031.
345
Houlden H, Baker M, Morris HR et al. (2001). Corticobasal
degeneration and progressive supranuclear palsy share a
common tau haplotype. Neurology 56: 17021706.
Hughes AJ, Daniel SE, Ben-Shlomo Y et al. (2002). The
accuracy of diagnosis of parkinsonian syndromes in a spe-
cialist movement disorder service. Brain 125: 861870.
Hutton M (2000). Missing tau mutation identified. Ann
Neurol 47: 417418.
Jackson JA, Jankovic J, Ford J (1983). Progressive supranuc-
lear palsy: clinical features and response to treatment in
sixteen patients. Ann Neurol 13: 273278.
Jankovic J (1984). Progressive supranuclear palsy: clinical
and pharmacological update. Neurol Clin 2: 473486.
Jellinger KA, Blancher C (1992). Neuropathology. In: I Lit-
van, Y Agid (Eds.), Progressive Supranuclear Palsy: Clin-
ical and Research Approaches.Oxford University Press,
Oxford, pp. 4488.
Josephs KA, Dickson DW (2003). Diagnostic accuracy of
progressive supranuclear palsy in the Society for Progres-
sive Supranuclear Palsy brain bank. Mov Disord 18:
10181026.
Josephs KA, Tsuboi Y, Dickson DW (2004). Creutzfeldt-
Jakob disease presenting as progressive supranuclear
palsy. Eur J Neurol 11: 343346.
Juh R, Kim J, Moon D et al. (2004). Different metabolic pat-
terns analysis of Parkinsonism on the 18F-FDG PET. Eur
J Radiol 51: 223233.
Katzenschlager R, Cardozo A, Cobo MRA et al.
(2003). Unclassifiable parkinsonism in two European ter-
tiary referral centres for movement disorders. Mov Disord
18: 11231131.
Kawashima M, Miyake M, Kusumi M et al. (2004). Preva-
lence of progressive supranuclear palsy in Yonago, Japan.
Mov Disord 19: 12391240.
Kertzman C, Robinson DL, Litvan I (1990). Effects of phy-
sostigmine on spatial attention in patients with progressive
supranuclear palsy. Arch Neurol 47: 13461350.
Kim YJ, Ichise M, Ballinger JR et al. (2002). Combination of
dopamine transporter and D2 receptor SPECT in the diag-
nostic evaluation of PD, MSA, and PSP. Mov Disord 17:
303312.
Kimber J, Mathias CJ, Lees AJ et al. (2000). Physiological,
pharmacological and neurohormonal assessment of auto-
nomic function in progressive supranuclear palsy. Brain
123: 14221430.
Kobari M, Fukuuchi Y, Shinohara T et al. (1992). Local cer-
ebral blood flow and its response to intravenous levodopa
in progressive supranuclear palsy. Comparison with Par-
kinsons disease. Arch Neurol 49: 725730.
Koller WC, Morantz R, Vetere-Overfield B et al. (1989).
Autologous adrenal medullary transplant in progressive
supranuclear palsy. Neurology 39: 10661068.
Kompoliti K, Goetz CG, Litvan I et al. (1998). Pharmacologi-
cal therapy in progressive supranuclear palsy. Arch Neurol
55: 10991102.
Kotake Y, Okuda K, Kamizono M et al. (2004). Detection
and determination of reticuline and N-methylcoculaurine
in the Annonaceae family using liquid chromatography-
346 D. J. BURN AND A. J. LEES
tandem mass spectrometry. J Chromatogr B Analyt Tech-
nol Biomed Life Sci 806: 7578.
Krack P, Marion MH (1994). Apraxia of lid opening, a
focal eyelid dystonia: clinical study of 32 patients. Mov
Disord 9: 610615.
Kristensen MO (1985). Progressive supranuclear palsy20
years later. Acta Neurol Scand 71: 177189.
Kuhn AA, Grosse P, Holtz K et al. (2004). Patterns of abnor-
mal motor cortex excitability in atypical parkinsonian syn-
dromes. Clin Neurophysiol 115: 17861795.
Lange KW, Tucha O, Alders GL et al. (2003). Differentiation
of parkinsonian syndromes according to differences in
executive functions. J Neural Transm 110: 983995.
Lannuzel A, Michel PP, Caparros-Lefebvre D et al.
(2002). Toxicity of Annonaceae for dopaminergic neu-
rons: potential role in atypical parkinsonism in Guade-
loupe. Mov Disord 17: 8490.
Larner AJ (2002). Did Charles Dickens describe progres-
sive supranuclear palsy in 1857? Mov Disord 17:
832833.
Lees AJ (1987). The Steele-Richardson-Olszewski syndrome
(progressive supranuclear palsy). In: CD Marsden, S Fahn
(Eds.), Movement Disorders 2, vol. 7. Butterworths, Lon-
don, 272287.
Lepore FE, Moudgil SS (2002). Procerus sign in progressive
supranuclear palsy. Neurology 58: 18661867.
Lewis J, McGowan E, Rockwood J et al. (2000). Neurofibril-
lary tangles, amyotrophy and progressive motor distur-
bance in mice expressing mutant (P301L) tau protein.
Nat Genet 25: 402405.
Litvan I (2001). Diagnosis and management of progressive
supranuclear palsy. Semin Neurol 21: 4148.
Litvan I, Chase TN (1992). Traditional and experimental
therapeutic approaches. In: I Litvan, (Ed.), Progressive
Supranuclear Palsy: Clinical and Research Approaches.
Oxford University Press, New York, pp. 254269.
Litvan I, Gomez C, Atack JR et al. (1989). Physostigmine
treatment of progressive supranuclear palsy. Ann Neurol
26: 404407.
Litvan I, Blesa R, Clark K et al. (1994). Pharmacological
evaluation of the cholinergic system in progressive supra-
nuclear palsy. Ann Neurol 36: 5561.
Litvan I, Agid Y, Calne D et al. (1996a). Clinical research
criteria for the diagnosis of progressive supranuclear palsy
(Steele-Richardson-Olszewski syndrome): report of the
NINDS-SPSP international workshop. Neurology 47: 19.
Litvan I, Hauw JJ, Bartko JJ et al. (1996b). Validity and
reliability of the preliminary NINDS neuropathologic cri-
teria for progressive supranuclear palsy and related disor-
ders. J Neuropathol Exp Neurol 55: 97105.
Litvan I, Mangone CA, McKee A et al. (1996c). Natural his-
tory of progressive supranuclear palsy (Steele-Richardson-
Olszewski syndrome) and clinical predictors of survival:
a clinicopathological study. J Neurol Neurosurg Psychiatry
60: 615620.
Litvan I, Campbell G, Mangone CA et al. (1997). Which
clinical features differentiate progressive supranuclear
palsy (Steele-Richardson-Olszewski syndrome) from
related disorders? A clinicopathological study. Brain
120: 6574.
Litvan I, Phipps M, Pharr VL et al. (2001). Randomized pla-
cebo-controlled trial of donepezil in patients with progres-
sive supranuclear palsy. Neurology 57: 467473.
Litvan I, Bhatia KP, Burn DJ et al. (2003). SIC task force
appraisal of clinical diagnostic criteria for parkinsonian
disorders. Mov Disord 18: 467486.
Lopez OL, Litvan I, Catt KE et al. (1999). Accuracy of four
clinical diagnostic criteria for the diagnosis of neurode-
generative dementias. Neurology 53: 12921299.
Maher ER, Lees AJ (1986). The clinical features and natural
history of the Steele-Richardson-Olszewski syndrome
(progressive supranuclear palsy). Neurology 36:
10051008.
Maraganore DM, Anderson DW, Bower JH et al.
(1998). Potential selection bias in autopsy series of Par-
kinsons disease and related disorders. Neurology 50:
A98A99.
Maraganore DM, Hernandez DG, Singleton AB et al.
(2001). Case-control study of the extended tau gene
haplotype in Parkinsons disease. Ann Neurol 50:
658661.
Mastaglia FL, Grainger K, Kee F et al. (1973). Progressive
supranuclear palsy (the Steele-Richardson-Olszewski syn-
drome): clinical and electrophysiological observations in
eleven cases. Proc Aust Assoc Neurol 10: 3544.
Masucci EF, Kurtzke JF (1989). Tremor in progressive
supranuclear palsy. Acta Neurol Scand 80: 296300.
Matsuo H, Takashima H, Kishikawa M et al. (1991). Pure
akinesia: an atypical manifestation of progressive supra-
nuclear palsy. J Neurol Neurosurg Psychiatry 54:
397400.
Mayr BJ, Bonelli RM, Niederwieser G et al. (2002). Zolpi-
dem in progressive supranuclear palsy. Eur J Neurol 9:
184185.
Millar D, Griffiths P, Zermansky AJ et al. (2006). Character-
izing behavioral and cognitive dysexecutive changes in
progressive supranuclear palsy. Mov Disord 21: 199207.
Mishina M, Ishii K, Mitani K et al. (2004). Midbrain hypo-
metabolism as early diagnostic sign for progressive supra-
nuclear palsy. Acta Neurol Scand 110: 128135.
Mokri B, Ahlskog JE, Fulgham JR et al. (2004). Syndrome
resembling PSP after surgical repair of ascending aorta
dissection or aneurysm. Neurology 62: 971973.
Montplaisir J, Petit D, Decary A et al. (1997). Sleep and
quantitative EEG in patients with progressive supranuclear
palsy. Neurology 49: 9991003.
Morris HR, Gibb G, Katzenschlager R et al. (2002a). Patho-
logical, clinical and genetic heterogeneity in progressive
supranuclear palsy. Brain 125: 969975.
Morris HR, Katzenschlager R, Janssen JC et al. (2002b).
Sequence analysis of tau in familial and sporadic progres-
sive supranuclear palsy. J Neurol Neurosurg Psychiatry
72: 388390.
Morris HR, Osaki Y, Holton J et al. (2003). Tau exon 1016
mutation FTDP-17 presenting clinically as sporadic young
onset PSP. Neurology 61: 102104.
 PROGRESSIVE SUPRANUCLEAR PALSY
Mudher A, Shepherd D, Newman TA, et al. (2004). GSK-
3beta inhibition reverses axonal transport defects and
behavioural phenotypes in Drosophila. Mol Psychiatry 9:
522530.
Muller J, Wenning GK, Wissel J et al. (2002). Botulinum
toxin treatment in atypical parkinsonian disorders asso-
ciated with disabling focal dystonia. J Neurol 249:
300304.
Murialdo A, Marchese R, Abbruzzese G et al. (2000). Neu-
rosyphilis presenting as progressive supranuclear palsy.
Mov Disord 15: 730731.
Nath U, Burn DJ (2000). The epidemiology of progressive
supranuclear palsy. Parkinsonism Relat Disord 6: 145153.
Nath U, Ben-Shlomo Y, Thomson R et al. (2001). The
prevalence of progressive supranuclear palsy (Steele-
Richardson-Olszewski syndrome) in the UK. Brain 124:
14381449.
Nath U, Ben-Shlomo Y, Thomson RG et al. (2003). Clinical
features and natural history of progressive supranuclear
palsy: a clinical cohort study. Neurology 60: 910916.
Nath U, Thomson RG, Wood R et al. (2005). Population-
based mortality rates and quality of death certification
in progressive supranuclear palsy (Steele-Richardson-
Olszewski Syndrome). J Neurol Neurosurg Psychiatry
78: 498502.
Neophytides A, Lieberman AN, Goldstein M et al.
(1982). The use of lisuride, a potent dopamine and seroto-
nin agonist, in the treatment of progressive supranuclear
palsy. J Neurol Neurosurg Psychiatry 45: 261263.
Netzel PJ, Sutor B (2001). Electroconvulsive therapy-respon-
sive depression in a patient with progressive supranuclear
palsy. J ECT 17: 6870.
Neumann M, Muller V, Gorner K et al. (2004). Pathological
properties of the Parkinsons disease-associated DJ-1 in
alpha-synucleinopathies and tauopathies: relevance for
multiple system atrophy and Picks disease. Acta Neuro-
pathol (Berl) 107: 489496.
Newman GC (1985). Treatment of progressive supranuclear
palsy with tricyclic antidepressants. Neurology 35:
11891193.
Nieforth KA, Golbe LI (1993). Retrospective study of drug
response in 87 patients with progressive supranuclear
palsy. Clin Neuropharmacol 16: 338346.
Oka M, Katayama S, Imon Y et al. (2001). Abnormal signals
on proton density-weighted MRI of the superior cerebellar
peduncle in progressive supranuclear palsy. Acta Neurol
Scand 104: 15.
Ondo W, Warrior D, Overby A et al. (2000). Computerized
posturography analysis of progressive supranuclear palsy:
a case-control comparison with Parkinsons disease and
healthy controls. Arch Neurol 57: 14641469.
Osaki Y, Ben-Shlomo Y, Lees AJ et al. (2003). Accuracy of
clinical diagnosis of progressive supranuclear palsy. Mov
Disord 19: 181189.
Pastor P, Pastor E, Carnero C et al. (2001). Familial atypical
progressive supranuclear palsy associated with homozig-
osity for the delN296 mutation in the tau gene. Ann Neu-
rol 49: 263267.
347
Pastor P, Ezquerra M, Perez JC et al. (2004). Novel haplo-
types in 17q21 are associated with progressive supranuc-
lear palsy. Ann Neurol 56: 249258.
Paviour DC, Lees AJ, Josephs KA et al. (2004). Frontotem-
poral lobar degeneration with ubiquitin-only-immunoreac-
tive neuronal changes: broadening the clinical picture to
include progressive supranuclear palsy. Brain 127:
24412451.
Pezzella FR, Paglia MG, Colosimo C (2004). Cerebrospinal
fluid analysis for Whipples disease in patients with pro-
gressive supranuclear palsy. Mov Disord 19: 220222.
Pharr V, Litvan I, Brat DJ et al. (1999). Ideomotor apraxia in
progressive supranuclear palsy: a case study. Mov Disord
14: 162166.
Piccini P, de Yebenez J, Lees AJ et al. (2001). Familial pro-
gressive supranuclear palsy: detection of subclinical cases
using 18F-dopa and 18Fluorodeoxyglucose positron emis-
sion tomography. Arch Neurol 58: 18461851.
Piccione F, Mancini E, Tonin P et al. (1997). Botulinum
toxin treatment of apraxia of eyelid opening in progressive
supranuclear palsy: report of two cases. Arch Phys Med
Rehabil 78: 525529.
Pillon B, Dubois B, Ploska A et al. (1991). Severity and spe-
cificity of cognitive impairment in Alzheimers, Hunting-
tons, and Parkinsons diseases and progressive
supranuclear palsy. Neurology 41: 634643.
Pirker W, Djamshidian S, Asenbaum S et al. (2002). Progres-
sion of dopaminergic degeneration in Parkinsons disease
and atypical parkinsonism: a longitudinal beta-CIT
SPECT study. Mov Disord 17: 4553.
Pittman AM, Myers AJ, Duckworth J et al. (2004). The
structure of the tau haplotype in controls and in pro-
gressive supranuclear palsy. Hum Mol Genet 13:
12671274.
Plotkin M, Amthauer H, Klaffke S et al. (2005). Combined
(123)I-FP-CIT and (123)I-IBZM SPECT for the diagnosis
of parkinsonian syndromes: study on 72 patients. J Neural
Transm 112: 677692.
Polo KB, Jabbari B (1994). Botulinum toxin-A improves the
rigidity of progressive supranuclear palsy. Ann Neurol 35:
237239.
Quinn NP (1997). Parkinsons disease: clinical features. In:
NP Quinn, (Ed.), Parkinsonism, vol. 6. Balliere Tindall,
London, pp. 113.
Radhakrishnan K, Thacker AK, Maloo JC et al. (1988).
Descriptive epidemiology of some rare neurological
diseases in Benghazi, Libya. Neuroepidemiology 7:
159164.
Rajput AH, Offord KP, Beard CM et al. (1984). Epidemiol-
ogy of parkinsonism: incidence, classification and mortal-
ity. Ann Neurol 16: 278282.
Rascol O, Sieradzan K, Peyro-Saint-Paul H et al.
(1998). Efaroxan, an alpha-2 antagonist, in the treatment
of progressive supranuclear palsy. Mov Disord 13:
673676.
Reitblat T, Polishchuk I, Dorodnikov E et al. (2003). Primary
antiphospholipid antibody syndrome masquerading as pro-
gressive supranuclear palsy. Lupus 12: 6769.
348 D. J. BURN AND A. J. LEES
Richter-Landsberg C, Bauer NG (2004). Tau-inclusion body
formation in oligodendroglia: the role of stress proteins and
proteasome inhibition. Int J Dev Neurosci 22: 443451.
Righini A, Antonini A, De Notaris R et al. (2004). MR ima-
ging of the superior profile of the midbrain: differential
diagnosis between progressive supranuclear palsy and Par-
kinsons disease. Am J Neuroradiol 25: 927932.
Rivaud-Pechoux S, Vidailhet M, Gallouedec G et al.
(2000). Longitudinal ocular motor study in corticobasal
degeneration and progressive supranuclear palsy. Neurol-
ogy 54: 10291032.
Rohs G (1996). Progressive supranuclear palsy: managing
the disabilities and providing nursing support. Axone 17:
6065.
Rojo A, Pernaute RS, Fontan A et al. (1999). Clinical genet-
ics of familial progressive supranuclear palsy. Brain 122:
12331245.
Romano S, Colosimo C (2001). Procerus sign in progressive
supranuclear palsy. Neurology 57: 19281929.
Rottach KG, Riley DE, DiScenna AO et al. (1996). Dynamic
properties of horizontal and vertical eye movements in
parkinsonian syndromes. Ann Neurol 39: 368377.
Sandyk R (1998). Transcranial AC pulsed applications of
weak electromagnetic fields reduces freezing and falling
in progressive supranuclear palsy: a case report. Int J Neu-
rosci 94: 4154.
Santacruz P, Uttl B, Litvan I et al. (1998). Progressive supra-
nuclear palsy: a survey of the disease course. Neurology
50: 16371647.
Sasaki N, Fukatsu R, Tsuzuki K et al. (1998). Advanced gly-
cation end products in Alzheimers disease and other neu-
rodegenerative diseases. Am J Pathol 153: 11491155.
Scaravilli T, Pramstaller PP, Salerno A et al. (2000). Neuro-
nal loss in Onufs nucleus in three patients with progres-
sive supranuclear palsy. Ann Neurol 48: 97101.
Schleider MA, Nagurney JT (1977). Progressive supranuclear
ophthalmoplegia. Association with cricopharyngeal dys-
function and recurrent pneumonia. JAMA 237: 994995.
Schofield EC, Caine D, Kril JJ et al. (2005). Staging disease
severity in movement disorder tauopathies: brain atrophy
separates progressive supranuclear palsy from corticobasal
degeneration. Mov Disord 20: 3439.
Schrag A, Ben-Shlomo Y, Quinn NP (1999). Prevalence of
progressive supranuclear palsy and multiple system atro-
phy: a cross-sectional study. Lancet 354: 17711775.
Schrag A, Good CD, Miszkiel K et al. (2000). Differentiation
of atypical Parkinsonian syndromes with routine MRI.
Neurology 54: 697702.
Schreckenberger M, Hagele S, Seissmeier T et al.
(2004). The dopamine D2 receptor ligand 18F-desmeth-
oxyfallypride: an appropriate fluorinated PET tracer for
the differential diagnosis of parkinsonism. Eur J Nucl
Med Mol Imaging 31: 11281135.
Schulz JB, Skalej M, Wedekind D et al. (1999). Magnetic
resonance imaging-based volumetry differentiates idio-
pathic Parkinsons syndrome from multiple system atro-
phy and progressive supranuclear palsy. Ann Neurol 45:
6574.
Seppi K, Schocke MFH, Esterhammer R et al. (2003). Diffu-
sion-weighted imaging discriminates progressive supra-
nuclear palsy from PD, but not from the parkinson
variant of multiple system atrophy. Neurology 60:
922927.
Shinotoh H, Namba H, Yamaguchi M et al. (1999). Positron
emission tomographic measurement of acetylcholinester-
ase activity reveals differential loss of ascending choliner-
gic systems in Parkinsons disease and progressive
supranuclear palsy. Ann Neurol 46: 6269.
Soliveri P, Monza D, Paridi D et al. (2000). Neuropsycholo-
gical follow up in patients with Parkinsons disease, stria-
tonigral degeneration-type multiple system atrophy, and
progressive supranuclear palsy. J Neurol Neurosurg Psy-
chiatry 69: 313318.
Sosner J, Wall GC, Sznajder J (1993). Progressive supranuc-
lear palsy: clinical presentation and rehabilitation of two
patients. Arch Phys Med Rehabil 74: 537539.
Stanford PM, Halliday GM, Brooks WS et al. (2000).
Progressive supranuclear palsy pathology caused by a
novel silent mutation in exon 10 of the tau gene: expan-
sion of the disease phenotype caused by tau gene muta-
tions. Brain 123: 880893.
Stanford PM, Brooks WS, Teber ET et al. (2004). Frequency of
tau mutations in familial and sporadic frontotemporal
dementia and other tauopathies. J Neurol 251: 10981104.
Tamai S, Almeida OP (1997). Nortriptyline for the treatment
of depression in progressive supranuclear palsy. J Am
Geriatr Soc 45: 10331034.
Tolosa E, Valldeoriola F, Marti MJ (1994). Clinical diagno-
sis and diagnostic criteria of progressive supranuclear
palsy (Steele-Richardson-Olszewski syndrome). J Neural
Transm Suppl 42: 1531.
Tomasiewicz HG, Flaherty DB, Soria JP et al. (2002). Trans-
genic zebrafish model of neurodegeneration. J Neurosci
Res 70: 734745.
Tsuboi Y, Slowinski J, Josephs KA et al. (2003). Atrophy of
the superior cerebellar peduncle in progressive supranuc-
lear palsy. Neurology 60: 17661769.
Urakami K, Wada K, Arai H et al. (2001). Diagnostic signif-
icance of tau protein in cerebrospinal fluid from patients
with corticobasal degeneration or progressive supranuclear
palsy. J Neurol Sci 183: 9598.
Van Gerpen JA, Ahlskog JE, Petty GW (2003). Progressive
supranuclear palsy phenotype secondary to CADASIL.
Parkinsonism Relat Disord 9: 367369.
van Slegtenhorst M, Lewis J, Hutton M (2000). The mole-
cular genetics of the tauopathies. Exp Gerontol 35:
461471.
Verny M, Jellinger KA, Hauw JJ et al. (1996). Progressive
supranuclear palsy: a clinicopathological study of 21
cases. Acta Neuropathol (Berl) 91: 427431.
Vidailhet M, Rivaud S, Gouidier-Khouja N et al. (1994). Eye
movements in parkinsonian syndromes. Ann Neurol 35:
420426.
Vodusek DB (2001). Sphincter EMG and differential dia-
gnosis of multiple system atrophy. Mov Disord 16:
600607.
 PROGRESSIVE SUPRANUCLEAR PALSY
Wakabayashi K, Takahashi H (2004). Pathological heteroge-
neity in progressive supranuclear palsy and corticobasal
degeneration. Neuropathology 24: 7986.
Walter U, Niehaus L, Probst T et al. (2003). Brain parench-
yma sonography discriminates Parkinsons disease and
atypical parkinsonian syndromes. Neurology 60: 7477.
Walter U, Dressler D, Wolters A et al. (2004). Sonographic
discrimination of corticobasal degeneration vs progressive
supranuclear palsy. Neurology 63: 504509.
Ward-Smith PA, Berry P (1990). Autologous transplantation
as a treatment for progressive supranuclear palsy. J Neu-
rosci Nurs 22: 100103.
Warmuth-Metz M, Naumann M, Csoti I et al. (2001). Measure-
ment of the midbrain diameter on routine magnetic reso-
nance imaging: a simple and accurate method of
differentiating between Parkinson disease and progressive
supranuclear palsy. Arch Neurol 58: 10761079.
Weiner WJ, Minagar A, Shulman LM (1999). Pramipexole in
progressive supranuclear palsy. Neurology 52: 873874.
Wermuth L, Joensen P, Bunger N et al. (1997). High preva-
lence of Parkinsons disease in the Faroe Islands. Neurol-
ogy 49: 426432.
349
Williams AC, Nutt J, Lake CR et al. (1979). Actions of bromo-
criptine in the Shy-Drager and Steele-Richardson-Olszewksi
syndromes. In: K Fuxe, DB Calne (Eds.), Dopaminergic
Ergot Derivatives and Motor Function.Pergamon Press,
Oxford, pp. 271283.
Williams DR, Paviour DC, Watt HC et al. (2004). Chara-
cteristics of two distinct clinical phenotypes observed in
pathologically proven progressive supranuclear palsy:
Richardsons syndrome and PSP-parkinsonism. Mov Disord
19: S328S329.
Wittman CW, Wszolek MF, Shulman JM et al. (2001). Tauo-
pathy in Drosophila: neurodegeneration without neurofi-
brillary tangles. Science 293: 711714.
Wolters A, Classen J, Kunesch E et al. (2004). Measure-
ments of transcallosally mediated cortical inhibition for
differentiating parkinsonian syndromes. Mov Disord 19:
518528.
Zemaitaitis MO, Kim SY, Halverson RA et al. (2003). Trans-
glutaminase activity, protein, and mRNA expression are
increased in progressive supranuclear palsy. J Neuropathol
Exp Neurol 62: 173184.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 48

Corticobasal degeneration

NATIVIDAD P. STOVER*, HARRISON C. WALKER AND RAY L. WATTS

University of Alabama at Birmingham, Birmingham, AL, USA

48.1. Historical aspects
Corticobasal degeneration (CBD) is a neurodegenera-
tive disorder that has gained the interest of clinicians
and scientists, especially over the last two decades.
The typical clinical presentation of CBD is one of an
atypical parkinsonian syndrome with cerebral cortical
signs such as apraxia or cortical sensory loss, similar
to the 3 cases described originally (Rebeiz et al.,
1967). The disorder was initially called corticodentato-
nigral degeneration with neuronal achromasia, based
on the pathological findings in the first cases. Other
names used include corticonigral degeneration with
neuronal achromasia, corticobasal ganglionic degen-
eration and myoclonic dystonia. The term cortico-
basal degeneration was initially used in 1989 (Gibb
et al., 1989) and more recently the term corticobasal
syndrome or complex has also been proposed to char-
acterize better the heterogeneity and overlap of the
clinical features and neuropathologic findings in cases
of CBD (Kertesz et al., 2000).
The observation that the aggregation of tau, a
microtubule-associated protein, is involved in the
pathology of several neurologic disorders has revolu-
tionized our understanding of CBD and its relationship
to other neurodegenerative diseases that are collec-
tively called tauopathies (Litvan, 1999; Goedert
et al., 2000; Tolnay and Probst, 2003; Cairns et al.,
2004). The identification of mutations in the tau gene
on chromosome 17 in familial cases of frontotemporal
dementia with parkinsonism (FTDP-17) (Verin et al.,
1997) and the overlapping clinical and pathological
features of CBD with other tauopathies emphasized
the importance of tau proteins in this group of disor-
ders: Picks disease, primary progressive aphasia
(PPA), progressive supranuclear palsy (PSP) (Steele
et al., 1964; Litvan et al., 1996), amyotrophic lateral
sclerosisparkinsonismdementia complex and argyro-
philic grain disease (AGD) (Tolnay and Clavaguera,
2004). In parallel, it has been discovered that abnorm-
alities of the vesicle-associated protein a-synuclein
underlie the pathology of Parkinsons disease (PD),
Lewy body dementia (LBD) and multiple system atro-
phy (MSA) (Wenning et al., 1994) and thus they com-
prise the synucleinopathies (Dickson, 1999b; Arai
et al., 2001b). Cases of CBD have clinical features that
also overlap with the synucleinopathies.
It is still debated whether CBD is a distinctive
nosological entity or a syndrome. Currently, we rec-
ognize two clinical phenotypes of CBD: the first is a
classic motor presentation with asymmetric parkinso-
nian symptoms and apraxia and/or cortical sensory
loss and the second is a presentation of dementia often
with focal cortical signs with or without parkinsonian
features (Hachinski, 1997; Kertesz and Munoz, 2004).
48.2. Description of the initial cases
James Parkinson described PD in 1817 and Jean-Martin
Charcot and his disciples drew emphasis to the cardinal
features of the disease in the last years of the 19th
century. They also described a number of parkinsonian
variants with atypical jerking movements and abnormal
posture in the limbs, described originally as hemiple-
gic parkinsonism (Charcot and Vulpian, 18611862;
Charcot, 18871888). It is possible that some of these
patients had CBD.
In 1925 J. Lhermitte described a clinical case sug-
gestive of CBD to the French Neurological Society:
A carpenter retired at age 67 because of progressive
right hand clumsiness. At age 72, he could no longer
walk independently and ambulated with a wide-based,

* Correspondence to: Natividad P. Stover, Department of Neurology, University of Alabama at Birmingham, 360 Sparks
Center, 1720 7th Avenue South, Birmingham, AL 35294-0017, USA. E-mail: npstover@uab.edu, Tel: 1-205-934-0683,
Fax: 1-205-996-4039.
352 N. P. STOVER ET AL.
shuffling gait with the right arm flexed. In addition,
his right arm moved involuntarily like a foreign
body. In spite of normal primary sensation, he could
not recognize objects placed in his right hand (Ballan
and Tison, 1997).
The initial three cases described by Rebeiz et al. at
the Massachusetts General Hospital (1967, 1968) pre-
sented a unique pattern of progressive neurological
disorder with motor impairment, affecting mainly the
left side of the body and characterized by stiffness,
slowness, clumsiness, numbness or deadness and
awkward movements of the left arm and leg as initial
symptoms. In 2 patients the leg was affected first with
progressive gait impairment. As the disease pro-
gressed, involuntary movements became prominent
with elevation and abduction of the limbs that came
on during attempted motor activity and when the
affected arm was being used the opposite limb exhib-
ited involuntary synkinesias. Each of the 3 cases had
some tremor, even if it was not the prominent feature.
There was progressive impairment in the use of
affected limbs without motor weakness except late in
the course of the disease. In 1 case, there was impaired
position sense, tactile localization, two-point discrimi-
nation and ability to recognize objects by touch and
another patient had impaired position sense. In all cases
there were increased tendon reflexes and increased
resistance to passive movements of the affected limbs
and severe finger contractures. With time the 3 pati-
ents developed impairment of speech and dysphagia.
Cognitive dysfunction was not a remarkable feature in
the clinical picture until later in the disease. The symp-
toms in the 3 patients started in late middle age and they
died 68 years after diagnosis.
Radiographic contrast studies showed cerebral atro-
phy in the 3 patients, more pronounced on the right than
on the left. None of the patients had seizures or myoclo-
nus. Electroencephalograms (EEG) showed slow- and
sharp-wave activity without specific changes. The rest
of the laboratory investigations were normal.
Postmortem examination of the brains revealed
asymmetric frontoparietal cortical atrophy. On micro-
scopic examination the most severe changes were in
the superomedial frontoparietal and Rolandic regions
with severe neuronal loss and disappearance of the
cells in the outer three cortical layers with astrocytic
gliosis and little microglial activation. Many neurons
in the deep cortical layers showed swelling of the cell
bodies frequently accompanied by vacuolization. The
swollen neurons often had eccentric nuclei without
Nissl substance in the cytoplasm that prompted the
terms achromatic and ballooned as descriptors and a toothbrush and saluting with the right arm. Fascicu-
these histological abnormalities colocalized with the
distribution of the neuronal loss. The white-matter
regions corresponding with areas of cortical atrophy
showed considerable demyelination and fibrous glio-
sis. The hippocampus, inferior and medial temporal
cortex and occipital regions were spared in the original
cases. Considerable loss of pigmented neurons in the
substantia nigra (SN) was observed in 2 of the cases
and was less marked in the third, mainly in the lateral
two-thirds. The subthalamic nucleus contained a few
swollen neurons and gliosis and in 2 of the cases there
was significant loss and swelling of nerve cells in the
central nuclei of the cerebellum with retrogade atrophy
of the superior cerebellar peduncles, as well as gliosis
of the red nuclei and the ventrolateral portion of the
thalamus. Those 2 cases also showed degeneration of
the corticospinal tracts in the brainstem and spinal
cord, most likely secondary to neuronal loss in the cer-
ebral cortex. The characteristic pathological findings
seen in other neurodegenerative diseases, such as
Lewy bodies, Pick bodies and amyloid plaques, were
not observed in the initial cases.
A case described initially as myoclonic dystonia
was reported by Obeso et al. in 1983; the patient
was followed until death and the pathology was char-
acteristic for CBD. This patient had clinical features
resembling PSP but pathological findings similar to
Picks disease. The patient had focal dystonia and
myoclonus of an arm, alien-hand phenomenon and
an akinetic-rigid syndrome and he developed supra-
nuclear gaze palsy, parkinsonism and mild cerebellar
signs. The pathology showed frontoparietal atrophy
with cortical cell loss, Picks disease cells with glio-
sis in the basal ganglia, midbrain tegmentun, SN and
locus ceruleus. The pathological examination also
showed inclusions in the SN that were called cortico-
basal inclusions, similar to the globose neurofibril-
lary tangles (NFT) of PSP. Some of the nigral
inclusions were similar to those seen in Picks dis-
ease (Obeso et al., 1985).
Watts et al. (1985) described a case with pathologic
correlation of CBD. The patient presented with stiff-
ness of the right arm and leg followed by progression
of the symptoms to the left side. There was a rapid,
irregular action tremor and impairment of balance that
progressed to inability to walk without assistance.
During the third year of disease, he developed dysar-
thria and poor semantic content in his language. He
had hypomimia, blepharospasm and saccadic break-
down of smooth pursuit eye movements. The right
arm and leg had severely increased tone and dystonic
posturing of the fingers. The patient lost the ability
to perform motor tasks previously learned like using
lations were seen in several muscle groups of the
upper and lower limbs. There was no family history of
 CORTICOBASAL DEGENERATION
neurologic disease. Electrophysiologic and laboratory
evaluations were normal. Imaging studies showed
peri-Rolandic cortical atrophy and signal attenuation
of the white matter beneath the left central sulcus.
Neuropathological examination revealed asymmetrical
cerebral cortical atrophy, worse on the left with neuro-
nal loss and reactive gliosis in all layers of the premo-
tor, anterior cingulate, inferior parietal, insula and
anterior temporal regions. White-matter changes con-
sisted of extensive loss of myelinated axons and glio-
sis. Occasional neuritic plaques were noted, but there
were no NFT. In areas not so severely affected there
were swollen neurons with achromasia. There was neu-
ronal loss in the SN bilaterally, but no Lewy bodies were
seen. No abnormalities were observed in the striatum,
globus pallidus, substantia innominata, amygdala,
hypothalamus, cerebellum, brainstem or spinal cord.
The peripheral nerves showed demyelination and
there were denervation changes in skeletal muscles.
Therapeutic trials with multiple agents were ineffective.
Several other authors have contributed clinical and
pathological descriptions of cases consistent with
CBD and the use of modern laboratory techniques in
recent years has helped to characterize the disease
and its relationship with the other neurodegenerative
disorders better.
In recent years a number of patients with atypical
parkinsonian syndromes and a predominance of demen-
tia have turned out to have the classical pathologic
picture of CBD (Grimes et al., 1999; Graham et al.,
2003a; Kurz, 2005). There are also reports of cases pre-
senting with clinical features of CBD that lack specific
pathological features (Lerner et al., 1992; Maraganore
et al., 1992; Giannakopoulos et al., 1995; Brown
et al., 1998).
48.3. Epidemiology
Epidemiologic studies in CBD are difficult because of
clinical diagnostic uncertainties and the lack of a bio-
logical marker. The incidence and prevalence of
CBD increase if the different clinical and pathological
phenotypes are considered as part of a syndrome or
complex. The incidence of non-Alzheimer and non-
vascular dementia cases is around 10% in cases from
brain banks (DLB, Picks disease and FTDP-17) and
this percentage may increase to 20% if CBD and
PSP are included (Tanner, 1996).
The age of onset of CBD is usually in later adult
life with a mean onset of symptoms at 63 (
7.7) years.
The youngest case with pathological confirmation was
34 years old. Some authors have suggested a predomi-
nance in women but both sexes are affected. There
is no clear ethnic preponderance and most of the
353
described cases are Caucasian. Most of the patients
reported have been sporadic, but some studies do sug-
gest a familial tendency. One of the original cases
described had a history of similar neurologic disorders
in several family members, possibly representing a
case of FTDP-17. There is no evidence at present that
any CBD cases are related to a toxic exposure or to an
infectious agent (Di Maria et al., 2000; DePold Hohler
et al., 2003).
48.4. Diagnosis
There have been several attempts to establish diagnos-
tic criteria for CBD, but a formal validation has not
been performed. Most of the cases diagnosed with
CBD in movement disorder clinics focus primarily
on motor symptoms. Signs of cortical impairment such
as apraxia or cortical sensory loss usually develop
within 13 years of onset, but in some series dementia
was the most frequent initial symptom in patients with
pathologically confirmed CBD (Bergeron et al., 1998;
Litvan et al., 2003).
Riley and Lang (1993) proposed a set of clinical
characteristics of CBD based on the review of 12
cases, 9 with pathological confirmation of CBD. The
clinical manifestations were divided as related to basal
ganglia dysfunction (bradykinesia/akinesia, rigidity,
dystonia, postural instability, falls, athetosis and oro-
lingual dyskinesias), cerebral cortical signs (cortical
sensory loss, apraxia, alien-limb phenomenon, demen-
tia, frontal-release signs and dysphasia) and other
manifestations (postural/action tremor, hyperreflexia,
impaired ocular motility, dysarthria, focal reflex
myoclonus, impaired eyelid motion and dysphagia).
The authors proposed inclusion and exclusion features
for the diagnosis of CBD to establish research criteria.
The inclusion criteria were defined as the presence of
rigidity plus one cortical sign (apraxia, cortical sensory
loss or alien limb) or asymmetric rigidity, dystonia and
focal reflex myoclonus. Other authors (Kumar et al.,
1998) also included as inclusion criteria an asym-
metric, progressive course, presence of higher cortical
dysfunction and a movement disorder consisting of an
akinetic-rigid syndrome, levodopa resistance, promi-
nent limb dystonia and reflex or focal myoclonus.
Exclusion criteria were defined as early dementia,
early vertical gaze palsy, rest tremor, severe auto-
nomic dysfunction, sustained responsiveness to levo-
dopa and lesions or imaging studies suggesting a
different diagnosis.
Watts et al. (1994) proposed major and minor
criteria to be used in the clinical diagnosis of CBD.
The major criteria were defined as akinesia, rigidity,
postural/gait disturbance, action/postural tremor,
354 N. P. STOVER ET AL.
alien-limb phenomenon, dystonia, myoclonus and cor-
tical signs. Minor criteria were described as chor-
eoathetosis, dementia, cerebellar signs, supranuclear
gaze abnormalities, frontal-release signs and blephar-
ospasm. A strong degree of asymmetry was also
necessary for the diagnosis of CBD.
Another study presented the description of 105
patients with different neurodegenerative diseases and
known pathologic correlation to a group of movement
disorders specialists, to investigate the accuracy of the
clinical diagnosis of CBD. The study evaluated 10
autopsy-proven cases of CBD from a movement disor-
der center and found that specificity of the diagnosis
of CBD cases using the clinical features was high but
the sensitivity was low, particularly in the first 3 years
of the disease. This finding suggests that CBD is most
likely underdiagnosed. In this study, the best initial
clinical predictors for the diagnosis of CBD included
limb dystonia, asymmetric parkinsonism, apraxia and
absence of balance or gait disturbances. There were
some cases with pathology consistent with PSP that
had limb dystonia as the predominant presenting sign
and most of the cases with an initial gait disorder
actually had pathology indicative of PSP. Other
clinical motor features commonly seen in CBD are
alien-limb phenomenon, choreoathetoid movements,
blepharospasm, eye movement abnormalities, myo-
clonus and speech and swallowing problems. This
study also mentioned cognitive and neuropsychiatric
symptoms among the frequent manifestations (Litvan
et al., 1997).
The statistical analyses in the study with 24 patients
pathologically diagnosed with PSP and 27 cases with
CBD identified two predictor models for CBD
patients. Patients with CBD presented with lateralized
motor and cognitive signs, whereas PSP patients often
had severe postural instability at onset, symmetric par-
kinsonism, vertical supranuclear gaze palsy and speech
problems and CBD patients with a non-motor phe-
notype had early frontal dementia and eventually
bilateral parkinsonism (Litvan et al., 1999).
Rinne et al. (1994) reported that the most common
motor presentation in a series of 36 patients with
pathologically proven or clinically probable diagnosis
of CBD was a useless arm due to any combination of
rigidity, akinesia, dystonia, apraxia or alien-limb phe-
nomena, with or without myoclonus. Of those patients,
20 presented with symptoms beginning in the upper
extremities and 10 in the lower extremities.
Other less common presentations of CBD include
combined arm and leg involvement with motor dysfunc-
tion, unilateral painful paresthesias and orofacial dyski-
nesias. The gradual extension of the symptoms to
the contralateral limbs, facial hypomimia, dysphagia,
dysarthria and postural instability often develop over
the ensuing years (Wenning et al., 1998).
48.4.1. Motor symptoms
The so-called typical cases of motor presentation in
CBD consist of limb clumsiness or difficulty using
the limb, with or without rigidity and difficulty coordi-
nating small, precise movements. An asymmetric, insi-
diously progressive parkinsonism, usually of the
bradykinetic or akinetic-rigid type, with or without tre-
mor, is typical (Schneider et al., 1997). The symptoms
respond poorly to levodopa treatment, although one-
third of patients may have some initial response, mak-
ing the diagnosis challenging before other signs and
symptoms appear. Akinesia, rigidity and apraxia are
the most common motor findings during the course
of the disease, occurring in over 90% of motor cases
within the first 3 years of illness. Postural instability,
gait disorder and speech disorder early in the course
of CBD are also frequent clinical features (Lang
et al., 1994a). Rigidity in one arm is probably the most
common parkinsonian feature documented in motor
CBD cases and this symptom alone can be severe
and very debilitating (Lang, 2000). There are also
cases reported with symptoms affecting the lower
limbs initially (Lalive et al., 2000).
The tremor in CBD differs from the typical resting
or postural tremor seen in PD. It is a faster (6 8 Hz)
tremor with action and postural components and it
has a more irregular, jerky quality. Myoclonic move-
ments are most frequently reported in the upper extre-
mities and they are usually superimposed on the
tremor.
Myoclonus develops in approximately half of
patients with CBD during the course of the illness
(Chen et al., 1992; Thompson et al., 1994). Myoclonus
may be preceded by a jerky tremor and it manifests
itself in the most affected limb early in the disease.
Myoclonus is most evident in distal muscles and it
may coexist with dystonia in the most affected limbs
as well (Brunt et al., 1995; Mima et al., 1998). The
myoclonus in CBD is best seen during action or main-
tenance of a posture; however, it can also be elicited
by other stimuli, including cutaneous or auditory sti-
muli. The myoclonus may be masked by the presence
of increased muscle tone (Thompson and Shibasaki,
2000; Lleo et al., 2002; Caviness, 2003).
Electrophysiologic studies show that the myoclonus
is mainly an action or reflex myoclonus, preceded by a
short-duration muscle discharge with simultaneous
activation of antagonistic muscles (Carella et al.,
1991, 1997). Brief trains of high-frequency myoclonic
discharges happen in clusters of 23 Hz and in action
 CORTICOBASAL DEGENERATION
myoclonus this activity occurs throughout the period of
voluntary muscle activation and in a pattern consistent
with corticospinal activation. The intracortical compo-
nent of the long latency in reflex myoclonus in CBD is
shorter than the intracortical processing of sensory input
in typical cortical reflex myoclonus. Cortical hyperex-
citability was demonstrated in some cases of CBD with
myoclonus, consistent with impaired cortical inhibitory
systems. Although myoclonus is commonly seen in
CBD, it is also described in later stages of Alzheimers
disease and in CreutzfeldtJakob disease (CJD), MSA,
Huntingtons disease and cerebellar degeneration
(Shibasaki, 1995; Thompson, 1995).
Dystonia is frequently observed in patients with
CBD and it has not been possible to differentiate his-
torically the onset of dystonia from the onset of other
features of CBD (Vanek and Jankovic, 2000). Dysto-
nia was described in the initial cases and other studies
reported the presence of dystonia in 4070% of cases
(with pathologic confirmation of CBD in a small num-
ber of these cases). Initial presentation with dystonia in
one arm has been reported in a majority of motor cases
of CBD. The dystonia is usually asymmetric and the
arm is the most frequently affected region. Usually
the hand and forearm are flexed and the arm is
adducted at the shoulder area. The fingers are typically
flexed at the metacarpophalangeal joints, extended or
flexed at the proximal and distal interphalangeal joints
and show variable degrees of fixed postures with or
without associated contractures. Head, neck, leg, knee,
foot (mainly inversion), trunk and toe (flexed or
extended) dystonia are less frequently observed (Oide
et al., 2002). Some patients have thumb, index and
middle fingers extended and fourth and fifth fingers
flexed. Axial dystonia (head, neck, trunk) is less fre-
quent and may include retrocollis, anterocollis or torti-
collis (Vanek and Jankovic, 2001). Oromandibular
dystonia, orofacial dyskinesias and blepharospasm
have been reported. Pain accompanying dystonia is
described in over 40% of cases; it can be very intense
and is usually associated with contractures (Stover
and Watts, 2001). Rigidity and bradykinesia are more
evident in the dystonic limbs. Spontaneous onset of
choreoathetoid movements in patients with and with-
out dystonia involving the limbs and facial muscles
may be present, usually associated with the dystonic
extremity (Riley and Lang, 2000).
Eye movement abnormalities in CBD are distinctive
from other movement disorders frequently misdiag-
nosed as CBD, such as PSP, and ocular findings may
therefore help to improve diagnostic accuracy in the
early stages of the disease (Pierrot-Deseilligny et al.,
1989; Pierrot-Deseilligny, 1994; Vidailhet et al.,
1994). In patients with CBD there is a significantly
355
increased latency of horizontal saccades bilaterally
compared with controls and patients with PSP. Vertical
saccades may be slightly impaired in patients with CBD
compared with PSP patients (except for upgaze in
elderly patients) (Rottach et al., 1996). In early stages
of CBD smooth pursuit may be slow and exhibit sacca-
dic breakdown, but the range of movements is generally
full (Hamilton, 2000; Rivaud-Pechoux et al., 2000;
Vidailhet and Rivaud-Pechoux, 2000). As the illness
progresses, patients with CBD gradually lose the ability
to initiate rapid saccades in response to verbal com-
mands; however, they retain both spontaneous saccades
and optokinetic nystagmus. Asymmetry of saccade
latency is also a helpful and persistent abnormality char-
acteristic of CBD cases. Consecutive evaluation of eye
movements separated by several months may therefore
help to differentiate among CBD, PSP and other atypi-
cal parkinsonian syndromes. Visuospatial dysfunction
has been described as the presenting symptom in CBD
(Tang-Wai et al., 2003).
Upper motor neuron syndromes and corticospinal
signs may be present in CBD patients and were
described in the early cases by several authors.
Speech problems and dysphagia are frequently
reported in patients with CBD, especially in later phases
of the disease as cortical and subcortical pathways
become involved (Frattali and Sonies, 2000). Motor
speech problems can range from monotonous voice,
dysphonia, echolalia or pallilalia to dysarthria or even
anarthria (Lang, 1992). Dysphagia usually appears at
later stages of the disease (Muller et al., 2001).
48.4.2. Cortical symptoms
The most frequent cortical symptoms are apraxia,
cortical sensory abnormalities, aphasia, alien-limb
phenomenon and frontal-release reflexes.
Apraxia is considered to be a hallmark of CBD
early in the disease and raises the possibility of a diag-
nosis if seen as part of the motor presentation. Differ-
ent types of apraxia can be seen in patients with CBD
depending not only on the area of cortex affected initi-
ally but also on the timeframe of disease progression
in which the apraxia is evaluated (Jacobs et al., 1994;
Okuda and Tachibana, 1994; Soliveri et al., 2003,
2005; Zadikoff and Lang, 2005).
Ideomotor apraxia has been the most frequent form
of apraxia in patients with CBD in several studies.
Ideomotor apraxia is manifested by impairment of tim-
ing, sequencing, spatial organization and mimicking of
movements. Patients with ideomotor apraxia commit
mainly temporal (irregular speed and sequencing) and
spatial errors (abnormal amplitude, orientation of
objects and movements and abnormal use of body
356 N. P. STOVER ET AL.
parts as objects). Ideomotor apraxia is associated with
damage to the parietal association areas, premotor cor-
tex and interhemispheric white-matter bundles that
connect them, as well as basal ganglia and thalamus
(Jacobs et al., 1999; Leiguarda et al., 2000).
Patients with CBD may also demonstrate ideational
and limb kinetic apraxia (Otsuki et al., 1997; Okuma
et al., 2000). Fingers and hand movements are more
commonly affected and the movements are awkward,
amorphous and contaminated with movements unne-
cessary to perform a task. This form of apraxia is
mainly seen with lesions of the premotor cortex with
or without associated parietal cortex or basal ganglia
involvement. Ideomotor and limb kinetic apraxia may
coexist in the same patient. Limb kinetic apraxia is
most frequently described in patients with mild dysto-
nia or rigidity (Merians et al., 1999; Ishiwata et al.,
2000; Leiguarda et al., 2003; Salter et al., 2004).
Ideational apraxia is a dysfunction of the praxis
conceptual system. It is an inability to sequence cor-
rectly different movements needed to perform a speci-
fic task (Poeck, 1983). The performance in ideational
apraxia is abnormal in the content and tool selection
(including perseverations and pantomime-related
errors) and it may be observed in later stages of the
disease or in patients with dementia and language dys-
function at presentation (De Renzi and Lucchelli,
1988). In limb kinetic apraxia the manipulative beha-
vior is affected by a decrease in dexterity and fine
movements in the affected limb (Peigneux et al.,
2001). More advanced cases of CBD make it more
difficult to appreciate apraxia due to the severe brady-
kinesia, rigidity and dystonia in the same limb (Caselli
et al., 1999).
Speech apraxia was described in 2 patients (1 with
pathological confirmation of CBD) as a presenting
sign in the evolution of the classical clinical motor
syndrome (Rosenfield et al., 1991). Orofacial apraxia
with dysarthria has been reported in CBD patients
(Ozsancak et al., 2000). Apraxia has been described
in PSP cases as well (Pharr et al., 2001; Denes, 2002).
Language disorders are frequently seen during the
course of CBD (Frattali et al., 2000; Graham et al.,
2003b) and most of the cases initially diagnosed with
PPA were shown to have pathological changes con-
sistent with FTDP-17 and CBD/PSP in the pathologic
evaluation (Black, 2000).
Involuntary synkinesias of the less affected limb are
seen in CBD patients when they attempt complex
movements with the more affected, contralateral limb.
Abnormalities of two-point discrimination and
somatosensory extinction to double simultaneous sti-
mulation may be present several years before apraxia
and other cortical symptoms become evident. In this
way, a focal sensory complaint in the setting of atypical
parkinsonism should raise the question of CBD.
The alien-limb phenomenon is a failure to recog-
nize ownership of an extremity in the absence of visual
cues, accompanied by observable involuntary motor
activity. It is associated with autonomous activity of
the affected extremity, which may be perceived by
the subject as outside his or her control (Goldberg
and Bloom, 1990; Fisher, 2000). Up to half of patients
with CBD may develop the alien-limb phenomenon,
often with coexisting dystonia (Banks et al., 1989;
Ball et al., 1993), myoclonus, apraxia, athetosis,
pseudoathetosis and signs of cortical sensory loss
dysfunction such as sensory neglect, astereognosis
and agraphesthesia (Doody and Jankovic, 1992). If
the dystonia or rigidity is severe enough to cause
contractures, these autonomous movements may be
limited. Most patients exhibit intermanual conflict,
mirror movements and difficulties with bimanual
coordination with compulsive synkinesias in the
opposite limb. Posturing and levitation are asso-
ciated with alien-limb phenomenon in CBD more
commonly than in other etiologies.
Olfaction is not affected in CBD (Wenning et al.,
1995; Muller et al., 2002a; Hawkes, 2003).
Eventually, many patients exhibit signs of corti-
cospinal dysfunction, with extensor plantar responses
and hyperreflexia. The differentiation of spasticity
from rigidity in these patients is clinically very diffi-
cult, but the loss of voluntary movement is almost cer-
tainly related in part to degeneration of primary and
secondary cortical motor regions that contribute to
the corticospinal tracts. In fairly advanced stages of
CBD, frontal-release signs (grasp, glabellar and exag-
gerated facial and palmomental reflexes) may become
prominent.
Urinary symptoms, mainly consisting of decreased
bladder capacity and detrusor overactivity, are fre-
quently seen in patients with CBD, especially in more
advanced stages (Sakakibara et al., 2004).
48.4.3. Cognitive and neuropsychiatric symptoms
Although many of the early CBD case reports described
little cognitive dysfunction, it is now accepted that this
may be the presenting and predominant feature in many
patients. Patients with CBD frequently show abnormal
cognitive and neuropsychological profiles in asso-
ciation with motor and praxis disorders. A spectrum of
different degrees of intellectual, memory and language
impairment may develop (Cummings et al., 1994).
Storage and recall information and temporospatial
orientation are usually preserved in early stages of
CBD where motor symptoms predominate (Pillon
 CORTICOBASAL DEGENERATION 357
et al., 1995; Levy et al., 1996). In one study with 11 cases Table 48.1
of neuropathologically confirmed CBD, all patients
Clinical manifestations of corticobasal degeneration
eventually developed cognitive deficits; the onset, nature
and severity of the impairment, however, varied widely. Motor signs and symptoms
Cognitive disturbances preceded or accompanied the Rigidity
onset of the movement disorder in 4 patients; an addi- Bradykinesia/akinesia
tional 3 patients developed memory loss, progressing to Dystonia (focal limb and blepharospasm)
more global dementia within 23 years prior to the onset Tremor: postural and action tremor
of motor symptoms. Another patient displayed mild Gait disorders/postural instability
Dysarthria
early memory impairment and, in 3 individuals, demen-
Dysphagia
tia was a late feature (Litvan et al., 1998).
Myoclonus
The memory disorders in CBD patients without Choreoathetosis
significant pathology in the temporal lobes and hippo- Orofacial dyskinesias
campus may be related to disruption of subcorticofrontal Hyperreflexia
circuits. This may explain the dysexecutive syndrome Impaired ocular movements
with abnormalities of dynamic motor control and execu- Impaired eyelid motion
tion similar to those described in other neurodegenera- Involuntary synkinesias
tive diseases related to CBD, most notably PSP (Bak Cortical signs and symptoms
et al., 2005). Those patients also have difficulties with Apraxia
motor programming, manifested by deficits in temporal Cortical sensory loss: abnormalities of two-point
discrimination, somatosensory extinction to double
organization, bimanual coordination and inhibition of
simultaneous stimulation, astereognosis, agraphesthesia
interfering motor activities, word fluency and switching
Alien-limb phenomenon
between different task sets and activities (Cummings Dysphasia/aphasia
and Litvan, 2000; Green, 2000; Pillon and Dubois, Frontal-release signs: grasp, glabellar, palmomental reflexes
2000). Those changes contrast with the findings in Alz- Cognitive and neuropsychiatric signs and symptoms
heimers disease, characterized by a true amnesic syn- Dementia
drome and linguistic disorders. CBD patients perform Apathy
worse on unimanual and bimanual dexterity compared Depression
with PSP patients. Verbal fluency and evocation of ver- Irritability/agitation
bal series are also impaired in CBD patients and there Disinhibition
is a tendency to lower scores in patients with initial Illusions
Delusions
right-sided symptoms (Monza et al., 2003).
Obsessive-compulsive behavior
The neuropsychological features most frequently
Sleep disorders
described in patients with CBD include depression, Somatic pain
apathy, irritability, anxiety, disinhibition, agitation,
disorders of sleep and high incidence of somatic
pain. It has been demonstrated that CBD patients with
left-sided symptoms (as a result of right hemisphere rates of depression to PD but lower rates of anxiety
involvement) manifested greater disinhibition, apathy, (Hargrave and Rafal, 1998). LBD has a high rate of
irritability and lower depression scores than patients visual hallucinations, a phenomenon not described in
with predominantly right-sided symptoms (Moretti pathologically confirmed CBD cases.
et al., 2005). Manifestations of obsessive-compulsive Rapid-eye movement (REM) sleep behavior disor-
disorder, including recurrent thoughts, repetitive acts, der has been associated with the synucleinopathies
indecisiveness, checking behaviors and preoccupation (Kimura et al., 1997; Boeve et al., 2001), but it has
with perfectionism, are also included in the neuropsy- also been reported in patients with CBD (Wetter
chological profile and they are described in both motor et al., 2002). Unilateral periodic limb movements of
and cognitive presentations of CBD. sleep have been seen in CBD as well (Iriarte et al.,
Contrasting the neuropsychiatric findings in CBD 2001) (Table 48.1).
with those found in other neurodegenerative disorders
is helpful in establishing a differential diagnosis. Com- 48.5. Pathology
pared with Alzheimers disease patients, CBD patients
have less apathy, agitation, anxiety and delusions. CBD as a distinctive pathological condition may have
Patients with FTDP-17 usually manifest more disinhi- several clinical presentations: on the other hand, a vari-
bition and euphoria. CBD patients manifest similar ety of pathologies can cause the classical syndrome that
358 N. P. STOVER ET AL.
was initially thought to be specific to the pathology of inferior olivary nuclei and cerebellar dentate nucleus
CBD. This may be better understood if the different suggests an alternative diagnosis such as MSA.
pathological findings are considered as part of a broader
syndrome. Bearing this in mind, we can describe the 48.5.2. Microscopic and biochemical findings
typical pathological hallmarks of the CBD syndrome.
In addition to the morphologic examination, immuno- The microscopic examination of cortical sections
histochemical stains and biochemical and genetic ana- stained with hematoxylin and eosin shows neuronal
lyses are directed to identify tau pathology and to rule loss and gliosis associated with vacuolar or spongiform
out other neurodegenerative processes (Feany et al., change of the upper cortical layers. The characteristic
1996; Litvan, 1997; Mirra and Hyman, 2002). cortical finding in CBD is the ballooned neuron (BN),
achromatic cells with swollen perikarya and eccentri-
48.5.1. Macroscopic findings cally displaced nuclei without Nissl substance. These
neurons have a pale and ballooned appearance (Mack-
Asymmetric atrophy of the frontoparietal cortex is enzie and Hudson, 1995) and they can be seen in other
the finding most consistently seen in typical cases tauopathies (Mori et al., 1996), Alzheimers disease
of CBD. Atrophy is usually more evident in the (Fujino et al., 2004), CJD (Nakazato et al., 1990) and
superior peri-Rolandic frontal gyrus, the pre- and amyotrophic lateral sclerosis. The presence of BN in
postcentral parasagittal gyri and the superior part of the peri-Rolandic region, however, is characteristic of
the parietal lobe. The asymmetry of the atrophy CBD. Immunocytochemical staining of the BN is posi-
usually correlates with the laterality of the clinical tive for phosphorylated neurofilament proteins, a--
manifestations. However, cases have been described crystallin and sometimes ubiquitin (Castellani et al.,
with asymmetric symptoms and the pathological 1995; Halliday et al., 1995). Notably, tau and a-synu-
exam showed no significant asymmetry with bilateral clein immunoreactivity are negative in BN (Fig. 48.1).
atrophy of the precentral gyrus and other cortical
regions variably affected. This lack of asymmetry is
usually seen late in patients with severe symptoms.
Cortical atrophy may be more generalized and include
the inferior frontal and temporal lobes in cases that
mainly present with cognitive problems and/or PPA.
The occipital lobe, hippocampus and parahippocampal
gyrus are usually spared. Of note, asymmetric parietal
lobe atrophy has been described in cases with pathol-
ogy consistent with Alzheimers disease (Kaida et al.,
1998).
As a consequence of the cortical atrophy, the ven-
tricles and cerebral aqueduct may be enlarged. If the
atrophy is significant, changes in the white matter
may be seen as well. The corpus callosum may be
atrophic (Yamauchi et al., 1998) and the anterior limb
of the internal capsule, corticospinal fascicles within
the base of the pons and the medullary pyramids may
show attenuation, in part related to retrograde cortical
atrophy. Other white-matter pathways, such as the
optic tract, anterior commissure and fornix, are usually
unaffected in the gross evaluation of CBD patients.
Involvement of subcortical gray matter varies
widely from case to case, but it is usually less severe
and variable than the cortical atrophy. The head of
the caudate nucleus may have a flattened appearance
and the thalamus in CBD cases tends to be smaller Fig. 48.1. A hematoxylin and eosin-stained section of frontal
than normal. Transverse sections of the brainstem cortex from the brain of a patient with corticobasal degeneration
show severe loss of neuromelanin pigment in the SN; shows a large ballooned neuron (large arrow) and another neu-
however, neuromelanin within the locus ceruleus ron with a cytoplasmic inclusion body (small arrow). Courtesy of
is usually preserved. Marked atrophy of the pons, Dr. K.A. Roth, UAB Division of Neuropathology.
 CORTICOBASAL DEGENERATION
Astrocytic plaques carry significant diagnostic value
and are considered the most specific histopathologic
features in CBD by some authors (Ishizawa and Dick-
son, 2001). They are mainly located in the neocortex,
appearing as an annular cluster of short processes that
resemble the neuritic plaque of Alzheimers disease;
however, these astrocytic plaques do not contain amy-
loid. Tau positivity in these lesions is derived from
astrocytes as demonstrated by double immunostaining
for tau and the astrocytic marker glial fibrillary acidic
protein. Other less characteristic tau-immunoareactive
astrocytic lesions are described in CBD, including
thorn-shaped astrocytes, which are found in all tauopa-
thies (Armstrong et al., 2001; Dickson, 2003).
Glial threads, which indicate dystrophic axonal and
glial processes in the gray and white matter, are
described in CBD (Komori et al., 1997; Richter-Lands-
berg and Bauer, 2004). Neuritic threads are less com-
mon than in Alzheimers disease. A key feature that
distinguishes CBD from Alzheimers disease is the
lack of both neuritic plaques and diffuse plaques in sil-
ver-stained material. Conversely, Alzheimers disease
does not exhibit the tau-positive glial inclusions
observed in CBD (Ikeda et al. 1994; Horoupian and
Wasserstein, 1999).
Silver stain preparations typically show the pre-
sence of NFT in affected areas. The tangles vary in
configuration from delicate thread-like structures to
compact globoid morphologies. The typical flame-
shaped appearance of NFT seen in Alzheimers
disease is less frequent in CBD (Ikeda et al., 1995;
Dickson et al., 1996; Dickson and Litvan, 2003). The
ultrastructure of tangles in CBD consists of paired
helical filaments or twisted filaments with a wider
diameter and longer periodicity than the filaments
present in Alzheimers disease. The tangles in PSP
are more uniform, compact and globoid in shape and
they consist of straight filaments at the ultrastructural
level (Collins et al., 1995; Dickson, 1999a).
Cell loss in the SN is usually severe with extraneur-
onal neuromelanin in phagocytes (melanophagia) and
residual neurons typically contain NFT. Lewy bodies
are not seen in CBD. The locus ceruleus, raphe nuclei,
tegmental gray matter, the subthalamic nuclei and the
ventrolateral nucleus of the thalamus may also contain
NFT. The cerebellar dentate nucleus, inferior olivary
nuclei, red nucleus, oculomotor complex and colliculi
are relatively spared but may show a variable degree
of neuronal loss and gliosis. The cerebellar cortex
may also show focal Purkinje cell axonal torpedoes
and Bergmann gliosis (Su et al., 2000; Piao et al.,
2002).
Apolipoprotein E epsilon 4 (APOE4) is a risk factor
for Alzheimers disease pathology in all neurodegen-
359
erative disorders, including synucleinopathies and
tauopathies; however, Alzheimers disease-type patho-
logic features are more likely to coexist with synuclei-
nopathies (Ingelson et al., 2001; Josephs et al., 2004b).
Cholinergic neuronal loss has been described in
patients with CBD and PSP pathological findings
(Kasashima and Oda, 2003). Spinal cord involvement
with the presence of neuropil threads and neuronal
inclusions has been described in CBD (Iwasaki et al.,
2005) and PSP patients as well (Kikuchi et al., 1999).
48.5.3. Tau pathology
Tau is a structural microtubule-associated phosphopro-
tein that stabilizes microtubules and promotes tubulin
polymerization, playing an important role in maintain-
ing neuronal integrity and axoplasmic transport (Mirra
et al., 1999; Forman et al., 2000). Tau undergoes
selective phosphorylation that determines its func-
tional state (Hanger et al., 2002). Normal tau is soluble
and heat-stable, but under pathological conditions it
becomes insoluble and forms aggregates as the result
of abnormal phosphorylation or abnormal ratios of
different isoforms (Buee and Delacourte, 1999).
The most important diagnostic finding in CBD and
tauopathies in general is the presence of abnormal tau-
positive deposits (Lee et al., 2001). The tau pathology
is extensive in CBD and is present within neurons and
glial cells of the cortex, subcortical nuclei and brain-
stem (Cordato et al., 2001). In most affected neurons,
abnormal tau immunoreactivity is present as diffuse
or granular cytoplasmic deposits, called pretangles
(Komori, 1999).
A characteristic feature of CBD and other tauopa-
thies that distinguishes them from Alzheimers disease
is the presence of tau-immunoreactive glial inclusions
in cell bodies and processes. The so-called astrocytic
plaques are the most characteristic astrocytic lesion
in CBD and there are mainly located in the neocortex.
The astrocytic plaques resemble the neuritic plaques of
Alzheimers disease; however, they do not contain
amyloid or dystrophic neurites. Another lesion, the
tufted astrocyte, consists of fibrillary accumulation
of tau within cell bodies and processes; it is believed
to be more characteristic of PSP than of CBD (Komori
et al., 1998).
The tau-positive inclusions in oligodendroglia,
known as coiled bodies, are argyrophilic structures
that are frequently present in the tauopathies. These
inclusions are distinct from the glial cytoplasmic
inclusions, considered the hallmark of MSA, which
are immunoreactive for ubiquitin and a-synuclein,
but negative for tau (Feany and Dickson, 1996;
Rademakers et al., 2004).
360 N. P. STOVER ET AL.
The caudate, putamen and globus pallidus may
contain tau-immunoreactive lesions, most frequently
pretangles, variable nerve cell depletion, gliosis and
NFT. The ventrolateral nucleus of the thalamus,
subthalamic nucleus, red nucleus, raphe nuclei and
tegmental gray matter may have similar lesions but
are usually less severely involved. NFT are common
in the locus ceruleus and SN. The latter structure
and the basal nucleus of Meynert may contain tau-
immunoreactive pre-tangles (Sergeant et al., 1999).
White-matter areas not contiguous with cortical
atrophy may also contain tau-immunoreactive thread-
like lesions and coiled bodies. The internal capsule
and thalamic fasciculus often have many thread-like
processes (Forman et al., 2002).
The minimal criteria for the pathologic diagnosis of
CBD are cortical and striatal tau-positive neuronal and
glial lesions, especially astrocytic plaques and thread-
like lesions in white and gray matter and neuronal
loss in cortical regions and in the SN (Lantos, 2000;
Dickson et al., 2002) (Fig. 48.2).
Fig. 48.2. Immunohistochemical staining for phosphory-
lated tau shows a rim of cytoplasmic reactivity in a
ballooned neuron (large arrow) and more diffuse staining
of another neuron (small arrow). Numerous thread-like
tau-immunoreactive processes are seen in the surrounding
neuropil. Courtesy of Dr. K.A. Roth, UAB Division of
Neuropathology.
48.5.4. Tau mutations and ultrastructure
Tau is the major component of the intracellular fila-
mentous deposits in the tauopathies. Tau pathology
in Alzheimers disease is thought to arise secondary
to b-amyloid pathology (Bancher et al., 1989; Goedert
and Jakes, 2005).
Some of the tau mutations have their primary effect
at the protein level, reducing the ability of the tau pro-
tein to interact with microtubules (Stanford et al.,
2004). Other mutations have their effect at the RNA
level, modifying the normal ratio of tau isoforms.
The splicing of mRNA transcripts from a single gene
on chromosome 17 generates a total of six isoforms
in adult human brain, with either three- or four-repeat
(3R or 4R) domains, depending upon whether exon 10
is expressed or not. Three of these isoforms contain
three microtubule-binding domains (3R) and three
contain four microtubule-binding domains (4R) (Dela-
courte, 1999). Abnormal protein aggregates in the
brain can be isolated as insoluble tau fractions and
analyzed for isoform composition and phosphorylation
state. Insoluble tau from CBD, PSP and AGD show
elevated 4R/3R ratios relative to Alzheimers disease
and controls (Togo et al., 2002; Tolnay et al., 2002;
de Silva et al., 2003; Katsuse et al., 2003; Miserez
et al., 2003). The tau protein may be hyperphosphory-
lated or abnormally phosphorylated (Arai et al., 2001a).
The mechanisms that lead to these tau abnormalities in
Alzheimers disease are still not well understood
(Ishizawa et al., 2002). In contrast, tau aggregates in
Picks disease consist of elevated levels of 3R tau.
Therefore, in these disorders there may be a fundamen-
tally different abnormality in tau processing, leading to
abnormal isoform composition, hyperphosphorylation
and protein aggregation.
In FTDP-17 two major types of mutation may
occur: missense mutations of exon 10 may lead to
mutant proteins that exhibit diminished affinity
for microtubules; alternatively, intronic mutations
(and some exon 10 mutations) stabilize the splicing
site so that higher levels of 4R tau are generated.
This latter situation is similar to what occurs in
PSP, CBD and AGD. Recently, a selective loss or
reduction in the levels of all six brain tau isoforms has
been described in a subset of sporadic cases with fronto-
temporal dementia and those cases are classified as
tau-deficiency tauopathies (Kawasaki et al., 1996;
Ksiezak-Reding et al., 1998; Godbolt et al., 2005).
Other genes and/or factors may also be essential for
the neurodegenerative process to occur, as shown by
FTDP-17 cases without tau mutation or deposition
and with ubiquitin-positive inclusions (van Swieten
et al., 2004).
 CORTICOBASAL DEGENERATION
Genetic analysis of tau has revealed several poly-
morphisms in the coding and non-coding regions that
represent two ancestral haplotypes, referred to as H1
and H2. In PSP and CBD, H1 homozygosity (H1/H1)
is overexpressed and found in close to 90% of patients
(Houlden et al., 2001), as opposed to only 60% of nor-
mal controls. These findings suggest that genetic poly-
morphisms of the tau gene somehow influence the risk
for developing the sporadic 4R diseases, CBD and PSP
(Oliveira et al., 2004; Pittman et al., 2005; Tuite et al.,
2005). H1/H1 genotype has also been associated with
PPA (Sobrido et al., 2003).
Tau epitopes are similar in CBD and PSP but differ-
ent from those in Alzheimers disease (Berry et al.,
2004). Molecular heterogeneity and posttranslational
modifications may influence the morphology and
stability of the abnormal filaments. Electron micro-
scopy of the paired helical filaments show that they
are wider in CBD cases and have a longer periodicity
of the helical twist, compared with filaments found
in Alzheimers disease. CBD filaments are primarily
composed of single- or double-stranded, highly phos-
phorylated polypeptides (15 or 29 nm wide and 62 or
133 kDa mass per unit length). Additionally, CBD fila-
ments have a less stable ultrastructure because they are
composed of two distinct protofilaments. In contrast,
Alzheimers disease has three highly phosphorylated
polypeptides of tau (Ksiezak-Reding et al., 1996)
(Table 48.2).
48.6. Imaging studies
An important characteristic to be considered when
evaluating the brain imaging of patients with suspected
CBD is asymmetric cortical atrophy, a feature that
is quite distinctive from other neurodegenerative
syndromes in the differential diagnosis of CBD
(Gimenez-Roldan et al., 1994; Savoiardo, 2003).
Serial evaluation of brain computed tomography
(CT) or magnetic resonance imaging (MRI) scans over
612-month intervals is generally more useful than an
isolated study. The abnormalities are best detected
with MRI, particularly in the fluid attenuated inversion
recovery (FLAIR) sequences.
Volumetric studies of the cortex and hemispheric
surface show that the more atrophic areas in CBD
are the parietal lobe and the anterior, middle and pos-
teroinferior frontal lobe. Asymmetric cortical atrophy
is frequently seen, contralateral to the most affected
side of the body in asymmetric presentations (Blin
et al., 1992; Hu et al., 2005). The subcortical white
matter underlying the atrophic cortex also exhibits
decreased volume (Doi et al., 1999; Groschel et al.,
2004). See Fig. 48.3.
361
Table 48.2
Pathologic findings of corticobasal degeneration
Macroscopic
Asymmetric atrophy: frontoparietal and parasagittal
Enlarged ventricles
Corpus callosum atrophy
Variable atrophy of subcortical structures (basal ganglia,
thalamus)
Pallor in substantia nigra
Atrophy of white matter
Microscopic
Neuronal loss and gliosis
Ballooned, achromatic neurons
Astrocytic plaques, mainly in the cortex
Glial threads in the cerebral cortex, white matter, striatum,
thalamus, cerebral peduncles, cerebellar dentate nucleus
and pons
Neurofibrillary tangles
Substantia nigra cell loss
Immunocytochemical Tau pathology
Neurons: granular cytoplasmic deposits (pretangles) or
diffuse aggregates.
Tau pathology in basal ganglia
Glia
Astrocytic plaques
Tufted astrocytes
Coiled bodies in oligodendroglia
Tau pathology in white matter
MRI in FTDP-17 and Picks disease patients typi-
cally demonstrates marked brain atrophy in the frontal
and temporal regions, usually in a symmetrical fash-
ion. Widening of the interpeduncular fossa secondary
to degeneration of frontopontine fibers is another ima-
ging finding frequently seen in the different neurode-
generative diseases that have prominent cerebral
cortical atrophy (Hosaka et al., 2002). The MRI of
patients with PSP shows atrophy in the midbrain and
brainstem without asymmetrical cortical atrophy.
Patients with Alzheimers disease have diffuse tem-
poral and hippocampal atrophy and in MSA of the oli-
vopontocerebellar atrophy type the atrophy is more
evident in the pons and cerebellum (Savoiardo et al.,
2000).
Asymmetric atrophy of the corpus callosum in the
most affected side with correspondent ventricular dila-
tation is frequently seen in confirmed cases of CBD.
Significant loss of callosal volume may appear in
Alzheimers disease, PSP and FTD compared to
controls. This morphologic change has a strong corre-
lation with the degree of cognitive impairment in
patients with Alzheimers disease and CBD, but not
in PD and PD with dementia cases. Neither the cortical
362 N. P. STOVER ET AL.
or corpus callosum atrophy or subcortical and periven-
tricular white-matter signal changes on MRI are speci-
fic to CBD (Laureys et al., 1999; Josephs et al., 2004a).
Functional imaging with positron emission tomo-
graphy (PET), single-photon emission computed
tomography (SPECT) and proton magnetic resonance
spectroscopy (PMRS) in suspected CBD cases can
provide a sensitive way to study changes in regional
cerebral blood flow (CBF), cerebral metabolism
(oxygen or glucose) and dopamine receptor binding.
SPECT study findings in CBD are variable and include
asymmetric frontotemporal perfusion and a wide range
of prefrontal abnormalities. Other cases show bifrontal
hypoperfusion with varying degrees of temporal and/or
parietal involvement (Eidelberg et al., 1991; Brooks,
2000). The presence of isolated, asymmetrical hypo-
perfusion contralateral to the most affected side of
the body is highly suggestive of CBD.
PET studies demonstrate asymmetrical cortical and
basal ganglia metabolism in patients clinically
diagnosed with CBD. Cases of MSA show decreased
metabolism in the basal ganglia and cerebellum and
in PSP there is decreased medial frontal metabolism
and increased metabolism of the lentiform nucleus in
relation to that of patients with PD. This study created
a template to serve as a statistical aid in diagnosing
different neurodegenerative disorders based upon
imaging findings. Studies of CBD show a relative
reduction in both metabolic rate and glucose radiotra-
cer uptake in several cortical areas, as well as the basal
ganglia and the insula, contralateral to the most
affected side (Eckert et al., 2005).
18
Fluorodopa (18F-dopa) PET and SPECT labeling
of the dopamine transporter by 2-carboxymethoxy
3(4-odophenyl)-tropane [123I] -CIT have demon-
strated homogeneous reduction in caudate and puta-
men signal to as low as 25% of normal values in
clinically diagnosed CBD, PSP and MSA, compared
with the asymmetric reduction in PD where binding
is selectively reduced in the putamen. The characteris-
tic pattern of asymmetrically reduced frontoparietal
cerebral cortical metabolism and/or CBF coupled with
equal reduction of 18F-dopa uptake in the caudate and
putamen provides strong supportive evidence in a
patient with a clinical diagnosis of CBD (Sawle
et al., 1989; Kreisler et al., 2005; Plotkin et al., 2005).
A PET study using a marker for peripheral benzo-
diazepine-binding sites which are expressed by acti-
vated microglia addressed the role of microglial
inflammatory responses in neurodegenerative disorders.
This study located the changes in the caudate nucleus,
the putamen, the SN, the pons, the pre- and postcentral
gyri and the frontal lobe. There was a broad heterogene-
ity within individual patients, especially in the basal
ganglia, that may represent overlap with other disorders
(Gerhard et al., 2004; Henkel et al., 2004).
Brain parenchyma sonography is a relatively new
technique using ultrasound to display tissue echogeni-
city of the brain through the skull. The results of these
studies need to be interpreted with caution, since the
cases do not have neuropathological confirmation.
Sonography has proved to be reliable and sensitive to
determine basal ganglia abnormalities in several
pathologies, including the SN in PD, the caudate
nucleus in Huntingtons disease and the lenticular
nuclei in dystonia. A study attempted to discriminate
between CBD and PSP with ultrasound, but the cases
did not have pathologic confirmation and the results
were inconclusive. CBD exhibits marked bilateral SN
hyperechogenicity; this is reported as the characteristic
finding in PD. According to some authors, cases of
PSP or MSA have normal echogenicity in the SN
(Walter et al., 2004).
Studies using proton magnetic resonance neuro-
spectroscopy correlated with EEG cartography con-
firmed the asymmetrical features of CBD cases with
only clinical diagnosis (Vion-Dury et al., 2004).
48.7. Electrophysiological studies
Electrophysiological studies may support the diagnosis
of CBD and give us information about asymmetrical
dysfunction. The EEG is usually normal during the
initial stages of the disease and may reveal non-speci-
fic asymmetric slowing in the more affected side in
later stages. The non-specific diffuse slowing can be
bilateral in advanced cases or in cases with predomi-
nant cognitive dysfunction at presentation. Electrophy-
siological studies of the tremor with accelerometry and
electromyography (EMG) have distinguished tremor
of CBD from the parkinsonian tremor: it is faster,
more irregular, more variable in amplitude, more evi-
dent during action and has a myoclonic component.
The myoclonus seen in CBD is a reflex myoclonus
but the cortical spike is not always recognized.
Results from studies of somatosensory evoked
potentials have not been conclusive in CBD. The
N30 frontal component has been found to be absent
unilaterally, bilaterally and with increased latency in
patients with clinically probable CBD. Motor evoked
potentials are reported as being prolonged in patients
with CBD (Okuda et al., 1998).
The P100 wave of the visual evoked potentials has
been reported to not differ significantly between differ-
ent types of dementia and age-matched control subjects.
Brainstem auditory evoked potentials are reported to be
abnormal with prolonged P300 and N200 latencies in
CBD (Homma et al., 1996; Lu et al., 1998). Routine
 CORTICOBASAL DEGENERATION
EMG is normal in early stages or may show changes
consistent with dystonia in the affected limbs. Nerve
conduction studies may show focal or generalized
neuropathy that is usually subclinical.
48.8. Laboratory studies
Serum copper and ceruloplasmin levels and heavy-
metal screens in blood and urine are normal in CBD
patients. Cerebrospinal fluid (CSF) analysis in patients
with CBD, PSP and Alzheimers disease show reduced
levels of b-amyloid peptide compared with control
subjects. Total tau protein levels are increased in
Alzheimers disease and the rest of the tauopathies
and may help to differentiate them from normal aging,
depression, synucleinopathies and vascular dementia.
However, the tau level in the CSF is inadequate to dif-
ferentiate among the different tauopathies (Arai et al.,
1997; Mitani et al., 1998; Paraskevas et al., 2005).
Levels of somatostatin were reported to be decreased
in some patients with autopsy confirmation of CBD.
48.9. Differential diagnosis and heterogeneity
The typical motor presentation of CBD is usually
sufficiently distinctive to allow a confident clinical diag-
nosis. PD is the most common misdiagnosis early in the
course of the disease (Boeve et al., 2002; Doran et al.,
2003; Kertesz et al., 2005). The best early clues that
can help to distinguish CBD from idiopathic PD are the
lack of sustained beneficial response to dopaminergic
medication and signs of cortical dysfunction, most nota-
bly apraxia and/or cortical sensory impairment. Based on
pathological findings of cases diagnosed as CBD, the
differential diagnosis needs to include Picks disease
(Lang et al., 1994b), PSP (Wakabayashi and Takahashi,
2004), dementia lacking distinctive histology or tau-
negative inclusions of the motor neuron disease type,
FTDP-17 (Reed et al., 2001) and PPA (Ferrer et al.,
2003). Primary dementing disorders should also be
included in the differential diagnosis of CBD. Other
diagnoses to consider are MSA, including olivoponto-
cerebellar atrophy and striatonigral degeneration
(Adams et al., 1964), diffuse Lewy body disease, Alzhei-
mers disease with extrapyramidal features, AGD
(Jellinger, 1998), parkinsonismdementiaamyotrophic
lateral sclerosis complex, widespread cerebrovascular
disease, variants of Binswangers disease, progressive
multifocal leukodystrophies (Bhatia et al., 1996; Van
Zanducke and Dehaene, 2000), variants of Azorean dis-
ease (Nakano et al., 1972; Sachdev et al., 1982) and
hemiparkinsonismhemiatrophy (Giladi and Fahn,
1992). CBD has presented as a Balints syndrome
(Mendez, 2000). A case of neurosyphilis resembling
363
CBD has been described as well (Benito-Leon et al.,
2004). If a patient presents with a rapidly progressive
CBD-like picture, prion-related disease should be con-
sidered (Cannard et al., 1998; Kovacs et al., 2002;
Josephs et al., 2004c; Kleiner-Fisman et al., 2004; Mor-
eaud et al., 2005).
PSP is the disorder most likely to be confused with
the motor presentation of CBD. PSP classically pre-
sents with prominent axial rigidity, postural instability
with early falls and abnormal vertical eye movements.
Atypical features such as asymmetric onset, oculomo-
tor impairment that is only mild, focal dystonia and
involuntary limb levitation resembling the alien-limb
phenomenon are the most frequent features that may
cause confusion with CBD (Table 48.3).
48.10. Therapy
Pharmacotherapy for CBD is currently of limited bene-
fit. This may be explained by the widespread pathologi-
cal involvement of cortical and subcortical systems and
the lack of biochemical and molecular explanations for
the pathophysiology of the disease. New therapeutic
approaches will be directed towards the development
of compounds that modify, correct or block the underly-
ing pathological mechanisms of CBD.
Some cases may show initial benefit with levodopa
or with dopamine agonists, but this benefit is usually
temporary. The primary treatment is symptomatic,
focused on alleviating the rigidity, dystonia, tremor,
myoclonus, neuropsychologic manifestations and other
symptoms (Lang, 2005).
48.10.1. Treatment of motor symptoms
Improvement was reported in only 24% of clinically
diagnosed CBD patients with carbidopa/levodopa
treatment. The rest of the dopaminergic agents (bro-
mocriptine, pergolide, pramipexole, ropinirole) may
produce more side-effects with less clinical benefit in
this group of patients. Clonazepam and other benzo-
diazepines have been the most beneficial agents for
action tremor and myoclonus. Baclofen and tizanidine
may improve rigidity. Anticholinergics have not been
beneficial and they have been poorly tolerated due to
cognitive side-effects and amantadine is of little or
no benefit (Kompoliti et al., 1998). Botulinum toxin
injections may be useful in the treatment of painful
focal limb dystonias, as well as in blepharospasm
(Cordivari et al., 2001; Muller et al., 2002b). Stereo-
tactic surgery for relief of severe painful limb dystonia
and parkinsonism has little or no benefit and is not
indicated in the treatment of atypical parkinsonian
syndromes (Fazzini et al., 1995).
364 N. P. STOVER ET AL.
Table 48.3
Differential diagnosis of patients with neurodegenerative diseases with motor and cognitive dysfunction

Diagnosis Clinical features Features which suggest an alternative diagnosis

CBD Asymmetric bradykinetic/akinetic parkinsonism Prominent ocular involvement, axial dystonia,

with lack of response to dopaminergic
treatment, dystonia, cortical sensory loss,
apraxia, asymmetric dystonia or rigidity,
alien-limb phenomenon, myoclonus,
cognitive dysfunction
FTD/PPA/PiD Behavioral disturbances and problems with
interpersonal interactions, disinhibition,
hyperorality, personality changes, dietary
changes, speech and language symptoms,
word-finding difficulties, memory loss
PSP Ophthalmoplegia (particularly vertical gaze
paresis), early gait impairment, frequent
falls, axial rigidity, dysarthria, dysphagia,
suboptimal response to levodopa therapy
MSA Symmetric rigidity, absence of rest tremor,
cerebellar and autonomic dysfunction, rapid
course, suboptimal response to levodopa
therapy, gait disorder
PD with dementia Asymmetric rest tremor, bradykinesia and
rigidity with dementia, memory loss,
responsive to levodopa therapy
AD with parkinsonism Early cognitive dysfunction (especially
memory loss), cortical dysfunction
(visuospatial deficits, aphasia, apraxia),
mild bradykinesia and rigidity
DLB Fluctuating symptoms, cognitive
dysfunction, psychosis induced or
worsened by dopaminergic therapy,
parkinsonism, gait disorder
CJD Rapid course of dementia, personality
changes, myoclonus, upper motor neuron
signs, cerebellar or extrapyramidal signs
aphasia, autonomic dysfunction, rest tremor
Gait disorder, early ocular involvement,
hallucinations, prominent extrapyramidal
symptoms, levodopa responsiveness,
progressive apraxia without dementia
Lack of ocular involvement, apraxia, cortical
sensory loss, prominent autonomic
dysfunction
Early ocular involvement, apraxia, cortical
signs, dementia
Symmetric rigidity, early ocular involvement,
suboptimal response to levodopa therapy,
apraxia, cortical sensory loss, prominent
autonomic dysfunction
Parkinsonism present prior to onset of
dementia, aphasia or apraxia without
significant memory loss, early gait
impairment, axial rigidity, ophthalmoplegia,
alien-limb phenomenon
Axial rigidity or dystonia, early ocular
involvement
Protracted course, isolated parkinsonism or
cortical dysfunction, levodopa
responsiveness

CBD, corticobasal degeneration; FTD, frontotemporal dementia; PPA, primary progressive aphasia; PiD, Picks disease; PSP, progressive
supranuclear palsy; MSA, multiple system atrophy; PD, Parkinsons disease; AD, Alzheimers disease; DLB, dementia with Lewy bodies;
CJD, CreutzfeldtJakob disease.

48.10.2. Treatment of cognitive and
neuropsychiatric symptoms
There is no clear evidence that treatment of cognitive
dysfunction with medications that enhance cholinergic
neurotransmission has much benefit; however, they may
be considered in early stages of the disease. Depression
and obsessive-compulsive symptomatology may be trea-
ted effectively with selective serotonin reuptake inhibitors
(SSRIs), but cautious titration and low doses are recom-
mended because these medications can exacerbate agita-
tion. Antidepressants with anticholinergic side-effects,
including tricyclic compounds, may exacerbate confu-
sion. Small doses of atypical neuroleptic medications
such as quetiapine, olanzapine or clozapine may be help-
ful for paranoid delusions, psychotic behavior, agitation,
irritability and sleep problems. The use of typical antipsy-
chotic medications such as haloperidol may worsen motor
symptoms of CBD and are not recommended.
Small doses of sedative hypnotic agents may be help-
ful for insomnia, but they may also exacerbate confusion
and agitation. Clonazepam is usually helpful and agents
such as diphenhydramine, chloral hydrate and zolpidem
may be useful as well, but they should be used cautiously.
 CORTICOBASAL DEGENERATION
48.10.3. Treatment of other symptoms
Gastrointestinal symptoms in CBD patients include
hypersalivation, dysphagia, nausea and constipation.
Excessive salivation may respond to small doses of
anticholinergic therapy, but side-effects are a limiting
factor in most cases.
The goal of treatment of the dysphagia is to main-
tain safe and efficient nutrition and hydration. Evalua-
tion with a barium swallow study may be necessary.
Treatment includes dietary modifications, positional
changes, swallowing maneuvers and exercises and sur-
gical interventions. Selection of foods with a consis-
tency that facilitates swallowing is critical. If patients
are not able to ingest enough food to meet nutritional
requirements, percutaneous feeding gastrostomy tube
placement may be necessary. The decision to place a
gastrostomy in a patient with a chronically progressive
neurodegenerative disease must be handled on an indi-
vidual basis, keeping in mind the wishes of the patient
or the patients surrogate.
Constipation in parkinsonism is due to colonic
hypomotility, colonic outlet dysfunction or both. Con-
stipation has also been associated with pelvic floor
dystonia. The use of stool softeners, increased fluid
intake, foods rich in fiber and laxatives may be benefi-
cial. Polyethylene glycol is another alternative for the
treatment of severe constipation.
Fig. 48.3. (A) and (B) T1 and T2-weighted brain images of a patient with corticobasal degeneration showing the asymmetric
cortical atrophy, contralateral to the most affected side
365
The urinary symptoms of CBD include urgency and
frequency and they may improve with the use of hyos-
cyamine, tolterodine or oxybutynin. Close observation
for central and peripheral side-effects is warranted
when using these or related medications.
Symptomatic orthostatic hypotension, although
more frequently seen in MSA, may be treated with
fludrocortisone or midodrine.
Other aspects of patient care, not involving pharma-
cotherapy, can be of special importance for these patients
and their families (Litvan, 2001). Physiotherapy is very
helpful for maintenance of mobility and prevention of
contractures. Pain related to dystonic posturing can be
lessened by maintenance of good range of motion and
occasionally splinting can be helpful. Occupational ther-
apy can help patients maintain some degree of functional
independence by providing specially made devices such
as eating utensils with large handles. Speech therapy
may offer practical suggestions and exercises to optimize
speech function and guard against aspiration secondary
to swallowing difficulty. Good home care assistance
can help prolong the time a patient remains at home
before requiring nursing-home placement.
Despite our best therapeutic efforts, regardless of
whether it presents with motor or cognitive symptoms,
CBD generally progresses to a state of bilateral rigid
immobility due to increased tone or apraxia and patients
usually die from aspiration pneumonia or urosepsis.
366 N. P. STOVER ET AL.
References
Adams RD, Van Bogaert L, Vander Eecken H (1964). Strao-
nigral degeneration. J Neuropathol Exp Neurol 23:
584608.
Arai H, Morikawa Y, Higuchi M et al. (1997). Cerebrospinal
fluid tau levels in neurodegenerative diseases with distinct
tau-related pathology. Biochem Biophys Res Commun
236 (2): 262264.
Arai T, Ikeda K, Akiyama H et al. (2001a). Distinct isoforms
of tau aggregated in neurons and glial cells in brains of
patients with Picks disease, corticobasal degeneration
and progressive supranuclear palsy. Acta Neuropathol
(Berl) 101 (2): 167173.
Arai Y, Yamazaki M, Mori O et al. (2001b). Alpha-synuclein-
positive structures in cases with sporadic Alzheimers
disease: morphology and its relationship to tau aggregation.
Brain Res 888 (2): 287296.
Armstrong RA, Cairns NJ, Lantos PL (2001). What does the
study of the spatial patterns of pathological lesions tell us
about the pathogenesis of neurodegenerative disorders?
Neuropathology 21 (1): 112.
Bak TH, Rogers TT, Crawford LM et al. (2005). Cognitive
bedside assessment in atypical parkinsonian syndromes.
J Neurol Neurosurg Psychiatry 76 (3): 420422.
Ball JA, Lantos PL, Jackson M et al. (1993). Alien hand sign
in association with Alzheimers histopathology. J Neurol
Neurosurg Psychiatry 56 (9): 10201023.
Ballan G, Tison F (1997). A historical case of probable cor-
ticobasal degeneration? Mov Disord 12 (6): 10731074.
Bancher C, Brunner C, Lassmann H et al. (1989). Accumula-
tion of abnormally phosphorylated tau precedes the forma-
tion of neurofibrillary tangles in Alzheimers disease.
Brain Res 477 (12): 9099.
Banks G, Short P, Martinez J et al. (1989). The alien hand
syndrome. Clinical and postmortem findings. Arch Neurol
46 (4): 456459.
Benito-Leon J, Alvarez-Linera J, Louis ED (2004). Neurosy-
philis masquerading as corticobasal degeneration. Mov
Disord 19 (11): 13671370.
Bergeron C, Davis A, Lang AE (1998). Corticobasal gang-
lionic degeneration and progressive supranuclear palsy
presenting with cognitive decline. Brain Pathol 8 (2):
355365.
Berry RW, Sweet AP, Clark FA et al. (2004). Tau epitope
display in progressive supranuclear palsy and corticobasal
degeneration. J Neurocytol 33 (3): 287295.
Bhatia KP, Morris JH, Frackowiak RS (1996). Primary
progressive multifocal leukoencephalopathy presenting as
an extrapyramidal syndrome. J Neurol 243 (1): 9195.
Black SE (2000). Aphasia in corticobasal degeneration. Adv
Neurol 82: 123133.
Blin J, Vidailhet MJ, Pillon B et al. (1992). Corticobasal degen-
eration: decreased and asymmetrical glucose consumption as
studied with PET. Mov Disord 7 (4): 348354.
Boeve BF, Silber MH, Ferman TJ et al. (2001). Association
of REM sleep behavior disorder and neurodegenerative
disease may reflect an underlying synucleinopathy. Mov
Disord 16 (4): 622630.
Boeve BF, Maraganore DM, Parisi JE et al. (2002). Cortico-
basal degeneration and frontotemporal dementia presenta-
tions in a kindred with nonspecific histopathology.
Dement Geriatr Cogn Disord 13 (2): 8090.
Brooks DJ (2000). Corticobasal degeneration. Functional
imaging studies in corticobasal degeneration. In: I Litvan,
CG Goetz, AE Lang (Eds.), Corticobasal Degeneration
Advances in Neurology, Vol. 82. Williams & Wilkins,
Philadelphia, pp. 209215.
Brown J, Lantos PL, Rossor MN (1998). Familial dementia
lacking specific pathological features presenting with
clinical features of corticobasal degeneration. J Neurol
Neurosurg Psychiatry 65 (4): 600603.
Brunt ER, van Weerden TW, Pruim J et al. (1995). Unique
myoclonic pattern in corticobasal degeneration. Mov
Disord 10 (2): 132142.
Buee L, Delacourte A (1999). Comparative biochemistry of
tau in progressive supranuclear palsy, corticobasal degen-
eration, FTDP-17 and Picks disease. Brain Pathol 9 (4):
681693.
Cairns NJ, Lee VM, Trojanowski JQ (2004). The cytoskeleton
in neurodegenerative diseases. J Pathol 204 (4): 438449.
Cannard KR, Galvez-Jimenez N, Watts RL (1998). Creutz-
feldt-Jakob disease presenting and evolving as rapidly pro-
gressive corticobasal degeneration. Neurology 50 (4):
A95.
Carella F, Scaioli V, Franceschetti S et al. (1991). Focal reflex
myoclonus in corticobasal degeneration. Funct Neurol
6 (2): 165170.
Carella F, Ciano C, Panzica F et al. (1997). Myoclonus in
corticobasal degeneration. Mov Disord 12 (4): 598603.
Caselli RJ, Stelmach GE, Caviness JN et al. (1999). A kine-
matic study of progressive apraxia with and without
dementia. Mov Disord 14 (2): 276287.
Castellani R, Smith MA, Richey PL et al. (1995). Evidence
for oxidative stress in Pick disease and corticobasal degen-
eration. Brain Res 696 (12): 268271.
Caviness JN (2003). Myoclonus and neurodegenerative
diseasewhats in a name? Parkinsonism Relat Disord
9 (4): 185192.
Charcot JM (18871888). Lecons du mardi: Policlinique de
la Salpetriere Bureaux du Progres Medical, Paris.
Charcot JM, Vulpian A (18611862). De la paralysie agi-
tante. Gazette Hebdomadaire de Medecine et de Chirurgie
8: 765767, 8: 816820, 9: 5459.
Chen R, Ashby P, Lang AE (1992). Stimulus-sensitive myo-
clonus in akinetic-rigid syndromes. Brain 115: 18751888.
Collins SJ, Ahlskog JE, Parisi JE et al. (1995). Progressive
supranuclear palsy: neuropathologically based diagnostic
clinical criteria. J Neurol Neurosurg Psychiatry 58 (2):
167173.
Cordato NJ, Halliday GM, McCann H et al. (2001). Cortico-
basal syndrome with tau pathology. Mov Disord 16 (4):
656667.
Cordivari C, Misra VP, Catania S et al. (2001). Treatment of
dystonic clenched fist with botulinum toxin. Mov Disord
16 (5): 907913.
Cummings JL, Litvan I (2000). Corticobasal degeneration.
Neuropsychiatric aspects of corticobasal degeneration. In: I
 CORTICOBASAL DEGENERATION
Litvan, CG Goetz, AE Lang (Eds.), Corticobasal Degenera-
tion. Advances in Neurology, Vol. 82. Williams & Wilkins,
Philadelphia, pp. 147152.
Cummings JL, Mega M, Gray K et al. (1994). The neuropsy-
chiatric inventory: comprehensive assessment of psycho-
pathology in dementia. Neurology 44 (12): 23082314.
Delacourte A (1999). Biochemical and molecular characteri-
zation of neurofibrillary degeneration in frontotemporal
dementias. Dement Geriatr Cogn Disord 10 (Suppl 1):
7579.
Denes G (2002). Comparison of apraxia in corticobasal degen-
eration and progressive supranuclear palsy. Neurology
58 (8): 1317.
DePold Hohler A, Ransom BR, Chun MR et al. (2003). The
youngest reported case of corticobasal degeneration.
Parkinsonism Relat Disord 10 (1): 4750.
De Renzi E, Lucchelli F (1988). Ideational apraxia. Brain
111 (Pt 5): 11731185.
de Silva R, Lashley T, Gibb G et al. (2003). Pathological
inclusion bodies in tauopathies contain distinct comple-
ments of tau with three or four microtubule-binding repeat
domains as demonstrated by new specific monoclonal
antibodies. Neuropathol Appl Neurobiol 29 (3): 288302.
Dickson DW (1999a). Neuropathologic differentiation of
progressive supranuclear palsy and corticobasal degenera-
tion. J Neurol 246 (Suppl 2): II6II15.
Dickson DW (1999b). Tau and synuclein and their role in
neuropathology. Brain Pathol 9 (4): 657661.
Dickson DW (2003). Neuropathology of parkinsonism. In:
R Pahwa, KE Lyons, WC Koller (Eds.), Handbook
of Parkinsons Disease. Marcel Dekker, Inc, New York,
pp. 203220.
Dickson DW, Litvan I (2003). Corticobasal degeneration.
In: DW Dickson, (Eds.), Neurodegeneration: The Molecu-
lar Pathology of Dementia and Movement Disorder. Neu-
ropath Press, Basel, Switzerland, pp. 115123.
Dickson DW, Feany MB, Yen SH et al. (1996). Cytoskeletal
pathology in non-Alzheimer degenerative dementia: new
lesions in diffuse Lewy body disease, Picks disease, and
corticobasal degeneration. J Neural Transm Suppl 47:
3146.
Dickson DW, Bergeron C, Chin SS et al. (2002). Office
of Rare Diseases of the National Institutes of Health.
Office of Rare Diseases neuropathologic criteria for corti-
cobasal degeneration. J Neuropathol Exp Neurol 61 (11):
935946.
Di Maria E, Tabaton M, Vigo T et al. (2000). Corticobasal
degeneration shares a common genetic background
with progressive supranuclear palsy. Ann Neurol 47 (3):
374377.
Doi T, Iwasa K, Makifuchi T et al. (1999). White matter
hyperintensities on MRI in a patient with corticobasal
degeneration. Acta Neurol Scand 99 (3): 199201.
Doody RS, Jankovic J (1992). The alien hand and related
signs. J Neurol Neurosurg Psychiatry 55 (9): 806810.
Doran M, du Plessis DG, Enevoldson TP et al. (2003). Patho-
logical heterogeneity of clinically diagnosed corticobasal
degeneration. J Neurol Sci 216 (1): 127134.
367
Eckert T, Barnes A, Dhawan V et al. (2005). FDG PET in
the differential diagnosis of parkinsonian disorders. Neu-
roimage 26 (3): 912921.
Eidelberg D, Dhawan V, Moeller JR et al. (1991). The meta-
bolic landscape of cortico-basal ganglionic degeneration:
regional asymmetries studied with positron emission
tomography. J Neurol Neurosurg Psychiatry 54: 856862.
Fazzini E, Dogali M, Beric A et al. (1995). The effects of
unilateral ventral posterior medial pallidotomy in patients
with Parkinsons disease and Parkinsons plus syndromes.
In: WC Koller, G Paulson (Eds.), Therapy of Parkinsons
Disease. Marcel Dekker, New York, pp. 353379.
Feany MB, Dickson DW (1996). Neurodegenerative disor-
ders with extensive tau pathology: a comparative study
and review. Ann Neurol 40 (2): 139148.
Feany MB, Mattiace LA, Dickson DW (1996). Neuropatholo-
gic overlap of progressive supranuclear palsy, Picks dis-
ease and corticobasal degeneration. J Neuropathol Exp
Neurol 55 (1): 5367.
Ferrer I, Hernandez I, Boada M et al. (2003). Primary pro-
gressive aphasia as the initial manifestation of corticobasal
degeneration and unusual tauopathies. Acta Neuropathol
(Berl) 106 (5): 419435.
Fisher CM (2000). Alien hand phenomena: a review with the
addition of six personal cases. Can J Neurol Sci 27 (3):
192203.
Forman MS, Lee VM, Trojanowski JQ (2000). New insights
into genetic and molecular mechanisms of brain degen-
eration in tauopathies. J Chem Neuroanat 20 (34): 225244.
Forman MS, Zhukareva V, Bergeron C et al. (2002). Signature
tau neuropathology in gray and white matter of corticobasal
degeneration. Am J Pathol 160 (6): 20452053.
Frattali CM, Sonies BC (2000). Speech and swallowing
disturbances in corticobasal degeneration. Adv Neurol
82: 153160.
Frattali CM, Grafman J, Patronas N et al. (2000). Language
disturbances in corticobasal degeneration. Neurology
54 (4): 990992.
Fujino Y, Delucia MW, Davies P et al. (2004). Ballooned
neurones in the limbic lobe are associated with Alzheimer
type pathology and lack diagnostic specificity. Neuro-
pathol Appl Neurobiol 30 (6): 676682.
Gerhard A, Watts J, Trender-Gerhard I et al. (2004). In vivo
imaging of microglial activation with [11C] (R)-PK11195
PET in corticobasal degeneration. Mov Disord 19 (10):
12211226.
Giannakopoulos P, Hof PR, Bouras C (1995). Dementia lack-
ing distinctive histopathology: clinicopathological evalua-
tion of 32 cases. Act Neuropathol (Berl) 89 (4): 346355.
Gibb WR, Luthert PJ, Marsden CD (1989). Corticobasal
degeneration. Brain 112: 11711192.
Giladi N, Fahn S (1992). Hemiparkinsonism-hemiatrophy
syndrome may mimic early-stage cortical-basal ganglionic
degeneration. Mov Disord 7 (4): 384385.
Gimenez-Roldan S, Mateo D, Benito C et al. (1994). Progressive
supranuclear palsy and corticobasal ganglionic degeneration:
differentiation by clinical features and neuroimaging techni-
ques. J Neural Transm Suppl 42: 7990.
368 N. P. STOVER ET AL.
Godbolt AK, Josephs KA, Revesz T et al. (2005). Sporadic
and familial dementia with ubiquitin-positive tau-negative
inclusions: clinical features of one histopathological
abnormality underlying frontotemporal lobar degenera-
tion. Arch Neurol 62 (7): 10971101.
Goedert M, Jakes R (2005). Mutations causing neurodegenera-
tive tauopathies. Biochim Biophys Acta 1739 (23): 240250.
Goedert M, Ghetti B, Spillantini MG (2000). Tau gene muta-
tions in frontotemporal dementia and parkinsonism linked
to chromosome 17 (FTDP-17). Their relevance for under-
standing the neurodegenerative process. Ann NY Acad Sci
920: 7483.
Goldberg G, Bloom KK (1990). The alien hand sign. Locali-
zation, lateralization and recovery. Am J Phys Med Reha-
bil 69 (5): 228238.
Graham NL, Bak TH, Hodges JR (2003a). Corticobasal degen-
eration as a cognitive disorder. Mov Disord 18 (11):
12241232.
Graham NL, Bak T, Patterson K et al. (2003b). Language
function and dysfunction in corticobasal degeneration.
Neurology 61 (4): 493499.
Green J (2000). Neuropsychological profiles in corticobasal
degeneration. In: J Green (Ed.), Neuropsychological Evalua-
tion of the Older Adult. Academic Press, San Diego, CA,
pp. 142143.
Grimes DA, Lang AE, Bergeron CB (1999). Dementia as the
most common presentation of cortical-basal ganglionic
degeneration. Neurology 53: 19691974.
Groschel K, Hauser TK, Luft A et al. (2004). Magnetic reso-
nance imaging-based volumetry differentiates progressive
supranuclear palsy from corticobasal degeneration. Neuro-
image 21 (2): 714724.
Hachinski V (1997). Frontotemporal degeneration, Pick dis-
ease, and corticobasal degeneration. Three entities or 1?
Arch Neurol 54 (11): 1429.
Halliday GM, Davies L, McRitchie DA et al. (1995). Ubiqui-
tin-positive achromatic neurons in corticobasal degenera-
tion. Acta Neuropathol (Berl) 90 (1): 6875.
Hamilton SR (2000). Neuro-ophthalmology of movement
disorders. Curr Opin Ophthalmol 11 (6): 403407.
Hanger DP, Gibb GM, de Silva R et al. (2002). The complex
relationship between soluble and insoluble tau in tauopa-
thies revealed by efficient dephosphorylation and specific
antibodies. FEBS Lett 531 (3): 538542.
Hargrave R, Rafal R (1998). Depression in corticobasal
degeneration. Psychosomatics 39 (5): 481482.
Hawkes C (2003). Olfaction in neurodegenerative disorder.
Mov Disord 18 (4): 364372.
Henkel K, Karitzky J, Schmid M et al. (2004). Imaging of
activated microglia with PET and [11C]PK 11195 in cor-
ticobasal degeneration. Mov Disord 19 (7): 817821.
Homma A, Harayama H, Kondo H et al. (1996). P300 find-
ings in patients with corticobasal degeneration. Brain and
Nerve 48 (10): 925929.
Horoupian DS, Wasserstein PH (1999). Alzheimers disease
pathology in motor cortex in dementia with Lewy bodies
clinically mimicking corticobasal degeneration. Acta
Neuropathol (Berl) 98 (3): 317322.
Hosaka K, Ishii K, Sakamoto S et al. (2002). Voxel-based
comparison of regional cerebral glucose metabolism
between PSP and corticobasal degeneration. J Neurol Sci
199 (12): 6771.
Houlden H, Baker M, Morris HR et al. (2001). Corticobasal
degeneration and progressive supranuclear palsy share a
common tau haplotype. Neurology 56 (12): 17021706.
Hu WT, Josephs KA, Ahlskog JE et al. (2005). MRI correlates
of alien leg-like phenomenon in corticobasal degeneration.
Mov Disord 20 (7): 870873.
Ikeda K, Akiyama H, Haga C et al. (1994). Argyrophilic
thread-like structure in corticobasal degeneration and
supranuclear palsy. Neurosci Lett 174 (2): 157159.
Ikeda K, Akiyama H, Kondo H et al. (1995). A study
of dementia with argyrophilic grains. Possible cytoske-
letal abnormality in dendrospinal portion of neurons
and oligodendroglia. Acta Neuropathol (Berl) 89 (5):
409414.
Ingelson M, Fabre SF, Lilius L et al. (2001). Increased risk
for frontotemporal dementia through interaction between
tau polymorphisms and apolipoprotein E epsilon4.
Neuroreport 12 (5): 905909.
Iriarte J, Alegre M, Arbizu J et al. (2001). Unilateral periodic
limb movements during sleep in corticobasal degenera-
tion. Mov Disord 16 (6): 11801183.
Ishiwata T, Suzuki A, Mochizuki H et al. (2000). [Progres-
sive limb-kinetic apraxia with myoclonus focal atrophy
in the postcentral gyrus and the supplementary motor
area.] No To Shinkei 52 (10): 925928.
Ishizawa K, Dickson DW (2001). Microglial activation par-
allels system degeneration in progressive supranuclear
palsy and corticobasal degeneration. J Neuropathol Exp
Neurol 60 (6): 647657.
Ishizawa T, Ko LW, Cookson N et al. (2002). Selective neu-
rofibrillary degeneration of the hippocampal CA2 sector is
associated with four-repeat tauopathies. J Neuropathol
Exp Neurol 61 (12): 10401047.
Iwasaki Y, Yoshida M, Hattori M et al. (2005). Widespread
spinal cord involvement in corticobasal degeneration. Acta
Neuropathol (Berl) 109 (6): 632638.
Jacobs DH, Adair JC, Heilman KM (1994). Visual grasp in
corticobasal degeneration. Ann Neurol 36 (4): 679680.
Jacobs DH, Adair JC, Macauley B et al. (1999). Apraxia in
corticobasal degeneration. Brain Cogn 40 (2): 336354.
Jellinger KA (1998). Dementia with grains (argyrophilic
grain disease). Brain Pathol 8 (2): 377386.
Josephs KA, Tang-Wai DF, Edland SD et al. (2004a). Cor-
relation between antemortem magnetic resonance imaging
findings and pathologically confirmed corticobasal degen-
eration. Arch Neurol 61 (12): 18811884.
Josephs KA, Tsuboi Y, Cookson N et al. (2004b). Apolipo-
protein E epsilon 4 is a determinant for Alzheimer-type
pathologic features in tauopathies, synucleinopathies, and
frontotemporal degeneration. Arch Neurol 61 (10):
15791584.
Josephs KA, Tsuboi Y, Dickson DW (2004c). Creutzfeldt-
Jakob disease presenting as progressive supranuclear
palsy. Eur J Neurol 11 (5): 343346.
 CORTICOBASAL DEGENERATION
Kaida K, Takeda K, Nagata N et al. (1998). Alzheimers dis-
ease with asymmetric parietal lobe atrophy: a case report.
J Neurol Sci 160 (1): 9699.
Kasashima S, Oda Y (2003). Cholinergic neuronal loss in the
basal forebrain and mesopontine tegmentum of progres-
sive supranuclear palsy and corticobasal degeneration.
Acta Neuropathol (Berl) 105 (2): 117124.
Katsuse O, Iseki E, Arai T et al. (2003). 4-Repeat tauopathy
sharing pathological and biochemical features of cortico-
basal degeneration and progressive supranuclear palsy.
Acta Neuropathol (Berl) 106 (3): 251260.
Kawasaki K, Iwanaga K, Wakabayashi K et al. (1996). Corti-
cobasal degeneration with neither argyrophilic inclusions
nor tau abnormalities: a new subgroup? Acta Neuropathol
91 (2): 140144.
Kertesz A, Munoz D (2004). Relationship between fronto-
temporal dementia and corticobasal degeneration/progres-
sive supranuclear palsy. Dement Geriatr Cogn Disord
17 (4): 282286.
Kertesz A, Martinez-Lage P, Davidson W et al. (2000). The
corticobasal degeneration syndrome overlaps progressive
aphasia and frontotemporal dementia. Neurology 55 (9):
13681375.
Kertesz A, McMonagle P, Blair M et al. (2005). The evolu-
tion and pathology of frontotemporal dementia. Brain
128 (Pt 9): 19962005.
Kikuchi H, Doh-ura K, Kira J et al. (1999). Preferential neu-
rodegeneration in the cervical spinal cord of progressive
supranuclear palsy. Acta Neuropathol (Berl) 97 (6):
577584.
Kimura K, Tachibana N, Aso T et al. (1997). Subclinical
REM sleep behavior disorder in a patient with corticobasal
degeneration. Sleep 20 (10): 891894.
Kleiner-Fisman G, Bergeron C, Lang AE (2004). Presenta-
tion of Creutzfeldt-Jakob disease as acute corticobasal
degeneration syndrome. Mov Disord 19 (8): 948949.
Komori T (1999). Tau-positive glial inclusions in progres-
sive supranuclear palsy, corticobasal degeneration and
Picks disease. Brain Pathol 9 (4): 663679.
Komori T, Arai N, Oda M et al. (1997). Morphologic dif-
ference of neuropil threads in Alzheimers disease,
corticobasal degeneration and progressive supranuclear
palsy: a morphometric study. Neurosci Lett 233 (23):
8992.
Komori T, Arai N, Oda M et al. (1998). Astrocytic plaques
and tufts of abnormal fibers do not coexist in corticobasal
degeneration and progressive supranuclear palsy. Acta
Neuropathol (Berl) 96 (4): 401408.
Kompoliti K, Goetz CG, Boeve BF et al. (1998). Clinical
presentation and pharmacological therapy in corticobasal
degeneration. Arch Neurol 55 (7): 957961.
Kovacs GG, Trabattoni G, Hainfellner JA et al. (2002). Muta-
tions of the prion protein gene phenotypic spectrum.
J Neurol 249 (11): 15671582.
Kreisler A, Defebvre L, Lecouffe P et al. (2005). Corticobasal
degeneration and Parkinsons disease assessed by HmPaO
SPECT: the utility of factorial discriminant analysis. Mov
Disord 20 (11): 14311438.
369
Ksiezak-Reding H, Tracz E, Yang LS et al. (1996). Ultrastruc-
tural instability of paired helical filaments from corticobasal
degeneration as examined by scanning transmission electron
microscopy. Am J Pathol 149 (2): 639651.
Ksiezak-Reding H, Yang G, Simon M et al. (1998). Assembled
tau filaments differ from native paired helical filaments as
determined by scanning transmission electron microscopy
(STEM). Brain Res 814 (12): 8698.
Kumar R, Bergeron C, Pollanen MS et al. (1998). Corticalba-
sal ganglionic degeneration. In: J Jankovic, E Tolosa
(Eds.), Parkinsons Disease and Movement Disorders,
3rd edn. Williams & Wilkins, Baltimore, pp. 297316.
Kurz AF (2005). Uncommon neurodegenerative causes of
dementia. Int Psychogeriatr 17 (Suppl 1): S35S49.
Lalive PH, Personeni O, Slosman DO et al. (2000). Lower
limb corticobasal degeneration. Eur Neurol 44 (4):
248249.
Lang AE (1992). Cortico basal ganglionic degeneration pre-
senting with progressive loss of speech output and orofa-
cial dyspraxia. J Neurol Neurosurg Psychiatry 55: 1101.
Lang AE (2000). Parkinsonism in corticobasal degeneration.
In: I Litvan, CG Goetz, AE Lang (Eds.), Corticobasal
Degeneration. Advances in Neurology, Vol. 82. Williams
& Wilkins, Philadelphia, pp. 8389.
Lang AE (2005). Treatment of progressive supranuclear
palsy and corticobasal degeneration. Mov Disord 20 (Suppl
12): S83S91.
Lang AE, Riley DE, Bergeron C (1994a). Cortical-basal
ganglionic degeneration. In: DB Calne, (Eds.), Neurode-
generative Diseases. WB Saunders, Philadelphia, pp.
877894.
Lang AE, Bergeron C, Pollanen MS et al. (1994b). Parietal
Picks disease mimicking cortical-basal ganglionic degen-
eration. Neurology 44: 14361440.
Lantos PL (2000). Diagnostic criteria for corticobasal degen-
eration. J Neurol Neurosurg Psychiatry 69 (5): 705706.
Laureys S, Salmon E, Garraux G et al. (1999). Fluorodopa
uptake and glucose metabolism in early stages of cortico-
basal degeneration. J Neurol 246 (12): 11511158.
Lee VM, Goedert M, Trojanowski JQ (2001). Neurodegen-
erative tauopathies. Annu Rev Neurosci 24: 11211159.
Leiguarda R, Merello M, Balej J (2000). Apraxia in cortico-
basal degeneration. Adv Neurol 82: 103121.
Leiguarda RC, Merello M, Nouzeilles MI et al. (2003).
Limb-kinetic apraxia in corticobasal degeneration: clinical
and kinematic features. Mov Disord 18 (1): 4959.
Lerner A, Friedland R, Riley D et al. (1992). Dementia with
pathological findings of corticobasal ganglionic degenera-
tion. Ann Neurol 32: 271.
Levy ML, Miller BL, Cummings JL et al. (1996). Alzheimer
disease and frontotemporal dementias. Behavioral distinc-
tions. Arch Neurol 53 (7): 687690.
Litvan I (1997). Progressive supranuclear palsy and cortico-
basal degeneration. Baillieres Clin Neurol 6 (1): 167185.
Litvan I (1999). Recent advances in atypical parkinsonian
disorders. Curr Opin Neurol 12 (4): 441446.
Litvan I (2001). Therapy and management of frontal lobe
dementia patients. Neurology 56 (11 Suppl 4): S41S45.
370 N. P. STOVER ET AL.
Litvan I, Agid Y, Jankovic J et al. (1996). Accuracy of clin-
ical criteria for the diagnosis of progressive supranuclear
palsy (Steele-Richardson-Olszewski syndrome). Neurol-
ogy 46 (4): 922930.
Litvan I, Agid Y, Goetz C et al. (1997). Accuracy of the clin-
ical diagnosis of corticobasal degeneration: a clinicopatho-
logic study. Neurology 48 (1): 119125.
Litvan I, Cummings JL, Mega M (1998). Neuropsychiatric
features of corticobasal degeneration. J Neurol Neurosurg
Psychiatry 65 (5): 717721.
Litvan I, Grimes DA, Lang AE et al. (1999). Clinical fea-
tures differentiating patients with postmortem confirmed
progressive supranuclear palsy and corticobasal degenera-
tion. J Neurol 246 (Suppl 2): II1II5.
Litvan I, Bhatia KP, Burn DJ et al. (2003). Movement
Disorders Society Scientific Issues Committee report:
SIC Task Force appraisal of clinical diagnostic criteria
for Parkinsonian disorders. Mov Disord 18 (5): 467486.
Lleo A, Rey MJ, Castellvi M et al. (2002). Asymmetric myo-
clonic parietal syndrome in a patient with Alzheimers
disease mimicking corticobasal degeneration. Neurologia
17 (4): 223226.
Lu CS, Ikeda A, Terada K et al. (1998). Electrophysiological
studies of early stage corticobasal degeneration. Mov
Disord 13 (1): 140146.
Mackenzie IR, Hudson LP (1995). Achromatic neurons in
the cortex of progressive supranuclear palsy. Acta Neuro-
pathol (Berl) 90 (6): 615619.
Maraganore DM, Ahlskog JE, Petersen RC (1992). Progres-
sive asymmetric rigidity with apraxia: a distinctive clinical
entity. Mov Disord 7 (1): 80.
Mendez MF (2000). Corticobasal ganglionic degeneration
with Balints syndrome. J Neuropsychiatry Clin Neurosci
12 (2): 273275.
Merians AS, Clark M, Poizner H et al. (1999). Apraxia dif-
fers in corticobasal degeneration and left-parietal stroke:
a case study. Brain Cogn 40 (2): 314335.
Mima T, Nagamine T, Ikeda A et al. (1998). Pathogenesis of
cortical myoclonus studied by magnetoencephalography.
Ann Neurol 43 (5): 598607.
Mirra SS, Hyman B (2002). Aging and dementia. In: D Gra-
ham, P Lantos (Eds.), Greenfields Neuropathology. Gray
Publishing, New York, pp. 195271.
Mirra SS, Murrell JR, Gearing M et al. (1999). Tau pathol-
ogy in a family with dementia and a P301L mutation in
tau. J Neuropathol Exp Neurol 58 (4): 335345.
Miserez AR, Clavaguera F, Monsch AU et al. (2003). Argyr-
ophilic grain disease: molecular genetic difference to other
four-repeat tauopathies. Acta Neuropathol (Berl) 106 (4):
363366.
Mitani K, Furiya Y, Uchihara T et al. (1998). Increased CSF tau
protein in corticobasal degeneration. J Neurol 245 (1): 4446.
Monza D, Ciano C, Scaioli V et al. (2003). Neurophysiologi-
cal features in relation to clinical signs in clinically diag-
nosed corticobasal degeneration. Neurol Sci 24 (1): 1623.
Moreaud O, Monavon A, Brutti-Mairesse MP et al. (2005).
Creutzfeldt-Jakob disease mimicking corticobasal degen-
eration clinical and MRI data of a case. J Neurol
252 (10): 12831284.
Moretti R, Torre P, Antonello RM et al. (2005). Cognitive
impairment in the lateralized phenotype of corticobasal
degeneration. Dement Geriatr Cogn Disord 20 (23):
158162.
Mori H, Oda M, Mizuno Y (1996). Cortical ballooned neu-
rons in progressive supranuclear palsy. Neurosci Lett
209 (2): 109112.
Muller A, Mungersdorf M, Reichmann H et al. (2002a).
Olfactory function in Parkinsonian syndromes. J Clin Neu-
rosci 9 (5): 521524.
Muller J, Wenning GK, Verny M et al. (2001). Progression
of dysarthria and dysphagia in postmortem-confirmed par-
kinsonian disorders. Arch Neurol 58 (2): 259264.
Muller J, Wenning GK, Wissel J et al. (2002b). Botulinum
toxin treatment in atypical parkinsonian disorders asso-
ciated with disabling focal dystonia. J Neurol 249 (3):
300304.
Nakano KK, Dawson DM, Spence A (1972). Machado dis-
ease. A hereditary ataxia in Portuguese emigrants to Mas-
sachusetts. Neurology 22: 4955.
Nakazato Y, Hirato J, Ishida Y et al. (1990). Swollen cortical
neurons in Creutzfeldt-Jakob disease contain a phosphory-
lated neurofilament epitope. J Neuropathol Exp Neurol 49:
197205.
Obeso JA, Rothwell JC, Lang AE et al. (1983). Myoclonic
dystonia. Neurology 33: 825830.
Obeso JA, Rothwell JC, Marsden CD (1985). The spectrum
of cortical myoclonus. From focal reflex jerks to sponta-
neous motor epilepsy. Brain 108: 193124.
Oide T, Ohara S, Yazawa M et al. (2002). Progressive supra-
nuclear palsy with asymmetric tau pathology presenting
with unilateral limb dystonia. Acta Neuropathol (Berl)
104 (2): 209214.
Okuda B, Tachibana H (1994). The nature of apraxia in cor-
ticobasal degeneration. J Neurol Neurosurg Psychiatry
57 (12): 15481549.
Okuda B, Tachibana H, Takeda M et al. (1998). Asymmetric
changes in somatosensory evoked potentials correlate with
limb apraxia in corticobasal degeneration. Acta Neurol
Scand 97 (6): 409412.
Okuma Y, Urabe T, Mochizuki H et al. (2000). Asymmetric
cortico-cortical inhibition in patients with progressive
limb-kinetic apraxia. Acta Neurol Scand 102 (4): 244248.
Oliveira SA, Scott WK, Zhang F et al. (2004). Linkage
disequilibrium and haplotype tagging polymorphisms in
the Tau H1 haplotype. Neurogenetics 5 (3): 147155.
Otsuki M, Soma Y, Yoshimura N et al. (1997). Slowly progres-
sive limb-kinetic apraxia. Eur Neurol 37 (2): 100103.
Ozsancak C, Auzou P, Hannequin D (2000). Dysarthria and
orofacial apraxia in corticobasal degeneration. Mov
Disord 15 (5): 905910.
Paraskevas GP, Kapaki E, Liappas I et al. (2005). The
diagnostic value of cerebrospinal fluid tau protein in
dementing and nondementing neuropsychiatric disorders.
J Geriatr Psychiatry Neurol 18 (3): 163173.
 CORTICOBASAL DEGENERATION
Peigneux P, Salmon E, Garraux G et al. (2001). Neural and
cognitive bases of upper limb apraxia in corticobasal
degeneration. Neurology 57 (7): 12591268.
Pharr V, Uttl B, Stark M et al. (2001). Comparison of
apraxia in corticobasal degeneration and progressive
supranuclear palsy. Neurology 56 (7): 957963.
Piao YS, Hayashi S, Wakabayashi K et al. (2002). Cerebellar
cortical tau pathology in progressive supranuclear palsy
and corticobasal degeneration. Acta Neuropathol (Berl)
103 (5): 469474.
Pierrot-Deseilligny C (1994). Saccade and smooth-pursuit
impairment after cerebral hemispheric lesions. Eur Neurol
34 (3): 121134.
Pierrot-Deseilligny C, Rivaud S, Pillon B et al. (1989).
Lateral visually-guided saccades in progressive supranuc-
lear palsy. Brain 112 (Pt 2): 471487.
Pillon B, Dubois B (2000). Memory and executive processes
in corticobasal degeneration. Adv Neurol 82: 91101.
Pillon B, Blin J, Vidailhet M et al. (1995). The neuropsycho-
logical pattern of corticobasal degeneration: comparison
with progressive supranuclear palsy and Alzheimers dis-
ease. Neurology 45 (8): 14771483.
Pittman AM, Myers AJ, Abou-Sleiman P et al. (2005). Link-
age disequilibrium fine-mapping and haplotype associa-
tion analysis of the tau gene in progressive supranuclear
palsy and corticobasal degeneration. J Med Genet
42 (11): 837846.
Plotkin M, Amthauer H, Klaffke S et al. (2005). Combined
123I-FP-CIT and 123I-IBZM SPECT for the diagnosis of
parkinsonian syndromes: study on 72 patients. J Neural
Transm 112 (5): 677692.
Poeck K (1983). Ideational apraxia. J Neurol 230 (1): 15.
Rademakers R, Cruts M, van Broeckhoven C (2004). The
role of tau (MAPT) in frontotemporal dementia and
related tauopathies. Hum Mutat 24 (4): 277295.
Rebeiz JJ, Kolodny EH, Richardson EP Jr (1967). Cortico-
dentatonigral degeneration with neuronal achromasia: a
progressive disorder of late adult life. Trans Am Neurol
Assoc 92: 2326.
Rebeiz JJ, Kolodny EH, Richardson EP Jr (1968). Cortico-
dentatonigral degeneration with neuronal achromasia.
Arch Neurol 18: 2033.
Reed LA, Wszolek ZK, Hutton M (2001). Phenotypic corre-
lations in FTDP-17. Neurobiol Aging 22 (1): 89107.
Richter-Landsberg C, Bauer NG (2004). Tau-inclusion body
formation in oligodendroglia: the role of stress proteins
and proteasome inhibition. Int J Dev Neurosci 22 (7):
443451.
Riley DE, Lang AE (1993). Cortical-basal ganglionic degen-
eration. In: MB Stern, WC Koller (Eds.), Parkinsonian
Syndromes. Dekker, New York, pp. 379392.
Riley DE, Lang AE (2000). Corticobasal degeneration. Clin-
ical diagnostic criteria. In: I Litvan, CG Goetz, AE Lang
(Eds.), Corticobasal Degeneration. Advances in Neurology,
Vol. 82. Williams & Wilkins, Philadelphia, pp. 2934.
Rinne JO, Lee MS, Thompson PD et al. (1994). Corticobasal
degeneration. A clinical study of 36 cases. Brain 117 (Pt 5):
11831196.
371
Rivaud-Pechoux S, Vidailhet M, Gallouedec G et al. (2000).
Longitudinal ocular motor study in corticobasal degenera-
tion and progressive supranuclear palsy. Neurology 54 (5):
10291032.
Rosenfield DB, Bogatka CJ, Viswanath NS et al. (1991).
Speech apraxia in corticobasal ganglionic degeneration.
Ann Neurol 30: 296297.
Rottach KG, Riley DE, DiScenna AO et al. (1996). Dynamic
properties of horizontal and vertical eye movements in
parkinsonian syndromes. Ann Neurol 39 (3): 368377.
Sachdev HS, Forno LS, Kane CA (1982). Joseph disease: a
multisystem degenerative disorder of the nervous system.
Neurology 32: 192195.
Sakakibara R, Uchiyama T, Yamanishi T et al. (2004). Urin-
ary function in patients with corticobasal degeneration;
comparison with normal subjects. Neurourol Urodyn
23 (2): 154158.
Salter JE, Roy EA, Black SE et al. (2004). Gestural imitation
and limb apraxia in corticobasal degeneration. Brain Cogn
55 (2): 400402.
Savoiardo M (2003). Differential diagnosis of Parkinsons
disease and atypical parkinsonian disorders by magnetic
resonance imaging. Neurol Sci 24 (Suppl 1): S35S37.
Savoiardo M, Grisoli M, Girotti F (2000). Corticobasal
degeneration. Magnetic resonance imaging in CBD,
related atypical parkinsonian disorders, and dementias.
In: I Litvan, CG Goetz, AE Lang (Eds.), Corticobasal
Degeneration. Advances in Neurology, Vol. 82. Williams
& Wilkins, Philadelphia, pp. 197208.
Sawle GV, Brooks DJ, Thompson PD et al. (1989). PET
studies on the dopaminergic system and regional cortical
metabolism in corticobasal degeneration. Neurology
39 (1): 163.
Schneider JA, Watts RL, Gearing M et al. (1997). Corticoba-
sal degeneration: neuropathologic and clinical heterogene-
ity. Neurology 48 (4): 959969.
Sergeant N, Wattez A, Delacourte A (1999). Neurofibrillary
degeneration in progressive supranuclear palsy and corti-
cobasal degeneration: tau pathologies with exclusively
exon 10 isoforms. J Neurochem 72 (3): 12431249.
Shibasaki H (1995). Myoclonus. Curr Opin Neurol 8 (4):
331334.
Sobrido MJ, Abu-Khalil A, Weintraub S et al. (2003). Possi-
ble association of the tau H1/H1 genotype with primary
progressive aphasia. Neurology 60 (5): 862864.
Soliveri P, Piacentini S, Paridi D et al. (2003). Distal-proxi-
mal differences in limb apraxia in corticobasal degenera-
tion but not progressive supranuclear palsy. Neurol Sci
24 (3): 213214.
Soliveri P, Piacentini S, Girotti F (2005). Limb apraxia in
corticobasal degeneration and progressive supranuclear
palsy. Neurology 64 (3): 448453.
Stanford PM, Brooks WS, Teber ET et al. (2004). Frequency
of tau mutations in familial and sporadic frontotemporal
dementia and other tauopathies. J Neurol 251 (9):
10981104.
Steele JC, Richardson JC, Olszewski J (1964). Progressive
supranuclear palsy. Arch Neurol 10: 333359.
372 N. P. STOVER ET AL.
Stover NP, Watts RL (2001). Corticobasal degeneration.
Semin Neurol 21: 4958.
Su M, Yoshida Y, Hirata Y et al. (2000). Degeneration of the
cerebellar dentate nucleus in corticobasal degeneration:
neuropathological and morphometric investigations. Acta
Neuropathol (Berl) 99 (4): 365370.
Tang-Wai DF, Josephs KA, Boeve BF et al. (2003). Pathologi-
cally confirmed corticobasal degeneration presenting with
visuospatial dysfunction. Neurology 61 (8): 11341135.
Tanner CM (1996). Epidemiologic approaches to cortical-
basal ganglionic degeneration. Mov Disord 11: 346357.
Thompson PD (1995). Myoclonus in corticobasal degenera-
tion. Clin Neurosci 3 (4): 203208.
Thompson PD, Shibasaki H (2000). Myoclonus in corticobasal
degeneration and other neurodegenerations. In: I Litvan,
CG Goetz, AE Lang (Eds.), Corticobasal Degeneration.
Advances in Neurology, Vol. 82. Williams & Wilkins,
Philadelphia, pp. 6981.
Thompson PD, Day BL, Rothwell JC et al. (1994). The myo-
clonus in corticobasal degeneration. Evidence for two forms
of cortical reflex myoclonus. Brain 117 (Pt 5): 11971207.
Togo T, Sahara N, Yen SH et al. (2002). Argyrophilic grain
disease is a sporadic 4-repeat tauopathy. J Neuropathol
Exp Neurol 61 (6): 547556.
Tolnay M, Clavaguera F (2004). Argyrophilic grain disease:
a late-onset dementia with distinctive features among
tauopathies. Neuropathology 24 (4): 269283.
Tolnay M, Probst A (2003). The neuropathological spectrum
of neurodegenerative tauopathies. IUBMB Life 55 (6):
299305.
Tolnay M, Sergeant N, Ghestem A et al. (2002). Argyrophilic
grain disease and Alzheimers disease are distinguished by
their different distribution of tau protein isoforms. Acta
Neuropathol (Berl) 104 (4): 425434.
Tuite PJ, Clark HB, Bergeron C et al. (2005). Clinical and
pathologic evidence of corticobasal degeneration and pro-
gressive supranuclear palsy in familial tauopathy. Arch
Neurol 62 (9): 14531457.
Vanek ZF, Jankovic J (2000). Corticobasal degeneration.
Dystonia in corticobasal degeneration. In: I Litvan, CG
Goetz, AE Lang (Eds.), Corticobasal Degeneration.
Advances in Neurology, Vol. 82. Williams & Wilkins,
Philadelphia, pp. 6167.
Vanek Z, Jankovic J (2001). Dystonia in corticobasal degen-
eration. Mov Disord 16 (2): 252257.
van Swieten JC, Rosso SM, van Herpen E et al. (2004).
Phenotypic variation in Frontotemporal dementia and
parkinsonism linked to chromosome 17. Dement Geriatr
Cogn Disord 17: 261264.
Van Zanducke M, Dehaene I (2000). A cortico-basal degen-
eration-like syndrome as first sign of progressive multifocal
leukoencephalopathy. Acta Neurol Belg 100 (4): 242245.
Verin M, Rancurel G, De Marco O et al. (1997). First familial
cases of corticobasal degeneration. Mov Disord 12 (1): 55.
Vidailhet M, Rivaud-Pechoux S (2000). Corticobasal degen-
eration. Eye movement disorders in corticobasal deg-
eneration. In: I Litvan, CG Goetz, AE Lang (Eds.),
Corticobasal Degeneration. Advances in Neurology, Vol.
82. Williams & Wilkins, Philadelphia, pp. 161167.
Vidailhet M, Rivaud S, Gouider-Khouja N et al. (1994).
Eye movements in parkinsonian syndromes. Ann Neurol
35 (4): 420426.
Vion-Dury J, Rochefort N, Michotey P et al. (2004). Proton
magnetic resonance neurospectroscopy and EEG cartogra-
phy in corticobasal degeneration: correlations with neu-
ropsychological signs. J Neurol Neurosurg Psychiatry
75 (9): 13521355.
Wakabayashi K, Takahashi H (2004). Pathological heteroge-
neity in progressive supranuclear palsy and corticobasal
degeneration. Neuropathology 24 (1): 7986.
Walter U, Dressler D, Wolters A et al. (2004). Sonographic
discrimination of corticobasal degeneration vs progressive
supranuclear palsy. Neurology 63 (3): 504509.
Watts RL, William RS, Growdon JH et al. (1985). Corticoba-
sal ganglionic degeneration. Neurology 35 (1): 178.
Watts RL, Mirra SS, Richardson EP (1994). Corticobasal gang-
lionic degeneration. In: CD Marsden, S Fahn (Eds.), Move-
ment Disorders 3. Butterworths, London, pp. 282299.
Wenning GK, Ben Shlomo Y, Magalhaes M et al. (1994).
Clinical features and natural history of multiple system
atrophy. An analysis of 100 cases. Brain 117 (Pt 4):
835845.
Wenning GK, Shephard B, Hawkes C et al. (1995). Olfactory
function in atypical parkinsonian syndromes. Acta Neurol
Scand 91 (4): 247250.
Wenning GK, Litvan I, Jankovic J et al. (1998). Natural his-
tory and survival of 14 patients with corticobasal degen-
eration confirmed at postmortem examination. J Neurol
Neurosurg Psychiatry 64 (2): 184189.
Wetter TC, Brunner H, Collado-Seidel V et al. (2002). Sleep
and periodic limb movements in corticobasal degenera-
tion. Sleep Med 3 (1): 3336.
Yamauchi H, Fukuyama H, Nagahama Y et al. (1998).
Atrophy of the corpus callosum, cortical hypometabolism,
and cognitive impairment in corticobasal degeneration.
Arch Neurol 55 (5): 609614.
Zadikoff C, Lang AE (2005). Apraxia in movement disor-
ders. Brain 128 (Pt 7): 14801497.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 49

Infectious basis to the pathogenesis of Parkinsons disease

V. DHAWAN1,2 AND K. RAY CHAUDHURI13*

1
Regional Movement Disorders Unit, Kings College Hospital, London, UK
2
University Hospital Lewisham, London, UK
3
Guys, Kings and St. Thomas School of Biomedical Medicine and Kings College, London, UK

49.1. Introduction 49.2. A Possible immunological basis and

The etiology of Parkinsons disease (PD) is unknown
but a considerable body of research suggests that a
variety of occupational, environmental and genetic
factors may play an important role (Ben-Shlomo,
1997). Infections have also been suggested as a cause
of PD both directly and indirectly (through occu-
pational exposure), stemming from the observation
that development of parkinsonism often followed the
influenza pandemic of the 1910s and encephalitis
lethargica (von Economos disease) often preceded
it (Ben-Shlomo, 1997; Lai et al., 2002). Since then,
several other possibilities of an infective basis to PD
and parkinsonism have been put forward and this
review examines the basis behind these observations.
PD occurs throughout the world across all races and
increases exponentially with age. The late onset
and slow-progressing nature of the disease have
prompted the consideration of environmental expo-
sure to agrochemicals, including pesticides, as a risk
factor. Moreover, increasing evidence suggests that
early-life occurrence of inflammation in the brain, as
a consequence of either brain injury or exposure to
infectious agents, may play a role in the pathogenesis
of PD. Most importantly, there may be a self-
propelling cycle of inflammatory process involving
brain immune cells (microglia and astrocytes) that
drives the slow yet progressive neurodegenerative
process. Differences in prevalence between identical
ethnic groups in different countries support the role
of an environmental factor, including an infectious
basis (Richards and Chaudhuri, 1996; Stoessl, 1999;
Chaudhuri et al., 2000).
a link with infection
Several studies have displayed evidence of immune
abnormalities in PD. These include the occurrence of
antineuronal antibodies, increases in human leukocyte
antigen-DR (HLA)-DR expression on cerebrospinal
fluid (CSF) monocytes and increases in HLA-DR
activated microglia in substantia nigra (SN). In one
study examining immune mediators in peripheral
lymphocytes of patients with PD, patients with PD
displayed a significantly greater population of circulat-
ing CD3 CD4 bright CD8 dull lymphocytes than
age-matched control subjects (Hisanaga et al., 2001).
These cells are known to increase after some specific
viral infections, hence raising the possibility of an
association between postinfectious immune abnormal-
ities and pathogenesis of PD. CD8dull and
CD4bright T cells have been associated with
EpsteinBarr virus (EBV), cytomegalovirus, human
herpes 6, human T-cell leukemia virus type-1 and
human immunodeficiency virus (HIV). However,
these have also been demonstrated in patients with
neoplasms as well as in small populations of healthy
adults and in patients with multiple sclerosis, myasthe-
nia gravis and during rejection of renal transplants.
The precise reasons behind why CD4 and CD8
T cells increase in PD and whether these circulating
lymphocytes contribute to the pathogenesis of neuro-
nal death in PD remain inconclusive and require
further investigation.
Salman and colleagues (1999) reported decreased
phagocytic function exhibited by peripheral blood
polymorphonuclears of PD patients, as shown by their

*Correspondence to: Dr. K. Ray Chaudhuri, 9th floor, Ruskin Wing, Kings College Hospital, Denmark Hill, London SE5 9RS,
UK. E-mail: Ray.chaudhuri@uhl.nhs.uk, Tel: 44-(0)208-333-3030, Ext. 6184, Fax: 44-(0)208-333-3093.
374 V. DHAWAN AND K. R. CHAUDHURI
impaired ability to engulf latex particles. Function of
phagocytes is significant in trying to combat bacterial
invasion or destruction of any foreign material,
thereby increasing the susceptibility of PD patients to
infection, but could be secondary to the disease rather
than playing a direct causative role in its pathogenesis.
Other immune abnormalities described in PD
include the occurrence of autoantibodies against neu-
ronal structures and an elevated number of microglia
cells expressing the histocompatibility glycoprotein
HLA-DR in the SN. An increased gamma delta ()
T-cell population and immunoglobulin G immunity
in CSF to heat shock proteins has been found in PD
(Fiszer, 2001). Impaired cytokine production by the
peripheral immune system in PD patients with a sig-
nificant decrease in the production of tumor necrosis
factor-a (TNF-a), interleukin (IL)-1a, IL-1b and IL-6
by peripheral blood mononuclear cells and TNF-a by
peripheral blood macrophages was demonstrated
by Hasegawa et al. (2000).
Rats with nigral injection of immunoglobulin
G (IgG) purified from the serum of 5 patients with PD
and 10 disease control patients suggested that PD IgG
can initiate a relatively specific inflammatory destruc-
tion of SN pars compacta neurons in vivo (Chen et al.,
1998).
A cytokine/CD23-dependent activation pathway of
inducible nitric oxide synthase, toxic oxidative species
and of proinflammatory mediators in glial cells and
their involvement in the pathophysiology of PD has
been suggested in a study by Hunot et al. (1999). Also
in a study in 1999, Linda et al. demonstrated that motor
neurons and nigral dopaminergic neurons (i.e. those
neurons that are susceptible to neurodegeneration in
diseases such as PD and amyotrophic lateral sclerosis),
in the brainstem of the adult rat, displayed high levels
of both major histocompatibility complex (MHC)
class I heavy-chain and b2-microglobulin mRNAs.
A deficiency in expression of MHC class I is thought
to impede CD8 T-cell recognition and target cell kill-
ing. These mechanisms may protect neurons and other
cells with low regenerative capacity from destruction
by T cells.
Antibodies raised against viral determinants some-
times cross-react with host proteins in immunohisto-
chemical studies and such cross-reacting antibodies
may thereby play a role in disease pathogenesis.
a-Synuclein, a neuronal protein, is reported to be a major
component of Lewy bodies (LBs) in PD, dementia with
LBs and common variants of Alzheimers disease. Gias-
son et al. (2000) developed a panel of antisynuclein
antibodies and performed immunohistochemical studies
showing that these antibodies label numerous LBs in
the SN of PD, thereby suggesting a role of pathological
forms of this protein in PD and related neurodegenerative
synucleinopathies.
It is possible that similar cross-reacting immune
responses are generated as part of the immune response
to natural infection with a virus. The cross-reactivity
between a virus and protein may bear important implica-
tions in elucidating infectious mechanisms in the patho-
genesis of PD. More specifically, studies have focused
on the possible role of the following organisms in the
pathogenesis of PD and related syndromes (Fig. 49.1):

HIV

Prion protein

Nocardia asteroides

Japanese encephalitis virus

Influenza A virus

Helicobacter pylori

Toxoplasma gondii
49.3. Review of clinical case reports
49.3.1. HIV spontaneous-onset extrapyramidal
symptoms in patients with HIV/AIDS
Movement disorders are recognized as a complication
of HIV/acquired immune deficiency syndrome (AIDS)
and may be both hypo- and hyperkinetic in nature.
Opportunistic infections or, occasionally, drug thera-
pies may be responsible, although in some cases there
may be no identifiable precipitant. Estimates of preva-
lence of movement disorders in HIV-seropositive
patients range between 0.006 and 14%, depending on
concurrent pharmacological therapy and the method of
analysis employed (Nath et al., 1987; Mirsattari et al.,
1998; De Mattos et al., 2002; Tse et al., 2004). Cardoso
(2002) proposed that clinically relevant movement disor-
ders are identified in 3% of patients with HIV infection
seen at tertiary referral centers and prospective follow-
up shows that 50% of patients with AIDS develop
tremor, parkinsonism or other extrapyramidal features.
Parkinsonism has been described in several cases with
HIV infection and AIDS, which result from lesions
caused by opportunistic infections such as toxoplasmo-
sis, which damage the basal ganglia connections
(Table 49.1). Parkinsonism, tremor and dystonia can also
result from dopaminergic dysfunction caused by cellular
action of dopamine-blocking agents (Table 49.2).
Extrapyramidal symptoms associated with HIV/
AIDS were described by Berger et al. (1984), who
noted the presence of tremor in 3 out of 165 patients
(0.02%) recently diagnosed with AIDS in Florida,
USA. Three years later Nath et al. (1987) published a
case report of 2 patients with AIDS and rest tremor.
The patients were both male, aged 57 and 37 years,
and had been diagnosed with AIDS 17 and 22 months
 INFECTIOUS BASIS TO THE PATHOGENESIS OF PARKINSONS DISEASE 375

A B

C D
Fig. 49.1. Possible infectious organisms implicated in cause of Parkinsons disease and parkinsonism. (A) Human immunode-
ficiency virus; (B) influenza; (C) Helicobacter pylori; (D) CJD (prion particles); (E) Toxoplasma; (F) Nocardia asteroides.

previously. Serological investigations and neuroima-
ging failed to identify obvious causes of parkinsonism
in these patients and a direct effect of HIV-1 on the
basal ganglia was hypothesized. Brain biopsy later
revealed cerebral Whipples disease in 1 of the patients
and it was suggested this may have contributed to the
clinical presentation.
In 1989 Carrazana et al. published a case report
of acute-onset parkinsonism associated with AIDS in
a 66-year-old female. The patient presented with a
2-week history of lethargy, tremor and slow, shuffling
gait and a 2-day history of fever. Her family had noted
her facial expression was reduced. Examination
revealed bilateral cogwheel rigidity, infrequent
376 V. DHAWAN AND K. R. CHAUDHURI
E F
Fig. 49.1. (Continued)
blinking, drooling, right pronator drift, right-sided
hyperreflexia and an extensor plantar response on the
right. Serum and CSF toxoplasma titers were elevated
and computed tomographic (CT) neuroimaging
revealed bilateral ring-enhancing lesions in the ante-
rior limb of the internal capsule, suggestive of cerebral
toxoplasmosis. HIV-1 in serum was positive. There
was a poor clinical response to levodopa and pyri-
methamine and sulfadiazine therapy were discontinued
following the development of pancytopenia. The
patient died secondary to septicemia within 5 months
of the onset of parkinsonian symptoms. Tolge and Fac-
tor (1991) reported a case of isolated focal dystonia in
the left hand and arm of a 29-year-old male, 5 months
after having received the diagnosis of HIV-1 infection.
Serum toxoplasma titer was elevated and a CT scan
revealed ring-enhancing lesions, typical of Toxo-
plasma abscesses, in the right lenticular nucleus and
right thalamus (Fig. 49.2).
Maggi et al. (2000) reported an AIDS patient who
developed cerebral opportunistic granulomatous
lesions and, subsequently, a parkinsonian akinetic-
rigid syndrome. The parkinsonian syndrome only
developed when the lesions involved basal ganglia
bilaterally.
Werring and Chaudhuri (1996) also described a
rapidly developing akinetic-rigid syndrome progres-
sing to akinetic mutism and death in a patient with
recently acquired HIV.
Parkinsonian symptoms of tremor, hypomimia and
gait disturbance caused by mesencephalic cryptococ-
cal abscesses in a 63-year-old man with AIDS
have also been reported (Bouffard et al., 2003). The
patients symptoms were initially attributed to early
PD; diagnoses of AIDS and cryptococcal infection
were made following his death due to cardiac arrest
8 months after the onset of his neurological symptoms.
Autopsy revealed bilateral cryptococcal abscesses in
the SN without any characteristic changes of cerebral
HIV infection or other obvious underlying pathology
(Bouffard et al., 2003). Bradykinesia and rigidity were
also reported in association with central nervous
system (CNS) tuberculosis in a 49-year-old male,
as the presenting manifestation of HIV infection (de La
Fuente-Aguado et al., 1996). The diagnosis of CNS
tuberculosis was made on the basis of neuroimaging
appearances (Fig. 49.3) and the growth of acid-fast
bacilli on a CSF smear. CD4 count at diagnosis was
133 cells/mm3. The case is interesting as parkinsonian
features resolved fully following 12 days of antitubercu-
losis therapy plus intravenous dexamethasone.
49.3.2. Postencephalitic parkinsonism (PEP)
49.3.2.1. Epidemiological aspects
A pandemic of encephalitis lethargica occurred
between 1919 and 1926, resulting in the emergence
of the syndrome of PEP. A younger age of onset of
Table 49.1

INFECTIOUS BASIS TO THE PATHOGENESIS OF PARKINSONS DISEASE

Summary of case reports of spontaneous-onset parkinsonism in patients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS)

Werring and De la
Berger et al. Nath et al. Carrazana Chaudhuri Fuente-Aguado Hersh et al. De Mattos Bouffard
Case reports of parkinsonism (1984) (1987) et al. (1989) (1996) et al. (1996 ) (2001) et al. (2002) et al. (2003) Total

Male 3 2 1 1 1 10 1 19
Female 1 3 4
Mean age (years) 47 66 38 49 37 37 63 44.1
Latency between Dx HIV/AIDS
and onset of EPS (months) 17 to22 0.5 1 0 4 5 0
Baseline CD4 count (cells/mm3) 1/1 110 438 133 227
EPS attributed to toxoplasmosis 1/14 2/23
EPS attributed to cryptococcosis 1/1 1/23
EPS attributed to CNS
tuberculosis 1/1 1/23
EPS attributed to PML 1/1 1/1
No cause found to explain EPS 2/2 1/1 12/13 15/23
Improvement with
antitoxoplasmosis Tx No No 0/2
Improvement with anti-TB Tx 1/1 1/1
Improvement with levodopa No No Yes Yes5/9 6/12
Improvement with HAART Yes 1/1
Deaths 1 1 8 1 11
Latency between onset of EPS
and death (months) 5 5 8 6

Dx, diagnosis; EPS, extrapyramidal symptoms; CNS, central nervous system; PML, progressive multifocal leukoencephalopathy; Tx, treatment; TB, tuberculosis; HAART, highly active antiretroviral
treatment; implies EPS began after diagnosis of HIV/AIDS; implies EPS began before HIV diagnosis.

377
378 V. DHAWAN AND K. R. CHAUDHURI
Table 49.2
Summary of case reports of dystonia in patients with human immunodeficiency virus (HIV)/acquired immune deficiency
syndrome (AIDS)

Nath et al. Tolge and De Mattos

Case reports of dystonia (1987) Factor (1991) et al. (2002) Total

Right-sided Male 1 1
Right-sided Female
Left-sided Male 1 1
Left-sided Female
Bilateral Male 1 1
Bilateral Female
Mean age (years) 35 29 28 30.7
Mean time between diagnosis of HIV/AIDS and onset of EPS 4 months 5 months
EPS attributed to basal ganglia toxoplasmosis 1/1 1/1 2/3
No cause found to explain EPS 1/1 1/3
Clinical improvement with antitoxoplasmosis treatment No No 0/2
Deaths 0

EPS, extrapyramidal symptoms.

implies EPS began after diagnosis of HIV/AIDS; implies EPS began before HIV diagnosis.

Fig. 49.2. Contrasted computed tomographic image in a patient presenting with focal dystonia. Cerebral toxoplasmosis
abscess in right lenticular nucleus and left temporal cortex (A) and right thalamus (B). Reproduced from Tolge and
Factor (1991), with permission.

disease (36.8 years) was reported from a group of
London hospitals compared to an age of onset of
54.7 years between 1900 and 1920 (Duvoisin et al.,
1963) At this time the age of onset of PEP (between
1921 and 1942) was 27.4 years. Studies from the USA
(Massachusetts General Hospital) also suggest that age
of diagnosis of parkinsonism between 1920 and 1924
was 27 years less than those diagnosed between 1919
and 1926 (Poskanzer and Schwab, 1963), suggesting
that the pandemic of 19191926 may have influenced
the earlier onset of disease in this group of patients.
Mortality data from England and Wales related to PD
showed that, although there is a fivefold increase in
death rates among people over 80 years of age, younger
people with PD had a lower mortality rate (Martyn,
1997). Although the possibility of a birth cohort rate
cannot be excluded, these data provide indirect
evidence that people born at the beginning of the
 INFECTIOUS BASIS TO THE PATHOGENESIS OF PARKINSONS DISEASE
Fig. 49.3. Computed tomography image in a patient present-
ing with parkinsonism. Hypodense cerebral lesion affecting
left external capsule, posterior limb of internal capsule and
lower region of left lenticular nuclei. The lesion did not show
enhancement to the intravenous contrast and was diagnosed
as central nervous system tuberculosis on the basis of cere-
brospinal fluid analysis. Reproduced from de La Fuente-
Aguado et al. (1996), with permission.
20th century suffered from an unusually high rate
of parkinsonism, thus supporting the notion that
encephalitis lethargica could have been implicated.
Reports from a recent study on 22 patients with an ence-
phalitis lethargica-like phenotype advocate that it is still
prevalent and is a postinfectious autoimmune CNS dis-
order with autoantibody targeting of basal ganglia and
SN neurons (Dale et al., 2002).
49.3.2.2. Case report-related observations
The Japanese B encephalitis virus is the first demon-
strated virus capable of producing nigral lesions and
causing parkinsonism. Pradhan et al. (1999) selected
5 patients from 52 patients with Japanese B encephali-
tis seen in an endemic zone, on the basis of isolated
lesions in the SN (revealed on imaging with magnetic
resonance imaging (MRI)) and performed detailed
clinical and laboratory evaluations. Examination dur-
ing acute illness revealed restricted eye movements,
opsoclonus, upbeating nystagmus and cogwheel
rigidity with reversal of consciousness and eye signs
after the acute illness. Parkinsonian features, such as
positive glabellar tap, facial impassivity, bradykinesia,
tremors and postural instability, became apparent as
379
these patients improved and were able to mobilize
and walk. Reversible mutism was observed in 3
patients during the acute phase. Response to levodopa,
amantadine and trihexiphenedyl was partial. All 5
patients were followed for more than 1 year, during
which time the parkinsonian features recovered
substantially.
Peatfield (1987) described 2 patients with a chronic
non-progressive illness beginning with excessive slee-
piness and personality change. Both had an atypical
movement disorder, clearly distinct from PD, with
impairment of memory and learning and relative pre-
servation of arithmetical, language and visuospatial
tasks, suggesting parkinsonism with a subcortical
dementia. CT scans of the brain showed atrophy of
deep structures and elevated Coxsackievirus antibody
titers. The author speculated that insidious viral ence-
phalitis (perhaps these cases would previously have
been described as encephalitis lethargica) could lead
to subcortical dementia.
Calne and Lees (1988) performed a detailed retro-
spective analysis of 11 long-standing (greater than 40
years) inmates in a hospital with neurological deficits
due to encephalitis lethargica. Retrospective informa-
tion was gathered from physicians and nurses
records, photographs, published narrative and hospital
charts dating back as far as 1931. They concluded that
neurological disabilities attributable to basal ganglia
damage frequently increase in late life, with deteriora-
tion being most marked in motor function and largely
sparing the intellect, special senses and somatosensory
system.
Picard et al. (1996) described a patient who went on
to develop a severe parkinsonian syndrome a few years
after being diagnosed with an encephalitic syndrome
associated with a prolonged lethargic state in his
childhood. He presented with axial dystonia and
stereotyped abnormal movements of the upper limbs,
with normal brain imaging. Fluorodopa positron emis-
sion tomography (PET) showed a significant bilateral
reduction of tracer accumulation in both putamens,
similar to that observed in patients with idiopathic
PD, and treatment with levodopa suppressed akinetic,
dystonic and dyskinetic symptoms in this patient.
These symptoms appeared to be related to a limited
lesion of the dopaminergic neurons of the zona
compacta of the SN.
Ghaemi et al. (2000) reported another case of a
74-year-old woman who developed an akinetic-rigid
Parkinson syndrome with tremor, hypokinesia, hypo-
mimia, rigidity and cogwheel phenomenon in all four
extremities following viral encephalitis. The diagnosis
was supported by a reactive CSF assay and a positive
influenza A IgA antibody titer (1:>160). PET studies
380 V. DHAWAN AND K. R. CHAUDHURI
showed an altered pattern of glucose and dopa metabo-
lism, clearly distinguishing it from idiopathic Parkin-
son syndrome.
49.3.2.3. Clinical features
Litvan and colleagues (1998) reported results of a
retrospective clinicopathologic study to determine the
validity of the clinical diagnosis of PEP by presenting
105 records with neuropathologic diagnoses of PEP
(n 7), progressive supranuclear palsy (n 24), PD
(n 15), dementia with LBs (n 14), multiple system
atrophy (n 16), corticobasal degeneration (n 10),
CreutzfeldtJakob disease (CJD: n 4) and other
dementia disorders (n 15) as clinical vignettes to
six neurologists who were unaware of the autopsy
findings. The neurologists own clinical diagnoses,
when compared with neuropathologic diagnoses,
displayed high reliability, sensitivity and positive
predictive values for the clinical diagnosis of PEP.
According to their data set, the best predictors for the
diagnosis of PEP included:
1. Onset below middle age
2. Symptom duration lasting more than 10 years
3. Presence of oculogyric crisis
A relevant history of encephalitis lethargica, pre-
sent in most PEP cases, was an important individual
diagnostic predictor. Other reported features include:
1. Sleep disturbances
2. Excessive daytime sleepiness
However, as the reported case histories suggest,
there is a wide phenotypic variation in cases labelled
as PEP, ranging from a levodopa-responsive syndrome
with PET appearances of idiopathic PD to a syndrome
of parkinsonism with early dementia.
49.3.3. Nocardia asteroides
Nocardia is a genus of aerobic Gram-positive bacteria
which forms filamentous cells that fragment into rod-
shaped or coccoid elements or L-forms (see Fig. 49.1).
It is found in soil, stagnant water and farming areas.
The link between Nocardia infection and parkinson-
ism was suggested by Beaman, a leading worker in
this field based on work in animal models (see section
49.4, below). Kohbata and Shimokawa (1993) detected
antibodies to coccoid and rod-shaped cells of Nocardia
in the serum of patients with PD. The antibodies
were demonstrated in all the 20/20 patients with PD
at a titer greater than 1:10 and 10 out of 14 controls.
The results suggested that PD patients amid age-
matched healthy volunteers are routinely exposed to
and naturally infected with Nocardia-related microor-
ganisms and thus disputed the link of parkinsonism
with Nocardia.
Subsequently, Hubble et al. (1995) used a serodiag-
nostic panel to determine antibodies specific for
Nocardia in PD patients by comparing sera from
healthy volunteers and from patients with culture-
proven nocardiosis. No difference in seropositivity
was found when PD patients were compared with their
age- and gender-matched controls (n 140). The
results reveal a high exposure rate of humans to
nocardial antigens, especially among men and older
individuals, and do not confirm the hypothesis that
nocardiosis may cause PD or parkinsonism, although
the authors acknowledge that serological testing may
not be optimal for the detection of Nocardia-related
CNS infection (Hubble et al., 1995).
N. asteroides are composed of both filamentous and
filterable forms. In a further study, Kohbata et al.
(1998) investigated the presence of acid-fast spherical
structures similar to filterable Nocardia at the
midbrain nigral lesions of 3 patients with PD. Many
clusters of acid-fast lipochrome bodies were present
in the vicinity of melanin-pigmented neurons in the
3 PD patients studied and none were observed in 3
control patients. Examination of adjacent hematoxylin
and eosin-stained sections indicated that they consisted
of yellow-green granules, bodies and aggregates in
ballooned glial cells. However, the results do not
confirm or refute the proposed link between Nocardia
and Parkinsons disease, and they suggest that the
immunological and genetic relationship between the
acid-fast lipochrome bodies and filterable Nocardia
should be investigated. In another experiment with
the midbrain sections of PD patients and controls,
acid-fast stain and antifilterable Nocardia antiserum
were used and confirmed the presence of filterable
forms of N. asteroides in the midbrain nigral lesions
that occur with PD (Kohbata et al., 2002).
Recently LeWitt and colleagues (2004) reliably
verified that, in mica models, prior infection with
certain strains of N. asteroides or, possibly, other
neurotoxic microorganisms in the environment caused
neuronal degeneration and various levodopa-
responsive and persisting motor disorders resembling
parkinsonism. They postulated that this might be an
etiological basis for this or for other neurodegenerative
disorders.
49.3.4. Helicobactor pylori
Altschuler (1996) suggested that gastric Helicobacter
pylori infection might be a cause for both idiopathic
PD and non-arteritic anterior optic ischemic neuropa-
thy, given the higher prevalence of gastrointestinal
 INFECTIOUS BASIS TO THE PATHOGENESIS OF PARKINSONS DISEASE
ulcers in both these diseases than reported in age- and
sex-matched controls or in the general population.
Charlett et al. (1999) investigated the role of H. pylori
of PD and the issue of cross-infection in familial
aggregation by checking H. pylori seropositivity in
33 elderly subjects with idiopathic parkinsonism and
39 siblings and controls). They found that both parkin-
sonians and siblings differed from controls in the odds
of being H. pylori-seropositive (odds ratios 3.04 (95%
confidence interval: 1.22, 7.63) and 2.94 (1.26, 6.86)
respectively, P < 0.02); seropositivity was present in
0.70 of sufferers. Familial transmission of chronic
infection was linked with causality.
H. pylori is one of the commonest of known
bacterial infections linked with peptic ulcer/non-ulcer
dyspepsia, immunosuppression and autoimmunity.
Dobbs et al. (2000) challenged the conventional con-
cept of a role of a neurotoxin as an environmental
cause of idiopathic parkinsonism by suggesting that
H. pylori-related acquired immunosuppression, predis-
posing to autoimmunity, could serve as a model for
the pathogenesis of parkinsonism and eradication of
H. pylori has the potential to change the approach to
parkinsonism.
The theory remains controversial, and a study
conducted by Wlodarek et al. (2003) found no relation
between PD and H. pylori infection. Another issue is
that H. pylori infection positivity affects levodopa
pharmacokinetics in PD, through direct degradation
of the drug or changes of gastroduodenal environment
(Brusa et al., 2004).
49.3.5. EpsteinBarr virus
Woulfe et al. (2000) suggested cross-reactivity
between monoclonal antibodies against EBV and a-
synuclein in the human brain. a-Synuclein has been
reported to be a major component of LBs in PD, demen-
tia with LBs and common variants of Alzheimers
disease. However, in continuation of the study, similar
experiments in 2002 failed to demonstrate elevated
anti-a-synuclein and anti-EBV latent membrane protein
antibodies in PD, thus refuting the association between
the virus and PD (Woulfe et al., 2002).
49.3.6. Transmissible spongiform encephalopathy
(prion protein-related disorders)
There are reports of parkinsonism developing in the
context of CJD. A case of coexistent clinical findings
of idiopathic PD and CJD was described in 1985 and
confirmed at autopsy (Ezrin-Waters et al., 1985).
An unusual case of CJD was identified in 1998, in
Geneva, Switzerland (Vingerhoets et al., 1998), where
381
a patient with histopathologically verified sporadic CJD
presented initially with diplopia, sleep disturbances
and levodopa-responsive parkinsonism. Unusually, he
did not dement and initially failed to fulfill the clinical
criteria for possible CJD after more than a year of
slow progression. It was proposed that CJD should be
included in the differential diagnosis of parkinson
plus syndromes until a different etiology has been
found or a histopathologic examination performed.
Nitrini et al. (2001) presented the clinical features
of 12 patients from a family with CJD associated with
a point mutation at codon 183 of the prion protein
gene. The duration of the symptoms until death ranged
from 2 to 9 years. Nine patients were first seen by
psychiatrists for behavioral disturbances. Eight
patients manifested parkinsonian signs. The authors
concluded that these clinical features bear a consider-
able resemblance to those described in frontotemporal
dementia and parkinsonism linked to chromosome 17
(FTDP-17), not usually considered in the differential
diagnosis of prion diseases.
A Japanese case of sporadic CJD presenting as
progressive supranuclear palsy with slowly progressing
neurological deficits for 2 years after onset was reported
in 2003 (Shimamura et al., 2003). Needle biopsy
revealed deposition of prion protein of a patchy/
perivacuolar type with spongiform degeneration.
Of late, 2 further cases of CJD presenting with a
progressive supranuclear palsy-like syndrome and
autopsy confirmation have been reported from the
USA (Josephs et al., 2004).
49.3.7. Leprosy
In early 2003, an international team of scientists con-
ducted a genome scan in Vietnamese multiplex leprosy
families and found that susceptibility to leprosy was
significantly linked to region q25 on the long arm of
chromosome 6 (Buschman and Skamene, 2004). In a
continuation of these findings, the team has pinpointed
the chromosome 6 susceptibility locus to the 5 regula-
tory promoter region shared by both the PD gene
PARK2 and its co-regulated gene PACRG. The surpris-
ing discovery has important implications for the under-
standing of leprosy pathogenesis and for the strategy of
genetic analysis of infectious diseases.
49.4. Animal studies
Potential associations between PD or parkinsonism-
like disease and exposure to various infectious agents
have been demonstrated in some animal studies.
The development of a rhythmic, uncontrolled
vertical shake of the head (45/second), tremulous
382 V. DHAWAN AND K. R. CHAUDHURI
movement, stooped posture and restlessness in female
BALB/c mice (head shakes were temporarily stopped
by treatment with levodopa) following intravenous
injection of various doses of log-phase Nocardia aster-
oides GUH-2 has been reported (Kohbata and Beaman,
1991). Studies show localization and growth of nocar-
dial cells within the brains and loss of Nissl substance
and tyrosine hydroxylase immunoreactivity in the
neurons of SN. Therefore, the authors speculate that
mice infected with N. asteroides may serve as a model
for studying parkinsonian signs and other degenerative
diseases involving extrapyramidal and pyramidal
systems.
In another study, in vivo and in vitro models were
utilized to measure the ability of N. asteroides GUH-2,
a neuroinvasive strain, to induce the apoptotic death of
dopaminergic cells (Tam et al., 2002). Apoptosis has
been implicated in dopaminergic neuronal dropout in
Parkinsons patients, causing a levodopa-responsive
movement disorder resembling parkinsonism.
Following infection with GUH-2, dopaminergic apop-
totic cells were identified in the SN of animals by in situ
end-labeling, which detects DNA fragmentation, com-
bined with fluorescent immunolabeling of tyrosine
hydroxylase-positive cells.
Nocardia otitidiscaviarum (GAM-5), isolated from
a patient with an actinomycetoma, produced signs
similar to PD following a non-lethal dose of intrave-
nous injection into Naval Medical Research Institute
(NMRI) mice (Diaz-Corrales et al., 2004). Fourteen
days after bacterial infection, most of the 60 mice
injected exhibited parkinsonian features characterized
by vertical head tremor, akinesia/bradykinesia, flexed
posture and postural instability. Dopamine levels were
reduced from 110  32.5 to 58  16.5 ng/mg protein
(47.2% reduction) in brain from infected mice exhibit-
ing impaired movements, whereas serotonin levels
were unchanged (191  44 ng/mg protein in control
and 175  39 ng/mg protein in injected mice).
Chapman et al. (2003) developed an in situ hybridi-
zation technique to detect nocardial 16S ribosomal
RNA, using a Nocardia-specific probe (B77) in the
cerebral cortical specimens from cynomolgus monkeys
at 48 hours, 3.5 months and 1 year after experimental
infection with N. asteroides. This in situ hybridization
procedure, applied in a blinded fashion to human SN
specimens with LBs, detected similar reactivity in
inclusions with the appearance of LBs, suggesting a
possible association between Nocardia and neurode-
generative disorders in which LBs are present. In
2004 a German study measured levels of dopamine
and its metabolites, homovanillic acid and 3,4-
dihydroxyphenylacetic acid, in brains of uninfected
and simian immunodeficiency virus (SIV)-infected
rhesus monkeys during the asymptomatic stage of the
infection (Jenuwein et al., 2004). Changes in cyclic
adenosine monophosphate (cAMP) and cAMP
response element-binding protein (CREB), two factors
involved in the signaling pathway of dopamine, were
also investigated. The brain regions examined were
the nucleus accumbens and the corpus amygdaloi-
deum, which are limbic structures of the basal ganglia
that are involved in the pathophysiology of psychiatric
disorders and substance abuse. Dopamine content was
reduced in both regions, nucleus accumbens and the
corpus amygdaloideum (limbic structures of the basal
ganglia that are involved in the pathophysiology of
psychiatric disorders) of SIV-infected monkeys
compared to uninfected animals. Moreover, dopamine
deficits were associated with a decrease in the expres-
sion of total CREB. Changes in dopamine signaling
were not related to pathology or viral load of the
investigated animals.
49.5. Conclusion
The precise cause of PD remains unknown.
Environmental factors, with their possible effects on
genetic susceptibility, are possible causal mechanisms.
Infections may form part of the environmental insult
which may predispose to PD or parkinsonism.
However, the evidence is weak and largely based on
anecdotal reports. The most robust causative link of
PD/parkinsonism and infection is the emergence of
PEP, although the current rates of prevalence and
incidence of PD do not suggest a stray/infective
encephalopathic basis.
Acknowledgments
We acknowledge the contribution of the following
fourth-year medical students, Gillian Lapthorn and
Yolanda Sydney Augustin, who performed their study
modules based on the theme of this article at Guys,
Kings and St. Thomass School of Medicine, London,
UK.
References
Altschuler E (1996). Gastric Helicobacter pylori infection as
a cause of idiopathic Parkinson disease and non-arteric
anterior optic ischemic neuropathy. Med Hypotheses 47:
413414.
Ben-Shlomo Y (1997). The epidemiology of Parkinsons
disease. Baillieres Clin Neurol 6: 5568.
Berger JR, Moskowitz L, Fischl M et al. (1984). The neurologic
complications of AIDS: Frequently the initial manifestation.
Neurology 34: 134135.
 INFECTIOUS BASIS TO THE PATHOGENESIS OF PARKINSONS DISEASE
Bouffard JP, Mena H, Ripple M et al. (2003). Mesencepha-
lic cryptococcal abscesses presenting with parkinsonism
as an initial manifestation of AIDS. Mov Disord 18:
13541357.
Brusa L, Pietroiusti A, Pierantozzi M et al. (2004). Long
term effects of Helicobacter pylori eradication on L-
DOPA absorption in Parkinsons disease patients. Mov
Disord 19: S387S399.
Buschman E, Skamene E (2004). Linkage of leprosy suscept-
ibility to Parkinsons disease genes. Int J Lepr Other
Mycobact Dis 72: 169170.
Calne DB, Lees AJ (1988). Late progression of post-encephalitic
Parkinsons syndrome. Can J Neurol Sci 15: 135138.
Cardoso F (2002). HIV-related movement disorders: Epide-
miology, pathogenesis and management. CNS Drugs 16:
663668.
Carrazana E, Rossitch E Jr, Samuels MA (1989). Parkinso-
nian symptoms in a patient with AIDS and cerebral toxo-
plasmosis. J Neurol Neurosurg Psychiatry 52: 14451447.
Chapman G, Beaman BL, Loeffler DA et al. (2003). In situ
hybridization for detection of nocardial 16S rRNA: Reactiv-
ity within intracellular inclusions in experimentally infected
cynomolgus monkeysand in Lewy body-containing
human brain specimens. Exp Neurol 184: 715725.
Charlett A, Dobbs RJ, Dobbs SM et al. (1999). Parkinsonism:
Siblings share Helicobacter pylori seropositivity and
facets of syndrome. Acta Neurol Scand 99: 2635.
Chaudhuri KR, Hu MT, Brooks DJ (2000). Atypical parkin-
sonism in Afro-Caribbean and Indian immigrants to UK.
Mov Disord 15: 1823.
Chen S, Le WD, Xie WJ et al. (1998). Experimental destruc-
tion of substantia nigra initiated by Parkinson disease
immunoglobulins. Arch Neurol 55: 10751080.
Dale RC, Church AJ, Surtees RA et al. (2002). Re-emergence
of encephalitis lethargica-like syndrome: Evidence of
CNS autoimmunity. Mov Disord 17: S260.
De La Fuente-Aguado J, Bordon J, Moreno J et al. (1996).
Parkinsonism in an HIV-infected patient with hypodense
cerebral lesion. Tubercle Lung Dis 77: 191192.
De Mattos JP, De Rosso AL, Correa RB et al. (2002). Move-
ment disorders in 28 HIV-infected patients. Arq Neuropsi-
quiatr 60: 525530.
Diaz-Corrales FJ, Colasante C, Contreras Q et al. (2004).
Nocardia otitidiscaviarum (GAM-5) induces parkinso-
nian-like alterations in mouse. Braz J Med Biol Res 37:
539548.
Dobbs SM, Dobbs RJ, Weller C et al. (2000). Link between
Helicobacter pylori infection and idiopathic parkinsonism.
Med Hypotheses 55: 9398.
Duvoisin RC, Yahr MD, Schweitzer MD et al. (1963). Par-
kinsonism before and since the epidemic of encephalitis
lethargica. Arch Neurol 9: 232236.
Ezrin-Waters C, Resch L, Lang AE (1985). Coexistence of
idiopathic Parkinsons disease and Creutzfeldt-Jakob
disease. Can J Neurol Sci 12: 272273.
Fiszer U (2001). Does Parkinsons disease have an immuno-
logical basis? The evidence and its therapeutic implica-
tions. BioDrugs 15: 351355.
383
Ghaemi M, Rudolf J, Schmulling S et al. (2000). FDG- and
Dopa-PET in postencephalitic parkinsonism. J Neural
Transm 107: 12891295.
Giasson BI, Jakes R, Goedert M et al. (2000). A panel of epi-
tope-specific antibodies detects protein domains distribu-
ted throughout human alpha-synuclein in Lewy bodies of
Parkinsons disease. J Neurosci Res 59: 528533.
Hasegawa Y, Inagaki T, Sawada M et al. (2000). Impaired
cytokine production by peripheral blood mononuclear
cells and monocytes/macrophages in Parkinsons disease.
Acta Neurol Scand 101: 159164.
Hersh BP, Rajendran PR, Battinelli D (2001). Parkinsonism
as the presenting manifestation of HIV infection: Improve-
ment on HAART. Neurology 56: 278279.
Hisanaga K, Asagi M, Itoyama Y et al. (2001). Increase in
peripheral CD4 bright CD8 dull T cells in Parkinson
disease. Arch Neurol 58: 15801583.
Hubble JP, Cao T, Kjelstrom JA et al. (1995). Nocardia
species as an etiologic agent in Parkinsons disease:
Serological testing in a case-control study. J Clin Microbiol
33: 27682769.
Hunot S, Dugas N, Faucheux B et al. (1999). FcepsilonRII/
CD23 is expressed in Parkinsons disease and induces,
in vitro, production of nitric oxide and tumor necrosis
factor-alpha in glial cells. J Neurosci 19: 34403447.
Jenuwein M, Scheller C, Neuen-Jacob E et al. (2004).
Dopamine deficits and regulation of the cAMP second
messenger system in brains of simian immunodeficiency
virus-infected rhesus monkeys. J Neurovirol 10: 163170.
Josephs KA, Tsuboi Y, Dickson DW (2004). Creutzfeldt-
Jakob disease presenting as progressive supranuclear
palsy. Eur J Neurol 11: 343346.
Kohbata S, Beaman BL (1991). L-dopa-responsive move-
ment disorder caused by Nocardia asteroides localized in
the brains of mice. Infect Immun 59: 181191.
Kohbata S, Shimokawa K (1993). Circulating antibody to
Nocardia in the serum of patients with Parkinsons
disease. Adv Neurol 60: 355357.
Kohbata S, Tamura T, Hayashi R (1998). Accumulation of
acid-fast lipochrome bodies in glial cells of the midbrain
nigral lesion in Parkinsons disease. Clin Diagn Lab
Immunol 5: 888893.
Kohbata S, Hayashi R, Tamura T (2002). An infection with
filterable forms of Nocardia asteroides in the midbrain
nigral lesion in Parkinsons disease. Mov Disord 17: S62.
Lai BC, Marion SA, Teschke K et al. (2002). Occupational
and environmental risk factors for Parkinsons disease.
Parkinsonism Relat Disord 8: 297309.
LeWitt PA, Beaman BL, Camp DM et al. (2004). Nocardia
asteroides: A possible environmental cause of Parkinsons
disease? Mov Disord 19: S222.
Linda H, Hammarberg H, Piehl F et al. (1999). Expression of
MHC class I heavy chain and beta2-microglobulin in rat
brainstem motoneurons and nigral dopaminergic neurons.
J Neuroimmunol 101: 7686.
Litvan II, Jankovic J, Goetz CG et al. (1998). Accuracy of
the clinical diagnosis of postencephalitic parkinsonism:
A clinicopathologic study. Eur J Neurol 5: 451457.
384 V. DHAWAN AND K. R. CHAUDHURI
Maggi P, De Mari M, Moramarco A et al. (2000). Parkinson-
ism in a patient with AIDS and cerebral opportunistic
granulomatous lesions. Neurol Sci 21: 173176.
Martyn CN (1997). Infection in childhood and neurological
diseases in adult life. Br Med Bull 53: 2439.
Mirsattari SM, Power C, Nath A (1998). Parkinsonism with
HIV infection. Mov Disord 13: 684689.
Nath A, Jankovic J, Pettigrew LC (1987). Movement
disorders and AIDS. Neurology 37: 3741.
Nitrini R, Teixeira da Silva LS, Rosemberg S et al. (2001).
Prion disease resembling frontotemporal dementia and
parkinsonism linked to chromosome 17. Arq Neuropsi-
quiatr 59: 161164.
Peatfield RC (1987). Basal ganglia damage and subcortical
dementia after possible insidious Coxsackie virus ence-
phalitis. Acta Neurol Scand 76: 340345.
Picard F, de Saint-Martin A, Salmon E et al. (1996). Post-
encephalitic stereotyped involuntary movements respon-
sive to L-Dopa. Mov Disord 11: 567570.
Poskanzer DC, Schwab RS (1963). Cohort analysis of
Parkinsons disease: Evidence for a single etiology related
to subclinical infection about 1920. J Chronic Dis 16:
961973.
Pradhan S, Pandey N, Shashank S et al. (1999). Parkinsonism
due to predominant involvement of substantia nigra in
Japanese encephalitis. Neurology 53: 17811786.
Richards M, Chaudhuri KR (1996). Parkinsons disease in
populations of African origin. Neuroepidemiology 15:
214221.
Salman H, Bergman M, Djaldetti R et al. (1999). Decreased
phagocytic function in patients with Parkinsons disease.
Biomed Pharmacother 53: 146148.
Shimamura M, Uyama E, Hirano T et al. (2003). A unique
case of sporadic Creutzfeldt-Jacob disease presenting as
progressive supranuclear palsy. Intern Med 42: 195198.
Stoessl AJ (1999). Etiology of Parkinsons disease. Can J
Neurol Sci 26 (Suppl 2), S5S12.
Tam S, Barry DP, Beaman L et al. (2002). Neuroinvasive
Nocardia asteroides GUH-2 induces apoptosis in the sub-
stantia nigra in vivo and dopaminergic cells in vitro. Exp
Neurol 177: 453460.
Tolge CF, Factor SA (1991). Focal dystonia secondary to
cerebral toxoplasmosis in a patient with acquired immue
deficiency syndrome. Mov disord 6: 6972.
Tse W, Cersosimo M, Gracies J et al. (2004). Movement dis-
orders and AIDS: A review. Parkinsonism Relat Disord
10: 323334.
Vingerhoets FJ, Hegyi I, Aguzzi A et al. (1998). An unusual
case of Creutzfeldt-Jakob disease. Neurology 51: 617619.
Werring DJ, Chaudhuri KR (1996). Human Immunodefi-
ciency virus-related progressive multifocal leukoencepha-
lopathy presenting with an akinetic rigid syndrome. Mov
Disord 11: 758761.
Wlodarek D, Pakszys W, Bujko J (2003). Helicobacter
pylori infection and its influence on Parkinsons disease.
Pol Merkuriusz Lek 15: 428431.
Woulfe J, Hoogendoorn H, Tarnopolsky M et al. (2000).
Monoclonal antibodies against Epstein-Barr virus cross-
react with alpha-synuclein in human brain. Neurology
55: 13981401.
Woulfe JM, Duke R, Middeldorp JM et al. (2002). Absence
of elevated anti-alpha-synuclein and anti-EBV latent
membrane protein antibodies in PD. Neurology 58:
14351436.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 50

Toxic causes of parkinsonism

NIRIT LEV*, ELDAD MELAMED AND DANIEL OFFEN

Laboratory of Neuroscience and Department of Neurology, Rabin Medical Center,

Petah-Tikva, Tel Aviv University, Tel Aviv, Israel

50.1. Introduction unwanted proteins leading to the accumulation and

Parkinsons disease (PD) is the most common neurode-
generative movement disorder, affecting 1% of the
population over 65 years of age. Clinically, most
patients present with a motor disorder and suffer from
bradykinesia, resting tremor, rigidity and postural
instability. Other manifestations include behavioral,
cognitive and autonomic disturbances. Pathologically,
PD is characterized by a progressive loss of dopaminer-
gic neurons in the substantia nigra pars compacta. How-
ever, PD is a widespread neurodegenerative disease,
which affects multiple areas in the central as well as
the peripheral nervous systems. The pathologic hall-
mark of PD is the appearance of cytoplasmic inclusions,
named Lewy bodies. Lewy bodies contain a heteroge-
neous mixture of insoluble, filamentous proteins and
lipids, including a-synuclein, ubiquitin, neurofilaments
and oxidized/nitrated proteins (Betarbet et al., 2002).
Nigral pathology in parkinsonian patients has been
shown to be associated with oxidative stress, mito-
chondrial dysfunction, excitotoxicity and inflamma-
tion. Oxidative stress-related changes, including
oxidative damage to proteins, lipids and DNA, as well
as decreased levels of reduced glutathione, have been
detected in PD brains (Jenner, 1998; Sherer et al.,
2003). Reactive oxygen species (ROS) are generated
during dopamine metabolism and by mitochondrial
respiration (Bahat-Stroomza et al., 2005). Within com-
plex I there is a site of electron leakage that produces
ROS (Kushnareva et al., 2002) and impaired complex
I activity enhances ROS formation (Betarbet et al.,
2002; Kushnareva et al., 2002). Failure of another sys-
tem, the ubiquitin-proteasome system (UPS), to clear
aggregation of cytotoxic proteins, has recently been
shown to play a major role in the pathogenesis of both
familial and sporadic forms of PD (McNaught et al.,
2002; Elkon et al., 2004).
PD is a multifactorial disease caused by both genetic
and environmental factors. However, most PD patients
suffer from a sporadic disease. The etiology of sporadic
PD is largely unknown and epidemiological studies
are conducted in order to define factors increasing the
risk for developing PD. Factors that may predispose
to dopaminergic cell loss, including mitochondrial
dysfunction and oxidative damage, could be common
to separate genetic and environmental etiologies.
Several studies were conducted in order to assess
the influence of hereditary factors of PD by studying
monozygotic (MZ) and dizygotic (DZ) twin pairs.
These studies, relying on [18F]-dopa positron emission
tomography (PET) findings, did find higher concor-
dance for subclinical striatal dopaminergic dysfunction
in twins (Burn et al., 1992; Holthoff et al., 1994;
Piccini et al., 1999; Laihinen et al., 2000). However,
several large studies based on clinical evaluation of
PD found low concordance rates for twins, emphasizing
environmental factors as the major risk factors for PD
(Duvoisin et al., 1981; Ward et al., 1983; Marttila
et al., 1988; Vieregge et al., 1992, 1999; Tanner et al.,
1999; Wirdefeldt et al., 2004, 2005). These findings
indicate that genetic factors do not play a major role
in causing typical PD (when the disease begins after
the age of 50 years).
The search for environmental risk factors for PD
revealed several risk factors as well as protective fac-
tors associated with PD. An inverse association

*Correspondence to: Dr. Nirit Lev, Laboratory of Neuroscience and Department of Neurology, Rabin Medical Center,
Petah-Tikva 49100, Israel. E-mail: lev.nirit@gmail.com, Tel: 972-3-937-6276, Fax: 972-3-937-6277.
386 N. LEV ET AL.
between smoking and PD was reported in many
studies (Grandinetti et al., 1994; Hernan et al., 2001;
Wirdefeldt et al., 2005). Nevertheless, the presence
of a confounder has not been ruled out. A recent study
found an increased risk for PD with several occupa-
tions: farming, health care and teaching (Goldman
et al., 2005). There is a growing body of evidence
implicating rural living, consumption of well water,
farming and pesticide exposure as environmental risk
factors for PD (Liou et al., 1997; Priyadarshi et al.,
2001). A meta-analysis of 22 epidemiologic studies
done by Priyadarshi et al. (2001) found that the odds
ratio (OR) for rural living is 1.56 (95% confidence
interval (CI) 1.172.07) and that the highest risk was
4.9 (95% CI 1.418.2) for living in a rural area for
more than 40 years. Exposure to well water and the risk
of contracting PD yielded a combined OR of 1.26 (95%
CI 0.961.64), increasing to 3.28 (95% CI 0.9311.51)
for exposure to well water for at least 1 year (Priyadarshi
et al., 2001). Farming was also associated with an
increased risk of getting PD, with combined OR of
1.42 (95% CI 1.051.91), (OR 5.2, 95% CI 1.617.7,
for farming over 20 years) (Priyadarshi et al., 2001).
The association of rural living, farming and well-water
drinking with PD may be related to exposure to potential
neurotoxins present in these areas, such as pesticides.
In contrast, Tanner et al. (1989) found that in China, liv-
ing in a village was associated with a decreased risk for
PD, whereas occupational or residential exposure to
industrial chemicals, printing plants or quarries was
associated with an increased risk of developing PD.
These findings are consistent with the hypothesis that
environmental exposure to certain agricultural or indus-
trial chemicals may be related to the development of PD.
The concept of silent neurotoxicity suggests that a
developmental exposure to a toxin may significantly
increase the vulnerability of the dopaminergic system,
which is unmasked by later challenges to the dopamine
system (Thiruchelvam et al., 2002; Uversky, 2004;
Cory-Slechta et al., 2005). Exposure to pesticides dur-
ing the postnatal period can produce permanent and
progressive lesions of the nigrostriatal dopamine sys-
tem and enhanced adult susceptibility to these pesti-
cides. Inflammation of the brain in early life caused by
exposure to infectious agents, toxicants or environmen-
tal factors has been suggested as a possible cause or con-
tributor to the later development of PD (Liu et al.,
2003). The inflammatory process in such cases may
involve activation of brain immune cells (microglia
and astrocytes), which release inflammatory and neuro-
toxic factors that in turn produce neurodegeneration
(Liu and Hong, 2003).
The finding of toxic causes of PD had a tremendous
importance on the scientific study of PD since it
helped develop animal models for this disease. The
two most common, classic animal models of PD rely
on toxic-induced parkinsonism induced by 1-methyl-
4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and
6-hydroxydopamine (6-OHDA) (Schober, 2004).
Other animal models were generated following the dis-
covery that agricultural chemicals, such as rotenone,
maneb and paraquat, when administered systemically,
can also induce specific features of PD (Betarbet
et al., 2002). In this chapter, we describe the current
knowledge of PD induced by neurotoxic compounds.
50.2. Agricultural chemicals
Several clinical and epidemiologic studies have
demonstrated that exposures to certain chemicals are
associated with increased incidence of PD (Landrigan
et al., 2005). Exposure to pesticides yielded an
increased risk for getting PD with combined OR of
1.85 (95% CI 1.312.60), with exposure for over 10
years increasing the risk to 5.81 (95% CI 1.9916.97)
(Priyadarshi et al., 2001). Baldi et al. (2003) found
an association between past occupational exposure to
pesticides, low cognitive performance and an
increased risk of developing PD. Levels of organo-
chlorines have been found to be elevated in the brains
of persons with PD (Fleming et al., 1994; Corrigan
et al., 2000). Epidemiologic data suggest a positive
doseresponse relationship between lifetime cumulative
exposure to paraquat and risk of PD (Liou et al., 1997).
50.2.1. Rotenone
Rotenone (Fig. 50.1A) is a natural compound, used as
an insecticide and a herbicide. Rotenone is a naturally
occurring complex ketone, derived from the roots of
Lonchocarpus species (Uversky, 2004). It is a com-
monly used pesticide and is also used in lakes and reser-
voirs to kill fish that are perceived as pests. Gardeners
commonly use it as the active ingredient of derris dust
or liquid preparations of derris, described as natural
herbicide, which are commonly found on the shelves
of garden centers (Jenner, 2001). Rotenone is a highly
lipophilic compound and readily crosses the blood
brain barrier (Betarbet et al., 2002; Uversky, 2004).
Rotenone is a highly selective inhibitor of complex
I of the mitochondrial respiratory chain (Sherer et al.,
2003). Sherer et al. (2003) demonstrated that rotenone
toxicity involved an oxidative mechanism. In neuro-
blastoma cells and a chronic midbrain slice model,
rotenone toxicity depended on an interaction with
complex I and was attenuated by antioxidants, sug-
gesting a causal role for oxidative damage. Rotenone
 TOXIC CAUSES OF PARKINSONISM
H2C
O O
O H3C+N
O O
CH3 O
CH3
A B
N H2
H C
HS C N
H2
HS Mn S
H H2
N C SH
S2C C N
H2 H
C D
Fig. 50.1. Pesticides and herbicides: chemical structure of (A) rotenone, (B) paraquat, (C) maneb and (D) atrazine.
toxicity depended on a direct interaction with complex I,
because cells expressing the rotenone-insensitive, sin-
gle-subunit NADH dehydrogenase of yeast, NDI1,
were resistant to rotenone toxicity. In this system,
electrons from complex I substrates are shunted
through NDI1 into downstream portions of the elec-
tron transport chain, thereby allowing mitochondrial
respiration. Rotenone toxicity does not result solely
from a bioenergetic defect since brain levels of rote-
none after chronic exposure are not sufficient to alter
mitochondrial respiration in isolated brain mitochon-
dria (Betarbet et al., 2000). In addition, Sherer et al.
(2003) found that similar adenosine triphosphate
depletion induced by 2-deoxyglucose was not toxic as
rotenone exposure. Panov et al. (2005) recently demon-
strated that it is not the primary inhibitory effect of rote-
none on the electron transport activity of complex I,
but the resulting secondary mechanism, increased
superoxide radical production, that is responsible
for the development of further structural and func-
tional damages to the mitochondria. They also found
that in vivo rotenone toxicity results in a substantial
loss of activity not only of complex I, but also of
complex II, probably mediated by ROS (Panov
et al., 2005).
The animal model induced by chronic systemic
rotenone administration includes clinical and patholo-
gic features similar to those of human PD, including
selective chronic and progressive degeneration of the
nigrostriatal system and the formation of inclusion
387
CH3
N+CH3
Cr Cr
NHC2H5
N
CS2 Cl N
H N CH3
NHCH
CH3
bodies similar to Lewy bodies (Betarbet et al., 2002).
It also induces oxidative stress and mitochondrial
complex I inhibition, found in human patients (Betarbet
et al., 2000, 2002; Liu et al., 2003; Sherer et al., 2003).
Rotenone infusion by osmotic pumps can induce a
chronically progressive degeneration of dopaminergic
and of some non-dopaminergic neurons in both the
basal ganglia and the brainstem (Hirsch et al., 2003).
Behaviorally, rotenone induces hypokinesia, flexed
posture and, in some rats, rigidity and paw shaking,
clinical findings that are similar to PD (Betarbet et al.,
2002).
The rotenone-induced degeneration of dopaminergic
neurons may not be solely attributable to an impairment
of neuronal mitochondrial complex I activity but may
also involve the activation of microglia (Gao et al.,
2002, 2003b). In vitro, rotenone-induced microglial
activation occurs before apparent neurodegeneration
(Gao et al., 2002). Activated microglia upregulate
cell surface markers such as the macrophage antigen
complex I and produce a variety of proinflammatory
cytokines, leading to ROS production. Synergistic
dopaminergic neurotoxicity was found with combined
exposure to rotenone and the inflammogen lipopolysac-
charide (Gao et al., 2003a).
Therefore, the rotenone-induced animal model
for PD recapitulates most of the pathological and clin-
ical features of PD, as well as central pathophysio-
logical mechanisms of the disease, strengthening the
environmental hypothesis of PD.
388 N. LEV ET AL.
50.2.2. Paraquat
An etiologic link has been suggested between PD
and the herbicide paraquat (1,10 -dimethyl-4,40 -bipyri-
dinium) (Fig. 50.1B) (Brooks, 1999; McCormack
et al., 2002). Paraquat is structurally similar to 1-
methyl-4-phenylpyridinium ion (MPP), the active
metabolite of MPTP (Uversky, 2004). The major neu-
rotoxic effect of paraquat is through the production of
ROS (Uversky, 2004).
Paraquat crosses the bloodbrain barrier slowly,
inefficiently and to a limited extent. However, detect-
able levels of the herbicide have been measured in the
central nervous system after its systemic injection into
rodents (Corasaniti et al., 1998). In experimental studies
in which paraquat has been administered to animals,
researchers have observed loss of substantia nigra dopa-
minergic neurons, depletion of dopamine, reduced
ambulatory activity and apoptotic cell death (Liu and
Hong, 2003; Liu et al., 2003). Subchronic exposure to
paraquat causes a dose-dependent decrease in substantia
nigra dopaminergic neurons, some decrease in striatal
dopamine nerve terminal density and also induces neu-
robehavioral syndrome characterized by reduced ambu-
latory activity (Brooks et al., 1999; Di Monte, 2001).
The exposure of mice to paraquat leads to a significant
increase in brain levels of a-synuclein and accumula-
tion of a-synuclein-containing inclusions within neu-
rons of the substantia nigra pars compacta, similar to
Lewy bodies (Manning-Bog et al., 2002).
50.2.3. Maneb
The organomanganese fungicide maneb (Fig. 50.1C),
which is largely used in agricultural regions for the
control of field crop pathologies, has been implicated
in PD. Maneb contains a major active fungicidal com-
ponent, manganese ethylene-bis-dithiocarbamate (Mn-
EBDC) and belongs to the dithiocarbamate fungicide
family. Permanent parkinsonism has been reported in
a man with chronic exposure to maneb (Meco et al.,
1994). Administration of maneb to experimental ani-
mal models has a depressant-like effect on the central
nervous system, involving the dopaminergic systems
(Uversky, 2004). In animal studies, early-life exposure
to a combination of paraquat and maneb produced
destructive effects on the nigrostriatal dopaminergic
system and abnormalities in motor response that were
more severe than those produced by either agent alone
(Thiruchelvam et al., 2000). These effects were esca-
lated by aging (McCormack et al., 2002; Thiruchelvam
et al., 2003). Exposure to maneb was also reported to
enhance MPTP uptake and to amplify its neurotoxicity
(Uversky, 2004).
50.2.4. Atrazine
Atrazine (2-chloro-4-ethylamino-6-isopropylamino-S-
triazine) (Fig. 50.1D), a chlorinated member of the
family of S-substituted triazines, is one of the most
widely employed herbicides in the world. It acts to
suppress photosynthesis by inhibiting electron trans-
fer at the reducing site of chloroplast complex II
(Rodriguez et al., 2005). Although it has limited solu-
bility in water, atrazine is frequently detected in
ground and surface waters in agricultural regions
(Rodriguez et al., 2005).
Rodriguez et al. (2005) demonstrated that sustained
low-level atrazine exposure in the diet can adversely
affect dopaminergic tracts of the central nervous sys-
tem, resulting in persistent increases in locomotor
activity, alterations in responsivity to the indirect
dopamine agonist amphetamine, changes in monoamine
levels and loss of neurons in the midbrain. Chronic atra-
zine exposure caused cell loss of both tyrosine hydr-
oxylase (TH)-immunoreactive cells and TH-negative
cells in the ventral tegmental area and substantia nigra
(Rodriguez et al., 2005).
50.2.5. Organochlorine compounds
High levels of organochlorine compounds in the substan-
tia nigra of PD brains were found, as compared to the
levels in cortical Lewy body dementia, Alzheimers
disease and non-demented non-parkinsonian controls
(Corrigan et al., 2000). The levels of the gamma iso-
mer of hexachlorocyclohexane (gamma-HCH, lindane;
Fig. 50.2A) were significantly higher in PD tissues
than in the other three groups (P < 0 .05). Dieldrin
(HEOD) was higher in PD brain than in Alzheimers dis-
ease or control brain, whereas 1,10 -(2,2-dichloroethenyl
diene)-bis(4-chlorobenzene) ( p, p-DDE; Fig. 50.2B) and
total Aroclor-matched polychlorinated biphenyls were
Cl
Cl
Cl Cl
Cl
Cl Cl
Cl
Cl Cl
A B
Fig. 50.2. Organochlorine compounds: chemical structure of
(A) gamma-hexachlorocyclohexane (lindane) and (B) 1,10 -
(2,2-dichloroethenyl diene)-bis(4-chlorobenzene ( p,p-DDE).
 TOXIC CAUSES OF PARKINSONISM
higher in PD compared with cortical Lewy body
dementia. Bhatt et al. (1999) described 5 patients who
developed acute reversible parkinsonism following
organophosphate pesticide exposure. Three of these
patients were family-related, therefore a genetic sus-
ceptibility to organochlorine pesticide-induced parkin-
sonism may account for susceptibility for developing
this syndrome.
These findings support the hypothesis derived from
epidemiological work and animal studies that organo-
chlorine insecticides produce a direct toxic action on
the dopaminergic tracts of the substantia nigra and
may contribute to the development of PD.
50.3. Metals
The possible involvement of heavy metals in the etiol-
ogy of PD follows primarily from the results of epide-
miological studies. In particular, exposure to
manganese, copper, lead, iron, mercury, zinc and alu-
minum appears to be a risk factor for PD (Uversky
et al., 2001). Long-term occupational exposure to cop-
per and manganese individually, as well as to dual
combinations of lead, copper and iron, were found to
indicate a significant risk for PD (Gorell et al., 1997,
1999, 2004). Analysis of the PD mortality rates in
Michigan (19861988) with respect to potential
heavy-metal exposure revealed that counties with an
industry in the paper, chemicals, iron or copper-related
categories had significantly higher PD death rates than
counties without these industries (Rybicki et al.,
1993). Another epidemiological study established an
increased risk for PD with occupational exposure to
manganese, iron and aluminum, especially when the
duration of exposure is longer than 30 years (Zayed
et al., 1990).
Quantifications of aluminum, calcium, copper, iron,
magnesium, manganese, silicon and zinc were per-
formed in urine, serum, blood and cerebrospinal fluid
(CSF) of 26 PD patients (Forte et al., 2004). The
results indicate the involvement of iron and zinc
(increased concentration in blood) as well as of copper
(decreased serum level) in PD (Forte et al., 2004).
Postmortem analysis of brain tissues from patients
with PD revealed an increase in total iron and zinc
content of the parkinsonian substantia nigra, whereas
copper levels were reduced and manganese levels were
unchanged (Dexter et al., 1991, 1992). Moreover, sev-
eral di- and trivalent metal ions caused significant
acceleration in the rate of a-synuclein fibril formation
(Uversky et al., 2001). Aluminum was the most effec-
tive, along with copper, iron, cobalt and manganese.
The effectiveness correlated with increasing ion
charge density (Uversky et al., 2001).
389
50.3.1. Iron
A central role of iron in the pathogenesis of PD, due to
its increased levels in substantia nigra pars compacta
dopaminergic neurons (Dexter et al., 1991, 1992; Double
et al., 2000) and reactive microglia and its capacity
to enhance production of ROS, has been discussed for
many years. Moreover, analysis of Lewy bodies in the
parkinsonian substantia nigra revealed high levels of iron
and the presence of aluminum (Hirsch et al., 1991).
Besides the accumulation of iron in the substantia
nigra of PD brains, derangements in iron metabolism
were identified. The substantia nigra of the PD brain
is characterized by a shift in the Fe2/Fe3 ratio
in favor of Fe3 (Berg et al., 2001). Furthermore,
mutated iron metabolism genes have now been shown
to be involved in neurodegeneration (Felletschin et al.,
2003; Grunblatt et al., 2004). The observations of the
ability of iron to induce aggregation and toxicity of
a-synuclein have reinforced the critical role of iron
in the pathogenesis of nigrostriatal injury (Berg et al.,
2001). Thus, iron redox state constitutes a pivotal fac-
tor contributing to the extent of protein misfolding and
aggregation in the substantia nigra of PD patients.
Unilateral injection of FeCl3 into the substantia nigra
of adult rats resulted in a substantial selective decrease
of striatal dopamine (95%) (Ben-Shachar and Youdim,
1991). Dopamine-related behavioral responses, such as
spontaneous movements in a novel space and rearing, were
significantly impaired, whereas amphetamine administra-
tion induced ipsilateral rotation in the iron-treated rats
(Ben-Shachar and Youdim, 1991). Wesemann et al.
(1994) found that intranigral-injected iron progressively
reduces striatal dopamine metabolism.
Neuromelanin has the ability to bind a variety of
metals and up to 20% of the total iron contained in
the substantia nigra from normal subjects is bound
within neuromelanin. Increased tissue iron found
in the parkinsonian substantia nigra may saturate
iron-chelating sites on neuromelanin (Gerlach et al.,
2003). It is hypothesized that this redox-active iron
could be released and involved in a Fenton-like reac-
tion, leading to an increased production of oxidative
radicals. The resultant radical-mediated cytotoxicity
may contribute to cellular damage observed in PD.
These studies indicate that the nigrostriatal dopaminer-
gic neurons are susceptible to the presence of ionic
iron and support the assumption that iron causes
dopaminergic neurodegeneration in PD.
50.3.2. Manganese
Manganese, an essential trace element, is one of the
most used metals in the industry. It is employed in
390 N. LEV ET AL.
the manufacture of steel and batteries, in water purifi-
cation, in bactericidal and fungicide agents and as an
antiknock agent in gasoline. Recently, several new man-
ganese compounds have been introduced as fungicide, as
antiknock agent in petrol (Mn tricarbonyl, MMT) and as
contrasting agent in nuclear magnetic resonance tomo-
graphy (MnDPDP) (Gerber et al., 2002). Manganese is
relatively non-toxic to the adult organism, except to the
brain, where it causes Parkinson-like symptoms when it
is chronically inhaled, even at moderate amounts (Gerber
et al., 2002). Manganism was reported in manganese
miners (Mergler and Baldwin, 1997). Hudnell (1999)
found that the risk of a Parkinson-like syndrome diag-
nosis is increased with continued manganese exposure
and aging. Chronic exposure to high levels of this metal
causes accumulation in the basal ganglia, resulting
in manganism, characterized by tremors, rigidity and
psychosis.
A cohort of patients who worked in a manganese-
smelting plant in Taiwan developed parkinsonism that
was almost certainly due to manganese intoxication. Six
of 13 individuals chronically exposed to a very high
ambient concentration of manganese developed basal
ganglia syndrome, characterized by gait dysfunction,
with particular difficulty walking backwards, bradyki-
nesia, micrographia and hypophonia (Olanow, 2004).
Some of the patients also had dystonia and intermittent
tremor (Olanow, 2004). Patients with manganese-
induced parkinsonism were reported to have a normal
striatal fluorodopa uptake on PET (Olanow, 2004).
However, a recent study reported decreased putamenal
fluorodopa uptake on PET (Racette et al., 2005). Dopa-
mine transporter (DAT) scan showed a slight decrease
in the putamen of manganism patients as compared
with that of the normal controls. It seems, then, that
the presynaptic dopaminergic terminals are not the main
targets of chronic manganese intoxication (Huang et al.,
2003).
Exposure of dopaminergic cells to an organic form
of manganese compound, methylcyclopentadienyl man-
ganese tricarbonyl (MMT), resulted in a rapid increase
in the generation of ROS, followed by the release
of mitochondrial cytochrome c into the cytoplasm and
N CH3
A B
Fig. 50.3. Chemical structure of (A) 1-methyl-4-phenylpyridinium ion (MPP) and (B) 6-hydroxydopmaine.
subsequent activation of caspase-9 and caspase-3. Cas-
pase-3-dependent proteolytic activation of protein
kinase C (PKC) delta was demonstrated to play a role
in oxidative stress-mediated apoptosis in dopaminergic
cells after exposure to manganese (Anantharam et al.,
2002).
50.3.3. Copper
Copper(II) was found to be the most effective metal
ion affecting a-synuclein to form oligomers (Paik
et al., 1999). Copper was recently found to promote
a-synuclein aggregation at physiologically relevant
concentrations by binding to the N-terminus (for
which copper has the highest affinity) (Rasia et al.,
2005).
These findings support the notion of PD as a metal-
associated neurodegenerative disorder.
50.4. MPTP
In 1982 severe Parkinson-like symptoms were described
among a group of drug users in northern California who
had taken synthetic heroin contaminated with MPTP
(Fig. 50.3A) (Davis et al., 1979; Langston et al., 1983,
1999; Ballard et al., 1985). Exposure to MPTP produced
bradykinesia and rigidity almost identical to those of
idiopathic PD and severe loss of dopaminergic neurons
in the substantia nigra (Davis et al., 1979; Langston
et al., 1999). These patients responded to treatment with
levodopa or bromocriptine, but rapidly developed treat-
ment-related complications, including fluctuations and
dyskinesias (Ballard et al., 1985; Langston et al.,
1999). In some patients, MPTP-induced PD appeared
almost immediately after exposure, whereas in others,
onset became evident only months or years later,
reflecting a progressive neurodegenerative process.
MPTP was shown to act selectively, specifically in-
juring dopaminergic neurons in the nigrostriatal system
in humans as well as in experimental animals (Langston
et al., 1999). Evidence was also found for ongoing
dopaminergic nerve cell loss without Lewy body forma-
tion in these patients (Langston et al., 1999). Many years
NH2
HO
OH
OH
 TOXIC CAUSES OF PARKINSONISM
later, postmortem examination of brains from persons
exposed to MPTP showed a marked microglial prolif-
eration in the substantia nigra pars compacta (Orr
et al., 2002).
MPTP is highly lipophilic and after systemic
administration rapidly crosses the bloodbrain barrier.
Subsequently, the protoxin MPTP is converted to
1-methyl-4-phenyl-2,3-dihydropyridium (MPDP) exclu-
sively in non-dopaminergic cells (especially in astrocytes
and serotonergic neurons) by monoamine oxidase B
(MAO-B) and then spontaneously oxidizes to MPP
and is released into the extracellular space (Nicklas
et al., 1987; Przedborski et al., 2001; Przedborski and
Vila, 2003). MPP enters the dopaminergic neurons
through DAT, as well as via the norepinephrine and ser-
otonin transporters (Javitch et al. 1985; Mayer et al.,
1986). Inside dopaminergic neurons, MPP can bind
to the vesicular monoamine transporter, which is asso-
ciated with an incorporation of MPP into synaptic vesi-
cles containing dopamine (Del Zompo et al., 1993).
In addition, MPP can accumulate within mitochondria,
where it inhibits complex I (Nicklas et al., 1987; Mizuno
et al., 1987), or it can remain inside the cytoplasm and
interact with cytosolic enzymes (Klaidman et al.,
1993). Since MPP is selectively taken up into dopami-
nergic neurons through the DAT and acts as a potent
inhibitor of mitochondrial complex I, it selectively poi-
sons the dopaminergic neurons. Surprisingly, Smeyne
et al. (2005) found that the susceptibility of substantia
nigra dopaminergic neurons to MPTP was inversely
related to the number of astrocytes. They also found that
Swiss Webster (MPTP-resistant) mice have a greater
number of astrocytes and a lower number of microglia
than C57Bl/6J (MPTP-sensitive) mice. Astrocytes
appear to provide protection to neurons against ROS-
mediated toxicity by multidimensional mechanisms
involving glutathione, phase II detoxifying enzymes
and neuronal growth factors (Smeyne et al., 2005).
One of the major implications of the discovery of
MPTP was the production of an effective experimental
model of PD by systemic toxin administration (Jenner,
2003). When injected into mice, MPTP causes a PD-
like syndrome with massive loss of nigral dopaminer-
gic neurons and striatal dopamine. MPTP injections
do not induce neuronal inclusions characteristic of
PD even after repeated injections (Vila et al., 2000).
Fornai et al. (2005) have recently developed a mouse
PD model that is based on continuous MPTP administra-
tion with an osmotic minipump that produced progres-
sive behavioral changes and triggered severe striatal
dopamine depletion with the formation of nigral inclu-
sions immunoreactive for ubiquitin and a-synuclein.
This continuous MPTP administration also led to the
inhibition of the UPS (Fornai et al., 2005). The toxic
391
effects of MPTP on nigral dopaminergic cells were most
evident in primates, therefore MPTP-lesioned monkeys
were developed and have now become the most relevant
and extensively used animal model of PD (Burns et al.,
1983; Stern, 1990). However, the MPTP-treated primate
is a model of selective nigral destruction and does not
reflect other pathological features of PD. MPTP is
mainly used in non-human primates and in mice but also
in several other species, such as dogs, cats, sheep, rats
and goldfish (Schober, 2004).
Biochemical and histological investigations have
demonstrated that MPTP-induced parkinsonism reflects
the human disease and has been important for under-
standing the pathophysiology of PD as well as for the
evaluation of the effects of various drug therapies and
efficacy of new surgical techniques such as fetal grafts,
pallidotomy and deep brain stimulation (Jenner, 2003).
50.5. Isoquinoline derivatives
Various isoquinoline derivatives were found in the brain
and are considered to be the endogenous neurotoxins
with neurochemical properties similar to those of MPTP
(Nagatsu, 1997; Antkiewicz-Michaluk, 2002; Naoi et al.,
2002; Storch et al., 2002). Among them, 1,2,3,4-tetrahy-
droisoquinoline (TIQ), 1-benzyl-TIQ and 1-methyl-5,
6-dihydroxy-TIQ (salsolinol) have the most potent neu-
rotoxic action (Nagatsu, 1997; Antkiewicz-Michaluk,
2002).
N-methyl-(R)-salsolinol, a dopamine-derived alka-
loid, selectively occurs in human brains and accu-
mulates in the nigrostriatal system (Naoi et al.,
2002). N-methyl-(R)-salsolinol is synthesized in the
human brain by two enzymes, an (R)-salsolinol
synthase and an N-methyltransferase, and accumu-
lates in the nigrostriatum in human brains (Maruyama
et al., 2000). The activity of a neutral N-methyltrans-
ferase in the striatum was found to determine the
level of MPP-like 1,2-dimethyl-6,7-dihydroxyiso-
quinolinium ion, an oxidation product of N-methyl-
(R)-salsolinol in the substantia nigra (Maruyama
et al., 2000). N-methyl-(R)-salsolinol is increased
in the CSF of PD patients (Maruyama et al., 1999)
and the activity of (R)-salsolinol N-methyltransferase
is increased in lymphocytes from PD patients
(Maruyama et al., 2000; Naoi et al., 2002).
The studies of animal and cellular models of PD
proved that salsolinol is selectively cytotoxic to dopa-
mine neurons. Exposure of human dopaminergic
neuroblastoma cells to salsolinol-induced apoptosis
by the activation of the apoptotic cascade initiated in
the mitochondria (Akao et al., 1999; Naoi et al.,
2000). 2[N]-methylated isoquinoline derivatives struc-
turally related to MPTP/MPP are selectively toxic to
392 N. LEV ET AL.
dopaminergic cells via uptake by the DAT and there- 6-OHDA models, also known as hemiparkinson
fore may play a role in the pathogenesis of PD (Storch model, the intact hemisphere serves as internal con-
et al., 2002). Cell death induced by salsolinol is due trol structure (Perese et al., 1989). Unilateral 6-OHDA
to impairment of cellular energy supply, caused in injection causes an asymmetric and quantifiable motor
particular by inhibition of mitochondrial complex II behavior (rotations) induced by systemic administra-
(succinate Q reductase) (Storch et al., 2000). On the tion of dopaminergic receptor agonists (e.g. apomor-
other hand, (R)-salsolinol proved to scavenge hydroxyl phine), levodopa or dopamine-releasing drugs (e.g.
radical produced by oxidation of dopamine (Naoi amphetamine).
et al., 1998). The neurotoxicity and neuroprotection
of catechol isoquinolines may be ascribed to their 50.7. Cycad (amyotrophic lateral sclerosis
oxidation and scavenging of radicals. Since PD is a parkinsonism dementia complex of Guam)
slowly progressing neurodegenerative disease, long-
term neurotoxic effects of isoquinolines may have a The Chamorro people of Guam have been afflicted
central role in its progression. with a complex of neurodegenerative diseases known
as amyotrophic lateral sclerosisparkinsonism demen-
50.6. 6-hydroxydopamine tia complex (ALS-PDC) with similarities to ALS,
Alzheimers disease and PD at a far higher rate than
6-OHDA (Fig. 50.3B)-induced nigrostriatal damage other populations throughout the world. Several other
is today one of the most common animal models used foci of endemic ALS-PDC were found in Asia and
in the research of PD. 6-OHDA is a hydroxylated ana- Oceania. Epidemiologic study has shown that prefer-
log of the natural neurotransmitter dopamine (Schober, ence for traditional Chamorro food is significantly asso-
2004). 6-OHDA-induced toxicity is relatively selective ciated with an increased risk for PD (Durlach et al.,
for catecholaminergic neurons, resulting from a prefer- 1997). The toxic cycad seed that was used in traditional
ential uptake of 6-OHDA by dopamine and noradre- food and medicine was found to contain various toxins
nergic transporters (Schober, 2004). The mechanisms and particularly have an excitotoxic amino acid beta-N-
involved in 6-OHDA toxicity include respiratory methylamino-L-alanine (L-BMAA) (Fig. 50.4) (Durlach
inhibition and oxidative stress, induced by free radical
formation. It is toxic to mitochondrial complex I
(Betarbet et al., 2002) and leads to the formation of
superoxide free radicals (Schober, 2004). Furthermore,
it has been shown that 6-OHDA treatment reduces
striatal glutathione and superoxide dismutase enzyme
activity (Schober, 2004).
Several studies have reported the presence of
6-OHDA in both rat and human brains as well as in
the urine of levodopa-treated PD patients (Curtius
et al., 1974; Andrew et al., 1993; Liao et al., 2003;
Maharaj et al., 2005). Dopamine chemically reacts with
iron and ascorbate, resulting in hydroxylated forms of
dopamine products, such as 6-OHDA (Maharaj et al.,
2005). 6-OHDA is easily oxidized and can also take
part in free radical-forming reactions, such as the meta-
bolic monoamine oxidation. Due to the high content of
dopamine, hydrogen peroxide and free iron in dopami-
nergic neurons, a non-enzymatic reaction between these
elements may possibly lead to the endogenous 6-OHDA
formation (Jellinger et al., 1995; Linert et al., 1996). A
Animal models based on 6-OHDA toxicity are
commonly used in the study of PD. Since systemically H2N CH2NHCH3
administered 6-OHDA fails to cross the bloodbrain
barrier, 6-OHDA has to be injected stereotactically COOH
into the brain. Preferred injection sites are the substan- B
tia nigra, medial forebrain bundle and striatum (Perese Fig. 50.4. Cycad toxin. (A) Cycad tree; (B) chemical struc-
et al., 1989; Przedborski et al., 1995). In the unilateral ture of beta-methylaminoalanine (BMAA).
 TOXIC CAUSES OF PARKINSONISM
et al., 1997; Spencer et al., 2005). Traditional feasting
on flying foxes may be related to the prevalence of neu-
ropathologic disease in Guam, since consumption of a
single flying fox may have resulted in an equivalent
BMAA dose obtained from eating 1741014 kg of
processed cycad flour, sufficiently high to result in
ALS-PDC neuropathologies (Cox and Sacks, 2002;
Banack and Cox, 2003). Therefore, cycad neurotoxins
are biomagnified within the Guam ecosystem.
Apoptosis was identified in histological sections of
brain and gut tissue of adult mice fed with seed prepara-
tions of cycad (Gobe, 1994). Shaw and Wilson (2003)
developed an animal model of ALS-PDC which mimics
all the essential features of the disease by feeding the
animals with washed cycad seeds.
50.8. Annonacin
An unusually high percentage of atypical forms of par-
kinsonism were discovered in Guadeloupe (French
West Indies). The patients are characterized by levo-
dopa-resistant symmetrical bradykinesia and rigidity,
postural instability, dementia and, after 25 years,
pseudobulbar palsy. The early occurrence of postural
instability followed by vertical supranuclear palsy sup-
ported the diagnosis of progressive supranuclear palsy
(PSP) in one-third of patients (Caparros-Lefebvre
et al., 1999, 2002).
The neurological syndrome was linked to regular
consumption of tropical plants of the Annonaceae
family, in particular Annona muricata (synonyms: cor-
ossol, soursop, guanabana, graviola), used for alimen-
tary and medicinal purposes (Lannuzel et al., 2003).
A similar clinical syndrome has also been reported in
Afro-Caribbean and Indian immigrants in England
who regularly consumed imported annonacea products
(Chaudhuri et al., 2000). The validity of this associa-
tion was strengthened by the partial regression of
symptoms in young patients who stopped consuming
these plants (Caparros-Lefebvre et al., 1999).
Annonacin (Fig. 50.5) is highly toxic to dopaminer-
gic and other mesencephalic neurons via a mechanism
that is not excitotoxic and occurs independently of
ROS (Lannuzel et al., 2003). Some of the compounds
found in A. muricata are potent complex I inhibitors
(Lannuzel et al., 2003). Annonacin was approximately
OH OH
O
H3C (H2C)10
Fig. 50.5. Chemical structure of annonacin.
393
as effective as rotenone but 50-fold more potent
than the prototypical dopaminergic neurotoxin MPP
(Lannuzel et al., 2003).
50.9. Methanol
Several case reports describe the development of
parkinsonism as an acute or delayed toxic effect of
exposure to vapors of methanol (McLean et al.,
1980; Ley and Gali, 1983; Verslegers et al., 1988;
Indakoetxea et al., 1990; Davis and Adair, 1999;
Hageman et al., 1999; Finkelstein and Vardi, 2002).
Methanol intoxication caused development of perma-
nent parkinsonism (McLean et al., 1980; Ley and
Gali, 1983; Verslegers et al., 1988; Indakoetxea et al.,
1990). Chronic exposure, even without episodes of
acute intoxication, caused parkinsonism, pyramidal
signs, cognitive decline and unresponsiveness to levo-
dopa (Hageman et al., 1999; Finkelstein and Vardi,
2002). The setting of prolonged exposure to methanol
vapors may exist in research laboratories and other
environments and pose the risk of similar delayed toxic
influences.
50.10. Carbon monoxide poisoning
Carbon monoxide (CO) exposure is a common cause
of toxic brain damage and its effects range from tran-
sient neurological dysfunction to coma and death
(Prockop, 2005). Parkinsonism is a common sequel
of CO poisoning (Lee and Marsden, 1994; Choi and
Cheon, 1999; Prockop, 2005). Choi and Cheon
(1999) followed 242 patients with CO poisoning.
Delayed movement disorder affected 13.2% of these
patients, of whom 71.9% suffered from parkinsonism
(9.5% of all patients with CO poisoning) (Choi and
Cheon, 1999). Other movement disorders described
after CO poisoning include dystonia, chorea, athetosis,
tremor and myoclonus (Choi and Cheon, 1999).
Movement disorders can develop during or immedi-
ately after acute CO poisoning, but are usually delayed
for weeks after acute anoxia. The median latency
between CO poisoning and the onset of parkinsonism
was 4 weeks (Choi and Cheon, 1999). Most patients
suffering from parkinsonism recovered gradually
within 6 months (Choi and Cheon, 1999).
O O CH3
OH OH
(H2C)4 (H2C)5
394 N. LEV ET AL.
Brain computed tomography findings of patients
with parkinsonism after CO poisoning shows low-
density lesions bilaterally in the white matter of the cere-
bral cortex and in the globus pallidus, which can also be
seen in non-parkinsonian patients with CO poisoning
(Lee and Marsden, 1994; Choi and Cheon, 1999). A spec-
trum of severity of magnetic resonance imaging (MRI)
findings after CO poisoning was described, including glo-
bus pallidus and white-matter lesions (Sohn et al., 2000;
Parkinson et al., 2002; Prockop, 2005). MR spectroscopy
(MRS) shows decreased n-acetyl aspartase in the white
matter and basal ganglia in some of the patients (Sohn
et al., 2000; Prockop, 2005).
Hara et al. (2002) studied the effects of CO expo-
sure on the dopaminergic system in rats by in vivo
brain microdialysis. Exposure of rats to CO (up to
0.3%) caused a marked increase in extracellular dopa-
mine in the striatum, probably through stimulation of
sodium-dependent dopamine release in addition to
suppressing dopamine metabolism. CO withdrawal
and subsequent reoxygenation enhanced the oxidative
metabolism of the increased extracellular dopamine,
preferentially mediated by MAO-A (Hara et al.,
2002). These findings might imply that CO toxicity
to the dopaminergic system is mediated, at least par-
tially, through the toxicity of dopamine and its reactive
substances, such as quinones and activated oxygen
species, generated via dopamine oxidation.
50.11. Conclusions
PD is a common and mostly sporadic disease. The
pathogenesis of PD is likely multifactorial and involves
genetic and environmental interactions. The discovery
that MPTP could induce parkinsonism was the first sub-
stantial evidence that this complex disease could result
from a single toxin. Evidence from multiple epidemio-
logical studies emphasizes the roles of environmental
risk factors. New findings arising from toxin-induced
animal models of PD highlight the possibility that
selective injury to the striatonigral dopaminergic sys-
tem may arise not only from the distinctive properties
of the toxin, but also from intrinsic susceptibility of
the dopaminergic neurons.
The dopaminergic neurons are more vulnerable
than other cell populations to mitochondrial complex
I inhibition and oxidative stress and several toxins
implicated in PD were demonstrated to act through
these mechanisms. These two mechanisms may be
interrelated, since inhibition of complex I results in
augmented production of ROS.
Combinations of environmental risk factors may
result in more profound nigrostriatal damage, as
was shown in animal and in vitro studies. Early-life
exposure to toxins may also induce an increased vulner-
ability and enhanced adult susceptibility to toxins.
These models of synergistic toxicity, as well as chemi-
cal-induced inflammatory response, may underlie the
effects of environmental agents on the pathogenesis of
PD. Another important factor is the individual sus-
ceptibility to a certain toxin defined by susceptibility
genes in PD, therefore a combination of genetic and
environmental factors is needed to produce the disease.
Revelation of the environmental factors that lead to
PD enabled the development of toxin-induced animal
models for PD. These models have a critical role in
the research of PD and enable the development and
assessment of new therapeutic strategies.
References
Akao Y, Nakagawa Y, Maruyama W et al. (1999). Apoptosis
induced by an endogenous neurotoxin, N-methyl(R)salso-
linol, is mediated by activation of caspase 3. Neurosci Lett
267: 153156.
Anantharam V, Kitazawa M, Wagner J et al. (2002). Cas-
pase-3-dependent proteolytic cleavage of protein kinase
Cdelta is essential for oxidative stress-mediated dopami-
nergic cell death after exposure to methylcyclopentadienyl
manganese tricarbonyl. J Neurosci 22: 17381751.
Andrew R, Watson DG, Best SA et al. (1993). The determi-
nation of hydroxydopamines and other trace amines in the
urine of parkinsonian patients and normal controls. Neuro-
chem Res 18: 11751177.
Antkiewicz-Michaluk L (2002). Endogenous risk factors in
Parkinsons disease: dopamine and tetrahydroisoquino-
lines. Pol J Pharmacol 54: 567572.
Bahat-Stroomza M, Gilgun-Sherki Y, Offen D et al. (2005).
A novel thiol antioxidant that crosses the blood brain bar-
rier protectsdopaminergic neurons in experimental models
of Parkinsons disease. Eur J Neurosci 21: 637646.
Baldi I, Lebailly P, Mohammed-Brahim B et al. (2003). Neu-
rodegenerative diseases and exposure to pesticides in the
elderly. Am J Epidemiol 157: 409414.
Ballard PA, Tetrud JW, Langston JW (1985). Permanent human
parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydro-
pyridine (MPTP): seven cases. Neurology 35: 949956.
Banack SA, Cox PA (2003). Biomagnification of cycad neu-
rotoxins in flying foxes: implications for ALS-PDC in
Guam. Neurology 61: 387389.
Ben-Shachar D, Youdim MB (1991). Intranigral iron injec-
tion induces behavioral and biochemical parkinsonism
in rats. J Neurochem 57: 21332135.
Berg D, Gerlach M, Youdim MB et al. (2001). Brain iron
pathways and their relevance to Parkinsons disease.
J Neurochem 79: 225236.
Betarbet R, Sherer TB, MacKenzie G et al. (2000). Chronic sys-
temic pesticide exposure reproduces features of Parkinsons
disease. Nat Neurosci 3: 13011306.
Betarbet R, Sherer TB, Greenamyre JT (2002). Animal mod-
els of Parkinsons disease. Bioessays 24: 308318.
 TOXIC CAUSES OF PARKINSONISM
Bhatt MH, Elias MA, Mankodi AK (1999). Acute and rever-
sible parkinsonism due to organophosphate pesticide
intoxication: five cases. Neurology 52: 14671471.
Brooks AI, Chadwick CA, Gelbard HA et al. (1999).
Paraquat elicited neurobehavioral syndrome caused by
dopaminergic neuron loss. Brain Res 823: 110.
Burn DJ, Mark MH, Playford ED et al. (1992). Parkinsons
disease in twins studied with 18F-dopa and positron emis-
sion tomography. Neurology 42: 18941900.
Burns RS, Chiueh CC, Markey SP et al. (1983). A primate
model of parkinsonism: selective destruction of dopami-
nergic neurons in the pars compacta of the substantia nigra
by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc
Natl Acad Sci USA 80: 45464550.
Caparros-Lefebvre D, Elbaz A (1999). Caribbean
Parkinsonism Study Group. Possible relation of atypical
parkinsonism in the French West Indies with consumption
of tropical plants: a case-control study. Lancet 354:
281286.
Caparros-Lefebvre D, Sergeant N, Lees A et al. (2002). Guade-
loupean parkinsonism: a cluster of progressive supranuclear
palsy-like tauopathy. Brain 125: 801811.
Chaudhuri KR, Hu MTM, Brooks DJ (2000). Atypical par-
kinsonism in Afro-Caribbean and Indian origin immi-
grants to the UK. Mov Disord 15: 1823.
Choi IS, Cheon HY (1999). Delayed movement disorders
after carbon monoxide poisoning. Eur Neurol 42: 141144.
Corasaniti MT, Strongoli MC, Rotiroti D et al. (1998). Para-
quat: a useful tool for the in vivo study of mechanisms of
neuronal cell death. Pharmacol Toxicol 83: 17.
Corrigan FM, Wienburg CL, Shore RF et al. (2000). Orga-
nochlorine insecticides in substantia nigra in Parkinsons
disease. J Toxicol Environ Health A 59: 229234.
Cory-Slechta DA, Thiruchelvam M, Barlow BK et al. (2005).
Developmental pesticide models of the Parkinson disease
phenotype. Environ Health Perspect 113: 12631270.
Cox PA, Sacks OW (2002). Cycad neurotoxins, consumption
of flying foxes, and ALS-PDC disease in Guam. Neurol-
ogy 58: 956959.
Curtius HC, Wolfensberger M, Steinmann B et al. (1974). Mass
fragmentography of dopamine and 6-hydroxydopamine.
Application to the determination of dopamine in human
brain biopsies from the caudate nucleus. J Chromatogr 99:
529540.
Davis GC, Williams AC, Markey SP et al. (1979). Chronic
Parkinsonism secondary to intravenous injection of meper-
idine analogues. Psychiatry Res 1: 249254.
Davis LE, Adair JC (1999). Parkinsonism from methanol
poisoning: benefit from treatment with anti-Parkinson
drugs. Mov Disord 14: 520522.
Del Zompo M, Piccardi MP, Ruiu S et al. (1993). Selective
MPP uptake into synaptic dopamine vesicles: possible
involvement in MPTP neurotoxicity. Br J Pharmacol
109: 411414.
Dexter DT, Carayon A, Javoy-Agid F et al. (1991). Alterations
in the levels of iron, ferritin and other trace metals in
Parkinsons disease and other neurodegenerative diseases
affecting the basal ganglia. Brain 114: 19531975.
395
Dexter DT, Jenner P, Schapira AH et al. (1992). Alterations in
levels of iron, ferritin, and other trace metals in neurode-
generative diseases affecting the basal ganglia. The Royal
Kings and Queens Parkinsons Disease Research Group.
Ann Neurol 32: S94S100.
Di Monte DA (2001). The role of environmental agents in
Parkinsons disease. Clin Neurosci Res 1: 419426.
Double KL, Gerlach M, Youdim MB et al. (2000). Impaired
iron homeostasis in Parkinsons disease. J Neural Transm
Suppl 60: 3758.
Durlach J, Bac P, Durlach V et al. (1997). Are age-related
neurodegenerative diseases linked with various types of
magnesium depletion? Magnes Res 10: 339353.
Duvoisin RC, Eldridge R, Williams A et al. (1981). Twin
study of Parkinson disease. Neurology 31: 7780.
Elkon H, Melamed E, Offen D (2004). Oxidative stress,
induced by 6-hydroxydopamine, reduces proteasome
activities in PC12 cells: implications for the pathogenesis
of Parkinsons disease. J Mol Neurosci 24: 387400.
Felletschin B, Bauer P, Walter U et al. (2003). Screening for
mutations of the ferritin light and heavy genes in Parkinsons
disease patients with hyperechogenicity of the substantia
nigra. Neurosci Lett 352: 5356.
Finkelstein Y, Vardi J (2002). Progressive parkinsonism in a
young experimental physicist following long-term expo-
sure to methanol. Neurotoxicology 23: 521525.
Fleming L, Mann JB, Bean J et al. (1994). Parkinsons dis-
ease and brain levels of organochlorine pesticides. Ann
Neurol 36: 100103.
Fornai F, Schluter OM, Lenzi P et al. (2005). Parkinson-
like syndrome induced by continuous MPTP infusion:
convergent roles of the ubiquitinproteasome system
and alpha-synuclein. Proc Natl Acad Sci USA 102:
34133418.
Forte G, Bocca B, Senofonte O et al. (2004). Trace and
major elements in whole blood, serum, cerebrospinal fluid
and urine of patients with Parkinsons disease. J Neural
Transm 111: 10311040.
Gao HM, Hong JS, Zhang W et al. (2002). Distinct role for
microglia in rotenone-induced degeneration of dopaminer-
gic neurons. J Neurosci 22: 782790.
Gao HM, Hong JS, Zhang W et al. (2003a). Synergistic
dopaminergic neurotoxicity of the pesticide rotenone and
inflammogen lipopolysaccharide: relevance to the etiology
of Parkinsons disease. J Neurosci 23: 12281236.
Gao HM, Liu B, Hong JS (2003b). Critical role for micro-
glial NADPH oxidase in rotenone-induced degeneration
of dopaminergic neurons. J Neurosci 23: 61816187.
Gerber GB, Leonard A, Hantson P (2002). Carcinogenicity,
mutagenicity and teratogenicity of manganese compounds.
Crit Rev Oncol Hematol 42: 2534.
Gerlach M, Double KL, Ben-Shachar D et al. (2003). Neuro-
melanin and its interaction with iron as a potential risk
factor for dopaminergic neurodegeneration underlying
Parkinsons disease. Neurotox Res 5: 3544.
Gobe GC (1994). Apoptosis in brain and gut tissue of mice
fed a seed preparation of the cycad Lepidozamia peroffs-
kyana. Biochem Biophys Res Commun 205: 327333.
396 N. LEV ET AL.
Goldman SM, Tanner CM, Olanow CW et al. (2005). Occu-
pation and parkinsonism in three movement disorders
clinics. Neurology 65: 14301435.
Gorell JM, Johnson CC, Rybicki BA et al. (1997). Occupa-
tional exposures to metals as risk factors for Parkinsons
disease. Neurology 48: 650658.
Gorell JM, Rybicki BA, Cole Johnson C et al. (1999). Occupa-
tional metal exposures and the risk of Parkinsons disease.
Neuroepidemiology 18: 303308.
Gorell JM, Peterson EL, Rybicki BA et al. (2004). Multiple
risk factors for Parkinsons disease. J Neurol Sci 217:
169174.
Grandinetti A, Morens DM, Reed D et al. (1994). Prospective
study of cigarette smoking and the risk of developing
idiopathic Parkinsons disease. Am J Epidemiol 139:
11291138.
Grunblatt E, Mandel S, Jacob-Hirsch J et al. (2004). Gene
expression profiling of parkinsonian substantia nigra pars
compacta; alterations in ubiquitin-proteasome, heat shock
protein, iron and oxidative stress regulated proteins, cell
adhesion/cellular matrix and vesicle trafficking genes.
J Neural Transm 111: 15431573.
Hageman G, van der Hoek J, van Hout M et al. (1999). Par-
kinsonism, pyramidal signs, polyneuropathy, and cognitive
decline after long-term occupational solvent exposure.
J Neurol 246: 198206.
Hara S, Mukai T, Kurosaki K et al. (2002). Modification of
the striatal dopaminergic neuron system by carbon monox-
ide exposure in free-moving rats, as determined by in vivo
brain microdialysis. Arch Toxicol 76: 596605.
Hernan MA, Zhang SM, Rueda-deCastro AM et al. (2001).
Cigarette smoking and the incidence of Parkinsons dis-
ease in two prospective studies. Ann Neurol 50: 780786.
Hirsch EC, Brandel JP, Galle P et al. (1991). Iron and alu-
minum increase in the substantia nigra of patients with
Parkinsons disease: an X-ray microanalysis. J Neurochem
56: 446451.
Hirsch EC, Hoglinger G, Rousselet E et al. (2003). Animal
models of Parkinsons disease in rodents induced by tox-
ins: an update. J Neural Transm Suppl 65: 89100.
Holthoff VA, Vieregge P, Kessler J et al. (1994). Discordant
twins with Parkinsons disease: positron emission tomo-
graphy and early signs of impaired cognitive circuits.
Ann Neurol 36: 176182.
Huang CC, Weng YH, Lu CS et al. (2003). Dopamine trans-
porter binding in chronic manganese intoxication. J Neu-
rol 250: 13351339.
Hudnell HK (1999). Effects from environmental Mn expo-
sures: a review of the evidence from non-occupational
exposure studies. Neurotoxicology 20: 379397.
Indakoetxea B, Lopez de Munain A, Marti-Masso JF et al.
(1990). Parkinsonism after methyl alcohol poisoning. Neu-
rologia 5: 238241.
Javitch JA, DAmato RJ, Strittmatter SM et al. (1985).
Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine: uptake of the metabolite
N-methyl-4-phenylpyridine by dopamine neurons explains
selective toxicity. Proc Natl Acad Sci USA 82:
21732177.
Jellinger K, Linert L, Kienzl E et al. (1995). Chemical evi-
dence for 6-hydroxydopamine to be an endogenous toxic
factor in the pathogenesis of Parkinsons disease. J Neural
Transm 46: 297314.
Jenner P (1998). Oxidative mechanisms in nigral cell death
in Parkinsons disease. Mov Disord 13: 2443.
Jenner P (2001). Parkinsons disease, pesticides and mito-
chondrial dysfunction. Trends Neurosci 24: 245246.
Jenner P (2003). The contribution of the MPTP-treated pri-
mate model to the development of new treatment strate-
gies for Parkinsons disease. Parkinsonism Relat Disord
9: 131137.
Klaidman LK, Adams JD Jr, Leung AC et al. (1993). Redox
cycling of MPP: evidence for a new mechanism invol-
ving hydride transfer with xanthine oxidase, aldehyde
dehydrogenase, and lipoamide dehydrogenase. Free Radic
Biol Med 15: 169179.
Kushnareva Y, Murphy AN, Andreyev A (2002). Complex I-
mediated reactive oxygen species generation: modulation
by cytochrome c and NAD(P) oxidation-reduction state.
Biochem J 368: 545553.
Laihinen A, Ruottinen H, Rinne JO et al. (2000). Risk for
Parkinsons disease: twin studies for the detection of
asymptomatic subjects using [18F]6-fluorodopa PET.
J Neurol 247: II110II113.
Landrigan PJ, Sonawane B, Butler RN et al. (2005). Early
environmental origins of neurodegenerative disease in
later life. Environ Health Perspect 113: 12301233.
Langston JW, Ballard P, Tetrud JW et al. (1983). Chronic
Parkinsonism in humans due to a product of meperidine-
analog synthesis. Science 219: 979980.
Langston JW, Forno LS, Tetrud J et al. (1999). Evidence of
active nerve cell degeneration in the substantia nigra of
humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydro-
pyridine exposure. J Ann Neurol 46: 598605.
Lannuzel A, Michel PP, Oglinger GUH et al. (2003). The
mitochondrial complex I inhibitor annonacin is toxic to
mesencephalic dopaminergic neurons by impairment of
energy metabolism. Neuroscience 121: 287296.
Lee MS, Marsden CD (1994). Neurological sequelae following
carbon monoxide poisoning clinical course and outcome
according to the clinical types and brain computed tomogra-
phy scan findings. Mov Disord 9: 550558.
Ley CO, Gali FG (1983). Parkinsonian syndrome after
methanol intoxication. Eur Neurol 22: 405459.
Liao PC, Kuo YM, Chang YC et al. (2003). Striatal formation
of 6-hydroxydopamine in mice treated with pargyline, pyro-
gallol and methamphetamine. J Neural Trans 110: 487494.
Linert W, Herlinger E, Jameson RF et al. (1996). Dopamine,
6-hydroxydopamine, iron, and dioxygentheir mutual
interactions and possible implication in the development of
Parkinsons disease. Biochim Biophys Acta 1316: 160168.
Liou HH, Tsai MC, Chen CJ et al. (1997). Environmental
risk factors and Parkinsons disease: a case-control study
in Taiwan. Neurology 48: 15831588.
 TOXIC CAUSES OF PARKINSONISM
Liu B, Hong JS (2003). Role of microglia inflammation-
mediated neurodegenerative diseases: mechanisms and
strategies for therapeutic intervention. J Pharmacol Exp
Ther 304: 17.
Liu B, Gao H, Hong J (2003). Parkinsons disease and expo-
sure to infectious agents and pesticides and the occurrence
of brain injuries: role of neuroinflammation. Environ
Health Perspect 111: 10651073.
Maharaj H, Sukhdev Maharaj D, Scheepers M et al. (2005).
l-DOPA administration enhances 6-hydroxydopamine
generation. Brain Res 1063: 180186.
Manning-Bog AB, McCormack AL, Li J et al. (2002). The
herbicide paraquat causes up-regulation and aggregation
of alpha-synuclein in miceparaquat and alpha-synu-
clein. J Biol Chem 277: 16411644.
Marttila RJ, Kaprio J, Koskenvuo M et al. (1988). Parkinsons
disease in a nationwide twin cohort. Neurology 38:
12171219.
Maruyama W, Abe T, Tohgi H et al. (1999). An endogenous
MPTP-like dopaminergic neurotoxin, N-methyl(R)salsoli-
nol, in the cerebrospinal fluid decreases with progression
of Parkinsons disease. Neurosci Lett 262: 1316.
Maruyama W, Strolin-Benedetti M, Naoi M (2000). N-
methyl(R)salsolinol and a neutral N-methyltransferase as
pathogenic factors in Parkinsons disease. Neurobiology
8: 5568.
Mayer RA, Kindt MV, Heikkila RE (1986). Prevention of
the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tet-
rahydropyridine by inhibitors of 3,4-dihydroxyphenylethy-
lamine transport. J Neurochem 47: 10731079.
McCormack AL, Thiruchelvam M, Manning-Bog AB et al.
(2002). Environmental risk factors and Parkinsons dis-
ease: selective degeneration of nigral dopaminergic neu-
rons caused by the herbicide paraquat. Neurobiol Dis 10:
119127.
McLean DR, Jacobs H, Mielke BW (1980). Methanol poi-
soning: a clinical and pathological study. Ann Neurol 8:
161167.
McNaught KS, Mytilineou C, Jnobaptiste R et al.
(2002). Impairment of the ubiquitin-proteasome system
causes dopaminergic cell death and inclusion body forma-
tion in ventral mesencephalic cultures. J Neurochem 81:
301306.
Meco G, Bonifati V, Vanacore N et al. (1994). Parkinsonism
after chronic exposure to the fungicide maneb (manganese
ethylene-bis-dithiocarbamate). Scand J Work Environ
Health 20: 301305.
Mergler D, Baldwin M (1997). Early manifestations of man-
ganese neurotoxicity in humans: an update. Environ Res
73: 92100.
Mizuno Y, Sone N, Saitoh T (1987). Effects of 1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenyl-
pyridinium ion on activities of the enzymes in the electron
transport system in mouse brain. J Neurochem 48:
17871793.
Nagatsu T (1997). Isoquinoline neurotoxins in the brain and
Parkinsons disease. Neurosci Res 29: 99111.
397
Naoi M, Maruyama W, Kasamatsu T et al. (1998). Oxidation
of N-methyl(R)salsolinol: involvement to neurotoxicity
and neuroprotection by endogenous catechol isoquino-
lines. J Neural Transm Suppl 52: 125138.
Naoi M, Maruyama W, Takahashi T et al. (2000). Involve-
ment of endogenous N-methyl(R)salsolinol in Parkinsons
disease: induction of apoptosis and protection by deprenyl.
J Neural Transm Suppl 58: 111121.
Naoi M, Maruyama W, Akao Y et al. (2002). Dopamine-
derived endogenous N-methyl-(R)-salsolinol: its role in
Parkinsons disease. Neurotoxicol Teratol 24: 579591.
Nicklas WJ, Youngster SK, Kindt MV et al. (1987). MPTP,
MPP and mitochondrial function. Life Sci 40: 721729.
Olanow CW (2004). Manganese-induced parkinsonism and
Parkinsons disease. Ann NY Acad Sci 1012: 209223.
Orr CF, Rowe DB, Halliday GM (2002). An inflammatory
review Parkinsons disease. Prog Neurobiol 68: 325340.
Paik SR, Shin HJ, Lee JH et al. (1999). Copper(II)-induced
self-oligomerization of alpha-synuclein. Biochem J 340:
821828.
Panov A, Dikalov S, Shalbuyeva N et al. (2005). Rotenone
model of Parkinson disease: multiple brain mitochondria
dysfunctions after short term systemic rotenone intoxica-
tion. J Biol Chem 280: 4202642035.
Parkinson RB, Hopkins RO, Cleavinger HB et al.
(2002). White matter hyperintensities and neuropsycholo-
gical outcome following carbon monoxide poisoning.
Neurology 58: 15251532.
Perese DA, Ulman J, Viola J et al. (1989). A 6-hydroxydopa-
mine-induced selective parkinsonian rat model. Brain Res
494: 285293.
Piccini P, Burn DJ, Ceravolo R et al. (1999). The role of
inheritance in sporadic Parkinsons disease: evidence from
a longitudinal study of dopaminergic function in twins.
Ann Neurol 45: 577582.
Priyadarshi A, Khuder SA, Schaub EA et al. (2001). Environ-
mental risk factors and Parkinsons disease: a metaanaly-
sis. Environ Res 86: 122127.
Prockop LD (2005). Carbon monoxide brain toxicity: clini-
cal, magnetic resonance imaging, magnetic resonance
spectroscopy, and neuropsychological effects in 9 people.
J Neuroimaging 15: 144149.
Przedborski S, Vila M (2003). The 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine mouse model: a tool to explore
the pathogenesis of Parkinsons disease. Ann NY Acad Sci
991: 189198.
Przedborski S, Levivier M, Jiang H et al. (1995). Dose-
dependent lesions of the dopaminergic nigrostriatal path-
way induced by intrastriatal injection of 6-hydroxydopa-
mine. Neuroscience 67: 631647.
Przedborski S, Jackson-Lewis V, Naini AB et al. (2001). The
parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-
pyridine (MPTP): a technical review of its utility and
safety. J Neurochem 76: 12651274.
Racette BA, Antenor JA, McGee-Minnich L et al. (2005).
[18F]FDOPA PET and clinical features in parkinsonism
due to manganism. Mov Disord 20: 492496.
398 N. LEV ET AL.
Rasia RM, Bertoncini CW, Marsh D et al. (2005). Structural
characterization of copper(II) binding to a-synuclein:
insights into the bioinorganic chemistry of Parkinsons
disease. Proc Natl Acad Sci USA 102: 42944299.
Rodriguez VM, Thiruchelvam M, Cory-Slechta DA (2005).
Sustained exposure to the widely used herbicide atrazine:
altered function and loss of neurons in brain monoamine
systems. Environ Health Perspect 113: 708715.
Rybicki BA, Johnson CC, Uman J et al. (1993). Parkinsons
disease mortality and the industrial use of heavy metals in
Michigan. Mov Disord 8: 8792.
Schober A (2004). Classic toxin-induced animal models of
Parkinsons disease: 6-OHDA and MPTP. Cell Tissue
Res 318: 215224.
Shaw CA, Wilson JM (2003). Analysis of neurological disease
in four dimensions: insight from ALS-PDC epidemiology
and animal models. Neurosci Biobehav Rev 27: 493505.
Sherer TB, Kim J-H, Betarbet R et al. (2003). Subcutaneous
rotenone exposure causes highly selective dopaminergic
degeneration and alpha-synuclein aggregation. Exp Neurol
179: 916.
Smeyne M, Jiao Y, Shepherd KR et al. (2005). Glia cell
number modulates sensitivity to MPTP in mice. Glia 52:
144152.
Sohn YH, Jeong Y, Kim HS et al. (2000). The brain lesion
responsible for parkinsonism after carbon monoxide poi-
soning. Arch Neurol 57: 12141218.
Spencer PS, Palmer VS, Ludolph AC (2005). On the decline and
etiology of high-incidence motor system disease in West
Papua (southwest New Guinea). Mov Disord 20: S119S126.
Stern Y (1990). MPTP-induced parkinsonism. Prog Neurobiol
34: 107114.
Storch A, Kaftan A, Burkhardt K et al. (2000). 1-Methyl-
6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol)
is toxic to dopaminergic neuroblastoma SH-SY5Y cells
via impairment of cellular energy metabolism. Brain Res
855: 6775.
Storch A, Ott S, Hwang YI et al. (2002). Selective dopami-
nergic neurotoxicity of isoquinoline derivatives related to
Parkinsons disease: studies using heterologous expression
systems of the dopamine transporter. Biochem Pharmacol
63: 909920.
Tanner CM, Chen B, Wang W et al. (1989). Environmental
factors and Parkinsons disease: a case-control study in
China. Neurology 39: 660664.
Tanner CM, Ottman R, Goldman SM et al. (1999). Parkinson
disease in twins: an etiologic study. JAMA 281: 341346.
Thiruchelvam M, Richfield EK, Baggs RB et al. (2000). The
nigrostriatal dopaminergic system as a preferential target
of repeated exposures to combined paraquat and maneb:
implications for Parkinsons disease. J Neurosci 20:
92079214.
Thiruchelvam M, Richfield EK, Goodman BM et al. (2002).
Developmental exposure to the pesticides paraquat and
maneb and the Parkinsons disease phenotype. Neurotoxi-
cology 23: 621633.
Thiruchelvam M, McCormack A, Richfield EK et al. (2003).
Age-related irreversible progressive nigrostriatal dopami-
nergic neurotoxicity in the paraquat and maneb model of
the Parkinsons disease phenotype. Eur J Neurosci 18:
589600.
Uversky VN (2004). Neurotoxicant-induced animal models
of Parkinsons disease: understanding the role of rotenone,
maneb and paraquat in neurodegeneration. Cell Tissue Res
318: 225241.
Uversky VN, Li J, Fink AL (2001). Metal-triggered struc-
tural transformations, aggregation, and fibrillation of
human alpha-synuclein: a possible molecular link between
Parkinsons disease and heavy metal exposure. J Biol
Chem 276: 4428444296.
Verslegers W, Van den Kerchove M, Crols R et al. (1988).
Methanol intoxication. Parkinsonism and decreased Met-
enkephalin levels due to putaminal necrosis. Acta Neurol
Belg 88: 163171.
Vieregge P, Schiffke KA, Friedrich HJ et al. (1992). Parkinsons
disease in twins. Neurology 42: 14531461.
Vieregge P, Hagenah J, Heberlein I et al. (1999). Parkinsons
disease in twins: a follow-up study. Neurology 53: 566572.
Vila M, Vukosavic S, Jackson-Lewis V et al. (2000). Alpha-
synuclein up-regulation in substantia nigra dopaminergic
neurons following administration of the parkinsonian toxin
MPTP. J Neurochem 74: 721729.
Ward CD, Duvoisin RC, Ince SE et al. (1983). Parkinsons
disease in 65 pairs of twins and in a set of quadruplets.
Neurology 33: 815824.
Wesemann W, Blaschke S, Solbach M et al. (1994). Intrani-
gral injected iron progressively reduces striatal dopamine
metabolism. J Neural Transm Park Dis Dement Sect 8:
209214.
Wirdefeldt K, Gatz M, Schalling M et al. (2004). No evidence
for heritability of Parkinson disease in Swedish twins.
Neurology 63: 305311.
Wirdefeldt K, Gatz M, Pawitan Y et al. (2005). Risk and pro-
tective factors for Parkinsons disease: a study in Swedish
twins. Ann Neurol 57: 2733.
Zayed J, Ducic S, Campanella G et al. (1990). Environmental
factors in the etiology of Parkinsons disease. Can J Neurol
Sci 17: 286291.
Further Reading
Di Monte DA (2003). The environment and Parkinsons dis-
ease: is the nigrostriatal system preferentially targeted by
neurotoxins? Lancet Neurol 2: 531538.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved
Chapter 51
Drug-induced parkinsonism
FEDERICO EDUARDO MICHELI* AND MARIA GRACIELA CERSOSIMO
University of Buenos Aires, Buenos Aires, Argentina
51.1. Introduction
Parkinsonism encompasses a heterogeneous group of
movement disorders, featuring resting tremor, rigidity,
bradykinesia and postural instability (Quinn, 1995),
which have a significant impact on an individuals
quality of life (Marinus et al., 2002). Whereas primary
parkinsonism includes progressive, neurodegenerative
disorders, Parkinsons disease (PD) being the most
common, it is known that secondary parkinsonism can
be induced by drugs or caused by toxins or metabolic
disorders.
Drug-induced movement disorders (DIMD), most
of them induced by antidopaminergic drugs, are some
of the most frequent causes of secondary movement
disorders, often causing severe psychosocial distur-
bance in both non-psychotic patients and patients with
schizophrenia (Caligiuri et al., 2000). In addition,
DIMD are a major cause of poor compliance with
treatment, which in turn is associated with relapses,
hospitalization and morbidity (Casey, 1991).
DIMD encompasses a broad spectrum of syndromes,
diverse in time of onset and in their clinical mani-
festations. Acute-onset syndromes develop in hours to
days and include acute akathisia, acute dystonic
reactions and neuroleptic malignant syndrome; parkin-
sonism develops over weeks and the tardive syndromes
typically develop after months or even years of expo-
sure to neuroleptic or other antidopaminergic drugs.
Although some types of DIMD can be successfully
treated, at present, no consistently effective treatment is
available for others which may become irreversible even
if the causative drug is discontinued, highlighting that
certain drugs are apt to cause persisting, if not permanent,
central nervous system (CNS) changes. Thus, attention
should focus on close monitoring and prevention.
*Correspondence to: Professor Federico Micheli, University of Buenos Aires, Hospital de Clnicas Jose de San Martn, Buenos
Aires, Argentina. E-mail: fmicheli@fibertel.com.ar
Interestingly enough, despite the wide interest
neurologists have shown in this subject in the last
15 years, the cause of these movement disorders is
apt to be overlooked, unless the physician has a good
understanding of the possible offending medications.
Therefore, the risks and benefits of drug therapy need
to be known and carefully considered by physicians.
Patients and their families should be duly informed
about them.
51.2. History
The modern history of DIMD starts in the early 1950s
when chlorpromazine was developed in France and
acknowledged as a breakthrough in the treatment of
psychosis (Delay et al., 1952; Delay and Deniker,
1956). However, initial enthusiasm was soon tempered
by its side-effects, including acute reactions such as
akathisia, dystonia and drug-induced parkinsonism
(DIP), which were soon documented (Steck, 1954;
Ayd, 1961).
The psychomotor apathy syndrome was described
after initial clinical trials with chlorpromazine in psy-
chiatric patients and was thought to be specific for this
drug. Later on, this finding was related to the akinesia
syndrome without hypertonia which had been pre-
viously described as the sequelae of encephalitis
lethargica by Lhermitte in 1923. At that time reser-
pine, a dopamine-depleting drug, known to induce an
akinetic state in animals (Carlsson, 1959) was noted
to cause a parkinsonian state in humans. This observa-
tions, coupled with the known histopathology of PD,
led to the discovery that dopamine is severely depleted
in PD (Ehringer and Hornykiewicz, 1960).
In 1954 Steck reported parkinsonism in patients trea-
ted with chlorpromazine and reserpine. He highlighted
400 F. E. MICHELI AND M. G. CERSOSIMO
that these manifestations were reversible and that they
rather resembled postencephalitic parkinsonism, but
not PD. He also reported akathisia, a common feature
in postencephalitic parkinsonism but not in PD, in his
cases.
More persistent or even permanent dyskinesias
were first recognized in the late 1960s (Uhnbrand
and Faurbye, 1969).
Currently, it is widely acknowledged that all dopa-
mine antagonists as well as other drugs that interfere
with the synthesis or release of dopamine have the
potential to produce DIP in predisposed individuals.
As DIP was initially recognized as secondary to
neuroleptics (from the Greek: which grip the nerves),
it almost became synonymous with neuroleptic-
induced parkinsonism. The use of antipsychotic drugs
in the treatment of psychosis led to the common occur-
rence of DIP in this population (Freyhan, 1959), which
was most likely underestimated in clinical practice
(Marti Masso et al., 1993).
For some time, it was suggested that appropriate
control of psychosis could only be accomplished when
DIP occurred, but this has been clearly shown to be
false, leaving DIP as an unwanted adverse effect of
neuroleptic drugs. The new class of antipsychotics,
denominated atypical neuroleptics, is at least as
effective as the older antipsychotics but is much less
likely to cause movement disorders.
Among the various types of DIMD secondary to
neuroleptics, DIP is one of the most frequent but is
often poorly recognized, and is frequently indistin-
guishable from idiopathic PD which purportedly results
from the blockade of striatal dopamine receptors.
It is now well known that drugs, with a wide range
of applications in medicine, beyond the treatment of
psychiatric illnesses and of diverse chemical nature,
may induce or exacerbate parkinsonism. In addition
to neuroleptics, selective serotonin reuptake inhibitors
(SSRIs), lithium, valproic acid, calcium channel block-
ers, antiarrhythmics, cholinergics, chemotherapeutics,
amphotericin B, estrogens and others have been impli-
cated and it seems that an ever-growing list will add
new potential causes for DIP.
Currently, neuroleptic drugs, including substituted
benzamides and calcium channel blockers, not always
used as antipsychotics, are probably the drugs most
commonly involved in DIP. It is known that the elderly
population is at an increased risk of DIMD, including
DIP, due to intrinsic factors and because such patients
are often treated with several drugs, including those
from self-medication (Gershanik, 1994).
Psychiatric patients treated with typical neurolepics
are well known to be at risk to develop DIP; however,
non-psychotic outpatients developing parkinsonism
often pose a dilemma as to the cause of their
movement disorder and drug therapy must always be
considered in the differential diagnosis. Which particu-
lar patient with parkinsonism will turn to be a case of
DIP or even PD aggravated or unmasked by drugs?
Clinicians need to answer these questions as accurately
as possible since a mistaken diagnosis may lead to
unnecessary therapies, often associated with unwanted
effects and an emotional and economic burden for
patients and their families. In brief, the wide range
and increasing list of drugs implicated in the produc-
tion of DIP pose a challenging task for the clinician
(Friedman, 1989).
51.3. Prevalence
DIP has been claimed to represent one of the most
frequent causes of secondary parkinsonism in clinical
practice (Teive et al., 2004), if not the most frequent
cause (Nguyen et al., 2004) in several countries, to
the point that many authors have suggested that DIP
should always be suspected when parkinsonian symp-
toms rapidly develop or worsen in a patient treated
with certain medications, particularly those with
antidopaminergic properties.
The estimates for DIP differ widely among differ-
ent series. Whereas PD is likely to account for up to
60% of patients with parkinsonism, the second leading
cause is DIP, detected in 20% of patients (Cardoso,
1995). However, regional estimates are extremely
variable.
A study of a population of 208 000 in a district
located in the English Midlands showed a PD preva-
lence of 108.4 per 100 000, which is roughly compar-
able with figures from Carlisle, England; Rochester,
Minnesota; and south-west Finland. In this population,
DIP was very uncommon (Aronson, 1985).
Conversely, a door-to-door, two-phase approach
study of parkinsonism prevalence in three elderly (over
65 years of age) population groups of central Spain
showed that, out of 118 subjects with parkinsonism,
81 had PD (68.6%), 26 DIP (22.0%), 6 parkinsonism/
dementia (5.1%), 3 vascular parkinsonism (2.5%) and
2 unspecified parkinsonism (1.7%). The prevalence
was 2.2% (95% confidence interval (CI), 1.82.6) for
all types of parkinsonism and 1.5% (95% CI, 1.21.8)
for PD (Benito-Leon et al., 1998).
To support the above, DIP has also been considered
the second leading cause of parkinsonism, only after
PD, and representing 1030% of all patients with
parkinsonism in Spain (Errea-Abad et al., 1998).
The incidence of parkinsonism and its specific types
was studied among residents of Olmsted County, USA,
between 1976 and 1990. They found 364 incident cases
 DRUG-INDUCED PARKINSONISM
of parkinsonism: 154 with PD (42%), 72 with DIP
(20%), 61 unspecified (17%), 51 with parkinsonism in
dementia (14%) and 26 with other causes (7%). PD
was the most common type of parkinsonism, followed
by parkinsonism in dementia in men and DIP in women
(Bower et al., 1999).
Similar findings have been reported in Japan, where
DIP is currently the second leading cause of parkin-
sonism together with idiopathic PD. The ratio of the
incidence of DIP to PD has been reported to be
between 1:2 and 1:5 (Kuzuhara, 1997).
In Italy the figures for DIP seem to be lower. A
population-based survey performed in eight Italian
municipalities detected 42 PD (62%), 8 parkinson-
ism/dementia (12%), 8 vascular parkinsonism (12%),
7 DIP (10%) and 3 cases of unclassified parkinsonism
(5.8%) (Baldereschi et al., 2000).
51.4. Symptoms
The differential diagnosis from PD on clinical grounds
is often troublesome as the clinical features of DIP
mimic those of PD, except for the rather rapid progres-
sion of symptoms in the latter (Kuzuhara, 1997).
Bradykinesia, rigidity, impaired postural reflexes
and tremor may occur.
However, some subtle differences may be
observed (Table 51.1): for example, DIP is often
associated with tardive dyskinesias (TDKs) and invol-
vement may be symmetrical. Rigidity and impaired
arm-swing are the most common early signs, with tre-
mor marking the onset in only about one-third of
cases (Ayd, 1961). The latter is often not relevant
and may even be absent (Akbostanci et al., 1999).
This could be due to either the younger age of most
patients with DIP or to differences between the two
conditions.
Table 51.1
Features that characterize drug-induced parkinsonism and Parkinsons disease
401
Bradykinesia is often the initial, most frequent
and often the only manifestation of DIP, featuring
hypomimia, loss of associated movements and speech
disturbances.
Symmetric clinical signs are felt to be the rule in
PD and often a clue to a correct diagnosis. However,
this may not always be the case and, as in PD, sub-
groups seem to exist. Caligiuri et al. (1989) studied
26 treated schizophrenic patients and 14 normal con-
trols for the presence and asymmetry of neuroleptic-
induced rigidity, to evaluate the sensitivity, reliability
and validity of a quantitative procedure, showing that
65% of the patients exhibited pathological rigidity.
Moreover, 76% of these patients displayed asymmetric
rigidity, and the remaining 24% exhibited bilateral
symptoms. Newly treated patients exhibited greater
rigidity on the right side as compared to patients who
had been consistently treated for at least 3 months.
They speculated that striatal dopaminergic activity
may be asymmetric and more marked in the right stria-
tum among recently treated patients (Caligiuri et al.,
1989). Even though this is a drug-induced syndrome,
signs may be asymmetric in half of the patients, as
illustrated by findings in a small number of patients
(Hardie and Lees, 1988; Sethi and Zamrini, 1990). In
addition PD may present a symmetrical onset in 4%
of cases (Rajput et al., 1993).
The complete triad of tremor, rigidity and bradyki-
nesia is only seen in a limited number of cases, as illu-
strated by the 25% observed in the series from Llau
et al. (1994).
Gait abnormalities are frequent manifestations of
DIP (Akbostanci et al., 1999) but a very uncommon
initial manifestation of PD. Interestingly enough, freez-
ing is frequently observed in patients with vascular
parkinsonism (57%), normal-pressure hydrocephalus
(56%) and generally in patients with neurodegenerative

Drug-induced parkinsonism Parkinsons disease

Symptoms at onset Bilateral and symmetric or asymmetric Unilateral or asymmetric

Onset Acute or subacute Chronic
Course with appropriate treatment Regressive Progressive
Response to anticholinergic drugs Evident Mild to moderate
Response to levodopa Poor Marked
Akathisia Present Absent
Other associated features Orobuccal dyskinesia and other choreic
manifestations, rabbit syndrome
Incidence of rest tremor < >
Gender > Females > Males
Freezing Uncommon Common
Seborrheic dermatitis > <
402 F. E. MICHELI AND M. G. CERSOSIMO
parkinsonism, including progressive supranuclear
palsy, multiple system atrophy and corticobasal gang-
lionic degeneration (45%). However, freezing seems
to be rare in patients with DIP who have a very low
risk for developing freezing (P < 0.00001; OR, 0.1)
compared to patients with other types of parkinsonism
(Giladi et al., 1997).
A significant number of patients treated with
phenothiazine or butyrophenone neuroleptic drugs with
no previous movement disorders develop abnormally
low tremor frequencies. As low-frequency tremors are
often associated with PD, it has been speculated that
they probably represent early signs of DIP (Arblaster
et al., 1993).
An increased prevalence of seborrheic dermatitis is
a well-known feature of idiopathic PD and postence-
phalitic parkinsonism. Evaluation of 42 hospitalized
patients with DIP and 47 hospitalized psychiatric
patients with movement disorders showed a statisti-
cally significant higher prevalence of clinically diag-
nosed seborrheic dermatitis in the DIP group (59.5%
versus 15%) (Binder and Jonelis, 1983).
As in PD, dysphagia may be a prominent and even
an early sign of DIP. A 74-year-old woman, without
prior symptoms of parkinsonism or dysphagia, pre-
sented the association of both after the administration
of trifluoperazine hydrochloride (Bashford and Bradd,
1996). Another patient complained of difficulty chew-
ing and swallowing as the initial manifestation of DIP.
The evaluation of dysphagia demonstrated abnormal-
ities during all stages of ingestion. However, the
prepharyngeal stages were disproportionately affected
when compared with those patients with PD and
similar levels of parkinsonian functional disability
(Leopold, 1996). Dysphagia is a potentially life-
threatening complication of DIP. Its early recognition
is of paramount importance as it enables treatment by
simple medical, physical and dietary manipulations.
51.5. Associated features
DIP can be associated with other movement disorders
which are known to be typically induced by drugs.
Quite often such movements require therapeutic
approaches which are different from, if not opposed
to, those needed for the treatment of parkinsonism.
Nevertheless, the presence of such movements is a
clue to the correct diagnosis of DIP. Although some
of them are acute (akathisia), tardive movement
disorders appear after long-term treatment with the
causative drug and moreover treatment poses a real
challenge.
Akathisia is a complex syndrome featuring a
subjective sense of inner restlessness with a compul-
sive need to move and objective motor manifestations
such as shifting of the body weight from foot to foot
while standing or crossing and uncrossing the legs
when sitting. It is a typical side-effect of neuroleptics
and often coexists with DIP (Kim and Byun, 2003).
Akathisia is extremely uncommon in PD, although
it has been documented in parkinsonian patients trea-
ted with neuroleptics (Prueter et al., 2003).
Rabbit syndrome features a rapid orofacial tremor,
frequently occurring as a long-term side-effect of
neuroleptic treatment. However, response to anticholi-
nergic medication and the frequent association with
DIP suggest that the underlying mechanism of rabbit
syndrome is similar to that of acute forms of DIP
(Wada and Yamaguchi, 1992).
Tardive tremor is defined according to Jankovic
(1995) as a high-amplitude, 48 Hz rest and postural
tremor developing after prolonged exposure to a drug.
Tardive tremor has been associated with neuroleptics
(Stacy and Jankovic, 1992) and other drugs, including
calcium channel blockers (Garcia-Ruiz et al., 1992).
Tardive dyskinesia (TDK) comprises hyperkinetic
involuntary movements, varying in localization and
appearance. The most common presentation involves
the oral and facial regions and is called bucco-linguo-
masticatory syndrome; however, in many cases finger
arm or toeleg movements are evident. Thoracic
movements (respiratory dyskinesias) and pelvic invol-
vement are also frequent. TD and DIP have been
hypothesized to reflect opposing states of dopamine
function as DIP TD occurs more frequently in the
elderly population (Crane and Smeets, 1974).
Tardive dystonia (TD) features sustained involun-
tary contractions of antagonist muscles causing slow
twisting movements or sustained postures. Dystonia
is more often localized in the oral region, causing oro-
mandibular involvement with either forced jaw open-
ing and tongue protrusion or diurnal bruxism
(Micheli et al., 1993); in the facial areas, producing
blepharospasm; in the neck, with several types of cer-
vical dystonia; and in the trunk, among others.
51.6. Course
DIP usually develops gradually within the first 3
months after the patient is exposed to the causative
drug (Friedman, 1989), although it may take several
months for the full-blown picture to manifest.
On rare occasions DIP can be caused by neuroleptic
withdrawal and has been labeled as withdrawal
emergent parkinsonism (Inoue and Janikowski,
1981), but no adequate explanation for this phenom-
enon has been provided. A possible clue, in some
cases treated concomitantly with neuroleptics and
 DRUG-INDUCED PARKINSONISM
anticholinergics, where both drugs are discontinued at
the same time, could be the different half-lives of these
drugs as well as the dissimilar duration of their action
on the CNS.
It is commonly acknowledged that DIP is usually a
benign condition that resolves rapidly after the causative
drug is withdrawn. Usually parkinsonian symptoms begin
to improve in several weeks and patients are relieved
from the symptoms usually within several months (Kuzu-
hara, 1997), although complete resolution may take over
a year (Marti-Masso and Poza, 1996, 1998).
Occasional cases with extremely unusual duration of
symptoms after discontinuance of the offending
drug have been described (Klawans et al., 1973).
Physicians should be acquainted with the potential long
duration of DIP in order to avoid diagnostic errors.
Despite the lack of clear-cut evidence, it is often
acknowledged that tolerance develops to DIP. This
assumption is supported by the observation that
withdrawal of anticholinergics co-administered with
neuroleptics is followed by rare cases of DIP.
Conversely, Kennedy et al. (1971) reported that 27 out
of 63 patients treated with trifluoperazine for more than
3 years continued to have tremor and 24 had rigidity.
However, a small number of patients may have
persistent parkinsonism. Whether this is an aging-
related effect remains unclear (Jeste et al., 1998).
DIP is reversible, with the possible exception of a
small percentage of elderly patients. Melamed et al.
(1991) described 2 young patients who developed DIP
during chronic treatment with neuroleptics for a psycho-
tic disorder. Parkinsonism not only persisted but even
progressed after discontinuation of the antipsychotic
drugs. One patient experienced tremor-predominant
parkinsonism whereas the other presented an akinetic-
rigid syndrome. Neither had TDK and they both bene-
fited from levodopa therapy. Such persistent DIP cases
have been interpreted as pre-existent subclinical PD
cases, uncovered by drug therapy. In theory, these drugs
may precipitate the degeneration of vulnerable, nigros-
triatal neurons by generating cytotoxic free radicals or
by attrition, due to accelerated neuronal firing rates.
Total disappearance of the clinical signs occurred
in 74% of the patients, whereas, in 15% of cases,
DIP led to the diagnosis of underlying idiopathic
PD in the series of Llau et al. (1994). This study
showed that almost 80% of DIP cases are due to
two pharmacological classes of agents: antidopami-
nergic agents and calcium channel blockers.
51.7. Diagnosis
In the setting of a psychiatric patient receiving neuro-
leptic drugs, the appearance of parkinsonian symptoms
403
should immediately alert the physician to consider DIP
as the first possible diagnosis. However, in non-
psychotic patients, the awareness of the clinician of
the harmful effects of the offending drugs is often insuf-
ficient to lead to a correct diagnosis, which is then
unfortunately delayed. Frequently DIMD, including
DIP, are misdiagnosed (Weiden et al., 1987).
Symptoms may be misleading as illustrated by
Hansen et al. (1992), who reported on the occurrence
of TDK and DIP in 101 inpatients, documenting mis-
recognition of both disorders by resident physicians,
that determined a DIP prevalence of 11% versus a
26% rate found by the researchers. Residents tended
to miss DIP in younger patients and in patients with
affective disorders in whom a differential diagnosis
with DIP may be troublesome.
Although radiological procedures, including posi-
tron emission tomography (PET) scans, have proven
abnormal in PD, they are not commercially avail-
able and the diagnosis is currently based on clinical
evaluation. Functional neuroimaging using (123I)
beta-carboxymethyoxy-3-beta-(4-iodophenyl) tropane
(CIT) and single-photon emission computed tomogra-
phy (SPECT) provide information on the integrity of
the dopaminergic system in vivo and are promising
diagnostic tools in early PD, and particularly in the
differential diagnosis between parkinsonism and
non-organic causes of similar symptoms.
Performing (123I) beta-CIT and SPECT imaging at
baseline appears to be a useful diagnostic approach to
detect patients thought to have parkinsonism at baseline
but who, after follow-up, do not have parkinsonism (Jen-
nings et al., 2004). These findings may be particularly
useful in the differential diagnosis of negative symptoms
of psychotic patients mimicking parkinsonism.
Other symptoms present in PD, such as depression,
asthenia, sense of weakness, sedation and effects
of understimulation, as have been reported in pati-
ents institutionalized for long periods of time
(Fleischhacker, 2000), may overlap with the underly-
ing psychiatric illness. There may also be drug-related
side-effects that are unrelated to the parkinsonism.
The striking similarity between the pattern of visual
contrast sensitivity loss in DIP and that in PD suggests that
a widespread dopaminergic deficiency, regardless of the
cause, may similarly affect vision (Bulens et al., 1989).
51.8. Pathology
Postmortem reports of DIP cases are limited and the
results are at odds. Bathia et al. (1993) reported a
patient with cranial dystonia who also had rest tremor
in one arm and who developed DIP while under
treatment. The patients brain was normal on autopsy.
404 F. E. MICHELI AND M. G. CERSOSIMO
Brown et al. (1996) examined caudate nuclei areas in
10 schizophrenic subjects with DIP and 25 schizophrenic
subjects without parkinsonian symptoms. The subjects
with parkinsonian symptoms were found to have statisti-
cally significant smaller right caudate nuclei and a trend
towards smaller left caudates. Cortical measurements
did not differ between the groups. The authors conclude
that the results support the contention that antipsychotic
drugs exert some CNS neurotoxic effects.
Rajput et al. (1982) reported 2 patients who developed
parkinsonism after treatment with neuroleptic drugs.
Clinical manifestations remitted completely when the
offending drugs were discontinued. Surprisingly, when
these cases came to autopsy, histological examination
in each patient disclosed abnormalities characteristic of
PD. Levels of homovanillic acid were low in both cases
and dopamine levels were reduced in the striatum in 1
case. It is postulated that these 2 patients had subclinical
PD that was unmasked by neuroleptics.
Bower et al. (2002) correlated the clinical features
with pathological findings in an autopsy series of cases
of parkinsonism in Olmsted County, MN, for the years
19761990. They came across 364 incidental cases of
parkinsonism, of which 235 were deceased at the time
of the study; 39 autopsied brains were available for
analysis (17% of deceased cases). Of the 8 cases given
the clinical diagnosis of DIP, 6 were found to have
basal ganglia pathology.
51.9. Differential diagnosis
A comprehensive drug history is essential when
evaluating a patient with parkinsonian signs.
Very few disorders can mimic DIP, and when the
features of parkinsonism and a drug history are clear,
the diagnosis of DIP is straightforward and the most
troublesome question that arises is whether the patient
has DIP only or subclinical PD uncovered by drug
exposure. Answering this question is of paramount
importance to both patients and doctors as the
prognosis of these disorders is quite different.
Unfortunately, a definitive diagnosis is often delayed;
meanwhile the patient is under careful observation.
Functional imaging of the dopamine transporter
(DAT) is useful to check the integrity of the dop-
aminergic system and is apt to be used in patients
with mild, incomplete or uncertain parkinsonism.
Imaging with various specific SPECT ligands for DAT
(N-omega-fluoropropyl-2-beta-carbomethoxy-3 beta-
(4-iodophenyl)nortropane, FP-CIT; 2-beta-carbometh-
oxy-3 beta-(4-iodophenyl)tropane [123I], beta-CIT;
N-((E)-3-iodopropen-2-yl)-2 beta-carbomethoxy-3
beta-(4-chlorophenyl)tropane [123I], IPT; [2-[[2-
[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]
oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]
ethanethiolato(3-)-N2,N20 ,S2,S20 ]oxo-[1R-(exo-exo)],
TRODAT) may give a measure of presynaptic neuronal
degeneration. Striatal uptake has been shown to correlate
with disease severity, in particular with bradykinesia and
rigidity, and could be useful to monitor disease progres-
sion in PD. Dopamine deficiency largely antedates clini-
cal manifestations and is always present, even in the
earliest clinical presentations of PD; a normal scan
suggests an alternative diagnosis such as DIP or essential
tremor, vascular parkinsonism (unless there is focal
basal ganglia infarction) or psychogenic parkinsonism.
Additional applications of this method include character-
izing dementia with parkinsonian features (abnormal
results in dementia with Lewy bodies, common in
Alzheimers disease); and differentiating juvenile-onset
PD (abnormal DAT) from dopa-responsive dystonia
(normal DAT) (Marshall and Grosset, 2003).
Recently it has been shown that striatal morphology
on a three-dimensional display of 123I-beta-CIT SPECT
data provides information that is of diagnostic signifi-
cance for PD. This morphometry can be done without
technically demanding region of interest analysis and
thus this technique may be suitable for routine clinical
use to study the integrity of the dopaminergic nigrostria-
tal system (Ichise et al., 1999). Moreover, it has been
reported to characterize the different types of parkinson-
ism (Lorenzo Bosquet et al., 2004).
Negative symptoms in psychotic patients have been
correlated with parkinsonian symptoms, some vegeta-
tive features of depression and with anticholinergic
doses, but not with negative symptoms and cognitive
features of depression or neuroleptic drugs. These
findings suggest that the assessment criteria for nega-
tive symptoms, depression and DIP overlap in treated
schizophrenic patients (Prosser et al., 1987).
A retrospective evaluation of the premorbid status of
patients within their first episode of psychosis showed
that lower sociability and withdrawal scores correlated
with increased time to treatment response, more severe
negative symptoms, deterioration of premorbid function-
ing and increased DIP. These findings suggest that, prior
to acute psychosis onset, certain behavioral precursors
reflecting premorbid functioning may predict subsequent
illness manifestations (Strous et al., 2004).
Psychogenic parkinsonism is extremely rare in
clinical practice. Tolosa et al. (2003) reviewed the
clinical features and results of DAT imaging in DIP
and psychogenic parkinsonism. These two conditions
normally give normal striatal DAT imaging results;
an abnormal result in either case could rule out both
conditions, corroborating a diagnosis of organic
parkinsonism in uncertain cases.
Severe DIP cases should also be differentiated from
catatonia, a probably underdiagnosed disorder (Van
der Heijden et al., 2005) in which tremor is absent.
 DRUG-INDUCED PARKINSONISM
Unfortunately the two conditions may coexist as some
patients with catatonia can be under treatment with
neuroleptics. Assessment of the patients mental state
can make the difference clear. Symptoms like waxy
flexibility and muteness are clues for the diagnosis of
catatonia. As lorazepam and electroconvulsive therapy
(ECT) are effective in treating catatonia, an early
diagnosis is required (Huang, 2005).
Among the various causes of parkinsonism other than
PD that must be considered in the differential diagnosis
of DIP, those degenerative, toxic, tumors or hydrocepha-
lus that combine mental changes, often requiring drug
therapy and movement disorders, are on the first line.
In young patients, both Wilsons and Huntingtons
disease cause parkinsonism and psychosis. Wilsons dis-
ease typically causes a prominent resting and postural
tremor as well as dysarthria. The peculiar dystonic facies
of Wilsons disease are strongly suggestive of this disor-
der. Huntingtons disease usually causes chorea in adults
and parkinsonism in children, but a parkinsonian (West-
phal) variant can occur in young adults. In this case a
positive family history for chorea is a rule.
Parkinsonism can also be a feature of normal-
pressure hydrocephalus, often associated with a gait
disorder that is rather atypical for DIP, urinary inconti-
nence and cognitive imapirment. Brain computed tomo-
graphy (CT) scans or magnetic resonance imaging
(MRI) scans are useful when considering this diagnosis.
In the last few years brain imaging has emerged
as a potentially useful tool to study the activity of
the basal ganglia as well as help in the diagnosis
of different types of movement disorder. Unfor-
tunately they are not yet widely available in clinical
practice.
51.10. Magnetic resonance spectroscopy
MR spectroscopy has been described as a useful tool
to monitor the neurobiological correlates of DIP and
other DIMD. The severity of DIP assessed by the
SimpsonAngus Scale significantly correlates with
the higher choline (Cho) concentration and moreover
tends to correlate with the higher N-acetyl-aspartate
(NAA) concentration in a group of patients (Yamasue
et al., 2003).
51.11. Positron emission tomography
Putamen 18F-dopa uptake of PD patients is reduced by
at least 35% at onset of symptoms; therefore, PET
scans can be used to detect preclinical disease in clini-
cally unaffected twins and relatives of patients with
PD. PET scans can be used to detect underlying nigral
pathology in patients with isolated tremor and patients
taking dopamine receptor-blocking agents who
405
become rigid. Patients with familial essential tremor
have normal, whereas those with isolated rest tremor
have consistently low, putamen 18F-dopa uptake. DIP
is infrequently associated with underlying nigral
pathology (Brooks, 1991).
51.12. Transcranial ultrasound (TCS)
Applying TCS, Berg et al. (1999) found that approxi-
mately 9% of healthy individuals exhibit an increased
substantia nigra (SN) echogenicity, a sonographic
feature that is often found in PD (Becker et al.,
1995). PET studies in 10 of these otherwise healthy
subjects with hyperechogenicity of the SN showed
reduced [18F]-dopa uptake of the striatum, suggesting
that elevated echogenicity of the SN in healthy adults
can be associated with subclinical dysfunction of the
dopaminergic nigrostriatal system (Berg et al., 1999).
As these patients could be at increased risk of developing
DIP, Berg et al. (2001) compared the echo pattern of
patients on neuroleptics who developed DIP with those
who did not show evidence of parkinsonian symptoms.
In a second study they compared the echo pattern with
the severity of the parkinsonian signs. Findings demon-
strated that patients with more extended hyperechogenic
areas at the SN were more susceptible to DIP, which was
more severe contralateral to the side of the more echo-
genic SN (Berg et al., 2001).
51.13. Risk factors
Studies addressing the identification of risk factors for
the development of DIP highlighted the noteworthy indi-
vidual susceptibility to develop DIP. It has been accepted
that both the drug potency and dose play a role in the
development of DIP, but this may not always be the case.
Although not all risk factors have been universally
accepted and some have even been challenged, we list
here the most frequently cited.
51.13.1. Age/dementia
Elderly patients and particularly those with associated
dementia are at greater risk than patients without
dementia for persistent drug-induced extrapyramidal
side-effects (Marti Masso and Poza, 1996; Caligiuri
et al., 2000).
Moghal et al. (1995) reported the presence of move-
ment disorders in an institutionalized elderly population
of Saskatchewan. Movement disorder was detected in
19% of cases. Most of these cases (16%) were female;
10% had essential tremor, 6% PD and 2.3% had DIP.
In a community incidence study, 7.2% had DIP (Rajput
et al., 1984) and a prevalence study reported 8.8% cases
of parkinsonism being DIP (Bharucha et al,. 1988).
406 F. E. MICHELI AND M. G. CERSOSIMO
To examine the natural history and pathogenesis of
parkinsonism in Alzheimers disease, 44 subjects with
clearly established senile dementia of the Alzheimer
type were studied for 66 months. Sixteen subjects
(36%) developed idiopathic parkinsonism and 12 sub-
jects (27%) developed DIP; the chief clinical features
of both types were bradykinesia and rigidity, but not
resting tremor. The presence of parkinsonism was
associated with global (rather than selective) cognitive
impairment, as determined by psychometric testing
and with a more rapid progression to advanced stages
of dementia (Morris et al., 1989).
The association between parkinsonism and Alzhei-
mers disease has received great attention in recent
years. It has been speculated that the occurrence of par-
kinsonism and Alzheimers disease is not a chance
association.
The pathological correlates of parkinsonism were
found to be heterogeneous in the postmortem examina-
tion of subjects with Alzheimers disease. Some of
them exhibited pathological features of PD, whereas
others had non-specific nigral lesions; and even in some
cases neither histological changes nor reduced neuronal
densities in the SN were observed (Morris et al., 1989).
The incidence and prevalence of DIP and TD are
significantly greater among elderly patients, whereas
akathisia seems to occur evenly across the age range
and dystonia is more common among younger patients
(Errea-Abad et al., 1998; Caligiuri et al., 2000).
Neuroleptic use is a common cause of DIP among
the elderly and this side-effect is frequently treated
by adding an anticholinergic or dopaminergic drug to
the regimen. The use of anticholinergic drugs presents
risks of additional drug side-effects; the use of dopa-
minergic drugs, generally not appropriate for DIP,
suggests that extrapyramidal neuroleptic side-effects
may often be mistaken for idiopathic PD in older
patients (Avorn et al., 1995).
51.13.2. Pre-existing movement disorders
There is general agreement that pre-existing extrapyr-
amidal signs increase the patients vulnerability to
develop significant DIMD (Caligiuri et al., 2000). To
support this, previous studies suggest that many
untreated schizophrenic patients exhibit motor distur-
bances. On the basis of these findings, the authors
hypothesized that pre-existing extrapyramidal move-
ment disorders may increase the risk of developing
DIP.
A number of studies have shown that in a variable
number of cases DIP is only the expression of subcli-
nical PD unmasked by the action of neuroleptics,
calcium channel blockers or other drugs known to
cause DIP. Several authors have shown that findings
suggest that DIP is associated with an increased risk
for PD (Chabolla et al., 1998).
51.13.3. Cigarette smoking
Several studies have shown that cigarette smoking
may have a protective effect as regards the risk for
PD (Allam et al., 2004).
Similarly, according to one study, schizophrenic
patients who smoke have significantly less cognitive
impairment (P < 0.02) and a lower prevalence of
DIP as compared to non-smokers (Sandyk, 1993).
Based on these findings, the author suggests that cigar-
ette smoking may protect against the development of
dementia and DIP in schizophrenia.
51.13.4. Genetics
The results of epidemiological studies indicate that
there is a hereditary predisposition to developing
DIP. Metzer et al. (1989) investigated the human
leukocyte antigen (HLA) antigen prevalence rates in
patients with neuroleptic DIP. They evaluated
neuroleptic-treated, chronic inpatients with Diagnostic
and Statistical Manual of Mental Disorders III
(DSM-III)-diagnosed schizophrenia, 29 with DIP and
23 without parkinsonian signs. They were tested for 23
type A, 43 type B, 4 type C and 10 type DR
HLA antigens and it was found that, in DIP patients,
HLA-B44 was significantly more prevalent, suggesting
that this HLA antigen could play a role in genetic or
immunologic susceptibility to develop DIP in some
patients.
A higher occurrence of a positive family history of
PD and/or essential tremor and of higher frequency
of secondary cases with PD and/or essential tremor
among close relatives of patients with parkinsonism
induced by cinnarizine and flunarizine as compared
to age-matched controls suggests the involvement
of a genetic susceptibility in developing this drug-
induced disorder. DIP could be regarded as a
multifactorial disease process resulting from potential
neurotoxicity of drugs on a background of inherited
predisposition (Negrotti et al., 1992).
51.13.5. Gender
The fact that women are at increased risk of develop-
ing DIP has been consistently reported by many inves-
tigators (Klawans et al., 1973; Llau et al., 1994; Marti
Masso and Poza, 1996; Errea-Abad et al., 1998).
In this regard a retrospective study carried out by Llau
et al. (1994) investigated the characteristics of DIP
 DRUG-INDUCED PARKINSONISM
notified to the Midi-Pyrenees Pharmacovigilance Centre,
France between 1983 and 1992 found that, among 3923
side-effects spontaneously reported between 1983 and
1992 to the center, 53 (1.4%) were DIP cases. Mean
age was 65
2 (sem) years (range 2188 years). DIP
appeared after a mean treatment duration of 473
142
days (range 1 day to 15 years) and occurred most fre-
quently in women (63%) (Llau et al., 1994). Estrogen-
related dopamine receptor blockade has been suggested
as a possible explanation for female preponderance
(Glazer et al., 1983). However, others have not found a
gender preponderance (Moleman et al., 1982).
51.13.6. Schizophrenia subtype
It is possible that DIP may relate to negative symptoms,
whereas TDK in schizophrenia may be a covariate of
positive symptoms. Sandyk and Kay (1992) studied
the relationship of TDK and DIP with psychopathology
clusters rated on the Positive and Negative Syndrome
Scale in schizophrenic patients and found that involun-
tary movements of TDK were significantly associated
with the activation cluster (P < 0.01), whereas DIP
was significantly associated with the anergia cluster
(P < 0.01). However, it has been speculated that the
positive correlation of DIP and negative symptoms
stems from the similarity between masked facies of
DIP and blunted affect of schizophrenics (Hoffman
et al., 1991).
51.13.7. Ventricular/brain ratio
It has been shown that the magnitude of DIP is
positively correlated with ventricular/brain ratio and
the severity of negative symptoms of schizophrenia
(Hoffman et al., 1991). On the basis of these findings
it is suggested that a large lateral ventricular size
may be associated with increased vulnerability to
develop DIP (Luchins et al., 1983).
51.13.8. Human immunodeficiency virus (HIV)
HIV infection is a risk factor for developing DIP and
acquired immunodeficiency syndrome (AIDS) patients
are more prone to develop this side-effect when exposed
to drugs liable to induce movement disorders. Pitagoras
de Mattos et al. (2002) reported on their 14 years experi-
ence (19861999) treating 2460 HIV-positive inpati-
ents; 1053 (42.8%) presented at least one neurological
manifestation and 28 (2.7%) had involuntary move-
ments. Half of them had parkinsonism and, surprisingly,
7 had enlarged ventricles, confirmed on CT scans. One
patient had a hypodense area with mass effect, sugges-
tive of toxoplasmosis of the right basal ganglia. One
407
had an enhancing lesion in the midbrain at the T1-
weighted MRI, which correlated with a homolateral
ophthalmoplegia and contralateral parkinsonism.
The authors concluded that parkinsonism was probably
secondary to HIV in 12, to metoclopramide in 1 and to
neurotoxoplasmosis in another 1, and that a diagnosis
of HIV should always be considered in young patients
with secondary parkinsonism:
By using stereological techniques, Reyes et al.
(1991) estimated the volume density of melanin and
counted the number of pigmented and non-pigmented
neuronal cell bodies in the pars compacta of the SN
of autopsied AIDS cases without any evidence of PD
or inflammation or necrosis of the midbrain. They
found that the total number of neuronal cell bodies
was 25% lower in AIDS patients than in age-matched
controls. The histopathological examination showed
nigral degeneration with neuronal loss, small neuronal
cell bodies packed with melanin, reactive astrocytosis
and extracellular melanin in the AIDS patients but not
in the controls, showing that a subclinical nigral degen-
eration is common in AIDS and could possibly explain
the higher susceptibility of some patients to DIP.
51.13.9. Drugs that may cause drug-induced
parkinsonism
It is accepted that roughly half of the parkinsonism
cases seen in a neurology practice are drug-induced
or aggravated, generally by psychotropic drugs
(Marti Masso and Poza, 1996). Llau et al. (1995)
reported on the characteristics and drugs inducing
unwanted movement disorders notified to a Regional
Drug Surveillance Centre between 1989 and 1993.
Of a total of 4000 general side-effects, 122 were
movement disorders, the most common of which was
DIP (40% of cases). They were mostly caused by neu-
roleptics, followed by antiemetics and calcium channel
blockers. In this regard flunarizine and cinnarizine are
some of the most common drugs causing DIP in the
countries where they are available (Teive et al., 2004).
This is probably the rule in most countries,
although there may be some intracountry regional
variations over time.
Marti Masso and Poza (1996) performed a retro-
spective study of DIP patients seen between January
1981 and December 1993 in Spain. Of the 306 cases
of parkinsonism seen, 56.8% were induced or aggra-
vated by drugs. The drugs implicated most often were
cinnarizine, sulpiride and flupentixol. Some patients
were on two of these drugs and a minority on three.
The number of DIP cases seen increased after 1986
and then remained stable through 1993. Between
1981 and 1988, the most often implicated drug in
408 F. E. MICHELI AND M. G. CERSOSIMO
DIP was cinnarizine, though its relative impact of drugs capable of inducing DIP is growing rapidly
decreased in later years (Errea-Abad et al., 1998). This and seems to be endless (Marti Masso et al., 1993).
is most likely due to the better knowledge of the pro- Table 51.2 lists drugs known to induce or aggravate
file of side-effects of these drugs. Nevertheless, the list parkinsonian symptoms.

Table 51.2
Drugs that may induce or aggravate parkinsonism

Acetophenazine Meperidine
Alcohol withdrawal Mesoridazine
Alizapride 3,4-Methylenedioxymethamphetamine
Alpha-methyldopa Metoclopramide
Amiodarone Mexiletine
Amoxapine Molindone
Amphotericin b Naproxen
Antiacids Nefazodone
Aprindine Nifedipine
Bethanechol Olanzapine
Bupivacaine Paclitaxel
Bupropion Papaverine
Buspirone Paroxetine
Captopril Pentoxifylline
Carboplatin Perfenazine
Cephaloridine Perhexiline
Ciclosporin Perphenazine
Cimetidine Pethidine
Citalopram Phenobarbital
Cyclophosphamide Phenytoin
Cytosine arabinoside Pimozide
Chloroquine Piperazine
Chlorpromazine Pirlindol
Chlorprothixene Procainamide
Cinnarizine Procaine
Cisapride Prochlorperazine
Clebopride Promethazine
Diazepam Propiverine
Diltiazem Pyridoxine
Disulfiram Remoxipride
Domperidone Reserpine
Droperidol Risperidone
Ecstasy Sertraline
Estrogen and oral contraceptives Sodium valproate
Ethinyl Sufentanil
Fentanyl Sulindac
Flunarizine Sulpiride
Fluoxetine Tacrina
Flupentixol Tetrabenazine
Fluphenazine Thiethylperazine
Flurbiprofen Tiapride
Gemcitabine Trifluoperazine
Gold Triflupromazine
Haloperidol Trimeprazine
Halothane Thioridazine
Isoflurane Thiothixene
Levopromazine Triperidol
Lithium Veralipride
Lorazepam Verapamil
Loxapine Ziprasidone
 DRUG-INDUCED PARKINSONISM
51.13.10. Neuroleptics
Neuroleptics are at present the most effective treatment
for schizophrenia (Lyne et al., 2004), but non-
compliance is a major problem, contributing to the
discontinuation of therapy and leading to relapses.
Though several factors play a role in this regard, one
of the most common side-effects is the development
of movement disorders induced by these drugs (Borison
et al., 1983). These unwanted effects led to the develop-
ment of a new generation of neuroleptics devoid of
extrapyramidal side-effects, also known as atypical
neuroleptics, the prototype of which is clozapine (Awad
and Voruganti, 2004).
The majority of prescriptions for antipsychotics in
developed countries in the past years have been for
atypical drugs and the tendency shows a progressive
increment. However, although most atypical neurolep-
tics rarely induce movement disorders in young
patients, most are liable to cause them in susceptible
populations, including elderly patients or those with
previous movement disorders, including subclinical
PD. In addition, most cause akathisia (Kurz et al., 1995).
Even though investigators agree on the clinical
manifestations and diagnosis of DIP, the mechanism
by which drugs induce symptoms and the identifica-
tion of the individuals at risk are still a matter of
conjecture.
Since the description of the first cases, it has been
obvious that a clear doseresponse correlation was
absent and a discrepancy between the amount of
neuroleptics taken and the development of parkinson-
ism was evident (Hall et al., 1956) suggesting that sim-
ply the blockade of dopamine receptors was not the
cause of DIP. Neuroimaging studies have suggested
that parkinsonism occurs after D2-receptor occupancy
exceeds 80% (Farde et al., 1992). However, the obser-
vation of parkinsonism at or above 60% occupancy
levels is very consistent with prior pathological
(Jellinger, 1986; Gibb, 1992) and neuroimaging
studies (Frost et al., 1993; Marek et al., 1996) of
patients with PD that suggest symptoms become clini-
cally manifest following the loss of as little as 50% of
nigrostriatal neurons. In addition, plasma neuroleptic
levels fail to correlate with DIP severity.
The possibility that the neurotoxic activity of
neuroleptics is related to their induced movement dis-
orders has been previously suggested. In two in vivo
studies, Ben Shachar et al. (1993, 1994) found that
haloperidol and phenotiazines induced a marked
increase in iron transport across the bloodbrain barrier
in rats and mice, resulting in increased concentration of
iron in basal ganglia, which in turn triggers in vivo
generation of hydroxyl radicals and oxidative stress.
409
Consistent with the suggested oxidative stress activity
of haloperidol, chronic treatment with the drug is accom-
panied by the formation of a neurotoxic pyridinium meta-
bolite (high-performance planar chromatography
HPPC), a tetra hydropyridine analog resembling those
of the pyridinium metabolite 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP), which induces par-
kinsonian symptoms (Bloomquist et al., 1994; Rollema
et al., 1994). Gil-ad et al. (2001) studied the neurotoxic
activity of different neuroleptics (typical and atypical)
in order to correlate these effects with DIMD. With the
exception of clozapine, a correlation was observed
between the drug-induced neurotoxicity and its known
associated movement disorders, suggesting a possible
functional relationship between the two phenomena.
Neurotoxic activity of neuroleptics was found in both
the NB cell line and the primary mouse embryo-selected
neuronal culture. Their results suggest that neuroleptic-
induced neurotoxicity is independent of dopamine. Pre-
vious studies (Chiueh et al., 1993; Offen et al., 1995;
Ziv et al., 1995) have shown that dopamine alone pos-
sesses a neurotoxic and apoptotic activity at high concen-
trations in different neuronal cultures. This effect was
attenuated by inhibitors of apoptosis and by some antiox-
idants (vitamin E and N-acetylcysteine), suggesting an
oxidative stress mechanism in the drug-induced toxicity
which leads to apoptotic cell death.
The expression of c-fos, an immediate early gene,
correlates with neuronal activation. Thus, Fos immu-
nohistochemistry has turned out to be a valuable
method for mapping pathways of the CNS (Curran
and Morgan, 1995). It has been reported that acute
administration of a typical neuroleptic, haloperidol,
produces a large increase in the number of Fos-posi-
tive neurons in the striatum, the nucleus accumbens
and the lateral septal nucleus in the brain of rats
(Robertson and Fibiger, 1992). By contrast, com-
pounds that are not likely to cause movement disorders
fail to increase Fos in the dorsolateral striatum or pro-
duce only minor elevations (Robertson and Fibiger,
1992). Propranolol has been reported to attenuate Fos
expression in regions of the rat brain that are likely
to be responsible for akathisia (Ohashi et al., 1998).
Benzamide derivatives, including sulpiride and
metoclopramide, have been the main cause of DIP in
recent years in Japan (Kuzuhara, 2000; Naito and
Kuzuhara, 2004).
51.13.11. Flunarizine and cinnarizine
Both drugs are calcium channel blockers but
flunarizine is 2.515 times more potent. Cinnarizine
was developed first and flunarizine is a cinnarizine
derivative and differs since it includes a piperazine
410 F. E. MICHELI AND M. G. CERSOSIMO
derivative in its molecule, like some neuroleptics and
antihistamine drugs (Chouza et al., 1986; Micheli
et al., 1987, 1989; Fernandez Pardal et al., 1988;
Negrotti and Calzetti, 1997; Teive et al., 2004). These
drugs have been widely employed in Spain and Latin
America in the treatment of dizziness, cerebrovascular
disorders and cognitive impairment. More recently,
they have also been used in the prevention of migraine
attacks (Lucetti et al., 1998) and as adjunctive treatment
for epilepsy (Chaisewikul et al., 2001). Movement
disorders secondary to these calcium antagonists were
first recognized by De Melo-Souza in Brazil and
reported at the IX Brazilian Congress of Neurology.
Subsequently they were widely recognized in most of
the countries where these drugs are available (Chouza
et al., 1986; Micheli et al., 1987, 1989; Fernandez Par-
dal et al., 1988; Marti Masso and Poza, 1996; Negrotti
and Calzetti, 1997; Teive et al., 2004). Curiously, most
of the reported cases have involved elderly women and
many of them showed depression as a prominent
feature. Recovery after withdrawal of flunarizine or
cinnarizine usually takes several months to complete
(Marti Masso and Poza, 1998).
The mechanism by which flunarizine and cinnari-
zine cause DIP and other movement disorders is not
completely understood but it is plausible that a presy-
naptic as well as a postsynaptic mechanism contribute
to the dopaminergic dysfunction. Mena et al. (1995)
investigated the effects of calcium channel antagonists
on the pharmacology of dopamine systems in vivo and
in vitro and demonstrated that flunarizine, cinnarizine
and diltiazem reduce the viability of dopamine-rich
human neuroblastoma cells in vitro. They concluded
that all calcium channel antagonists tested reduced
dopamine neurotransmission in vitro and in vivo, but
the evidence of toxicity for dopamine cells in vitro is
restricted to flunarizine, cinnarizine and diltiazem,
the latter only seldom associated with DIP (Dick and
Barold, 1989).
Based on animal models and laboratory studies, flu-
narizine and cinnarizine have been shown to inhibit
the energy-dependent vesicular dopamine uptake
(Terland and Flatmark, 1999), block dopamine D2-
receptor (Brucke et al., 1995) and inhibit cathecola-
mine transport (Vaccari, 1993) and mitochondrial
complexes I and II (Veitch and Hue, 1994).
51.13.12. Selective serotonin reuptake inhibitors
Regardless of the general claim that SSRIs do not
induce or worsen parkinsonism (DellAgnello et al.,
2001), in recent years several cases have been reported
of movement disorders as a result of treatment with
selective SSRIs. Symptoms include dystonia, akathisia
and parkinsonism (Leo, 1996; Spigset, 1999; Pina
Latorre et al., 2001).
Serotonin modulates dopamine in the basal ganglia
by inhibiting its production and release. Thus, an
increase in serotonergic transmission may cause parkin-
sonism, particularly in susceptible patients, including
those with subclinical PD and elderly patients.
Ectasy and related derivatives which share a basic
amphetamine structure and exert stimulatory effects
in humans have been found to have a possible antipar-
kinsonian effect in animal experimental models
(Schmidt et al., 2002). Curiously, ecstasy has recently
been suspected to cause DIP (OSuilleabhain and
Giller, 2003). For the last 20 years 3,4-methylenediox-
ymethamphetamine (MDMA: also known as ecstasy)
has become a widely used recreational drug. Metham-
phetamine binds to the DAT in presynaptic terminals
and reverses dopamine transport (Sulzer et al., 1993).
Loss of dopaminergic neuronal terminals in human
postmortem tissue has been documented in chronic
methamphetamine users and in experimental animals
treated with methamphetamine. Based on such evi-
dence, there is concern that loss of neuronal markers
may represent terminal degeneration, predisposing to
parkinsonism as the individual becomes older. Recent
studies suggest that MDMA can cause toxicity to
dopamine-containing neurons in monkeys (OShea
and Colado, 2003).
51.14. Treatment
Particular care should be taken in treating patients who
are at risk of developing DIP or other DIMD with
drugs that are known to cause such side-effects. Neu-
roleptic drugs should be used according to strict cri-
teria and during the period when they are necessary.
The benefit should be weighed against the possible
side-effects before the decision to treat a patient with
a potential harmful drug is reached. When more than
one drug is apt to benefit the patient, the less harmful
drug obviously has to be prescribed. When the offend-
ing drug is required, as in the case of a psychotic
patient, the antipsychotic should be replaced by an
atypical neuroleptic.
If prevention fails, the most effective therapy for
DIP is cessation of the offending drug. Most patients
will become symptom-free after 12 months off the
causative drug but occasional patients require up to a
year or even longer for complete resolution to occur.
A small number of patients never recover completely
or partially recover and after some time exhibit signs
of parkinsonism again, raising the question as to
 DRUG-INDUCED PARKINSONISM
whether they had subclinical PD that was unmasked by
the administration of the drug. The autopsy findings of
typical histologic features of PD in patients who had
DIP during life supports this notion (Rajput et al.,
1982). Medical therapy is indicated when discontinu-
ance of the offending drug does not result in improve-
ment or if the patient requires therapy with the
causative drug.
DIP may improve with the use of anticholinergics
(Saltz et al., 2000) and there seems to be no difference
between the efficacy of the two most popular anticho-
linergics. A single-blind study compared the clinical
efficacy of biperiden hydrochloride and benzhexol in
the treatment of neuroleptic-induced parkinsonism.
Both drugs were highly effective and all patients
responded to medication. No significant difference
was observed between the two treatment groups when
individual symptoms were examined (Rosen, 1963;
Jensen and Amdisen, 1964; Magnus, 1980). However,
this therapy should be avoided in the elderly or demen-
ted patients or those with concurrent TD. Side-effects,
including mouth dryness, constipation, blurred vision
and essentially memory disturbances and delirium,
are more prevalent in the elderly. On the other hand,
TD symptoms worsen on anticholinergic therapy.
Amantadine, a putative dopaminergic compound
known to be therapeutically effective in idiopathic and
postencephalitic parkinsonism, is an alternative to
anticholinergic drugs (Kelly and Abuzzahab, 1971;
Kelly et al., 1974). In a double-blind placebo-controlled
cross-over study of 39 psychiatric inpatients, amanta-
dine and trihexyphenidyl were equally effective in
treating DIP, and amantadine produced fewer and less
severe side-effects. The authors suggest that amanta-
dine is an effective alternative to atropine-like agents,
with fewer implications for long-term risk of tardive
TD (Fann and Lake, 1976).
After a few months, most cases of DIP subside and for
that reason a practical approach should include tapering
of these drugs after 23 months to evaluate spontaneous
improvement (Horiguchi and Nishimatsu, 1992).
An alternative, and practical, approach is to use
ECT when appropriate, which transiently ameliorates
parkinsonism and treats psychosis (Goswami et al.,
1989). ECT has been claimed to produce some benefit
in occasional patients with DIP. A patient with schi-
zoaffective disorder and anticholinergic refractory
neuroleptic-induced parkinsonism manifested a
marked increase of parkinsonian symptoms and dystonia
after ECT (Hanin et al., 1995). As DIP, TD and TDK
have also been shown to improve with ECT adminis-
tration (Ananth et al., 1979), whereas tic syndromes
have achieved mixed results. In animals, ECT
411
enhances dopamine-mediated effects and increases
gamma-aminobutyric acid concentrations in the
CNS. Optimal parameters relevant to the antiparkin-
sonism effects of ECT require further study (Faber
and Trimble, 1991).
Previous investigations reported in the literature
have found propranolol to attenuate tremor in PD,
but no significant differences in attenuation of DIP
tremor by propranolol and placebo could be documented
(Metzer et al., 1993).
The results of a preliminary study suggest that, in
schizophrenic patients with acute psychosis, the addi-
tion of vitamin E to neuroleptic medication at the initia-
tion of treatment shows a trend towards a decrease in
the severity of acute DIMD. Unfortunately, it does not,
however, affect the severity of acute akathisia. Vitamin
E did not interfere with the antipsychotic effect of the
neuroleptic medication (Dorfman-Etrog et al., 1999).
The association between DIP and other movement
disorders, especially TD, poses a challenge as they
are responsive to pharmacological agents with antago-
nistic properties. Unfortunately, there is no adequate
answer to this question and results are often poor. It
has been proposed that dopamine-depleting drugs like
reserpine and tetrabenazine may be of benefit in some
cases, improving TD without worsening parkinsonism
(Fahn and Mayeux, 1980).
The issue as to whether treatment should be used to
treat symptoms of parkinsonism or used prophylacti-
cally to prevent the development of DIP has been a mat-
ter of conjecture. In clinical practice many
psychiatrists initiate treatment with neuroleptics and
anticholinergics concomitantly. Currently the routine
use of prophylactic anticholinergics is not recom-
mended and is clearly contraindicated in the elderly.
An individualized riskbenefit assessment is necessary
for the younger patient in whom prophylactic use of
anticholinergic drugs is considered (Mamo et al., 1999).
References
Akbostanci MC, Atbasoglu EC, Balaban H (1999). Tardive
dyskinesia, mild drug-induced dyskinesia, and drug-
induced parkinsonism: risk factors and topographic
distribution. Acta Neurol Belg 99: 176181.
Allam MF, Campbell MJ, Hofman A et al. (2004). Smoking
and Parkinsons disease: systematic review of prospective
studies. Mov Disord 19: 614621.
Ananth J, Samra D, Kolivakis T (1979). Amelioration of
drug-induced Parkinsonism by ECT. Am J Psychiatry
136 (8): 1094.
Arblaster LA, Lakie M, Mutch WJ et al. (1993). A study of
the early signs of drug induced parkinsonism. J Neurol
Neurosurg Psychiatry 56 (3): 301303.
412 F. E. MICHELI AND M. G. CERSOSIMO
Aronson TA (1985). Persistent drug-induced parkinsonism.
Biol Psychiatry 20 (7): 795798.
Avorn J, Bohn RL, Mogun H et al. (1995). Neuroleptic drug
exposure and treatment of parkinsonism in the elderly: a
case-control study. Am J Med 99 (1): 4854.
Awad AG, Voruganti LN (2004). Impact of atypical antipsy-
chotics on quality of life in patients with schizophrenia.
CNS Drugs 18: 877893.
Ayd FJ (1961). A survey of drug-induced extrapyramidal
reactions. JAMA 175: 10541060.
Baldereschi M, Di Carlo A, Rocca WA et al. (2000). Parkin-
sons disease and parkinsonism in a longitudinal study:
two-fold higher incidence in men. ILSA Working Group.
Italian Longitudinal Study on Aging. Neurology 55 (9):
13581363.
Bashford G, Bradd P (1996). Drug-induced Parkinsonism
associated with dysphagia and aspiration: a brief report.
J Geriatr Psychiatry Neurol 9 (3): 133135.
Becker G, Seufert J, Bogdahn U et al. (1995). Degeneration
of substantia nigra in chronic Parkinsons disease visua-
lized by transcranial color-coded real-time sonography.
Neurology 45: 182184.
Ben Shachar D, Livne E, Spanier I et al. (1993). Iron
modulates neuroleptics induced effects related to the
dopaminergic system. Isr J Med Sci 29: 587592.
Ben Shachar D, Livne E, Spanier I et al. (1994). Typical and
atypical neuroleptics induce alteration in blood brain
barrier and brain 59Fe c13 uptake. J Neurochem 62:
112118.
Benito-Leon J, Bermejo-Pareja F, Rodrguez J et al. (2003).
Neurological Disorders in Central Spain (NEDICES)
Study Group. Prevalence of PD and other types of parkin-
sonism in three elderly populations of central Spain. Mov
Disord 18 (3): 267274.
Berg D, Becker G, Zeiler B et al. (1999). Vulnerability of the
nigrostriatal system as detected by transcranial ultrasound.
Neurology 53: 10261031.
Berg D, Jabs B, Merschdorf U et al. (2001). Echogenicity of
substantia nigra determined by transcranial ultrasound
correlates with severity of parkinsonian symptoms induced
by neuroleptic therapy. Biol Psychiatry 50: 463467.
Bharucha NE, Bharucha EP, Bharucha AE et al. (1988). Pre-
valence of Parkinsons disease in the Parsi community of
Bombay, India. Arch Neurol 45 (12): 13211323.
Binder RL, Jonelis FJ (1983). Seborrheic dermatitis in neuro-
leptic-induced parkinsonism. Arch Dermatol 119 (6):
473475.
Bloomquist J, King E, Wright A et al. (1994). 1-methyl-
4-phenylpyridinium-like neurotoxicity of a pyridinium
metabolite derived from haloperidol; cell culture and neu-
rotransmitter uptake studies. J Pharmacol Exp Ther 270:
822830.
Borison RL, Hitri A, Blowers AJ et al. (1983). Antipsychotic
drug action: clinical, biochemical, and pharmacological
evidence for site specificity of action. Clin Neuropharma-
col 6: 137150.
Bower JH, Maraganore DM, McDonnell SK et al. (1999).
Incidence and distribution of parkinsonism in Olmsted
County, Minnesota, 19761990. Neurology 52 (6):
12141220.
Bower JH, Dickson DW, Taylor L et al. (2002). Clinical
correlates of the pathology underlying parkinsonism: a
population perspective. Mov Disord 17 (5): 910916.
Brooks DJ (1991). Detection of preclinical Parkinsons
disease with PET. Geriatrics 46 (Suppl 1): 2530.
Brown KW, Wardlaw JM, White T et al. (1996). Caudate
nucleus area in drug-induced parkinsonism. Acta Psychiatr
Scand 94 (5): 348351.
Brucke T, Wober C, Podreka I et al. (1995). D2 receptor
blockade by flunarizine and cinnarizine explains extrapyr-
amidal side effects. A SPECT study. J Cereb Blood Flow
Metab 15: 513518.
Bulens C, Meerwaldt JD, van der Wildt GJ et al. (1989).
Visual contrast sensitivity in drug-induced Parkinsonism.
J Neurol Neurosurg Psychiatry 52 (3): 341345.
Caligiuri MP, Bracha HS, Lohr JB (1989). Asymmetry of
neuroleptic-induced rigidity: development of quantitative
methods and clinical correlates. Psychiatry Res 30 (3):
275284.
Caligiuri MR, Jeste DV, Lacro JP (2000). Antipsychotic-
induced movement disorders in the elderly: epidemiology
and treatment recommendations. Drugs Aging 17 (5):
363384.
Cardoso F (1995). Treatment of Parkinson disease. Arq Neu-
ropsiquiatr 53 (1): 110.
Carlsson A (1959). The occurrence, distribution and physio-
logical role of catecholamines in the nervous system.
Pharmacol Rev 11: 490493.
Casey DE (1991). Neuroleptic drug-induced extrapyramidal
syndromes and tardive dyskinesia. Schizophr Res 4:
109120.
Chabolla DR, Maraganore DM, Ahlskog JE et al. (1998).
Drug-induced parkinsonism as a risk factor for Parkin-
sons disease: a historical cohort study in Olmsted County,
Minnesota. Mayo Clin Proc 73 (8): 724727.
Chaisewikul R, Baillie N, Marson AG (2001). Calcium
antagonists as an add-on therapy for drug-resistant
epilepsy. Cochrane Database Syst Rev (4): CD002750.
Review.
Chiueh CC, Miyake H, Peng T (1993). Role of dopamine
autoxidation, hydroxyl radical generation and calcium
overload in underlying mechanisms involved in MPTP
induced Parkinsonism. Adv Neurol 60: 251258.
Chouza C, Scaramelli A, Caamano JL et al. (1986). Parkin-
sonism, tardive dyskinesia, akathisia, and depression
induced by flunarizine. Lancet 7 (1): 13031304.
Crane GE, Smeets RA (1974). Tardive dyskinesia and drug
therapy in geriatric patients. Arch Gen Psychiatry 30:
341343.
Curran T, Morgan JI (1995). Fos: an immediate-early tran-
scription factor in neurons. J Neurobiol 26: 403412.
Delay J, Deniker P (1956). Chlorpromazine and neuroleptic
treatment in psychiatry. J Clin Exp Psychopathol 17: 1924.
 DRUG-INDUCED PARKINSONISM
Delay J, Deniker P, Harl JM (1952). Utilisation en therapeu-
tique psychiatrique dune phenothiazine daction centrale
elective (4560 RP). Ann Med Psychol 110: 112117 .
DellAgnello G, Ceravolo R, Nuti A et al. (2001). SSRIs do
not worsen Parkinsons disease: evidence from an
open-label, prospective study. Clin Neuropharmacol 24:
221227.
Dick RS, Barold SS (1989). Diltiazem-induced parkinson-
ism. Am J Med 87 (1): 9596.
Dorfman-Etrog P, Hermesh H, Prilipko L et al. (1999). The
effect of vitamin E addition to acute neuroleptic treatment
on the emergence of extrapyramidal side effects in schizo-
phrenic patients: an open label study. Eur Neuropsycho-
pharmacol 9: 475477.
Ehringer H, Hornykiewicz O (1960). Verteilung von
noradrenalen und dopamine (3-hydroxytyramine) im
gehirn des menschen und ihr berhatten bei erkrankingen
des extrapyramidalen systems. Klin Wochenschr 24:
12361239.
Errea-Abad JM, Ara-Callizo JR, Aibar-Remon C (1998).
Drug-induced parkinsonism. Clinical aspects compared
with Parkinson disease. Rev Neurol 27 (155): 3539.
Faber R, Trimble MR (1991). Electroconvulsive therapy in
Parkinsons disease and other movement disorders. Mov
Disord 6 (4): 293303.
Fahn S, Mayeux R (1980). Unilateral Parkinsons disease
and contralateral tardive dyskinesia: a unique case with
successful therapy that may explain the pathophysiology
of these two disorders. J Neural Transm Suppl 16:
179185.
Fann WE, Lake CR (1976). Amantadine versus trihexyphe-
nidyl in the treatment of neuroleptic-induced parkinson-
ism. Am J Psychiatry 133 (8): 940943.
Farde L, NordstriSm AL, Wiesel FA et al. (1992). Posi-
tron emission tomographic analysis of central D1 and
D2 dopamine receptor occupancy inpatients treated
with classical neuroleptics and clozapine: relation to
extrapyramidal side effects. Arch Gen Psychiatry 49:
538544.
Fernandez Pardal M, Fernandez Pardal J, Micheli F (1988).
Aggravation of Parkinsons disease by cinnarizine. J Neu-
rol Neurosurg Psychiatry 51: 158159.
Fleischhacker W (2000). Negative symptoms in patients with
schizophrenia with special reference to the primary versus
secondary distinction. Encephale 26 Spec No 1: 1214.
Freyhan FA (1959). Therapeutic implications of differential
effects of new phenothiazine compounds. Am J Psychiatry
115: 577585.
Friedman JH (1989). Drug-induced movement disorders. In:
WJ Weiner, AE Lang (Eds.), Movement Disorders: a
Comprehensive Survey. Futura Publishing Co. Inc, Mount
Kisco, New York, pp. 4183.
Frost JJ, Rosier AJ, Reich SG et al. (1993). Positron emis-
sion tomographic imaging of the dopamine transporter
with 11C-WIN 35,428 reveals marked declines in mild
Parkinsons disease. Ann Neurol 34: 423431.
413
Garcia-Ruiz PJ, Garcia de Yebenes J, Jimenez-Jimenez
FJ et al. (1992). Parkinsonism associated with calcium
channel blockers: a prospective follow-up study. Clin
Neuropharmacol 15: 1926.
Gershanik OS (1994). Drug-induced parkinsonism in the
aged. Recognition and prevention. Drugs Aging 5 (2):
127132.
Gibb WR (1992). Melanin, tyrosine hydroxylase, calbindin
and substance P in human midbrain and substantia nigra
in relation to nigrostriatal projections and differential neu-
ronal susceptibility in Parkinsons disease. Brain Res 581:
283291.
Gil-ad I, Shtaif B, Shiloh R et al. (2001). Evaluation of the
neurotoxic activity of typical and atypical neuroleptics:
relevance to iatrogenic extrapyramidal symptoms. Cell
Mol Neurobiol 21: 705716.
Giladi N, Kao R, Fahn S (1997). Freezing phenomenon in
patients with parkinsonian syndromes. Mov Disord
12 (3): 302305.
Glazer WM, Naftolin F, Moore DC et al. (1983). The rela-
tionship of circulating estradiol to tardive dyskinesia in
men and postmenopausal women. Psychoneuroendocrinol-
ogy 8: 429434.
Goswami U, Dutta S, Kuruvilla K et al. (1989). Electrocon-
vulsive therapy in neuroleptic-induced parkinsonism. Biol
Psychiatry 26: 234238.
Hall RA, Jackson RB, Swaim JM (1956). Neurotoxic reac-
tions resulting from chlorpromazine administration.
JAMA 161: 214218.
Hanin B, Lerner Y, Srour N (1995). An unusual effect of
ECT on drug-induced parkinsonism and tardive dystonia.
Convuls Ther 11: 271274.
Hansen TE, Brown WL, Weigel RM et al. (1992). Under-
recognition of tardive dyskinesia and drug-induced parkin-
sonism by psychiatric residents. Gen Hosp Psychiatry
14 (5): 340344.
Hardie RJ, Lees AJ (1988). Neuroleptic-induced Parkinsons
syndrome: clinical features and results of treatment with
levodopa. J Neurol Neurosurg Psychiatry 51: 850854.
Hoffman WF, Ballard L, Turner EH et al. (1991). Three-year
follow-up of older schizophrenics: extrapyramidal syn-
dromes, psychiatric symptoms, and ventricular brain ratio.
Biol Psychiatry 30 (9): 913926.
Horiguchi J, Nishimatsu O (1992). Usefulness of antiparkin-
sonian drugs during neuroleptic treatment and the effects
of clonazepam on akathisia and parkinsonism occurred
after antiparkinsonian drug withdrawal: a double-blind
study. Jpn J Psychiatry 46: 733739.
Huang TL (2005). Lorazepam and diazepam rapidly relieve
catatonic signs in patients with schizophrenia. Psychiatry
Clin Neurosci 59 (1): 5255.
Ichise M, Kim YJ, Erami SS et al. (1999). Functional mor-
phometry of the striatum in Parkinsons disease on three-
dimensional surface display of 123I-beta-CIT SPECT
data. J Nucl Med 40 (4): 530538.
Inoue F, Janikowski AM (1981). Withdrawal akinesia.
J Neurol Neurosurg Psychiatry 44: 958.
414 F. E. MICHELI AND M. G. CERSOSIMO
Jankovic J (1995). Tardive syndromes and other drug-
induced movement disorders. Clin Neuropharmacol 18:
197214.
Jellinger K (1986). Overview of morphologic changes in
Parkinsons disease. In: MD Yahr, KJ Bergman (Eds.),
Advances in Neurology, Vol. 45, Raven Press, New York,
pp. 118.
Jennings DL, Seibyl JP, Oakes D et al. (2004). (123I) beta-CIT
and single-photon emission computed tomographic imaging
vs clinical evaluation in Parkinsonian syndrome: unmasking
an early diagnosis. Arch Neurol 61 (8): 12241229.
Jensen K, Amdisen A (1964). Treatment of drug-induced
parkinsonism: a comparison between UK-738, orphena-
drine, and a placebo in a double blind study. Psychophar-
macologia 192: 301305.
Jeste DV, Lohr JB, Eastham JH et al. (1998). Adverse neuro-
biological effects of long-term use of neuroleptics: human
and animal studies. J Psychiatr Res 32 (34): 201214.
Kelly JT, Abuzzahab FS Sr (1971). The antiparkinson prop-
erties of amantadine in drug-induced parkinsonism. J Clin
Pharmacol New Drugs 11 (3): 211214.
Kelly JT, Zimmermann RL, Abuzzahab FS et al. (1974). A
double-blind study of amantadine hydrochloride versus
benztropine mesylate in drug-induced parkinsonism.
Pharmacology 12 (2): 6573.
Kennedy PF, Hershon HI, McGuire RJ (1971). Extrapyr-
amidal disorders after prolonged phenothiazine therapy.
Br J Psychiatry 118: 509518.
Kim JH, Byun HJ (2003). Prevalence and characteristics of
subjective akathisia, objective akathisia, and mixed akathi-
sia in chronic schizophrenic subjects. Clin Neuropharma-
col 26 (6): 312316.
Klawans HL Jr, Bergen D, Bruyn GW (1973). Prolon-
ged drug-induced Parkinsonism. Confin Neurol 35 (6):
368377.
Kuzuhara S (1997). Drug-induced parkinsonism. Nippon
Rinsho 55 (1): 112117.
Kuzuhara S (2000). Essential points to differentiate various
diseases causing parkinsonism. Nippon Rinsho 58 (10):
20492053.
Kurz M, Hummer M, Oberbauer H et al. (1995). Extrapyra-
midal side effects of clozapine and haloperidol. Psycho-
pharmacology (Berl) 118: 5256.
Leo RJ, Lichter DG, Hershey LA (1995). Parkinsonism asso-
ciated with fluoxetine and cimetidine: a case report. J Ger-
iatr Psychiatr Neurol 84: 231233.
Leopold NA (1996). Dysphagia in drug-induced parkinson-
ism: a case report. Dysphagia 11 (2): 151153.
Llau ME, Nguyen L, Senard JM et al. (1994). Drug-induced
parkinsonian syndromes: a 10-year experience at a regio-
nal center of pharmaco-vigilance. Rev Neurol (Paris)
150 (11): 757762.
Llau ME, Senard JM, Rascol O et al. (1995). Movement disorders
induced by drugs: experience at a pharmaco-vigilance center
over five years. Therapie 50 (5): 425427.
Lorenzo Bosquet C, Miquel Rodriguez F, Roca Bielsa I et al.
(2004). Differential diagnosis of parkinsonism using
dopamine transporters brain SPECT. Med Clin (Barc)
122 (9): 325328.
Lucetti C, Nuti A, Pavese N et al. (1998). Flunarizine in
migraine prophylaxis: predictive factors for a positive
response. Cephalagia 18: 349352.
Luchins DJ, Jackman H, Meltzer HY (1983). Lateral ventri-
cular size and drug-induced Parkinsonism. Psychiatry Res
9 (1): 916.
Lyne J, Kelly BD, OConnor WT (2004). Schizophrenia:
a review of neuropharmacology. Ir J Med Sci 173:
155159.
Magnus RV (1980). A comparison of biperiden hydrochlor-
ide (Akineton) and benzhexol (Artane) in the treatment
of drug-induced Parkinsonism. J Int Med Res 8 (5):
343346.
Mamo DC, Sweet RA, Keshavan MS (1999). Managing
antipsychotic-induced parkinsonism. Drug Saf 20: 269275.
Marek KL, Seibyl JP, Zoghbi SS et al. (1996). 123-ICIT/
SPECT imaging demonstrates bilateral loss of dopamine
transporters in hemi-Parkinsons disease. Neurology 46:
231237.
Marinus J, Ramaker C, Van Hilten JJ et al. (2002). Health
related quality of life in Parkinsons disease: a systematic
review of disease specific instruments. J Neurol Neurosurg
Psychiatry 72: 241248.
Marshall V, Grosset D (2003). Role of dopamine transporter
imaging in routine clinical practice. Mov Disord 18 (12):
14151423.
Marti Masso JF, Poza JJ (1996). Drug-induced or aggravated
parkinsonism: clinical signs and the changing pattern of
implicated drugs. Neurologia 11: 1015.
Marti-Masso JF, Poza JJ (1998). Cinnarizine-induced parkin-
sonism: ten years later. Mov Disord 13: 453456.
Marti Masso JF, Carrera N, Urtasun M (1993). Drug-induced
parkinsonism: a growing list. Mov Disord 8 (1): 125.
Melamed E, Achiron A, Shapira A et al. (1991). Persistent
and progressive parkinsonism after discontinuation of
chronic neuroleptic therapy: an additional tardive syn-
drome? Clin Neuropharmacol 14 (3): 273278.
Mena MA, Garcia de Yebenes MJ, Tabernero C et al.
(1995). Effects of calcium antagonists on the dopamine
system. Clin Neuropharmacol 18: 410426.
Metzer WS, Newton JE, Steele RW et al. (1989). HLA anti-
gens in drug-induced parkinsonism. Mov Disord 4 (2):
121128.
Metzer WS, Paige SR, Newton JE (1993). Inefficacy of
propranolol in attenuation of drug-induced parkinsonian
tremor. Mov Disord 8 (1): 4346.
Micheli F, Pardal MF, Gatto M et al. (1987). Flunarizine-
and cinnarizine-induced extrapyramidal reactions. Neurol-
ogy 37: 881884.
Micheli F, Fernandez Pardal M, Gatto M et al. (1993). Brux-
ism secondary to chronic antidopaminergic drug exposure.
Clin Neuropharmacol 16 (4): 315323.
Micheli FE, Pardal MM, Giannaula R et al. (1989). Move-
ment disorders and depression due to flunarizine and
cinnarizine. Mov Disord 4: 139146.
 DRUG-INDUCED PARKINSONISM
Moghal S, Rajput AH, Meleth R et al. (1995). Prevalence of
movement disorders in institutionalized elderly. Neuroepi-
demiology 14 (6): 297300.
Moleman P, Schmitz PJ, Ladee GA (1982). Extrapyramidal
side effects and oral haloperidol: an analysis of explanatory
patient and treatment characteristics. J Clin Psychiatry 43:
492496.
Morris JC, Drazner M, Fulling K et al. (1989). Clinical and
pathological aspects of parkinsonism in Alzheimers dis-
ease. A role for extranigral factors? Arch Neurol 46 (6):
651657.
Naito Y, Kuzuhara S (2004). Essential points to differentiate
various diseases causing parkinsonism. Nippon Rinsho
62 (9): 16081616.
Negrotti A, Calzetti S (1997). A long-term follow-up study
of cinnarizine- and flunarizine-induced parkinsonism.
Mov Disord 12: 107110.
Negrotti A, Calzetti S, Sasso E (1992). Calcium-entry blockers-
induced parkinsonism: possible role of inherited suscepti-
bility. Neurotoxicology 13 (1): 261264.
Nguyen N, Pradel V, Micallef J et al. (2004). Drug-induced
parkinson syndromes. Therapie 59 (1): 105112.
Offen D, Ziv I, Gorodin S et al. (1995). Dopamine-induced
programmedcell death in mouse thymocytes. Biochem
Biophys Acta 1268: 171177.
Ohashi K, Hamamura T, Lee Y et al. (1998). Propranolol
attenuates haloperidol-induced Fos expression in discrete
regions of rat brain: possible brain regions responsible
for akathisia. Brain Res 802: 134140.
OShea E, Colado MI (2003). Is frequent dosing with ecstasy
a risky business for dopamine-containing neurons? Trends
Pharmacol Sci 24: 272274.
OSuilleabhain P, Giller C (2003). Rapidly progressive
parkinsonism in a self-reported user of ecstasy and other
drugs. Mov Disord 18 (11): 13781381.
Pina Latorre MA, Modrego PJ, Rodilla F et al. (2001).
Parkinsonism and Parkinsons disease associated with
long-term administration of sertraline. J Clin Pharm Ther
26: 111112.
Pitagoras de Mattos J, Zuma de Rosso AL, Branco Correa
R et al. (2002). Movement disorders in 28 HIV-infected
patients. Arq Neuropsiquiatr 60: 525530.
Prosser ES, Csernansky JG, Kaplan J et al. (1987). Depres-
sion, parkinsonian symptoms, and negative symptoms in
schizophrenics treated with neuroleptics. J Nerv Ment
Dis 175 (2): 100105.
Prueter C, Habermeyer B, Norra C et al. (2003). Akathisia as
a side effect of antipsychotic treatment with quetiapine in
a patient with Parkinsons disease. Mov Disord 18:
712713.
Quinn NP (1995). Parkinsonism: recognition and differential
diagnosis. BMJ 310; 44: 7452.
Rajput AH, Rozdilsky B, Hornykienicz O (1982). Reversible
drug-induced parkinsonism, clinicopathologic study of
two cases. Neurology 39: 644646.
Rajput AH, Offord KP, Beard CM et al. (1984). Epidemiol-
ogy of parkinsonism: incidence, classification, and mortal-
ity. Ann Neurol 16: 278282.
415
Rajput AH, Pahwa R, Pahwa P et al. (1993). A Prognostic
significance of the onset mode in parkinsonism. Neurol-
ogy 43 (4): 829830.
Reyes MG, Faraldi F, Senseng CS et al. (1991). Nigral
degeneration in acquired immune deficiency syndrome
(AIDS). Acta Neuropathol (Berl) 82: 3944.
Robertson GS, Fibiger HC (1992). Neuroleptics increase
c-fos expression in the forebrain: contrasting effects of
haloperidol and clozapine. Neuroscience 46: 315328.
Rollema H, Skolnik M, DEngelbronner J et al. (1994). P(C)-
like neurotoxicity of a pyridinium metabolite derived from
haloperidol: in vivo microanalysis and in vitro mitochon-
drial studies. J Pharmacol Exp Ther 268: 380387.
Rosen A (1963). Drug-induced parkinsonism and its treat-
ment with Akineton. Ther Umsch 20: 912.
Saltz BL, Woerner MG, Robinson DG et al. (2000). Side
effects of antipsychotic drugs. Avoiding and minimizing
their impact in elderly patients. Postgrad Med 107 (2):
169178.
Sandyk R (1993). Cigarette smoking: effects on cognitive
functions and drug-induced parkinsonism in chronic schi-
zophrenia. Int J Neurosci 70 (34): 193197.
Sandyk R, Kay SR (1992). Positive and negative move-
ment disorders in schizophrenia. Int J Neurosci 66 (34):
143151.
Schmidt WJ, Mayerhofer A, Meyer A et al. (2002). Ecstasy
counteracts catalepsy in rats, an anti-parkinsonian effect?
Neurosci Lett 330: 251254.
Sethi KD, Zamrini EY (1990). Asymmetry in clinical fea-
tures of drug-induced parkinsonism. J Neuropsychiatry
Clin Neurosci 2 (1): 6466.
Spigset O (1999). Adverse reactions of selective serotonin
reuptake inhibitors: reports from a spontaneous reporting
system. Drug Saf 20: 277287.
Stacy M, Jankovic J (1992). Tardive tremor. Mov Disord 7:
5357.
Steck H (1954). Le syndrome extrapyramidal et diencephali-
que au cours de traitments au Largactril et au serpasil. Ann
Med Psychol 2: 737744.
Strous RD, Alvir JM, Robinson D et al. (2004). Premorbid
functioning in schizophrenia: relation to baseline symp-
toms, treatment response, and medication side effects.
Schizophr Bull 30 (2): 265278.
Sulzer D, Maidment NT, Rayport S (1993). Amphetamine
and other weak bases act to promote reverse transport of
dopamine in ventral midbrain neurons. J Neurochem 60:
527535.
Teive HA, Troiano AR, Germiniani FM et al. (2004). Flunar-
izine and cinnarizine-induced parkinsonism: a historical
and clinical analysis. Parkinsonism Relat Disord 10 (4):
243245.
Terland O, Flatmark T (1999). Drug-induced parkinsonism:
cinnarizine and flunarizine are potent uncouplers of the
vacuolar H-ATPase in catecholamine storage vesicles.
Neuropharmacology 38: 879882.
Tolosa E, Coelho M, Gallardo M (2003). DAT imaging in
drug-induced and psychogenic parkinsonism. Mov Disord
18 (Suppl 7): S28S33.
416 F. E. MICHELI AND M. G. CERSOSIMO
Uhnbrand L, Faurbye A (1969). Reversible and irreversible
dyskinesias after treatment with perphenazine, chlorpro-
mazine, reserpine and electroconvulsive therapy. Psycho-
pharmacology (Berl) 1: 408418.
Vaccari A, Saba P, Gessa G (1993). Potent, extra-channel influ-
ence of several calcium-channel modulators on striatal bind-
ing of [3H]tyramine. Neurochem Res 18: 11251130.
Van der Heijden FM, Tuinier S, Arts NJ et al. (2005). Catatonia:
disappeared or under-diagnosed? Psychopathology 38: 38.
Veitch K, Hue L (1994). Flunarizine and cinnarizine inhibit
mitochondrial complexes I and II: possible implication
for parkinsonism. Mol Pharmacol 45: 158163.
Wada Y, Yamaguchi N (1992). The rabbit syndrome and
antiparkinsonian medication in schizophrenic patients.
Neuropsychobiology 25 (3): 149152.
Weiden PJ, Mann JJ, Haas G et al. (1987). Clinical
nonrecognition of neuroleptic-induced movement
disorders: a cautionary study. Am J Psychiatry 144:
11481153.
Yamasue H, Fukui T, Fukuda R et al. (2003). Drug-induced
parkinsonism in relation to choline-containing compounds
measured by 1H-MR spectroscopy in putamen of chroni-
cally medicated patients with schizophrenia. Int J Neurop-
sychopharmacol 6 (4): 353360.
Ziv I, Melamed E, Nardi N et al. (1995). Dopamine induces
apoptosis-like cell death in cultured chick sympathetic
neuronsa possible novel pathogenic mechanism in
Parkinsons disease. Neurosci Lett 170: 136140.
Further Reading
Bhatia K, Daniel SE, Marsden CD (1993). Orofacial dysto-
nia and rest tremor in a patient with normal brain pathol-
ogy. Mov Disord 8 (3): 361362.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 52

Vascular parkinsonism

YACOV BALASH1 AND AMOS D. KORCZYN2*

1
Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
2
Sieratzki Chair of Neurology, Tel-Aviv University Medical School, Ramat-Aviv, Israel

Parkinsons disease (PD) is a degenerative brain
disease consisting of a progressive loss of dopaminer-
gic neurons in the substantia nigra (SN) and other neu-
ronal systems in certain brain areas. A loss of 6070%
of the nearly 450 000 dopamine-producing neurons of
the SN pars compacta and related decrease of the
dopamine level at the striatum must occur before PD
symptoms will take place. Several other diseases share
some clinical features of PD, like tremor, muscle rigid-
ity, hypokinesia and bradykinesia, gait instability and
freezing of gait. These disorders, collectively called
parkinsonian, can sometimes be clearly distinguished
from PD, although on other occasions the distinction
is difficult. Neuroimaging data (e.g. single-photon
emission computed tomography, SPECT), drug
response or the pathological demonstration of specific
changes in the SN or elsewhere can help in such cases.
The present review will discuss one of these entities,
called vascular parkinsonism (VP).
In 1929 Critchley, after analysis of the literature,
described five types of parkinsonism induced, accord-
ing to his opinion, by cerebrovascular diseases in
elderly patients. He identified the first (commonest)
type as rigidity, fixed facies and short-stepping gait
with absence of rest tremor; the second type is similar
but with the addition of pseudobulbar manifestations;
the third type has the addition of dementia and incon-
tinence; the fourth type shows signs of pyramidal dis-
ease; and the fifth has superimposition of a cerebellar
syndrome.
Critchley suggested that VP is a spectrum of hetero-
geneous syndromes resulting from multiple vascular
(arteriosclerotic or syphilitic) lesions in the basal
ganglia (BG), rather than a certain idiopathic disease.
This concept was criticized by Schwab and England
(1968) and Parkes et al. (1974), who claimed that a coin-
cidence or superposition of vascular changes in some
patients with PD could account for this overlap. Many
years later Critchley himself corrected his basic idea
of arteriosclerosis as a possible cause of PD and termed
the condition arteriosclerotic pseudoparkinsonism,
considered as alien to PD both clinically and pathogen-
etically (Critchley, 1981). Nevertheless, the neurologi-
cal entity of VP remains a matter of debate ever since.
Up to now, VP and PD are not clearly separated clini-
cally and for example are lumped together in the Ninth
Revision of the International Classification of Diseases
(ICD-9) as item 332.0 without any differentiation
between arteriosclerotic and idiopathic, primary
parkinsonism (ICD-9-CM International Classification
of Diseases, 2005).
Until recently, VP remained a poorly defined
clinicopathological entity, which overlaps with other
diagnoses. There are few pathologically verified
cases with suitable clinical correlation. The clinical
diagnosis of VP may be difficult and sometimes its
confirmation is only possible by neuropathological
examination, which is still considered the gold
standard for making the definite diagnosis of VP
(Jellinger, 2002). However, pathological diagnosis of
VP is non-specific and the changes are largely those
of small-vessel disease. Because of this fact there are
doubts whether VP should be regarded as a clinical
entity or, more correctly, whether VP is a variant of
small-vessel brain disease, manifested neurologically
by parkinsonian-like features, usually accompanied
by additional neurological signs (Zijlmans et al.,
2004).

*Correspondence to: Professor Amos D. Korczyn, Tel-Aviv University Medical School, Sieratzki Chair of Neurology,
Ramat-Aviv 69978, Israel. Email: amosk@tasmc.health.gov.il, Tel: 972-3-697-4229, Fax: 972-3-640-9113.
418 Y. BALASH AND A. D. KORCZYN
52.1. Parkinsonism associated with
brainstem lesions
Vascular lesions to the brain can cause almost any con-
stellation of neurological symptoms, depending on the
site of the lesions and other factors, and parkinsonism
cannot be assumed to be as exception. Thus, focal hemor-
rhagic and ischemic brainstem strokes were shown to
produce contralateral parkinsonian signs. To illustrate
the point we can discuss a case of a patient in whom right
hemiparkinsonism was diagnosed following hemorrhage
into the left SN. Technetium-99m hexamethylpropylene
amine oxime (99mTc-HMPAO) single photon emission
computed tomography (SPECT) showed reduced uptake
in the left putamen, globus pallidus (GP) and thalamus
(Abe and Yanagihara, 1996). The SPECT abnormalities
were assumed to be the result of the stroke, rather than
a coincidental abnormality.
In another report, a patient developed right-sided
cogwheel rigidity and resting tremor. In this case the
magnetic resonance imaging (MRI) scan showed a
contralateral midbrain hemorrhage affecting the SN
and n-isopropyl-p-123I iodoamphetamine (123I-IMP)
SPECT images showed reduced radioisotope uptake
in the left striatum, thalamus and frontal lobe (Inoue
et al., 1997).
These cases had in common an apoplectic appearance
of unilateral parkinsonian signs, which are the logical
result of an ischemic or hemorrhagic lesion of the SN
or the nigrostriatal tract and therefore constitute the most
straightforward examples of VP. Such cases should have
an acute onset, be non-progressive and even improve
spontaneously over time and respond to levodopa. How-
ever, such cases are extremely rare. Microscopically
such cases should not contain Lewy bodies.
The etiology of vascular damage should not
necessarily be atherosclerotic. Unilateral rest tremor
associated with bilateral extrapyramidal syndrome
responsive to levodopa was seen in a 25-year-old
man 7 months after subarachnoid hemorrhage due to
rupture of a peduncular subthalamic arteriovenous
malformation (Defer et al., 1994).
Parkinsonism has been described in patients with
central nervous system vasculitis (Fabiani et al.,
2002), rheumatoid arthritis (Ertan et al., 1999; Hrycaj
et al., 2003), systemic lupus erythematosus (Tan
et al., 2001; Garcia-Moreno and Chacon, 2002), anti-
phospholipid syndrome (Milanov and Bogdanova,
2001; Adhiyaman et al., 2002; Huang et al., 2002),
disseminated intravascular coagulation (Yoritaka
et al., 1997) and some neuroinfections like syphilis
(Critchley, 1929; Sandyk, 1983; Pineda et al., 2000).
Not unexpectedly, most patients had additional
manifestations, consistent with the damaged area. Of
course, more extensive lesions due to basilar occlusion
will also affect the SN but the extrapyramidal signs
will be overshadowed by other manifestations of
brainstem dysfunction.
Acute or subacute parkinsonism was also observed
as a result of tentorial herniations with brainstem
compression in patients with subdural hematomas of
traumatic or hypertensive etiology or as a result of
rupture of arterial aneurysms (Cosi and Tonali, 1964;
Pau et al., 1989; Trosch and Ransom, 1990; Turjanski
et al., 1997). In some of these cases parkinsonism
improved following removal of the hematoma (Sunada
et al., 1996), but in others it persisted and usually
responded to levodopa (Trosch and Ransom, 1990).
Sudden onset of small-stepping gait with stooped pos-
ture, severe akinesia and freezing of gait and increased
muscle tone with bilateral cogwheel phenomenon in
the arms was seen in a patient with a small high-
density lesion in the medial side of the right cerebral
peduncle and a lens-shaped low-density lesion in
the left putamen. On T1- and T2-weighted MRI
images a low signal was seen in a right peduncular
lesion extending to the SN, which was also partially
destroyed. The parkinsonism rapidly improved and
completely disappeared within 2 weeks. The high-
density lesion of the right peduncle also disappeared
on CT (Miyagi et al., 1992). Interestingly, destruc-
tion of the left subthalamic nucleus by hematoma
can improve contralateral parkinsonian rigidity after
extinction of the ballistic movement phase (Yamada
et al., 1992).
Kim (2001) reported patients with (hemi)parkinson-
ism after infarction in the territory of the anterior cer-
ebral artery. Parkinsonism was usually related to large
lesions involving the supplementary motor area and
observed after the motor dysfunction improved in
patients with initially severe limb weakness.
In patients with clinically suspected VP, the com-
parison of levodopa response with the pathologically
confirmed presence of macroscopic vascular damage
in the nigrostriatal pathway and cell loss in the SN
showed that the majority of patients with good or
excellent response to levodopa had infarcts or lacunae
in the SN in the absence of Lewy bodies (Zijlmans
et al., 2004).
These anecdotal cases of vascular lesions of the SN
or nigrostriatal pathway had features resembling PD,
including responsiveness to levodopa. However, the
follow-up, long-term prognosis and special features
of the dopaminergic treatment in relation to PD are
unknown. Motor fluctuations, so common in advanced
PD (Korczyn, 1972), have not so far been described in
cases such as these. Neither had a gradual increase in
dose over the years been documented. These cases
 VASCULAR PARKINSONISM
then typically consist of a non-progressive, levodopa-
responsive (hemi)parkinsonism of acute onset.
52.2. Parkinsonism associated with basal
ganglia lesions
Ischemic infarcts in the territory of the lenticulostriate
arteries were said to be the most frequent cause of
unilateral parkinsonism (Friedman et al., 1986;
Kulisevsky et al., 1996; Fenelon and Houeto, 1997;
Sibon et al., 2004a). In these cases, there was an acute
onset of the disorder with supportive imaging data to
suggest the vascular etiology.
A lateralized subacute parkinsonism with CT evi-
dence of a single lacunar infarct in the contralateral
BG was described by Lazzarino et al. (1990). A clini-
cal syndrome indistinguishable from PD, in which
postmortem examination revealed extensive lacunar
infarctions of the BG without evidence of coexistent
PD, was also reported (Murrow et al., 1990). However,
subdivision of parkinsonian patients with lacunar
infarcts in the BG into those with lacunes in the caudate
nucleus, lentiform nucleus or both did not correlate with
the clinical presentation (Reider-Groswasser et al.,
1995). Lacunar infarctions in the BG are frequently
observed in patients without parkinsonism and even in
completely asymptomatic cases. The extrapyramidal
signs, if present, can be asymmetrical without consis-
tent relationship to the side of the lacuna (Inzelberg
et al., 1994).
Specific regions of the brain, such as central white
matter, GP and hippocampus, are selectively vulnerable
to carbon monoxide (CO) (Koehler and Traystman,
2002). Parkinsonism after CO poisoning could be seen
in 10% of sufferers from CO encephalopathy (Choi,
2002). The most frequent signs are symmetric rigidity,
hypokinesia, masked face, glabellar sign, grasping,
short-step gait and retropulsion. Rest tremor has not
been observed but intentional tremor may occasionally
be found. The latency before the appearance of parkin-
sonism varies from 2 weeks to 6 months, but most
frequently occurs within 1 month of CO exposure.
Together with the parkinsonism, all patients have mild
to severely impaired cognitive functions. Other com-
mon symptoms are mutism, gait disturbances and
urinary incontinence. Extreme cases manifest a general
akinetic-mute state up to bed-bound (Lee and Marsden,
1994). Neither levodopa nor anticholinergic drugs were
shown to be effective. However, nearly 80% of patients
improved or recovered spontaneously within 6 months
(Choi, 2002).
Abnormally high signal bilaterally in the GP on T1-
weighted MRI images was observed in patients
419
following short terms after exposure to CO (Silverman
et al., 1993). MRI abnormalities augmented with CT
findings that revealed bilateral lucencies of the GP
suggested that their damage is of vascular origin, prob-
ably hemorrhagic infarction (Bianco and Floris, 1996).
Old necrotic lesions of the GP were earlier found on CT
scans (Klawans et al., 1982). No correlation between
the neuroimaging findings and the development of
parkinsonism has, however, been demonstrated (Choi,
2002). The damage in CO poisoning, however, is not
restricted to the BG and the direct role of the BG
damage is unknown in these cases.
52.3. Parkinsonism with white-matter lesions
A more common picture is that of short-stepped gait
with or without freezing (Giladi et al., 1997), lead-pipe
rigidity, no or mild upper-limb involvement, absence
of rest tremor, which develops insidiously, and nega-
tive response to levodopa (FitzGerald and Jankovic,
1989; Chang et al., 1992; Yamanouchi and Nagura,
1995; van Zagten et al., 1998; Winikates and Jankovic,
1999). Pseudobulbar palsy is observed in nearly half
of the patients (Yamanouchi and Nagura, 1995). The
patients frequently have cognitive decline and detrusor
overactivity (Cummings, 1994; Holstein et al., 1994).
Long tract signs in the limbs, indicating damage to
the corticospinal tracts, are found in more then half
of patients (Yamanouchi and Nagura, 1997). Many of
these patients have vascular risk factors and particu-
larly hypertension. The evolution of this disease is
typically slow, occurring over several month or even
years (Inzelberg et al., 1994), an evolution similar to
that seen in PD. Brain imaging shows diffuse subcortical
white-matter damage, not unlike that seen in patients
with Binswangers disease, sometimes accompanied by
unilateral or bilateral BG infarcts (Demirkiran et al.,
2001). Loss of postural reflexes and gait abnormalities
seen in these cases may indicate extrapyramidal features,
but are difficult to disassociate from coexisting spasticity
and the slowness may also reflect pyramidal, rather than
extrapyramidal, damage.
Comparing the brain pathology in these patients
with that in matched patients with Binswangers dis-
ease who had no parkinsonism according to clinical
records failed to reveal any significant differences in
the extent of BG damage (Yamanouchi and Nagura,
1997), thus pointing to the central role of white-matter
damage. The number of oligodendrocytes in the fron-
tal white matter of VP patients was significantly less
than in age-matched normal control subjects, but
significantly more than in those with Binswangers
disease. Widespread lesions in the frontal white matter
420 Y. BALASH AND A. D. KORCZYN
with only meager lesions in the BG were the main
pathological features of VP. The extent of frontal
white-matter pallor tended to be less broad in VP
than in Binswangers disease without parkinsonism
(Yamanouchi and Nagura, 1997). Marked atrophy in
the frontal cortex as well as lacunar lesions around
the lateral ventricles in VP were previously shown by
Grundl et al. (1991). The exact pathogenesis of these
white-matter changes is debated and likely heteroge-
neous, but generally thought to represent areas of
chronic or recurrent partial ischemia. Although
patients with BG lacunar infarct could recover sponta-
neously, those with frontal lobe infarcts could remain
static and those with periventricular and deep subcorti-
cal white-matter lesions usually had progressive
deterioration (Chang et al., 1992).
From the clinical and pathological data presented so
far, it seems that VP can occur as an acute syndrome,
resulting from lesions of the SN or the nigrostriatal
tract. These cases would be unilateral, non-progressive
and respond well to levodopa.
Diffuse white-matter damage, resulting from micro-
vascular lesions, typically manifests as a combination
of extrapyramidal, pyramidal and sometimes vascular
changes, frequently with cognitive decline
(Fig. 52.1). These cases would not typically respond
to levodopa, because the lesions involve the ascending
loop of the BGthalamiccortical loop (Bergman and
Deuschl, 2002), distal to the striatal site of action of
dopamine. Such cases are best described as pseudopar-
kinsonian because the extrapyramidal features are only
part of a more extensive clinical picture and because
of a lack of response to dopaminergic drugs.
BG lacunae are quite common in the elderly, fre-
quently without parkinsonian signs. If parkinsonian
signs do exist they do not bear a clear relationship to
the side of the lesion. The etiology of most BG lesions
is microvascular and in fact many, perhaps most, cases
with BG lacunae also have white-matter lesions and it
is best to look at these cases as reflecting an incidental
manifestation of BG lesions, whereas the principal
changes responsible for the motor dysfunction occur
in the white matter.
52.3.1. Brain imaging
The integrity of the nigrostriatal pathway can be
inferred from radioligand studies, in which the chemi-
cals used have affinity to the dopamine transporter
molecules at the terminals of the dopaminergic
synapses in the BG.
Small studies failed to find specific changes in VP
patients and indeed were not significantly different from
those in healthy individuals. The characteristic reduc-
tion of the uptake is pronounced in the contralateral
putamen of PD patients with unilateral symptoms, but
not in VP (Tzen et al., 2001). Normal striatal 123I-FP-
CIT binding with no significant differences in striatal
or subregional binding ratios compared with those of
the controls was seen in patients with VP. PD patients
had significantly diminished striatal binding compared
with that of controls (Lorberboym et al., 2004). As
compared to normal controls, patients with VP had sig-
nificant reduction of the ratio between N-acetylaspartate
and creatine plus phosphocreatine in the frontal cortex

Fig. 52.1. T1 and T2 magnetic resonance images of a 73-year-old patient with severe parkinsonism resistant to levodopa, gait
disorders, freezing of gait, recurrent falls and urinary urgency. Multiple infarcts are seen in the basal ganglia and brain white
matter as well as periventricular white-matter changes (own observation).
 VASCULAR PARKINSONISM
(Abe et al., 2000), suggesting a lesion beyond the clas-
sical extrapyramidal system.
52.3.2. Transcranial ultrasonography
The structurally normal SN could be visualized using
ultrasound waves delivered through a cranial
window, similar to that when flow in the middle
cerebral arteries is examined (Fig 52.2).
This method can distinguish between lesions affect-
ing the SN directly, such as PD and other disorders
causing extrapyramidal features (Berg et al., 1999). This
effect is based on the high iron level in the SN, thought to
promote generation of reactive oxygen species (Berg
et al., 2002) and has been shown to be specific to PD
(Berg et al., 2005). Thus, if all PD patients show a
bilateral SN hyperechogenicity, a low echogenic SN,
particularly combined with hyperechogenic lentiform
nuclei, could suggest other kinds of parkinsonism
(Walter et al., 2002; Behnke et al., 2005).
52.3.3. Additional methods of diagnosis of vascular
parkinsonism
Non-motor differences between VP and PD could be
used in the differential diagnosis:
1. Measurement of myocardial innervation may contri-
bute to the differential diagnosis of parkinsonism
421
(Berding et al., 2003; Goldstein, 2004). In patients
with PD, even without clinical evidence of autonomic
failure, reduction in iodine-123-metaiodobenzylgua-
nidine (123I-MIBG) uptake on scintigraphy occurs in
the heart. This is considered to be a specific finding
for PD and useful for the differential diagnosis from
other parkinsonian syndromes, occurring even in the
earliest stage of the disease (Taki et al., 2000). Parkin-
sonian syndromes other than PD did not demonstrate
reduction in MIBG uptake.
2. Testing olfactory function could be helpful in
differentiating VP from PD (Katzenschlager
et al., 2004). For example, olfactory function,
diagnosed according to the Pennsylvania smell
identification test, was significantly better in VP
patients than in PD and did not differ from normal
controls.
3. Colonic transit time measured in VP patients was
normal (about 59 hours), as opposed to PD
(Hardoff et al., 2001), where markedly slow transit
is observed (Jost et al., 1994).
52.3.4. Parkinsons disease versus vascular
parkinsonism: comparison of pathophysiology
PD results from the slowly progressive death of
selected populations of neurons, including the neuro-
melanin-containing dopaminergic neurons of the pars

Fig. 52.2. Sonographic image of the midbrain axial section in a patient with PD. The butterfly-shaped midbrain section of
low echogenicity is surrounded by the hyperchogenic basal cisterns (encircled area, centre of fig.). Note the marked hyperecho-
genicity of the left SN. This area is encircled for computerized measurement. Courtesy of Prof. Heinz Reichmann from the
Department of Neurology, Technical University of Dresden, Germany.
422 Y. BALASH AND A. D. KORCZYN
compacta of the SN, some other catecholaminergic
and serotoninergic brainstem nuclei, the cholinergic
nucleus basalis of Meynert, hypothalamic neurons
and small cortical neurons (particularly in the cingu-
late gyrus and entorhinal cortex), as well as the olfac-
tory bulb, sympathetic ganglia and parasympathetic
neurons in the gut (Korczyn, 1993; Braak and Braak,
2000).
According to the accepted model, dopamine loss
increases the activity of the indirect pathway and
reduces the activity of the direct pathway (Wich-
mann and DeLong, 2003). The final result of these
changes is an overexcitation of the main output
nuclei of the BG, GP interna and SN pars reticulata,
leading to inhibition of the thalamocortical motor
system. If the latter is essentially important in the
pathogenesis of rigidity, bradykinesia and loss of
postural reflexes, the white-matter lesions affecting
the latter pathway should result in a similar pheno-
type. However, these should not respond to levodopa
since there is no dopamine loss and in any case the
site of action of dopamine, the BG, is disconnected
from the motor cortex. Thompson and Marsden
(1987) suggested that the gait disorder of Binswan-
gers disease is probably due to diffuse vascular
lesions disrupting the interconnecting fiber tracts
between the BG and the motor cortex. Multiple lacu-
nar subcortical infarcts interrupting thalamocortical
drive are critical for the development of VP (Bhatia
and Marsden, 1994; van Zagten et al., 1998; Peralta
et al., 2004).
Three characteristic features of presynaptic process
affecting the dopaminergic system in PD are:
1. A major reduction of striatal levodopa uptake
of the nigrostriatal pathways (Leenders, 1997;
Broussolle et al., 1999; Brooks, 2004; Thobois
et al., 2004) which is correlated with degeneration
of the SN neurons found by pathological studies
(Jellinger, 2002; Snow, 2003). This process may be
accompanied by increased raclopride binding of
postsynaptic dopamine receptors in the putamen as
a sign of postsynaptic hypersensitivity in de novo,
drug-naive PD patients (Antonini et al., 1994; Kaasi-
nen et al., 2000).
2. An obvious effect of levodopa, which can be
seen particularly at the early stages of PD
(Hornykiewicz, 2002).
3. Presence of pathologic hallmarks degenerating
ubiquitin-positive neuronal processes or neurites
(Lewy neurites), which have been found in all
affected brainstem regions and especially at the
dorsal motor nucleus of the vagus and later in
the SN (Braak et al., 1999; Gai et al., 2000).
Thus, PD is a neurodegenerative disease, which
selectively affects certain categories of neurons,
chiefly manifests as a progressive diminution of
dopamine level in the nigrostriatal system, induces an
overactivation of the output nuclei of the BG and
STN and inhibits the thalamocortical motor system.
VP is a clinical syndrome that may have similarities
to the cardinal motor manifestations of PD. Approxi-
mately 10% of cases of parkinsonism clinically recog-
nized as PD could pathologically be the result of
cerebrovascular disease and, in contrast, the emer-
gence of one or more clinical signs of parkinsonism
was revealed in 30% patients after stroke (Sibon
et al., 2004b). As distinct from PD, however, VP is
the result of endothelial dysfunction and arteriolo-
sclerosis causing lacunar strokes or punctate hemor-
rhages, disseminated mainly in the centrum
semiovale and/or BG. Risk factors of cerebrovascular
disease, like hypertension, diabetes mellitus type 2,
hyper-/dyslipidemia, hyperhomocysteinemia, previous
stroke history and genetic predisposition are usually
present (Keskin and Yurdakul, 1996; Ekinci et al.,
2004).
In the pathogenesis of VP without a direct lesion
affecting the SN, the dopamine level and its
metabolites in the cerebrospinal fluid should be normal
(Loeffler et al., 1995). Thus, the accepted explanation
is that the clinical symptoms in VP are related to post-
synaptic lesions of the nigrostriatal system mainly as a
result of a patchy destruction of neurons or axons at
the putamen, GP and probably the cerebral white
matter.
52.4. Conclusions
VP is not a homogenous syndrome. Its etiology may
be atherosclerotic in many cases, but it could result
from embolic, arteritic or hemorrhagic processes.
Pathophysiologically, two forms of VP should be con-
sidered: the first affects the nigrostriatal system unilat-
erally. A discrete lesion of the SN or the nigrostriatal
pathway should be seen in imaging. These patients
should have an acute onset, should not progress and
should respond to levodopa. The other, much more
common group, consists of patients presenting at more
advanced age and with predominantly lower-body
involvement and gait abnormalities rather than tremor.
A history of stroke, heart disease, arterial hypertension
and other risk factors for stroke support a vascular ori-
gin of these symptoms. Usually, these patients do not
have the typical parkinsonian rest tremor. In these
cases imaging demonstrates an extensive white-matter
disease.
 VASCULAR PARKINSONISM
BG lesions are frequently seen in patients with
parkinsonian symptoms, but their relationship to the
pathology is unclear since the onset of parkinsonism
is rarely acute and not strictly contralateral to the
damage (typically, a small lacuna). Moreover, some
people with similar lacunae do not demonstrate any
clinical manifestations. Probably, this VP syndrome
is the result of coexistent white-matter changes.
These cases are most likely to represent the entity of
pseudoparkinsonism, as defined by Critchley. The
extensive damage ensures that a patient suffers not
only from increased muscle tone and bradykinesia,
but typically also from cognitive decline, pseudobulbar
syndrome, posture and gait instability and urinary
incontinence. Obviously these patients will respond
poorly to levodopa and there is an urgent need to
develop drugs that could help these patients.
References
Abe K, Yanagihara T (1996). Hemiparkinsonism following
haemorrhage in the contralateral substantia nigra.
Neuroradiology 38 (Suppl 1): S67S69.
Abe K, Terakawa H, Takanashi M et al. (2000). Proton
magnetic resonance spectroscopy of patients with
parkinsonism. Brain Res Bull 52: 589595.
Adhiyaman V, Meara RJ, Bhowmick BK (2002). Anti-
phospholipid syndrome and dystonia-parkinsonism: need
for anticoagulation. Parkinsonism Relat Disord 8: 215.
Antonini A, Schwarz J, Oertel WH et al. (1994). [11C]raclo-
pride and positron emission tomography in previously
untreated patients with Parkinsons disease: influence of
L-dopa and lisuride therapy on striatal dopamine
D2-receptors. Neurology 44: 13251329.
Behnke S, Berg D, Naumann M et al. (2005). Differentiation
of Parkinsons disease and atypical parkinsonian syn-
dromes by transcranial ultrasound. J Neurol Neurosurg
Psychiatry 76: 423425.
Berg D, Becker G, Zeiler B et al. (1999). Vulnerability of the
nigrostriatal system as detected by transcranial ultrasound.
Neurology 53: 10261031.
Berg D, Roggendorf W, Schroder U et al. (2002). Echogeni-
city of the substantia nigra: association with increased iron
content and marker for susceptibility to nigrostriatal
injury. Arch Neurol 59: 9991005.
Berg D, Merz B, Reiners K et al. (2005). Five-year follow-up
study of hyperechogenicity of the substantia nigra in
Parkinsons disease. Mov Disord 20: 383385.
Berding G, Schrader CH, Peschel T et al. (2003). [N-methyl
11C]meta-Hydroxyephedrine positron emission tomogra-
phy in Parkinsons disease and multiple system atrophy.
Eur J Nucl Med Mol Imaging 30: 127131.
Bergman H, Deuschl G (2002). Pathophysiology of
Parkinsons disease: from clinical neurology to basic
neuroscience and back. Mov Disord 17 (Suppl 3):
S28S40.
423
Bhatia KP, Marsden CD (1994). The behavioural and motor
consequences of focal lesions of the basal ganglia in man.
Brain 117: 859876.
Bianco F, Floris R (1996). MRI appearances consistent with
haemorrhagic infarction as an early manifestation of car-
bon monoxide poisoning. Neuroradiology 38 (Suppl 1):
S70S72.
Braak H, Braak E (2000). Pathoanatomy of Parkinsons dis-
ease. J Neurol 247 (Suppl 2): II3II10.
Braak H, Sandmann-Keil D, Gai W et al. (1999). Extensive
axonal Lewy neurites in Parkinsons disease: a novel
pathological feature revealed by alpha-synuclein immuno-
cytochemistry. Neurosci Lett 265: 6769.
Brooks DJ (2004). Neuroimaging in Parkinsons Disease.
Neurorx 1: 243254.
Broussolle E, Dentresangle C, Landais P et al. (1999). The
relation of putamen and caudate nucleus 18F-Dopa uptake
to motor and cognitive performances in Parkinsons dis-
ease. J Neurol Sci 166: 141151.
Chang CM, Yu YL, Ng HK et al. (1992). Vascular pseudo-
parkinsonism. Acta Neurol Scand 86: 588592.
Choi IS (2002). Parkinsonism after carbon monoxide poison-
ing. Eur Neurol 48: 3033.
Cosi V, Tonali P (1964). Acute Parkinson syndrome follow-
ing subarachnoid hemorrhage in a schizophrenic subject.
Riv Patol Nerv Ment 85: 287301.
Critchley M (1929). Arteriosclerotic parkinsonism. Brain 52:
2383.
Critchley M (1981). Arteriosclerotic pseudoparkinsonism.
In: FC Rose, R Capildeo (Eds.), 74: Pitman, London, pp.
745752.
Cummings JL (1994). Vascular subcortical dementias: clini-
cal aspects. Dementia 5: 177180.
Defer GL, Remy P, Malapert D et al. (1994). Rest tremor
and extrapyramidal symptoms after midbrain haemor-
rhage: clinical and 18F-dopa PET evaluation. J Neurol
Neurosurg Psychiatry 57: 987989.
Demirkiran M, Bozdemir H, Sarica Y (2001). Vascular par-
kinsonism: a distinct, heterogeneous clinical entity. Acta
Neurol Scand 104 (2): 6367.
Ekinci B, Apaydin H, Vural M et al. (2004). Two siblings
with homocystinuria presenting with dystonia and parkin-
sonism. Mov Disord 19: 962964.
Ertan S, Fresko I, Apaydin H et al. (1999). Extrapyramidal
type rigidity in rheumatoid arthritis. Rheumatology
(Oxford) 38: 627630.
Fabiani G, Teive HA, Germiniani FM et al. (2002). Reversi-
ble parkinsonian syndrome in systemic and brain vasculi-
tis. Mov Disord 17: 601604.
Fenelon G, Houeto JL (1997). Unilateral parkinsonism fol-
lowing a large infarct in the territory of the lenticulostriate
arteries. Mov Disord 12: 10861090.
FitzGerald PM, Jankovic J (1989). Lower body parkinsonism:
evidence for vascular etiology. Mov Disord 4: 249260.
Friedman A, Kang UJ, Tatemichi TK et al. (1986). A case
of parkinsonism following striatal lacunar infarction.
J Neurol Neurosurg Psychiatry 49: 10871088.
424 Y. BALASH AND A. D. KORCZYN
Gai WP, Yuan HX, Li XQ et al. (2000). In situ and in vitro
study of colocalization and segregation of alpha-synuclein,
ubiquitin, and lipids in Lewy bodies. Exp Neurol 166:
324333.
Garcia-Moreno JM, Chacon J (2002). Juvenile parkinsonism
as a manifestation of systemic lupus erythematosus: case
report and review of the literature. Mov Disord 17:
13291335.
Giladi N, Kao R, Fahn S (1997). Freezing phenomenon in
patients with parkinsonian syndromes. Mov Disord 12:
302305.
Goldstein DS (2004). Functional neuroimaging of sympa-
thetic innervation of the heart. Ann NY Acad Sci 1018:
231243.
Grundl W, Ziegler R, Westphal KP et al. (1991). Parkinsons
syndrome: cranial computed-tomography findings.
Their dependence on sex and age. Acta Med Hung 48:
127136.
Hardoff R, Sula M, Tamir A et al. (2001). Gastric emptying
time and gastric motility in patients with Parkinsons
disease. Mov Disord 16: 10411047.
Holstein J, Chatellier G, Piette F et al. (1994). Prevalence of
associated diseases in different types of dementia among
elderly institutionalized patients: analysis of 3447 records.
J Am Geriatr Soc 42: 972977.
Hornykiewicz O (2002). L-DOPA: from a biologically inac-
tive amino acid to a successful therapeutic agent. Amino
Acids 23: 6570.
Hrycaj P, Korczowska I, Lacki JK (2003). Severe Parkin-
sons disease in rheumatoid arthritis patient treated with
infliximab. Rheumatology (Oxford) 42: 702703.
Huang Z, Jacewicz M, Pfeiffer RF (2002). Anticardiolipin
antibody in vascular parkinsonism. Mov Disord 17:
992997.
ICD-9-CM International Classification of Diseases (2005),
9th Rev: Clinical Modification Vol. 1. Practice Manage-
ment Information Corporation.
Inoue H, Udaka F, Takahashi M et al. (1997). Secondary
parkinsonism following midbrain hemorrhage. Rinsho
Shinkeigaku 37: 266269.
Inzelberg R, Bornstein NM, Reider I et al. (1994). Basal
ganglia lacunes and parkinsonism. Neuroepidemiology
13: 108112.
Jellinger KA (2002). Vascular parkinsonismneuropathological
findings. Acta Neurol Scand 105: 414415.
Jost WH, Jung G, Schimrigk K (1994). Colonic transit time
in non-idiopathic Parkinsons syndrome. Eur Neurol 34:
329331.
Kaasinen V, Ruottinen HM, Nagren K et al. (2000). Upregu-
lation of putaminal dopamine D2 receptors in early
Parkinsons disease: a comparative PET study with
[11C] raclopride and [11C] N-methylspiperone. J Nucl
Med 41: 6570.
Katzenschlager R, Zijlmans J, Evans A et al. (2004). Olfac-
tory function distinguishes vascular parkinsonism from
Parkinsons disease. J Neurol Neurosurg Psychiatry 75:
17491752.
Keskin S, Yurdakul F (1996). Parkinsonian manifestations in
a patient with homocystinuria. Parkinsonian manifesta-
tions in a patient with homocystinuria. Child Neurol 11:
235236.
Kim JS (2001). Involuntary movements after anterior cere-
bral artery territory infarction. Stroke 32: 258261.
Klawans HL, Stein RW, Tanner CM et al. (1982). A pure
parkinsonian syndrome following acute carbon monoxide
intoxication. Arch Neurol 39: 302304.
Koehler RC, Traystman RJ (2002). Cerebrovascular effects
of carbon monoxide. Antioxid Redox Signal 4: 279290.
Korczyn AD (1972). Pathophysiology of drug-induced dys-
kinesias. Neuropharmacology 11: 601607.
Korczyn AD (1993). The gut in PD. Neurology 43: 629630.
Kulisevsky J, Berthier ML, Avila A et al. (1996). Unilateral
parkinsonism and stereotyped movements following a
right lenticular infarction. Mov Disord 11: 752754.
Lazzarino LG, Nicolai A, Toppani D (1990). Subacute par-
kinsonism from a single lacunar infarct in the basal gang-
lia. Acta Neurol (Napoli) 12: 292295.
Loeffler DA, LeWitt PA, DeMaggio AJ et al. (1995). Mar-
kers of dopamine depletion and compensatory response
in striatum and cerebrospinal fluid. J Neural Transm Park
Dis Dement Sect 9: 4553.
Lorberboym M, Djaldetti R, Melamed E et al. (2004).
123I-FP-CIT SPECT imaging of dopamine transporters
in patients with cerebrovascular disease and clinical diag-
nosis of vascular parkinsonism. J Nucl Med 45:
16881693.
Lee MS, Marsden CD (1994). Neurological sequelae follow-
ing carbon monoxide poisoning clinical course and out-
come according to the clinical types and brain computed
tomography scan findings. Mov Disord 9: 550558.
Leenders KL (1997). Pathophysiology of movement disor-
ders studied using PET. J Neural Transm Suppl 50: 3946.
Milanov I, Bogdanova D (2001). Antiphospholipid syndrome
and dystonia-parkinsonism. A case report. Parkinsonism
Relat Disord 7: 139141.
Miyagi K, Imaizumi T, Nagura H et al. (1992). A case of
transient parkinsonism due to mesencephalic hemorrhage.
Rinsho Shinkeigaku 32: 743746.
Murrow RW, Schweiger GD, Kepes JJ et al. (1990). Parkin-
sonism due to a basal ganglia lacunar state: clinicopatho-
logic correlation. Neurology 40: 897900.
Parkes JD, Marsden CD, Rees JE et al. (1974). Parkinsons
disease, cerebroarteriosclerosis, and senile dementia. Q J
Med 43: 4961.
Pau A, Brambilla M, Cossu M et al. (1989). Parkinsonism in
the presence of intracranial extracerebral haematomas.
Acta Neurochir (Wien) 96: 159160.
Peralta C, Werner P, Holl B et al. (2004). Parkinsonism fol-
lowing striatal infarcts: incidence in a prospective stroke
unit cohort. J Neural Transm 111: 14731483.
 VASCULAR PARKINSONISM
Pineda DA, Buritica O, Sanchez JL et al. (2000). Parkinso-
nian syndromes in Medellin (Colombia). Rev Neurol 31:
936943.
Reider-Groswasser I, Bornstein NM, Korczyn AD (1995).
Parkinsonism in patients with lucanar infarcts of the basal
ganglia. Eur Neurol 35: 4649.
Sandyk R (1983). Parkinsonism secondary to neurosyphilis.
A case report. S Afr Med J 63: 665666.
Schwab RS, England AC (1968). Parkinson syndromes due
to various specific causes. In: PJ Vinken, GW Bruyn
(Eds.), Vol. 6, North-Holland Publishing Co, Amsterdam,
pp. 227247.
Sibon I, Guyot M, Allard M et al. (2004a). Parkinsonism
following anterior choroidal artery stroke. Eur J Neurol
11: 283284.
Sibon I, Fenelon G, Quinn NP et al. (2004b). Vascular par-
kinsonism. J Neurol 251: 513524.
Silverman CS, Brenner J, Murtagh FR (1993). Hemorrhagic
necrosis and vascular injury in carbon monoxide poison-
ing: MR demonstration. AJNR Am J Neuroradiol 14:
168170.
Snow B (2003). Objective measures for the progression of
Parkinsons disease. J Neurol Neurosurg Psychiatry 74:
287.
Sunada I, Inoue T, Tamura K et al. (1996). Parkinsonism due
to chronic subdural hematoma. Neurol Med Chir (Tokyo)
36: 99101.
Taki J, Nakajima K, Hwang EH et al. (2000). Peripheral
sympathetic dysfunction in patients with Parkinsons
disease without autonomic failure is heart selective and
disease specific. Eur J Nucl Med 27: 566573.
Tan EK, Chan LL, Auchus AP (2001). Reversible parkinsonism
in systemic lupus erythematosus. J Neurol Sci 193: 5357.
Thobois S, Jahanshahi M, Pinto S et al. (2004). PET and
SPECT functional imaging studies in Parkinsonian syn-
dromes: from the lesion to its consequences. Neuroimage
23: 116.
Thompson PD, Marsden CD (1987). Gait disorder of subcor-
tical arteriosclerotic encephalopathy: Binswangers
disease. Mov Disord 2: 18.
425
Trosch RM, Ransom BR (1990). Levodopa-responsive par-
kinsonism following central herniation due to bilateral
subdural hematomas. Neurology 40: 376377.
Turjanski N, Pentland B, Lees AJ et al. (1997). Parkinsonism
associated with acute intracranial hematomas: an [18F]
dopa positron-emission tomography study. Mov Disord
12: 10351038.
Tzen KY, Lu CS, Yen TC et al. (2001). Differential diagno-
sis of Parkinsons disease and vascular parkinsonism by
(99m)Tc-TRODAT-1. J Nucl Med 42: 408413.
Van Zagten M, Lodder J, Kessels F (1998). Gait disorder and
parkinsonian signs in patients with stroke related to small
deep infarcts and white matter lesions. Mov Disord 13:
8995.
Walter U, Wittstock M, Benecke R et al. (2002). Substantia
nigra echogenicity is normal in non-extrapyramidal cere-
bral disorders but increased in Parkinsons disease.
J Neural Transm 109: 191196.
Wichmann T, DeLong MR (2003). Pathophysiology of Par-
kinsons disease: the MPTP primate model of the human
disorder. Ann NY Acad Sci 991: 199213.
Winikates J, Jankovic J (1999). Clinical correlates of vascu-
lar parkinsonism. Arch Neurol 56: 98102.
Yamada A, Takeuchi H, Miki H (1992). Unilateral abolition
of parkinsonian rigidity after subthalamic nucleus hemor-
rhage. Rinsho Shinkeigaku 32: 887889.
Yamanouchi H, Nagura H (1995). Cerebrovascular parkin-
sonismclinicopathologic study. Rinsho Shinkeigaku
35: 14571458.
Yamanouchi H, Nagura H (1997). Neurological signs and
frontal white matter lesions in vascular parkinsonism.
A clinicopathologic study. Stroke 28: 965969.
Yoritaka A, Hattori T, Hattori Y, Mori H, Matsuoka S, Shirai
T, Kondo T, Mizuno Y (1997). A 85-year-old woman with
the onset of progressive gait disturbance at 80 years of the
age. No To Shinkei 49: 379389.
Zijlmans JC, Daniel SE, Hughes AJ, Revesz T, Lees AJ (2004).
Clinicopathological investigation of vascular parkinsonism,
including clinical criteria for diagnosis. Mov Disord 19:
630640.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 53

Old age and Parkinsons disease

ALEX RAJPUT AND ALI H. RAJPUT*

University of Saskatchewan, Saskatoon, SK, Canada

53.1. Introduction
There is no uniformly agreed definition of old age. For
the purpose of this chapter, we will use the commonly uti-
lized employment-related retirement age of 65 as the start
of old age (Desai et al., 1990; Canadian Study of Health
and Aging Working Group, 1994; Moghal et al., 1994,
1995). The proportion of the elderly has been steadily
rising for several decades in western countries (Rowe,
1988). Therefore, the frequency of those disorders that
are concentrated in old age is progressively increasing.
The motor manifestations of Parkinsons disease
(PD) include bradykinesia, rigidity, tremor, postural
abnormality, gait abnormality, impaired postural ref-
lexes, extraocular movement abnormality, presence
of primitive reflexes and reduced facial expression.
Some similar features also seen in the normal elderly.
The most common variant of Parkinson syndrome
(PS: parkinsonism) is the Lewy body disease also
known as PD or idiopathic PD (Jellinger, 1987; Duvoi-
sin and Golbe, 1989; Rajput et al., 1991c; Bower et al.,
1999; Robinson and Rajput, 2005). The primary focus
of this chapter will be on aging and PD, with brief
consideration of the less common variants of PS and
of other disorders that may mimic PD.
Normal posture and gait depend on vestibular,
visual, proprioceptive and motor functions and an abil-
ity to adjust to the postural sway. There is a decline in
vestibular (Parker, 1994), visual (Kline et al., 1982;
Matjucha and Katz, 1994), proprioceptive (Drachman
et al., 1994) and motor functions (Drachman et al.,
1994), as well as reduced muscle mass (Lexell et al.,
1988) in old age. In addition, there is increased pos-
tural sway (Maki et al., 1990; Baloh et al., 1994), pos-
tural instability (Weiner et al., 1984; Ross et al., 2004),
stooped posture (Ross et al., 2004) and reduced range
of vertical gaze (Jenkyn et al., 1985) with aging. These
age-related anatomical and physiological changes lead
to a slowed motor function (bradykinesia) and altera-
tions in station, posture, gait and postural reflexes, all
of which are well-known features of PD. Therefore,
normal changes of aging need to be distinguished from
PD in elderly persons. Most PS, including PD, are con-
centrated in later age. Thus, the incidence of PS and
PD rises sharply with advancing age.
The pathological hallmark of PD is a marked loss
of substantia nigra pigmented neurons and neuronal
Lewy body inclusions (Jellinger, 1987; Duvoisin and
Golbe, 1989; Rajput et al., 1991c). Autopsy studies
show that a significant proportion of the elderly with
no clinical features of PS have incidental Lewy body
inclusions in the brain. The frequency of incidental
Lewy body inclusions in autopsy brains rises with
age, reaching 13% in the ninth decade (Graybiel
et al., 1990; Fearnley and Lees, 1991; Gibb, 1991;
Ross et al., 2004). The incidental Lewy body cases
are believed to represent a preclinical stage of PD
(Fearnley and Lees, 1991; Gibb, 1991; Ross et al.,
2004) who would develop clinical features of PD with
time or with an added stress of neuroleptic use (Rajput
et al., 1982). The elderly have a disproportionately
large number of other diseases (Rowe, 1988). They
receive more prescription and non-prescription drugs
compared to the younger population and have a higher
incidence of drug adverse effects, including parkinson-
ism (Blaschke et al., 1985; Rowe, 1988; Desai et al.,
1990). Other disorders which are common in old age,
notably stroke and Alzheimers disease, may be asso-
ciated with clinical features of parkinsonism. When
all these factors are considered together, the elderly
represent a large segment of the population with an
increased risk of developing parkinsonism or PD.

*Correspondence to: Professor Ali H. Rajput, University of Saskatchewan, Royal University Hospital, 103 Hospital Drive,
Saskatoon, SK S7N OW8, Canada. E-mail: ali.rajput@saskatoonhealthregion.ca, Tel: (306) 966-8009, Fax: (306) 966-8030.
428 A. RAJPUT AND A. H. RAJPUT
The onset of PS is very rare before age 30 years
(Rajput et al., 1984a; Marttila, 1987; Bower et al.,
1999) and the incidence and prevalence rates rise with
age. Whereas there were 0.8/105 new cases of PS
before age 30 years and 26.5/105 new cases per year
between ages 50 and 59 years, the annual incidence
rose to 211.6 between ages 70 and 79 and was 304.8/
105 for those aged 8099 years in one community
(Bower et al., 1999). Assuming no competing cause
of death, the risk of developing PS was estimated at
0.7% by age 60 and 7.5% by age 90 years (Bower
et al., 1999).
The other major consideration is the survival after
onset of disease, as that would impact the number of
PS cases in old age. Levodopa is the most widely used
drug for PD in industrialized countries (Global Parkin-
sons Disease Survey (GPDS) Steering Committee,
2002). Patients treated with levodopa have a
significantly longer survival after onset of illness
(Rajput, 2001) compared to untreated cases and that
observed in the past (Hoehn and Yahr, 1967). Higher
incidence and prolonged survival result in higher
prevalence rates in the elderly population.
Bennett et al. (1996) studied the prevalence of par-
kinsonism in community residents 65 years and older.
The overall prevalence of PS between age 65 and 74
years was 14.9%, between 75 and 85 years it was
29.5% and in those over age 85 years the prevalence
rate was 52.4%. In another community-based study,
Schoenberg et al. (1985) reported that the prevalence
rate of PS in those over 75 years was more than seven
times higher compared to those aged 4060 years.
Because of the similarities between normal aging
and PD motor features, the first question the neuro-
logist must answer is whether the clinical features are
an indication of old age or of PD.
53.2. Normal aging and Parkinsons disease
As noted above, some of the motor manifestations of
aging resemble PS. Because there are no readily avail-
able biological markers to distinguish between normal
aging and parkinsonism, the best tool is careful clinical
assessment (Weiner et al., 1984; Jenkyn et al., 1985;
Sudarsky, 1990, 1994; Rajput, 1993c). The presence
of two of the three cardinal features of bradykinesia,
rigidity and resting tremor are needed for a clinical
diagnosis of PS (Rajput et al., 1991a, 2002; Rajput,
1994a; de Rijk et al., 1997). Impaired postural reflexes
are not used as additional evidence for PS diagnosis in
the elderly (Rajput et al., 1991c; Rajput, 1994a), as
they are also seen in a large proportion of the normal
elderly (Weiner et al., 1984; Ross et al., 2004).
Impaired postural reflexes evolve relatively late in
younger cases and are used to classify the clinical
severity of the disease (Hoehn and Yahr, 1967; Fahn
et al., 1987).
53.2.1. Bradykinesia of old age and parkinsonism
The akinesiahypokinesiabradykinesia complex
implies slowed motor function. Akinesia is the inabil-
ity to initiate movement, hypokinesia indicates
reduced amplitude of movement and bradykinesia im-
plies slowed speed of movement (Marsden, 1989). In
clinical practice, these three features are collectively
referred to as bradykinesia. Bradykinesia is the cardi-
nal feature of PD and other variants of PS (Webster,
1968; Fahn et al., 1987; Marsden, 1989; Rajput et al.,
1991c; Rajput, 1994a). The clinical manifestations of
bradykinesia are similar in all variants of parkinson-
ism, though there may be different anatomical sites
of involvement. Slowed motor function is also a part
of normal aging (Duncan and Wilson, 1989; Drachman
et al., 1994; Bennett et al., 1996; Ross et al., 2004).
Distinction between the normal age-related slowing
and bradykinesia of parkinsonism is therefore impor-
tant. Table 53.1 summarizes features that are helpful
in distinguishing between age-related slowing, PS
and some other neurological and focal abnormalities
which may cause motor slowing.
Bradykinesia as a symptom reported by PD patients
depends on the lifestyle. In general, the motor activ-
ities that require repeated change in direction are
impaired early. Someone who jogs or walks for exer-
cise may note a foot dragging when tired, a piano
player may report being unable to play certain notes
and a writer would find slowed and smaller handwrit-
ing. Slowing of other activities, e.g. walking, easing
gracefully into a chair and difficulty turning in bed
are other common complaints. In clinical practice, bra-
dykinesia is tested by observing the patient as he/she
sits, talks, walks and when asked to perform certain
motor tasks.
The normal automatic arm-swing with walking,
hand gestures during conversation and facial expres-
sion are all reduced in parkinsonism. Simons et al.
(2004) studied 19 PD patients and 26 healthy controls
for emotional expression during conversation and
while watching videos and for the ability to use an
emotional facial gesture or imitate facial movements.
All these factors were reduced in PD cases compared
to controls (Simons et al., 2004). In a microcomputer-
based observation, Katsikitis (1988) noted that, when
watching funny cartoons, parkinsonian patients smiled
less frequently than the controls.
 OLD AGE AND PARKINSONS DISEASE 429
Table 53.1
Motor slowing in aging, parkinsonism and some other disorders

Other nervous system

Normal age-related Parkinsonism Focal pathology pathology (central or
slowing bradykinesia emulating slowing peripheral) causing slowing

Symmetry of Symmetrical Often Asymmetrical Frequently asymmetrical

findings asymmetrical
Focal Normal Normal Abnormal Normal
examination
Tone Normal Increased Normal (if pain and May have paratonia in
rigidity joint movement demented cases Spasticity
restriction if corticospinal
discounted). Test at involvement Decreased if
unaffected joint lower motor neuron
helpful to identify pathology
normal tone
Sensory Normal (except vibration As in normal As in normal aging May be impaired depending
function reduction in feet) aging on the nature of lesion
Reflexes Normal symmetrical As in normal As in normal aging Hyperactive with extensor
(ankle jerks may be aging plantar or hypoactive
hypoactive) Plantars depending on site of lesion.
flexor Frequently asymmetrical
Muscle Normal Normal Normal, but patient Reduced or inconsistent
strength unable to exert fully
due to pain or joint
restriction
Rest tremor Absent Usually present Absent Absent
Facial Normal Reduced Normal Normal
expression
Handwriting Normal Micrographia Normal Normal
Speech Normal Low volume Normal Normal

The smooth face of young age becomes wrinkled in
the elderly. Facial immobility in PD results in a mask-
like face and prolonged facial immobility leads to a
smoother and younger-looking face. Since the facial
wrinkles develop over many years, the reduced facial
expression must exist for a long time before parkinson-
ism is clinically evident. Depression, which is com-
mon in PD, adds to the reduced facial expression.
Motor slowing is most pronounced in those activ-
ities that require repetitive, simultaneous or sequential
movements. Repetitive movements of finger/thumb-
tapping, forearm pronation/supination, fist-opening/
closing and foot-tapping are common clinical maneu-
vers utilized to assess bradykinesia (Fahn et al.,
1987). With repeated movements, the amplitude of
the movement declines and the movement may arrest.
The total slowing of an activity is more pronounced
than the sum total of the slowing of each component
of the complex movement (Marsden, 1989).
In most PD patients, the bradykinesia and rigidity
are of comparable severity when the standardized
assessments are done (Webster, 1968; Fahn et al.,
1987). However, the pathophysiology of bradykinesia
and rigidity may not be the same in elderly cases.
Levodopa which relieves rigidity may not improve
bradykinesia in advanced PD (Marsden, 1989).
Asymmetry of bradykinesia without any other focal
or neurological cause is a strong indication of PD.
That should, however, be assessed with more than
one activity. We have observed asymmetrically
reduced arm-swing without any other features of PS
in several otherwise neurologically normal members
of one family. It is not uncommon for the elderly to
have a shoulder problem which restricts movements.
When there is evidence of localized motor function
slowing, ask the patient if there is pain associated with
the movement and evaluate the area for any mechani-
cal or pain-related passive movement restriction at the
430 A. RAJPUT AND A. H. RAJPUT
joint. Detailed assessment of sensory function, motor
strength, tone and reflexes, as noted in Table 53.1, is
a valuable adjunct to distinguish parkinsonism from
age-related slowing and other disorders. The age-related
slowing is typically symmetrical and generalized.
Although bradykinesia due to PD is often asymmetrical,
it is more often symmetrical in multiple system atrophy
and in progressive supranuclear palsy.
The severity of bradykinesia in PD is reported to
correlate with the degree of striatal dopamine loss
(Ehringer and Hornykiewicz, 1960b, 1998; Hornykie-
wicz and Kish, 1986; Agid et al., 1987, 1989; Agid,
1991). We investigated the relationship between Uni-
fied Parkinsons Disease Rating Scale (UPDRS)-based
bradykinesia (Fahn et al., 1987) and the striatal dopa-
mine levels in PD. The striatal dopamine loss and the
severity of bradykinesia revealed a correlation in
the akinetic-rigid PD cases but not in the tremor-domi-
nant or the mixed clinical picture cases (unpublished
observations).
53.2.2. Tone change in old age, parkinsonism and
some other disorders
The major tone abnormality in PS is rigidity. It is clini-
cally similar in different variants of PS. Some PS
patients may also manifest dystonia.
Tone is defined as involuntary resistance to passive
movement. In testing tone, one depends on patient
cooperation. The patient is asked to relax: neither to
assist nor resist the passive movement attempted by
the examiner. In the normal elderly, there is no change
in tone. Rigidity may manifest as continued smooth
resistance to passive movement through the entire
range of movement. That is known as lead-pipe rigid-
ity. More often in rigidity, the increased tone is asso-
ciated with recurring interruptionsa ratchety quality
known as cogwheel rigidity.
When asked to relax, most patients do so and allow
satisfactory assessment of tone. The instructions may
need to be repeated to ensure patient cooperation dur-
ing the passive movement. Rigidity in PD patients is
predictably reproducible and is approximately equal
in the muscles with opposite mode of action (Findley
and Koller, 1995). Cogwheel rigidity is usually
observed in patients who have hypertonicity as well
as tremor. However, some patients with no visible tre-
mor may also manifest cogwheel rigidity. The patient
may try to cooperate and actively move the body part
in the same direction as the examiner moves it. In such
case, the passive movement should be performed irre-
gularly so that the patient cannot predict and oppose
or facilitate the movement. Distracting the patient by
asking a question may be helpful in the evaluation.
Cognition and language impairment are more com-
mon in the elderly and impact their ability to cooperate
for adequate assessment. They may resist passive
movement proportional to the force applied by the
examiner. Alternatively, the patient may oppose the
passive movement intermittently, giving it a feeling of
cogwheel rigidity. This is known as paratonia or gegen-
halten (Klawans, 1981; Jenkyn et al., 1985; Rajput,
1993c). Such tone abnormality is not reproducible in a
predictable fashion (Jenkyn et al., 1985; de la Monte
et al., 1989; Rajput, 1993c).
Dystonia is characterized by co-contraction of ago-
nist and antagonist muscles. The force of muscle con-
traction is, however, unequal in the opposing muscle
groups. On passive movement, there is greater resis-
tance when the part is moved away from the dystonic
posture compared to when the movement is attempted
in the same direction as the dystonic posture. Dystonia
may be associated with intermittent tremor mainly
when the body part is moved away from the dystonic
position. This is known as dystonic tremor.
The increased tone with corticospinal tract lesions
is known as spasticity. It is characterized by a velocity
-dependent catch which is followed by a release
without further resistance, as seen in opening or clos-
ing a pocket knife. It is, therefore, called clasp-knife
hypertonicity. Although spasticity and rigidity are easy
to distinguish in most cases, in cases with mild spasti-
city the distinction from rigidity may be difficult. The
following maneuver may be helpful: Have the patient
lie on his/her back, lift one leg with one hand under
the heel and put your other arm under the extended
knee of the patient. Now suddenly release the heel grip
and allow the leg to flex at the knee, falling towards
the examining table. In case of spasticity, there will
be an initial catch and then the leg will drop to the
table rapidly. In the case of rigidity, the leg falls down
at a steady speed throughout the downward movement.
An additional distinguishing feature is the change in
reflexes. Muscle stretch reflexes are hyperactive in cor-
ticospinal lesions but there is little, if any, change in PD.
The plantar response is extensor in corticospinal tract
lesions whereas in PD the plantar reflex is flexor or
equivocal. In some PS patients, there is spontaneous
or ambulation-related dorsiflexion of the big toe. This
dystonic posture is called striatal toe (Duvoisin,
1990). When the plantar reflex is performed, the big
toe does not extend further but may flex.
53.2.3. Tone testing and tremor disorders
The presence of medium- or large-amplitude tremor
may produce rhythmic interruption of the passive move-
ment known as cogwheeling phenomenon (Findley
 OLD AGE AND PARKINSONS DISEASE
et al., 1981; Findley and Koller, 1995). In such cases
increased tone on reinforcement is known as Froments
phenomenon. During examination, when the ratchety
feeling first emerges, stop further movement and gently
hold the body part still. In Froments phenomenon, the
rhythmic movement continues. If, on the other hand,
there is cogwheel rigidity related to PD, there would
be no continuation of the rhythmic movement. In
patients with head tremor, when the passive move-
ment is performed in the direction of the tremor, there
may be cogwheeling and on reinforcement Froments
phenomenon. Passive movement in the direction
where there is no tremor will help determine the tone
more accurately. In PD-related neck rigidity, there
will be resistance in all directions of neck movements
lateral flexion and turning the head from side to
side. Special attention should be paid to the elderly
431
who are likely to have degenerative cervical spine
changes. If there is still a doubt about the nature of
the cogwheeling at a joint, e.g. at wrist, the tone
should be tested at another joint where there is no tre-
mor, such as the shoulder.
Table 53.2 summarizes the tone change in the normal
elderly, parkinsonism and selected disorders.
53.2.4. Station, posture and postural reflexes in old
age and Parkinsons disease
The manner or attitude of standing is known as station
and the position of the whole body and its different
parts indicates the posture. Visual, vestibular and
proprioceptive functions, which are critical for main-
taining normal posture, all decline with normal aging
(Kline et al., 1982; Drachman et al., 1994; Matjucha

Table 53.2
Tone changes in elderly Parkinsons disease and selected conditions

Cogwheeling phe-
Parkinsons Spasticity Paratonia nomenon (Froments
Normal elderly disease rigidity (mild) (gegenhalten) phenomenon)

Characteristic Equal and normal Resistance Increased tone Irregular, Rhythmic

resistance in sustained and Velocity- intermittently Interruption of
all directions equal in opposite dependent increased tone or passive movement
of movement directions of catch progressively coinciding with
movement. clasp-knife greater tremor. Rhythmic
Reproducible resistance on resistance to
attempted passive movement
movement only seen on
Unpredictable reinforcement in
tremor-producing
conditions
Froments
phenomenon
Symmetry Symmetrical Usually Frequently Usually May be symmetrical
asymmetrical asymmetrical symmetrical or asymmetrical
depending on
tremor location
Reflexes Normal Reduced Normal. May have Exaggerated Usually normal Normal
at ankles striatal toe and extensor
Plantars flexor plantar
response
Tremor Absent Frequently part of Absent Absent Prominent feature
Parkinsons
disease
Reinforcement- No significant Usually May increase Unpredictable Rhythmic
related tone change. asymmetrical slightly change symmetrical
increase Minimal, if increase increase
any, and is (Froments
symmetrical phenomenon)
432 A. RAJPUT AND A. H. RAJPUT
and Katz, 1994; Parker, 1994). There is normally
swaying of the body while in the standing position;
this increases with advancing age (Maki et al., 1990;
Baloh et al., 1994; Bennett et al., 1996; Du Pasquier
et al., 2003; Fransson et al., 2004). Dizziness is the
subjective sensation of instability. By the age of 65
years, 30%, and by age 80 years, 66% of the general
population would have experienced dizziness at some
time (Luxon, 1984). This subjective feeling adds to
postural instability in older individuals.
Normal elderly people have a slightly wide base
when standing and walking (Drachman et al., 1994).
The body becomes flexed at the neck and trunk (Ross
et al., 2004) but the knees and elbows remain straight
in old age. By contrast, in PD patients, there is flex-
ion at the neck, trunk, hips, knees and elbows. Those
changes are more pronounced in multiple system
atrophy. In progressive supranuclear palsy, the posture
is erect, with the neck in a normal or even extended
position. When asked to stand erect, advanced PD
patients have difficulty maintaining the erect posture
for several seconds, whereas the normal elderly can
do that easily.
The ability to regain balance after spontaneous
sway or when the body is actively perturbed from
standing position depends on the integrity of the pos-
tural reflexes. Maki et al. (1990) noted that both spon-
taneous and induced sway of balance are exaggerated
in old age, regardless of whether the eyes are open or
closed. Increased anteroposterior displacement velo-
city in the elderly has been reported in other studies
(Du Pasquier et al., 2003; Fransson et al., 2004). The
most pronounced velocity change is seen in those
who have a fear of falling. With vibratory perturbation
applied to the gastrocnemius muscle, the elderly used
higher-frequency motion and complex dynamics to
adjust compared to younger persons (Fransson et al.,
2004). The elderly also have a reduced capability to
use visual information to adjust to perturbation. In gen-
eral, the elderly have more difficulty in compensating
for balance perturbation (Fransson et al., 2004).
In the clinical setting, postural stability is tested as
follows: The patient is asked to stand with eyes open
and feet approximately shoulderwidth apart. He/she
is asked to resist a sudden pull by the examiner. The
patient is advised to take one step if necessary to
regain balance and is assured that the examiner will
not allow him/her to fall. Depending on the size and
agility of the patient, there will be a different degree
of force required to displace. The force of the pull
should be such as would reasonably displace the per-
son so the capability to regain balance can be assessed.
Initially, the examiner applies a pull in the forward
direction. Following that, the same maneuver is
repeated in the backward direction (Weiner et al.,
1984; Fahn et al., 1987; Sudarsky, 1990). This is
known as the pull test. If the patient takes no or one
step, that is considered normal. When there are two
to three steps it is considered as slight impairment
of postural reflexes. Four or more steps on pull or
when the patient would fall if not prevented is defi-
nitely abnormal (Fahn et al., 1987). The global clinical
severity of PD is measured using the pull test as a
major parameter (Hoehn and Yahr, 1967; Fahn et al.,
1987).
Impaired postural reflexes are part of normal aging
(Tinetti et al., 1988; Rajput, 1993c; Ross et al., 2004).
Postural reflexes were impaired in 43% between age
60 and 69 years and in 70% of individuals between
ages 80 and 89 in persons who had no neurological
or other identifiable cause (Weiner et al., 1984). Pro-
gressive decline of postural reflexes was reported in
a longitudinal study of normal elderly people (Wilson
et al., 2002). Thus, the postural instability as tested
in the clinical setting is also a part of the normal aging
process. It can not be utilized therefore as a require-
ment for the diagnosis of PD in the elderly. However
it can be used as an adjunct when the other cardinal
features of PD bradykinesia, rigidity and tremor
are evident, especially if those abnormalities are asy-
mmetrical (Tinetti et al., 1988; Rajput et al., 1991c;
Rajput, 1993a, b, c). Although the PD-related loss of
postural reflexes may improve with levodopa, the
age-related abnormality does not benefit from medical
therapy.
53.2.5. Gait abnormality in old age and Parkinsons
disease
In normal elderly people, the gait is slightly wide-
based, slow and the strides are shorter compared to
younger individuals but the heel strike and the arm-
swing are normal (Rajput, 1993c; Drachman et al.,
1994). In normal elderly people, the stride velocity
declines by 1020% by age 80 years (Sudarsky,
1990; Winter et al., 1990) and they adopt a more con-
servative gait to reduce the risk of falling (Menz et al.,
2003). Individuals who have an exceptionally slow or
abnormal pattern of ambulation are classified as hav-
ing a gait disorder. It is estimated that 15% of persons
60 years and older have a gait abnormality (Sudarsky,
1990). Sudarsky and Ronthal (1983) assessed 50 indi-
viduals who had a mean 1-year duration of gait diffi-
culty. They found that 10% of those cases had other
features of parkinsonism and improved on levodopa.
In approximately 15% of elderly gait disorder cases,
no cause is discovered despite extensive investiga-
tions (Sudarsky and Ronthal, 1983; Sudarsky, 1990).
 OLD AGE AND PARKINSONS DISEASE
Such cases are classified as having idiopathic
(Sudarsky and Ronthal, 1983) or senile gait disorder
(Koller et al., 1983). Senile gait is characterized by
stooped posture, broad base, reduced arm-swing, stiff
turns and a tendency to fall (Koller et al., 1983).
Gait and balance abnormalities with no identifiable
neurological disease were evaluated prospectively in
70 healthy ambulatory elderly subjects (mean 79
years, range 7488) (Whitman et al., 2001). Brain
magnetic resonance imaging (MRI) studies were per-
formed at baseline and 4 years later. Those who devel-
oped gait and balance problems had a significantly
greater mean increase in volume of T2-weighted
white-matter hyperintensities on brain MRI (Whitman
et al., 2001).
PD is the most common movement disorder result-
ing in gait abnormality in the elderly. The gait is char-
acterized by flexed posture, narrow base, slow and
short shuffling steps, slow multistep turning, loss of
heel strike, reduced toe elevation, reversal of ankle
flexion/extension movement, reduced movement at
the knee joints, loss of dynamic vertical force and loss
of backward-directed sheer force resulting in a ten-
dency to propulsion (Forssberg et al., 1984). A Parkin-
son patient may break into an uncontrollable forward
run, known as festination. Because of the impaired
postural reflexes, any perturbation may result in invo-
luntarily walking forward (propulsion) or walking
backward (retropulsion).
Freezing of gait may be evident as start hesitation
on approaching an obstacle or on attempts to change
direction ambulatory efforts needed to overcome a
block (Bloem et al., 2004). Abnormal gait, freezing
of gait and impaired postural reflexes are all major
problems at advanced stages of PD (Hoehn and Yahr,
1967; Fahn et al., 1987; Bloem et al., 2004) and lead
to significant functional handicap and falls. One study
noted that, compared to healthy controls, the relative
risk of recurrent falls in PD cases over a period of 6
months was nine times greater (Bloem et al., 2004).
In moderately advanced PD patients, the gait may
improve with visual guided patterns (Forssberg et al.,
1984; Suteerawattananon et al., 2004) and with audi-
tory cues (Suteerawattananon et al., 2004). Prior to
the advent of levodopa therapy, no drug reversed the
impaired postural reflexes and gait abnormality in PD
significantly. On modern drugs, some patients may
regain those functions. Freezing of gait is difficult to
treat. Response to treatment is less than satisfactory
during advanced stages of PD, but some improvement
may be seen on dopaminergic drugs and on selegiline
(Bloem et al., 2004). Freezing of gait during the off
period may improve on levodopa (Schaafsma et al.,
2003). Freezing of gait is more common in older PD
433
patients. However, freezing of gait as an initial mani-
festation of PD is not different in young- and old-
age-onset cases (Bloem et al., 2004). On the other
hand, postural instability and gait disturbance with
PD onset are more common in old age (Bloem et al.,
2004).
In the parkinsonian variant of multiple system atro-
phy, the gait abnormality is similar to PD, but it mani-
fests early and the decline is more rapid than in PD
(Rajput et al., 1972, 1993a). In progressive supranuclear
palsy cases, the posture is erect and the gait is character-
ized by a high-stepping and robotic quality. Progres-
sive supranuclear palsy cases have predominantly
axial akinetic-rigid features and supranuclear ophthal-
moplegia. Nearly one-half of the autopsy-confirmed
cases were reported without ophthalmoplegia in one
study (Birdi et al., 2002). Most progressive supra-
nuclear palsy cases show no significant improvement
on levodopa (Birdi et al., 2002).
53.2.6. Gait apraxia
In gait apraxia cases, the functional abnormality is
restricted to walking and there is no motor weakness,
sensory loss or cerebellar dysfunction in the lower
limbs to account for the gait difficulty. Typically,
these patients have an erect posture, slightly broad
base, difficulty initiating gait, reduced cadence (steps
per minute) and short shuffling and hesitating steps,
as if glued to the floor (Estanol, 1981; Fisher,
1982; Sudarsky and Ronthal, 1983; Forssberg et al.,
1984; Sudarsky, 1990). Unlike the PD cases, the gait
apraxia patients do not improve with visual or auditory
cues and are unable to mimic a normal gait (Forssberg
et al., 1984; Suteerawattananon et al., 2004). There is a
marked dissociation between the leg functions in the
supine and sitting positions compared to that during
walking. Gait apraxia patients are able to use the lower
limbs for activities such as writing on the floor with a
foot while in the sitting position, kicking an imaginary
ball and emulating bicycle riding in the supine posi-
tion. However, in the weight-bearing position, the
execution of the lower-limb motor activity required
for walking is markedly impaired. By contrast, in mild
to moderate PD cases, the impairment of lower-limb
function during non-weight-bearing and the weight-
bearing activities is similar. Della Sala et al. (2002)
reported a case of gait apraxia due to a stroke affecting
bilateral supplementary motor areas. In normal-
pressure hydrocephalus, the exact site pathology is
not known (Fisher, 1982; Sudarsky and Simon,
1987). The normal-pressure hydrocephalus patients
often manifest dementia, frontal-release signs and
bladder incontinence (Estanol, 1981). In some of those
434 A. RAJPUT AND A. H. RAJPUT
cases, the gait abnormality may be the only manifesta-
tion (Fisher, 1982; Sudarsky and Simon, 1987). Rare
patients with gait apraxia may have extensor plantar
responses. Resting tremor, which is a common feature
of PD, is not seen with gait apraxia. Limb bradykinesia
and rigidity, the other major features of PD, are not
seen in either the upper or the lower limbs when
assessed in the sitting or supine position. The gait
apraxia patients do not improve on levodopa.
Table 53.3 summarizes gait in the normal elderly, PD
and gait apraxia patients.
53.2.7. Eye movements in the elderly and
in Parkinsons disease
gaze increased with age. The frequencies for upgaze
and downgaze impairments, respectively, were 6%
and 8% for those aged 6569 years, increasing to
29% and 34% for those 80 years and older (Jenkyn
et al., 1985). Gaze impairment is characteristic of
progressive supranuclear palsy (Steele et al., 1964;
Jackson et al., 1983; Birdi et al., 2002). It is also seen
in rare multiple system atrophy patients (Jankovic
et al., 1993) and we have observed it in an autopsy
confirmed PD cases.
Oculogyric crisis was a feature of postencephalitic
parkinsonism but is also seen in some cases of drug-
induced parkinsonism (DIP) and in dopa-responsive
dystonia (Rajput, 1973).

Voluntary and pursuit upward gaze movement of 5
mm or less and downward gaze deviation of 7 mm
or less are considered abnormal (Jenkyn et al., 1985).
In a study of more than 2000 normal volunteers 50
93 years old, impairment of upward and downward
53.2.8. Primitive reflexes in the elderly and
in Parkinsons disease
Grasp and other primitive reflexes seen in childhood
are suppressed during development but may re-emerge

Table 53.3
Posture and gait in normal elderly, Parkinsons disease and gait apraxia

Clinical features Normal elderly Parkinsons disease Gait apraxia

Base (distance between feet) Slightly wider than at Narrow Broad

younger age
Symmetry of abnormality Symmetrical Usually asymmetrical Symmetrical
Functions in the involved Normal and symmetrical Impaired regardless of Impaired only when
lower limb weight-bearing or not weight-bearing but
(no dissociation) normal when not weight-
bearing (dissociation
pronounced and early)
Upper-limb motor function Normal Impaired on the involved side Normal
Arm-swing Normal Reduced on involved side Normal
Posture Erect or neck and trunk Generalized flexion neck, As in normal elderly
flexion trunk, hip, knee, elbow
Postural reflexes May be normal or impaired Impaired in moderately Impaired early
advanced disease
Foot-tapping in sitting or lying Normal Affected side slow and As in normal elderly
position progressively slower
Gait abnormality Uncommon increases Late manifestation usually Major problem early
with age manifestation
Visual and auditory cue No change in gait Improve gait No improvement in gait
Tremor Absent Frequently seen typically As in normal elderly
resting
Dementia Absent In about one-third of cases Common but not invariable
Reflexes Normal (may be As in normal (may have May be brisk may have
reduced at ankles) striatal toe) Babinski sign
Grasp reflex Normal Usually negative Usually positive
Bladder function Normal Normal or hypertonic or Incontinence common
hypotonic bladder
Levodopa response None Improvement None
 OLD AGE AND PARKINSONS DISEASE
in old age (Bennett et al., 1996; Schott and Rossor,
2003). Typically, PD patients have a reduced rate of
eye-blinking, resulting in a reptilian stare. Normally,
the glabellar reflex habituates after 24 taps. Sustained
glabellar reflex was observed in 10% of normal volun-
teers ages 6569 years and in 37% of those aged 80
years and older (Jenkyn et al., 1985). In PD, this reflex
may persist and in rare cases it may produce blephar-
ospasm. Spontaneous blepharospasm is rare in PD
but is more common in progressive supranuclear palsy
cases. Repeated blinking after a tap at the bridge of the
nose (Myersons sign) is common in PD. A positive
snout reflex correlates with advancing age (Koller
et al., 1982). As the primitive reflexes are common
in the normal elderly, their presence cannot be used
as evidence of PD.
53.3. Pathophysiological consideration
of motor abnormalities in the elderly
The presence of some parkinson-like motor features in
the elderly suggests that PD and old age may share
pathophysiological mechanisms. The most consistent
pathology in PD is a marked loss of substantia nigra pig-
mented neurons and Lewy body inclusions (Jellinger,
1987; Gibb and Lees, 1988b; Duvoisin and Golbe,
1989; Gibb, 1991; Rajput et al., 1991c; Robinson and
Rajput, 2005). The characteristic biochemical finding
in PD is a marked striatal dopamine loss (Ehringer and
Hornykiewicz, 1960a; Rajput, 2002) and an uneven
subregional pattern of dopamine decline (Kish et al.,
1988). Improvement of PD motor symptoms is almost
universal in those patients who can tolerate an adequate
dose of levodopa (Birkmayer and Hornykiewicz, 1961,
1998; Cotzias et al., 1967; Rajput et al., 1990c).
Several studies have compared the pathological and
biochemical findings of PD with the normal elderly
population who may manifest some parkinsonian-like
features. One study (Ross et al., 2004) observed that
the elderly who had a stooped posture, postural
instability or undue motor slowing had significantly
reduced neuronal cell counts in the dorsolateral quad-
rant of the substantia nigra pars compacta. The counts
were lowest when all three signs were present (Ross
et al., 2004). A detailed study (Fearnley and Lees,
1991) revealed that the regional pattern of substantia
nigra loss in normal aging (dorsal tier) is different from
PD (ventral tier). They concluded that age-related loss
of dorsal tier substantia nigra pars compacta neurons is
not important in the pathogenesis of PD (Fearnley and
Lees, 1991). Resting tremor has not been observed in
elderly individuals without clinical PD, nor in cases
with incidental Lewy body inclusions only (Ross et al.,
2004). This indicates that resting tremor is not a feature
435
of normal aging and is a major distinguishing feature
between PD and normal elderly.
Striatal dopaminergic denervation has been reported
in normal aging. Positron emission tomography (PET)
studies revealed reduced dopaminergic functions in
grandparents compared to their grandchildren (Cordes
et al., 1994). Reduced striatal dopamine levels are
reported in normal elderly autopsy brains (Kish et al.,
1992). However, the pattern of the brain regional dopa-
mine loss is different in normal aging (Kish et al., 1992)
and PD (Kish et al., 1988). The rate of dopaminergic
denervation was estimated to be twice as high in PD
compared to normal aging (Scherman et al., 1989). It
was concluded that dopamine deficiency does not play
a role in normal aging (Scherman et al., 1989). Unlike
PD, age-related slowing does not improve on levodopa.
It is therefore concluded that the substantia nigra loss
and the associated dopamine loss characteristic of PD
do not account for the Parkinson-like features of normal
aging.
53.4. Tremor disorders in old age
Tremor is the most common movement disorder in
human adults (Jankovic and Fahn, 1980; Findley and
Gresty, 1981; Rautakorpi et al., 1982a, b; Louis
et al., 1995). The two most common tremor disorders
are PD and essential tremor (ET) (Haerer et al.,
1982; Rautakorpi et al., 1982a; Moghal et al., 1994;
Salemi et al., 1994; Mayeux et al., 1995; Louis et al.,
1996). Both PD and ET are concentrated in old age
(Haerer et al., 1982; Rautakorpi et al., 1982b; Rajput
et al., 1984a, b; Schoenberg et al., 1985; Bharucha
et al., 1988; Bergareche et al., 2001). There is no lit-
erature evidence that postural/kinetic tremor is part
of the normal aging process and rest tremor is never
a part of normal aging. There is clinical overlap
between PD and ET-associated tremors. The character-
istic tremor of PD is at rest, but these cases may also
have postural/kinetic tremor. Rest tremor is not a fea-
ture of normal aging (Rajput, 1994a; Bennett et al.,
1996; Ross et al., 2004), although it is seen in nearly
every PD case (Rajput et al., 1990a, 1991a), and in
some ET patients (Rajput et al., 2004b).
The elderly more often use medications that enhance
the physiological tremor, making it clinically evident.
This makes it difficult to distinguish drug-induced tre-
mor from pathological tremor, including ET. Medica-
tions that may cause or worsen underlying tremor
include tricyclics, monoamine oxidase inhibitors, val-
proic acid, corticosteroids, calcium channel blockers,
amiodarone, sympathomimetics and rugs for asthma,
including theophylline (Desai et al., 1990; Koller
et al., 1994; Kelly et al., 1995; LeWitt, 1995).
436 A. RAJPUT AND A. H. RAJPUT
53.5.1. Parkinsonian tremor
The characteristic parkinsonian tremor is resting tre-
mor, i.e. when the body part is fully supported against
gravity to prevent muscle activity. The postural and
kinetic tremor that is characteristic of ET is also seen
in a significant proportion of PD patients (Jankovic
et al., 1995, 1999). Tremor is the most common initial
symptom reported by PD patients (Hoehn and Yahr,
1967; Martin et al., 1973; Gibb and Lees, 1988a;
Rajput et al., 1991a). The upper-limb tremor onset
was noted 13 times more frequently compared to the
lower-limb rest tremor onset in an autopsy study of
PD (Rajput et al., 1993a). James Parkinson was so
impressed with the tremor in PD that he called the
disorder shaking palsy. The PD tremor is usually
intermittent at the start and appears under stress. Pro-
gressively lower-level stress triggers tremor and even-
tually the tremor may become persistent (Hallett,
1986). We observed 1 patient who had a 33-year his-
tory of intermittent upper-limb tremor which only
appeared under stress before the other classical fea-
tures of PD appeared. Putting the patient under stress
is helpful in establishing the presence of rest tremor.
It can be done by having the patient perform one or
multiple tasks simultaneously. While the patient is
lying on the examining table, ask him/her to squeeze
your finger with one hand, close the eyes tightly while
you try to open them and have the patient count back-
wards from 100 by 7s. This maneuver would bring out
resting tremor in the opposite upper limb and both
lower limbs. Upper-limb resting tremor on both sides
can be simultaneously evaluated as follows: in the
supine position, the patient is asked to close his/her
eyes tightly, count backwards from 100 by 7s and
forcefully dorsiflex both ankles against resistance
(with the examiner opposing the dorsiflexion).
In most patients, the parkinsonian resting tremor pro-
duces limited or no functional disability as it improves
with activity. After reaching the peak severity (amp-
litude and persistence), the tremor may become less pro-
nounced or cease altogether (Stern, 1987; Birdi et al.,
2002). When tremor is only present in the resting
position but in no other situation, it is a sign of PS
(Rajput, 1994b; Bennett et al., 1996; Rajput et al.,
2004b; Rajput and Rajput, 2004; Ross et al., 2004).
53.5.2. Essential tremor
ET can manifest at any age, from childhood to old age
(Haerer et al., 1982; Rajput et al., 1984b; Koller et al.,
1994). The incidence and the prevalence rates of ET
increase markedly in old age (Haerer et al., 1982; Rau-
takorpi et al., 1982a, b; Rajput et al., 1984b; Bain
et al., 1994; Salemi et al., 1994). In a population study
using door-to-door interviews and neurological exams
in Turkey, 4% of those aged 40 years and older had
ET (Dogu et al., 2003). In a Finnish study, 5.6% of
the population over age 40 years had ET (Rautakorpi
et al., 1982b) whereas 13% of those between the ages
of 70 and 79 years had ET. We found ET prevalence
rates of 14% in the community (Moghal et al., 1994)
and 10% in the chronic care institution population
(Moghal et al., 1995) aged 65 years and older. Life
expectancy in ET is normal (Rajput et al., 1984b).
The tremor frequency in ET changes with time.
The tremor in young ET cases has a higher frequency
(810 Hz) than PD tremor (46 Hz). ET tremor fre-
quency deceases by 0.060.08 Hz/year (Elble, 2000).
Therefore, with time, ET tremor frequency may
become indistinguishable from PD. The tremor ampli-
tude progressively increases in ET (Stiles, 1976; Elble,
1986; Calzetti et al., 1987) and becomes more wide-
spread throughout the body (Rajput et al., 2004b).
Classical ET is kinetic and/or postural (Louis, 2001),
but nearly one-third of the autopsy-verified ET
patients developed resting tremor in the upper or lower
limbs, without bradykinesia or rigidity (Rajput et al.,
2004b). In the past, such cases were classified as
senile tremor (Koller et al., 1994; Kelly et al.,
1995). Autopsy studies revealed similar brain histol-
ogy in classical ET and those with additional resting
tremor (Rajput et al., 2004b). Therefore, the term
senile tremor is no longer justified.
Coarse tremor can produce cogwheeling and
Froments phenomenon, which may be misinterpreted
as a sign of parkinsonism. Clinical distinction between
that and the rigidity of PS has been discussed above.
In a large series of pathologically verified ET
patients, 15% subsequently developed dopa-responsive
parkinsonism (Rajput et al., 2004b): 5% had Lewy
body disease and 10% progressive supranuclear palsy
that was undiagnosed during life. Making a distinction
between ET cases that develop resting tremor alone
and those with additional PS can be challenging. If a
known ET patient develops unilateral resting tremor,
rigidity and bradykinesia, a second diagnosis of PS is
justified (Rajput et al., 1991a, b, 1993b, 2004b).
Most ET patients developing resting tremor in old
age. However, when the ET first manifests in child-
hood, such evolution may occur at a younger age, indi-
cating that rest tremor evolution is related to the
duration of the ET. We have observed an accelerated
emergence of rest tremor in ET patients when both
parents had ET, suggesting that a higher degree of
genetic abnormality increases the risk of rest tremor.
The beneficial effect of alcohol on tremor is not
specific to distinguish ET from parkinsonian tremor
 OLD AGE AND PARKINSONS DISEASE
or other causes of action tremor, as each may or may
not improve with alcohol (Rajput et al., 1975; Koller
and Biary, 1984).
The available literature indicates that ET and PD
are two different disorders and the risk of developing
PD in ET cases is comparable to that in the general
population (Rajput et al., 2004b).
Since there are no biological markers specific for ET
or PD, in the event of clinical uncertainty, a therapeutic
trial on levodopa for up to 8 weeks is justified. Whereas
PD patients improve, there is no benefit to ET.
53.6. Parkinsons disease in old age
Epidemiology, major clinical features, non-motor
manifestations of PD, other parkinsonian syndromes
and details of treatment are covered in the appropriate
chapters of this volume. We will focus on those fea-
tures that have special significance for PD in old age.
PD in elderly patients can be divided into two main
categories: (1) those with an early age at onset and sur-
viving to old age; and (2) patients in whom the PD
first manifests in old age.
When the disease begins at a younger age, nearly all
patients in the industrialized countries would have
received levodopa (Global Parkinsons Disease Survey
(GPDS) Steering Committee, 2002) before reaching old
age. Most of those patients are likely to have motor
response fluctuations and/or dyskinesia (Rajput et al.,
2002), freezing of gait (Bloem et al., 2004) and a reduced
therapeutic benefit (Rajput et al., 1984c, 2002). Such
patients are most likely to have been previously treated
with dopamine agonists and the other currently available
agents. The treatment options in such cases are limited.
Levodopa and adjunct catecholamine-O-methyltransfer-
ase inhibitors, entacapone or tolcapone (where available)
are probably the safest options for this group of patients.
If a patient is well controlled and has stage 2 (Hoehn and
Yahr, 1967; Fahn et al., 1987) disability, there is no need
to change the drugs.
53.6.1. Parkinsons disease beginning in old age
In one community study (Bower et al., 1999), the inci-
dence of PS rose sharply with age. In the same commu-
nity (Rocca et al., 2001), the age-specific incidence was
unchanged over several decades but there was an
increased incidence of DIP in those aged 70 years and
older (Rocca et al., 2001). In a study of 6584-year-old
population, the annual incidence of PS was 529.7/105
whereas it was 326.3/105 for clinically diagnosed PD
(Baldereschi et al., 2000). Thus the incidence of PD con-
tinues to rise with advancing age (Mayeux et al., 1995;
Bower et al., 1999; Rocca et al., 2001).
437
The diagnosis of PD in the elderly needs careful
consideration of the age-related motor changes which
may be mistaken for PD and vice versa, as discussed
above. Community-based surveys indicate that
between 35 and 41% of parkinsonian cases (mostly
the elderly) remain undiagnosed (Schoenberg et al.,
1985; Morgante et al., 1992). In a survey of commu-
nity residents 65 years and older, we observed that
50% of parkinsonian cases were undiagnosed (Moghal
et al., 1994). The undiagnosed patients are usually
those who do not have prominent tremor or those in
whom the tremor is erroneously interpreted as a man-
ifestation of aging. A patient who is not diagnosed
remains untreated and, therefore, will suffer unneces-
sarily. In one case, a 60-year-old mother of seven chil-
dren (including one nurse) noted that she could not
look after her household. The children concluded that
she was getting old and was, therefore, placed in a
private care-home where she was expected to go to
the dining area to eat. However, she could not do that
and her condition deteriorated. At that point, she was
hospitalized. Neurological exam revealed stage 4
(Hoehn and Yahr, 1967; Fahn et al., 1987) akinetic-
rigid PD which improved on levodopa. Another exam-
ple is that of an elderly man who had been in a nursing
home for several years. With an impending influenza
season, he was prescribed amantadine. The attending
physician was surprised to see that the patient improved
remarkably to the point that he could be discharged
from the nursing home. Since the diagnosis of PD is
based on clinical observations alone, a trial of levodopa
is justified when in doubt.
Tremor is the most common first manifestation of
PD, ranging from 41% (Gibb and Lees, 1988a) to
70.5% (Hoehn and Yahr, 1967) in different studies. In
autopsy-verified cases, we noted that tremor alone was
the first manifestation in 49% of PS cases (Rajput
et al., 1993a). The first symptom was upper-limb tremor
alone in 41% and lower-limb tremor alone in 3% of PS
cases. Tremor in conjunction with other parkinsonian
motor features was the first manifestation in 53% of
PS cases (Rajput et al., 1993a). Postural instability and
gait difficulty (PIGD) at onset are reported to be more
common among the elderly (Zetusky et al., 1985; Jan-
kovic et al., 1990). Whereas 56% of the tremor-onset
parkinsonian cases had only Lewy body PD pathology,
27% of the PIGD cases had similar pathology (Rajput
et al., 1993a). Clinical studies (Zetusky et al., 1985;
Jankovic et al., 1990) and clinicopathological studies
(Rajput et al., 1993a) indicate that the PIGD onset cases
have a less favorable prognosis. Such cases are more
likely to suffer from other variants of PS than PD
(Rajput et al., 1993a), which accounts for some unfa-
vorable outcomes. Since tremor is not a feature of
438 A. RAJPUT AND A. H. RAJPUT
normal aging, new-onset tremor should arouse the suspi-
cion of PD. Rest tremor is the most reliable distinguish-
ing feature between normal aging and PS (Rajput et al.,
1991a, 1993a; Brooks et al., 1992; Rajput, 1994a; Kelly
et al., 1995). Isolated lower-limb rest tremor onset has
even higher diagnostic value in PD (Rajput et al.,
1990b, 1993a).
The most common variant of PS is the Lewy body
disease (Rajput et al., 1984a, 1991c; Jellinger, 1987;
Duvoisin and Golbe, 1989; Gibb, 1991; Hughes
et al., 1992), also known as idiopathic PD. There are
other uncommon variants, such as neurofibrillary tan-
gle pathology, which is focused on the substantia nigra
(Rajput et al., 1989). Clinical distinction between PD
and other variants of PS is not always possible (Rajput
et al., 1991c; Hughes et al., 2002). However, parkin-
sonism, when the pathology is focused on the substan-
tia nigra, can be clinically recognized accurately in
85% of cases (Rajput et al., 1991c). The multiple sys-
tem atrophy Parkinson subtype (Rajput et al., 1972,
1991c; Quinn, 1989; Rajput, 1994a, b) has a younger
age at onset, but in rare autopsy cases we have
observed it to begin in old age. The most prominent
clinical features are symmetrical bradykinesia and
rigidity but very little tremor. The presence of early
autonomic dysfunction and corticospinal tract or cere-
bellar dysfunction is helpful in distinguishing multiple
system atrophy from PD. The progression of disability
in the multiple system atrophy cases is more rapid and
the response to levodopa is less favorable than in PD
(Quinn, 1989; Rajput et al., 1990c, 1991c, 1993a). Pro-
gressive supranuclear palsy, on the other hand, has
similar age of onset as PD. The motor manifestations
are symmetrical with predominant axial involvement.
The posture is erect, tremor is not a prominent feature
(Birdi et al., 2002) and supranuclear ophthalmoplegia
is a characteristic manifestation.
Levodopa is the drug of first choice in PD cases
with onset at 75 years or older. In the 6575-year
age group, depending on health status, one may use
amantadine or a dopamine agonist initially.
Though selegiline is generally well tolerated, it has
only a mild symptomatic benefit and we do not use it
often. Anticholinergics frequently cause adverse
effects and we avoid using them in the elderly.
The response to levodopa therapy is most favorable
in PD. Response to levodopa treatment is not diagnostic
of the underlying pathology, as other PS variants of par-
kinsonism may also improve (though the response is
less robust and of shorter duration) (Rajput et al.,
1990c; Birdi et al., 2002). The functional decline in
patients with late-age PD onset is more rapid compared
to younger-age-onset cases (Gibb and Lees, 1988a;
Goetz et al., 1988; Hietanen and Teravainen, 1988;
Jankovic et al., 1990). Late-onset age by itself does
not unduly shorten survival when the age and sex are
taken into account (Rajput et al., 1997). The accelerated
disability in the old-age-onset PD cases may be due in
part to aging or concurrent senile gait (Koller et al.,
1983) or gait apraxia (Sudarsky and Simon, 1987).
At any given time, approximately one-third of PD
cases have dementia (Rajput and Rozdilsky, 1975;
Marttila and Rinne, 1976; Rajput et al., 1987, 1997;
Mayeux et al., 1988; Rajput, 1992; Uitti et al., 1993,
1996) and over 5 years new cases of dementia
emerged 35 times more commonly in PD compared
to age-matched controls (Mindham et al., 1982; Rajput
et al., 1987; Mayeux et al., 1988; Marder et al., 1991;
Rajput, 1992; Aarsland et al., 2003). When compared
with the early-onset cases, dementia was reported to
be nearly 10 times more common in the old-age-onset
PD cases (Hietanen and Teravainen, 1988; Mayeux
et al., 1988, 1990; Hobson and Meara, 2004). Com-
pared to the non-demented cases, demented PD cases
have a shortened survival (Uitti et al., 1996; Rajput
et al., 1997) compared to non-demented cases. (See
Ch. 18 for further discussion of dementia in PD.)
Dyskinesia is a common adverse effect of levodopa
therapy. It has been suggested that the incidence of
dyskinesia is different among young- and old-age-
onset cases. Kostic et al. (1991) compared 25 PD cases
with onset before age 40 years (mean 33.5 years) with
25 PD patients who had onset at a later age (mean 55.8
years). After 3 years of levodopa therapy there was a
significantly higher (72% versus 28%) incidence of dys-
kinesia in the early-onset cases. Gibb and Lees (1988a)
compared PD patients with mean onset at 38 years
with those at mean onset at 73 years. They detected no
difference in the duration of levodopa exposure before
dyskinesia onset. We have observed levodopa-induced
dyskinesia emerging early and on a small dose in some
old-age-onset cases. The age-related difference with
respect to levodopa-induced dyskinesia was not evident
in our PD autopsy series (Rajput et al., 2002).
The dyskinesia and wearing-off phenomena repre-
sent opposite ends of the spectrum for motor response
complications. Dyskinesia is most common at the peak
plasma level of levodopa, whereas the wearing off
coincides with the lowest plasma level. As expected,
dopamine metabolism in the autopsy brains was found
to be accelerated in the wearing-off compared to dyski-
nesia cases (Rajput et al., 2004a). Similar observations
were reported on PET scanning in PD wearing-off cases
(Fuente-Fernandez et al., 2001).
DIP is a well-known complication of dopamine-
depleting and receptor-blocking agents that was first
recognized in the 1960s (Ayd, 1961; Delay and Deniker,
1968; Friedman, 1992). The DIP incidence is second
 OLD AGE AND PARKINSONS DISEASE 439
only to PD in community studies of PS (Rajput et al., stroke patients, 6 (0.4%) developed parkinsonism
1984a; Bower et al., 1999). The elderly take a large (Alarcon et al., 2004). The onset of PS was rapid after
number of drugs, have age-related striatal dopamine approximately 4 months of stroke. Five of the 6 cases
loss (Kish et al., 1992) and up to 13% have preclinical had persistent parkinsonian features with initial improve-
pathology of PD, known as incidental Lewy body dis- ment on levodopa. The lesions were located in the mid-
ease (Ross et al., 2004). DIP is, therefore, more common brain/pons, caudate/internal capsule, lentiform nucleus,
in older individuals (Rajput, 1984, 1986; Friedman, the frontal cortex or frontal subcortex.
1992; Bower et al., 1999) and that incidence increases
with age (Bower et al., 1999). In more than 90% of these
53.7.2. Alzheimers disease and parkinsonism
cases, the parkinsonism emerges within 90 days of
neuroleptic initiation (Friedman, 1992). Some such
Alzheimers disease, a common disorder in the
patients have no known pathology, whereas others with
elderly, may be associated with parkinsonian features
a preclinical PD pathology would develop parkinsonian
in some patients (Molsa et al., 1984; Bennett et al.,
features on a modest neuroleptic dose (Rajput et al.,
1989; Morris et al., 1989; Tyrrell and Rossor, 1989;
1982). Although akinesia appears early in the DIP cases,
Soininen et al., 1992). Longer reaction time (bradyki-
that is due in part to the tranquilizing effect of the
nesia) and increased muscle tone (rigidity) are signif-
neuroleptics. The drug-induced patients do not always
icantly more common in Alzheimers disease patients
present an akinetic-rigid picture and may have clinical
compared to normal controls (Kischka et al., 1993).
features that are indistinguishable from idiopathic PD
In a longitudinal study, the bradykinesia rate nearly
(Rajput et al., 1982, 1991c; Hardie and Lees, 1988; Burn
doubled and rigidity frequency multiplied by nearly
and Brooks, 1993). We have observed reversible drug-
six times after 3 years in Alzheimers disease cases
induced tremor-dominant parkinsonism in an individual
(Soininen et al., 1992). When the Alzheimers disease
who had a strong family history of PD. Theoretically,
patients were treated with neuroleptics, nearly every-
the DIP should be symmetrical, but that is not always
one developed bradykinesia and rigidity (Soininen
the case.
et al., 1992), but tremor was not a prominent feature
Parkinsonism due to dopamine-depleting or recep-
in these cases. Morris et al. (1989) followed 44 clini-
tor-blocking drugs improves when the offending agent
cally diagnosed Alzheimers disease patients and 58
is discontinued (Friedman, 1992); however, it may
controls. At baseline, neither group had parkinsonian
take several months to resolve. The best treatment
features. At the end of 66 months, at least one of
option for such cases is discontinuing the offending
the three clinical features of parkinsonism resting
agent. A careful history of drug intake is, therefore,
tremor, bradykinesia and rigidity was detected in
important in elderly parkinsonian cases.
36% of Alzheimers cases compared to 5% in the
Anticholinergics are theoretically the best agents
control subjects. An additional 27% of Alzheimers
for the symptomatic treatment of DIP. However, the
cases developed at least one cardinal feature of parkin-
elderly do not tolerate these drugs well. Amantadine
sonism within 6 months of exposure to neuroleptics
and levodopa can be tried for symptomatic control.
(Morris et al., 1989).
The use of prophylactic anticholinergics in subjects
In a pathological study, histological findings were
treated with neuroleptics is not recommended, as only
such that a diagnosis of Alzheimers disease and of
a small proportion would develop DIP. Additionally,
Lewy body PD each could be made (Rajput et al.,
cholinergic-blocking agents produce significant
1993c). Two clinical patterns were detected. One
adverse effects in the elderly. If the neuroleptics can-
group presented with PS and dementia developed sev-
not be discontinued, atypical antipsychotic agents
eral years later. In the other group, the dementia and
such as olanzapine, clozapine or quetiapine should
parkinsonism onset were simultaneous (Rajput et al.,
be substituted to reduce the possibility of DIP
1993c). Those with PD at onset improved on levodopa
(Friedman, 1992).
until the onset of dementia, when they developed
small-amplitude irregular jerky postural and kinetic
53.7. Parkinsonism in other diseases of old age tremor and the levodopa response declined. In those
53.7.1. Stroke and parkinsonism who manifested PD and Alzheimers disease simulta-
neously, the typical resting tremor of PD was not a pro-
Stroke and parkinsonism are covered in detail in minent feature and the response to levodopa was poor,
Chapter 52. Although both stroke and PS are concen- producing major psychiatric side-effects (Rajput et al.,
trated in old age, there is no evidence that stroke 1993c). Alzheimers disease, dementia and PD overlap
produces Lewy body PD. In a recent report of 1500 will be discussed in detail in Chapters 18 and 60.
440 A. RAJPUT AND A. H. RAJPUT
References
Aarsland D, Andersen K, Larsen JP et al. (2003). Prevalence
and characteristics of dementia in Parkinson disease: an
8-year prospective study. Arch Neurol 60: 387392.
Agid Y (1991). Parkinsons disease: pathophysiology.
Lancet 337: 13211324.
Agid Y, Javoy-Agid F, Ruberg M (1987). Biochemistry of
neurotransmitters in Parkinsons disease. In: CD Marsden,
S Fahn (Eds.), Movement Disorders 2. Butterworths and
Co, London, pp. 166230.
Agid Y, Cervera P, Hirsch E et al. (1989). Biochemistry of
Parkinsons disease 28 years later: a critical review. Mov
Disord 4: S126S144.
Alarcon F, Zijlmans JC, Duenas G et al. (2004). Post-stroke
movement disorders: report of 56 patients. J Neurol Neu-
rosurg Psychiatry 75: 15681574.
Ayd FJ (1961). A survey of drug-induced extrapyramidal
reaction. JAMA 175: 10541060.
Bain PG, Findley LJ, Thompson PD et al. (1994). A study of
hereditary essential tremor. Brain 117: 805824.
Baldereschi M, De Carlo A, Rocca WA et al. (2000). ILSA
Working Group. Parkinsons disease and parkinsonism in
a longitudinal study. Two-fold higher incidence in men.
Neurology 55: 13581363.
Baloh RW, Fife TD, Zerling L et al. (1994). Comparison of
static and dynamic posturography in young and older normal
people. J Am Geriatr Soc 42 (4): 405412.
Bennett DA, Beckett LA, Murray AM et al. (1996). Prevalence
of parkinsonian signs and associated mortality in a commu-
nity population of older people. N Engl J Med 334: 7176.
Bennett RG, Greenough WB, Gloth FMI et al. (1989). Extra-
pyramidal signs in dementia of Alzheimer type. Lancet
2 (8676): 1392.
Bergareche A, De La Puento E, Lopez de Munain A et al.
(2001). Prevalence of essential tremor: a door-to-door sur-
vey in Bidasoa, Spain. Neuroepidemiology 20: 125128.
Bharucha NE, Bharucha AE, Bharucha EP et al. (1988). Pre-
valence of Parkinsons disease in the Parsi Community of
Bombay, India. Arch Neurol 45: 13211323.
Birdi S, Rajput AH, Fenton M et al. (2002). Progressive
supranuclear palsy diagnosis and confounding features
report on 16 autopsied cases. Mov Disord 17 (6):
12551264.
Birkmayer W, Hornykiewicz O (1961). The effect of L-
3,4-dihydroxyphenylalanine (L-DOPA) on akinesia in
parkinsonism. Wien Klin Wochenschr 73 (45): 787788.
Birkmayer W, Hornykiewicz O (1998). The effect of L-3,
4-dihydroxyphenylalanine (DOPA) on akinesia in
parkinsonism. Parkinsonism Relat Disord 4: 5960.
Blaschke TF, Nies AS, Mamelok RD (1985). Principles of
therapeutics. In: AG Gilman et al. (Eds.), The Pharmaco-
logical Basis of Therapeutics, 7th edn, McMillan Publish-
ing Company, New York, pp. 4965.
Bloem BR, Hausdorff JM, Visser JE et al. (2004). Falls and
freezing of gait in Parkinsons disease: a review of two
interconnected, episodic phenomena. Mov Disord 19 (8):
871884.
Bower JH, Maraganore DM, McDonnell SK et al. (1999).
Incidence and distribution of parkinsonism in Olmsted
County, Minnesota, 19761990. Neurology 52: 12141220.
Brooks DJ, Playford ED, Ibanez V et al. (1992). Isolated
tremor and disruption of the nigrostriatal dopaminergic sys-
tem: an 18F-dopa PET study. Neurology 42: 15541560.
Burn DJ, Brooks DJ (1993). Nigral dysfunction in drug-
induced parkinsonism: an 18F-dopa PET study. Neurology
43: 552556.
Calzetti S, Baratti M, Findley LJ (1987). Frequency/ampli-
tude characteristic of postural tremor of the hands in a
population of patients with bilateral essential tremor:
implications for the classification and mechanism of essen-
tial tremor. J Neurol Neurosurg Psychiatry 50: 561567.
Canadian Study of Health and Aging Working Group
(1994). Canadian study of health and aging: study meth-
ods and prevalence of dementia. CMAJ 150 (6): 899913.
Cordes M, Snow BJ, Cooper S et al. (1994). Age-dependent
decline of nigrostriatal dopaminergic function: a positron
emission tomographic study of grandparents and their
grandchildren. Ann Neurol 36: 667670.
Cotzias GC, Van Woert MH, Schiffer LM (1967). Aromatic
amino acids and modification of parkinsonism. N Engl
J Med 276: 374379.
de la Monte SM, Wells SE, Hedley-Whyte ET et al. (1989).
Neuropathological distinction between Parkinsons
dementia and Parkinsons plus Alzheimers disease. Ann
Neurol 26: 309320.
de Rijk MC, Rocca WA, Anderson DW et al. (1997).
A population perspective on diagnostic criteria for Parkin-
sons disease. Neurology 48: 12771281.
Delay J, Deniker P (1968). Drug-induced extrapyramidal
syndromes. In: PJ Vinken, GW Bruyn (Eds.), Handbook
of Clinical Neurology.6th edn., Elsevier, North Holland,
Inc, New York, pp. 248266.
Della Sala S, Francescani A, Spinnler H (2002). Gait apraxia
after bilateral supplementary motor area lesion. J Neurol
Neurosurg Psychiatry 72: 7785.
Desai T, Rajput AH, Desai HB (1990). Use and abuse of
drugs in the elderly. Prog Neuropsychopharmacol Biol
Psychiatry 14: 779784.
Dogu O, Sevim S, Camdeviren H et al. (2003). Prevalence of
essential tremor: door-to-door neurologic exams in Mersin
Province, Turkey. Neurology 61: 18041806.
Drachman DA, Long RR, Swearer JM (1994). Neurological
evaluation of the elderly patient. In: ML Albert, JE Knoefel
(Eds.), Clinical Neurology of Aging, 2nd edn. Oxford
University Press, New York, pp. 159180.
Du Pasquier RA, Blanc Y, Sinnreich M et al. (2003). The
effect of aging on postural stability: a cross sectional and
longitudinal study. Neurophysiol Clin 33 (5): 213218.
Duncan G, Wilson JA (1989). Extrapyramidal signs in
normal elderly. (Letter to the Editor) Lancet 2 (8676): 1392.
Duvoisin RC (1990). The differential diagnosis of parkinson-
ism. In: GM Stern, (Ed.), Parkinsons Disease. The John
Hopkins University Press, Baltimore, pp. 431466.
Duvoisin RC, Golbe LI (1989). Toward a definition of
Parkinsons disease. Neurology 39: 746.
 OLD AGE AND PARKINSONS DISEASE
Ehringer H, Hornykiewicz O (1960a). Distribution of nora-
drenaline and dopamine (3-hydroxytyramine) in human
brain: their behaviour in extrapyramidal system diseases.
Klin Wochenschr 38: 12361239.
Ehringer H, Hornykiewicz O (1960b). Verteilung von nora-
drenalin und dopamin (3-hydroxytyramin) im gehirn des
menschen und ihr verhalten bei erkrankungen des extra-
pyramidalen systems. Klin Wochenschr 38: 12361239.
Ehringer H, Hornykiewicz O (1998). Distribution of noradre-
naline and dopamine (3-hydroxytyramine) in the human
brain and their behavior in diseases of the extrapyramidal
system. Parkinsonism Relat Disord 4: 5357.
Elble RJ (1986). Physiologic and essential tremor. Neurol-
ogy 36: 225231.
Elble RJ (2000). Essential tremor frequency decreases with
time. Neurology 55: 15471551.
Estanol BV (1981). Gait apraxia in communicating hydroce-
phalus. J Neurol Neurosurg Psychiatry 44: 305308.
Fahn S, Elton RL (1987), UPDRS Development Committee.
Unified Parkinsons disease rating scale. In: S Fahn et al.
(Eds.), Recent Developments in Parkinsons disease, 2nd
edn. Macmillan Healthcare Information. Florham Park,
NJ, pp. 153305.
Fearnley JM, Lees AJ (1991). Ageing and Parkinsons disease:
substantia nigra regional selectivity. Brain 114: 22832301.
Findley LJ, Gresty MA (1981). Tremor. Br J Hosp Med 26:
1632.
Findley LJ, Koller WC (1995). Definitions and behavioral clas-
sifications. In: WC Koller, LJ Findley (Eds.), Handbook of
Tremor Disorders. Marcel Dekker Inc., New York, pp. 15.
Findley LJ, Gresty MA, Halmagyi GM (1981). Tremor and
cogwheel phenomena and clonus in Parkinsons disease.
J Neurol Neurosurg Psychiatry 44: 534546.
Fisher CM (1982). Hydrocephalus as a cause of disturbances
of gait in the elderly. Neurology 32: 13581363.
Forssberg H, Johnels B, Steg G (1984). Is parkinsonian gait
caused by a regression to an immature walking pattern?
In: RG Hasler, JF Christ (Eds.), Advances in Neurology,
40th edn. Raven Press, New York, pp. 375379.
Fransson PA, Kristinsdottir EK, Hafstrom A et al. (2004).
Balance control and adaptation during vibratory perturba-
tions in middle-aged and elderly humans. Eur J Appl
Physiol 91: 595603.
Friedman JH (1992). Drug-induced parkinsonism. In: AE Lang,
WJ Weiner (Eds.), Drug-Induced Movement Disorders. Futura
Publishing Co., Inc, Mount Kisco, New York, pp. 4183.
Fuente-Fernandez R, Lu JQ, Sossi V et al. (2001). Biochem-
ical variations in the synaptic level of dopamine precede
motor fluctuations in Parkinsons disease: PET evidence
of increased dopamine turnover. Ann Neurol 49: 298303.
Gibb WRG (1991). Neuropathology of the substantia nigra.
Eur Neurol 31 (Suppl 1): 4859.
Gibb WR, Lees AJ (1988a). A comparison of clinical and
pathological features of young- and old-onset Parkinsons
disease. Neurology 38: 14021406.
Gibb WRG, Lees AJ (1988b). The relevance of the Lewy
body to the pathogenesis of idiopathic Parkinsons disease.
J Neurol Neurosurg Psychiatry 51: 745752.
441
Global Parkinsons Disease Survey (GPDS) Steering Com-
mittee (2002). Factors impacting on quality of life in Par-
kinsons disease: results from an international survey.
Mov Disord 17 (1): 6067.
Goetz CG, Tanner CM, Stebbins GT et al. (1988). Risk
factors for progression in Parkinsons disease. Neurology
38: 18411844.
Graybiel AM, Hirsch EC, Agid Y (1990). The nigrostriatal
system in Parkinsons disease. Adv Neurol 53: 1729.
Haerer AF, Anderson DW, Schoenberg BS (1982). Preva-
lence of essential tremor: results from the Copiah County
Study. Arch Neurol 39: 750751.
Hallett M (1986). Differential diagnosis of tremor. In: PJ
Vinken, GW Bruyn, HL Klawans (Eds.), Handbook of
Clinical Neurology; Extrapyramidal Disorders, 49th edn.
Elsevier Science Publishing Co., Inc, New York, pp.
583595.
Hardie RJ, Lees AJ (1988). Neuroleptic-induced Parkinsons
syndrome: clinical features and results of treatment with
levodopa. J Neurol Neurosurg Psychiatry 51: 850854.
Hietanen M, Teravainen H (1988). The effect of age of disease
onset on neuropsychological performance in Parkinsons
disease. J Neurol Neurosurg Psychiatry 51: 244249.
Hobson P, Meara J (2004). Risk and incidence of dementia
in a cohort of older subjects with Parkinsons disease in
the United Kingdom. Mov Disord 19 (9): 10431049.
Hoehn MM, Yahr MD (1967). Parkinsonism: onset, progres-
sion, and mortality. Neurology 17: 427442.
Hornykiewicz O, Kish SJ (1986). Biochemical pathophysiol-
ogy of Parkinsons disease. In: MD Yahr, KJ Bergmann
(Eds.), Advances in Neurology, Vol. 45, Raven Press,
New York, pp. 1934.
Hughes AJ, Daniel SE, Kilford L et al. (1992). Accuracy of
clinical diagnosis of idiopathic Parkinsons disease: a clin-
ico-pathological study of 100 cases. J Neurol Neurosurg
Psychiatry 55: 181184.
Hughes AJ, Daniel SE, Ben-Schlomo Y et al. (2002). The
accuracy of diagnosis of parkinsonian syndromes in a spe-
cialist movement disorder service. Brain 125: 861870.
Jackson JA, Jankovic J, Ford J (1983). Progressive supranuc-
lear palsy: clinical features and response to treatment in 16
patients. Ann Neurol 13: 273278.
Jankovic J, Fahn S (1980). Physiologic and pathologic tre-
mors Diagnosis, mechanism, and management. Ann Intern
Med 93: 460465.
Jankovic J, McDermott M, Carter J et al. (1990). Parkinson
Study Group. Variable expression of Parkinsons disease:
a base-line analysis of the DATATOP cohort. Neurology
40: 15291534.
Jankovic J, Rajput AH, Golbe LI et al. (1993). What is it?
Case 1, 1993: parkinsonism, dysautonomia, and ophthal-
moparesis. Mov Disord 8 (4): 525532.
Jankovic J, Beach J, Schwartz K et al. (1995). Tremor and
longevity in relatives of patients with Parkinsons disease,
essential tremor, and control subjects. Neurology 45: 645648.
Jankovic J, Schwartz KS, Ondo W (1999). Re-emergent tre-
mor of Parkinsons disease. J Neurol Neurosurg Psychiatry
67: 646650.
442 A. RAJPUT AND A. H. RAJPUT
Jellinger K (1987). The pathology of parkinsonism. In: CD
Marsden, S Fahn (Eds.), Movement Disorders 2. Butter-
worths and Co., London, pp. 124165.
Jenkyn LR, Reeves AG, Warren T et al. (1985). Neurological
signs in senescence. Arch Neurol 42: 11541157.
Katsikitis MPI (1988). A study of facial expression in Par-
kinsons disease using a novel microcomputer-based
method. J Neurol Neurosurg Psychiatry 51: 362366.
Kelly J, Taggart HM, McCullagh P (1995). Normal and
abnormal tremor in the elderly. In: LJ Findley, WC Koller
(Eds.), Handbook of Tremor Disorders. Marcel Dekker,
Inc, New York, pp. 351370.
Kischka U, Mandir AS, Ghika J et al. (1993). Electrophysio-
logic detection of extrapyramidal motor signs in Alzhei-
mers disease. Neurology 43: 500505.
Kish SJ, Shannak K, Hornykiewicz O (1988). Uneven
pattern of dopamine loss in the striatum of patients with
idiopathic Parkinsons disease. N Engl J Med 318:
876880.
Kish SJ, Shannak K, Rajput A et al. (1992). Aging produces
a specific pattern of striatal dopamine loss: implications
for the etiology of idiopathic Parkinsons disease. J Neuro-
chem 58: 642648.
Klawans HL (1981). Abnormal movements in the elderly.
Sandorama (Special Issue): 1518.
Kline D, Sekuler R, Dismukes K (1982). Social issues,
human needs, and opportunities for research on the effects
of age on vision: an over-view. In: R Sekuler, D Kline,
K Dismukes (Eds.), Aging and Human Visual Function.
Alan R Liss, New York, pp. 36.
Koller WC, Biary N (1984). Effect of alcohol on tremors:
comparison with propranolol. Neurology 34: 221222.
Koller WC, Glatt S, Wilson RS et al. (1982). Primitive
reflexes and cognitive function in the elderly. Ann Neurol
12: 302304.
Koller WC, Wilson R, Glatt S et al. (1983). Senile gait; correlation
with computed tomographic scan. Ann Neurol 13: 343344.
Koller WC, Hubble JP, Busenbark KL (1994). Essential tre-
mor. In: DB Calne, (Ed.), Neurodegenerative Diseases.
WB Saunders Co., Philadelphia, pp. 717742.
Kostic V, Przedborski S, Flaster E et al. (1991). Early devel-
opment of levodopa-induced dyskinesias and response
fluctuations in young-onset Parkinsons disease. Neu-
rology 41: 202205.
LeWitt PA (1995). Tremor induced or enhanced by pharma-
cological means. In: LJ Findley, WC Koller (Eds.), Hand-
book of Tremor Disorders. Marcel Dekker, Inc, New
York, pp. 473481.
Lexell J, Taylor CC, Sjostrom M (1988). What is the cause of
the ageing atrophy? Total number, size and proportion of
different fiber types studied in whole vastus lateralis muscle
for 15- to 83-year-old men. J Neurol Sci 84: 275294.
Louis ED (2001). Essential tremor. N Engl J Med 345:
887891.
Louis ED, Marder K, Cote L et al. (1995). Differences in the
prevalence of essential tremor among elderly African
Americans, whites, and Hispanics in northern Manhattan,
NY. Arch Neurol 52: 12011205.
Louis ED, Marder K, Cote L et al. (1996). Prevalence of a
history of shaking in persons 65 years of age and older:
diagnostic and functional correlates. Mov Disord 11:
6369.
Luxon LM (1984). A bit dizzy. Br J Hosp Med 32: 315.
Maki BE, Holliday PJ, Fernie GR (1990). Aging and postural
control A comparison of spontaneous-and induced-sway
balance tests. J Am Geriatr Soc 38 (1): 19.
Marder K, Leung D, Tang M et al. (1991). Are demented
patients with Parkinsons disease accurately reflected in
prevalence surveys? A survival analysis. Neurology 41:
12401243.
Marsden CD (1989). Slowness of movement in Parkinsons
disease. Mov Disord 4 (Suppl 1): S26S37.
Martin WE, Loewenson RB, Resch JA et al. (1973). Parkin-
sons disease: clinical analysis of 100 patients. Neurology
23: 783790.
Marttila RJ (1987). Epidemiology. In: WC Koller, (Ed.),
Handbook of Parkinsons Disease. Marcel Dekker, Inc,
New York, pp. 3550.
Marttila RJ, Rinne UK (1976). Dementia in Parkinson dis-
ease. Acta Neurol Scand 54: 431441.
Matjucha ICA, Katz B (1994). Neuro-ophthalmology of aging.
In: ML Albert, JE Knoefel (Eds.), Clinical Neurology of
Aging.2nd edn., Oxford University Press, New York p. 447.
Mayeux R, Stern Y, Rosenstein R et al. (1988). An estimate
of the prevalence of dementia in idiopathic Parkinsons
disease. Arch Neurol 45: 260262.
Mayeux R, Chen J, Mirabello E et al. (1990). An estimate of
the incidence of dementia in idiopathic Parkinsons dis-
ease. Neurology 40: 15131517.
Mayeux R, Marder K, Cote LJ et al. (1995). The frequency
of idiopathic Parkinsons disease by age, ethnic group,
and sex in northern Manhattan, 19881993. Am J Epide-
miol 142: 820827.
Menz HB, Lord SR, Fitzpatrick RC (2003). Age-related dif-
ferences in walking stability. Age Ageing 32 (2): 137142.
Mindham RHS, Ahmed SWA, Clough CG (1982). A con-
trolled study of dementia in Parkinsons disease. J Neurol
Neurosurg Psychiatry 45: 969974.
Moghal S, Rajput AH, DArcy C et al. (1994). Prevalence of
movement disorders in elderly community residents. Neu-
roepidemiology 13: 175178.
Moghal S, Rajput AH, Meleth R et al. (1995). Prevalence of
movement disorders in institutionalized elderly. Neuroepi-
demiology 14: 297300.
Molsa PK, Marttila RJ, Rinne UK (1984). Extrapyramidal
signs in Alzheimers disease. Neurology 34: 11141116.
Morgante L, Rocca WA, Di Rosa AE et al. (1992). Preva-
lence of Parkinsons disease and other types of parkinson-
ism: a door-to-door survey in three Sicilian municipalities.
Neurology 42: 19011907.
Morris JC, Drazner M, Fulling K et al. (1989). Clinical and
pathological aspects of parkinsonism in Alzheimers dis-
ease. Arch Neurol 46: 651657.
Parker SW (1994). Dizziness in the elderly. In: ML Albert,
JE Knoefel (Eds.), Clinical Neurology of Aging. 2nd edn.,
Oxford University Press, New York, pp. 569579.
 OLD AGE AND PARKINSONS DISEASE
Quinn N (1989). Multiple system atrophythe nature of
the beast. J Neurol Neurosurg Psychiatry 1 (Special Suppl)
(7800): 7889.
Rajput AH (1973). Levodopa in dystonia musculorum
deformans. Lancet 1: 432.
Rajput AH (1984). Drug induced parkinsonism in the
elderly. Geriatr Med Today 3: 99107.
Rajput AH (1986). Parkinsons disease in the elderly. Med
North Am 1 (38): 101106.
Rajput AH (1992). Prevalence of dementia in Parkinsons
disease. In: SJ Huber, JL Cummings (Eds.), Parkinsons
Disease. Neurobehavioral Aspects. Oxford University
Press, New York, pp. 119131.
Rajput AH (1993a). Accuracy of clinical diagnosis of idio-
pathic Parkinsons disease. J Neurol Neurosurg Psychiatry
56: 938939.
Rajput AH (1993b). Diagnosis of PD. Letter. Neurology 43:
16291630.
Rajput AH (1993c). Parkinsonism, aging and gait apraxia.
In: MB Stern, WC Koller (Eds.), Parkinsonian Syndromes.
Marcel Dekker, Inc, New York, pp. 511532.
Rajput AH (1994a). Clinical features and natural history of
Parkinsons disease (special consideration of aging). In:
DB Calne, (Ed.), Neurodegenerative Diseases. 1st edn,
WB Saunders Company, Philadelphia, pp. 555571.
Rajput AH (1994b). Clinical features of tremor in extrapyra-
midal syndromes. In: LJ Findley, WC Koller (Eds.),
Handbook of Tremor Disorders. Marcel Dekker, Inc,
New York, pp. 275291.
Rajput AH (2001). Levodopa prolongs life expectancy and is
non-toxic to substantia nigra. Parkinsonism Relat Disord
8: 95100.
Rajput AH (2002). Contributions of human brain biochem-
ical studies to movement disorders. Parkinsonism Relat
Disord 8: 425431.
Rajput AH, Rajput A (2004). Movement disorders and aging.
In: RL Watts, WC Koller (Eds.), Movement Disorders. Neuro-
logic Principles & Practice, 2nd edn. McGraw-Hill, New
York, pp. 837853.
Rajput AH, Rozdilsky B (1975). Parkinsonism and dementia:
effects of L-dopa. Lancet 1: 1084.
Rajput AH, Kazi KH, Rozdilsky B (1972). Striatonigral
degeneration response to levodopa therapy. J Neurol Sci
16: 331341.
Rajput AH, Jamieson H, Hirsch S et al. (1975). Relative effi-
cacy of alcohol and propranolol in action tremor. Can
J Neurol Sci 2: 3135.
Rajput AH, Rozdilsky B, Hornykiewicz O et al. (1982).
Reversible drug-induced parkinsonism Clinicopathologic
study of two cases. Arch Neurol 39: 644646.
Rajput AH, Offord KP, Beard CM et al. (1984a). Epidemiol-
ogy of parkinsonism: incidence, classification, and mortal-
ity. Ann Neurol 16: 278282.
Rajput AH, Offord KP, Beard CM et al. (1984b). Essential
tremor in Rochester, Minnesota: a 45-year study. J Neurol
Neurosurg Psychiatry 47: 466470.
Rajput AH, Stern W, Laverty WH (1984c). Chronic low dose
therapy in Parkinsons disease: an argument for delaying
levodopa therapy. Neurology 34 (8): 991996.
443
Rajput AH, Offord KP, Beard CM et al. (1987). A case control
study of smoking habits, dementia and other illnesses in
idiopathic Parkinsons disease. Neurology 37: 226232.
Rajput AH, Uitti RJ, Sudhakar S et al. (1989). Parkinsonism
and neurofibrillary tangle pathology in pigmented Nuclei.
Ann Neurol 25: 602606.
Rajput AH, Rozdilsky B, Ang L (1990a). Site(s) of lesion
and resting tremor. Ann Neurol 28 (No.2): 296297.
Rajput AH, Rozdilsky B, Rajput AH (1990b). Essential leg
tremor. Neurology 40: 1909.
Rajput AH, Rozdilsky B, Rajput A et al. (1990c). Levodopa
efficacy and pathological basis of Parkinson syndrome.
Clin Neuropharmacol 13 (6): 553558.
Rajput AH, Rozdilsky B, Ang L (1991a). Occurrence of resting
tremor in Parkinsons disease. Neurology 41: 12981299.
Rajput AH, Rozdilsky B, Ang L et al. (1991b). Clinico-
pathological observations in essential tremor. Report of 6
cases. Neurology 41: 14221424.
Rajput AH, Rozdilsky B, Rajput A (1991c). Accuracy of
clinical diagnosis in parkinsonisma prospective study.
Can J Neurol Sci 18: 275278.
Rajput AH, Pahwa R, Pahwa P et al. (1993a). Prognostic sig-
nificance of the onset mode in parkinsonism. Neurology
43: 829830.
Rajput AH, Rozdilsky B, Ang L et al. (1993b). Significance
of parkinsonian manifestations in essential tremor. Can
J Neurol Sci 20: 114117.
Rajput AH, Rozdilsky B, Rajput A (1993c). Alzheimers dis-
ease and idiopathic Parkinsons disease coexistence.
J Geriatr Psychiatry Neurol 6: 170176.
Rajput AH, Uitti RJ, Rajput AH et al. (1997). Timely levo-
dopa (LD) administration prolongs survival in Parkinsons
disease. Parkinsonism Relat Disord 3 (3): 159165.
Rajput AH, Fenton ME, Birdi S et al. (2002). Clinical-patho-
logical study of levodopa complications. Mov Disord
17 (2): 289296.
Rajput AH, Fenton ME, Di Paolo T et al. (2004a). Human
brain dopamine metabolism in levodopa-induced dys-
kinesia and wearing-off. Parkinsonism Relat Disord 10:
221226.
Rajput A, Robinson C, Rajput AH (2004b). Essential tremor
course and disability: a clinicopathological study of 20
cases. Neurology 62: 932936.
Rautakorpi I, Marttila RJ, Takala J et al. (1982a). Occur-
rences and causes of tremors. Neuroepidemiology 1:
209215.
Rautakorpi I, Takala J, Marttila RJ et al. (1982b). Essential
tremor in a Finnish population. Acta Neurol Scand 66:
5867.
Robinson CA, Rajput AH (2005). The Neuropathology of
Parkinsons Disease and Other Parkinsonian Disorders-
Vol. 8493, CRC Press, Boca Raton, pp. 15901595.
Rocca WA, Bower JH, McDonnell SK et al. (2001). Time
trends in the incidence of parkinsonism in Olmsted
County, Minnesota. Neurology 57: 462467.
Ross GW, Petrovitch H, Abbott RD et al. (2004). Parkinso-
nian signs and substantia nigra neuron density in decen-
dents elders without PD. Ann Neurol 56: 532539.
444 A. RAJPUT AND A. H. RAJPUT
Rowe JW (1988). Aging and geriatric medicine. In: JB
Wyngaarden, LH Smith (Eds.), Cecil Textbook of Medi-
cine. WB Saunders, Philadelphia, pp. 2127.
Salemi G, Savettieri G, Rocca WA et al. (1994). Prevalence
of essential tremor: a door-to-door survey in Terrasini,
Sicily. Neurology 44 (1): 6164.
Schaafsma JD, Balash Y, Gurevich T et al. (2003). Character-
ization of freezing of gait subtypes and the response of
each to levodopa in Parkinsons disease. Eur J Neurol
10 (4): 391398.
Scherman D, Desnos C, Darchen F et al. (1989). Striatal
dopamine deficiency in Parkinsons disease: role of aging.
Ann Neurol 26: 551557.
Schoenberg BS, Anderson DW, Haerer AF (1985). Preva-
lence of Parkinsons disease in the biracial population
of Copiah County, Mississippi. Neurology 35 (6):
841845.
Schott JM, Rossor MN (2003). The grasp and other primitive
reflexes. J Neurol Neurosurg Psychiatry 74: 558560.
Simons G, Pasqualini MC, Reddy V et al. (2004). Emotional
and non-emotional facial expressions in people with Par-
kinsons disease. J Int Neuropsychol Soc 10: 521535.
Soininen H, Laulumaa V, Helkala EL et al. (1992). Extrapyra-
midal signs in Alzheimers disease: a 3-year follow-up study.
J Neural Transm Park Dis Dement Sect 4 (2): 107119.
Steele JC, Richardson JC, Olszewski J (1964). Progressive
supranuclear palsy: a heterogeneous degeneration invol-
ving the brain stem, ganglia and cerebellum with vertical
gaze and pseudobulbar palsy, nuchal dystonia and demen-
tia. Arch Neurol 10: 333359.
Stern G (1987). Prognosis in Parkinsons disease. In: CD
Marsden, S Fahn (Eds.), Movement Disorders 2. Butter-
worth and Co. Ltd, London, pp. 9198.
Stiles RN (1976). Frequency and displacement amplitude
relations for normal hand tremor. J Appl Physiol 40 (1):
4454.
Sudarsky L (1990). Geriatrics: gait disorders in the elderly.
N Engl J Med 322: 14411446.
Sudarsky L (1994). Gait disturbances in the elderly. In: ML
Albert, JE Knoefel (Eds.), Clinical Neurology of Aging.
2nd edn., Oxford University Press, New York, pp. 483492.
Sudarsky L, Ronthal M (1983). Gait disorders among elderly
patients A survey study of 50 patients. Arch Neurol 40:
740743.
Sudarsky L, Simon S (1987). Gait disorder in late-life hydro-
cephalus. Arch Neurol 44: 263267.
Suteerawattananon M, Morris GS, Etnyre BR et al. (2004).
Effects of visual and auditory cues on gait in individuals
with Parkinsons disease. J Neurol Sci 219 (12): 6369.
Tinetti ME, Speechley M, Ginter SF (1988). Risk factors for
falls among elderly persons living in the community.
N Engl J Med 319: 17011707.
Tyrrell PJ, Rossor MN (1989). Extrapyramidal signs in
dementia of Alzheimer type. Lancet 2 (8668): 920.
Uitti RJ, Ahlskog JE, Maraganore DM et al. (1993). Levodo-
pa therapy and survival in idiopathic Parkinsons disease:
Olmsted County project. Neurology 43: 19181926.
Uitti RJ, Rajput AH, Ahlskog JE et al. (1996). Amantadine
treatment is an independent predictor of improved survival
in Parkinsons disease. Neurology 46: 15511556.
Webster DD (1968). Critical analysis of disability in Parkin-
sons disease. Mod Treat 5 (2): 257282.
Weiner WJ, Nora LM, Glantz RH (1984). Elderly inpatients:
postural reflex impairment. Neurology 34: 945947.
Whitman GT, Tang T, Lin A et al. (2001). A prospective
study of cerebral white matter abnormalities in older
people with gait dysfunction. Neurology 57: 990994.
Wilson RS, Schneider JA, Beckett LA et al. (2002). Progres-
sion of gait disorder and rigidity and risk of death in older
persons. Neurology 58: 18151819.
Winter DA, Patla AE, Frank JS et al. (1990). Biomechanical
walking pattern changes in the fit and healthy elderly.
Phys Ther 70 (6): 340347.
Zetusky WJ, Jankovic J, Pirozzolo FJ (1985). The Hetero-
geneity of Parkinsons disease: clinical and prognostic
implications. Neurology 35: 522526.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 54

Other degenerative processes

J. CARSTEN MOLLER* AND WOLFGANG H. OERTEL

Department of Neurology, Philipps-University Marburg, Marburg, Germany

54.1. Frontotemporal dementia and
parkinsonism linked to chromosome 17
(FTDP-17) and related disorders
Previously, several familial parkinsonismdementia syn-
dromes, such as disinhibitiondementiaparkinsonism
amyotrophy complex and autosomal-dominant
parkinsonism and dementia with pallidopontonigral
degeneration, were distinguished (Wszolek et al.,
1992; Lynch et al., 1994). Subsequently, according
to a consensus conference, these syndromes were
summarized and termed FTDP-17 (Foster et al.,
1997). In 1998 this disease was found to be caused by
mutations in the tau gene in several affected families
(Hutton et al., 1998). At least 26 different mutations
are known, with the exon-10 P301L missense mutation
being most prevalent (Wszolek et al., 2003). Subse-
quently, several transgenic mouse models of FTDP-17
have been developed based on these mutations (Lewis
et al., 2000). Tau is an intracellular protein that pro-
motes the assembly and stabilization of microtubules.
Mutations in the tau gene can be distinguished into
two types (Rosso and van Swieten, 2002):
1. The first type of (missense) mutations reduces the
ability of the tau protein to bind to microtubules.
2. The second type of mutation results in a change in
the ratio (and subsequent accumulation) of tau
isoforms with three amino acid repeats to those
with four amino acid repeats.
Neuropathologically, frontotemporal and basal
ganglia atrophy and substantia nigra depigmentation
are usually found. Microscopic examination reveals
neuronal loss and gliosis of variable intensity, tau-
positive intraneuronal (and glial) inclusions without
the characteristics of Pick bodies and ballooned neu-
rons (Foster et al., 1997). The estimated total number
of affected patients from 62 known families was 470
in 2003 (Wszolek et al., 2003).
The mean age at disease onset is 49 years and
the average disease duration is 8.5 years (Wszolek
et al., 2003). The principal central nervous system
(CNS) manifestations consist of motor, cognitive and
behavioral disturbances (Foster et al., 1997). Motor
symptoms include:

akinetic-rigid parkinsonian features without
resting tremor

dystonia

spasticity

supranuclear gaze palsy

occasionally amyotrophy
The cognitive disturbances comprise impaired
executive functions: visuospatial orientation and com-
mon memory functions are relatively preserved until
later stages of the disease. The behavioral symptoms
include:

impaired social conduct

hyperorality

hyperphagia

obsessive stereotyped behavior

psychosis
Most patients harboring exon-10 missense and
intronic mutations in the tau gene develop a parkinson-
ism-predominant phenotype (Wszolek et al., 2003).
However, FTDP-17 features a wide range of phenoty-
pic variations between kindreds with different tau
mutations but also among family members from the
same kindred. This issue has recently been confirmed
by a prospective study in two siblings carrying the
S305N tau mutation, in whom different rates of change
in whole-brain and ventricular volume as measured by
magnetic resonance imaging (MRI) were found

*Correspondence to: PD Dr. med. Jens Carsten Moller, Klinik fur Neurologie, Philipps-Universitat Marburg, Rudolf-Bultmann-Str. 8,
35039 Marburg, Germany. E-mail: carsten.moeller@med.uni-marburg.de, Tel: 49-6421-286-5200, Fax: 49-6421-286-7055.
446 J. C. MOLLER AND W. H. OERTEL
(Boeve et al., 2005). Useful diagnostic criteria are in
general: (1) age at disease onset between the third and
the fifth decade; (2) rapid disease progression; (3) par-
kinsonism-plus symptoms (i.e. akinetic-rigid features
associated with early falls, supranuclear gaze palsy,
apraxia, dystonia and lateralization); (4) frontotemporal
dementia; and (5) personality and behavioral abnor-
malities (Wszolek et al., 2003). The diagnosis can be
confirmed by genetic testing, if available. Structural
and functional imaging often reveals frontotemporal
atrophy and/or hypometabolism.
There is a wide range of possible differential
diagnoses, including sporadic tauopathies such as pro-
gressive supranuclear palsy, corticobasal ganglionic
degeneration and Picks disease. Apart from FTDP-17,
there are also other types of familial frontotemporal
dementia (FTD), i.e. ubiquitin-positive FTD and demen-
tia lacking distinctive histology (Morris et al., 2001).
Ubiquitin-positive FTD can be accompanied by histolo-
gical features of (clinically often inapparent) motor neu-
rone disease (Paviour et al., 2004). Ubiquitin-positive
FTD is possibly caused by mutations in the valosin-
containing protein and may overlap with dementia lack-
ing distinctive histology (Josephs et al., 2004; Watts
et al., 2004; Schroder et al., 2005). Parkinsons disease
(PD) with dementia, dementia with Lewy bodies
and Alzheimers disease represent further differential
diagnoses of FTDP-17.
A specific therapy is not known. Paients usually
show poor response to levodopa. Psychiatric treatment
is usually necessary and often proves challenging
despite pharmacological and behavioral therapies.
54.2. Neurodegeneration with brain iron
acculumation (NBIA)
This disorder was first reported in 1922 in a sibship
characterized by gait impairment resulting from
rigidity of legs and feet deformity and mental
deterioration with juvenile onset. The condition was
subsequently named HallervordenSpatz syndrome
(HSS) (Hallervorden and Spatz, 1922). In response to
the unethical activities of Hallervorden and Spatz dur-
ing World War II, it has been suggested that the name
HSS is replaced by the term NBIA.
Recently, it has been shown that this disorder can
be due to mutations in the gene for pantothenate kinase
2 (PANK2) (Taylor et al., 1996; Zhou et al., 2001).
This type of NBIA is known as pantothenate kinase-
associated neurodegeneration (PKAN). It is usually
an autosomal-recessive disorder, although in some
cases the PANK2 mutation was suggested to be semi-
dominant. In one study, PANK2 mutations were found
in all patients with classic NBIA and in one-third of
those with so-called atypical disease (Hayflick et al.,
2003). Classic NBIA was assumed in patients with
disease onset during the first two decades, dystonia
and high globus pallidus iron with characteristic radio-
graphic appearance. The term atypical disease was
applied to individuals not fitting the above criteria
but with radiographic evidence of increased basal
ganglia iron (Zhou et al., 2001). Patients with the clas-
sic variant of the disease were usually shown to have
mutations resulting in predicted protein truncation
(Hayflick et al., 2003). The precise pathophysiology
of PKAN is still unknown. PANK2 catalyzes the
initial step in coenzyme A synthesis. It has thus been
suggested that the PANK2 mutations lead to coenzyme
A depletion associated with defective membrane bio-
synthesis (Zhou et al., 2001). Accordingly, it has been
shown that some point mutations indeed result in a
reduced catalytic activity during coenzyme A synth-
esis and that the most common mutation (G521R) is
associated with a decreased production of mature
PANK2 (Kotzbauer et al., 2005).
Besides accumulated cysteine, which would nor-
mally condense with phosphopantothenate, may form
complexes with iron and cause oxidative damage in
the brain (Hayflick et al., 2003). Neuropathologically,
the most striking feature of NBIA is the rust-brown
pigmentation of the globus pallidus and pars reticulata
of substantia nigra. On the microscopic level, iron
granules were found in neurons, microglial cells
and astrocytes. Some iron was also localized extra-
cellularly. Furthermore, mulberry concretions were
observed in tissue and regarded as so-called pseudo-
calcium. A further prominent finding of the disease
is a widely distributed distal axonal swelling. These
swellings may be surrounded by glial cells and contain
pigment granules, particularly when located in globus
pallidus or pars reticulata of substantia nigra. These
structures are known as spheroid bodies (Hallervorden
and Spatz, 1922; Swaiman, 1991) and resemble those
found in neuroaxonal dystrophy (Seitelberger, 1957),
but in the latter the spheroids in the pallidum store
fatty material and not pigments. These neuropathologi-
cal alterations are accompanied by some loss of
neurons and myelinated fibers as well as by gliosis.
In analogy to PD, Lewy body-like intraneuronal inclu-
sions containing a-synuclein were also observed in
NBIA (Galvin et al., 2000). No sufficient epidemiolo-
gical data of this group of rare disorders are available.
Dooling et al. (1974) examined 42 patients who
fulfilled both clinical and neuropathological criteria
for NBIA. Onset of disease occurred in 24 patients
before the age of 10 and 39 patients were ill before
age 22. The mean duration of disease was 11 years.
Gait difficulty and postural impairment were noted as
 OTHER DEGENERATIVE PROCESSES
initial symptoms in 37 patients. This may have been
the result of spasticity, whereas symptoms of extrapyr-
amidal dysfunction could be delayed by 1 year to
several years. However, the usual course included pro-
gression of rigidity and presence of posture abnormal-
ities. Other basal ganglia signs were observed,
including dystonia in 23 patients, choreoathethosis in
19 patients and tremor without any distinctive charac-
ter in 15 patients. Additionally, cognitive impairment
was common and, in 9 out of 42 patients, seizures
occurred (Dooling et al., 1974). Besides personality
changes such as impulsivity and violent outbursts,
depression and emotional lability were observed in
patients with atypical disease and PANK2 mutations
(Hayflick et al., 2003). In general, there was a wide
spectrum of variation in the clinical manifestations of
NBIA. It is noteworthy that 1 case of late-onset PKAN
presenting as familial parkinsonism was reported
(Jankovic et al., 1985). Apart from the CNS mani-
festations, foot deformities were frequently observed
and skin pigmentation was noted in some cases
(Wigboldus and Bruyn, 1968).
A summary of the clinical presentation of NBIA
based on a genotypephenotype analysis is provided
below. Several obligatory and corroborative symptoms
for the diagnosis of NBIA were defined in 1991
(Swaiman, 1991). The obligatory symptoms were:
1. onset during the first two decades of life
2. a progressive course
3. evidence of extrapyramidal dysfunction
The corroborative symptoms included:
1. pyramidal tract signs
2. progressive mental deterioration,
3. hypodensities in basal ganglia on MRI
4. occurrence of seizures
5. ophthalmological symptoms, such as retinitis
pigmentosa or optic atrophy
6. positive family history
7. abnormal cytosomes in circulating lymphocytes
and sea-blue histiocytes in bone marrow
A recent genotypephenotype analysis provided a
novel concept of the clinical presentation of NBIA:
patients with classic NBIA and PANK2 mutations
had a mean age of onset of 3.4 years; usually presented
with gait or postural symptoms; featured dystonia,
dysarthria, rigidity and choreoathetosis; and frequently
developed spasticity and cognitive decline, whereas
atypical NBIA patients with PANK2 mutations had a
mean age of onset of 13.7 years and featured less
severe and more slowly progressive extrapyramidal
symptoms. Furthermore, patients with classic disease
447
more often suffered from retinopathy. Conversely,
atypical patients more frequently presented with
speech problems as part of the early disease (Hayflick
et al., 2003). Besides, patients with a younger age of
onset (< 20 years) may have a higher frequency of dys-
tonia, gait disturbance and tremor, whereas parkinson-
ism seems more common in late-onset disease ( 20
years) (Thomas et al., 2004).
Possible differential diagnoses of PKAN include
Wilsons disease, Huntingtons disease, chorea
acanthocytosis (CHAC), neurometabolic disorders
and other types of NBIA such as NBIA without
PANK2 mutations, neuroferritinopathy and acerulo-
plasmenia. Neuroferritinopathy is a recently recog-
nized, dominantly inherited movement disorder
caused by a mutation of the ferritin light-chain gene
(Curtis et al., 2001). The clinical phenotype of this
disorder is highly variable, with symptoms beginning
in the third to sixth decade. Chorea, dystonia or an
akinetic-rigid syndrome can predominate (Crompton
et al., 2005). Aceruloplasmenia is an autosomal-
recessive disorder of iron metabolism characterized
by diabetes, retinal degeneration and progressive
neurodegeneration with extrapyramidal disorders,
ataxia and dementia (Gitlin, 1998). In addition, HARP
syndrome (hypoprebetalipoproteinemia, acanthocyto-
sis, retinitis pigmentosa, pallidal degeneration) was
shown to be allelic with PKAN (Ching et al., 2002).
Clinical diagnosis of NBIA can be confirmed by
MRI and genetic testing, if available. Laboratory
investigations do not normally reveal any distinctive
abnormalities, except that some patients feature vacuo-
lated circulating lymphocytes containing abnormal
cytosomes and sea-blue histiocytes in bone marrow
(Swaiman et al., 1983). Computed tomography (CT)
in patients with NBIA has been reported to show atro-
phy and low-density lesions in basal ganglia (Dooling
et al., 1980). MRI using a high-field-strength unit (1.5
Tesla) showed decreased signal intensity in the glo-
bus pallidus and pars reticulata of substantia nigra in
T2-weighted images, which is compatible with heavy-
metal (iron) deposits and a small area of hyperintensity
in the internal segment of pallidum, constituting the so-
called eye of the tiger sign (Rutledge et al., 1987; Sethi
et al., 1988). In all (homozygous and heterozygous)
PKAN patients, whether classic or atypical, MRI showed
the eye of the tiger sign, whereas this pattern was not
seen in atypical patients without PANK2 mutations
(Hayflick et al., 2003).
There is no specific therapy for NBIA. Sympto-
matic management, such as using levodopa and dopa-
mine agonists, may be beneficial to patients (Swaiman,
1991). Hypothetically, supplementation of panthothe-
nate could ameliorate the symptoms in patients with
448 J. C. MOLLER AND W. H. OERTEL
PANK2 mutations (Hayflick et al., 2003). Simple case
reports in the media described a dramatic improve-
ment with pantothenate, but no studies have been
performed yet.
54.3. Hemiparkinsonhemiatrophy (HPHA)
syndrome
HPHA is defined by the occurrence of a body
hemiatrophy with features of a highly asymmetric,
often levodopa-responsive parkinsonism more promi-
nent on the side of the hemiatrophy (Klawans, 1981;
Buchman et al., 1988). An association with contralat-
eral brain atrophy was also shown (Giladi et al.,
1990). Although no systematic genetic studies have
yet been performed, parkin mutations were found in
1 patient with HPHA (Pramstaller et al., 2002). It has
been reported that lesions of the postcentral gyrus
before the age of 3 are associated with a relative small-
ness of the contralateral parts of the body (Penfield
and Robertson, 1943). Accordingly, it was suggested
that the occurrence of parkinsonism in HPHA patients
is related to an additional subcortical lesion (Klawans,
1981). Supporting this point of view, Giladi et al.
(1990) presented neuroradiological evidence of a con-
tralateral brain hemiatrophy in 64% of their patients.
Since an association between perinatal asphyxia, brain
hemiatrophy and delayed-onset hemidystonia has
been shown, HPHA could represent an example of a
movement disorder with delayed onset as a conse-
quence of neonatal brain injury (Giladi et al., 1990).
Other authors reported 4 patients with dopa-responsive
dystonia and hemiatrophy (Greene et al., 2000). Since
dopa-responsive dystonia results from a purely
biochemical deficit in the brain, these authors sug-
gested that a deficiency of the nigrostriatal dopamine
system may by itself be sufficient to cause body hemi-
atrophy. However, neonatal ablation of the nigrostria-
tal pathway did not influence limb development in
rats (Hebb et al., 2002). A variable response to levo-
dopa and striatal hypometabolism, as shown by 18F-
fluorodeoxyglucose and positron emission tomography
(PET), suggests that both pre- and postsynaptic mec-
hanisms contribute to HPHA. No postmortem analysis
has been performed. So far reports on a total of 42
patients have been published.
Patients suffer from a body hemiatrophy with small
and narrow extremities on one side. There is a wide
variation in the degree of hemiatrophy: in some
patients the face, arm and a leg were affected, whereas
in other patients only the hand seemed to be affected.
The most likely part of the hand to demonstrate hemi-
atrophy was the thumb. It has to be kept in mind that
there is normal asymmetry of the two halves of the
human body. The term normal asymmetry should
only be applied to differences in opposite limb length
that are not visually apparent in the absence of mea-
surements (Halperin, 1931). Interestingly, 1 probable
patient showed no hemiatrophy, but an enlarged late-
ral ventricle as a sign of brain hemiatrophy (Giladi
et al., 1990). With respect to the CNS manifestations,
Buchman et al. (1988) reported that the mean age of
onset of parkinsonism was 43.7 years. The course of
the disease was slowly progressive, i.e. the mean dura-
tion of disease until initiation of levodopa therapy was
14.2 years. In contrast, in patients suffering from
idiopathic PD, levodopa treatment was started after
4.1 years (Buchman et al., 1988). Furthermore, no pro-
gression to a Hoehn and Yahr stage greater than III
was observed (Buchman et al., 1988). Eight out of 15
patients remained asymmetric after the development
of bilateral disease. Giladi et al. (1990) found a
more variable clinical course; for instance, one patient
progressed from Hoehn and Yahr stage I to V during
off periods within 2.5 years. Ipsilateral dystonic
movements, sometimes presenting as the first symp-
tom, often occur early in the course of the disease
before exposure to levodopa. A total of 10 out of 15
patients showed tremor as their initial symptom. Apart
from the parkinsonian features, pyramidal tract
dysfunction ipsilateral to the side of HPHA was pre-
sent in 8 out of 15 patients (Buchman et al., 1988).
Psychiatric symptoms are not usually a major feature
of this syndrome. In the differential diagnosis early-
onset PD has to be considered. Common features are
early age of onset and unilateral symptoms with mild
progression. The main differences are the evidence of
ipsilateral hemiatrophy and the prominence of early
dystonia in HPHA patients. Therefore, the diagnosis
depends on a thorough physical examination. More-
over, in the beginning the differential diagnosis may
include corticobasal ganglionic degeneration, since
HPHA may mimic its early stage (Giladi and Fahn,
1992). Due to the involvement of the nigrostriatal
dopaminergic system, the level of homovanillic acid
in the cerebrospinal fluid can be reduced. Central
motor conduction time as measured by transcranial
magnetic stimulation was normal in 2 HPHA patients
(Nardone et al., 2003). CT and MRI showed contralat-
eral brain asymmetry in 64% of investigated patients
(Giladi et al., 1990). However, Buchman et al. (1988)
found no evidence of cerebral hemiatrophy (cortical
or ventricular asymmetry) in 11 out of 12 patients.
Studies using 18F-fluorodeoxyglucose and PET show-
ed a focal hypometabolism in the basal ganglia and
the medial frontal cortex of the contralateral side,
whereas 18F-fluorodopa and PET revealed a reduction
in the striatal 18F-fluorodopa uptake. Hence the former
 OTHER DEGENERATIVE PROCESSES
examination might be useful to distinguish HPHA
from typical unilateral PD (Przedborski et al., 1993,
1994). This observation was not confirmed by other
authors (Pramstaller et al., 2002).
Seven out of 9 investigated patients showed a good
response to levodopa therapy and 7 out of 8 patients
responded well to a combination of amantadine and
anticholinergics (Buchman et al., 1988). Other investi-
gators found a good response to levodopa treatment in
7 out of 11 patients (Giladi et al., 1990). One patient
showed a dramatic improvement after subthalamic
nucleus stimulation (Giladi et al., 1990).
54.4. Chorea acanthocytosis
Acanthocytes are erythrocytes with changed morphol-
ogy bearing spicules of variable length and breadth
(Brecher and Bessis, 1972). If they occur in associa-
tion with neurological symptoms, the term neuroa-
canthocytosis is used. Four different types of
neuroacanthocytosis are known: acanthocytes are
observed in abetalipoproteinemia, the so-called Bas-
senKornzweig syndrome and in familial hypobetali-
poproteinemia (Kornzweig and Bassen, 1957; Young
et al., 1987). Furthermore, they are detectable in
CHAC (Critchley et al., 1968; Levine et al., 1968).
Finally, the McLeod syndrome represents a clinical
entity that is characterized by the occurrence of
acanthocytes and neurological symptoms (Allen
et al., 1961; Swash et al., 1983).
In addition there are some other conditions in which
a sporadic association with acanthocytes has been
described, i.e. PKAN and mitochondrial encephalo-
myopathies (Hardie, 1989). In adults CHAC is prob-
ably the most important disease. CHAC patients
usually feature chorea, oromandibular dyskinesias,
dementia, seizures and peripheral neuropathy. Addi-
tionally, parkinsonism may occur either with chorea
or as a subsequent feature, when the hyperkinetic
movement disorder subsides (Yamamoto et al., 1982;
Spitz et al., 1985). CHAC is an autosomal-recessive
disorder. The disease gene on chromosome 9q21 has
been identified and named chorein (Rampoldi et al.,
2001; Ueno et al., 2001). In 43 CHAC patients, 57 dif-
ferent chorein mutations were found, indicating a
strong allelic heterogeneity with no single mutation
causing the majority of cases (Dobson-Stone et al.,
2002). Most mutations, however, lead to premature
termination codons and therefore predict the absence
or marked reduction of chorein. A transgenic mouse
model featuring a mild phenotype and a late-adult
onset has recently been established (Tomemori et al.,
2005). The function of chorein is not known. Due to
homology studies it has been hypothesized that the
449
gene product could be involved in intracellular protein
cycling. Absence of chorein may therefore lead to
destabilization of the plasma membrane structure and
hence acanthocytosis (Rampoldi et al., 2001).
The suggested occurrence of CHAC without
acanthocytes may indicate that the gene can be vari-
ably expressed in different tissues and may cause
neurological abnormalities alone. In a family with
CHAC featuring an autosomal-dominant transmission
and polyglutamine-containing neuronal inclusions
abnormalities of the membrane protein band 3 were
demonstrated by gel electrophoresis of red blood cell
membranes (Walker et al., 2002). Neuropathologically,
the brains of CHAC patients showed enlargement
of the ventricles, particularly of the frontal horns.
Caudate and putamen were the most severely affected
brain areas showing atrophy, neuronal loss and
gliosis. Depletion of small- and medium-sized striatal
neurons was most apparent. Involvement of globus
pallidus was also present and in some cases thalamus
and the anterior horns of spinal cord showed neuronal
loss and mild gliosis (Rinne et al., 1994b). The sub-
stantia nigra of 3 CHAC patients was investigated
in more detail (Rinne et al., 1994a): in CHAC with
parkinsonism a reduced neuronal density (particularly
in the ventrolateral region) of the substantia nigra
was determined, whereas in 1 CHAC patient without
parkinsonian features the number of neurons was at
the lower limit of the control range. Epidemiological
data for this rare disease are not available.
The mean age of onset of CHAC was 32 years, ran-
ging from 8 to 62 years. The most striking symptoms
were involuntary movements affecting the orofacial
region and the limbs, presenting as orofacial dyskine-
sias and limb chorea (Sakai et al., 1981). The former
can cause tongue- and lip-biting and very often inter-
feres with speech and swallowing. Accordingly,
involuntary vocalizations were frequently observed.
In some cases, the predominant manifestation was
dystonia rather than chorea. Furthermore, Yamamoto
et al. (1982) and Hardie (1989) described the occur-
rence of akinetic-rigid features simultaneously with
the appearance of hyperkinetic disorders in 2 out of 2
and 5 out of 19 cases, respectively. Spitz et al.
(1985) reported 2 CHAC cases presenting as tics, that
were progressively replaced or masked by progressive
parkinsonism. In 2 out of 19 patients, no movement
disorder could be established, indicating that this
might not be a necessary condition (Hardie et al.,
1991). Additionally, hypo- or areflexia was repeatedly
found. In many cases muscle wasting occurred and
axonal neuropathy was demonstrated (Serra et al.,
1987). Moreover, one-third of patients suffered from
seizures and in more than half of the cases cognitive
450 J. C. MOLLER AND W. H. OERTEL
impairment, psychiatric features and personality
change were seen (Hardie, 1989; Hardie et al., 1991).
The most frequent psychiatric symptoms were impul-
sive and distractable behavior, apathy and loss of
insight. Additionally, depression, anxiety, paranoid
delusions and obsessive-compulsive features were
observed.
The correct diagnosis depends on the combination
of significant acanthocytosis with normal plasma lipo-
proteins and neurological abnormalities. In this context
the clinical picture of CHAC with a predominantly
hyperkinetic movement disorder, personality change
and cognitive impairment may resemble that of
Huntingtons disease. Therefore, in any suspected case
of Huntingtons disease acanthocytosis should be
excluded. Usually diagnosis of Huntingtons disease
will be confirmed by neurogenetic methods. This
may be the case for CHAC in the future as well, but
at present its genetic diagnosis is costly and time-con-
suming due to its genetic heterogeneity.
Several methods are known to prove significant
acanthocytosis. The most efficient method is probably
the examination of a wet preparation of isotonically
diluted blood samples (Storch et al., 2005). The nor-
mal range of acanthocytes in this kind of preparation
is < 6.3%. Scanning electron microscopy may be help-
ful in measuring the extent of the erythrocyte morpho-
logical abnormalities in some cases (Hardie et al.,
1991). Apart from acanthocytosis, modestly elevated
creatine kinase levels have been reported (Sakai
et al., 1981). Other laboratory parameters show no
abnormalities. In contrast to BassenKornzweig syn-
drome and to familial hypobetalipoproteinemia,
decreased serum lipid levels are not found in CHAC.
Western blotting of patient erythrocyte membranes in
order to assess the expression level of chorein may
soon become available (Dobson-Stone et al., 2004).
CT revealed cortical or occasional caudate atrophy as
significant features (Serra et al., 1987; Hardie et al.,
1991). MRI showed focal and symmetric signal
abnormalities in the caudate and lentiform nuclei in 3
out of 4 cases (Hardie et al., 1991). In another study
increased signal intensity accompanied by scattered
bright spots in the striatum in T2-weighted images
was observed (Tanaka et al., 1998). PET revealed the
following alterations: mean posterior putamen 18F-
fluorodopa uptake was reduced to 42% of normal;
depressed frontal and striatal blood flow was seen;
and a loss of caudate and putamen D2-receptors was
observed (Brooks et al., 1991; Tanaka et al., 1998).
Because there is no specific treatment known,
therapy remains symptomatic. However, parkinsonian
symptoms did not respond to high dosages of levodopa
(Spitz et al., 1985) and the response of the involuntary
movements to drug treatment was generally poor
(Hardie, 1989). Severe trunk spasms were improved
by bilateral thalamic stimulation in 1 case (Burbaud
et al., 2002).
54.5. Pallidonigroluysian degeneration
The pallidal, pallidonigral, pallidoluysian and pallido-
nigroluysian degenerations (PNLD) include a number
of familial or sporadically occurring movement disor-
ders, clinically defined by a slowly progressive course
and a wide variety of extrapyramidal symptoms. This
category of disorders has previously been classified
into four distinct groups:
1. pure pallidal atrophy,
2. pure pallidoluysian atrophy
3. extended forms of pallidal degeneration, i.e. palli-
donigral and pallidoluysionigral atrophy
4. variable forms of these subtypes with other
cerebrospinal degenerations (Jellinger, 1986).
For instance, the separately described pallidopyra-
midal disease (see section 54.6, below) could be
considered a member of this group (Jellinger, 1986).
Furthermore, the relation of the familial pallidonigral
system degeneration with cystic damage reported by
McCormick and Lemmi (1965) to PNLD is not
known. Finally, in a small number of cases there is
evidence of a possibly different movement disorder,
characterized by the isolated degeneration of the
external pallidum or status marmoratus of the basal
ganglia in association with the occurrence of intraneur-
onal polyglucosan (Bielschowsky) bodies (Yagishita
et al., 1983).
In this section we focus on PNLD. In most of the
reported families this condition appears to be of
autosomal-recessive inheritance (Jellinger, 1986).
Recently, a mutation in the microtubule-associated
protein tau, i.e. a substitution at codon 279, has been
found in a PNLD case (Yasuda et al., 1999; Wszolek
et al., 2000). This observation and the histopathologi-
cal demonstration of hyperphosphorylated tau in 1
PLND case indicate that this disorder may be a tauopa-
thy (Mori et al., 2001). It is not clear whether pallidal,
pallidoluysian and pallidonigral degeneration are pos-
sibly tauopathies as well. Neuropathologically, a
degeneration of the pallidum alone or in association
with the substantia nigra and/or the nucleus
subthalamicus (of Luys) is found. A progressive loss
of nerve cells and fibers accompanied by proportional
gliosis has been found in these areas (Jellinger, 1986).
The changes may vary in their extent. In rare instances
they might be associated with further degenerative
lesions in other extrapyramidal, motor neuron or
 OTHER DEGENERATIVE PROCESSES
spinocerebellar systems. A pure pallidal atrophy with
gliosis and locally differing neuronal loss was reported
by Lange et al. (1970).
In another case of pure pallidal atrophy, morpho-
metric analysis revealed a shrinkage of the globus
pallidus externus to 59% and the globus pallidus inter-
nus to 37% of normal, but the neuron density did not
seem to be affected (Aizawa et al., 1991). Bilateral
symmetrical loss of neurons and myelin with gliosis
mainly in the outer pallidum was combined with pallor
of the ansa lenticularis and atrophy of subthalamic
nucleus in a case of pallidoluysian degeneration (van
Bogaert, 1947).
These changes are consistent with the findings
observed in the various (extended) forms of this group
of neurodegenerative disorders. Other observations
include the occurrence of corpora amylacea through-
out the CNS and brown granular deposits showing a
positive reaction to iron in the degenerated nuclei
and the striatum in PNLD (Kosaka et al., 1981; Kawai
et al., 1993). Furthermore, hyperphosphorylated tau
was observed in 1 patient with PNLD (Mori et al.,
2001). No epidemiological data are available due to
the small number of investigated cases.
Nosologically, PNLD and its related disorders
should be distinguished from autosomal-dominant
striatal degeneration (ADSD), another rare basal gang-
lia disease (Kuhlenbaumer et al., 2004). ADSD is
characterized by onset in the fourth or fifth decade,
slow progression and prominent dysarthria with mild
hypokinesia, manifesting mainly as gait disturbance.
MRI usually shows a signal increase in the striatum
in T2-weighted images.
PNLD and its related disorders demonstrate an insi-
dious onset and a slowly progressive course. Onset of
illness in familial cases was between ages 5 and 40
and in sporadic cases between ages 30 and 64.
Depending on the variable pattern of morphological
alterations, there may be distinct predominant symp-
toms. In pure pallidal degeneration the clinical picture
is characterized by the development of progressive
choreoathetotic hyperkinesias with axial dystonia, fol-
lowed by the appearance of progressive rigidity.
Finally, the involuntary movements are overcome by
permanent rigidity and the patients become bed-ridden
(Jellinger, 1986). In contrast, Aizawa et al. (1991)
reported a case of pallidal degeneration with an
extreme slowness of movements without rigidity as
the main symptom. In pallidoluysian degeneration,
additional symptoms are torticollis, head tremor and
distal movements with or without a ballistic component
(Jellinger, 1986). Another case of pallidoluysian
degeneration presented with 20 years of progressive
generalized dystonia, dysarthria, gait disorder, verti-
451
cal gaze palsy and bradykinesia (Wooten et al.,
1993). In PNLD the most apparent symptoms are
progressive akinesia and rigidity with little or no tre-
mor (Jellinger, 1986). Additionally, upward gaze
palsy or Parinauds syndrome has been observed. A
PNLD case with rapidly progressive hemidystonia
has been reported (Vercueil et al., 2000).
In conclusion, a wide spectrum of different clinical
manifestations exists, depending on the spatial and
temporal pattern of effect of the distinct brain areas.
Consequently, because of their rarity, the clinical cor-
relates of the distinct forms are still not well described.
Familial occurrence of the combination of progressive
rigidity and choreoathethosis or torsion dystonia with
an early onset may suggest one of these disorders.
The disorders may be accompanied by mental dete-
rioration, but intellectual impairment may be absent,
even in advanced disease stages (Jellinger, 1986).
A history of psychosis was reported in several cases
(Klawans, 1981; Kawai et al., 1993). The PNLD patient
with the mutation in the tau gene featured dementia
whereas no dementia was observed in the case with
the accumulation of hyperphosphorylated tau (Yasuda
et al., 1999; Mori et al., 2001). Except for the CNS
symptoms, no other clinical manifestations are known.
The diagnosis of these rare conditions can only be
proven by means of postmortem examination. Possible
differential diagnoses include juvenile parkinsonism,
idiopathic torsion dystonia, PKAN, dentatorubral-
pallidoluysian atrophy, progressive supranuclear palsy,
multiple system atrophy, corticobasal ganglionic degen-
eration and others. Sequencing of the tau gene, if
available, should be performed. Routine laboratory data
are unremarkable. CT in younger patients was normal
(Jellinger, 1986); minimal atrophy of the brainstem
and dilatation of the sylvian fissure were seen in a sin-
gle case (Aizawa et al., 1991). MRI of the brain in a
patient with pallidoluysian degeneration showed no
abnormalities (Wooten et al., 1993). T2-weighted
MRI demonstrated increased signal intensity in palli-
dum and substantia nigra in a PNLD patient with hemi-
dystonia (Vercueil et al., 2000). Furthermore,
contralateral cortical hyperperfusion was observed in
this patient.
Treatment with levodopa has produced only equivo-
cal improvement of the movement disorder (Aizawa
et al., 1991; Yamamoto et al., 1991). However, 1
patient with dystonic symptoms was reported to benefit
from baclofen (Wooten et al., 1993).
54.6. Pallidopyramidal disease
Pallidopyramidal disease is thought to be an autosomal-
recessive disorder with onset in the second or early third
452 J. C. MOLLER AND W. H. OERTEL
decade, with a clinical picture consisting of parkinson-
ism and pyramidal tract signs (Davison, 1954; Horowitz
and Greenberg, 1975; Tranchant et al., 1991; Nisipeanu
et al., 1994). Furthermore, a syndrome was reported that
is closely related but not identical to pallidopyramidal
disease. It is called KuforRakeb syndrome and addi-
tionally characterized by supranuclear upgaze paresis
and dementia (Najim al-Din et al., 1994). The disease
locus for KuforRakeb syndrome has been mapped to
chromosome 1p36 (Hampshire et al., 2001). The patho-
genesis of pallidopyramidal disease is unknown. Until
now only one autopsy in a non-familial patient 50 years
after onset has been performed (Davison, 1954). A pal-
lor of the pallidal segments, slight shrinkage and cellu-
lar change of the substantia nigra, a thinning of the ansa
lenticularis and early demyelination of the pyramids
and crossed pyramidal tracts were observed. The latter
extended from the lower parts of the medulla oblongata
into the spinal cord. Until now 11 familial and 4 non-
familial cases of pallidopyramidal disease have been
described.
Pallidopyramidal disease is characterized by its
CNS symptoms. In general, disease onset occurred
during the second or the early third decade. The two
siblings reported by Horowitz and Greenberg (1975)
developed their first symptoms in the first decade of
life. The classical parkinsonian features were observed
in all cases. Pyramidal tract signs, consisting of hyper-
reflexia, spastic muscle tone and bilateral extensor
plantar responses, were also found. In the patients
described by Nisipeanu et al. (1994) the occurrence
of pyramidal tract signs preceded the appearance of
extrapyramidal symptoms. Only a slow progression
of the disorder was noted: the 2 patients investigated
by Horowitz and Greenberg (1975) were still ambula-
tory after 1013 years of disease. No diurnal variation
was observed. Some patients examined by Davison
(1954) showed additional symptoms such as horizontal
nystagmus, intention tremor, poor memory and
impaired intelligence. Psychiatric symptoms have not
been observed in this syndrome. However, 1 patient
reported by Davison had impaired intelligence.
Furthermore, 3 out of the 5 patients with KuforRakeb
syndrome were demented (Najim al-Din et al., 1994).
The diagnostic possibilities are limited. Evidence of
isolated extrapyramidal and pyramidal signs and
normal laboratory and neuroradiologic investigations
in a young adult are suggestive of pallidopyramidal
disease. Possible differential diagnoses are juvenile
parkinsonism and levodopa-responsive dystonia.
No biochemical criteria for diagnosis are known.
Three out of the 4 patients examined by Nisipeanu
et al. (1994) were subjected to cranial CT and MRI.
No abnormalities were found. Patients suffering from
KuforRakeb syndrome showed, in contrast, general-
ized atrophy on MRI with pronounced atrophy of the
lentiform nuclei and the pyramids (Najim al-Din
et al., 1994). PET with 18F-fluorodopa was performed
in 2 patients with pallidopyramidal disease and
showed marked dopaminergic denervation of the stria-
tum (Remy et al., 1995). PET with 11C-flumazenil
demonstrated a marked decrease in benzodiazepine-
receptor density in the precentral gyrus and the mesial
frontal cortex (Pradat et al., 2001).
Extrapyramidal symptoms improved with levodopa
therapy. Typically, the pyramidal symptoms were not
influenced by this treatment. However, Tranchant
et al. (1991) reported a worsening of pyramidal tract
signs due to the medication regimen. Response to
levodopa was somewhat variable; most patients
responded rapidly to low doses, with improvement
persisting for a long period. After many years of treat-
ment, wearing-off phenomena occurred. The daily
dose of levodopa used in the patients reported by
Nisipeanu et al. (1994) was 5001000 mg.
54.7. Rett syndrome
Rett syndrome is a progressive neurodegenerative dis-
order which is reported almost exclusively in females
and characterized by a wide spectrum of motor and
behavioral abnormalities. It was first described by Rett
(1966, 1977) and subsequently investigated by other
authors (Hagberg et al., 1983; Hagberg and
Witt-Engerstrom, 1986). It has been proposed that Rett
syndrome is the result of an X-linked-dominant
mutation with mortality for hemizygous males, with
each case representing a new mutation (Comings,
1986). De novo mutations, possibly in a particular
open reading frame, of the gene encoding X-linked
methyl-CpG-binding protein 2 (MeCP2) have been
identified as a cause of Rett syndrome (Amir et al.,
1999; Mnatzakanian et al., 2004). Methylation of
CpG dinucleotides in genomic DNA represents a fun-
damental epigenetic mechanism of gene expression
control. MeCP2 likely causes transcriptional repres-
sion through an interaction with core histones since
the MeCP2-binding domain was shown to associate
with histone deacetylases. Mutations in the MeCP2
gene have been identified in 7590% of sporadic
cases and approximately 50% of the rare familial cases
(Shahbazian and Zoghbi, 2001). However, MECP2
mutations can also be found in individuals lacking
the clinical features of Rett syndrome (Hagberg
et al., 2002). Genotypephenotype studies suggest that
the pattern of X-chromosome inactivation has a more
prominent effect on clinical severity than the type of
mutation (Shahbazian and Zoghbi, 2001). It still
 OTHER DEGENERATIVE PROCESSES
remains to be determined why mutations of the widely
expressed MECP2 gene give rise to a predominantly
neuronal phenotype.
Recently, DLX5 was identified as one of the genes
probably targeted by MECP2 (Horike et al., 2005).
Loss of MECP2 caused overexpression of this tran-
scription factor important for GABAergic neurons.
Autopsy studies showed diffuse cerebral atrophy with
a decrease in brain weight of 1434% compared to that
of age-matched controls with increased amounts of
lipofuscin and, occasionally, mild astrocytosis.
Moreover, mild but inconsistent spongy changes of
white matter were found. Most apparent was a low
level of pigmentation of the substantia nigra, whereas
the number of nigral neurons was normal (Jellinger
and Seitelberger, 1986). In addition, selective dendritic
alterations in the cortex of patients with Rett syndrome
were reported (Armstrong et al., 1995). The preva-
lence of Rett syndrome is estimated to be about 0.44/
10 000 (Kozinetz et al., 1993).
The most typical symptoms are stereotyped
movements and gait disturbance. A four-stage model
for the description of Rett syndrome was proposed
(Hagberg and Witt-Engerstrom, 1986). Stage 1 is
defined by developmental stagnation, hypotonia
and deceleration of head growth (onset 6 months to
1.5 years). Stage 2 is characterized by loss of func-
tional hand use, stereotypic hand-wringing, loss of
expressive language, rapid developmental regression
and occasional seizures (onset 13 or 4 years). Stage
3 is termed a pseudostationary period because of some
restitution of communication, but increasing ataxia,
hyperreflexia and rigidity, as well as breathing dys-
function and bruxism, are observed. After several
years stage 4 develops with the so-called late motor
deterioration and growth retardation. With respect to
extrapyramidal dysfunction, bruxism (97%), oculogy-
ric crises (63%) and parkinsonism and dystonia
(59%) are common features (FitzGerald et al., 1990).
Myoclonus and choreoatheosis were seen only infre-
quently. In younger patients (i.e. < 4 years) hyperki-
netic disorders were more evident, whereas in older
patients (i.e. > 8 years) the bradykinetic syndrome
tended to predominate. Drooling (75%), rigidity
(44%) and bradykinesia (41%) were the most often
observed parkinsonian symptoms.
Sleep disturbances, mainly in the early stages, are
frequently present in Rett syndrome. They are charac-
terized by an overall increase in daytime sleep and a
delayed sleep onset at night. Despite their mental
retardation and their loss of expressive language, these
patients tend to appear happy and enjoy close physical
contact. Rett syndrome leads not only to neurological
abnormalities, but also to dysfunction of other organs
453
(Braddock et al., 1993). Gastrointestinal complaints
include constipation and weight loss. Swallowing
difficulties are also common. Furthermore, an unusual
breathing pattern with central apnea intermixed with
hyperventilation is frequently observed. Scoliosis
often occurs. Patients with Rett syndrome have signif-
icantly longer corrected QT intervals and T-wave
abnormalities on electrocardiograms that might
explain sudden death in Rett syndrome (Sekul et al.,
1994).
Criteria for the diagnosis of Rett syndrome were
initially developed by The Rett Syndrome Diagnostic
Criteria Work Group (1988). These criteria have been
revised in the light of the recent advances in the under-
standing of the molecular biology of Rett syndrome
(Hagberg et al., 2002). Necessary criteria for the diag-
nosis of Rett syndrome are apparently normal prenatal
and perinatal history; a largely normal (or delayed) psy-
chomotor development through the first 6 months; nor-
mal head circumference at birth; postnatal deceleration
of head growth in the majority; loss of purposeful hand
skills at the age of 0.52.5 years; stereotypic hand
movements; emerging social withdrawal, communica-
tion dysfunction, loss of learned words and cognitive
impairment; and impaired or failing locomotion. Sup-
portive criteria include awake disturbances of breath-
ing; bruxism; impaired sleep pattern from early
infancy; abnormal muscle tone; peripheral vasomotor
disturbances; scoliosis/kyphosis progressing through
childhood; growth retardation; and small hands and
feet. Diagnostic criteria for variant Rett syndrome have
also been developed (Hagberg and Skjeldal, 1994). Par-
kinsonism has not so far been included among the diag-
nostic criteria of Rett syndrome or variant Rett
syndrome. Infantile autism is one of the most important
differential diagnoses. Further differential diagnoses
include other neurodevelopmental disorders with men-
tal retardation and motor impairment. Sequencing of
the MECP2 gene, if available, is advisable.
It was proposed that hyperammonemia could be an
essential sign of this condition (Rett, 1966, 1977), but
further investigations did not reproduce the findings of
hyperammonemia in most patients (Hagberg et al.,
1983). Significant reductions in the metabolites of
norepinephrine, dopamine and serotonin, as well as
an elevation of biopterin in the cerebrospinal fluid,
constituted the first detected biochemical alterations
(Zoghbi et al., 1989). Additionally, there is evidence
of elevation of lactate, pyruvate, alpha-ketoglutarate,
malate and glutamate in the cerebrospinal fluid
(Hamberger et al., 1992; Matsuishi et al., 1994). MRI
indicated a global hypoplasia of the brain and progres-
sive cerebellar atrophy increasing with age (Murakami
et al., 1992). An increased density of D2-receptors in
454 J. C. MOLLER AND W. H. OERTEL
the striatum of patients suffering from Rett syndrome
using single-photon emission spectroscopy (SPECT)
imaging was found (Chiron et al., 1993). 18F-fluoro-
deoxyglucose PET showed several areas of hypometa-
bolism with markedly lower metabolism in the
occipital lobes (Naidu et al., 1992). Furthermore, a mild
presynaptic deficit of nigrostriatal activity was demon-
strated by 18F-fluorodopa and PET (Dunn et al., 2002).
There is no specific treatment. Naltrexone appears to
provide clinical benefit in the treatment of breathing dys-
function and cognitive impairment (Percy et al., 1994).
Furthermore, bromocriptine and l-carnitine can be tried
to improve certain disease symptoms (Zappella et al.,
1990; Plioplys and Kasnicka, 1993). Lamotrigine and
topiramate have been used for seizure control
(Kumandas et al., 2001; Goyal et al., 2004). Symptomatic
therapeutic approaches also include physiotherapy and
music therapy (Armstrong et al., 1995).
References
Aizawa H, Kwak S, Shimizu T et al. (1991). A case of adult
onset pure pallidal degeneration. I. Clinical manifestations
and neuropathological observations. J Neurol Sci 102:
7682.
Allen FH, Krabbe FMR, Corcoran PA (1961). A new pheno-
type (McLeod) in the Kell blood group system. Vox Sang
6: 555560.
Amir RE, Van den Veyver IB, Wan M et al. (1999). Rett
syndrome is caused by mutations in X-linked MECP2,
encoding methyl-CpG-binding protein 2. Nat Genet 23:
185188.
Armstrong D, Dunn JK, Antalffy B et al. (1995). Selective
dendritic alterations in the cortex of Rett syndrome. J Neu-
ropathol Exp Neurol 54: 195201.
Boeve BF, Tremont-Lukats IW, Waclawik AJ et al. (2005).
Longitudinal characterization of two siblings with
frontotemporal dementia and parkinsonism linked to
chromosome 17 associated with the S305N tau mutation.
Brain 128: 752772.
Braddock SR, Braddock BA, Graham JM Jr (1993). Rett
syndrome. An update and review for the primary pediatri-
cian. Clin Pediatr (Phila) 32: 613626.
Brecher G, Bessis M (1972). Present status of spiculed red
cells and their relationship to the discocyte-echinocyte
transformation: a critical review. Blood 40: 333344.
Brooks DJ, Ibanez V, Playford ED et al. (1991). Presynaptic
and postsynaptic striatal dopaminergic function in neuroa-
canthocytosis: a positron emission tomographic study.
Ann Neurol 30: 166171.
Buchman AS, Goetz CG, Klawans HL (1988). Hemiparkin-
sonism with hemiatrophy. Neurology 38: 527530.
Burbaud P, Rougier A, Ferrer X et al. (2002). Improvement
of severe trunk spasms by bilateral high-frequency stimu-
lation of the motor thalamus in a patient with chorea-
acanthocytosis. Mov Disord 17: 204207.
Ching KH, Westaway SK, Gitschier J et al. (2002). HARP
syndrome is allelic with pantothenate kinase-associated
neurodegeneration. Neurology 58: 16731674.
Chiron C, Bulteau B, Loch C et al. (1993). Dopaminergic D2
receptor SPECT imaging in Rett syndrome: increase of
specific binding in striatum. J Nucl Med 34: 17171721.
Comings DE (1986). The genetics of Rett syndrome: the
consequences of a disorder where every case is a new
mutation. Am J Med Genet Suppl 1: 383388.
Critchley EM, Clark DB, Wikler A (1968). Acanthocytosis
and neurological disorder without betalipoproteinemia.
Arch Neurol 18: 134140.
Crompton DE, Chinnery PF, Bates D et al. (2005). Spectrum
of movement disorders in neuroferritinopathy. Mov Dis-
ord 20: 9599.
Curtis AR, Fey C, Morris CM et al. (2001). Mutation in the
gene encoding ferritin light polypeptide causes dominant
adult-onset basal ganglia disease. Nat Genet 28: 350354.
Davison C (1954). Pallido-pyramidal disease. J Neuropathol
Exp Neurol 13: 5059.
Dobson-Stone C, Danek A, Rampoldi L et al. (2002). Muta-
tional spectrum of the CHAC gene in patients with chorea-
acanthocytosis. Eur J Hum Genet 10: 773781.
Dobson-Stone C, Velayos-Baeza A, Filippone LA et al. (2004).
Chorein detection for the diagnosis of chorea-acanthocytosis.
Ann Neurol 56: 299302.
Dooling EC, Schoene WC, Richardson EP Jr (1974). Haller-
vorden-Spatz syndrome. Arch Neurol 30: 7083.
Dooling EC, Richardson EP Jr, Davis KR (1980). Computed
tomography in Hallervorden-Spatz disease. Neurology 30:
11281130.
Dunn HG, Stoessl AJ, Ho HH et al. (2002). Rett syndrome:
investigation of nine patients, including PET scan. Can J
Neurol Sci 29: 345357.
FitzGerald PM, Jankovic J, Percy AK (1990). Rett syndrome
and associated movement disorders. Mov Disord 5:
195202.
Foster NL, Wilhelmsen K, Sima AA et al. (1997). Frontotem-
poral dementia and parkinsonism linked to chromosome
17: a consensus conference. Ann Neurol 41: 706715.
Galvin JE, Giasson B, Hurtig HI et al. (2000). Neuro-
degeneration with brain iron accumulation, type 1 is
characterized by alpha-, beta-, and gamma-synuclein
neuropathology. Am J Pathol 157: 361368.
Giladi N, Fahn S (1992). Hemiparkinsonism-hemiatrophy
syndrome may mimic early-stage cortical-basal ganglionic
degeneration. Mov Disord 7: 384385.
Giladi N, Burke RE, Kostic V et al. (1990). Hemiparkinson-
ism-hemiatrophy syndrome: clinical and neuroradiologic
features. Neurology 40: 17311734.
Gitlin JD (1998). Aceruloplasminemia. Pediatr Res 44:
271276.
Goyal M, ORiordan MA, Wiznitzer M (2004). Effect of
topiramate on seizures and respiratory dysrhythmia in Rett
syndrome. J Child Neurol 19: 588591.
Greene PE, Bressman SB, Ford B et al. (2000). Parkinsonism,
dystonia, and hemiatrophy. Mov Disord 15: 537541.
 OTHER DEGENERATIVE PROCESSES
Hagberg B, Aicardi J, Dias K et al. (1983). A progressive
syndrome of autism, dementia, ataxia, and loss of purpose-
ful hand use in girls: Retts syndrome: report of 35 cases.
Ann Neurol 14: 471479.
Hagberg B, Hanefeld F, Percy A et al. (2002). An update on
clinically applicable diagnostic criteria in Rett syndrome.
Comments to Rett Syndrome Clinical Criteria Consensus
Panel Satellite to European Paediatric Neurology Society
Meeting, Baden Baden, Germany, 11 September. Eur J
Paediatr Neurol 6: 293297.
Hagberg B, Witt-Engerstrom I (1986). Rett syndrome: a sug-
gested staging system for describing impairment profile
with increasing age towards adolescence. Am J Med
Genet Suppl 1: 4759.
Hagberg BA, Skjeldal OH (1994). Rett variants: a suggested
model for inclusion criteria. Pediatr Neurol 11: 511.
Hallervorden J, Spatz H (1922). Eigenartige Erkrankung im
extrapyramidalen System mit besonderer Beteiligung des
Globus pallidus und der Substantia nigra. Z Gesamte
Neurol Psychiatr 79: 254302.
Halperin G (1931). Normal asymmetry and unilateral hyper-
trophy. Arch Intern Med 48: 676684.
Hamberger A, Gillberg C, Palm A et al. (1992). Elevated
CSF glutamate in Rett syndrome. Neuropediatrics 23:
212213.
Hampshire DJ, Roberts E, Crow Y et al. (2001). Kufor-
Rakeb syndrome, pallido-pyramidal degeneration with
supranuclear upgaze paresis and dementia, maps to 1p36.
J Med Genet 38: 680682.
Hardie RJ (1989). Acanthocytosis and neurological impair-
menta review. Q J Med 71: 291306.
Hardie RJ, Pullon HW, Harding AE et al. (1991). Neuroa-
canthocytosis. A clinical, haematological and pathological
study of 19 cases. Brain 114: 1349.
Hayflick SJ, Westaway SK, Levinson B et al. (2003). Genet-
ic, clinical, and radiographic delineation of Hallervorden-
Spatz syndrome. N Engl J Med 348: 3340.
Hebb MO, Lang AE, Fletcher PJ et al. (2002). Neonatal
ablation of the nigrostriatal dopamine pathway does not
influence limb developments in rats. Exp Neurol 177:
547556.
Horike S, Cai S, Miyano M et al. (2005). Loss of silent-chro-
matin looping and impaired imprinting of DLX5 in Rett
syndrome. Nat Genet 37: 3140. [Epub 2004 Dec 2019].
Horowitz G, Greenberg J (1975). Pallido-pyramidal syn-
drome treated with levodopa. J Neurol Neurosurg Psychia-
try 38: 238240.
Hutton M, Lendon CL, Rizzu P et al. (1998). Association of
missense and 50 -splice-site mutations in tau with the
inherited dementia FTDP-17. Nature 393: 702705.
Jankovic J, Kirkpatrick JB, Blomquist KA et al. (1985).
Late-onset Hallervorden-Spatz disease presenting as
familial parkinsonism. Neurology 35: 227234.
Jellinger K (1986). Pallidal, pallidonigral, and pallidoluysio-
nigral degenerations including association with thalamic
and dendate degenerations. In: PJ Vinken, GW Brun
(Eds.), Handbook of Clinical Neurology. Elsevier,
Amsterdam, pp. 445463.
455
Jellinger K, Seitelberger F (1986). Neuropathology of Rett
syndrome. Am J Med Genet Suppl 1: 259288.
Josephs KA, Jones AG, Dickson DW (2004). Hippocampal
sclerosis and ubiquitin-positive inclusions in dementia
lacking distinctive histopathology. Dement Geriatr Cogn
Disord 17:342345.
Kawai J, Sasahara M, Hazama F et al. (1993). Pallidonigro-
luysian degeneration with iron deposition: a study of three
autopsy cases. Acta Neuropathol (Berl) 86: 609616.
Klawans HL (1981). Hemiparkinsonism as a late complica-
tion of hemiatrophy: a new syndrome. Neurology 31:
625628.
Kornzweig AL, Bassen FA (1957). Retinitis pigmentosa,
acanthrocytosis and heredodegenerative neuromuscular
disease. AMA Arch Ophthalmol 58: 183187.
Kosaka K, Matsushita M, Oyanagi S et al. (1981). Pallido-
nigro-luysial atrophy with massive appearance of corpora
amylacea in the CNS. Acta Neuropathol (Berl) 53:
169172.
Kotzbauer PT, Truax AC, Trojanowski JQ et al. (2005).
Altered neuronal mitochondrial coenzyme a synthesis in
neurodegeneration with brain iron accumulation caused
by abnormal processing, stability, and catalytic activity
of mutant pantothenate kinase 2. J Neurosci 25: 689698.
Kozinetz CA, Skender ML, MacNaughton N et al. (1993).
Epidemiology of Rett syndrome: a population-based reg-
istry. Pediatrics 91: 445450.
Kuhlenbaumer G, Ludemann P, Schirmacher A et al.
(2004). Autosomal dominant striatal degeneration
(ADSD): clinical description and mapping to 5q135q14.
Neurology 62: 22032208.
Kumandas S, Caksen H, Ciftci A et al. (2001). Lamotrigine
in two cases of Rett syndrome. Brain Dev 23: 240242.
Lange E, Poppe W, Scholtze P (1970). Familial progressive
pallidum atrophy. Eur Neurol 3: 265267.
Levine IM, Estes JW, Looney JM (1968). Hereditary neuro-
logical disease with acanthocytosis. Arch Neurol 19:
403409.
Lewis J, McGowan E, Rockwood J et al. (2000). Neurofibril-
lary tangles, amyotrophy and progressive motor distur-
bance in mice expressing mutant (P301L) tau protein.
Nat Genet 25: 402405.
Lynch T, Sano M, Marder KS et al. (1994). Clinical
characteristics of a family with chromosome 17-linked dis-
inhibition-dementia-parkinsonism-amyotrophy complex.
Neurology 44: 18781884.
Matsuishi T, Urabe F, Percy AK et al. (1994). Abnormal
carbohydrate metabolism in cerebrospinal fluid in Rett
syndrome. J Child Neurol 9: 2630.
McCormick WF, Lemmi H (1965). Familial degeneration of
the pallidonigral system. Neurology 15: 141153.
Mnatzakanian GN, Lohi H, Munteanu I et al. (2004). A pre-
viously unidentified MECP2 open reading frame defines a
new protein isoform relevant to Rett syndrome. Nat Genet
36: 339341.
Mori H, Motoi Y, Kobayashi T et al. (2001). Tau accumula-
tion in a patient with pallidonigroluysian atrophy. Neu-
rosci Lett 309: 8992.
456 J. C. MOLLER AND W. H. OERTEL
Morris HR, Kanh MN, Janssen JC et al. (2001). The genetic
and pathological classification of familial frontotemporal
dementia. Arch Neurol 58: 18131816.
Murakami JW, Courchesne E, Haas RH et al. (1992). Cere-
bellar and cerebral abnormalities in Rett syndrome: a
quantitative MR analysis. AJR Am J Roentgenol 159:
177183.
Naidu S, Wong DF, Kitt C et al. (1992). Positron emission
tomography in the Rett syndrome: clinical, biochemical
and pathological correlates. Brain Dev 14: S75S79.
Najim al-Din AS, Wriekat A, Mubaidin A et al. (1994).
Pallido-pyramidal degeneration, supranuclear upgaze
paresis and dementia: Kufor-Rakeb syndrome. Acta
Neurol Scand 89: 347352.
Nardone R, Lochner P, Tezzon F (2003). Hemiparkinson-
hemiatrophy syndrome: a transcranial magnetic stimulation
study. Electromyogr Clin Neurophysiol 43: 235240.
Nisipeanu P, Kuritzky A, Korczyn AD (1994). Familial
levodopa-responsive parkinsonian-pyramidal syndrome.
Mov Disord 9: 673675.
Paviour DC, Lees AJ, Josephs KA et al. (2004). Front-
otemporal lobar degeneration with ubiquitin-only-
immunoreactive neuronal changes: broadening the clinical
picture to include progressive supranuclear palsy. Brain
127: 24412451.
Penfield W, Robertson JSM (1943). Growth asymmetry due
to lesions of the post central cortex. Arch Neurol Psychia-
try 50: 405430.
Percy AK, Glaze DG, Schultz RJ et al. (1994). Rett
syndrome: controlled study of an oral opiate antagonist,
naltrexone. Ann Neurol 35: 464470.
Plioplys AV, Kasnicka I (1993). L-carnitine as a treatment
for Rett syndrome. South Med J 86: 14111412.
Pradat PF, Dupel-Pottier C, Lacomblez L et al. (2001). Case
report of pallido-pyramidal disease with supplementary
motor area involvement. Mov Disord 16: 762764.
Pramstaller PP, Kunig G, Leenders K et al. (2002). Parkin
mutations in a patient with hemiparkinsonism-hemiatro-
phy: a clinical-genetic and PET study. Neurology 58:
808810.
Przedborski S, Goldman S, Levivier M et al. (1993). Brain
glucose metabolism and dopamine D2 receptor analysis
in a patient with hemiparkinsonism-hemiatrophy syndrome.
Mov Disord 8: 391395.
Przedborski S, Giladi N, Takikawa S et al. (1994). Metabolic
topography of the hemiparkinsonism-hemiatrophy syn-
drome. Neurology 44: 16221628.
Rampoldi L, Dobson-Stone C, Rubio JP et al. (2001). A con-
served sorting-associated protein is mutant in chorea-
acanthocytosis. Nat Genet 28: 119120.
Remy P, Hosseini H, Degos JD et al. (1995). Striatal dopa-
minergic denervation in pallidopyramidal disease demon-
strated by positron emission tomography. Ann Neurol
38: 954956.
Rett A (1966). [On an until now unknown disease of a con-
genital metabolic disorder.] Krankenschwester 19:
121122.
Rett A (1977). Cerebral atrophy with hyperammonaemia.
In: PJ Vinken, GW Bruyn (Eds.), Handbook of Clinical
Neurology. Elsevier, Amsterdam, pp. 305329.
Rinne JO, Daniel SE, Scaravilli F et al. (1994a). Nigral degen-
eration in neuroacanthocytosis. Neurology 44: 16291632.
Rinne JO, Daniel SE, Scaravilli F et al. (1994b). The neuro-
pathological features of neuroacanthocytosis. Mov Disord
9: 297304.
Rosso SM, van Swieten JC (2002). New developments in
frontotemporal dementia and parkinsonism linked to chro-
mosome 17. Curr Opin Neurol 15: 423428.
Rutledge JN, Hilal SK, Silver AJ et al. (1987). Study of
movement disorders and brain iron by MR. AJR Am J
Roentgenol 149: 365379.
Sakai T, Mawatari S, Iwashita H et al. (1981). Choreoa-
canthocytosis. Clues to clinical diagnosis. Arch Neurol
38: 335338.
Schroder R, Watts GD, Mehta SG et al. (2005). Mutant valo-
sin-containing protein causes a novel type of frontotem-
poral dementia. Ann Neurol 57: 457461.
Seitelberger F (1957). Zur Morphologie und Histochemie der
degenerativen Axonveranderungen vom Zentralnervensys-
tem. Proceedings of the 3rd International Congress of
Neuropathology 12: 7147.
Sekul EA, Moak JP, Schultz RJ et al. (1994). Electrocardio-
graphic findings in Rett syndrome: an explanation for sud-
den death? J Pediatr 125: 8082.
Serra S, Xerra A, Scribano E et al. (1987). Computerized
tomography in amyotrophic choreo-acanthocytosis.
Neuroradiology 29: 480482.
Sethi KD, Adams RJ, Loring DW et al. (1988). Hallervor-
den-Spatz syndrome: clinical and magnetic resonance
imaging correlations. Ann Neurol 24: 692694.
Shahbazian MD, Zoghbi HY (2001). Molecular genetics of
Rett syndrome and clinical spectrum of MECP2 muta-
tions. Curr Opin Neurol 14: 171176.
Spitz MC, Jankovic J, Killian JM (1985). Familial tic
disorder, parkinsonism, motor neuron disease and acantho-
cytosis: a new syndrome. Neurology 35: 366370.
Storch A, Kornhass M, Schwarz J (2005). Testing for
acanthocytosis A prospective reader-blinded study in
movement disorder patients. J Neurol 252: 8490.
Swaiman KF (1991). Hallervorden-Spatz syndrome and
brain iron metabolism. Arch Neurol 48: 12851293.
Swaiman KF, Smith KA, Trock GL et al. (1983). Sea-blue
histiocytes, lymphocytic cytosomes and 59Fe-studies in
Hallervorden-Spatz syndrome. Neurology 33: 301305.
Swash M, Schwartz MS, Carter ND et al. (1983). Benign X-
linked myopathy with acanthocytes (McLeod syndrome).
Its relationship to X-linked muscular dystrophy. Brain
106: 717733.
Tanaka M, Hirai S, Kondo S et al. (1998). Cerebral hypoper-
fusion and hypometabolism with altered striatal signal
intensity in chorea-acanthocytosis: a combined PET and
MRI study. Mov Disord 13: 100107.
Taylor TD, Litt M, Kramer P et al. (1996). Homozygosity
mapping of Hallervorden-Spatz syndrome to chromosome
20p12.3p13. Nat Genet 14: 479481.
 OTHER DEGENERATIVE PROCESSES
The Rett Syndrome Diagnostic Criteria Work Group
(1988). Diagnostic criteria for Rett syndrome. Ann Neurol
23: 425428.
Thomas M, Hayflick SJ, Jankovic J (2004). Clinical hetero-
geneity of neurodegeneration with brain iron accumul-
ation (Hallervorden-Spatz syndrome) and pantothenate
kinase-associated neurodegeneration. Mov Disord 19:
3642.
Tomemori Y, Ichiba M, Kusumoto A et al. (2005). A gene-
targeted mouse model for chorea-acanthocytosis. J Neuro-
chem 92: 759766.
Tranchant C, Boulay C, Warter JM (1991). [Pallido-pyrami-
dal syndrome: an unrecognized entity]. Rev Neurol (Paris)
147: 308310.
Ueno S, Maruki Y, Nakamura M et al. (2001). The gene
encoding a newly discovered protein, chorein, is mutated
in chorea-acanthocytosis. Nat Genet 28: 121122.
van Bogaert L (1947). Aspects cliniques et pathologiques des
atrophies pallidales et pallido-luysiennes progressives.
J Belge Neurol Psychiatr 47: 268286.
Vercueil L, Hammouti A, Andriantseheno ML et al. (2000). Pal-
lido-Luysio-Nigral atrophy revealed by rapidly progressive
hemidystonia: a clinical, radiologic, functional, and neuro-
pathologic study. Mov Disord 15: 947953.
Walker RH, Morgello S, Davidoff-Feldman B et al.
(2002). Autosomal dominant chorea-acanthocytosis with
polyglutamine-containing neuronal inclusions. Neurology
58: 10311037.
Watts GD, Wymer J, Kovach MJ et al. (2004). Inclusion
body myopathy associated with Paget disease of bone
and frontotemporal dementia is caused by mutant
valosin-containing protein. Nat Genet 36: 377381.
Wigboldus JM, Bruyn GW (1968). Hallervorden-Spatz dis-
ease. In: PJ Vinken, GW Bruyn (Eds.), Diseases of the
Basal Ganglia: Handbook of Clinical Neurology. Elsevier,
Amsterdam, pp. 604631.
Wooten GF, Lopes MB, Harris WO et al. (1993). Pallidoluy-
sian atrophy: dystonia and basal ganglia functional anat-
omy. Neurology 43: 17641768.
457
Wszolek ZK, Pfeiffer RF, Bhatt MH et al. (1992). Rapidly
progressive autosomal dominant parkinsonism and demen-
tia with pallido-ponto-nigral degeneration. Ann Neurol 32:
312320.
Wszolek ZK, Uitti RJ, Hutton M (2000). A mutation in the
microtubule-associated protein tau in pallido-nigro-luysian
degeneration. Neurology 54: 20282030.
Wszolek ZK, Tsuboi Y, Farrer M et al. (2003). Hereditary
tauopathies and parkinsonism. Adv Neurol 91: 153163.
Yagishita S, Itoh Y, Nakano T et al. (1983). Pleomorphic
intra-neuronal polyglucosan bodies mainly restricted to
the pallidium. A case report. Acta Neuropathol (Berl) 62:
159163.
Yamamoto T, Hirose G, Shimazaki K et al. (1982). Move-
ment disorders of familial neuroacanthocytosis syndrome.
Arch Neurol 39: 298301.
Yamamoto T, Kawamura J, Hashimoto S et al. (1991). Palli-
do-nigro-luysian atrophy, progressive supranuclear palsy
and adult onset Hallervorden-Spatz disease: a case of aki-
nesia as a predominant feature of parkinsonism. J Neurol
Sci 101: 98106.
Yasuda M, Kawamata T, Komure O et al. (1999). A muta-
tion in the microtubule-associated protein tau in pallido-
nigro-luysian degeneration. Neurology 53: 864868.
Young SG, Bertics SJ, Curtiss LK et al. (1987). Genetic ana-
lysis of a kindred with familial hypobetalipoproteinemia.
Evidence for two separate gene defects: one associated
with an abnormal apolipoprotein B species, apolipopro-
tein B-37; and a second associated with low plasma con-
centrations of apolipoprotein B-100. J Clin Invest 79:
18421851.
Zappella M, Genazzani A, Facchinetti F et al. (1990). Bro-
mocriptine in the Rett syndrome. Brain Dev 12: 221225.
Zhou B, Westaway SK, Levinson B et al. (2001). A novel
pantothenate kinase gene (PANK2) is defective in Haller-
vorden-Spatz syndrome. Nat Genet 28: 345349.
Zoghbi HY, Milstien S, Butler IJ et al. (1989). Cerebrospinal
fluid biogenic amines and biopterin in Rett syndrome. Ann
Neurol 25: 5660.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 55

Hydrocephalus and structural lesions

JOHN G. L. MORRIS1*, BRIAN OWLER2, MARIESE A. HELY1 AND VICTOR S. C. FUNG1

1
Department of Neurology, 2Department of Neurosurgery,
Westmead Hospital, Sydney, NSW, Australia

55.1. Introduction and subdural hematoma. He had impaired con-

One of the first clues implicating the substantia nigra in
the pathogenesis of parkinsonism was the finding by
Blocq and Marinesco (1894) of a mass in that part of the
midbrain in a patient with contralateral hemiparkinson-
ism. Yet structural lesions of the brain are rarely asso-
ciated with parkinsonism. The clinical presentation of
such lesions may however mimic those of parkinsonism,
leading to diagnostic confusion. In this chapter, we discuss
the syndrome of normal-pressure hydrocephalus (NPH)
and how it relates to parkinsonism. We also discuss
parkinsonism in the setting of structural lesions such as
arteriovenous malformations (AVMs) and brain tumors.
55.2. Normal-pressure hydrocephalus
To most neurologists, the syndrome of NPH is hard to
understand and disappointing to treat. This is a paradoxi-
cal disorder: the ventricles of the brain enlarge, yet
the pressure within is not increased. Lowering the
(normal) pressure in the ventricles by inserting a shunt
may improve symptoms, yet the size of the ventricles is
usually unchanged (Meier and Mutze, 2004). To under-
stand this curious disorder it is useful to start with the
seminal descriptions written over 40 years ago.
55.2.1. Historical aspects
In 1965, Hakim and Adams described 3 patients with
hydrocephalus associated with normal cerebrospinal
fluid (CSF) pressure.
The first patient was a 16-year-old with commu-
nicating hydrocephalus (demonstrated on air
encephalography) following a severe head injury
sciousness which worsened after this procedure
and improved with drainage of the lateral ventri-
cles. CSF pressure by lumbar puncture (LP)
remained normal (< 200 mm of water) through-
out his hospital stay. The second patient was a
52-year-old trombone player with a 1-year his-
tory of progressive apathy, slowness of thinking,
unsteadiness of gait and incontinence of urine.
CSF pressure was normal and it was noted that
the patient improved transiently after lumbar
puncture. A lumbar air encephalogram and right
occipital ventriculogram showed generalized
enlargement of the ventricular system. Following
the insertion of a ventriculoatrial shunt, his clin-
ical state again improved and this was sustained.
The third case was a 43-year-old man with fluctu-
ating conscious level associated with communi-
cating hydrocephalus complicating a major
head injury. CSF pressures were normal but
he was noted to improve after lumbar puncture.
He eventually showed gradual improvement
following ventriculoatriostomy.
The authors addressed the question of why the ven-
tricles were enlarged in the face of normal CSF pres-
sure and suggested that the hydrocephalus was due to
a transient period of raised ventricular pressure and
that, once expanded, the size of the ventricles was
maintained by CSF pressures lower than that which
caused the dilatation in the first place. This has been
explained by invoking the laws of physics propounded
by the French mathematicians Blaise Pascal (1623
1662) and Pierre Simon de la Place (17491827).
According to Pascals law, the pressure applied to an

*Correspondence to: Professor John Morris, Department of Neurology, Westmead Hospital, Sydney, NSW 2145, Australia.
E-mail: jmorris@mail.usyd.edu.au, Tel: 61 02-9845-6793, Fax: +61 02-9635-6684.
460 J. G. L. MORRIS ET AL.
enclosed fluid is transmitted undiminished to every
portion of the fluid and to the walls of the containing
vessel and, according to LaPlaces law, the larger the
vessel radius, the larger the wall tension required to
withstand a given internal pressure. The force exerted
on the wall of a fluid-containing vessel represents the
product of pressure times surface area. This explains
the everyday experience that, when blowing up a
childs balloon, inflation occurs maximally in the body
of the balloon rather than the neck. Thus, a given pres-
sure of CSF would be expected to have a greater force
when applied to the walls of enlarged ventricles than
smaller ones. A pressure of 180 mm of water could
be regarded as pathological in the presence of dilated
ventricles and lowering the pressure might have a ben-
eficial effect. As we will discuss later, there are rea-
sons for not accepting this approach as it applies to
the ventricles of the brain.
In a second paper in the same year (Adams et al.,
1965), the authors described a further 3 cases who
having become helplessly demented . . . regained full
mental function as a result of a shunt that reduced
the normal pressure to even lower levels.
Case 1 was a 60-year-old woman with a 6-month
history of forgetfulness, unsteadiness of gait and
urinary incontinence. She was noted on exami-
nation to be gay and witty but her history
was rambling, her stride was shortened and the
tendon reflexes, particularly in her legs, were
brisk. Her CSF pressure was 175 mm. Following
a lumbar air encephalogram, which showed
massive enlargement of the entire ventricular
system, she developed akinetic mutism. Her
CSF pressures now rose to 300 mm water. She
remained in this state for several weeks and then
improved greatly after insertion of a ventricu-
loatrial shunt. That this improvement was
related to the shunt was supported by a marked
deterioration which followed blockage of the
shunt after a fall. Case 2 was a 66-year-old
woman with a history of forgetfulness and falls
over a period of a few months. She was pleasant
and gracious on examination but her memory
was poor. Reflexes were brisk and her stride
length was reduced. Following an air encepha-
logram, which showed gross dilatation of the
entire ventricular system, she became drowsy,
incontinent, unable to walk and mute. CSF pres-
sure was 200 mm. She remained in this state for
some weeks but improved greatly after insertion
of a ventriculoatrial shunt. Case 3 was a
62-year-old man with slowness of thought,
unsteadiness of gait and incontinence from
obstructive hydrocephalus due to a cyst of the
third ventricle. Lumbar CSF pressures were
normal. He recovered after a Torkildsen (ventri-
culocisternostomy) shunting procedure.
It is important to note that the cognitive impairment
in cases 1 and 2 was mild until they had air encephalo-
grams. The benefit of withdrawing spinal fluid on the
clinical state before embarking on shunting was again
recorded. The authors contrasted their cases, who had
early loss of balance, with patients with Alzheimers
disease, where disturbance of gait is a late feature. They
noted that the ventricles also enlarge in Alzheimers
disease due to wasting of brain tissue (hydrocephalus
ex vacuo) and correctly anticipated that differentiation
of Alzheimers disease and normal-pressure hydroce-
phalus is a problem that will recur. They noted that
raised intracranial pressure, even up to 700 mm of water,
is often well tolerated in conditions, such as pseudotumor
cerebri (idiopathic/benign intracranial hypertension),
where the ventricles are small, and suggested that the triad
of features which they described slowness of thought,
incontinence of the bladder and gait disturbance were
due to compression of the frontal lobes by the anterior
horns of the lateral ventricles. Concerning the lower-limb
hyperreflexia, they noted that the long fibers from the leg
area of the primary motor cortex descend around the
dilated ventricle and undergo the greatest stretching
(Yakovlev, 1947). That enlargement was maximal in the
lateral ventricles was attributed to this being the largest
part of the ventricular system.
These two papers aroused great interest, not least
because here was another possibly treatable cause of
dementia. Experience, however, has modified this view.
55.2.2. Clinical features
Hakim and Adams papers encouraged neurologists to
look for hydrocephalus in patients with the triad of cog-
nitive impairment, incontinence and gait disturbance,
particularly when the hazardous procedure of air ence-
phalography was replaced by computed tomography
(CT) and magnetic resonance imaging (MRI) scanning.
Results of shunting were often disappointing. Numer-
ous papers have been written and opposing positions
taken (Bret et al., 2002). Editorials abound (Vanneste,
1994; Bradley, 2001; Silverberg, 2004). In one review,
535 articles were retrieved from Medline (Hebb and
Cusimano, 2001). As a result of these studies, there is
now a much greater understanding of the sort of patient
who is likely to benefit from shunting.
The syndrome of NPH now refers to patients with
a characteristic disturbance of gait and balance
 HYDROCEPHALUS AND STRUCTURAL LESIONS
(Fisher, 1982) which is improved by shunting of an
acquired, usually communicating, hydrocephalus.
Impairment of cognition and incontinence of urine
may also be present. Most importantly, and contrary
to the interpretation widely placed on the original
two publications, NPH is not a treatable cause
of dementia where this is the major, sole or initial
presenting problem (Vanneste, 1994).
Idiopathic and secondary forms of NPH are recog-
nized. About half the cases are idiopathic with onset
most commonly in the sixth decade of life or later.
Symptomatic NPH, due to prior subarachnoid hemor-
rhage, meningitis or head trauma, presents at a younger
age (Bradley, 2000).
NPH must be differentiated from chronic or
arrested hydrocephalus, which is often non-communi-
cating, develops early in life but may not present until
adulthood. It is not uncommonly picked up as an
incidental finding in a patient being investigated for
unrelated symptoms. Here the hydrocephalus is com-
pensated. The head is large and, on imaging, the cere-
bral mantle attenuated (Fig. 55.1.) and the CSF
pressure is usually normal. These patients can decline,
usually in their 40s and 50s, probably due to the effect
of aging in a brain with decreased neuronal reserve. It
is important to measure the diameter of the skull in
Fig. 55.1. Computed tomography scan showing a cortical
rim with gross enlargement of the lateral ventricles in a
28-year-old female with a greatly enlarged head.
461
hydrocephalus as these patients may present with
similar problems of gait, balance and cognition as
those with NPH but their underlying pathophysiology
and management are different. For completeness,
mention should also be made of acute/obstructive
hydrocephalus where the main presenting features of
headache, nausea, vomiting and visual disturbance
relate to raised intracranial pressure.
The main clinical features are discussed below.
55.2.2.1. Gait
Disturbance of gait is the principal symptom of NPH
(Fisher, 1982). Of 30 patients studied by Miller
Fisher (Fisher, 1982), all of whom had responded to
shunting or CSF removal, gait disturbance was the
only manifestation of the disorder in 14. Ten patients
also had cognitive impairment but in no case did this pre-
cede the gait disturbance. Features of the gait included
staggering, falls, shuffling and slow, multistepped, pre-
carious turning. Although weakness which worsened on
exercise was a common symptom, there was no weakness
on formal examination and movement of the legs on the
bed was normal. Fisher regarded it as a frontal gait
apraxia. Eleven patients had grasp or sucking reflexes.
Estanol (1981), in a study of 6 patients with commu-
nicating hydrocephalus, noted that patients, who could
readily make cycling movements with their legs on the
bed, locked and were barely able to walk as soon as
they bore weight on their legs. He described the patient
with this disorder as hopelessly glued to the floor,
unable to take a step. In attempting to walk he might
shuffle with short steps. His equilibrium was poor and
he might fall while attempting to move. Estanol viewed
the gait disturbance as a limb-kinetic apraxia of gait
induced by proprioceptive stimuli to the feet on standing.
He also noted that, although these patients had signs of
frontal lobe dysfunction such as grasp reflexes and perse-
veration in the Luria fist, edge and palm test, they did
not have ideomotor apraxia in the upper limbs.
Vanneste (1994) took issue with the term gait
apraxia, as it applies to NPH, on the grounds that
patients with this disorder execute nearly intact walking
movements when minimally supported or lying down
(though the ability to perform a motor sequence in one
setting but not another is surely one of the hallmarks of
apraxia). Features of the gait which he emphasized
included difficulty in initiating gait, postural instability
and shuffling. Hyperreflexia and extensor plantar
responses were often present. A similarity with the gait
seen in subcortical arteriosclerotic encephalopathy
(Thompson and Marsden, 1987) was commented upon.
In a definitive review, Nutt et al. (1993) discussed
the gait, which has variously been called frontal gait
462 J. G. L. MORRIS ET AL.
disorder, gait apraxia, frontal ataxia, marche petit pas,
senile gait, lower-half parkinsonism and arteriosclerotic
parkinsonism. They characterized the frontal gait disor-
der as follows: variable base (narrow to wide), short
steps, shuffling, start and turn hesitation, and . . . dise-
quilibrium. Widening of the base, upright posture and
preservation of arm-swing were features, when present,
which helped to distinguish it from a parkinsonian gait.
Festination, retropulsion and propulsion were more
suggestive of parkinsonism than a frontal gait disorder.
The authors also disliked the term apraxia, noting that
these patients usually have little evidence of apraxia
in the upper limbs. Invoking Hughlings Jacksons sen-
sorimotor hierarchy, they preferred the designation
frontal gait disorder under the general heading of
highest-level equilibrium and locomotor disturbance.
(The other types of highest-level gait disturbance
listed by Nutt and colleagues are cautious gait, subcor-
tical disequilibrium, frontal disequilibrium and isolated
gait ignition failure.) Whatever label is applied, this
type of gait disturbance is most commonly associated
with lesions of the frontal lobes, particularly the mesial
parts (Ahlberg et al. 1988).
Liston and colleagues (2003) reviewed the role of
the frontal lobe in movement, dividing it into three
main anatomical components: (1) primary motor cor-
tex, which controls muscle force and direction of move-
ment; (2) premotor area (PMA), which couples motor
acts to environmental (external) cues; and (3) supple-
mentary motor area (SMA), which is involved in motor
preparation and the execution of complex voluntary
movements and is internally cued by output from the
basal ganglia. In parkinsonism, it is postulated that gait
ignition failure, bradykinesia and freezing result from
disordered internal cueing of the SMA by the basal
ganglia. Movement may be initiated or improved by
external cues. Patients with vascular highest-level gait
disorders may have three types of gait abnormality:
1. Ignition apraxia, characterized by gait ignition
failure, difficulty with turns and freezing, is asso-
ciated with infarcts in the basal ganglia/thalamus/
SMA connections in the periventricular white
matter. These patients have a failure of internal
cueing and are helped by external cues, as with
Parkinsons disease (PD).
2. Equilibrium apraxia, where the main problem is
loss of balance, is associated with infarcts in the
sensory/PMA pathways or in their connections in
the periventricular white matter. Such patients
are not helped by external cues.
3. Mixed-gait apraxia, characterized by gait ignition
failure and disequilibrium, is associated with lesions
affecting the connections of both SMA and PMA.
Clues as to where NPH fits into this scheme are
provided by a study comparing the gait disorder of
NPH with that of PD (Stolze et al., 2001). In both dis-
orders, gait velocity was reduced due to a diminished
and variable stride length. In NPH, unlike PD, the gait
was broad-based and arm-swing relatively preserved.
Although gait was markedly improved in PD by exter-
nal cues such as a metronome and floor stripes, this
was less apparent in NPH. The gait of NPH conforms
with the equilibrium apraxia designation of Liston and
colleagues (2003), perhaps reflecting disconnection of
the PMA in the periventricular white matter, though
there are other possibilities (see below).
55.2.2.2. Incontinence
Urinary incontinence is a late sign of NPH (Vanneste,
1994). In Miller Fishers series (Fisher, 1982) of 30
patients, bladder symptoms were present in 12.
Urgency and frequency were the early features leading
to incontinence in 8 patients. Cystometrograms showed
strong contractions to increments in volume as small as
20 ml. In no patient was incontinence the only manifes-
tation of NPH. Urodynamic studies in another series
(Ahlberg et al., 1988) also found hyperreflexia and
detrusor instability but without evidence of defective
sphincter control. Incontinence sans gene (unembar-
rassed incontinence), where there is a lack of concern
at incontinence due to frontal dementia, is not a feature
of NPH (Vanneste, 1994). Urinary symptoms in NPH
are attributed to damage to the periventricular pathways
to the sacral bladder center (Ahlberg et al., 1988).
55.2.2.3. Cognitive changes
In Miller Fishers series (Fisher, 1982), the changes in
mentation were usually difficult to separate from the
changes that might occur in anyone in their seventies
or eighties. In one patient, there was profound memory
disturbance (but this was in the era before MRI, so there
may have been other reasons for this). Cognitive impair-
ment is usually mild, with forgetfulness, apathy, inatten-
tion, decreased speed of information-processing and
impaired ability to manipulate acquired knowledge
(Thomsen et al., 1986; Vanneste, 1994). Features of cor-
tical impairment, such as aphasia, apraxia and agnosia,
are absent. In further contradistinction to Alzheimers
disease, but similar to PD, delayed recall may be mark-
edly impaired whereas delayed recognition is preserved
(Vanneste, 1994). Iddon and colleagues (1999) noted
impairment in executive function involving reasoning,
anticipation, goal establishment, strategy formation,
shifting mental set and error monitoring in patients with
NPH. These pointed to impaired function of the prefron-
tal cortex. Although improvement was noted in some
 HYDROCEPHALUS AND STRUCTURAL LESIONS 463
aspects of cognition following shunting, patients who
fulfilled the criteria of dementia remained significantly
impaired after shunting.
In summary, where dementia is the major problem,
causes other than NPH need to be considered, and the
benefits to the patient from shunting are disappointing
(Iddon et al., 1999; Savolainen et al., 2002).

55.2.2.4. Investigations
55.2.2.4.1. Computed tomography/magnetic
resonance imaging
The diagnosis of NPH hinges upon finding ventricu-
lar enlargement out of proportion to cerebral atrophy
(Vanneste, 1994) in the appropriate clinical setting.
On CT scanning there is enlargement of the ventricu-
lar system without significant gyral atrophy
(Fig. 55.2). This is in contrast to the ventricular enlar-
gement seen in cerebral atrophy associated with
degenerative disease such as Alzheimers disease
(Fig. 55.3). In NPH there is rounding of the frontal
horns and enlargement of the temporal horns without
hippocampal atrophy, as shown by dilatation of the
perihippocampal fissures (Silverberg, 2004). In Alzhei- Fig. 55.3. Computed tomography scan showing ventricular
mers disease, the perihippocampal fissures are typically enlargement with frontal and perisylvian atrophy.
markedly dilated (Figs. 55.4 and 55.5). Measurement of
the cross-sectional volume of the hippocampus on MRI
may be useful in further distinguishing NPH from
Alzheimers disease (Golomb et al., 1994).

Fig. 55.4. Axial magnetic resonance imaging scan (flare

sequence) showing ventricular enlargement and perisylvian
Fig. 55.2. Enlargement of the ventricular system without atrophy, with frontal and occipital periventricular lucencies
gyral atrophy. (ependymitis granularis a normal finding).
464 J. G. L. MORRIS ET AL.
Fig. 55.5. Coronal magnetic resonance imaging scan (T2-
weighted) showing ventricular dilatation, perisylvian atrophy
and dilatation of the perihippocampal fissures.
Periventricular lucencies on CT are a normal find-
ing around the frontal and occipital horns but are
accentuated in NPH (Figure 55.4). On MRI fluid-atte-
nuated inversion recovery (FLAIR) sequences, these
findings are more marked and in NPH may extend
around the entire perimeter of the lateral ventricles.
These changes are thought to result from transependy-
mal CSF leakage. Deep white-matter lesions, which
are discontinuous with the ventricular wall, are usually
due to infarcts (Fig. 55.6) or perivascular (Virchow
Robin) spaces. Small white-matter infarcts are very
common in the elderly and even more common in
the setting of NPH (Bradley et al., 1991), where their
presence may predispose to ventricular dilatation by
softening the brain parenchyma (see below) (Bradley,
2001). The dilemma for the clinician is that, if the
patients symptoms are due to white-matter infarcts,
shunting would not be expected to improve matters.
On the other hand, patients with such lesions may still
benefit from the procedure (Tullberg et al., 2002), sug-
gesting that there is a reversible component in the
pathophysiology of their symptoms (see below).

Fig. 55.6. (A) Axial magnetic resonance imaging (MRI) scan (fluid-attenuated inversion recovery (FLAIR) sequence),
showing enlarged lateral ventricles and perisylvian fissures, frontal and occipital periventricular lucencies, high signal inten-
sity lesions (due to probable gliosis not VirchowRobin spaces) and a low signal intensity lesion in the periventricular
white matter but not contiguous with the ventricular wall. (B) Axial MRI scan (T2-weighted), a little lower, in the same
patient as in (A).
 HYDROCEPHALUS AND STRUCTURAL LESIONS
T2-weighted images may show a CSF flow void sign
(Bradley et al., 1986) due to increased CSF flow velo-
city in the aqueduct in NPH, but the value of this sign
is disputed (Vanneste, 1994).
55.2.2.4.2. Cerebrospinal fluid tap test
A test for NPH that is available to all clinicians is the CSF
tap test. A lumbar puncture is performed using a large-
caliber spinal needle, and, after measuring CSF pressure,
2040 ml of CSF is removed. If the pressure is high and
the patient is relaxed, this might be considered enough
evidence to undertake shunting. If the pressure is normal,
the decision regarding inserting a shunt is determined by
the clinical response to the tap. If the patients gait
improves then the test is positive and the patient should
undergo shunting. A negative result does not preclude a
possible benefit, since, even after implantation of a shunt,
there may be a delay of some days or even a week or two.
Thus, although a positive response is useful, the false-
negative rate is high (Haan and Thomeer, 1988).
55.2.2.4.3. Pressure-monitoring and infusion studies
In specialized centers, overnight CSF pressure monitor-
ing may be done using an Ommaya or Rickham reservoir
connected to the lateral ventricle, or a parenchymal intra-
cranial pressure monitor. In normal subjects, waves of
increased pressure may be seen, particularly during
sleep. In NPH, these so-called Lundberg B waves occur
with increased amplitude, duration and frequency.
Frequent B waves of > 9 mmHg amplitude are thought
to predict a successful response to CSF shunting
(Crockard et al., 1977; Borgesen et al., 1979; Reilly,
2001). However their absence does not exclude a diag-
nosis of NPH or beneficial response to shunting.
CSF dynamics can also be investigated with CSF
infusion or perfusion studies. A number of different
methods have been described, including constant-rate,
constant-pressure and bolus methods. We (BO) have
used the constant-rate CSF infusion study, as
described by Czosnyka et al. (1996). This test can be
performed via the lumbar route or via a CSF reservoir.
Two needles are used, one through which CSF pres-
sure is recorded and another through which normal
saline is infused at a rate of 1.01.5 ml/min. After a
period of 10 minutes, during which the baseline CSF
pressure is recorded, the CSF infusion is started. CSF
pressure rises until it reaches a new equilibrium pres-
sure. The CSF pulse pressure is noted to rise as the
mean CSF pressure rises. Once a stable equilibrium
CSF pressure has been established, CSF infusion
ceases and CSF pressure is noted to return to its base-
line. The difference between equilibrium and baseline
pressure divided by the infusion rate provides a value
for the resistance to CSF absorption (Rcsf). In addition,
a number of other parameters can be calculated,
including elastance and the pressure volume index.
465
Rcsf represents the CSF pressure that must be applied
to the CSF system to produce an absorption rate of 1
ml of CSF per minute at equilibrium. The normal Rcsf
is < 10 mmHg/ml per min (Albeck et al., 1991) but is
usually raised in NPH. The Copenhagen Symposium
on NPH in 1990 concluded that an Rcsf > 11 mmHg/
ml per min was suggestive of NPH. Gjerris and Borgesen
(1992), using the lumbar-ventricular CSF infusion
method, found that, of 271 patients shunted for NPH,
no patient with an Rcsf < 12 mmHg/ml per min
responded to CSF shunting whereas 80% with Rcsf
>12.5 mmHg/ml per min did. Similar findings have
been reported by Lundar and Nornes (1990). In a more
recent study (Boon et al., 2000) involving 95 patients
followed for 1 year, it was suggested that the best strat-
egy for management of patients thought to have NPH
was to shunt only those patients with a Rcsf >18
mmHg/ml per min, or if the Rcsf was lower, only those
with objective clinical evidence and CT evidence
of NPH.
55.2.3. Mechanisms
55.2.3.1. Hydrocephalus
Hakim and Adams explanation of ventricular enlarge-
ment in the face of normal CSF pressure is no longer
accepted. An initial period of raised CSF pressure may
occur in some cases of secondary NPH but there is very
little evidence for this in idiopathic NPH. The laws of
Pascal and LaPlace, although relevant to a balloon blown
up in air, are less applicable to the cerebral ventricles
which, as they enlarge, compress the parenchyma of
the brain against the skull wall, increasing rather than
decreasing resistance to further expansion.
Could enlargement of the ventricles be due to the
intermittent rise in pressure that occurs with B waves?
Probably not, for these reflect alterations in cerebral
blood volume within the brain.
There is an increase in the resistance to CSF outflow
or absorption in NPH. In secondary NPH this is due to
obstruction of arachnoid villi or arachnoid adhesions
resulting from previous subarachnoid hemorrhage or
meningitis. In idiopathic NPH, chronic meningeal thick-
ening has been described at autopsy (DeLand et al.,
1972; Akai et al., 1987). Patients with NPH often also
exhibit a convexity block when air, contrast or radio-
graphic tracers is injected into the subarachnoid space.
Chronic disease and involution of the arachnoid granula-
tions may be seen in NPH (Gilles and Davidson, 1971).
Akai et al. (1987) noted that the numbers of arachnoid
villi were decreased in the lateral lacunae of patients
with NPH. It is likely that the disorder of CSF circulation
in secondary and idiopathic NPH is similar, although in
idiopathic NPH it is more gradual in onset.
Impairment of CSF reabsorption however, would not
explain why the ventricles enlarge when the pressure
466 J. G. L. MORRIS ET AL.
inside is not increased. There is increasing evidence that
it is changes in the viscoelastic properties of brain tissue
with age and disease that predispose to ventricular
enlargement (Earnest et al., 1974). Hypertension is a
known risk factor for NPH. Akai et al. (1987) found
that patients with NPH demonstrated marked sclerosis
of the small arteries and arterioles of the subependy-
mal region, deep white matter, thalamus and basal
ganglia. Small lacunae were frequent in these regions
with focal softening of the tissue. Significant vascular
changes have also been reported at autopsy in patients
with shunt-responsive NPH who died from other
causes (Lorenzo et al., 1974; Newton et al., 1989).
55.2.3.2. Neurological features
It is not established how chronic hydrocephalus causes
the associated neurological features. Expansion of the
ventricular system could impact on the function of a
number of structures. Hakim and Adams proposed that
Fig. 55.7. For full color figure, see plate section. Coronal
section of the brain showing proximity of the fibers arising
from the mesial part of the motor cortex to the lateral ventricle.
Adapted from Figure 10.178, page 725, Romanes (1981).
the gait disturbance resulted from stretching of axons
in the periventricular white matter. As shown in
Figures 55.7 and 55.8, the pyramidal fibers closest to
the ventricles in the corona radiata are those arising
from the leg area of the motor cortex. Although this
might account for the hyperreflexia of the lower limbs,
it would not explain the gait disturbance which, as
described above, has the features of a higher-order gait
disturbance usually associated with lesions of the
mesial frontal lobes. Also in close proximity to the
lateral ventricles is the anterior cerebral artery
(Fig. 55.9A). Stretching of this artery (Fig. 55.9B)
may cause frontal lobe ischemia, but no evidence has
been found for this from PET studies (Brooks et al.,
1986). Cerebral blood flow (CBF) is maximally
impaired in the tissue adjacent to the ventricles,
improving progressively with distance from the ventri-
cles (Momjian et al., 2004). Ischemia of the basal
ganglia interfering with the cortico-striato-pallido-tha-
lamo-cortical motor loop has been proposed (Curran
and Lang, 1994) but this might be expected to produce
a gait similar to parkinsonism with improvement with
cues, which is not the case (Stolze et al., 2000). Dis-
connection of the frontal lobes by ischemia of the
medial nuclei of the thalami (Owler et al., 2004)
would account for both the gait and frontal pattern of
cognitive impairment (Fung et al., 1997) in NPH.
Another structure implicated in the neurological fea-
tures of NPH is the posterior corpus callosum, which
is compressed against the falx cerebri as the ventricles
enlarge (Jinkins, 1991). The posterior region of the
Fig. 55.8. The motor homunculus. Reproduced from Penfield
and Rasmussen (1950), with permission from Macmillan.
 HYDROCEPHALUS AND STRUCTURAL LESIONS
Fig. 55.9. For full color figure, see plate section. (A) Proximity of the anterior cerebral artery to the lateral ventricle. Adapted
from Duus (1989). (B). Sagittal magnetic resonance imaging scan showing relationship of the anterior cerebral artery to the
enlarged lateral ventricle in normal-pressure hydrocephalus.
corpus callosum contains crossed corticostriate fibers
and association fibers between the vestibular cortical
areas. Similarly, involvement of the medial and lateral
striae as well as the fornix is proposed as a mechanism
for disturbance of memory (Del Bigio, 1993).
55.2.4. Treatment
55.2.4.1. Some observations
The identification and treatment of NPH by shunting can
be one of the most rewarding in neurological practice:
A 74-year-old man presented with a 67-year
history of difficulty in walking and stooped pos-
ture, for which he had been taking levodopa,
without benefit. There were occasional spells
where his feet got stuck and he had fallen on a
number of occasions. His wife reported a decline
in memory commensurate with her own. For 2
years he had had urge incontinence. On exami-
nation, his face lacked expression and he walked
with a festinating gait on a broadened base and
with preserved (rapid) arm-swing. He turned en
bloc. There was mild cogwheel rigidity in the
upper limbs but no bradykinesia. Tendon
reflexes were present but reduced. Plantars were
flexor. CT scan showed enlarged ventricles with-
out cortical atrophy (Fig. 55.10A). Following
insertion of a ventriculoperitoneal (VP) shunt,
the ventricles reduced in size (Figure 55.10B,
postshunt) but there was only minimal initial
improvement in his gait. Over the next few
months his gait improved and when videoed 7
467
months after surgery it had returned to normal,
the difference between the pre- and postshunt
videos being most striking.
It is of interest that, although the ultimate result in
this patient was most gratifying, the improvement after
shunting was not immediate, causing the treating neu-
rologist to wonder in the immediate postoperative per-
iod whether he had made the right decision in referring
the patient for surgery. This delay in improvement
may reflect recovery of stretched axons in the vicinity
of the ventricles. Harder to explain is the improvement
which follows shunting when the ventricular size
remains unchanged:
A 73-year-old man presented with progressive
difficulty in walking for a year. Prior to that he
had been able to ski. There was urge incontinence
and no evidence of cognitive impairment. On
examination, he struggled to get out of the chair
and walked very slowly on a broad base and with
a tendency to shuffle. He was able to rise from a
crouching position and could stand on his toes
and heels. Power in the limbs was normal. The
reflexes were all hard to elicit. Tone was not
increased. There was no sensory loss. The arms
were normal. An MRI scan showed marked dila-
tation of the ventricles without gyral atrophy
(Fig. 55.11). Following ventriculostomy, he
became confused, incontinent of urine and bed-
bound for several days. Over the next month, he
slowly improved to the point where he could walk
468 J. G. L. MORRIS ET AL.

Fig. 55.10. Computed tomography scan: dilated ventricles: (A) preshunt; (B) postshunt.

Fig. 55.11. Axial magnetic resonance imaging scan (T1-weighted) showing enlargement of the lateral ventricles: (A) preshunt;
(B) sagittal view.
 HYDROCEPHALUS AND STRUCTURAL LESIONS
Fig. 55.12. Axial magnetic resonance imaging (T1-weighted) showing enlargement of the lateral ventricles: (A) postshunt; (B)
sagittal view.
unsupported. A postshunt MRI showed no change
in ventricular size (Fig. 55.12). Over the next few
months he continued to improve and, when
reviewed and revideoed after 7 months, he was
walking normally.
Improvement was also delayed in this patient and
no less impressive than the previous patient, yet the
ventricular size looks much the same. This finding is
the rule rather than the exception (Meier and Mutze,
2004). This may reflect the fact that current VP shunts
have valves in them which prevent the pressure falling
so low as to cause the hemispheres to collapse and
invite the formation of subdural hematomas. In Meier
and Mutzes study, 80% of 80 patients shunted for
NPH had no change in ventricular size, yet 59% of
these were judged to have made a good to excellent
improvement and a further 17% a satisfactory
improvement. Such findings lend support to the
hypothesis that shunting produces its benefit by means
other than relieving stretch on axons adjacent to the
ventricles. One such mechanism is improved blood
flow to the brain parenchyma.
The response of CBF to shunting has been studied
using a variety of techniques. Although some investiga-
tors found an increase in CBF after shunting (Tanaka
et al., 1997), it was often not sustained (Graff-Radford
et al., 1987). Other investigators reported no change in
CBF after shunting (Meixensberger et al., 1989) and
that there was no relationship to outcome (Klinge
469
et al., 1999). Others reported that, although global CBF
was not improved, the pattern of CBF was improved in
shunt-responders (Waldemar et al., 1993).
More recently (Silverberg et al., 2003; Silverberg,
2004), it has been proposed that changes in the normal
circulation of CSF in NPH may result in a failure to
clear toxic molecules such as amyloid--peptide, pre-
disposing to the development of Alzheimers disease,
which has an increased incidence in biopsy-studied
cases of NPH (Golomb et al., 2000). A trial of CSF
shunting to slow the progression of Alzheimers disease
is currently underway.
55.2.4.2. Shunting
Shunting is the treatment of choice in NPH. As origin-
ally suggested by Adams et al. (1965), the aim is to
decrease CSF pressure to even less than normal. The
response to shunting varies widely between studies:
2580%, with a mean of 50% (Vanneste et al., 1992).
Of 1047 patients included in this review, the response
to shunting was notably better in secondary NPH
(64%) compared to idiopathic NPH (50%). Marked
improvement was noted in 46% of patients with second-
ary NPH compared to 33% with idiopathic NPH.
The most common form of CSF shunt used in NPH
is a VP shunt, although ventriculoatrial shunting is
also popular. Both are generally favored over lumbo-
peritoneal shunting, which often poses problems in
the elderly.
470 J. G. L. MORRIS ET AL.
55.2.4.2.1. Complications of shunting
The most common complications of shunting are
infection and blockage. Less common complications
include subdural hematoma, stroke, shunt disconnec-
tion, erosion of the distal catheter through the skin or
internal viscus, thrombosis around atrial catheters and
shunt nephritis. Vanneste et al. (1992) performed a
risk/benefit study of idiopathic NPH using 1047
patients obtained from 19 studies from the literature.
The benefit/harm ratio in patients with idiopathic
NPH was 1.7 and increased to 6 if high-risk patients
with significant comorbidity were excluded. This is
not a procedure to be undertaken lightly.
A complication of shunting that deserves special
attention is that of subdural hematoma. This occurs
in patients with large ventricles with relatively thin
cortical mantles when there is overdrainage of CSF.
The cortical mantle collapses, separating away from
the dura and tearing overstretched subdural veins.
NPH patients are particularly prone to this complication
(Symon et al., 1972).
55.2.4.2.2. Reasons for shunt failure
As discussed previously, clinical improvement in patients
with NPH after CSF shunting is usually not immediate.
Gait disorder and urinary incontinence are the first symp-
toms to improve and may do so within days but often take
several weeks. Improvement in mental function is less
predictable and is usually the last symptom to improve;
it may take several months. Failure of the shunt to
provide worthwhile benefit can be due to a number of
factors: (1) technical problems with the pump itself; (2)
complications of shunting, such as subdural hematoma;
(3) irreversible pathophysiological changes in the brain
parenchyma relating to coexisting disease, such as hyper-
tensive small-vessel disease or Alzheimers disease.
55.2.4.3. Drugs and other treatments
Drugs have little place in the management of NPH.
There is no evidence that reducing CSF production
with drugs such as acetazolamide is beneficial. From
the preceding discussions, it might be anticipated that
control of hypertension may lessen the predisposition
to developing NPH.
55.2.5. Association between parkinsonism and
hydrocephalus
Curran and Lang (1994) have drawn attention to cases
of levodopa-responsive parkinsonism associated with
hydrocephalus. It is helpful to consider these:
Patient 1 was a 16-year-old boy with headaches
and papilledema secondary to aqueduct stenosis.
He improved with VP shunting but later became
drowsy when the shunt blocked. After shunt revi-
sion, he was noted to have tremor, rigidity and
akinesia and Parinauds syndrome. The parkin-
sonian features persisted and were markedly
improved by levodopa.
Patient 2 was a 16-year-old man with headache,
bilateral sixth-nerve palsies and papilledema
from hydrocephalus secondary to a pineal mass.
A VP shunt was inserted and he was given radio-
therapy. After repeated episodes of shunt
obstruction requiring revisions, he became bra-
dykinetic and rigid. These features improved
markedly with levodopa.
Patient 3, aged 7, developed tremor, unsteadi-
ness of gait, headache, vomiting and listlessness
associated with aqueduct stenosis. He improved
with a VP shunt. Again, after periods of repeated
shunt obstructions, he became parkinsonian with
tremor and rigidity. This too improved with levo-
dopa. After some months the levodopa was
withdrawn without return of his parkinsonism.
Patient 4 presented at age 9 with headache,
papilledema and Parinauds syndrome due to
aqueduct stenosis. Her symptoms improved with
a Torkildsen ventriculocisternal shunt. At age
26, she presented again with personality change
and generalized bradykinesia. The ventricles
were not enlarged but the shunt was noted to
be wrapped around the brainstem and was
replaced with a VP shunt. Her parkinsonism per-
sisted and was not improved by levodopa. Later
a CT scan revealed a small left thalamic bleed.
An 18F-dopa PET scan was normal, suggesting
that her parkinsonism was postsynaptic.
Patient 5 was a 69-year-old man who developed
parkinsonism, shown at postmortem to be due to
progressive supranuclear palsy in the setting of
NPH and diffuse cerebrovascular disease.
Patient 6, aged 72, was similar in presentation
to case 5, but with no pathological study.
Patient 7, aged 72, presented with a 10-year history
of asymmetrical limb slowing, gait disturbance and
incontinence associated with hydrocephalus. He
improved with shunting but later developed pro-
gressive parkinsonism with tremor and bradykine-
sia. This partially improved with levodopa. Later
he developed a vertical supranuclear gaze palsy.
At pathology he was found to have typical features
of advanced idiopathic PD.
Patient 8, aged 68, presented with gait instability,
generalized rigidity and right-arm resting tre-
mor. Within a year he was incontinent and had
 HYDROCEPHALUS AND STRUCTURAL LESIONS 471
cognitive changes. A CT scan showed hydroce-
phalus and all his symptoms resolved with a VP
shunt. Three months later his symptoms returned
and he was found to have small bilateral resol-
ving subdural hematomas. He initially improved
with levodopa but his parkinsonism and dementia
continued to decline over the next 2 years. An
MRI scan showed multiple areas of subcortical
high signal change. An 18F-dopa PET scan
showed decreased fluorine accumulation in the
putamen but not the caudate.
Patient 9, aged 67, with a previous history of
severe head injury, presented with parkinsonism
which responded to levodopa. Five years later
she had an episode of confusion and a CT scan
showed enlarged ventricles. Over the next 2
years she became progressively more demented
and parkinsonian.

55.2.5.1. Comment
Cases 13, all young, show that parkinsonism can
occur subacutely as a complication of obstructive
hydrocephalus involving the aqueduct. In these
patients, the clinical picture was very different from
the cases of NPH described above: they had symptoms
and signs of raised intracranial pressure with head-
ache, drowsiness and papilledema. Their parkinsonism
may have resulted from direct injury to the substantia
nigra, as there was evidence of midbrain damage
(patient 1 had Parinauds syndrome and patient 2 com-
pression of the midbrain by a pineal tumor) and they
responded to levodopa. Cases 59, all aged 67 or
older, illustrate that Occams razor whereby, in a
medical context, an attempt should be made to explain
all symptoms on the basis of a single disease is often
not a useful exercise in the elderly, where degenerative
parkinsonian syndromes such as idiopathic PD and
progressive supranuclear palsy may coexist with
cerebrovascular disease and NPH.
55.3. Other structural lesions
Dopa-responsive parkinsonism is described below in
association with a number of structural lesions.
55.3.1. Arteriovenous malformation
55.3.1.1. Intracerebral hemorrhage
Our colleague Aggarwal (Ling et al., 2002) reported a
case of dopa-responsive parkinsonism following a
hemorrhage into the right temporal lobe from an AVM:
A 46-year-old man developed a symmetrical
parkinsonian syndrome 7 weeks after presenting
Fig. 55.13. Axial T2-weighted magnetic resonance imaging
scan showing high signal intensity changes in the right tem-
poral lobe.
with a seizure, decreased level of consciousness,
a dilated right pupil and left hemiparesis from a
large right temporal intracerebral hemorrhage.
The hemorrhage was evacuated together with a
small AVM. His signs included bradykinesia,
rigidity, start hesitation and poor postural
reflexes, without a resting tremor. He also had
signs of a Parinauds syndrome. CT and MRI
of the brain demonstrated changes in the right
temporal lobe associated with the hemorrhage
but no abnormality of the basal ganglia or mid-
brain (Fig. 55.13). Levodopa therapy produced
a dramatic improvement within a few days of
commencement. He still required this treatment
2 years after the bleed. Three years after the
event he died from heat stroke after jogging. At
postmortem, marked neuronal loss with gliosis
was observed in the substantia nigra and super-
ior colliculi. There were no areas of infarction.
No Lewy bodies, neurofibrillary tangles or glial
cytoplasmic inclusion bodies were seen (M
Rodrigues, personal communication).
Like cases 13 of Curran and Lang (1994), it seems
likely that the parkinsonism in this case was the result
of damage to the nigrostriatal tract in the midbrain by
compression, in this case from an expanded temporal
lobe. Similar cases have been described in association
with subdural hematoma (Trosch and Ransom, 1990).
472 J. G. L. MORRIS ET AL.
55.3.1.2. Midbrain cavernoma
We have had a patient with dopa-responsive parkin-
sonism associated with a cavernoma involving one
substantia nigra:
She presented in 1975 at the age of 34 with tremor
of the left hand. She was put on levodopa, which
abolished her symptoms. When reviewed in 1991,
she had a coarse resting tremor and mild akinesia
confined to the left arm. In follow-up since that
time, she has reported that the effect of each dose
of levodopa wears off after about 2 hours. When
she is on she has no tremor and her Unified Par-
kinsons Disease Rating Scale (UPDRS) score is
5; when she is off it is 30. She has never had dys-
kinesia and never had signs on the other side. MRI
scans (Fig. 55.14) showed an area of increased
signal in the right cerebral peduncle with some
surrounding low signal on T2-weighted images,
suggesting the presence of hemosiderin. No abnor-
mal feeding vessels were seen on magnetic
resonance angiography. The features were of

Fig. 55.14. (A) T1-weighted magnetic resonance imaging (MRI) scan showing hypointense lesion in the pars compacta of the
right cerebral peduncle. (B) T2-weighted MRI scan showing low signal area (hemosiderin) around a small high signal area
(methemoglobin)in the right midbrain. (C) Coronal view of (B).
 HYDROCEPHALUS AND STRUCTURAL LESIONS
Fig. 55.15. For full color figure, see plate section. b-Carbo-
methoxy-3b-(4-iodophenyl)tropane (b-CIT) single-photon emis-
sion computed tomography (SPECT) scan showing reduced
formation of dopamine transporter in the right caudate nucleus.
a cavernoma. SPECT images (Fig. 55.15) were
obtained using [123I]2b-carboxymethoxy-3b-
iodophenyl tropane (beta-CIT) which labels presy-
naptic dopamine transporter (DAT) and [123I]
iodobenzamide (IBZM), which labels the postsy-
naptic D2-receptors. There was a dramatic reduc-
tion in presynaptic dopaminergic binding
ipsilateral to the lesion (Fig. 55.15) that was more
marked in the caudate than putamen, the opposite
of the putamencaudate gradient that is found in
idiopathic PD. Ipsilateral postsynaptic and con-
tralateral pre- and postsynaptic dopaminergic
uptakes were normal.
It is unlikely that this patient has unrelated idio-
pathic PD, as there has been almost no progression in
her disability over a period of 30 years. The cavernoma
Fig. 55.16. (A) Axial postgadolinium T1-weighted magnetic resonance imaging scan showing a large meningioma indenting
the left cerebral hemiphere; (B) T2-weighted, coronal view.
473
is on the appropriate side of the midbrain to produce
hemiparkinsonism. It seems likely that the right
nigrostriatal tract has been damaged by pressure from
the cavernoma or associated bleeding.
55.3.2. Tumor
Tumors rarely, if ever, cause parkinsonism. Some-
times, however, the clinical features produced by a
tumor may be mistaken for PD:
A 52-year-old right-handed man presented with a
6-month history of difficulty using his right hand.
His writing had lost fluency and become small.
He had difficulty doing up buttons and getting
his wallet out of his pocket. He had a tendency
to trip with the right foot. On examination, he
did not swing the right arm when he walked.
There was minimal lag in the right arm compared
with the left when he raised them and there was
no weakness. Tone was increased on the right
side. He had difficulty performing piano-playing
movements with the right hand. Reflexes were
brisker on the right side. The plantars were
flexor. A scan was done because of the hyperre-
flexia. This showed a 7
5
4 cm meningioma
indenting the left cerebral hemisphere maximally
over the motor strip (Fig. 55.16).
474 J. G. L. MORRIS ET AL.
55.3.2.1. Comment
Both neurologists who examined this patient at presen-
tation were impressed by the abnormality of finger
movement of the right side which was interpreted, in
the absence of weakness, as akinesia due to PD. The
increase in tone and loss of arm-swing lent support
to this. It seems likely that abnormality of finger
movement was due to a limb-kinetic apraxia, which
may present in a very similar manner to akinesia.
55.3.3. Lesions of the striatum/globus
pallidus/thalamus
In Bhatia and Marsdens (1994) extensive review, iso-
lated lesions of the striatum/globus pallidus rarely, and
of the thalamus never, caused pure parkinsonism. Par-
kinsonism occurred in 9% of 240 cases, all associated
with bilateral lesions and only rarely with rest tremor.
Most cases followed toxic/metabolic lesions, making
strict exclusion of nigrostriatal pathology difficult.
55.3.4. Supplementary motor area resection
Patients undergoing surgery involving the motor path-
ways can provide insights into the mechanism of the
motor deficit in parkinsonism:
A 24-year-old man with a history of intractable
seizures had the left SMA resected (Fig. 55.16).
There were no clinical signs before surgery.
Following surgery, he was initially mute and had
right-side weakness. An MRI scan shows the extent
of the resection (Fig. 55.17). Over the next few
Fig. 55.17. (A) T1-weighted magnetic resonance imaging scan: sagittal view showing high signal changes (due to blood pro-
ducts) over the mesial surface of the left cerebral hemisphere; (B) coronal view.
days his speech improved, as did the power on the
right side. There was reduction in amplitude of
right-hand movements involving opening and
closing the fingers and difficulty in making
piano-playing movements involving the index and
middle fingers, similar to what is seen in
parkinsonism. Most striking, however, was the
inability to coordinate the movement of the two
hands. He could clap with one hand or the other
but not both simultaneously. All of these features
gradually disappeared over the next few weeks,
leaving him with normal hand function.
55.3.4.1. Comment
The relationship between the SMA and akinesia in
parkinsonism has been reviewed by Williams et al.
(2002): Activity in the SMA is a major contributor to
the Bereitschaftspotential that precedes self-generated
movements and this potential is reduced in PD.
Imaging studies confirm impaired activation of SMA
during some movements in untreated PD; this is reversi-
ble using the dopaminergic agonist apomorphine. It is
of interest therefore that our patient showed features
similar to the akinesia of parkinsonism following SMA
resection, though the more striking abnormality was in
loss of bimanual coordination.
55.4. Incidence of structural lesions
in parkinsonism
Most reports of structural lesions associated with
parkinsonism are of single cases or of retrospective
 HYDROCEPHALUS AND STRUCTURAL LESIONS
studies of hospital records. Some information on the
incidence of structural lesions in patients presenting
with parkinsonism is provided by the long-term Syd-
ney Multicenter study of PD (Hely et al., 1994). Of
149 de novo patients diagnosed as having PD by 26
Sydney neurologists and followed by author MAH
for up to 20 years, 13 were found in the first 2 years
to be atypical, of which structural lesions relevant to
the parkinsonism were seen in 2:
A 60-year-old man who had presented with fea-
tures of a mixed resting and postural tremor, mild
but definite rigidity and bradykinesia, developed a
wide-based gait soon after presentation. He was
found to have a pinealoma compressing the mid-
brain and causing hydrocephalus (Fig. 55.18).
He responded to shunting and did not continue
with parkinsonian medication.
55.4.1. Comment
There were changes in the midbrain on CT scanning
and it seems likely that his transient parkinsonian
features were due to compression of the substantia
nigra or nigrostriatal tract by the pinealoma.
A 37-year-old man presented with a 3-year history
of resting tremor, bradykinesia and rigidity
Fig. 55.18. (A) Non-contrast computed tomopgraphy (CT) scan showing a calcified mass in the pineal gland. (B) Non-contrast
CT scan in the same patient showing low-density change in the region of the aqueduct.
475
confined to the right side of his body. He was found
to have a cystic lesion in the contralateral thala-
mus and lentiform nucleus (Fig. 55.19), probably
secondary to a severe head injury at age 13 (for
which he underwent bilateral burrhole evacuation
of subdural hematomas). He responded well to
levodopa 300 mg/day and benztropine 15 mg/day
and his symptoms remained confined to the right
side over 10 years of follow-up.
55.4.2. Comment
It seems likely that his hemiparkinsonism was related
to the previous head injury, though it began 21 years
after the injury. The symptoms were non-progressive
and contralateral to the lesion, which probably repre-
sented a cavity from an old hematoma. The response
to levodopa was surprising and suggests that the lesion
also involved the nigrostriatal tract.
55.5. Summary and conclusions
Structural pathology of the brain can mimic the clini-
cal features of parkinsonism. Those involving the
substantia nigra or the nigrostriatal tract can lead to
the classical features associated with idiopathic PD,
476 J. G. L. MORRIS ET AL.
Fig. 55.19. Non-contrast computed tomography scan show-
ing hypodense area in the left thalamus.
including asymmetry, rest tremor, akinesia, rigidity
and, most importantly, responsiveness to levodopa.
Lesions of the striatum/globus pallidus/thalamus rarely
cause pure parkinsonism. When it does occur, such
postsynaptic parkinsonism is not usually levodopa-
responsive. Data from patients with parkinsonism sec-
ondary to structural lesions lead to the conclusion that
the parkinsonism results from loss of dopaminergic
modulation of striatal activity, not from loss of func-
tion due to lesions of the striatum itself.
NPH produces a clinical picture that is very different
from PD (Fig. 55.20). The major motor impairment is
gait disturbance, which most closely resembles that
seen in multilacunar states or frontal-lobe syndromes.
As softening of the brain parenchyma by multiple
infarcts predisposes to ventricular enlargement, there is
considerable overlap between NPH and the multilacunar
state. Where most of the neurological deficit relates to
infarction, the response to shunting is likely to be poor.
Finally, cortical lesions involving the motor and
premotor cortex can cause alterations in fine finger
movements similar to what is seen in parkinsonism.
These are best considered as limb-kinetic apraxia
rather than akinesia as there are no associated signs
such as rigidity or rest tremor.
Fig. 55.20. For full color figure, see plate section. Diffusion
tensor magnetic resonance imaging scan of a patient with
normal-pressure hydrocephalus showing thinning of the for-
ceps minor (red), forceps major (green) and compression of
the corona radiata (blue).
Acknowledgments
We thank Drs Somerville, Aggarwal, Bleasel and
Duggins for permission to describe their patients and
Dr Lavier Gomes for his help with the scans.
References
Adams RD, Fisher CM, Hakim S et al. (1965). Symptomatic
occult hydrocephalus with normal cerebrospinal-fluid pres-
sure. A treatable syndrome. N Engl J Med 273: 117126.
Ahlberg J, Norlen L, Blomstrand C et al. (1988). Outcome of
shunt operation on urinary incontinence in normal pres-
sure hydrocephalus predicted by lumbar puncture. J Neu-
rol Neurosurg Psychiatry 51 (1): 105108.
Akai K, Uchigasaki S, Tanaka U et al. (1987). Normal pres-
sure hydrocephalus. Neuropathological study. Acta Pathol
Jpn 37 (1): 97110.
Albeck MJ, Borgesen SE, Gjerris F et al. (1991). Intracranial
pressure and cerebrospinal fluid outflow conductance in
healthy subjects. J Neurosurg 74 (4): 597600.
Bhatia KP, Marsden CD (1994). The behavioural and motor
consequences of focal lesions of the basal ganglia in man.
Brain 117 (Pt 4): 859876.
Blocq P, Marinesco G (1894). Sur un cas de tremblement
Parkinsonien hemiplegique symptomatique dune tumeur
du peduncle cerebrale. Rev Neurol (Paris) 2: 265.
Boon AJ, Tans JT, Delwel EJ et al. (2000). The Dutch
normal-pressure hydrocephalus study. How to select
patients for shunting? An analysis of four diagnostic
criteria. Surg Neurol 53 (3): 201207.
 HYDROCEPHALUS AND STRUCTURAL LESIONS
Borgesen SE, Gjerris F, Sorensen SC (1979). Intracranial
pressure and conductance to outflow of cerebrospinal fluid
in normal-pressure hydrocephalus. J Neurosurg 50 (4):
489493.
Bradley WG (2000). Normal pressure hydrocephalus: new
concepts on etiology and diagnosis. AJNR Am J Neurora-
diol 21 (9): 15861590.
Bradley WG (2001). Normal pressure hydrocephalus and deep
white matter ischemia: which is the chicken, and which is
the egg? AJNR Am J Neuroradiol 22 (9): 16381640.
Bradley WG Jr, Kortman KE, Burgoyne B (1986). Flowing
cerebrospinal fluid in normal and hydrocephalic states:
appearance on MR images. Radiology 159 (3): 611616.
Bradley WG Jr, Whittemore AR, Watanabe AS et al. (1991).
Association of deep white matter infarction with chronic
communicating hydrocephalus: implications regarding
the possible origin of normal-pressure hydrocephalus.
AJNR Am J Neuroradiol 12 (1): 3139.
Bret P, Guyotat J, Chazal J (2002). Is normal pressure hydro-
cephalus a valid concept in 2002? A reappraisal in five
questions and proposal for a new designation of the syn-
drome as chronic hydrocephalus. J Neurol Neurosurg
Psychiatry 73 (1): 912.
Brooks DJ, Beaney RP, Powell M et al. (1986). Studies on
cerebral oxygen metabolism, blood flow, and blood
volume, in patients with hydrocephalus before and after
surgical decompression, using positron emission tomogra-
phy. Brain 109 (Pt 4): 613628.
Crockard HA, Hanlon K, Duda EE et al. (1977). Hydrocepha-
lus as a cause of dementia: evaluation by computerised
tomography and intracranial pressure monitoring. J Neurol
Neurosurg Psychiatry 40 (8): 736740.
Curran T, Lang AE (1994). Parkinsonian syndromes asso-
ciated with hydrocephalus: case reports, a review of the
literature, and pathophysiological hypotheses. Mov Disord
9 (5): 508520.
Czosnyka M, Whitehouse H, Smielewski P et al. (1996).
Testing of cerebrospinal compensatory reserve in shunted
and non-shunted patients: a guide to interpretation based
on an observational study. J Neurol Neurosurg Psychiatry
60 (5): 549558.
Del Bigio MR (1993). Neuropathological changes caused by
hydrocephalus. Acta Neuropathol (Berl) 85 (6): 573585.
DeLand FH, James AE Jr, Ladd DJ et al. (1972). Normal
pressure hydrocephalus: a histologic study. Am J Clin
Pathol 58 (1): 5863.
Duus P (1989). Topical Diagnosis in Neurology, 2nd edn,
Thieme Medical Publishers, New York.
Earnest MP, Fahn S, Karp JH et al. (1974). Normal pressure
hydrocephalus and hypertensive cerebrovascular disease.
Arch Neurol 31 (4): 262266.
Estanol BV (1981). Gait apraxia in communicating hydroce-
phalus. J Neurol Neurosurg Psychiatry 44 (4): 305308.
Fisher CM (1982). Hydrocephalus as a cause of disturbances
of gait in the elderly. Neurology 32 (12): 13581363.
Fung VS, Morris JG, Leicester J et al. (1997). Clonic perse-
veration following thalamofrontal disconnection: a distinc-
tive movement disorder. Mov Disord 12 (3): 378385.
477
Gilles FH, Davidson RI (1971). Communicating hydrocepha-
lus associated with deficient dysplastic parasagittal
arachnoidal granulations. J Neurosurg 35 (4): 421426.
Gjerris F, Borgesen SE (1992). Current concepts of measure-
ment of cerebrospinal fluid absorption and biomechanics
of hydrocephalus. Adv Tech Stand Neurosurg 19:
145177.
Golomb J, de Leon MJ, George AE et al. (1994). Hippocam-
pal atrophy correlates with severe cognitive impairment in
elderly patients with suspected normal pressure hydroce-
phalus. J Neurol Neurosurg Psychiatry 57 (5): 590593.
Golomb J, Wisoff J, Miller DC et al. (2000). Alzheimers
disease comorbidity in normal pressure hydrocephalus:
prevalence and shunt response. J Neurol Neurosurg Psy-
chiatry 68 (6): 778781.
Graff-Radford NR, Rezai K, Godersky JC et al. (1987).
Regional cerebral blood flow in normal pressure hydroce-
phalus. J Neurol Neurosurg Psychiatry 50 (12): 15891596.
Haan J, Thomeer RT (1988). Predictive value of temporary
external lumbar drainage in normal pressure hydrocepha-
lus. Neurosurgery 22 (2): 388391.
Hakim S, Adams RD (1965). The special clinical problem of
symptomatic hydrocephalus with normal cerebrospinal
fluid pressure. Observations on cerebrospinal fluid hydro-
dynamics. J Neurol Sci 2 (4): 307327.
Hebb AO, Cusimano MD (2001). Idiopathic normal pressure
hydrocephalus: a systematic review of diagnosis and out-
come. Neurosurgery 49 (5): 11661184.
Hely MA, Morris JG, Reid WG et al. (1994). The Sydney
multicentre study of Parkinsons disease: a randomised,
prospective five year study comparing low dose bromo-
criptine with low dose levodopa-carbidopa. J Neurol Neu-
rosurg Psychiatry 57 (8): 903910.
Iddon JL, Pickard JD, Cross JJ et al. (1999). Specific patterns
of cognitive impairment in patients with idiopathic normal
pressure hydrocephalus and Alzheimers disease: a pilot
study. J Neurol Neurosurg Psychiatry 67 (6): 723732.
Jinkins JR (1991). Clinical manifestations of hydrocephalus
caused by impingement of the corpus callosum on the
falx: an MR study in 40 patients. AJNR Am J Neuroradiol
12 (2): 331340.
Klinge PM, Berding G, Brinker T et al. (1999). A positron
emission tomography study of cerebrovascular reserve
before and after shunt surgery in patients with idiopathic
chronic hydrocephalus. J Neurosurg 91 (4): 605609.
Ling MJ, Aggarwal A, Morris JG (2002). Dopa-responsive
parkinsonism secondary to right temporal lobe haemorrah-
age. Mov Disord 17 (2): 402404.
Liston R, Mickelborough J, Bene J et al. (2003). A new
classification of higher level gait disorders in patients
with cerebral multi-infarct states. Age Ageing 32 (3):
252258.
Lorenzo AV, Bresnan MJ, Barlow CF (1974). Cerebrospinal
fluid absorption deficit in normal pressure hydrocephalus.
Arch Neurol 30 (5): 387393.
Lundar T, Nornes H (1990). Determination of ventricular
fluid outflow resistance in patients with ventriculomegaly.
J Neurol Neurosurg Psychiatry 53 (10): 896898.
478 J. G. L. MORRIS ET AL.
Meier U, Mutze S (2004). Correlation between decreased
ventricular size and positive clinical outcome following
shunt placement in patients with normal-pressure hydroce-
phalus. J Neurosurg 100 (6): 10361040.
Meixensberger J, Brawanski A, Ullrich OW et al. (1989).
Cerebral blood flow in low pressure hydrocephalus. Psy-
chiatry Res 29 (3): 307308.
Momjian S, Owler BK, Czosnyka Z et al. (2004). Pattern of
white matter regional cerebral blood flow and autoregula-
tion in normal pressure hydrocephalus. Brain 127 (Pt 5):
965972.
Newton H, Pickard JD, Weller RO (1989). Normal pressure
hydrocephalus and cerebrovascular disease: findings of
postmortem. J Neurol Neurosurg Psychiatry 52 (6): 804.
Nutt JG, Marsden CD, Thompson PD (1993). Human walk-
ing and higher-level gait disorders, particularly in the
elderly. Neurology 43 (2): 268279.
Owler BK, Pena A, Momjian S et al. (2004). Changes in cer-
ebral blood flow during cerebrospinal fluid pressure
manipulation in patients with normal pressure hydroce-
phalus: a methodological study. J Cereb Blood Flow
Metab 24 (5): 579587.
Penfield W, Rasmussen T (1950). The Cerebral Cortex of
Man. New York, Macmillan.
Reilly P (2001). In normal pressure hydrocephalus, intracra-
nial pressure monitoring is the only useful test. J Clin
Neurosci 8 (1): 6667.
Romanes GJ (ed.). (1981). Cunninghams Textbook of Anat-
omy, 12th edn. Oxford University Press, New York.
Savolainen S, Hurskainen H, Paljarvi L et al. (2002). Five-
year outcome of normal pressure hydrocephalus with or
without a shunt: predictive value of the clinical signs, neu-
ropsychological evaluation and infusion test. Acta Neuro-
chir (Wien) 144 (6): 515523.
Silverberg GD (2004). Normal pressure hydrocephalus (NPH):
ischaemia, CSF stagnation or both. Brain 127 (Pt 5):
947948.
Silverberg GD, Mayo M, Saul T et al. (2003). Alzheimers
disease, normal-pressure hydrocephalus, and senescent
changes in CSF circulatory physiology: a hypothesis. Lan-
cet Neurol 2 (8): 506511.
Stolze H, Kuhtz-Buschbeck JP, Drucke H et al. (2000). Gait
analysis in idiopathic normal pressure hydrocephalus
which parameters respond to the CSF tap test? Clin
Neurophysiol 111 (9): 16781686.
Stolze H, Kuhtz-Buschbeck JP, Drucke H et al. (2001).
Comparative analysis of the gait disorder of normal pres-
sure hydrocephalus and Parkinsons disease. J Neurol
Neurosurg Psychiatry 70 (3): 289297.
Symon L, Dorsch NW, Stephens RJ (1972). Pressure waves in
so-called low-pressure hydrocephalus. Lancet 2 (7790):
12911292.
Tanaka A, Kimura M, Nakayama Y et al. (1997). Cerebral
blood flow and autoregulation in normal pressure hydroce-
phalus. Neurosurgery 40 (6): 11611165.
Thompson PD, Marsden CD (1987). Gait disorder of subcor-
tical arteriosclerotic encephalopathy: Binswangers dis-
ease. Mov Disord 2 (1): 18.
Thomsen AM, Borgesen SE, Bruhn P et al. (1986). Prognosis
of dementia in normal-pressure hydrocephalus after a
shunt operation. Ann Neurol 20 (3): 304310.
Trosch RM, Ransom BR (1990). Levodopa-responsive par-
kinsonism following central herniation due to bilateral
subdural hematomas. Neurology 40 (2): 376377.
Tullberg M, Hultin L, Ekholm S et al. (2002). White matter
changes in normal pressure hydrocephalus and Binswan-
ger disease: specificity, predictive value and correlations
to axonal degeneration and demyelination. Acta Neurol
Scand 105 (6): 417426.
Vanneste J, Augustijn P, Dirven C et al. (1992). Shunting
normal-pressure hydrocephalus: do the benefits outweigh
the risks? A multicenter study and literature review. Neu-
rology 42 (1): 5459.
Vanneste JA (1994). Three decades of normal pressure
hydrocephalus: are we wiser now? J Neurol Neurosurg
Psychiatry 57 (9): 10211025.
Waldemar G, Schmidt JF, Delecluse F et al. (1993). High
resolution SPECT with [99mTc]-d,l-HMPAO in normal
pressure hydrocephalus before and after shunt operation.
J Neurol Neurosurg Psychiatry 56 (6): 655664.
Williams D, Tijssen M, Van Bruggen G et al. (2002).
Dopamine-dependent changes in the functional connectiv-
ity between basal ganglia and cerebral cortex in humans.
Brain 125 (Pt 7): 15581569.
Yakovlev PI (1947). Paraplegias of hydrocephalics (clinical
note and interpretation). Am J Ment Defic 51: 561576.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 56

Calcification of the basal ganglia

JENNIFER S. HUI* AND MARK F. LEW

University of Southern California, Los Angeles, CA, USA

56.1. Introduction calcifications of the BG are found in approximately

Calcification of the basal ganglia (BG) has been known
and described since 1850 by Delacour, and histologically
defined as cerebral blood vessel calcifications by
Bamberger in 1855. The observations of these scien-
tists, however, are rarely credited today. In 1930, the
German pathologist Fahr described a case of calcifica-
tion in the cerebral vessels in a patient with likely
hypoparathyroidism (HP). Fahrs disease has since
become a disputed term and a relative misnomer, given
that calcifications in his case occurred in predominantly
white matter, sparing the BG (Klein and Vieregge,
1998). Confusion regarding the nomenclature and
classification of BG calcifications persists, with Fahrs
disease used in varying contexts encompassing BG cal-
cinosis of differing etiologies, symptoms and clinical
significance. To clarify, the descriptive term bilateral
striopallidodentate calcinosis (BSPDC) has been pro-
posed to describe idiopathic, symmetric calcifications
of the BG resulting in characteristic clinical features
and will be used throughout this chapter (Manyam,
1990; Manyam et al., 2001b).
56.2. Epidemiology
56.2.1. Incidental calcifications of the basal ganglia
Epidemiologic studies expanded rapidly with the
widespread use of computed tomography (CT) in the
1970s, resulting in increased sensitivity of detecting
BG calcifications over skull plain films (Fig. 56.1).
Nevertheless, prevalence estimates of BG calcifica-
tions in the general population have varied widely
due to non-standardized radiographic and clinical
criteria. Authors have generally agreed that incidental
0.31.2% of all subjects undergoing routine brain CT
examination (Koller et al., 1979; Murphy, 1979; Sachs
et al., 1979; Brannan et al., 1980; Cohen et al., 1980;
Fenelon et al., 1993). When found, these calcifications
are usually punctate and restricted to the globus palli-
dus, although few studies report consistent symptoms
related to dysfunction of BG pathways. Harrington
et al. (1981) reviewed the CT scans of 7000 patients
and found 42 patients (0.6%) with BG calcifications
and normal serum electrolytes, calcium and phosphate
levels. Clinical correlations of these patients included
epilepsy, headache, stroke or dementia, but no symp-
toms related to BG involvement. Likewise, Sachs
et al. (1979) found 14 patients out of 3800 CT exami-
nations (0.4%) with bilateral BG calcifications, the
majority having seizures or psychic symptoms.
Finally, the diversity of symptoms found in a series
of 14 of 4219 (0.3 %) consecutive patients with calci-
fications and normal metabolic profiles led to the con-
clusion that further diagnostic procedures were not
warranted if symmetric BG lesions were incidentally
found on brain CT (Koller et al., 1979).
Other authors, however, have advocated an evalua-
tion of calcium metabolism in cases of incidental BG
calcifications. In particular, Sachs et al. (1982)
reported that 10% (2/20) of incidentally revealed BG
calcifications revealed a diagnosis of primary HP.
However, these cases were specifically referred for
evaluation of neurologic symptoms, comprising a
potentially higher-risk group than found with other,
consecutively derived CT series. In most reported
cases of incidental BG calcinosis, serum calcium and
phosphorus levels are normal, as seen in a collective
total of 88 subjects reported by Koller et al. (1979),

*Correspondence to: Dr. Jennifer S. Hui, University of Southern California, 1520 San Pablo St., Suite 3000, Los Angeles, CA
90033, USA. E-mail: jhui@surgery.usc.edu
480 J. S. HUI AND M. F. LEW
Table 56.1
Etiology of basal ganglia calcifications
Idiopathic Congenital
Incidental calcifications Cockaynes syndrome
(physiologic) Mitochondrial
BSPDC myopathies
Familial Tuberous sclerosis
Autosomal dominant/ Neurofibromatosis
recessive Downs syndrome
Sporadic Hallervorden-Spatz
syndrome
Endocrine disorders Methemoglobinopathies
Hypoparathyroidism
Pseudohypoparathyroidism Toxic/anoxic
Pseudo- Lead intoxication
Fig. 56.1. Skull film demonstrating basal ganglia calcifica- pseudohypoparathyroidism Carbon monoxide
tions in a patient with hypoparathyroidism. Courtesy of Hyperparathyroidism intoxication
University of Southern California Department of Radiology. Hypothyroidism Radiation therapy
Methotrexate
Infectious Long-term
Cohen et al. (1980) and Brannan et al. (1980), except Toxoplasmosis antiepileptics
for 2 cases of previously known HP. Cystercercosis
Given the relative scarcity of pathologic conditions HIV/AIDS Autoimmune
Tuberculosis Systemic lupus
associated with incidental BG calcifications, most have
Viral encephalitis erythematosus
concluded that the radiologic finding can be regarded as
a manifestation of physiologic senescence (Murphy, HIV, human immunodeficiency virus; AIDS, acquired immunodefi-
1979; Brannan et al., 1980; Cohen et al., 1980). This ciency syndrome.
concept is supported by a population-based study show-
ing a relatively high prevalence (18.6%) of BG calcifi-
cations in healthy elderly subjects aged 85 years,
subcortical white matter, as distinguished by large,
suggesting that this finding is more common in older
confluent areas of hyperdense signal on brain CT
persons (Ostling et al., 2003). Similarly, Cohen et al.
(Fig. 56.2).
(1980) found that, among 32 patients with incidental
Conditions associated with symptomatic BG calci-
BG calcifications, 25 were above the age of 60 years.
fications can be classified into idiopathic or secondary
Together, these epidemiologic findings suggest that it
causes (Table 56.1). Of the secondary causes, primary
is reasonable to evaluate further patients with incidental
HP is the most common, with estimates of BG cal-
BG calcifications who are younger than age 40 years,
cification occurring in 6993% of those with the disor-
those with symptoms related to BG dysfunction or HP
der, as identified on brain CT imaging (Sachs et al.,
(such as tetany) or those with dense or multiple areas
1982; Illum and Dupont, 1985). Illum and Dupont
of cerebral calcification outside the globus pallidus.
(1985) found that 69% (11/16) of subjects with pri-
mary HP and 100% (8/8) of those with pseudo-HP
56.2.2. Symptomatic calcifications of the basal showed calcification in the BG. Distribution of the
ganglia lesions included the globus pallidus in all cases, with
most subjects demonstrating additional deposits in
A subset of BG calcifications exists for which there the striatum, thalamus, dentate and centrum semiovale.
are identifiable metabolic or degenerative causes Sachs et al. (1982) surveyed 14 patients with primary
(Table 56.1). In contrast to those incidental cases without HP, 13 of which demonstrated bilateral intracerebral
a known etiology, these symptomatic calcifications are calcifications (93%), 9 located in the BG. In both
often associated with a progressive syndrome of parkin- studies, patients had been diagnosed with HP for over
sonism, dystonia, chorea and tremor. Although milder 10 years, with symptoms of tetany or seizures starting
forms of symptomatic cases may occur, those who are in childhood. Parkinsonian signs of hypokinesia,
clinically affected share a radiographic presentation of rigidity or tremor were present in only 3 of 12 subjects
massive calcification of the striatum, cerebellum and in the series of Sachs et al. (1982).
 CALCIFICATION OF THE BASAL GANGLIA 481

A B

C
Fig. 56.2. (A) Mild, (B) moderate and (C) severe forms of bilateral striopallidodentate calcinosis (BSPDC). Courtesy of University
of Southern California Department of Radiology.
482 J. S. HUI AND M. F. LEW
56.3. Bilateral striopallidodentate calcinosis
Although reports of parkinsonian syndromes have
been relatively rare in association with HP and other
secondary causes of BG calcinosis, parkinsonism is a
frequent presentation of idiopathic familial cases of
massive BG calcification, popularly known as Fahrs
disease (Lowenthal, 1986). Endocrinologic evaluations
in these cases do not reveal abnormalities in calcium
or phosphorus metabolism. Now termed BSPDC, the
disorder can be seen in familial, autosomal-dominant,
autosomal-recessive or, less commonly, sporadic
patterns (Manyam, 1990; Manyam et al., 2001a).
Unlike incidental or some secondary causes of BG
calcinosis, familial BSPDC carries a poor prognosis.
The true prevalence of the disorder remains unknown
due to the evolving clinical and radiographic diag-
nostic criteria and its predominantly case-report
description in the literature. In all likelihood
BSPDC is rare, although cases with lesser calci-
fication appearing in routine CT imaging cannot
be excluded as early presentations of BSPDC without
a detailed family history, including radiographic
evidence.
56.3.1. Clinical features
Among multiple reports of BSPDC, a fairly uniform
clinical presentation has emerged, featuring a progres-
sive syndrome with varying symptoms of dementia,
dysarthria, parkinsonism, pyramidal and cerebellar
signs (Ellie et al., 1989; Manyam et al., 1992, 2001a,
b; Kobari et al., 1997; Warren et al., 2002). Onset of
symptoms typically occurs between 30 and 50 years
and cognitive symptoms are not uncommon. Given
the relative uniformity of features distinct to BSPDC,
Manyam et al. (2001b) established the Fahrs disease
registry, retaining the popular name for sake of
familiarity. Inclusion criteria included: (1) radiologic
evidence of bilateral, symmetric calcifications in the
BG, dentate, thalamus or cerebral white matter; (2)
normal childhood development; and (3) absence of
parathyroid disorder. All subjects were examined clini-
cally and provided a detailed family history. Cases
reported in the literature that met inclusion criteria
were also included (n 61).
In the combined registry and literature cases
(n 99), 67 were symptomatic and 32 were asympto-
matic. The symptomatic group demonstrated a signifi-
cantly higher mean age (
sd) (47
15) compared to
the asymptomatic group (32
20) and were more than
twice as likely to be men (45:22). Men were also more
likely to have intracranial calcifications compared
to women (57:42, P < 0.01). This predominance of
men in the symptomatic group has been suggested in
other reviews of the literature (Ellie et al., 1989;
Kobari et al., 1997). Kobari et al. (1997) found a simi-
lar ratio, in which over half of symptomatic cases of
brain calcification were men (21:11). Ellie et al.
(1989) reported a more conservative male-to-female
ratio (11:13) in the symptomatic group, but, like the
registry, noted that older patients (> 45 years) were
more likely to be clinically affected.
The clinical features of patients in the registry were
separated into 11 categories, the most common symp-
tom being movement disorders (55%), with over half
of these cases manifesting parkinsonism (57%),
followed by chorea, tremor and dystonia (Manyam
et al., 2001b). Cognitive impairment was the second
most commonly observed symptom (39%), along with
cerebellar (36%) and speech (36%) disorders. Unlike
cases of HP-associated calcifications, seizures were
relatively uncommon, accounting for 9% of all
symptoms. There was considerable overlap of symp-
toms, although the number of subjects displaying more
than one symptom was not specified. Families can
demonstrate interfamilial heterogeneity.
The cognitive aspects of BSPDC have been well
documented and anatomically supported by previously
described frontalsubcortical circuits (Cummings
et al., 1983; Alexander et al., 1986). Lopez-Villegas
et al. (1996) published a case-control study of the
neuropsychological symptoms of subjects with BG
calcinosis > 5 mm, illustrating significant executive
and visuospatial dysfunction, a similar pattern to other
disorders affecting deep gray-matter structures
(e.g. Parkinsons disease, Huntingtons disease, pro-
gressive supranuclear palsy). Psychiatric symptoms
were also more common in those with calcification
compared to controls, with 22.2% meeting criteria for
mood disorder and 33.3% for obsessive-compulsive
disorder (n 18). In addition, frank psychosis in
BSPDC has been seen alone or in conjunction with
other movement disorders (Cummings et al., 1983;
Rosenberg et al., 1991; Lauterbach et al., 1994), with
one report of three siblings, each with BG calcifica-
tions and symptoms of schizophrenia, making the like-
lihood of coincidental diagnoses unlikely (Rosenberg
et al., 1991). Finally, Cummings et al. (1983) even
suggested that BSPDC presents with two distinct
clinical patterns: an early-onset psychotic syndrome
and a late-onset group with motor and cognitive
symptoms, although delayed tardive effects from early
pharmacologic treatment of psychosis could not be
discounted.
Several variations of the BSPDC clinical syndrome
have been published in case-report format, including
a patient with subacute dementia occurring over 6
 CALCIFICATION OF THE BASAL GANGLIA
months affecting memory, executive functioning and
mood without motor impairment (Benke et al., 2004).
Warren et al. (2002) reported a patient with corticoba-
sal degeneration manifesting as left-sided rigidity and
apraxia, a left extensor plantar response and startle
myoclonus. Finally, a particularly unique case of a
12-year-old girl with transient parkinsonism lasting
10 days was found after she had drunk a cup of tea,
associated with multiple gray- and white-matter
calcifications on brain CT (Yoshikawa and Abe, 2003).
56.3.2. Radiography and clinical correlations
In virtually all reported cases of incidental, secondary
and idiopathic causes of BG calcinosis, calcification
in the brain is nearly symmetrical and, in BSPDC,
restricted to the central nervous system (Lowenthal,
1986). In cases meeting criteria for the Fahrs disease
registry, calcification was mainly seen in the dentate
nucleus, BG, thalamus and centrum semiovale with
varying severity (Figs. 56.2 and 56.3) (Manyam
et al., 2001b). There were no consistent patterns of
calcification within families. Symptomatic patients
showed a significantly greater amount of calcification
compared to asymptomatic individuals, suggesting a
doseresponse relationship. Longitudinal changes
Fig. 56.3. Dentate calcification in bilateral striopallidoden-
tate calcinosis (BSPDC). Courtesy of University of Southern
California Department of Radiology.
483
were documented in 1 subject over a decade with
serial CT scans, showing a progressive increase in
total calcium deposits from age 50 to 57, then a
decrease corresponding to cerebral atrophy at age 60.
This pattern of progressive calcification correlating
with worsening symptoms over time has been cross-
sectionally observed in other studies, suggesting a
cumulative pathologic effect. In multigenerational
families with BSPDC, for instance, younger generations
are often asymptomatic with milder degrees of
calcification, whereas older relatives present with the
progressive clinical syndrome. In a father-and-son
series by Ellie et al. (1989), a 48-year-old man presented
with progressive speech impairment and cerebellar
ataxia with multiple areas of dense cerebral calcifica-
tion, with his asymptomatic 22-year-old son demon-
strating less extensive calcifications of the globus
pallidus. In another familial report, Moskowitz et al.
(1971) reported 5 patients in one family with BG
calcifications. Of the 5 subjects, the two eldest (ages
47 and 58 years) presented with parkinsonism, whereas
the younger individuals (aged 1330 years) were
asymptomatic. The severity of calcifications was not
measured.
Alternatively, other familial reports of BSPDC have
found that younger generations were more severely
affected, both clinically and radiographically, suggest-
ing a possible role for genetic anticipation (Kobari
et al., 1997). This observation has been supported by
the recent identification of a chromosomal locus for
BG calcification, showing a younger age of onset with
each genetic transmission (see below) (Geschwind
et al., 1999). As a result of these varying opinions
regarding the individual prognosis of BG calcinosis,
it is difficult to predict who will become symptomatic
from BSPDC, although it appears that more extensive
calcifications correlate with increasing severity of
symptoms.
56.3.3. Genetics of BSPDC
Variations in familial expression have revealed several
inheritance patterns of BSPDC, the most common of
which is an autosomal-dominant pattern. Autosomal-
recessive (Smits et al., 1983) and X-linked (Naderi
et al., 1993) inheritance patterns of BG calcinosis have
also been described, although these cases are often
associated with endocrine disorders such as HP or
have inadequate pedigrees consisting of only one
affected generation, limiting the certainty of genetic
transmission patterns. Of the 99 patients included in
the Fahrs disease registry, 73 patients belonged to
14 families, demonstrating a clear autosomal-dominant
inheritance of BSPDC. Of the remaining patients, 12
484 J. S. HUI AND M. F. LEW
were grouped as familial without a clear pattern of
inheritance and 14 were sporadic cases.
Moskowitz et al. (1971) were among the first to report
an entire family with autosomal-dominant BSPDC,
examining 15 members spanning at least two genera-
tions, with documented male-to-male transmission. Five
subjects had BG calcification and 10 did not have calci-
fication, as detected on skull films rather than CT,
perhaps underestimating its prevalence. In another
extensive familial study, Manyam et al. (2001a) evalu-
ated 27 members of a family over four generations, with
18 showing radiographic evidence of brain calcifications
in an autosomal-dominant pattern. Three patients were
symptomatic with parkinsonism, one, interestingly, with
autopsy-confirmed Parkinsons disease and another
without Lewy bodies on autopsy.
The chromosomal locus for one family with
idiopathic BG calcifications has been localized to
chromosome 14q (Geschwind et al., 1999). Geschwind
et al. clinically and genetically examined 28 members
of a multigenerational family using linkage analysis,
of which 12 had BG calcifications. The family demon-
strated autosomal-dominant inheritance patterns over
four generations, with symptoms ranging from combi-
nations of parkinsonism, dystonia and tremor. The aver-
age age at onset of symptoms was 37 years, appearing to
decrease over three successive generations by an aver-
age of > 20 years, such that the third generation had
symptom onset from ages 512 years.
The discovery of such a prominent pattern of anti-
cipation is somewhat surprising, given its lack of
consistent documentation in the current literature;
however, it points to the possibility of a triplet repeat
mutation as a cause of some cases of BSPDC. Several
candidate genes within the 14q locus have been men-
tioned, including a proteosome subunit, somatostatin
receptor, kinesin receptor, paraplegin and the A kinase
anchor protein (Geschwind et al., 1999). It will be
important to determine whether other families with
autosomal-dominant BSPDC have mutations in the
same locus or whether there are several mutations
leading to the variations in phenotype for this disorder.
56.3.4. Pathophysiology
The pathogenesis of BG calcifications and BSPDC is
unknown. Numerous histochemical studies and
experimental models have been conducted to define
the nature of these calcifications. Several different
patterns of calcification have been shown histologically,
associated with neuronal loss and gliosis in the BG and
dentate (Matsumoto et al., 1998; Tsuchiya et al., 2002).
On gross inspection, chalky yellow mineral deposits
in the dentate and striatum are found, microscopically
corresponding to granular and stippling calcium
deposits within the parenchyma and along capillaries
(Manyam et al., 2001a). Matsumoto et al. (1998) found
intense calcification surrounding veins in the BG and
white matter, with loss of myelin sheaths and axons in
a patient with cerebral lupus. Fujita et al. (2003)
described three histologic patterns of cerebral calcifica-
tion in a variety of neurodegenerative diseases, includ-
ing Alzheimers disease, Pick disease and diffuse
neurofibrillary tangles with calcification (DNTC), a
disorder demonstrating Fahrs-like calcification in
the BG. Type 1 histology involved diffuse deposition
within the tunica media of small and medium-sized
vessels; type 2 consisted of spherical concretions in
the parenchyma; and type 3 included rows of small
calcifications lying along capillaries. This latter,
pericapillary pattern of calcification may reflect the
pattern most commonly seen in BPSDC, given its
reproducibility in multiple histologic studies and its
frequent presence in DNTC (Duckett et al., 1977;
Matsumoto et al., 1998; Manyam et al., 2001a; Fujita
et al., 2003). Other histologic patterns, however, such
as intracellular deposits with minimal neuronal death,
have also been reported (Takashima and Becker,
1985; Mahy et al., 1999).
The molecular composition of cerebral calcifications
consists of hydroxyapatite crystals assembled from
various bone matrix proteins, a structure not unlike
physiologic calcifications found elsewhere in the body
(Smeyers-Verbeke et al., 1975; Fujita et al., 2003).
Detailed chemical analyses of these deposits reveal that
calcium and phosphorus are present in the greatest
proportion, followed by trace quantities of magnesium,
zinc, aluminum and iron (Smeyers-Verbeke et al., 1975;
Duckett et al., 1977). Whether the deposits represent a
primary deposition or dystrophic change from prior
ischemic insult has yet to be determined.
Several proposed mechanisms exist for the formation
of BG calcifications, including altered vessel permeabil-
ity to calcium (Lowenthal, 1986), changes in blood flow
and resulting tissue ischemia (Lowenthal, 1986; Uygur
et al., 1995), synaptic excitotoxicity (Mahy et al.,
1999) or local shifts in calcium concentration, possibly
due to parathyroid hormone-responsive enzymes (Low-
enthal, 1986; Kurup and Kurup, 2002). Uygur et al.
(1995) demonstrated decreased regional blood flow in
the BG and frontal cortices through a brain SPECT
study of a patient with BSPDC. However, it is not
known whether this finding is a result or cause of the
cerebral calcifications. Animal models of excitotoxicity
have suggested a role for glutamate in calcium deposit
formation, using the excitatory amino acid, ibotenic
acid, to induce calcified inclusions in astrocytes in an
in vivo rat brain (Mahy et al., 1999).
 CALCIFICATION OF THE BASAL GANGLIA 485
Table 56.2
Treatment of idiopathic bilateral striopallidodentate calcinosis with dopaminergic medication

Source Number of cases Response Drug received

Klawans et al. (1976) 1 No improvement Levodopa 1

Manyam et al. (2001a) 6 Improvement Levodopa 2
No medication given 3
No improvement Levodopa 1
Berendes and Dorstelmann 1 No improvement Levodopa 1
(1978)
Harati et al. (1984) 3 Mild improvement Amantadine 1
No medication given 2

56.3.5. Treatment of parkinsonism in BSPDC
The parkinsonism of BSPDC has been variable with
respect to response to dopaminergic treatment. Klawans
et al. (1976) described a case of levodopa-resistant par-
kinsonism in association with BG calcifications, treated
unsuccessfully for 30 months with levodopa doses up
to 7 g/day, suggesting a dopaminergic postsynaptic
receptor site dysfunction. Conversely, Manyam et al.
(2001a) reported a levodopa-responsive case of BSPDC
at doses of 1200 mg/day. Characteristic Lewy bodies,
however, were found on autopsy, suggesting that the
patient had levodopa-responsive Parkinsons disease
and BSPDC concurrently (Manyam et al., 2001a). Ver-
mersch et al. (1992) also described levodopa-responsive
BG calcinosis in patients who were already diagnosed
with Parkinsons disease prior to their CT scans. In addi-
tion, these calcifications were mostly unilateral, without
mention of their extent or severity, opening the possibi-
lity that these cases were radiographically distinct from
the BSPDC syndrome. In a review of the literature in
which treatment of BSPDC was reported, 3/6 patients
improved with dopaminergic treatment, 3/6 did not
improve and 5 patients did not receive treatment
(Table 56.2). This number of publications to date is
insufficient to identify a consistent pattern regarding
treatment of BSPDC.
56.4. Summary
Calcification of the BG occurs in many contexts, ran-
ging from incidental findings to disorders of mineral
metabolism and familial forms of cerebral calcinosis.
BSPDC, also known as Fahrs disease, is an idiopathic,
familial form of calcification of the BG presenting as a
combination of parkinsonism, dementia and cerebellar
signs. Although the terminology of BG calcifications
remains controversial, the clinical findings of severe
forms remain predictable within a spectrum of fre-
quently disabling symptoms. The underlying patho-
physiology is not yet well understood. It is possible,
however that clues from genetic evaluation, although
the presentation is varied, may lead to a more detailed
understanding of BSPDC. Additionally, data gleaned
from an ongoing registry of BSPDC patients may be
instrumental to improving our basic knowledge of this
disorder over time.
References
Alexander GE, DeLong MR, Strick PL (1986). Parallel orga-
nization of functionally segregated circuits linking basal
ganglia and cortex. Annu Rev Neurosci 9: 357381.
Bamberger H (1855). Beobachtungen und bemerkungen uber
hirnkrankheiten. Verh Phy Med Ges 6: 325328.
Benke T, Karner E, Seppi K et al. (2004). Subacute dementia
and imaging correlates in a case of Fahrs disease. J Neurol
Neurosurg Psychiatry 75: 11631165.
Berendes K, Dorstelmann D (1978). Unsuccessful treatment
with levodopa of a parkinsonian patient with calcification
of the basal ganglia. J Neurol 218: 5154.
Brannan TS, Burger AA, Chaudhary MY (1980). Bilateral
basal ganglia calcifications visualised on CT scan. J Neurol
Neurosurg Psychiatry 43: 403406.
Cohen CR, Duchesneau PM, Weinstein MA (1980). Calcifi-
cation of the basal ganglia as visualized by computed
tomography. Neuroradiology 134: 9799.
Cummings JL, Gosenfeld LF, Houlihan JP et al. (1983). Neu-
ropsychiatric disturbances associated with idiopathic
calcification of the basal ganglia. Biol Psychiatry 18:
591601.
Delacour A (1850). Ossification des capillaries du cerveau.
Annu Med Psychol 2: 458461.
Duckett S, Galle P, Escourolle R et al. (1977). Presence of
zinc, aluminum, magnesium in striopallidodentate (SPD)
calcifications (Fahrs disease): Electron probe study. Acta
Neuropathol (Berl) 38: 710.
Ellie E, Julien J, Ferrer X (1989). Familial idiopathic strio-
pallidodentate calcifications. Neurology 39: 381385.
486 J. S. HUI AND M. F. LEW
Fahr I (1930). Idiopathipathische verkalking der hirume
fasse. Zbl Allf Path 50: 129133.
Fenelon G, Gray F, Paillard F et al. (1993). A prospective
study of patients with CT detected pallidal calcifications.
J Neurol Neurosurg Psychiatry 56: 622625.
Fujita D, Terada S, Ishizu H et al. (2003). Immunohistologi-
cal examination on intracranial calcification in neurode-
generative diseases. Acta Neuropathol (Berl) 259264.
Geschwind DH, Loginov M, Stern JM (1999). Identificatoin of
a locus on chromosome 14q for idiopathic basal ganglia cal-
cification (Fahr disease). Am J Hum Genet 65: 764772.
Harati Y, Jackson JA, Benjamin E (1984). Adult onset idio-
pathic familial brain calcifications. Arch Intern Med 144:
24252427.
Harrington MG, Macpherson P, McIntosh WB et al.
(1981). The significance of the incidental finding of basal
ganglia calcification on computed tomography. J Neurol
Neurosurg Psychiatry 44: 11681170.
Illum F, Dupont E (1985). Prevalences of CT-detected calcifi-
cation in the basal ganglia in idiopathic hypoparathyroidism
and pseudoparathyroidism. Neuroradiology 27: 3237.
Klawans HL, Lupton M, Simon L (1976). Calcification
of the basal ganglia as a cause of levodopa-resistant
parkinsonism. Neurology 26: 221225.
Klein C, Vieregge P (1998). The confusing history of Fahrs
disease. Neurology 50 (Suppl 4): A59.
Kobari M, Nogawa S, Sugimoto Y et al. (1997). Familial
idiopathic brain calcification with autosomal dominant
inheritance. Neurology 48: 645649.
Koller WC, Cochran JW, Klawans HL (1979). Calcification
of the basal ganglia: Computerized tomography and clini-
cal correlation. Neurology 29: 328333.
Kurup RK, Kurup PA (2002). Hypothalamic digoxin related
membrane Na-K ATPase inhibition and familial basal
ganglia calcification. Neurosci Res 42: 3544.
Lauterbach EC, Spears TE, Prewett MJ et al. (1994). Neu-
ropsychiatric disorders, myoclonus, and dystonia in
calcification of basal ganglia pathways. Biol Psychiatry
35: 345351.
Lopez-Villegas D, Kulisevsky J, Deus J et al. (1996). Neu-
ropsychological alterations in patients with computed
tomography-detected basal ganglia calcification. Arch
Neurol 53: 251256.
Lowenthal A (1986). Striopallidodentate calcifications
(chapter 24). In: PJ Vinken, GW Bruyn, HL Klawans
(Eds.), Handbook of Clinical Neurology, Vol. 5, Elsevier
Science Publishers, New York, pp. 417436.
Mahy N, Prats A, Riveros A et al. (1999). Basal ganglia cal-
cification induced by excitotoxicity: An experimental
model characterised by electron microscopy and X-ray
microanalysis. Acta Neuropathol (Berl) 98: 217225.
Manyam BV (1990). Bilateral strio-pallido-dentate calcino-
sis: A proposed classification of genetic and secondary
causes. Mov Disord 5: 94.
Manyam BV, Bhatt MH, Moore WD et al. (1992). Bilateral
striopallidodentate calcinosis: Cerebropsinal fluid, ima-
ging, and electrophysiological studies. Ann Neurol 31:
379384.
Manyam BV, Walters AS, Keller IA et al. (2001a). Parkin-
sonism associated with autosomal dominant bilateral strio-
pallidodentate calcinosis. Parkinsonism Relat Disord 7:
289295.
Manyam BV, Walters AS, Narla KR (2001b). Bilateral
striopallidodentate calcinosis: Clinical characteristics of
patients seen in a registry. Mov Disord 16: 258264.
Matsumoto R, Shintaku M, Suzuki S et al. (1998). Cere-
bral perivenous calcification in neuropsychiatric lupus
erythematosus: A case report. Neuroradiology 40: 583586.
Moskowitz MA, Winickoff RN, Heinz ER (1971). Familial
calcification of the basal ganglions: A metabolic and
genetic study. N Engl J Med 285: 7277.
Murphy MJ (1979). Clinical correlations of CT scan-detected
calcifications of the basal ganglia. Ann Neurol 6: 507511.
Naderi S, Colakoglu Z, Luleci G (1993). Calcification of
basal ganglia associated with pontine calcification in four
cases: A radiologic and genetic study. Clin Neurol Neuro-
surg 95: 155157.
Ostling S, Andreasson LA, Skoog I (2003). Basal ganglia
calcification and psychotic symptoms in the very old. Int
J Geriatr Psychiatry 18: 983987.
Rosenberg DR, Neylan TC, el-Alwar M et al. (1991). Neu-
ropsychiatric symptoms associated with idiopathic calcifi-
cation of the basal ganglia. J Nerv Ment Dis 179: 4849.
Sachs C, Ericson K, Erasmie U et al. (1979). Incidence of
basal ganglia calcifications on computed tomography.
J Comput Assist Tomogr 3: 339344.
Sachs C, Sjoberg H, Ericson K (1982). Basal ganglia calcifi-
cations on CT: Relation to hypoparathyroidism. Neurology
32: 779782.
Smeyers-Verbeke J, Michotte Y, Pelsmaeckers J et al.
(1975). The chemical composition of idiopathic nonarter-
iosclerotic cerebral calcifications. Neurology 25: 4857.
Smits MG, Gabreels FJM, Thijssen HOM et al.
(1983). Progressive idiopathic strio-pallido-dentate calcino-
sis (Fahrs disease) with autosomal recessive inheritance.
Report of three siblings. Eur Neurol 22: 5864.
Takashima S, Becker L (1985). Basal ganglia calcification in
Downs syndrome. J Neurol Neurosurg Psychiatry 48:
6164.
Tsuchiya K, Nakayama H, Iritani S et al. (2002). Distribution
of basal ganglia lesions in diffuse neurofibrillary tangles
with calcification: A clinicopathological study of five
autopsy cases. Acta Neuropathol (Berl) 103: 555564.
Uygur GA, Liu Y, Hellman RS et al. (1995). Evaluation of
regional cerebral blood flow in massive intracerebral cal-
cifications. J Nucl Med 36: 610612.
Vermersch P, Leys D, Pruvo J et al. (1992). Parkinsons disease
and basal ganglia calcifications: Prevalence and clinico-radi-
ological correlations. Clin Neurol Neurosurg 94: 213217.
Warren JD, Mummery CJ, Al-Din AS et al. (2002). Cortico-
basal degeneration syndrome with basal ganglia calcifi-
cation: Fahrs disease as a corticobasal look-alike? Mov
Disord 17: 563567.
Yoshikawa H, Abe T (2003). Transient parkinsonism in
bilateral striopallidodentate calcinosis. Pediatr Neurol 29:
7577.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 57

Trauma and Parkinsons disease

OSCAR S. GERSHANIK*

Laboratory of Experimental Parkinsonism, ININFA-CONICET, Buenos Aires, Argentina

57.1. Introduction responsible for the development of PD were not only

The relationship between trauma and Parkinsons dis-
ease (PD) and/or parkinsonism can be approached
from different perspectives. We may focus, from an
epidemiological perspective, on the existence of pre-
ceding trauma, to either the head or other body parts,
as a risk factor for the subsequent development of
PD; on the other hand, trauma may be the cause of
secondary parkinsonism through different mec-
hanisms; or we may look at the effects of trauma on
pre-existing PD. All these approaches have been
extensively dealt with in the literature and we will
try to review them as comprehensively as possible to
bring the reader an updated discussion on the subject
(for reviews, see: Factor et al., 1988; Koller et al.,
1989; Stern, 1991; Jankovic, 1994; Lees, 1997; Krauss
and Jankovic, 2002).
Trauma has long been held suspect as one of the
contributing factors to the development of PD. Some
of the earliest references in this regard date back to
James Parkinson himself, who speculated, as he had
no solid evidence to substantiate it, that the disease
might be the consequence of a direct injury to the
brainstem or the dural sheath surrounding it. He rea-
soned that, given the range of mobility that the upper
segment of the spine had, this would make this region
more susceptible to trauma (Parkinson, 1817). In their
comprehensive historical review on the concept of
trauma as an etiology of parkinsonism, Factor and col-
laborators (1988) thoroughly discuss not only the pre-
vailing medical theories surrounding this issue in the
19th and early 20th century, but the socioeconomic
factors that may have fueled them, among them the
passing of the first workmens compensation legisla-
tion. Of interest is the fact that traumatic factors held
those sustained in the head, but different kinds of per-
ipheral trauma (cuts, bruises, skin punctures, burns,
usually in the subsequently affected limb or body part).
Exposure to a damp environment and emotional trauma
were also believed to be capable of inducing parkin-
sonism. Charcot (cited by Factor et al., 1988) advanced
the ascending neuritis hypothesis to explain the rela-
tionship between peripheral trauma and PD. According
to this hypothesis, a peripheral injury would induce an
ascending inflammatory reaction along the nerves that
eventually reached the central nervous system. In the
first part of the 20th century, several French authors
reported the development of parkinsonism as a conse-
quence of concussion associated with mesencephalic
lesions in soldiers involved in World War I. Later on,
in 1928, postmortem analysis of the brain of a patient
who developed parkinsonism after sustaining a bullet
injury to the head, showing hemorrhagic lesions at
the basal ganglia level, gave credence for the first time
to the existence of true cases of posttraumatic parkin-
sonism (Factor et al., 1988). Almost contemporary with
this observation was the report by Patrick and Levy
(1922) claiming that, in 15% of the cases of PD they
had followed and studied, trauma was a contributing
factor to its development. It was not until 1934, when
Grimberg published his thorough analysis on paralysis
agitans and trauma, that objective criticism of the
hypothesis of trauma-induced parkinsonism was raised.
Grimberg dismissed 84 out of 86 cases reported since
1873 onwards as not being related to trauma based
on a number of factors (misdiagnosis, no definite
history of trauma, pre-existing parkinsonian symptoma-
tology antedating the causative trauma, unclear tem-
poral relationship between the occurrence of the
trauma and the onset of parkinsonism, lack of a clear

*Professor Oscar S. Gershanik, Department of Neurology, Centro Neurologico-Hospital Frances, Director, Laboratory of
Experimental Parkinsonism, ININFA-CONICET, La Rioja 951 (1221) Buenos Aires, Argentina. E-mail: gersha@gmail.com
488 O. S. GERSHANIK
pathophysiological mechanism to explain such an asso-
ciation) (Grimberg, 1934). His review, together with the
one published more recently in this same Handbook by
Schwab and England in 1968, concluded that it was
only in cases severe enough to cause traumatic injury
to the midbrain, subsequently ascertained by the post-
mortem finding of hemorrhage in that same region, that
one could establish a causal relationship between
trauma and the development of parkinsonism (Schwab
and England, 1968). These conclusions are only applic-
able to the diagnosis of posttraumatic parkinsonism. A
different conceptual framework has to be applied to
the still controversial issue of trauma as a risk factor
for the development of PD.
57.2. Trauma as a risk factor for the
development of Parkinsons disease
Current theories on the etiology and pathogenesis
of PD consider this disorder to be multifactorial and
the result of a combination of a genetic predisposi-
tion possibly interacting with environmental factors.
That genes play a role in the etiology of PD is sup-
ported at present by the discovery of at least 11 forms
of genetic parkinsonism that share clinical features
and possibly pathogenetic mechanisms with the more
common, as yet sporadic, form of the disease (Corti
et al., 2005; OMIM Database, 2005). The quest for
environmental exogenous triggering factors has
remained elusive and only supported through indirect
evidences gathered from numerous and extensive epide-
miological studies. Age, sex, dietary habits, infections,
environmental toxins and trauma are among the factors
considered by these studies (Lai et al., 2002; Allam
et al., 2003).
Although a number of epidemiological studies
addressing this question find a positive association
between past history of trauma and later development
of PD, a larger number dispute these findings.
Table 57.1 lists the majority of published epidemiolo-
gical studies that have looked at the issue of trauma as
a risk factor for PD. Fourteen out of 19 case-control
studies originating in different parts of the world,
involving more than 1500 patients and over 2000 con-
trols, failed to find a positive association between pre-
existing trauma and PD (for references, see
Table 57.1). In addition, two very important cohort
studies, the Rotterdam and the Olmsted county/Mayo
Clinic studies, were also unable to establish a link
between the development of PD and past history of
head trauma (Williams et al., 1991; De Rijk et al.,
1996). These studies included patients with reported
head trauma of enough severity to cause loss of
consciousness or amnesia, residual neurologic deficits
and skull fracture that were subsequently followed
for a prolonged period of time. Morbidity ratios were
not elevated for PD or other neurodegenerative disor-
ders such as Alzheimers and motor neurone diseases
(Williams et al., 1991; De Rijk et al., 1996).
In only seven case-control studies, five of them car-
ried out in North America (USA and Canada), one in
the UK and one in Taiwan, was a positive association
found.
In the London study, Godwin-Austen and colla-
borators (1982) interviewed 350 patients and controls,
trying to establish the relationship between smoking
and PD and its association with several risk factors.
They found that PD patients were more likely to have
had head injury associated with loss of consciousness
than controls. Unfortunately, as this was not the pri-
mary interest of this study, no numbers are given and
the level of significance of this finding is not provided.
Factor and Weiner (1991) interviewed 97 patients
and 64 controls (spouses) seen consecutively in an
outpatient clinic. In 32% of PD patients and 17% of
controls there was a prior history of head trauma of
any degree of severity (P < 0.05); when head trauma
with alteration of consciousness was considered, the
association was maintained at the same level of signif-
icance (20.6% of patients and 8% of controls).
In the study by Stern et al. (1991), a detailed ana-
lysis of various environmental exposures and early
life experiences was conducted in 80 patients with
old-onset PD (age older than 60), 69 young-onset
patients (age younger than 40: young-onset Parkin-
sons disease (YOPD)) and 149 age- and sex-matched
controls. They found that at least one episode of
trauma severe enough to cause vertigo, dizziness,
blurred or double vision, seizures or convulsions, tran-
sient memory loss, personality changes or paralysis
occurred more frequently in both old and young-
onset patients prior to disease onset than in controls.
This difference was found to be significant (odds ratio
2.7; P < 0.05).
The study by Semchuk et al. (1993) was carried
out in Calgary, Canada, and included 130 patients
with neurologist-confirmed idiopathic parkinsonism
and 2 matched controls adjusted by age and sex
obtained randomly from the same community
(random-digit dialing). They used a multivariate con-
ditional logistic regression analysis method in which
they controlled for any potential confounding or
interaction between the different exposure variables
considered. In four of the eight logistic regression
models used, having a history of head trauma was
significantly associated with the risk of developing
PD (P < 0.001), second only to the existence of a
positive family history.
 TRAUMA AND PARKINSONS DISEASE 489
Table 57.1
Trauma and Parkinsons disease: epidemiological studies

Number of
Author Year patients/controls Type of study Association Location

Nuti et al. 2004 190/190 Case-control No Tuscany, Italy

Bower et al. 2003 196/196 Case-control Yes Minnesota, USA
P < 0.02
Tsai et al. 2002 30 YOPD/30 Case-control Yes Taiwan, China
60 LOPD P < 0.002
Preux et al. 2000 140/280 Case-control No France
Taylor et al. 1999 140/147 Case-control Yes Boston, USA
P < 0.0001
Werneck and Alvarenga 1999 92/110 Case-control No Rio de Janeiro, Brazil
Kuopio et al. 1999 123/246 Case-control No Turku, Finland
Smargiassi et al. 1998 86/86 Case-control No Emilia Romagna, Italy
McCann et al. 1998 224/310 Case-control No Queensland and NSW,
Australia
De Michele et al. 1996 116/232 Case-control No Campania/Molise, Italy
Seidler et al. 1996 380/379 Case-control No Germany
De Rijk et al. 1996 Rotterdam cohort Cohort No The Netherlands
Yang et al. 1994 90/90 Case-control No China
Morano et al. 1994 74/148 Case-control No Caceres, Spain
Semchuk et al. 1993 130/260 Case-control Yes Calgary, Canada
P < 0.001
Butterfield et al. 1993 63/68 Case-control No Oregon, USA
Stern et al. 1991 149/149 Case-control Yes USA/Canada
P < 0.05
Factor and Weiner 1991 97/64 Case-control Yes Miami/Albany, USA
P < 0.05
Williams et al. 1991 Olmsted county Cohort No Minnesota, USA
cohort (821)
Hofman et al. 1989 86/172 Case-control No The Netherlands
Tanner et al. 1987 100/200 Case-control No China
Ward et al. 1983 65/65 Case-control No USA/Canada/UK
Godwin-Austen et al. 1982 350/350 Case-control Yes London, UK
More likely

YOPD, young-onset Parkinsons disease; LOPD, late-onset Parkinsons disease.

Taylor et al. (1999) recruited 140 PD (examined and
followed by neurologists and movement disorders spe-
cialists) cases from the Boston University Medical Cen-
ter, USA. Controls were in-laws or friends of the
patients (n 147). For this study a positive history of
head trauma was considered when it was severe enough
to cause loss of consciousness, blurred or double vision,
dizziness, seizures or memory loss, rather than mere
bruising, bleeding or stitches. Twenty-five percent of
the cases versus 7.5% of the controls had a history of
head trauma according to this study. This difference
was found to be highly significant (P < 0.0001).
The most recent studies finding a positive associa-
tion between head trauma and PD are those of Tsai
et al. (2002) and Bower et al. (2003), carried out in
Taiwan and Minnesota respectively. In Tsais study
YOPD cases were compared to late-onset cases and
controls. They included 30 cases with age of onset
before 40, 30 young controls and 60 late-onset cases.
All participants in the study were administered a struc-
tured questionnaire in which all the potential risk factors
under analysis were included. In the case of self-
reported head injuries the information was verified
against medical records to ascertain its validity. A multi-
ple logistic regression analysis was used to examine the
significance of all risk factors simultaneously. When
compared with late-onset PD patients, YOPD had a sub-
stantially higher percentage of head injuries (37% versus
490 O. S. GERSHANIK
10%; P < 0.002). Although the difference in the
percentage having head injury was not statistically
significant between YOPD and controls, the proportion
of those having such an experience in the patient group
was more than doubled (37% versus 17%). It is indeed
interesting to note that this study found head trauma to
be a risk factor only for YOPD and not for PD in
general. The study by Bower et al. (2003) has several
distinguishing features that differentiate it from other
case-control studies. They conducted a population-based
case-control study of incident PD cases and population
controls nested within the Olmsted county cohort. The
three key features of their study were the population-
based nature, the nesting within a records linkage system
and the use of information about head trauma that was
recorded historically before the onset of PD. They
included 196 case-control pairs matched for age and
sex. Because of the peculiar design of this study I
believe it is interesting to analyze the results in more
detail than in the previous studies. There were 13 head
trauma events in the PD cases versus only 3 in the con-
trols, this difference being statistically significant (P <
0.02). This association, however, was only restricted to
the more severe cases. There was no difference in the
frequency of mild head trauma with amnesia as the resi-
dual symptom between cases and controls. However, the
frequency of mild head trauma with loss of conscious-
ness combined with moderate or severe trauma was sig-
nificantly higher in cases (5.6%) than in controls (0.5%).
Using the frequency of head trauma among controls esti-
mated in their study (1.5%), the authors computed a
population-attributable risk for head trauma in PD of
5%. In men, head trauma was significantly more fre-
quent in cases (9.9%) than in controls (1.7%). In
women, the frequency of head trauma was the same in
cases and controls (1.3%); however, the numbers were
small (one event each). When they stratified cases by
median age at onset of PD, the analysis showed no sig-
nificant difference between cases and controls for
patients with earlier age at onset. However, there was
a significantly higher frequency of head trauma in cases
(6.4%) than controls (0.0%) for patients with later onset
(P < 0.02) (Bower et al., 2003). These findings are in
absolute contrast to those of Tsai et al. (2002) and no
reasonable explanation can be advanced to account for
these differences.
All of these studies were published after the intro-
duction of levodopa, thus including levodopa-respon-
siveness as one of the diagnostic criteria, and the
majority of them were conducted using very strict
methodological approaches. It is therefore difficult
to interpret these apparently conflicting findings. Sev-
eral explanations can be offered to account for these
differences. Methodological differences among the
different studies, both in regard to case ascertainment
and data evaluation, including definition of head injury
or trauma, may be the cause of this discrepancy. All
case-control studies are retrospective and in those
reporting an association between head injury and PD,
the average interval between the reported trauma and
the onset of the disease was 33.3 years. After so many
years it is possible that recall bias may influence
the outcome of these studies. Patients with chronic
diseases are more likely than healthy individuals
to recall any significant event in their lives that may
offer an explanation for their present predicament.
They are always looking for possible connections
between life experiences and disease onset, as indivi-
duals carrying a chronic disease often feel unfairly
dealt with by life.
Unfortunately these arguments do not necessarily
hold up to thorough scrutiny. In Factors study (Factor
and Weiner, 1991) the association was still significant
whether they considered any type of trauma or severe
enough trauma to cause alteration of consciousness,
suggesting that differences in definition of head injury
may not be the cause of the discrepancy. If recall bias
was the confounding factor, older patients would have
reported more episodes of head trauma than patients
30 years their younger, which was not the case in the
study by Stern et al. (1991), comparing young-onset
with old-onset cases. In their study there was no differ-
ence in the prevalence of head trauma prior to disease
onset between the two groups. We are therefore left
with an unresolved dilemma, as no single retrospective
study is free of methodological flaws or limitations in
its ability to detect significant differences between the
populations under study.
It is worth noting that, even in those studies in
which there were no statistically significant differ-
ences between cases and controls in regard to preva-
lence of head trauma, the PD group always had a
higher frequency of reported head injuries than the
controls. However, not even in those studies finding
a positive association was head trauma the sole predic-
tor, as it was usually associated with family history
and exposure to other environmental factors (well-
water drinking, pesticide use, etc.) (Semchuk et al.,
1993; Taylor et al., 1999).
Head trauma might therefore be one of several risk
factors acting in combination in a predisposed indivi-
dual that precipitate the cascade of events leading to
the development of PD. Head trauma may increase the
risk of PD only in those individuals who carry a specific
polymorphism of a susceptibility gene. This hypothesis
refers to a model of geneenvironment interaction that
has also been proposed for Alzheimers disease (Bower
et al., 2003).
 TRAUMA AND PARKINSONS DISEASE
In a few of the publications reporting a positive
association between head trauma and an increased risk
of developing PD there have been attempts at finding
the factors underlying this association. Three major
hypotheses have been put forward (Factor and Weiner,
1991; Bower et al., 2003), as described below.
First, an isolated episode of head trauma could lower
the number of nigral cells, on top of which the normal
decline of dopaminergic neurons occurring with age
would be superimposed. This concept, also designated
as the single-hit hypothesis originally proposed by
Calne and Langston (1983), has been abandoned for sev-
eral reasons, the most important being the difference
between the regional pattern of neuronal loss in PD com-
pared to normal aging (Fearnley and Lees, 1991). More-
over, studies using fluorodopa positron emission
tomography (PET) suggest that the rate of decline in
striatal uptake is more rapid in PD than in normal aging
(Morrish et al., 1998).
Second, it has been proposed that head injury could
somehow cause a disruption of the bloodbrain barrier,
thus allowing exogenous neurotoxins to enter the central
nervous system and trigger the cascade of nigral degen-
eration (Graves et al., 1990). The finding of polymorpho-
nuclear leukocyte infiltration of the brain tissue
following a head trauma, on the other hand, may be an
indication of immune-mediated changes leading to neu-
rodegeneration (Bower et al., 2003). Both mechanisms
may be secondary to trauma-induced disruption of the
bloodbrain barrier and could eventually cause a delayed
neurodegenerative process.
Finally, it has been proposed that head trauma may
trigger an acute-phase response, causing the overex-
pression of one or several proteins that would eventually
lead to cytoplasmic protein aggregation and cell death.
This is in line with current theories suggesting that PD
is the result of a complex disorder of the ubiquitin-pro-
teasome system involved in protein degradation. By
analogy, there is some evidence that the synthesis of
apolipoprotein E, of -amyloid precursor protein or
both increases markedly in the brain after head injury,
leading to the trauma-related hypothesis of Alzheimers
disease (Bower et al., 2003).
At the cellular and molecular level, the mechanisms
underlying secondary or delayed cell death following
traumatic brain injury (TBI) are poorly understood.
Experimental models of TBI suggest that diffuse and
widespread neuronal damage and loss are progressive
and prolonged for months to years after the initial
insult in selectively vulnerable regions of the cortex,
hippocampus, thalamus, striatum and subcortical
nuclei (McIntosh et al., 1998). The cellular and mole-
cular events triggered by TBI include possible altera-
tions in intracellular calcium with resulting changes
491
in gene expression, activation of reactive oxygen spe-
cies, activation of intracellular proteases (calpains),
expression of neurotrophic factors and activation of
cell death genes (apoptosis) (McIntosh et al., 1998;
Bramlett and Dietrich, 2003). In addition, elevation
of proinflammatory cytokines has also been demon-
strated in animal models of brain trauma which could
further exacerbate the neuronal damage initially
induced by the head injury (Liu et al., 2003). All these
factors may play a role in mediating delayed cell death
after trauma. TBI, according to some, should be con-
sidered as both an inflammatory and/or a neurodegen-
erative disease. A research report by Uryu et al. (2003)
has linked TBI to age-dependent synuclein (Syn)
pathology in mice. Of interest is the fact that both
genetically induced and sporadic PD have been linked
to Syn deposition and pathology. Therefore any
mechanism leading to modifications in the expression
of Syn and/or its pathological deposition could be rele-
vant to the understanding of the pathogenesis of PD.
In Uryus paper, at 1 week post-TBI, the aged mouse
brain showed a transient increase of a- and b-Syn
immunoreactivity (IR) in the neuropil as well as an
induction of g-Syn IR in subcortical axons. This was
associated with strong labeling of striatal axon bundles
by antibodies to altered or nitrated epitopes in a-Syn
as well as by antibodies to inducible nitric oxide
synthase. The latter findings are highly suggestive, as
it is well known that nitration of a-Syn is a common fea-
ture of pathological forms of this protein in the Lewy
bodies of diverse synucleinopathies (Uryu et al., 2003).
57.3. Posttraumatic parkinsonism
In addition to considering trauma to the head as an epi-
demiological risk factor in the etiology of PD, both cen-
tral lesions directly affecting the nigrostriatal tract and
those indirectly caused by severe cranial trauma and
peripheral trauma have been linked to the development
of parkinsonism.
57.3.1. Central lesions and parkinsonism
Single trauma to the head, as well as repetitive TBI
such as that seen in boxers, can be the cause of second-
ary forms of parkinsonism.
57.3.1.1. Parkinsonism caused by a single trauma
to the head
Parkinsonism is an infrequent complication of a single
trauma to the head, although rare instances of this syn-
drome caused by penetrating injuries to the brainstem
by either a bullet or a knife have been reported (Koller
492 O. S. GERSHANIK
et al., 1989). The majority of authors conclude that the
development of a parkinsonian syndrome after trauma
to the head is more often seen in cases in which the
injury is severe enough to result in a comatose or
vegetative state; in these cases, the resulting parkinso-
nian syndrome is usually associated with mental status
changes, cranial nerve dysfunction, pyramidal tract
dysfunction and cerebellar disorders (Factor et al.,
1988; Jellinger, 2003). In Grimbergs seminal review
of 86 cases of posttraumatic parkinsonism reported
between 1873 and 1922, he concluded that only 2 of
the cases could be accepted as posttraumatic in nature
as the trauma was severe enough to produce perma-
nent damage to specific areas of the brain; the trauma
directly involved the head; and there was an unequivo-
cal temporal relationship between the head injury and
the development of parkinsonism (Grimberg, 1934;
Jankovic, 1994). Nevertheless, even in survivors of
severe head injury, the occurrence of parkinsonism is
rare, as was the case in the large series reported by
Krauss and Jankovic (2002). In a follow-up of 221
out of 264 survivors of severe head injury who had
been admitted to hospital with a Glasgow Coma Score
of 8 or less, only 2 cases of parkinsonism were
observed (0.9%). Similarly, in Jellingers (1989) per-
sonal series of 520 autopsy cases of parkinsonism
there were only 3 cases (0.6%) in which parkinsonism
had developed after severe head injury with or without
persistent vegetative state (PVS) and was associated
with multiple brainstem damage resulting from trans-
tentorial herniation; all of those brains had bilateral
vascular necrotic lesions or anoxic scars in substantia
nigra and other parts of the brainstem or basal ganglia.
More recently, the same author (Jellinger, 2003) in a
letter to the editor of the Journal of Neurology, Neuro-
surgery and Psychiatry, commented on his observa-
tions made in a series of 125 patients with PVS
following head injury and survival times ranging from
1 to 10 years. There were 49 survivors and, in 19 of
them, a mainly symmetrical, moderate to severe,
parkinsonian syndrome was present. Treatment with
levodopa induced partial or full improvement of symp-
tomatology in 15, whereas 4 patients showed complete
recovery from both PVS and parkinsonism. An addi-
tional 15 patients, upon recovery from the initial
PVS, developed a progressive parkinsonian syndrome
in which rigidity and bradykinesia were present in all
cases, whereas in only 6 of them was it associated with
unilateral or bilateral resting tremor. Thirty-four of
the cases underwent magnetic resonance imaging
(MRI) examination; in 32 of them, unilateral or bilat-
eral lesions in the midbrain were present. Of the origi-
nal series, 32 cases survived for at least 2 months
without significant improvement of PVS until death;
neuropathological examination performed in 16 cases
presenting with mild to severe parkinsonian features
revealed multiple lesions in the rostral brainstem with
unilateral or bilateral focal lesions in the substantia
nigra. Of importance is the fact that it was not possible
to establish a clear correlation between the severity of
the pathology and the severity of the parkinsonian symp-
tomatology. Moreover, there have been reports of signif-
icant pathological involvement of the substantia nigra
following head injury without the development of a par-
kinsonian syndrome (Zijlmans et al., 2002; Jellinger,
2003). In the case reported by Zijlmans et al. (2002), con-
firmation of nigrostriatal damage was obtained through
both MRI and dopamine transporter binding at the striatal
level. Imaging studies showed in the T2-weighted
sequence the presence of a hypointense lesion involving
the right anteromedial substantia nigra and the right sub-
thalamic nucleus indicative of a previous hemorrhage.
N-omega-flouropropyl-2beta-carboxymethoxy-3beta-
{4-iodophenyl} tropane single-photon emission com-
puted tomography ([123I]FP-CIT SPECT) binding was
completely abolished in the right striatum and caudate
nucleus, demonstrating an almost total loss of presynap-
tic dopamine terminals. The absence of parkinsonian
symptomatology could be explained, according to the
authors, by the concomitant involvement of the ipsilat-
eral subthalamic nucleus (Zijlmans et al., 2002).
Since Grimbergs review and in addition to Krauss
and Jellingers reports, there have been numerous pub-
lications documenting isolated cases or small series of
patients presenting with parkinsonian features after
sustaining head injuries causing varying degrees of
brain dysfunction. Aside from a few cases due to direct
trauma to the midbrain (knife or bullet injury) or a
blunt head injury causing lesions at the basal ganglia
level (Nayernouri, 1985; Giroud et al., 1988; Koller
et al., 1989; Rondot et al., 1994; Doder et al., 1999;
Bhatt et al., 2000; Matsuda et al., 2003; Kivi et al.,
2005) (Table 57.2), the majority of the remaining
cases are related to chronic subdural hematomas
(CSH), indirectly causing involvement of subcortical
structures. In a review of the literature, Wiest et al.
(1999) were able to identify 16 published cases of par-
kinsonism secondary to CSH, in addition to their own
case; 7 additional patients were indirectly cited by the
author as reported in two of his referenced papers. The
association between CHS and movement disorders is
not frequent and has been estimated to occur in about
2% of patients. The majority of the patients reported
were male, with an age range of 3883 years, and
presented within days to weeks after a trivial head
injury with variable clinical symptomatology (focal
deficit, general deterioration with headache, nausea,
loss of sphincter control) associated to a parkinsonian
 TRAUMA AND PARKINSONS DISEASE 493
Table 57.2
Posttraumatic parkinsonism

Author Year No. of cases Mechanism of head injury Associated features

Bruetsch et al. 1935 1 A 60-year-old man fell on a concrete surface, None mentioned
striking the occiput. Parkinsonian features
developed 8 months later. On autopsy, there
were fracture of the occipital and petrous
bones; depigmentation of the nigra, petechial
hemorrhages in the striatum (cited by Koller
et al., 1989)
Morsier GDz 1960 1 Bullet injury to the substantia nigra None mentioned
(cited by Koller et al., 1989)
Nayernouri 1985 1 A 37-year-old man received a blunt head injury Coma
causing coma. After 10 days the patient
regained consciousness and developed an
akinetic-rigid syndrome. A CT scan revealed
bilateral low-density lesions of the substantia
nigra
Giroud et al. 1988 1 A 61-year-old man sustained a facial Coma
concussion and became comatose. After
recovery he developed bilateral tremor at
rest, rigidity and bradykinesia. A CT scan
performed 6 hours after the trauma revealed
bilateral striatal hematomas
Rondot et al. 1994 1 A 38-year-old man attempted suicide with a Coma and right
firearm. The bullet lodged in the left hemiplegia, residual
midbrain. He recovered from coma over 15 hemiparesis with
days, developing resting and postural tremor spasticity, brisk tendon
associated with akinesia. A fluorodopa PET reflexes, Babinski sign,
scan showed reduced uptake in the left hemidystonia
striatum
Doder et al. 1999 1 A 36-year-old man sustained a skull fracture in Abulia, forgetfulness
a road accident; he remained unconscious for
24 hours. Six weeks later he developed a
coarse resting tremor and bradykinesia on the
right side. MRI showed a lesion involving
the left caudate and lenticular nucleus
Bhatt et al. 2000 3 Three males aged 35, 39 and 46, all involved in Coma
traffic accidents. Loss of consciousness with Right hemiparesis in one;
recovery after a variable period (hours30 disorientation, right-
days). Between 20 days and 5 months they sided weakness and
developed an asymmetric akinetic-rigid slurred incoherent
syndrome with rest tremor. There was speech in another
clinical improvement with levodopa. In all
there was variable, asymmetrical,
hemorrhagic involvement of the substantia
nigra and/or putamen (MRI)
Matsuda et al. 2003 3 Three males aged 14, 27 and 51, all involved in Coma
traffic accidents. All comatose on admission. Spasticity and cognitive
Patients remained in a persistent vegetative deterioration in one, left
state for 312 months. In all 3 cases there hemiparesis and oculo-
were asymmetrical rigidity, akinesia or motor palsy in another,
tremor, with asymmetrical brainstem injury non-parkinsonian motor
on MRI examination. Levodopa improved involvement and
both the motor and cognitive status of the cognitive deterioration
patients in another

(Continued)
494 O. S. GERSHANIK

Table 57.2
(Continued)

Author Year No. of cases Mechanism of head injury Associated features

Kivi et al. 2005 1 In a pedestrian accident a 59-year-old woman Hemiparesis, hyperreflexia

sustained a severe head injury with a and Babinskis sign
predominantly left brachiofacial hemiparesis.
Several weeks after the trauma, clinical signs
of a left-side hemiparkinsonism developed
(resting tremor, hypophonia, hypomimia).
Axial MRI (FLAIR) of the midbrain of the
patient showed a hypointense lesion of the
anterior part of the red nucleus and posterior
part of the substantia nigra, indicating a
hemosiderin deposit due to a previous
hematoma

CT, computed tomography; PET, positron emission tomography; MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion
recovery.

syndrome (in two-thirds of cases a complete parkinso-
nian syndrome was present). In a few cases, aside from
mild headache, the only symptomatology present was
pure parkinsonism. Surgical evacuation of the hemato-
mas resulted in complete remission of the symptoma-
tology in the majority of cases. In a few cases there
was residual symptomatology (both parkinsonian and
non-parkinsonian) after surgery. Incomplete remission
was more frequently observed in bilateral hematomas.
Several mechanisms have been proposed to explain
the development of secondary parkinsonism to CSH:
among them, direct mechanical compression of the
basal ganglia, interference with its vascular supply or
metabolic changes. Hemispheric displacement due to
the hematoma may lead to distortion and compression
of the midbrain, causing potentially reversible distur-
bances at different levels of the nigrostriatal pathway.
However, most patients with a subdural hematoma of
similar location do not develop parkinsonism, suggest-
ing, in the view of some authors, that those patients
who in fact develop a parkinsonian syndrome are espe-
cially vulnerable to injury to the dopaminergic system
or are already in the preclinical stages of PD (Trosch
and Ransom, 1990; Hageman and Horstink, 1994;
Wiest et al., 1999).
In the majority of cases of posttraumatic parkinson-
ism reported in the literature, the parkinsonian sympto-
matology did not develop immediately after the
trauma. A delay of several days, weeks or even months
is usually the case, sometimes making it difficult to
establish a clear-cut cause-and-effect relationship
between the traumatic event and the development of
parkinsonism, except in those cases in whom damage
to the nigrostriatal tract can be demonstrated, either
through imaging techniques or at autopsy. The reasons
for this delay can be diverse; the initial brain injury
caused by the trauma can set in motion a cascade of
biochemical and metabolic changes that may lead to
further neuronal damage; or in turn, the delay may
be necessary for the development of sprouting, rem-
yelinization, ephaptic transmission or central synaptic
reorganization (Jankovic, 1994).
57.3.1.2. Parkinsonism caused by repetitive trauma
to the head (boxers encephalopathy)
A peculiar syndrome secondary to chronic TBI asso-
ciated with boxing occurs in approximately 1820% of
professional boxers (Friedman, 1989). It was Martland
who in 1928 first described this syndrome in the medical
literature, followed by numerous reports that helped
delineate the syndrome, including the presence of parkin-
sonian symptomatology ((Critchley, 1957; Roberts,
1969), cited by Factor et al., 1988; Stern, 1991). It is
usually referred to in the literature as boxers encephalo-
pathy, punch-drunk syndrome or dementia pugilis-
tica, and includes parkinsonian features and varying
degrees of cognitive and behavioral impairments in its
clinical presentation (Jordan, 2000). It has been reported
to be more common in second-rate and slugging-type
fighters (Guterman and Smith, 1987). Incidence and
severity correlate with the length of the boxing career,
number of bouts and increased sparring (Guterman and
Smith, 1987; Jordan, 2000; Krauss and Jankovic, 2002).
The parkinsonian features of this syndrome include gait
 TRAUMA AND PARKINSONS DISEASE
disequilibrium, cogwheel rigidity, bradykinesia, hypo-
phonia and even a resting tremor; other neurologic man-
ifestations frequently present are: dementia, cerebellar
dysfunction, marked dysarthria and pyramidal tract signs
(Stern, 1991; Krauss and Jankovic, 2002). Neurological
symptoms usually become manifest long after the end
of the boxing career, on average 16 years after the last
fight (Jankovic, 1994). The encephalopathy may run a
progressive course or remain stable at any level. Three
stages of clinical deterioration have been described, con-
sisting initially of affective disturbances and additional
psychiatric symptoms; later on there is worsening of the
psychiatric manifestations and parkinsonism gradually
develops. Finally in the last stage there is significant
decrease of cognitive function together with signs of
more extensive neurological involvement (cerebellar
and pyramidal) (Guterman and Smith, 1987).
The neuropathology of boxers encephalopathy was
classically described by Corsellis et al. (1973) in a
postmortem study of 15 boxers. In addition to pete-
chial hemorrhages in the cortex and brainstem and
gliosis of the cerebellum, he found marked loss of pig-
mented neurons in the substantia nigra, especially in
the lateral and intermediate cell groups, without Lewy
bodies. Numerous neurofibrillary tangles without
senile plaques were present in the cerebral cortex. Cor-
sellis cases were more recently re-examined using
immunocytochemical methods and an antibody raised
to the beta-protein present in Alzheimers disease pla-
ques. In all cases with substantial tangle formation
there was evidence of extensive beta-protein immunor-
eactive deposits (plaques). These diffuse plaques
were not visible with Congo red or standard silver
stains, which may explain Corsellis failure to detect
the presence of senile plaques. The degree of beta-pro-
tein (amyloid component) deposition was comparable
to that seen in Alzheimers disease (Roberts et al.,
1990). These data suggest that Alzheimers disease
and boxers encephalopathy may share common
pathogenetic mechanisms and perhaps its development
is linked to the presence of a genetic predisposition
(Stern, 1991; Jankovic, 1994; Jordan, 2000; Krauss
and Jankovic, 2002). Recent studies in professional
boxers, establishing a correlation between the presence
of the e4 allele and significantly greater scores on a
scale measuring chronic encephalopathy, lend support
to this hypothesis (Jordan et al., 1997). The observed
neuropathology of this syndrome is presumed to be
the result of the cumulative effects of repeated subcli-
nical concussions secondary to rotational and shearing
acceleration forces induced by direct blows to the head
(Krauss and Jankovic, 2002). The rapid rotation of
the cranium in relation to a relatively stationary brain
495
may cause stretching and rupturing of vessels, focal
ischemia, petechial hemorrhages, axonal injury and
edema. It is possible that the long axons of the nigrostria-
tal tract are particularly vulnerable to the effects of
mechanical shearing produced by trauma to the head
(Jankovic, 1994). Several in vivo studies have explored
the functional consequences of these lesions; proton
magnetic resonance spectroscopy studies have demon-
strated a significant reduction in the concentration of
N-acetylaspartate in the striatum of patients with
boxers encephalopathy, suggesting the existence of
terminal field involvement and striatal neuronal loss
in addition to nigral damage (Davie et al., 1995).
PET may help in differentiating these cases from
idiopathic parkinsonism, as in patients with boxers
encephalopathy mean caudate and putamen [18F]dopa
uptake is similarly reduced by approximately 40%
when compared to controls and mean caudate uptake
is much lower than that observed in idiopathic parkin-
sonism, suggesting that in boxers encephalopathy
there is a uniform loss of nigrostriatal terminal
function (Turjanski et al., 1997).
57.3.2. Peripheral lesions and parkinsonism
The role of peripheral trauma in the development of
secondary parkinsonism is still an unresolved issue
and evidence supporting this relationship is scarce
and inconclusive (Factor et al., 1988; Koller et al.,
1989). In Factor et al.s (1988) review of the historical
concept of trauma as etiology of parkinsonism, most of
the cases of peripherally induced parkinsonism
reported in the late 19th and early 20th centuries could
be dismissed as not related for lack of conclusive
evidence and probably stimulated by the passing of
workmens compensation laws. Even Charcots
ascending neuritis hypothesis of the mechanism
by which peripheral trauma could lead to the develop-
ment of parkinsonism, although convenient, does
not resist a thorough analysis (Factor et al., 1988).
Nevertheless, more recently, Schott (1986), Jankovic
(1994) and Cardoso and Jankovic (1995) contributed
to the re-emergence of the hypothesis that peripheral
trauma could somehow contribute to the etiology of
parkinsonism.
In Schotts review (1986) of 10 patients in whom
various involuntary movement disorders developed
after trauma that was predominantly or entirely periph-
eral, 3 of the cases corresponded to parkinsonism. The
interval between injury and onset of parkinsonian
symptomatology ranged from 48 hours to 4 weeks;
the injured and painful part was the area initially
affected by involuntary movements, although more
496 O. S. GERSHANIK
widespread involvement subsequently occurred. These
clinical features, which resembled the phenomena
experienced by some patients with causalgia, led the
author to believe in the possibility of common
mechanisms.
Cardoso and Jankovic (1995), in reviewing the
records of patients evaluated in the Movement Disor-
ders Clinic at Baylor College of Medicine, Houston,
TX, USA between 1977 and 1993, found 28 patients
in whom the onset of tremor, parkinsonism or both
was antatomically and temporally related to local
injury. Eleven of these patients had parkinsonian fea-
tures in addition to tremor (both postural and resting);
in a few cases, dystonia, myoclonus and a complex
regional pain syndrome were also present. In all cases
the development of parkinsonian symptoms was tem-
porally related to the occurrence of trauma (latency
to onset 46.6
56.0 days) and the anatomical region
where the symptoms began was that involved in the
peripheral injury; nevertheless the movement disorder
displayed a tendency to spread beyond the original site
of injury. In 3 of the patients [18F]dopa PET uptake in
the striatum was decreased, similar to what is found in
classical idiopathic parkinsonism; however, only 6 of
the patients responded to levodopa therapy; a family
history of essential tremor was present in 2. It could
be argued that the occurrence of parkinsonism after
peripheral trauma was purely coincidental or that in
fact peripheral trauma could unmask subclinical par-
kinsonism or worsen pre-existing subtle parkinsonian
symptoms that had been previously undetected. The
possibility that peripheral injury could somehow in-
duce plastic changes and central motor reorganization
through modifications in spinal excitability, retrograde
axonal transport of neurotrophic factors or upregula-
tion of immediate early-response genes was discussed
by Cardoso and Jankovic (1995).
Using the criteria of Jankovic (1994) and Cardoso
and Jankovic (1995) for the diagnosis of parkinsonism
induced by a peripheral injury, Morris et al. (1998)
reported on a case of parkinsonism following electrical
injury to the hand and reviewed 9 additional cases
reported in the literature. Their case was a 39-year-
old man who sustained an electrical injury to his right
hand; 34 weeks later he developed progressive brady-
kinesia and rigidity initially confined to the right upper
extremity. Upon examination 3 years later the parkin-
sonian symptomatology had spread, involving the ipsi-
lateral lower extremity and the contralateral arm.
Levodopa significantly improved the symptomatology;
however, the patient could not obtain sustained benefit
because of gastric intolerance. An MRI failed to
demonstrate the presence of a central lesion and an
[18F]dopa PET scan showed asymmetrically reduced
putamenal uptake. Speculations on the mechanism of
action of electrical injury as a triggering factor for
the development of parkinsonism are similar to those
originally postulated by Jankovic (1994) and Cardoso
and Jankovic (1995). Quinn and Maraganore (2000),
in a letter to the editor discussing Morris et al.s
(1998) report, strongly question the validity of their
assertions on the basis of epidemiological data and
biological plausibility.
57.4. Worsening of parkinsonism by trauma
Anecdotal reports referred in the literature and in the
authors own experience support the notion that
trauma, as well as other medical conditions (such as
infections and surgery) may occasionally worsen par-
kinsonian symptomatology in patients with an estab-
lished diagnosis of PD (Goetz and Stebbins, 1991;
Wiest et al., 1999; Chou and Gutmann, 2001). Goetz
and Stebbins (1991) followed 10 parkinsonian patients
who sustained trauma to the head in motor vehicle
accidents; in all cases disability significantly increased
immediately after trauma, to return to baseline levels
in the ensuing weeks. This transient deterioration did
not cause persistent increased disability or an altera-
tion in the natural course of the disease. In Wiest
et al.s (1999) and Chou and Gutmanns (2001) cases
with a long-standing history of levodopa-responsive
PD, the presence of rapid deterioration of pre-existing
symptomatology in the context of frequent falls and
occasional head trauma suggested the possibility of
subdural hematoma. Imaging studies confirmed the
presence of subdural hematoma in both cases. After
surgical evacuation of the hematomas the patients
returned to their baseline levels in a few days.
There is, however, no clear explanation to account
for this phenomenon; on the other hand, there is
experimental evidence that in behaviorally normal rats
with partial lesions of the nigrostriatal rats, a stressful
stimulus (glucose deprivation, electrical tail shock or
exposure to severe cold) may unmask a previously
undetected motor deficit (akinesia) (Snyder et al.,
1985). It may be argued that in these animals the
stressful stimuli triggered a series of biochemical
events that altered a precarious compensatory state.
Similarly, the degree of clinical disability in PD
patients may be the result of a balance between the
degree of nigrostriatal damage, compensatory en-
dogenous mechanisms and medication. Any stress-
ful stimuli, be it trauma, infection or surgery, may
break this delicate balance and cause transient
increased disability.
 TRAUMA AND PARKINSONS DISEASE
57.5. Conclusions
After careful evaluation of all the evidence reviewed
thus far we may conclude:
1. Although several case-control and two cohort studies
failed to establish that trauma to the head can influ-
ence the subsequent development of PD, others have,
in fact, found that severe head trauma increases the
risk of PD. It is perhaps valid to assume that history
of preceding head trauma, together with family his-
tory and other environmental factors, plays at least
a partial role in the etiology of PD.
2. Albeit infrequent, posttraumatic parkinsonism
resulting from direct injury to the basal ganglia
and substantia nigra or indirect involvement of
these structures secondary to a severe cranial
trauma does indeed exist.
3. Repetitive cranial trauma such as that experienced
by boxers may result in the development of a form
of parkinsonism associated with other motor,
behavioral and cognitive disorders encompassed
in boxers encephalopathy.
4. The possible occurrence of parkinsonism induced
by peripheral trauma is still controversial and
there is not enough supportive evidence to accept
its existence.
5. Trauma, as well as infectious disorders, surgical
interventions and stress, may aggravate pre-
existing PD.
References
Allam MF, del Castillo AS, Navajas RF (2003). Parkinsons
disease risk factors. Rev Neurol 36 (8): 749755.
Bhatt M, Desai J, Mankodi A et al. (2000). Posttraumatic
akinetic-rigid syndrome resembling Parkinsons disease:
a report on three patients. Mov Disord 15 (2): 313317.
Bower JH, Maraganore DM, Peterson BJ et al. (2003). Head
trauma preceding PD: a case-control study. Neurology
60 (10): 16101615.
Bramlett HM, Dietrich WD (2003). Synuclein aggregation: pos-
sible role in traumatic brain injury. Exp Neurol 184: 2730.
Butterfield PG, Valanis BG, Spencer PS et al. (1993). Envir-
onmental antecedents of young-onset Parkinsons disease.
Neurology 43: 11501158.
Calne DB, Langston JW (1983). Etiology of Parkinsons dis-
ease. Lancet 2: 14571459.
Cardoso F, Jankovic J (1995). Peripherally induced tremor
and Parkinsonism. Arch Neurol 52: 263270.
Chou SM, Gutmann L (2001). Deteriorating parkinsonism
and subdural hematomas. Neurology 57 (7): 1925.
Corsellis JA, Bruton CJ, Freeman-Browne D (1973). The
aftermath of boxing. Psychol Med 3 (3): 270303.
497
Corti O, Hampe C, Darios F et al. (2005). Parkinsons dis-
ease: From causes to mechanisms. C R Biol 328 (2):
131142.
Davie CA, Pirtosek Z, Barker GJ et al. (1995). Magnetic
resonance spectroscopic study of parkinsonism related to
boxing. J Neurol Neurosurg Psychiatry 58 (6): 688691.
De Michele G, Filla A, Volpe G et al. (1996). Environmental
and genetic risk factors in Parkinsons disease: A case-
control study in Southern Italy. Mov Disord 11 (1): 1723.
De Rijk MC, Bretleler MMB, Ott A et al. (1996). Risk fac-
tors for Parkinsons disease: The Rotterdam Study. J Neu-
rol 243 (Suppl 2): S8.
Doder M, Jahanshahi M, Turjanski N et al. (1999). Parkin-
sons syndrome after closed head injury: A single case
report. J Neurol Neurosurg Psychiatry 66 (3): 380385.
Factor SA, Weiner WJ (1991). Prior history of head trauma
in Parkinsons disease. Mov Disord 6 (3): 225229.
Factor SA, Sanchez-Ramos J, Weiner WJ (1988). Trauma as
an etiology of parkinsonism: A historical review of the
concept. Mov Disord 3 (1): 3036.
Fearnley JM, Lees AJ (1991). Ageing and Parkinsons dis-
ease: Substantia nigra regional selectivity. Brain 114:
22832301.
Friedman JH (1989). Progressive parkinsonism in boxers.
South Med J 82 (5): 543546.
Giroud M, Vincent MC, Thierry A et al. (1988). Parkinsonian
syndrome caused by traumatic hematomas in the basal
ganglia. Neurochirurgie 34 (1): 6163.
Godwin-Austen RB, Lee PN, Marmot MG et al. (1982).
Smoking and Parkinsons disease. J Neurol Neurosurg
Psychiatry 45 (7): 577581.
Goetz CG, Stebbins GT (1991). Effects of head trauma from
motor vehicle accidents on Parkinsons disease. Ann Neu-
rol 29: 191193.
Graves AB, White E, Koepsell TD et al. (1990). The asso-
ciation between head trauma and Alzheimers disease.
Am J Epidemiol 131 (3): 491501.
Grimberg L (1934). Paralysis agitans and trauma. J Nerv
Ment Dis 79: 1442.
Guterman A, Smith RW (1987). Neurological sequelae of
boxing. Sports Med 4 (3): 194210.
Hageman AT, Horstink MW (1994). Parkinsonism due to a
subdural hematoma. Mov Disord 9 (1): 107108.
Hofman A, Collette HJ, Bartelds AI (1989). Incidence and
risk factors of Parkinsons disease in The Netherlands.
Neuroepidemiology 8 (6): 296299.
Jankovic J (1994). Post-traumatic movement disorders:
Central and peripheral mechanisms. Neurology 44 (11):
20062014.
Jellinger K (1989). Trauma as an etiologic agent in Parkinson
disease. Mov Disord 4 (1): 9092.
Jellinger KA (2003). Parkinsonism and persistent vegetative
state after head injury. J Neurol Neurosurg Psychiatry
75 (7): 1082.
Jordan BD (2000). Chronic traumatic brain injury associated
with boxing. Semin Neurol 20 (2): 179185.
498 O. S. GERSHANIK
Jordan BD, Relkin NR, Ravdin LD et al. (1997). Apolipopro-
tein E epsilon4 associated with chronic traumatic brain
injury in boxing. JAMA 278 (2): 136140.
Kivi A, Trottenberg T, Kupsch A et al. (2005). Levodopa-
responsive posttraumatic parkinsonism is not associated
with changes of echogenicity of the substantia nigra.
Mov Disord 20 (2): 258260.
Koller WC, Wong GF, Lang A (1989). Posttraumatic move-
ment disorders: A review. Mov Disord 4 (1): 2036.
Krauss JK, Jankovic J (2002). Head injury and posttraumatic
movement disorders. Neurosurgery 50 (5): 927939.
Kuopio AM, Marttila RJ, Helenius H et al. (1999). Environ-
mental risk factors in Parkinsons disease. Mov Disord
14 (6): 928939.
Lai BC, Marion SA, Teschke K et al. (2002). Occupational
and environmental risk factors for Parkinsons disease.
Parkinsonism Relat Disord 8 (5): 297309.
Lees AJ (1997). Trauma and Parkinson disease. Rev Neurol
153 (10): 541546.
Liu B, Gao HM, Hong JS (2003). Parkinsons disease and
exposure to infectious agents and pesticides and the occur-
rence of brain injuries: Role of neuroinflammation.
Environ Health Perspect 111 (8): 10651073.
Martland HS (1928). Punch drunk. JAMA 91:11031107.
Matsuda W, Matsumura A, Komatsu Y et al. (2003). Awa-
kenings from persistent vegetative state: Report of three
cases with parkinsonism and brain stem lesions on MRI.
J Neurol Neurosurg Psychiatry 74 (11): 15711573.
McCann SJ, LeCouteur DG, Green AC et al. (1998). The
epidemiology of Parkinsons disease in an Australian
population. Neuroepidemiology 17 (6): 310317.
McIntosh TK, Saatman KE, Raghupathi R et al. (1998). The
Dorothy Russell Memorial Lecture. The molecular and
cellular sequelae of experimental traumatic brain injury:
Pathogenetic mechanisms. Neuropathol Appl Neurobiol
24: 251267.
Morano A, Jimenez-Jimenez FJ, Molina JA et al. (1994). Risk-
factors for Parkinsons disease: Case-control study in the pro-
vince of Caceres, Spain. Acta Neurol Scand 89 (3): 164170.
Morris HR, Moriabadi NF, Lees AJ et al. (1998). Parkinson-
ism following electrical injury to the hand. Mov Disord
13 (3): 600602.
Morrish PK, Rakshi JS, Bailey DL et al. (1998). Measuring
the rate of progression and estimating the preclinical per-
iod of Parkinsons disease with [18F]dopa PET. J Neurol
Neurosurg Psychiatry 64: 314319.
Nayernouri T (1985). Posttraumatic parkinsonism. Surg Neu-
rol 24 (3): 263264.
Nuti A, Ceravolo R, DellAgnello G et al. (2004). Environ-
mental factors and Parkinsons disease: A case-control
study in the Tuscany region of Italy. Parkinsonism Relat
Disord 10: 481485.
OMIM Online Mendelian Inheritance in Man Database,
2005. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db
OMIM
Parkinson J (1817). An Essay on the Shaking Palsy. Whit-
tingham and Rowland, for Sherwood Neely and Jones,
London.
Patrick HU, Levy PM (1922). Parkinsons disease. A clinical
study of one hundred and forty-six cases. Arch Neurol
Psychiat 7:711720.
Preux PM, Condet A, Anglade C et al. (2000). Parkinsons
disease and environmental factors. Matched case-control
study in the Limousin region, France. Neuroepidemiology
19 (6): 3337.
Quinn N, Maraganore D (2000). Parkinsonism following
electrical injury to the hand. Mov Disord 15 (3): 587588.
Roberts GW, Allsop D, Bruton C (1990). The occult after-
math of boxing. J Neurol Neurosurg Psychiatry 53 (5):
373378.
Rondot P, Bathien N, de Recondo J et al. (1994). Dystonia-
parkinsonism syndrome resulting from a bullet injury in
the midbrain. J Neurol Neurosurg Psychiatry 57 (5): 658.
Schwab RS, England AC (1968). Parkinsonism due to var-
ious specific causes. In: Vinken PJ, Bruyn GW, (Eds.),
Handbook of Clinical Neurology, 1st. edn, Vol. 6. North
Holland Publishing Co, Amsterdam, pp. 230233.
Schott GD (1986). Induction of involuntary movements by
peripheral trauma: An analogy with causalgia. Lancet
2 (8509): 712716.
Seidler A, Hellenbrand W, Robra BP et al. (1996). Possible
environmental, occupational, and other etiologic factors
for Parkinsons disease: A case-control study in Germany.
Neurology 46 (5): 12751284.
Semchuk KM, Love EJ, Lee RG (1993). Parkinsons disease:
A test of the multifactorial etiologic hypothesis. Neurol-
ogy 43 (6): 11731180.
Smargiassi A, Mutti A, De Rosa A et al. (1998). A case-con-
trol study of occupational and environmental risk factors
for Parkinsons disease in the Emilia-Romagna region of
Italy. Neurotoxicology 19 (45): 709712.
Snyder AM, Stricker EM, Zigmond MJ (1985). Stress-
induced neurological impairments in an animal model of
parkinsonism. Ann Neurol 18: 544551.
Stern M, Dulaney E, Gruber SB et al. (1991). The epide-
miology of Parkinsons disease. A case-control study of
young-onset and old-onset patients. Arch Neurol 48 (9):
903907.
Stern MB (1991). Head trauma as a risk factor for Parkin-
sons disease. Mov Disord 6 (2): 9597.
Tanner CM, Chen B, Wang WZ et al. (1987). Environmental
factors in the etiology of Parkinsons disease. Can J Neu-
rol Sci 14 (3 Suppl): 419423.
Taylor CA, Saint-Hilaire MH, Cupples LA et al. (1999).
Environmental, medical, and family history risk factors
for Parkinsons disease: A New England-based case con-
trol study. Am J Med Genet 88 (6): 742749.
Trosch RM, Ransom BR (1990). Levodopa-responsive par-
kinsonism following central herniation due to bilateral
subdural hematomas. Neurology 40 (2): 376377.
Tsai CH, Lo SK, See LC et al. (2002). Environmental risk
factors of young onset Parkinsons disease: A case-control
study. Clin Neurol Neurosurg 104 (4): 328333.
Turjanski N, Lees AJ, Brooks DJ (1997). Dopaminergic
function in patients with posttraumatic parkinsonism: An
18F-dopa PET study. Neurology 49 (1): 183189.
 TRAUMA AND PARKINSONS DISEASE
Uryu K, Giasson BI, Longhi L et al. (2003). Age-dependent
synuclein pathology following traumatic brain injury in
mice. Exp Neurol 184 (1): 214224.
Ward CD, Duvoisin RC, Ince SE et al. (1983). Parkinsons
disease in 65 pairs of twins and in a set of quadruplets.
Neurology 33: 815824.
Werneck AL, Alvarenga H (1999). Genetics, drugs and
environmental factors in Parkinsons disease: A case-con-
trol study. Arq Neuropsiquiatr 57 (2-B): 347355.
Wiest RG, Burgunder JM, Krauss JK (1999). Chronic sub-
dural haematomas and Parkinsonian syndromes. Acta
Neurochir (Wien) 141 (7): 753757.
499
Williams DB, Annegers JF, Kokmen E et al. (1991). Brain
injury and neurologic sequelae: A cohort study of demen-
tia, parkinsonism, and amyotrophic lateral sclerosis. Neu-
rology 41 (10): 15541557.
Yang J, Wu Z, Lou X (1994). A case-control study on risk
factors in etiology of Parkinsons disease. Zhonghua Liu
Xing Bing Xue Za Zhi 15 (1): 69.
Zijlmans J, Booij J, Valk J et al. (2002). Posttraumatic tre-
mor without parkinsonism in a patient with complete con-
tralateral loss of the nigrostriatal pathway. Mov Disord
17 (5): 10861088.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 58

Psychogenic parkinsonism

VASILIKI KOUKOUNI AND KAILASH P. BHATIA*

Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London,
London, UK

58.1. Definition the Toronto Western Hospital, over a period of 20

The term psychogenic is derived from a Greek word
meaning created by the soul and is applied to dis-
eases that cannot be attributed to a certain lesion or
dysfunction of a system. Parkinsonism is defined by
a constellation of features, the hallmark being brad-
ykinesia associated with tremor, rigidity and impair-
ment of postural reflexes. The most common cause is
Parkinsons disease (PD). There are other forms of
parkinsonism, including the so-called atypical parkin-
sonian conditions, like multiple systems atrophy
(MSA) or progressive supranuclear palsy (PSP), and
also acquired or secondary forms of parkinsonism.
Some of them can be accompanied by cognitive dec-
line and psychiatric manifestations. Although psy-
chogenic forms of a variety of different movement
disorders, such as psychogenic dystonia or psycho-
genic tremor, have been well described in the literature
over the years, little is mentioned about psychogenic
parkinsonism.
58.2. Epidemiology
Psychogenic parkinsonism is perhaps the rarest of the
different forms of the psychogenic movement disor-
ders (PMD). In retrospective studies conducted in
large movement disorder clinics it accounted for
only 1.97% of all PMDs (Fahn and Williams, 1988;
Factor et al., 1995; Miyasaki et al., 2003) and 0.5%
or less of all patients presenting with parkinsonism
(Factor et al., 1995; Lang et al., 1995). In 1995, Factor
et al. described 28 patients with PMDs, 2 of whom
were diagnosed as having psychogenic parkinson-
ism (7%). At the Movement Disorders Clinic of
months, 64 patients were diagnosed with PMD and
psychogenic parkinsonism accounted for 6.1% of
these (Miyasaki et al., 2003). In another series from
Columbia-Presbyterian Medical Center, New York,
USA, including 131 patients, the respective figure
was 1.9% (Fahn and Williams, 1988).
58.3. Natural history
In 1988, Walters et al. described the case of a 64-
year-old man who presented with atypical symptoms
of parkinsonism that resolved spontaneously 1 year
after the discontinuation of levodopa. Since then,
two large studies have been performed regarding psy-
chogenic parkinsonism. Of the 14 cases of psycho-
genic parkinsonism described by Lang et al. (1995)
in three academic movement disorders centers, the
average age of the patients was 47 years (range 21
63 years). Both sexes were equally involved, in con-
trast to the other PMD, where there is usually a
female predisposition (Fahn and Williams, 1988;
Koller et al., 1989; Monday and Jankovic, 1993;
Kim et al., 1999). The mean duration of the symp-
toms prior to the diagnosis was 5 years, ranging from
4 months to 13 years. In one recent study, reported
only in abstract form, from three large movement dis-
order centers in Augusta, GA, USA and London, UK,
a retrospective chart review of 9 patients diagnosed
with psychogenic parkinsonism was reported
(Morgan et al., 2004). The mean age of onset of the
symptoms was 50 years, with a range of 3472
years, and the disease duration varied from several
months to 28 years. Interestingly, there was a 2:1
male-to-female ratio.

*Correspondence to: Prof. Kailash Bhatia, Institute of Neurology, Sobell Department of Motor Neuroscience and Movement
Disorders, 7 Queen Square, London WC1N 3BG, UK. E-mail: kbhatia@ion.ucl.ac.uk, Tel: 44-20-7837-3611, Ext: 4253,
Fax: 44-20-7676-2175.
502 V. KOUKOUNI AND K. P. BHATIA
58.4. Clinical manifestations
The onset of the disease is abrupt in the vast majority
of patients, which is unlike typical PD. According to
the studies performed by Lang et al. (1995) and Mor-
gan et al. (2004), there was an abrupt onset in about
two-thirds of patients (71.2% and 78% respectively).
Precipitating factors such as work-related injuries and
motor vehicle accidents with minor injuries that possi-
bly may not have involved the head are a common
feature (Lang et al., 1995). A total of 43% of the patients
studied by Lang and 77% of those studied by Morgan
presented with unilateral symptoms, typically involving
the dominant-hand side.
The most prominent feature is tremor, which bore
all the characteristics of psychogenic tremor. Classical
PD tremor is asymmetric, pill-rolling, resting tremor at
a rate of 34 Hz, involving the thumb and index fin-
ger. A faster tremor of 67 Hz can appear on keeping
the arms outstretched. On the other hand, psychogenic
tremor can be present at rest and persist even during
position and intentional movements, at the same fre-
quency (Koller et al., 1989). Although wrists, elbows
and shoulders are commonly affected, fingers are
rarely involved, unlike typical PD (Deuschl et al.,
1998). Another important characteristic is variability.
The tremor may increase when the attention is drawn
to the affected limb or when the patient is asked about
it and can improve dramatically or even disappear
when the patients attention is withdrawn from the
area involved (Campbell, 1979) or if the patient is dis-
tracted by mental activity (e.g. mental arithmetic) or
complex motor tasks (e.g. finger-to-nose and tandem
walking) (Elble and Koller, 1990). Parkinsonian rest
tremor, e.g. in PD, quite often appears when the
patient is walking or being distracted. Entrainment,
meaning change of the original tremor frequency to
match the frequency of a repetitive task performed in
another limb (e.g. tapping) or side-to-side tongue
movements (Kim et al., 1999), is also common.
Koller and Biary (1989) suggested that PD patients
are capable of voluntarily suppressing their tremor for
an average of 48 seconds, if they are allowed to con-
centrate on it, in contrast to the psychogenic patients
where the opposite tends to happen. The psychogenic
tremor can also vary in terms of direction (e.g. from
supinationpronation orientation to flexionextension)
(Koller et al., 1989) and amplitude (e.g. when a limb is
weighed) (Deuschl et al., 1998).
As pointed out by Lang et al. (1995), limb rigidity
is uncommon and, when it is present, the examiner
has a sense of voluntary resistance. This also subsides
when the patient is distracted. Deuschl et al. (1998)
suggested that there is a co-activation of agonist and
antagonist muscles in psychogenic tremor that is sup-
ported by electromyographic (EMG) analysis and clin-
ical evaluation, which can produce a cogwheel-like
resistance to passive movement, which subsides when
the patient is relaxed.
True bradykinesia with typical arrests in movement
is never observed, although all the patients in Langs
series (Lang et al., 1995) demonstrated slowness of
voluntary movements and in some of them this was
their initial and main complaint. Slowness is present
throughout the performance of rapid repetitive and
alternating movements, but without the fatiguing and
decreasing amplitude that is seen in true parkinsonian
patients. The patients often seem to struggle and put
more effort than needed into performing the tasks. They
are grimacing, sighing and look exhausted and may use
their whole body in order to do a minor movement.
Despite the severe slowness, some patients may demon-
strate exquisite ability in doing specific tasks, like writ-
ing with normal speed (Lang et al., 1995). Some of the
patients seen by Lang et al. (1995) demonstrated facial
masking, but in the majority of them it was attributed
to an underlying depression.
Walking can be slow and stiff, with reduced or even
absent arm-swing on the affected side. The arm may
be held tightly extended and adducted to the side and
this can persist while running. The patients usually
respond in a theatrical way on postural stability test-
ing, flinging up both their arms (even the affected
one) equally and symmetrically and retropulsing but
never falling (Lang et al., 1995). An exaggerated star-
tle, when the backwards pull test is performed to test
postural stability, is often seen.
Another important feature noted by both studies
done by Lang et al. (1995) and Morgan et al. (2004)
is that disability is usually maximal from the early
stages of the disease and affects all aspects of every-
day life. Most patients give up work and are some-
times unable to perform their normal daily activities.
Most patients also complain of multiple other somatic
symptoms, like generalized fatigue, non-specific pains,
memory disturbance and impaired vision, and have signs
like give-away weakness of a limb or non-anatomic
sensory loss (Lang et al., 1995).
Fahn and Williams (1988) published a classification
of psychogenic dystonia, which can be applied to all
PMDs. According to this, a movement disorder can
be classified as: (1) documented, meaning symptoms
are relieved by psychotherapy, suggestion or placebo
or the patient is witnessed as being free of symptoms
when left alone; (2) clinically established, meaning
the movement disorder is inconsistent over time or is
 PSYCHOGENIC PARKINSONISM
incongruent with the classic condition and any of the
following are present: other definitely psychogenic
neurologic signs, multiple somatizations or an obvious
psychiatric disturbance; (3) probably psychogenic,
meaning that movements are inconsistent or incongru-
ent with the classic movement disorder but no other
features provide support for a diagnosis of psychogeni-
city or that the movement disorder is consistent and
congruent with the classic disorder but other features
of psychogenicity are present; and (4) possibly psycho-
genic, meaning it is suspected that the movements are
psychogenic if an obvious emotional disturbance is
present. Most psychogenic PD patients would fall into
the documented or clinically established categories.
58.5. Diagnosis
The first clues of psychogenicity in a patient present-
ing with parkinsonism can be obtained by history
(Table 58.1). This may include a history of a psychia-
tric disease or a long medical history involving multi-
ple operations, admissions to hospitals and a long
catalog of diagnostic tests previously done. Events
prior to the onset of the disease, such as accidents,
stressful situations or work-related injuries with litiga-
tion or compensation pending, can be indicative of a
possible non-organic cause of the symptoms. An
impressive fact is that PMDs are more frequent in
Table 58.1
Clues suggesting psychogenic parkinsonism (Lang et al.,
1995)
Onset Often abrupt
Course Static, maximum disability early
Distribution Dominant side most affected
Tremor Rest, postural, action: reduces with
distraction/ concentration, increases
with attention
Rigidity Voluntary resistance, cogwheeling
absent, may decrease with distraction
Bradykinesia No true fatiguing, marked slowness,
bizarre features
Gait Atypical, arm held stiffly at side,
antalgic if pain is associated
Postural stability Extreme or bizarre responses to
minimal displacement
Other neurologic False weakness, non-anatomic sensory
features loss
Psychiatric Varied, usually evident but accurate
features definition not always possible
Other Litigation, compensation (receiving or
pending)
503
people employed in health professions (Koller et al.,
1989; Fahn, 1994; Kim et al., 1999) and in those who
have witnessed the disorder in other family members
(Koller et al., 1989). Elements in clinical examination
are also revealing as well as responses to therapeutic
procedures (Table 58.2). The use of placebo as diag-
nostic and therapeutic procedure remains controver-
sial, as it gives rise to ethical considerations and can
affect the physicianpatient relationship. It is sug-
gested by Sa et al. (2004) that the use of placebo
should be reserved for cases in which the diagnosis
of psychogenicity remains uncertain after a thorough
investigation and follow-up. It can also prove useful
in the differential diagnosis of complex movement dis-
orders and in cases where organic and psychogenic
etiologies coexist (Monday and Jankovic, 1993; Koller
Table 58.2
Clues suggesting that a movement disorder may be
psychogenic (Miyasaki et al., 2003; Sa et al., 2004)
Historical
1. Abrupt onset
2. Static course
3. Spontaneous remissions
4. Obvious psychiatric disturbance
5. Multiple somatizations
6. Employed in health profession
7. Pending litigation or compensation
8. Presence of secondary gain
9. Young age
Clinical
1. Inconsistent character of movement (amplitude,
frequency, distribution, selective ability)
2. Paroxysmal movement disorder
3. Movements increase with attention or decrease with
distraction
4. Ability to trigger or relieve the abnormal movements
with unusual or non-physiological interventions. (e.g.
trigger points of the body)
5. False weakness
6. False sensory complaints
7. Self-inflected injuries
8. Deliberate slowness of movements
9. Functional disability out of proportion to exam findings
10. Movement abnormality that is bizarre, multiple or
difficult to classify
Therapeutic responses
1. Unresponsive to appropriate medications
2. Response to placebos
3. Remission with psychotherapy
504 V. KOUKOUNI AND K. P. BHATIA
et al., 2002). When there is strong evidence for psy-
chogenic parkinsonism, sodium amytal can be used
alternatively, as it may ameliorate psychogenic tremor.
Furthermore, spontaneous remissions and improve-
ment of symptoms with psychiatric consultation and
psychotherapy are strongly suggestive of their psy-
chogenic origin (Fahn, 1994). Admission to hospital
can prove beneficial, as it allows continuous observa-
tion of the patient, as well as psychiatric estimation
and intervention. Investigations including imaging
(computed tomography (CT) and magnetic resonance
imaging (MRI)) may be useful in order to exclude a
structural lesion. Relevant blood tests should always
be performed in order to exclude possible organic con-
ditions and also convince the patient that the physi-
cian pays the appropriate attention to the patients
complaints (Fahn, 1994; Sa et al., 2004).
As PD and other parkinsonian disorders have a pre-
synaptic dopaminergic defect, dopamine transporter
(DAT) single-photon emission computed tomography
(SPECT) and fluorodopa (18F-dopa) positron emission
tomography (PET) scans may be useful to differentiate
psychogenic parkinsonism from organic parkinsonian
conditions. It should be kept in mind that DAT SPECT
and 18F-dopa PET scans can be normal in dopa-
responsive dystonia-parkinsonism, manganese and
neuroleptic-induced parkinsonism, akinetic-rigid Hun-
tingtons disease, X-linked parkinsonism and other
conditions (Lang et al., 1995). There are also a small
number of PD patients in whom scans were found to
be apparently normal (Whone et al., 2003). In Langs
series (Lang et al., 1995) 4 patients underwent 18F-dopa
PET; the scan was abnormal in only 1 patient and this
raised the suspicion of an underlying organic PD. In
Morgans series (Morgan et al., 2004), DAT SPECT
scans were performed in 2 patients and they both
proved to be normal. In any case, an abnormal result
on DAT or 18F-dopa PET would be in favor of organic
parkinsonism (Tolosa et al., 2003).
Electrophysiological studies, including EMG,
accelerometry (Zeuner et al., 2003) and frequency ana-
lysis (Brown and Thompson, 2001), have been used in
the literature for the establishment of the psychogenic
origin of the tremor, but they do not have much use in
the day-to-day clinical service. Psychogenic tremor
has a frequency of less than 6 Hz, as hardly anyone
can produce a voluntary tremor over 7 Hz (Elble and
Koller, 1990). Large fluctuations in tremor amplitude
(e.g. with weighing) and frequency and also improve-
ment of tremor with distractibility are noted during
the examination. It should, however, be kept in mind
that patients with PD or essential tremor can demon-
strate variations in tremor amplitude with stress or
emotion, but these are only minimal (Koller et al.,
1989). Also drug treatment can reduce the tremor
amplitude but it will not affect the frequency (Koller
et al., 1989). Zeuner et al. (2003), used accelerometry
to measure frequency changes during tapping in a
group of psychogenic tremor patients and a group with
parkinsonian and essential tremor patients. They con-
cluded that a significant absolute change in tremor
frequency and marked variability in tapping were
noted in psychogenic tremor patients and suggested
that the change in frequency is more characteristic
than entrainment in those patients.
It should be emphasized that patients with organic
PMDs can demonstrate additional psychogenic symp-
toms, which usually affect the same part of the body as
the underlying organic movement disorder (Ranawaya
et al., 1990). This, along with the fact that psychogenic
parkinsonism is mainly a diagnosis of exclusion, makes
the diagnosis a challenging issue that should be estab-
lished with extreme caution, preferably by a movement
disorders specialist or an experienced neurologist, with
the assistance of a psychiatrist.
58.6. Psychiatric diagnosis
It would be useful to define some of the conditions
seen in patients with psychogenic disorders, according
to the American Psychiatric Associations (1995)
Diagnostic and Statistical Manual of Mental Disor-
ders (DSM-IV). In somatoform disorders, the symp-
toms suggest a general medical condition but they
cannot be fully explained by the presence of a specific
medical disorder, exposure to a substance or by any
other mental disorder and cause significant distress
or impairment in social, occupational or other areas
of functioning. The symptoms are not intentionally
produced or feigned. They include somatization and
conversion disorders. Somatization disorders begin
before the age of 30 and occur over a period of many
years, resulting in medical treatment or significant im-
pairment in social, occupational or other areas of
functioning. Conversion disorder is characterized by
symptoms or deficits affecting voluntary motor or sen-
sory function that suggest a neurological or other
medical condition and is usually preceded by conflicts
or other stressors. On the other hand, factitious disor-
ders, such as Munchausens syndrome, are intention-
ally produced and the motivation is for the patient to
assume the sick role. In malingering the symptoms
are again intentionally produced and motivated by
external incentives (e.g. avoiding work or military
duty or obtaining compensation).
The establishment of the underlying psychiatric dis-
order in psychogenic parkinsonism and all other psy-
chogenic disorders, although crucial for diagnosis
 PSYCHOGENIC PARKINSONISM
and treatment, is not always possible. In Langs series
(Lang et al., 1995) there was evidence of somatoform
disorders (35.7%), especially conversion disorders
and depression (14.3%), in some patients and litigation
or compensation issues in a few others (21.4%),
whereas the psychiatric disorder was not clearly iden-
tified in 3 of them (21.4%). In other series, regarding
other PMDs, the most common psychiatric diagnoses
were depression, anxiety and conversion and somatiza-
tion disorders (Koller et al., 1989; Factor et al., 1995;
Kim et al., 2003).
58.7. Treatment
When the diagnosis of psychogenic parkinsonism is
established, it should be presented to the patient
with extreme caution and a non-judgmental character,
to gain trust and acceptance. It should be pointed out
that the parkinsonism is not due to a lesion or a
severe dysfunction of the nervous system and that it
can be fully resolved with the appropriate approach.
A neuropsychiatric evaluation should be suggested,
especially to those who had a long-standing disease
with multiple investigations and ineffective treatments
(Sa et al., 2004). It is important that the patient is
approached in a way that does not make him/her feel
that he/she is crazy. It was suggested by Ford et al.
(1995) that a possible neurobiological explanation for
the patients symptoms could be presented. It should
perhaps be explained that the mind and the body are
in strong association with each other and that dysfunc-
tion of the one can affect the other, as happens with
numerous other diseases (Fahn, 1994). A psychiatrist
should be involved, preferably early in the course
of the investigation, providing psychotherapy and
positive reinforcement. Cognitive-behavioral therapy
should also be considered. As discussed earlier, the
use of placebo is controversial and should only be used
to establish the diagnosis (Fahn, 1994). Alternatively,
mild antidepressants and anxiolytics can be used to
manage the underlying depression and anxiety, along
with a periodical neurological assessment (Koller
et al., 2002).
58.8. Prognosis
The prognosis for functional recovery is variable and
relatively poor. In a follow-up study of patients with
medically unexplained movement disorders, the pre-
senting symptom remained unchanged in 14% of
patients, although in 38% of them it had worsened
(Crimlisk et al., 1998). A prospective study done by
Feinstein et al. (2001) regarding the psychiatric out-
come in patients with PMDs revealed that there was
505
a persistence in abnormal movements in more than
90% of patients. In Langs series (Lang et al., 1995),
2 patients had spontaneous long remissions, 1 had
complete but short remission and one had marked but
incomplete response to psychotherapy and haloperidol.
In Morgans series (Morgan et al., 2004), 5 patients
attended follow-up; 2 of them had abrupt resolution
of their symptoms, 1 was cured after intensive inpati-
ent psychotherapy and 2 remained convinced that they
had PD. Generally, in all PMDs, the prognosis depends
on the underlying psychiatric disorder, the acute or
insidious onset and the course of the disease, the pre-
morbid functioning and the presence of an identifiable
trigger. The prognosis is supposed to be better when
the onset of the disease is acute, with a short dura-
tion of symptoms and when there is a specific emo-
tional event that preceded the onset of the disease of
a previously healthy individual (Koller et al., 2002).
Conversion disorders with recent onset are considered
to have better prognoses than factitious disorders
and malingering, which usually respond poorly and
unpredictably (Miyasaki et al., 2003).
References
American Psychiatric Association (1995). Diagnostic and
Statistical Manual of Mental Disorders, 4th edn. (DSM-
IV). International Version with ICD-10 Codes, Washing-
ton DC, pp. 457487.
Brown P, Thompson PD (2001). Electrophysiological aids to
the diagnosis of psychogenic jerks, spasms, and tremor.
Mov Disord 16 (4): 595599.
Campbell J (1979). The shortest paper. Neurology 29: 1633.
Crimlisk HL, Bhatia KP, Cope H et al. (1998). Slater revis-
ited: 6 year follow-up study of patients with medically
unexplained motor symptoms. BMJ 316: 582586.
Deuschl G, Koster B, Lucking CH et al. (1998). Diagnostic
and pathophysiological aspects of psychogenic tremors.
Mov Disord 13: 294302.
Elble RJ, Koller WC (1990). Unusual forms of tremor. In:
RJ Elble, WC Koller (Eds.), Tremor. The Johns Hopkins
University Press, Baltimore, pp. 154157.
Factor SA, Podskalny GD, Molho ES (1995). Psychogenic
movement disorders: frequency, clinical profile and char-
acteristics. J Neurol Neurosurg Psychiatry 59: 406412.
Fahn S (1994). Psychogenic movement disorders. In: CD
Marsden, S Fahn (Eds.), Movement Disorders.3rd edn. -
Buttenw Heinem, Oxford, pp. 359372.
Fahn S, Williams PJ (1988). Psychogenic dystonia. Adv
Neurol 50: 431455.
Feinstein A, Stergiopoulos V, Fine J et al. (2001). Psychiatric
outcome in patients with a psychogenic movement disor-
der: A prospective study. Neuropsychiatry Neuropsychol
Behav Neurol 14 (3): 169176.
Ford B, Williams DT, Fahn S (1995). Treatment of psychogenic
movement disorders. In: R Kurlan, (Ed.). Treatment of Move-
ment Disorders. JP Lippincott, Philadelphia, pp. 475485.
506 V. KOUKOUNI AND K. P. BHATIA
Kim YJ, Pakiam ASI, Lang AE (1999). Historical and clini-
cal features of psychogenic tremor: review of 70 cases.
Can J Neurol Sci 26: 190195.
Koller WC, Biary NM (1989). Volitional control of involun-
tary movements. Mov Disord 4 (2): 153156.
Koller WC, Lang AE, Vetre-Overfield B et al. (1989). Psycho-
genic tremors. Neurology 39: 10941099.
Koller WC, Marjama-Lyons J, Troster AJ (2002). Psychogenic
movement disorders. In: JJ Jankovic, E Tolosa (Eds.),
Parkinsons Disease and Movement Disorders. Lippincott,
Philadelphia, pp. 546552.
Lang AE, Koller WC, Fahn S (1995). Psychogenic parkin-
sonism. Arch Neurol 52: 802810.
Miyasaki JI, Sa DS, Galvez-Jimenez N et al. (2003). Psychogenic
movement disorders. Can J Neurol Sci 30 (Suppl 1): S94S100.
Monday K, Jankovic J (1993). Psychogenic myoclonus. Neu-
rology 43: 349352.
Morgan JC, Mir P, Mahapatra RK et al. (2004). Psychogenic
parkinsonism: clinical features of a large case series. Mov
Disord 19 (Suppl 9): S345S346.
Ranawaya R, Riley D, Lang A (1990). Psychogenic dyskine-
sias in patients with organic movement disorders. Mov
Disord 5: 127133.
Sa DS, Galvez-Jimenez N, Lang AE (2004). Psychogenic
movement disorders. In: R Watts, WC Koller (Eds.),
Movement Disorders, Neurologic Principles and Prac-
tice, 2nd edn. McGraw Hill, New York, pp. 891914.
Tolosa E, Coehlo M, Gallardo M (2003). DAT Imaging in
drug-induced and psychogenic parkinsonism. Mov Disord
18 (Suppl 7): S28S33.
Whone AL, Watts RL, Stoessl AJ et al. (2003), REAL-PET
Study Group. Slower progression of Parkinsons disease
with ropinirole versus levodopa: The REAL-PET study.
Ann Neurol 54: 93101.
Walters AS, Boudwin J, Wright D et al. (1988). Three hys-
terical movement disorders. Psychol Rep 62: 979985.
Zeuner KE, Shoge RO, Goldstein SR et al. (2003). Accelerome-
try to distinguish psychogenic from essential or parkinsonian
tremor. Neurology 61: 584550.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 59

Parkinsonism and dystonia

RUTH H. WALKER*

Movement Disorders Clinic, Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY
and Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA

59.1. Introduction in patients with generalized dystonia from a variety of

causes, symptoms often develop asymmetrically and
59.1.1. The dopamine connection
remain worse on one side throughout the course of the
disease. A number of the pediatric metabolic genetic
The commonalities and distinctions between parkin-
disorders cause specifically orofacial dyskinesias.
sonism and dystonia have long intrigued clinicians
Some authors have described the movements seen in
and researchers in the field of movement disorders.
dystonia as bradykinetic, but the slowness of actions in
The clinical features of both can be seen in conditions
dystonia is of a different quality to that seen in PD, being
in which dopaminergic neurotransmission is impaired;
due to an increase in muscle activation in a pattern which
however, dystonia can also be seen in a wide variety of
counteracts the intended movement, hypothesized to be a
other conditions, in which the pathophysiology is far
consequence of decreased inhibition of unwanted motor
from clear. Dysfunction of the dopaminergic system
activity (Mink, 1996, 2003; Perlmutter et al., 1997; Kaji,
in parkinsonism has been known since the 1960s; in
2001). This is in contrast to difficulty in initiating move-
dystonia this has been inferred from empirical evi-
ment (akinesia), due to inadequate and discoordinated
dence for many years and is slowly becoming clarified
muscle activity and prolongation of movement time,
from scientific studies.
superimposed upon muscle rigidity, as seen in Parkinsons
disease (PD) (Hallett, 2003).
59.1.2. Phenomenology of dystonia

Phenomenologically, dystonia is classified as a hyper- 59.1.3. Classification of dystonia

kinetic movement disorder, in which involuntary mus-
cle contractions result in abnormal postures and
movements (Fahn et al., 1998). An imbalance of flexor
and extensor activity may cause hyperextension or
flexion at a joint, which is often, although not invari-
ably, dynamic. In some cases, alternation of flexion
and extension results in tremor, rather than abnormal
posture, which may confuse the diagnosis. In other
cases, particularly those due to secondary causes (e.g.
structural brain lesions), the abnormal posture is fixed
and does not resolve during relaxation or even sleep.
Dystonia can affect any part of the body and often
has a characteristic distribution in different diseases.
Axial involvement may be present in combination with
axial parkinsonism. A strictly unilateral presentation
may indicate a contralateral structural lesion; however,
The classification of dystonia is in a state of flux, as var-
ious genes become identified as causes of what used to be
called idiopathic dystonia. The term primary is now
used for cases in which dystonia is the major, and often
the sole, symptom. These are typically due to genetic
causes and other etiologies, such as a structural lesion,
must be excluded by clinical, radiological and laboratory
evaluations (Fahn et al., 1998). In addition, there must be
no response to levodopa, excluding dopa-reponsive dys-
tonia (DRD) (Fahn et al., 1998; Bressman, 2004).
Secondary dystonias are those in which dystonia is due
to another disease process (Fahn et al., 1998; Bressman,
2004). This may be one of the inherited dystonia-plus syn-
dromes, in which dystonia is part of a symptom complex,
such as myoclonusdystonia or DRD; acquired, such as a

*Correspondence to: Ruth H. Walker, Department of Neurology, James J. Peters Veterans Affairs Medical Center (127), 130 W.
Kingsbridge Road, Bronx NY 10468, USA. E-mail: ruth.walker@mssm.edu, Tel: 1-718-584-9000-x5915, Fax: 1-718-741-4708.
508 R. H. WALKER
structural lesion, for example stroke, tumor or head trauma 59.1.4. Pathophysiology
or drug-induced; or heredodegenerative, in which dystonia
may be a manifestation of an inherited disease such as According to the commonly accepted model of the
Huntingtons disease (HD), spinocerebellar ataxia (SCA) basal ganglia (Albin et al., 1989; DeLong, 1990), the
type III, Lubag (Filipino X-linked dystoniaparkinsonism) direct and indirect pathways from the striatum have
or chromosome 17 frontotemporal dementia and parkin- opposing effects upon the activity of the subthalamic
sonism. In addition, secondary dystonia may be present nucleus (STN) and its projection targets, the internal
in the apparently sporadic (and rarely inherited) parkinso- segment of the globus pallidus (GPi) and the substantia
nian syndromes, including idiopathic PD, multiple system nigra pars reticulata (SNpr) (Fig. 59.1A). These nuclei
atrophy (MSA), corticobasal degeneration (CBD) and pro- are viewed as the main source of output of the basal
gressive supranuclear palsy (PSP). ganglia and send inhibitory projections to a number
In this review, the disorders have been classified as of targets, including the thalamus centromedian pars
parkinsonian disorders with dystonia, dystonic dis- fascicularis (CM-pf), the pedunculopontine nucleus
orders with parkinsonism and mixed movement dis- (PPN) and the substantia nigra pars compacta (SNpc).
orders, in which the phenomenology may vary and The projection from the striatum to the GPi the direct
there may be variety of neurologic features, including pathway is GABAergic and inhibits the activity of
dystonia and parkinsonism. GPi neurons. The projection from the striatum to the
 PARKINSONISM AND DYSTONIA 509

Fig. 59.1. For full color figure, see plate section. (A) During normal function of the basal ganglia, the direct pathway from the
striatum inhibits neurons of the internal segment of the globus pallidus (GPi), disinhibiting the motor pattern generator, con-
sisting of the motor thalamic nuclei and their projections to the cortex. The neurons which select the motor program are repre-
sented as being surrounded by a network, controlled by the indirect pathway, which reduces the generation of unwanted
movements. (B) In Parkinsons disease, with loss of the dopaminergic input to the striatum, the direct pathway is less active,
with increased activity of the inhibitory neurons of the GPi, which further inhibit the motor pattern generators. The indirect
pathway is disinhibited by the loss of dopamine, resulting in a decreased inhibition of the subthalamic nucleus (STN) and
the GPi. The surround-inhibitory neurons of the GPi also have increased activity and unselected movements are also
decreased. Dashed lines, decreased activity; thicker lines, increased activity. (C) In dystonia, there is increased activity of
the direct pathway, with decreased inhibition of the thalamocortical motor pattern generators. There is decreased surround inhi-
bition via the indirect pathway, with loss of inhibition of unselected movements. GABA, gamma-aminobutyric acid;
SNcSNpc, substantia nigra pars compacta; GPe, globus pallidus pars externa. Adapted from Mink (2003) with permission.
Copyright # 2003, American Medical Association. All rights reserved.

globus pallidus pars externa (GPe), the indirect path-
way, is also GABAergic and an increase in activity
of this pathway inhibits the GABAergic GPe and disin-
hibits the STN. The STN sends an excitatory projection
to the GPi and SNpr, thus the neuronal activity of these
structures usually changes in parallel.
In PD a decrease in the dopaminergic input to the
striatum results in decreased activation of the direct
pathway by dopamine D1-receptors and decreased
inhibition of the GPi. The indirect pathway is inhibited
by dopamine D2-receptors, thus dopamine depletion
results in increased activity of the inhibitory striato-
GPe pathway. These neurons inhibit the GPe, which
reduces its inhibition of the glutamatergic STN neu-
rons (Bergman et al., 1994) (Fig. 59.1B). The STN
shows an increase in activity, resulting in increased sti-
mulation by STN neurons of the internal segment of
the GPi and the SNpr (Carpenter et al., 1981; Kitai
and Kita, 1987) and increased activity in the projec-
tions from these structures. This model has been borne
out by data from a variety of animal models of dopa-
mine depletion and intraoperative recordings in PD
(Wichmann et al., 1994; Eidelberg et al., 1997; Rodriguez
et al., 1998; Vitek et al., 1998).
Alterations in regional blood flow in various brain
areas reflect changes in neuronal activity in PD and
correlate to some extent with the above model (Eidel-
berg et al., 1990; Jenkins et al., 1992; Playford et al.,
1992). A correspondence is seen with disease severity
(Eidelberg et al., 1995) and these alterations can be
normalized by various therapeutic interventions (Jen-
kins et al., 1992; Playford et al., 1992; Jahanshahi
et al., 1995; Eidelberg et al., 1996; Fukuda et al.,
2001). However, these metabolic studies represent
levels of synaptic activity and do not distinguish
between excitatory or inhibitory neurons, or afferents
or interneurons, so do not necessarily help us under-
stand the precise mechanism of dysfunction in PD at
a neuronal level.
In another model which has been proposed, based
upon a center-surround pattern, the direct pathway
serves to activate a motor program and the indirect path-
way focuses and selects movements by inhibiting
unwanted motor programs (Mink, 1996, 2003; Perlmutter
et al., 1997; Kaji, 2001). Thus, in PD, there is less acti-
vation of motor programs via the direct pathway and
excessive focusing via the indirect pathway, resulting in
inadequate movement (Fig. 59.1B).
510 R. H. WALKER
In dystonia, the converse may be proposed: increased
D1-mediated stimulation of the direct pathway and
increased D2-mediated inhibition of the indirect pathway
to the GPe, with disinhibition of the GPe, an increase in
the inhibitory GPe-subthalamic pathway, with resultant
decreased STN activity and thus decreased GPi neuronal
activity (Mink, 1996, 2003; Berardelli et al., 1998; Kaji,
2001) (Fig. 59.1C). According to the model, this would
cause increased activation and loss of selectivity of motor
pattern generators and decreased inhibitory surround
(Mink, 1996, 2003), resulting in the excessive muscle
contractions and the overflow of movements which we
see clinically.
Dysfunction of the direct pathway in dystonia is
suggested by an increase in the striatal-GPi pathway
activity seen on functional imaging (Eidelberg et al.,
1995). This would result in a decrease in GPi activity
and disinhibition of the thalamus.
There are data supporting dysfunction of the indir-
ect pathway; however these are harder to interpret
and to translate to the model. Whatever the mechan-
ism, the changes must ultimately be explicable in
terms of loss of a component of the basal ganglia, as
dystonia can be seen in a number of neurodegenerative
disorders, in addition to those cases in which there is
no evidence of neurodegeneration, for example in
DYT1 dystonia or when is a medication side-effect.
There is evidence of decreased dopamine D2-receptor
binding (Perlmutter et al., 1998). However, decreased
D2-receptor binding was also found in non-manifesting
DYT1 mutation carriers (Asanuma et al., 2005). One
explanation was that this was to a lesser extent than in
symptomatic carriers. Alternatively, additional factors
may be required for the motor symptoms to manifest
clinically. Other functional imaging (Eidelberg, 1998;
Meunier et al., 2001) and neuropsychological studies
(Heiman et al., 2004) of non-manifesting DYT1 carriers
also suggested subtle changes in brain networks which
do not manifest as a movement disorder.
In contrast to DYT1 dystonia, in DRD an increase
in dopamine D2-receptors was found, with unchanged
D1 and dopamine transporter labeling (Rinne et al.,
2004). The model (Figure 59.1C) predicts decreased
activity of the striato-GPe connection of the indirect
pathway in dystonia, which could be as a consequence
of inhibition from increased postsynaptic dopamine
D2 stimulation. However, it is not known whether
the tracer imaging results demonstrate a primary or
compensatory change and whether the D2-receptors
are pre- or postsynaptic. Additionally the DRD
patients were being treated with levodopa, making it
difficult to interpret the data and fit them to the model.
Recent work upon the neuropathology of Lubag
(DYT3) suggests a possible mechanism for dopaminergic
hyperactivity as the etiology of dystonia (Goto et al.,
2005) (discussed in more detail on p. 514).
Other studies suggest changes in the sensorimotor
cortex in dystonia. For example, an increase in size
in receptive fields of cortical sensory neurons and a
loss of specificity of cortical motor topography has been
observed in dystonia (Byl et al., 1996; Lenz et al., 1999;
Bara-Jimenez et al., 2000; Quartarone et al., 2003).
Decreased cortical inhibition in focal hand dystonia
(Ridding et al., 1995; Ikoma et al., 1996; Sohn and Hal-
lett, 2004), likely due to a reduction in cortical gamma-
aminobutyric acid (GABA) (Levy and Hallett, 2002)
suggests that decreased focusing is present in the sen-
sorimotor cortex, either as a primary or secondary phe-
nomenon. There is evidence for aberrant neuronal
plasticity in dystonia in experimental situations (Byl
et al., 1996) and in clinical practice, when focal dystonia
develops as the consequence of excessive performance
of the same task, as is seen in musicians and other
task-specific dystonia. The presence of a sensory trick
or geste antagoniste, when the patient can correct
the movement with a light touch, certainly suggests
involvement of sensory circuits.
When dystonia is due to a structural lesion of the
putamen, the model would predict that neurons of
the indirect pathway were preferentially damaged, as
decreased function of the first connection of the indir-
ect pathway is postulated (as opposed to increased
activity in the striato-GPi direct pathway). There is
as yet no neuropathological evidence to support this,
thus we do not know whether the model fits these clin-
ical situations. In addition, the model does not explain
why pallidotomy should reduce the symptoms of dys-
tonia. However, intraoperative recordings from small
numbers of patients with dystonia undergoing surgery
suggest that neuronal firing patterns show abnormal
bursting patterns rather than an absolute reduction in
rate (Vitek et al., 1999; Silberstein et al., 2003) and
that it is the information thus encoded which causes
the loss of movement selectivity.
The model proposes different mechanisms for the
different clinical manifestations of basal ganglia dys-
function. The presence of both simultaneously due to
a single disease process suggests a topographical var-
iation in signal processing, possibly within a single
structure of the basal ganglia.
59.1.5. The function of dopamine in the striatum
The precise function of dopamine within the striatum at
the synaptic level still remains to be fully elucidated.
The relationship between dopamine and glutamate
release from corticostriatal afferents is complex and inter-
dependent. Glutamatergic corticostriatal axons synapse
 PARKINSONISM AND DYSTONIA
on the heads of spines of striatal medium spiny neurons,
with nigrostriatal dopaminergic terminals synapsing on
the spine shafts, thus the release of dopamine is ideally
positioned anatomically to modulate the effect of inputs
from sensorimotor cortex (Smith et al., 1994).
The effect of dopamine upon the postsynaptic med-
ium spiny neurons which bear dopamine receptors
depends upon a number of variables. These include dopa-
mine receptor subtype (Calabresi et al., 1987, 1997),
recent activation by corticostriatal glutamate release in
a single spike or burst (long-term potentiation or long-
term depression (Calabresi et al., 1996; Arbuthnott
et al., 2000)), hyperpolarization by GABAergic inputs
(from globus pallidus or local axon collaterals) and
probably other factors as yet undetermined.
Release of dopamine itself is also modified by a
number of factors, including recent neuronal activity
(Cragg, 2003), corticostriatal afferents (Avshalumov
et al., 2003), inputs from cholinergic interneurons
(Partridge et al., 2002; Rice and Cragg, 2004), nitric
oxide synthase-containing interneurons (Saka et al.,
2002) and GABAergic afferents (Juranyi et al., 2003).
In addition, dopamine modulates glutamate release
from corticostriatal terminals via dopamine D2-recep-
tors (Bamford et al., 2004a, b). Evidence from these
studies suggests that dopamine facilitates more active,
but inhibits less active, corticostriatal inputs (Bamford
et al., 2004b). Dopamine also facilitates the effects of
glutamatergic inputs upon medium spiny neurons, via
postsynaptic D1-receptors (Flores-Hernandez et al.,
2002). In combination, these mechanisms serve to
reinforce selection of more active signals and to filter
out weaker ones. This may be represented in the cir-
cuit diagram (Fig. 59.1) by the center-surround
model being present in the striatum as well as further
downstream in the globus pallidus.
When dopamine is decreased, as in PD, there may
be a loss of facilitation of corticostriatal signals from
the motor cortex, with resultant difficulty in initiation
and slowness of movement. In dystonia, there appears
to be an excess of movement, often following the
initiation of a specific action. This may be the conse-
quence of a loss of signal selection, with unwanted corti-
costriatal signals being transmitted as discussed above.
There is evidence from functional imaging studies of
alterations in various indicators of striatal dopaminergic
neurotransmission in DYT1 dystonia (Playford et al.,
1993; Perlmutter et al., 1998) and DRD (Rinne et al.,
2004); however, these results should be interpreted with
caution. Preliminary evidence from transgenic mice car-
rying a mutation of torsinA, the cause of DYT1 dystonia
(Shashidharan et al., 2002, 2005; Bao et al., 2006) and
from a small number of humans with DYT1 dystonia
(Augood et al., 2002; Rostasy et al., 2003), suggested that
511
dopamine levels were decreased and turnover increased.
Clearly further study is necessary to determine the
precise nature of dopaminergic dysfunction in dystonia.
59.2. Parkinsonian disorders with dystonia
(Table 59.1)
59.2.1. Parkinsons disease (sporadic)
Dystonia may be a feature of PD in a variety of cir-
cumstances. A frequent early manifestation of PD is
with limb, typically leg, dystonia. This may persist as
a feature during off periods, particularly during the
night and early morning, when patients are not medi-
cated for an extended period. Such dystonia is distinct
from the dystonia seen during on periods, in that it is
fixed and painful. Characteristically this is described
as a painful cramp of the calf muscles and foot, with
the foot and toes plantar-flexed. It is possible that the
foot region of the putamen is particularly vulnerable
to disruptions of dopaminergic function. In addition
to the foot dystonia seen in early PD, both child-
hood-onset DYT1 dystonia (Bressman et al., 1998)
and DRD (Segawa and Nomura, 1993) typically pre-
sent with foot dystonia, before spreading more ros-
trally. The body is represented topographically in the
putamen, with the foot region being located dorsally
(Gerardin et al., 2003); therefore, there may be an ana-
tomic reason for the location of this symptom.
Truncal dystonia, resulting in forward and/or lateral
flexion of the spine (camptocormia) is seen in
advanced PD (Djaldetti et al., 1999) and may respond
to dopaminergic agents or deep brain stimulation
(DBS), but often becomes fixed. This can be a
severely disabling feature of the disease. Dystonia of
other regions has also been reported in PD, including
cervical, cranial and upper limb (Katchen and Duvoi-
sin, 1986; LeWitt et al., 1986; Poewe et al., 1988;
Morrison and Patterson, 1992).
Dystonia is often a component of levodopa-induced
dyskinesias. Levodopa-induced dyskinesias can be
seen as blood levels of medication are increasing or
wearing off (onoff dyskinesias) or at the peak dose of
medication. Peak-dose dyskinesias involve the arms,
trunk and neck and are usually choreiform but may
incorporate more sustained involuntary muscle contrac-
tions, either alone or in combination with rapid, flowing
movements. Onoff dyskinesias tend to involve the
legs and often have a dystonic component. The dyskine-
sias which occur as levodopa or dopamine levels are
changing are hypothesized to be the result of an
imbalance of dopamine transmission between different
pathways or possibly between adjacent striatal micro-
circuits. Therapies which smooth out serum/brain
512 R. H. WALKER
Table 59.1
Parkinsonian disorders in which dystonia may occur

Other
neurological Other
Disease Inheritance Dystonia Parkinsonism features Genetic tests useful tests

Parkinsons disease Sporadic, , off, Subcortical Parkin, DJ-1, Response to

AR, AD peak- dementia PINK1, levodopa,
dose a-synuclein, dopamine
LRRK2 transporter
imaging
Postencephalitic Sporadic Dementia
parkinsonism
Progressive Sporadic Dementia,
supranuclear vertical gaze
palsy palsy
Corticobasal Sporadic Focal cortical
degeneration signs, alien
limb
Multiple system Sporadic Autonomic, Fe in putamen on
atrophy cerebellar MRI
Primary pallidal Sporadic Chorea
degeneration
Frontotemporal AD, Dementia tau
dementia and sporadic
parkinsonism
Neuronal Sporadic Dementia,
intermediate corticospinal
filament disease

AD, autosomal dominant; AR, autosomal recessive; absent; mild; moderate; marked; MRI, magnetic resonance imaging.

levodopa/dopaminergic levels are usually beneficial,
such as catechol-O-methyltransferase inhibitors or the
use of longer-acting dopaminergic agents. DBS of the
STN is also helpful as it enables less dopaminergic
medication to be used.
59.2.2. Inherited Parkinsons disease
There is debate as to whether disease due to some of
the causative mutations identified to date, such as of
parkin and PARK8, can truly be called PD, as the
pathologic hallmark, the Lewy body, is often (but not
invariably) absent in these cases (Singleton, 2004).
However, the clinical criteria in terms of symptom-
atology, disease progression and response to levodopa
are otherwise identical to idiopathic PD, so for the
purpose of classification they are included here.
Mutation of the parkin gene typically results in dis-
ease onset in the 20s and 30s and may be the result of
either heterozygosity or homozygosity for mutant
alleles. Dystonia, sometimes exercise-induced (Khan
et al., 2003), is often a presenting feature in these
patients, but appears to be more related to young age
of onset rather than the presence of the causative muta-
tion (Quinn et al., 1987; Khan et al., 2003; Lohmann
et al., 2003; Tan et al., 2003b). The response to levo-
dopa is usually striking and this feature, in combina-
tion with prominent dystonia, may even suggest a
diagnosis of DRD (Tassin et al., 2000).
Autosomal-dominant inheritance, for example of a-
synuclein (Polymeropoulos et al., 1997) or LRRK2
(Zimprich et al., 2004) mutations, tends to result in more
typical disease. Autosomal-recessive inheritance of
mutations of other genes causing early-onset PD, DJ-1
(Bonifati et al., 2003) and PINK1 (Valente et al., 2004),
do not appear to be specifically characterized by dysto-
nia, although the rarity of these mutations as a cause of
either sporadic or familial early-onset PD (Clark et al.,
2004), means that a typical phenotype is not yet fully
characterized.
59.2.3. Postencephalitic parkinsonism
Postencephalitic parkinsonism was the consequence of
von Economos encephalitis, which affected many
people in the earlier part of the 20th century. Although
 PARKINSONISM AND DYSTONIA
this pandemic was temporally coincident with the
influenza pandemic, it has not been confirmed that
encephalitis lethargica was due to the influenza virus.
This condition is often understood to be a hypoki-
netic-rigid syndrome; however, dystonia and other
hyperkinetic movements were quite prominent (Evi-
dente et al., 1998; Albanese, 2003). Dystonia usually
appeared to be cranial segmental in distribution,
although the limbs were also involved (Morrison and
Patterson, 1992; Evidente et al., 1998).
Contemporary encephalitides may occasionally
cause this syndrome. For example, parkinsonism and
dystonia have been reported following Japanese ence-
phalitis (Murgod et al., 2001).
59.2.4. Progressive supranuclear palsy
The dystonias seen in this parkinsonian neurodegen-
erative condition are strikingly different from those
seen in PD. Blepharospasm is a frequent feature and
may be functionally very limiting, but responds well
to botulinum toxin injection. Extension of the trunk
and neck is characteristic, with retropulsion, unlike in
PD, where there tends to be forward flexion. Although
usually associated with a diagnosis of CBD, limb
dystonia has been reported in neuropathologically
confirmed PSP (Barclay and Lang, 1997; Oide et al.,
2002). Diagnostic pathological changes are neuro-
fibrillary tangles in the basal ganglia and midbrain.
Dystonic dyskinesias are rare as a side-effect of
levodopa therapy in this condition, but may occur
(Barclay and Lang, 1997; Tan et al., 2003a). Func-
tional benefits from dopaminergic medications in
PSP and the following conditions are usually minimal.
59.2.5. Corticobasal degeneration
CBD is characterized by an asymmetric presentation of
parkinsonism, dystonia and cortical deficits, due to
pathology of the basal ganglia and cortex. Limb dystonia
may result in flexion contractures of the hand and arm.
The leg tends to be extended at the knee and the foot
plantar-flexed and inverted. The alien-limb phenom-
enon may be seen, in which the patients hand performs
involuntary semipurposeful movements and is presumed
to be due to involvement of cortical motor areas.
59.2.6. Multiple system atrophy
The parkinsonism of MSA is due to degeneration of the
GABAergic medium spiny striatonigral neurons, which
receive inputs from the nigrostriatal dopaminergic
neurons. In addition, degeneration of either cerebellar
outputs or neurons of the autonomic nervous system
513
comprises the syndrome. Typically, the parkinsonism is
midline with marked axial rigidity and falling and cervi-
cal antecollis is often seen (Boesch et al., 2002). Limb
dystonia may also be present (Boesch et al., 2002).
59.2.7. Frontotemporal dementia and
parkinsonism
This disease can be seen in an autosomal-dominant
familial form, associated with heterozygous mutation
of the gene for tau protein on chromosome 17 (Hutton
et al., 1998), or may be sporadic. Neuropathologically,
mutations of tau result in typical deposits of this protein
(Taniguchi et al., 2004). In cases due to tau mutations,
parkinsonism, rather than frontotemporal dementia,
may be associated with a particular genetic haplotype
(Walker et al., 2002a) and dystonia, particularly cranial,
may be present (Walker et al., 2002a).
59.2.8. Primary pallidal degeneration
Rarely, cases of bradykinesia and dystonia have been
reported in which neuropathological changes were
limited to the globus pallidus (Aizawa et al., 1991).
The onset was in adulthood and the disease was dis-
tinct from PD in that there was no increase in muscle
tone. Onset at younger age has also been reported,
associated with marked rigidity and more choreiform
and dystonic movements.
59.2.9. Neuronal intermediate filament inclusion
disease
This rare sporadic disorder may present with a variety of
neurologic features, including frontotemporal dementia,
behavioral change, corticospinal signs and parkinsonism
in young adulthood (Cairns et al., 2004). Limb dystonia
may also be seen, along with supranuclear palsy and buc-
cal apraxia. The diagnosis is made neuropathologically
with the finding of characteristic neuronal inclusions
which are immunoreactive for phosphorylated intermedi-
ate filament (Cairns et al., 2004).
59.3. Dystonic disorders with parkinsonism
Only dystonic conditions with parkinsonian features are
described in detail here. These and the other genetically
defined dystonias are summarized in Table 59.2
59.3.1. Lubag (DYT3)
X-linked dystonia-parkinsonism is found solely amon-
gst Filipinos from the province of Capiz on the island
of Panay (Lee et al., 1976). Although mostly males are
514 R. H. WALKER
Table 59.2
The genetically defined dystonias with genes and gene products (where known)

Name Inheritance Gene Location Protein Parkinsonism

DYT1 Primary torsion dystonia AD DYT1 9q34 torsinA

DYT2 Generalized early onset AR ? ? ?
DYT3 Lubag X-linked DYT3 Xq31.1 Multiple transcript
system
DYT4 Whispering dysphonia AD ? ATP7B ? 13q14.3 ? Copper-transporting
ATPase 2
DYT5 Dopa-responsive AD GCH-1 14q22.1 GTP cyclohydrolase-1
dystonia AR TH 11p15.5 Tyrosine hydroxylase
DYT6 Adolescent-onset mixed AD 8p ?
DYT7 Adult cervical and AD 18p ?
upper-limb dystonia
DYT8 Paroxysmal non- AD 2q23 ?
kinesogenic
dyskinesia
DYT9 Episodic AD 1p21 ?
choreoathetosis/ataxia
spasticity
DYT10 Paroxysmal kinesogenic AD 16p Sodium channels?
choreoathetosis/
dystonia
DYT11 Myoclonus-dystonia AD SGCE 7q21 E-sarcoglycan
DYT12 Rapid-onset dystonia- AD ATP1A3 19q13 Na/K-ATPase
parkinsonism a3 subunit
DYT13 Cranal, cervical and AD 1p36.13 ?
upper-limb dystonia 32
DYT14 Dopa-responsive AD 14q13 ?
dystonia
DYT15 Myoclonus dystonia AD 18p.11 ?

AD, autosomal dominant; AR, autosomal recessive; absent; mild; moderate; marked; ATPase, adenosine triphosphatase; GTP,
guanosine triphosphate.

affected, symptomatic carrier females have occa-
sionally been reported, but tend to have a milder
phenotype (Waters et al., 1993b; Evidente et al.,
2004). Onset is from the teens to the mid-40s, with
progression over 57 years and then stabilization.
Presentation is often with focal dystonia (lubag
describes the twisting movements and wa-eg, the
abnormal sustained postures, in the local Illongo dia-
lect) and may vary widely (Evidente et al., 2002).
Parkinsonism (sud-sud, named for the shuffling gait)
may be an early or presenting feature and most
patients have mixed features. There is minimal
response to levodopa and antidystonic agents (Evi-
dente et al., 2002). A benefit has been reported with
the GABA-A receptor agonist zolpidem (Evidente,
2002).
The causative gene has been identified as coding
for a multiple transcript system whose function is not
yet known (Nolte et al., 2003).
An elegant study comparing the neuropathology
of parkinsonian cases with dystonic cases found, in dys-
tonic cases, predominant loss of striatal projection neu-
rons in striosomes and patchy loss in the surrounding
matrix (Goto et al., 2005). This work supports the
three-pathway model of basal ganglia function, which
emphasizes the relative roles of striosomes and matrix
(Graybiel et al., 2000). According to this model, loss of
the inhibitory striosomal projection to the SNpc results
in increased dopaminergic activity, thus causing
increased activity of the neurons of the direct pathway
and hence the decreased activity of the GPi, in ac-
cordance with the traditional model (Fig. 59.1C). As the
disease progresses, striatal neuronal loss becomes more
widespread and loss of the striato-GPi neurons, which
were previously hyperactive, results in parkinsonism.
Other previous reports have also shown mosaic
degeneration of the striatum in Lubag (Waters et al.,
1993a; Singleton et al., 2004).
 PARKINSONISM AND DYSTONIA
This diagnosis should be considered in any Filipino,
even women, presenting with any movement disorder
and a detailed family history should be taken so that
appropriate counseling can be given (Evidente et al.,
2002).
An Italian family has been reported with parkinson-
ism and dystonia affecting males in an apparently X-
linked manner (Fabbrini et al., 2005). Linkage to the
DYT3 locus was demonstrated, but no disease-causing
mutations were detected in the gene.
59.3.2. Dopa-responsive dystonia (Segawa disease)
(DYT5, DYT14)
DRD is due to a variety of mutations of the gene for gua-
nosine triphosphate cyclohydrolase-1 (GTP-CH1) (Ichi-
nose et al., 1999) or for tyrosine hydoxylase (TH).
GTP-CH1 is a key enzyme involved in the synthesis of
tetrahydrobiopterin, which is a necessary cofactor for
the synthesis of TH. DRD is typically autosomal-domi-
nant with incomplete penetrance, affecting females more
than males (Furukawa et al., 1998). Autosomal-recessive
inheritance of mutations of the gene for TH may also be
responsible for a very similar disease (Hoffmann et al.,
2003). Another locus responsible for autosomal-domi-
nant DRD has been identified on chromosome 14,
although the gene product is not yet known (Nygaard
et al., 1993). Onset is in childhood, with mixed features
of parkinsonism and lower-limb dystonia. Very young
onset with severe spasticity may be mistaken for cerebral
palsy (Nygaard et al., 1994). This disorder is characteris-
tically exquisitely responsive to low or moderate doses of
levodopa and even young children who are misdiagnosed
for a number of years may recover significant function.
Neuropathologically, there is decreased immunoreac-
tivity for TH in the SNpc, but no signs of neuronal loss or
Lewy bodies (Ichinose et al., 1999; Grotzsch et al.,
2002).
59.3.3. Rapid-onset dystonia-parkinsonism
(DYT12)
This disorder is inherited in an autosomal-dominant
manner (Brashear et al., 1998) and is due to muta-
tion of ATP1A3 which encodes for the a3 subunit
of Na/K-ATPase (de Carvalho et al., 2004). The
onset may be in the teens or 20s and is often seen fol-
lowing a period of physiologic stress, such as pro-
longed physical exertion, fever or childbirth, when
symptoms evolve over a period of hours or days and
then plateau. Dystonia typically affects the cranial
musculature or the limbs and patients have addition-
ally bradykinesia, dysphagia, dysarthria and gait
515
instability. From a single case report there are no
neuropathological abnormalities (Pittock et al., 2000).
59.4. Mixed movement disorders
59.4.1. Autosomal-dominant (Table 59.3)
59.4.1.1. Huntingtons disease
The juvenile form of this genetic disorder, with age of
onset younger than 20 years, known as the Westphal
variant, is characterized by a parkinsonian presenta-
tion, often with marked dystonia. These tend to result
from paternal inheritance, when there is greater
instability of the trinucleotide repeat expansion.
In adult-onset HD, as the disease advances, chorea
often gives way to more parkinsonian and dystonic
features, with severe bradykinesia or akinesia, rigidity
and postural impairment (Penney et al., 1990; Kremer
et al., 1992). Rarely, HD may even present as levo-
dopa-responsive parkinsonism with very mild chorea
(Reuter et al., 2000). The juvenile form may also
respond to both levodopa (Low and Allsop, 1973) and
dopamine agonists (Bonelli et al., 2002), suggesting that
the deficit is of presynaptic nigral dopaminergic neu-
rons. Although degeneration of striatal medium spiny
neurons is well documented as the primary neuropatho-
logic abnormality, loss of neurons from the SN, both
pars compacta and pars reticulata, has also been
described (Bugiani et al., 1984; Oyanagi et al., 1989).
One clue to the diagnosis of HD is, of course, a
positive family history, although in consideration of
late-onset disease or non-paternity, a negative pedigree
should not pre-empt genetic testing.
59.4.1.2. Huntingtons disease-like 2
Huntingtons disease-like 2 (HDL2) (Margolis et al.,
2001) is a trinucleotide repeat expansion disease
(Holmes et al., 2001), which bears a striking resem-
blance to HD in many clinical, genetic and neuro-
pathological aspects. The genetic mutation associated
with HDL2 has been characterized as a CTG/CAG tri-
nucleotide repeat expansion within the junctophilin-3
(JPH3) gene on chromosome 16q24.3 (Holmes et al.,
2001). In the normal population the repeat length
ranges from 6 to 27 CTG/CAG triplets, whereas
affected individuals have 4158 triplets. The repeat
lies within an alternatively spliced exon of JPH3 and
because of variable splice acceptor sites may encode
either polyalanine or polyleucine or may be untrans-
lated. Whether the expanded repeat is translated or
even transcribed remains unknown.
There can be marked variations in phenotype
and parkinsonism, chorea or dystonia may be present
(Walker et al., 2003a). The initial symptoms are often
516 R. H. WALKER
Table 59.3
Mixed movement disorders in which parkinsonism and dystonia may both occur; autosomal-dominant (AD), X-linked
inheritance and sporadic

Other neurolo-
Disease Inheritance Dystonia Parkinsonism gical features Affected protein Other useful tests

Huntingtons disease AD Chorea Huntingtin

Huntingtons disease-like 2 AD Chorea Junctophilin-3 Acanthocytosis
(10%)
Spinocerebellar ataxia III AD Chorea Ataxin 3
Spinocerebellar ataxia 17 AD Chorea TATA-binding
protein
Dentatorubropallidoluysian AD Chorea, Atrophin
atrophy ataxia
Neuroferritinopathy AD Chorea Ferritin light Ferritin, Fe in basal
chain ganglia on MRI
Fahrs disease AD, other Ataxia, chorea, ? Calcification on
(idiopathic basal cognitive, neuroimaging;
ganglia calcification) behavioral rule out
changes parathyroid
disease
McLeod syndrome X-linked Chorea, XK Kell and Kx ag,
seizures, acanthocytosis,
peripheral CK, LFTs
neuropathy
Neuroleptic-induced Sporadic
(acute)
Tardive dyskinesia Sporadic ? Chorea
Alzheimers disease Sporadic, Dementia, Presenilin,
AD rigidity amyloid
precursor
protein

absent; mild; moderate; marked; CK, creatine kinase; LFTs, liver function tests; MRI, magnetic resonance imaging.

a change in personality and cognitive functioning, evol-
ving over 10 years or more to frank dementia. The neuro-
logic presentation varies within families and in some
cases changes with evolution of the disease. The relation-
ship between clinical features and size of the trinucleo-
tide repeat expansion at this point remains uncertain,
although, as in HD, the size of the repeat correlates
inversely with the age of onset (Margolis et al., 2004).
The range of phenotypes is similar to that observed in
HD, although parkinsonism can be prominent in adult-
onset cases, as compared with HD when this presentation
is usually associated with juvenile onset with very long
repeat expansions. The mechanism of the phenotypic
variation in HDL2 remains to be determined.
All patients reported to date have been of African
ancestry (Holmes et al., 2001; Margolis et al., 2001,
2004) and no patients of Caucasian ancestry have yet
been found (Andrew et al., 1994; Bauer et al., 2002;
Stevanin et al., 2002). Occasionally, acanthocytosis
can be found on peripheral blood smear, resulting in
confusion of the diagnosis with neuroacanthocytosis
(Walker et al., 2002b, 2003b).
59.4.1.3. Spinocerebellar ataxias and
dentatorubropallidoluysian atrophy
The phenotypes of the SCAs can involve movement
disorders, in addition to signs and symptoms of cere-
bellar neurodegeneration. These neurodegenerative
disorders are inherited in an autosomal-dominant man-
ner and are usually due to expanded trinucleotide
repeats within various proteins. The size of the expan-
sions does not in general appear to correlate with the
phenotype.
The most common SCA in most populations, SCA
III (MachadoJoseph disease) can present with parkin-
sonism, dystonia and chorea, usually in association
with the typical cerebellar signs and eye findings.
 PARKINSONISM AND DYSTONIA
A variety of movement disorders may be seen in
SCA 17, including parkinsonism, dystonia and chorea
(Stevanin et al., 2003; Zuhlke et al., 2003), in addition
to the typical phenotype of ataxia, dementia and
hyperreflexia.
SCA II has been reported to present with levodopa-
responsive parkinsonism (Shan et al., 2001; Furtado
et al., 2004) but not dystonia.
Dentatorubropallidoluysian atrophy (DRPLA) is
found more often in Japanese populations, but rarely
in Caucasian (Le Ber et al., 2003; Martins et al., 2003)
or African-American (Burke et al., 1994) families and
may present with movement disorders, including dys-
tonia, myoclonus and chorea. Usual features are ataxia
and dementia. Seizures are common in patients with
onset below the age of 20, but tend to decrease with time
and are rare in older-onset patients.
59.4.1.4. Neuroferritinopathy
This is one of the disorders that falls under the classi-
fication of neurodegeneration with brain iron accu-
mulation (NBIA), as the mutation of ferritin light
chain results in iron deposition in the basal ganglia
(Curtis et al., 2001). However, unlike the other disor-
ders (panthothenate kinase-associated neurodegenera-
tion, aceruloplasminemia; see below), most of which
are inherited in an autosomal-recessive fashion, this
is an autosomal-dominant disorder. This may result
in a variety of movement disorders, including chorea,
dystonia and parkinsonism (Crompton et al., 2004;
Mir et al., 2004), with onset at age 4055 years. Cog-
nitive impairment is not normally seen, although it can
occasionally be a feature (Wills et al., 2002). Serum
ferritin values tend to be below, or at the lower end
of, the normal range.
59.4.1.5. Fahrs Disease
Fahrs disease (idiopathic basal ganglia calcifica-
tion; IBGC) refers to a heterogeneous group of disor-
ders in which there is deposition of calcium in the
basal ganglia and other cerebral regions, particularly
the deep cerebellar nuclei. The clinical picture may
include dystonia, parkinsonism, chorea, ataxia, cog-
nitive impairment and behavioral changes. In one
family, linkage to 14q was demonstrated (IBC1)
(Geschwind et al., 1999) although the gene has not
yet been identified. In several other families with auto-
somal-dominant inheritance, linkage to this locus was
excluded (Brodaty et al., 2002; Oliveira et al., 2004).
In other families (Reske-Nielsen et al., 1988;
Younes-Mhenni et al., 2002), the pattern of inheritance
and additional clinical features suggest mitochondrial
inheritance.
517
59.4.2. X-linked recessive (Table 59.3)
59.4.2.1. McLeod syndrome
The X-linked McLeod neuroacanthocytosis syndrome
(Symmans et al., 1979; Takashima et al., 1994; Danek
et al., 2001) is similar to autosomal-recessive chorea-
acanthocytosis (ChAc) (see below) in its neurological
presentation, but other organ systems are also involved.
Onset of clinical symptoms is typically in mid to late
adulthood (Danek et al., 2001; Jung et al., 2001a).
Patients may present with subtle neurobehavioral
changes, particularly subcortical dementia, which are
sometimes only fully recognized when the movement
disorder develops. In addition to chorea, dystonia and
parkinsonism may also be seen. Facial hyperkinesias
with dysarthria and involuntary vocalizations are fre-
quent, although the self-mutilating lip-biting seen in
autosomal-recessive ChAc is not characteristic. Periph-
eral sensorimotor neuropathy and areflexia are typical.
Seizures are seen in 50% and can usually be controlled
with standard anticonvulsant medications.
Cardiomyopathy is present in approximately two-
thirds of patients and cardiac arrhythmias may be a
significant source of morbidity and mortality (Danek
et al., 2001). Elevated serum creatine kinase (often
into the 1000s) is an invariable finding and frank myo-
pathy is common (Kawakami et al., 1999; Danek et al.,
2001). Liver enzymes are elevated and hepatospleno-
megaly is present in 40% of patients and may lead to
evaluation for liver disease prior to neurologic presen-
tation (Walker et al., 2005).
Often patients are identified, as was the eponymous
subject McLeod, at blood banks by blood antigen typ-
ing. Rare patients with the McLeod red blood cell
antigen phenotype, but without any neurological or
systemic abnormalities, have been reported (Jung
et al., 2003; Walker et al., in press). Occasionally car-
rier females have been symptomatic, presumably due
to X-chromosome inactivation (Hardie et al., 1991;
Ueyama et al., 2000; Jung et al., 2001a).
Neuroimaging typically shows a decrease in basal
ganglia volume (Danek et al., 2001), although white-
matter changes have also been reported (Nicholl
et al., 2004). Neuropathologic findings appear non-
specific, with neuronal loss and reactive gliosis (Brin
et al., 1993; Geser et al., 2006).
The phenotype is defined by the characteristics of
the red blood cell (RBC) Kell antigen system (Allen
et al., 1961), the third most important erythrocyte anti-
gen system after ABO and rhesus. Mutation of the XK
gene causes reduced or absent XK protein. As the XK
protein is closely associated with the Kell proteins and
determines Kell antigen expression, this results in a
reduction in the Kell protein on the RBC membrane
518 R. H. WALKER
(Russo et al., 1998). Patients thus have absent Kx anti- to the clinical appearance of parkinsonism (Rinne
gen expression and reduced Kell antigen expression. et al., 1994).
The diagnosis can only be confirmed at specialized
laboratories which have the requisite panel of anti-Kell 59.4.3.2. Wilsons disease
and anti-Kx antibodies. XK may function as a membrane
This autosomal-recessive disorder of copper metabo-
transport protein (Ho et al., 1994) and has been found in
lism may present with a variety of abnormal move-
muscle and brain in addition to RBCs (Ho et al., 1994;
ments. The causative mutation is of the ATP7B
Jung et al., 2001a, b; Russo et al., 2000). This abnormal-
gene, resulting in an inability to transport copper on to
ity of RBC membrane proteins is presumably the cause
ceruloplasmin, with resultant copper accumulation in
of the characteristic acanthocytosis.
brain, liver, cornea and elsewhere. The typical neurolo-
gical presentation is with an asymmetric, flapping arm
59.4.3. Autosomal-recessive (Table 59.4) tremor, which may vary in amplitude, distribution and
59.4.3.1. Chorea-acanthocytosis the position in which it is elicited. The gait is often
affected and may be parkinsonian or cerebellar. Dysto-
ChAc, previously known as neuroacanthocytosis or
nia of the face, tongue and pharynx can be seen, which,
LevineCritchley syndrome (Levine et al., 1960;
in combination with cerebellar dysfunction, may result
Critchley et al., 1968), is an autosomal-recessive disor-
in dysarthria. The classic risus sardonicus of Wilsons
der due to a mutation of the VPS13A gene (formerly
disease is due to dystonia affecting the lower facial mus-
CHAC) (Velayos-Baeza et al., 2004) located on chro-
cles. A hereditary whispering dysphonia (DYT4) is
mosome 9q21 (Rubio et al., 1999; Ueno et al., 2001).
associated with Wilsons disease (Elwes and Saunders,
Similar to XK (see above), this protein appears to be
1986).
involved in membrane processing and sorting, which
Limb and trunk dystonia can also be a feature,
may account for the RBC membrane abnormalities.
although these are extremely uncommon as a presen-
The movement disorder in this neurodegenerative
tation of Wilsons disease in the absence of hepatic
disease is typically chorea, presenting in young to
features. In a series of patients with cervical dystonia
mid-adulthood with marked lingual-buccal-facial dyski-
as the sole symptom, no cases of Wilsons disease
nesia and self-mutilation (Rampoldi et al., 2002). As
were detected (Risvoll and Kerty, 2001).
with several other basal ganglia disorders described
On neuroimaging and neuropathological evaluation,
here, these patients may present with psychiatric
the basal ganglia and brainstem are consistently
(Rovito and Pirone, 1963; Bruneau et al., 2003), beha-
affected by abnormal copper deposition (Magalhaes
vioral or cognitive problems. Dystonia is found in 50%
et al., 1994; Sener, 2003; Page et al., 2004), thus the
of patients (Rampoldi et al., 2002). Other abnormal
presence of movement disorders is not surprising.
movements are often seen, including vocal and motor
The importance of awareness of Wilsons disease as
tics (Saiki et al., 2004). Parkinsonism is reported in
part of the differential diagnosis of movement disor-
32% of patients (Rampoldi et al., 2002) and may be a
ders is that it is one of the few etiologies that can be
presenting feature (Bostantjopoulou et al., 2000).
effectively treated, thus a high level of suspicion is
Widespread involvement of the nervous system is sug-
always warranted. Testing for serum ceruloplasmin
gested by the presence of seizures, cognitive impair-
levels, 24-hour copper excretion and slit-lamp exami-
ment and peripheral neuropathy. Outside the nervous
nation for KayserFleischer rings are all necessary to
system, the liver and spleen may be enlarged, with
exclude the diagnosis.
abnormal liver function tests, although this is less com-
mon than in McLeod syndrome (Rampoldi et al.,
2002). Unlike McLeod syndrome, cardiomyopathy is 59.4.3.3. Aceruloplasminemia
very rare. Deficiency of ceruloplasmin, due to autosomal-reces-
A Japanese family with apparent autosomal-domi- sive inheritance of mutations of the gene for cerulo-
nant inheritance of this disorder, documented muta- plasmin, results in iron deposition in the retina,
tions of VPS13A and an apparently identical pancreas, cerebellum and basal ganglia (Miyajima,
phenotype to the autosomal-recessive form has been 2003; Xu et al., 2004). Typical presentation is of ret-
reported (Saiki et al., 2003). Diagnosis of this disorder inal degeneration and diabetes mellitus in the 20s. In
can be confirmed by a quantitative test for chorein the 40s and 50s neurological signs appear, usually
(Dobson-Stone et al., 2004). ataxia. Subsequently dystonia, especially orofacial, par-
Neuropathologically, there is degeneration of the kinsonism and chorea, may develop. Dementia may
caudate nucleus and putamen and there may be manifest in later years. Symptomatic heteroplasmic
marked loss of substantia nigra neurons, corresponding carriers have also been reported.
Table 59.4
Mixed movement disorders in which parkinsonism and dystonia may both occur; autosomal-recessive (AR) inheritance
Chorea-acanthocytosis
Wilsons disease
Aceruloplasminemia
Pantothenate kinase-
associated
neurodegeneration
GM1 gangliosidosis type 3
GM2 gangliosidosis late-
onset
NiemannPick type C
Gaucher disease type III
Glutaric aciduria
2-Hydroxyglutaric
aciduria
Homocystinuria
Biotin-responsive basal
ganglia disease
Juvenile neuronal ceroid
lipofuscinosis
Adult neuronal ceroid
lipofuscinosis
Neuronal intranuclear
(hyaline) inclusion
disease
AD, autosomal dominant; AR, autosomal recessive; absent; mild; moderate; marked; CK, creatine kinase; LFTs, liver function tests; MRI, magnetic resonance imaging.
Inheritance Dystonia Parkinsonism Other neurological features Affected protein Other tests
AR Chorea, peripheral neuropathy, Chorein Acanthocytosis, CK, LFTs,
seizures chorein assay
AR Tremor, ataxia ATP7B Ceruloplasmin, Cu
excretion, Kayser
Fleischer rings
AR Ataxia, chorea Ceruloplasmin Fe on MRI in basal ganglia
AR Chorea, spasticity, dementia, Pantothenate kinase 2 Acanthocytes (8%)
retinal degeneration
PARKINSONISM AND DYSTONIA
AR Cerebellar, dysarthria, dementia b-galactosidase Bone marrow foam or
Gaucher-like cells
AR / Cerebellar, spasticity, seizures, Hexosaminidase A High T2 in basal ganglia on
peripheral neuropathy, MRI
supranuclear vertical gaze palsy
AR Supranuclar vertical gaze palsy, Sphingomyelinase Bone marrow sea-blue
cerebellar, intention tremor histiocytes
AR (facial) Seizures, myoclonus, horizontal Glucocerebroside Bone marrow Gaucher
gaze palsy cells
AR Encephalopathy Glutaryl-coenzyme A Urinary amino acids
dehydrogenase
AR Encephalopathy, seizures 2-hydroxyglutaric acid Urinary amino acids
dehydrogenase (l or d
isoform)
AR / Vascular thrombosis, mental Cystathione beta-synthase Urinary amino acids
retardation
AR Encephalopathy, quadriparesis, ?Biotin transporter Biotin-responsiveness
spasicity, seizures
AR Dementia, seizures, visual loss CLN3 Skin biopsy
AR (facial) Epilepsy, myoclonus dementia; Skin biopsy
extrapyramidal signs, dementia
AR (also Cerebellar, corticospinal Neuropathology
sprodic,
AD?)
519
520 R. H. WALKER
Copper metabolism is not disturbed by the lack
of ceruloplasmin. However, as ceruloplasmin func-
tions as a ferroxidase, iron oxidation from Fe2 to
Fe3 is impaired and neurons are also more vulnerable
to oxidative stress. Neuropathologically, astrocytes
and neurons laden with iron are found in the cerebel-
lum, basal ganglia and cortex (Miyajima, 2003; Xu
et al., 2004).
59.4.3.4. Pantothenate kinase-associated
neurodegeneration
The disorder now known as pantothenate kinase-asso-
ciated neurodegeneration (PKAN) is due to mutations
of pantothenate kinase 2 (PANK2) located on chromo-
some 20p13 (Zhou et al., 2001). The course in typical
cases is of disease onset by the age of 10 years with
dystonia and a rapid progression over the next 10 years
(Hayflick et al., 2003). Orofacial and limb dystonia,
choreoathetosis and spasticity are characteristic early
features. Approximately one-third of typical cases
develop cognitive impairment and two-thirds have
retinopathy. The typical magnetic resonance imaging
(MRI) eye of the tiger pattern of iron deposition in
the globus pallidus was seen in the majority of these
patients (Hayflick et al., 2003; Hartig et al., 2006).
8% of typical PANK patients have acanthocytosis.
The occasional reported association of decreased pre-
betalipoprotein levels (hypoprebetalipoproteinemia,
acanthocytosis, retinitis pigmentosa and pallidal degen-
eration: HARP syndrome) (Orrell et al., 1995; Malan-
drini et al., 1996) in patients with PANK2 mutations
(Ching et al., 2002) does not appear to be of clinical sig-
nificance and may be observed in normal subjects
(Houlden et al., 2003; Danek and Hegele, 2004).
In atypical cases disease onset is after the age of 20,
with dystonia, rigidity and gait freezing, but slower
progression. Early speech difficulty, with pallilalia or
dysarthria, is common, as are cognitive decline and
personality change. These patients do not tend to have
retinopathy. In one-third of these there is a mutation
of PANK2 and the diagnostic MRI finding, whereas
in two-thirds PANK2 mutations were not found, nor
was there the typical MRI image (Hayflick et al.,
2003). These are classified as NBIA without PANK2
mutation.
The majority of clinically typical cases are due to
mutations of PANK2 causing protein truncation. Pan-
tothenate kinase catalyzes the rate-limiting step in the
synthesis of coenzyme A from vitamin B5 (pantothe-
nate). The amount of active enzyme correlates with
the disease phenotype, as typical patients have no
active enzyme but atypical patients, in whom there is
a missense mutation of PANK2, may have some
enzyme function (Hayflick et al., 2003). The distribu-
tion of the neurological lesions is thought to relate to
the accumulation of iron and other neurotoxic sub-
stances and to local tissue demand for coenzyme A
(Zhou et al., 2001).
59.4.3.5. GM1 gangliosidosis
The late-onset, chronic form (adult; type 3) of GM1
gangliosidosis is slowly progressive and may present
during childhood or as late as the fourth decade. This
form affects only the central nervous system and does
not affect the skeletal system. Dystonia is often
marked, especially orofacial, and dysarthria and dys-
phagia may be severe. Features of parkinsonism are
also reported (Goldman et al., 1981; Uyama et al.,
1992; Yoshida et al., 1994; Muthane et al., 2004).
MRI frequently shows bilateral putaminal hyperinten-
sities on T2 sequences (Uyama et al., 1992; Muthane
et al., 2004).
59.4.3.6. GM2 gangliosidosis
The late-onset forms of GM2 gangliosidosis may
occur in childhood, adolescence or adulthood as either
subacute or chronic forms. Dystonia and choreoatheto-
sis have been reported in the subacute forms, along
with dysarthria, speech loss, ataxia, spasticity, seizures
and behavioral changes (Meek et al., 1984; Hardie
et al., 1988; Nardocci et al., 1992). In general, cerebel-
lar and corticospinal abnormalities tend to predomi-
nate over basal ganglia-related symptomatology.
Parkinsonism has rarely been reported (Inzelberg and
Korczyn, 1994). Supranuclear ophthalmoplegia and
oculomotor apraxia may occur (Specola et al., 1990)
and thus this disorder should be considered in atypical
presentations of PSP.
59.4.3.7. NiemannPick type C
This disorder may present in childhood or even late into
adulthood with cerebellar signs, intention tremor and
dysarthria. Dystonia and chorea-athetosis may be pre-
sent and, as with GM2 gangliosidosis, the presence of
supranuclear gaze palsy, specifically loss of vertical
gaze, may lead this disorder to resemble PSP (Coleman
et al., 1988; Cardoso and Camargos, 2000).
59.4.3.8. Gaucher disease type III
The neuropathic form of this disease presents from
childhood until early adulthood, with action myo-
clonus and seizures and a supranuclear palsy of hori-
zontal gaze. Occasionally facial grimacing may be
observed. An association between heterozygous car-
riers of the mutation and variably treatment-responsive
parkinsonism has been reported (Tayebi et al., 2003;
 PARKINSONISM AND DYSTONIA
Aharon-Peretz et al., 2004; Goker-Alpan et al., 2004).
It is hypothesized that mutations of the glucocere-
brosidase gene confer susceptibility to parkinsonism,
possibly by interfering with protein degradation in
the SNpc.
59.4.3.9. Glutaric aciduria
Glutaric acidura typically presents with generalized dys-
tonia and parkinsonism may also be a feature (Gascon
et al., 1994), in addition to the other features of encepha-
lopathy. Often the presentation is catastrophic in early
infancy, but occasionally it may present more gradually
in later childhood or even adulthood. On MRI, dilation
of the sylvian fissures and lesions of the putamen can
be seen.
2-Hydroxyglutaric aciduria is considerably rarer
and has been reported as a cause of parkinsonism with
dystonia (Owens and Okun, 2004).
59.4.3.10. Homocystinuria
Movement disorders are uncommon in this disorder,
which is characterized by marfanoid features, cataracts,
vascular thrombosis and variable mental retardation.
Occasionally severe dystonia may be seen (Hagberg
et al., 1970; Davous and Rondot, 1983; Kempster
et al., 1988; Berardelli et al., 1991). Parkinsonism has
occasionally been reported (Keskin and Yurdakul,
1996), in one case in the brother of a patient with severe
dystonia (Ekinci et al., 2004).
59.4.3.11. Biotin-responsive basal ganglia disease
This disorder, probably of autosomal-recessive inheri-
tance, was reported in a series of 10 patients, who had
onset in infancy of a subacute encephalopathy, pro-
gressing to dystonia, quadriparesis, cogwheel rigidity,
cranial neuropathies and seizures (Ozand et al.,
1998). Symptoms improved remarkably with the
administration of biotin, but recurred when it was
discontinued.
59.4.3.12. Neuronal ceroid lipofuscinoses
The combination of dystonia and parkinsonism has not
been reported in the various forms of neuronal ceroid
liposcinosis; however, they are individually rare fea-
tures at different stages of the disease, indicating the
potential for basal ganglia involvement. Mutations of
a number of genes (CLN1, CLN2, CLN3, CLN5,
CLN6, CLN8) for endosomal-lysosomal proteins have
been reported to be associated with different disease
phenotypes (Mole, 2004).
Dystonia has occasionally been reported in the
infantile form, along with an unusual phenotype
521
of microcephaly and hypotonia, with atrophy of the
caudate nuclei, due to a mutation of CLN2 (Simonati
et al., 2000). This encodes for a lysosomal enzyme
tripetidyl peptidase.
In the juvenile form (late-onset Batten disease;
SpielmeyerVogt disease), usually due to mutations
of CLN3, a gene for a membrane protein of unknown
function, involvement of the extrapyramidal system
is typically a late feature, following intellectual
decline, visual loss and seizures (Aberg et al., 2001).
Rigidity and impaired postural reflexes usually occur
late, although occasionally may be presenting features.
Dystonia may sometimes be seen (Boustany et al.,
1988).
The adult form (Kufs disease) may present in one of
two forms, with epilepsy, myoclonus dementia and
extrapyramidal signs (Yoshioka et al., 1999; Nijssen
et al., 2002) or with behavioral disturbances, dementia
and facial dyskinesias. Parkinsonism has been reported
(Nijssen et al., 2002), but not dystonia. The gene has
been assigned the name CLN4, but it has not as yet
been identified.
59.4.3.13. Neuronal intranuclear hyaline inclusion
disease
This is a heterogeneous disorder diagnosed neuro-
pathologically with widespread intranuclear inclusions
throughout the central, peripheral and autonomic ner-
vous system (Takahashi-Fujigasaki, 2003). The onset
may be at any age and those with young onset tend
to have parkinsonism and dystonia, in addition to
behavioral changes, corticospinal, cerebellar signs
and seizures. Autosomal-recessive inheritance is sug-
gested by several affected sib-pairs, although in one
family autosomal-dominant inheritance was apparent
(Takahashi-Fujigasaki, 2003).
59.4.4. Sporadic (Table 59.3)
59.4.4.1. Drug-induced syndromes
Treatment with the classic dopamine receptor-blocking
antipsychotic agents, such as thorazine, chlorproma-
zine, haloperidol, perphenazine and many others, may
result in an acute dystonic crisis characterized by
extension of the neck and rolling up of the eyes in
the head, known as an oculogyric crisis. This happens
particularly in young males following initiation of
therapy with an intramuscular depot injection. These
episodes respond well to intravenous anticholinergic
agents and these medications are often given orally
prophylactically.
The dopamine receptor-blocking effects of the neu-
roleptics are well-recognized as a cause of iatrogenic
522 R. H. WALKER
parkinsonism, but are becoming less widespread as the
atypical antipsychotics, such as clozapine, olanzepine,
quetiapine, aripiprazole and ziprasidone, are used
more extensively. Although risperidone was initially
classified as an atypical antipsychotic, clinical experi-
ence demonstrates that it may often cause parkin-
sonism, especially in patients with an underlying
neurodegenerative process, and thus should be avoided
in these patients. Once the offending medication
is removed, the symptoms of parkinsonism should
resolve.
There is less awareness of the potential side-effects
of other dopamine receptor-blocking agents not used
as neuroleptics, such as metoclopramide, compazine,
flunarizine and cinnarizine, but these medications can
also be responsible for the generation of the same
range of movement disorders.
The more serious and long-lasting consequence of
classic neuroleptic use is tardive dyskinesia. Chorei-
form orofacial dyskinesias are the most typical form,
but tardive dystonias are not uncommon, including
blepharospasm, spasmodic dysphonia, cervical and
truncal dystonia. The movements may emerge as the
medication is discontinued or whilst it is still being
used. In the latter situation, patients may manifest both
dystonia and parkinsonism.
59.4.4.2. Alzheimers disease
A variety of movement disorders can be seen in
Alzheimers disease. Myoclonus may be seen in spora-
dic cases and in patients with presenilin mutations.
Occasional families with mutations of amyloid precur-
sor protein may have prominent parkinsonism and
myoclonus (Edwards-Lee et al., 2005), but this is not
typical. Generalized rigidity is often a feature of late-
stage disease and facial masking may give a parkinso-
nian appearance. Retrocollis can also occur and
responds well to injection of botulinum toxin.
Patients with Alzheimers disease are particularly
vulnerable to side-effects of medications, in particular
to parkinsonism or dystonia induced by neuroleptics,
including risperidone (Magnuson et al., 2000). Truncal
dystonia (Pisa syndrome) has been reported following
the use of acetylcholinesterase inhibitors (Kwak
et al., 2000; Miyaoka et al., 2001).
59.5. Therapy
Therapy for these disorders ideally would be directed
towards the etiologic causes; however, in the majority
of cases this is not possible. The challenge in sympto-
matic treatment when both parkinsonism and dystonia
are present is to improve both aspects of the movement
disorder, without the treatment for one exacerbating
the other.
In a small number of disorders, therapy is definitive
and essential to minimize disease progression. It is
important to consider the diagnosis of dopa-responsive
dystonia, especially in pediatric cases with an atypical
presentation which may resemble cerebral palsy
(Nygaard et al., 1994). A diagnostic trial of levodopa
is obligatory in most cases of dystonia and definitely
in cases with concomitant parkinsonism. The diagnosis
of Wilsons disease is also important to consider in
almost every unusual presentation of a movement dis-
order, in order to institute the appropriate therapy if
indicated.
Parkinsonism may respond to dopaminergic agents,
especially if there is impairment of the nigrostriatal
pathway, rather than of the striatal medium spiny pro-
jection neurons which bear the postsynaptic dopamine
receptors. Levodopa/carbidopa is usually the first-line
medication and should be increased very cautiously,
with careful monitoring for worsening of psychiatric
symptoms and hyperkinetic movements. The usual
strategy is gradually to increase the levodopa over a
number of weeks to approximately 2000 mg, if toler-
ated, and then slowly to decrease the dose. If there is
no benefit from this, then dopamine receptor agonists
should be tried. Benefits have been reported in patients
with secondary parkinsonism of a variety of etiologies
(Low and Allsop, 1973; Bonelli et al., 2002; Tayebi
et al., 2003; Goker-Alpan et al., 2004).
Treatment of dystonia may be frustrating and the
use of systemic medications may result in exacerbation
of neuropsychiatric symptoms. Local injections of
botulinum toxin may be helpful. The armamentarium
of potentially effective medications includes agents
with a wide variety of mechanisms of action. Anticho-
linergics, benzodiazepines, anticonvulsants and baclo-
fen (oral or intrathecal (Ford et al., 1996; Walker
et al., 2000)) may all be useful, but results can be quite
variable. The newer atypical antipsychotics, such as
quetiapine, clozapine, aripiprazole and ziprasidone,
may also have benefits, with less potential for exacer-
bating parkinsonism or causing tardive dyskinesias as
can be seen with the typical antipsychotics.
DBS of either the GPi or the STN has become
accepted as treatment for advanced PD and can also
have good results in primary (Toda et al., 2004;
Vidailhet et al., 2005) or tardive (Trottenberg et al.,
2005) dystonia. In general, secondary parkinsonian or
dystonic (Eltahawy et al., 2004) disorders do not tend
to benefit from surgical interventions, probably due
to more extensive disruption of neuronal pathways
than in primary dystonia or PD. Occasional cases
 PARKINSONISM AND DYSTONIA
may respond (Wohrle et al., 2003; Umemura et al.,
2004). A case report of DBS of the GPi in HD (Moro
et al., 2004) was promising, although in a case of ChAc
it was not beneficial (Wihl et al., 2001). The motor thala-
mus has also been proposed as a potentially promising
site for DBS and has been reported as having positive
results in a patient with ChAc (Burbaud et al., 2002).
It is suspected that the mechanisms of action of
DBS in PD and dystonia are different as the stimula-
tion parameters at which benefits are seen may differ
significantly in the two conditions. It is postulated that
blocking disordered neuronal signaling from the out-
put nuclei of the basal ganglia, the GPi and SNpr, is
the critical aspect of DBS; however, this therapy is
still poorly understood.
A number of the disorders described here may pre-
sent initially with subtle psychiatric or neurobeha-
vioral features. The use of neuroleptics may mask the
correct diagnosis, being presumed to be the cause of
any movement disorders that develop. A high degree
of suspicion is necessary as well as alertness for the
presence of additional neurologic or medical features,
a family history or an unusual disease course that
may provide important clues to the correct diagnosis.
59.6. Conclusion
The phenomenology and pathophysiology of diseases in
which parkinsonism and dystonia coexist may lead us to
important insights into the function of the basal ganglia
and of dopamine specifically. An anatomically related
vulnerability to dopamine dysfunction, presumably
within the putamen, is suggested by the pattern of onset,
for example, the prominence of foot dystonia in early
PD, childhood-onset DYT1 dystonia and DRD. Distur-
bances in dopaminergic neurotransmission are clearly
implicated in parkinsonism and dystonia. However,
the benefits of mere replacement are limited, particu-
larly in dystonia, and it is evident that dopamine is more
than an onoff switch for movement. The partial
positive effects seen with the wide variety of medica-
tions used therapeutically in dystonia suggest complex
interactions of a number of different neurotransmitters.
Sound scientific methodology requires that we do
not infer the function of a specific component in a sys-
tem by the consequences of its dysfunction. However,
it is impossible to resist speculating about the role of
dopamine in motor programs and how its deficiency
may result in both impaired and excessive movement.
Models of basal ganglia function are invaluable in
designing experiments and potential therapeutic strate-
gies. The limitation of the models in explaining the
coexistence of hypo- and hyperkinetic disorders sug-
gests that yet another layer of complexity is required.
523
References
Aberg LE, Rinne JO, Rajantie I et al. (2001). A
favorable response to antiparkinsonian treatment in juve-
nile neuronal ceroid lipofuscinosis. Neurology 56:
12361239.
Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R (2004).
Mutations in the glucocerebrosidase gene and Parkinsons
disease in Ashkenazi Jews. N Engl J Med 351:
19721977.
Aizawa H, Kwak S, Shimizu T et al. (1991). A case of adult
onset pure pallidal degeneration. I. Clinical manifestations
and neuropathological observations. J Neurol Sci 102:
7682.
Albanese A (2003). Dystonia in parkinsonian syndromes.
Adv Neurol 91: 351360.
Albin RL, Young AB, Penney JB (1989). The functional
anatomy of basal ganglia disorders. Trends Neurosci 12:
366375.
Allen FH, Krabbe SM, Corcoran PA (1961). A new pheno-
type (McLeod) in the Kell blood-group system. Vox Sang
6: 555560.
Andrew SE, Goldberg YP, Kremer B et al. (1994). Hunting-
ton disease without cag expansionphenocopies or errors
in assignment. Am J Hum Genet 54: 852863.
Arbuthnott GW, Ingham CA, Wickens JR (2000). Dopamine
and synaptic plasticity in the neostriatum. J Anat 196:
587596.
Asanuma K, Ma Y, Okulski J et al. (2005). Decreased striatal
D2 receptor binding in non-manifesting carriers of the
DYT1 dystonia mutation. Neurology 64: 347349.
Augood SJ, Hollingsworth Z, Albers DS et al. (2002). Dopa-
mine transmission in DYT1 dystonia: A biochemical and
autoradiographical study. Neurology 59: 445448.
Avshalumov MV, Chen BT, Marshall SP et al. (2003). Gluta-
mate-dependent inhibition of dopamine release in striatum
is mediated by a new diffusible messenger, H2O2.
J Neurosci 23: 27442750.
Bamford NS, Robinson S, Palmiter RD et al. (2004a). Dopa-
mine modulates release from corticostriatal terminals.
J Neurosci 24: 95419552.
Bamford NS, Zhang H, Schmitz Y et al. (2004b). Heterosyn-
aptic dopamine neurotransmission selects sets of corticos-
triatal terminals. Neuron 42: 653663.
Bao L, Patel JC, Walker RH et al. (2006). Alterations in
striatal dopamine release in DYT1 mice: implications for
early onset dystonia. Neuroscience Meeting Planner 78.8/
JJ1 Society for Neuroscience online.
Bara-Jimenez W, Shelton P, Hallett M (2000). Spatial discri-
mination is abnormal in focal hand dystonia. Neurology
55: 18691873.
Barclay CL, Lang AE (1997). Dystonia in progressive supra-
nuclear palsy. J Neurol Neurosurg Psychiatry 62:
352356.
Bauer I, Gencik M, Laccone F et al. (2002). Trinucleotide
repeat expansions in the junctophilin-3 gene are not found
in Caucasian patients with a Huntingtons disease-like
phenotype. Ann Neurol 51: 662.
524 R. H. WALKER
Berardelli A, Thompson PD, Zaccagnini M et al. (1991).
Two sisters with generalized dystonia associated with
homocystinuria. Mov Disord 6: 163165.
Berardelli A, Rothwell JC, Hallett M et al. (1998). The patho-
physiology of primary dystonia. Brain 121: 11951212.
Bergman H, Wichmann T, Karmon B et al. (1994). The
primate subthalamic nucleus. II. Neuronal activity in the
MPTP model of parkinsonism. J Neurophysiol 72:
507520.
Boesch SM, Wenning GK, Ransmayr G et al. (2002).
Dystonia in multiple system atrophy. J Neurol Neurosurg
Psychiatry 72: 300303.
Bonelli RM, Niederwieser G, Diez J et al. (2002). Pramipex-
ole ameliorates neurologic and psychiatric symptoms in a
Westphal variant of Huntingtons disease. Clin Neuro-
pharmacol 25: 5860.
Bonifati V, Rizzu P, Squitieri F et al. (2003). DJ-1( PARK7),
a novel gene for autosomal recessive, early onset parkin-
sonism. Neurol Sci 24: 159160.
Bostantjopoulou S, Katsarou Z, Kazis A et al. (2000). Neu-
roacanthocytosis presenting as parkinsonism. Mov Disord
15: 12711273.
Boustany RM, Alroy J, Kolodny EH (1988). Clinical classi-
fication of neuronal ceroid-lipofuscinosis subtypes. Am
J Med Genet Suppl 5: 4758.
Brashear A, Butler IJ, Ozelius LJ et al. (1998). Rapid-onset
dystonia-parkinsonism: a report of clinical, biochemical,
and genetic studies in two families. Adv Neurol 78:
335339.
Bressman SB (2004). Dystonia genotypes, phenotypes, and
classification. Adv Neurol 94: 101107.
Bressman SB, de Leon D, Raymond D et al. (1998). Clinical-
genetic spectrum of primary dystonia. Adv Neurol 78:
7991.
Brin MF, Hays A, Symmans WA et al. (1993). Neuropathol-
ogy of McLeod phenotype is like chorea-acanthocytosis
(CA). Can J Neurol Sci 20 (Suppl 4): 234.
Brodaty H, Mitchell P, Luscombe G et al. (2002). Familial
idiopathic basal ganglia calcification (Fahrs disease)
without neurological, cognitive and psychiatric symptoms
is not linked to the IBGC1 locus on chromosome 14q.
Hum Genet 110: 814.
Bruneau MA, Lesperance P, Chouinard S (2003). Schizophre-
nia-like presentation of neuroacanthocytosis. J Neuropsy-
chiatry Clin Neurosci 15: 378380.
Bugiani O, Tabaton M, Cammarata S (1984). Huntingtons
disease: Survival of large striatal neurons in the rigid
variant. Ann Neurol 15: 154156.
Burbaud P, Vital A, Rougier A et al. (2002). Minimal tissue
damage after stimulation of the motor thalamus in a case
of chorea-acanthocytosis. Neurology 59: 19821984.
Burke JR, Wingfield MS, Lewis KE et al. (1994). The Haw
River syndrome: dentatorubropallidoluysian atrophy
(DRPLA) in an African-American family. Nat Genet 7:
521524.
Byl NN, Merzenich MM, Jenkins WM (1996). A primate
genesis model of focal dystonia and repetitive strain
injury: I. Learning-induced dedifferentiation of the repre-
sentation of the hand in the primary somatosensory cortex
in adult monkeys. Neurology 47: 508520.
Cairns NJ, Grossman M, Arnold SE et al. (2004). Clinical
and neuropathologic variation in neuronal intermediate
filament inclusion disease. Neurology 63: 13761384.
Calabresi P, Mercuri N, Stanzione P et al. (1987). Intracellu-
lar studies on the dopamine-induced firing inhibition of
neostriatal neurons in vitro: Evidence for D1 receptor
involvement. Neuroscience 20: 757771.
Calabresi P, Pisani A, Mercuri NB et al. (1996). The corti-
costriatal projection: From synaptic plasticity to dysfunc-
tions of the basal ganglia [see comments]. Trends
Neurosci 19: 1924.
Calabresi P, Saiardi A, Pisani A et al. (1997). Abnormal
synaptic plasticity in the striatum of mice lacking dopa-
mine D2 receptors. J Neurosci 17: 45364544.
Cardoso F, Camargos S (2000). Juvenile parkinsonism: a
heterogeneous entity. Eur J Neurol 7: 467471.
Carpenter MB, Carleton SC, Keller JK et al. (1981). Connec-
tions of the subthalamic nucleus in the monkey. Brain Res
224: 129.
Ching KHL, Westaway SK, Gitschier J et al. (2002). HARP
syndrome is allelic with pantothenate kinase-associated
neurodegeneration. Neurology 58: 16731674.
Clark LN, Afridi S, Mejia-Santana H et al. (2004). Analysis
of an early-onset Parkinsons disease cohort for DJ-1
mutations. Mov Disord 19: 796800.
Coleman RJ, Robb SA, Lake BD et al. (1988). The diverse
neurological features of Niemann-Pick disease type C: a
report of two cases. Mov Disord 3: 295299.
Cragg SJ (2003). Variable dopamine release probability and
short-term plasticity between functional domains of the
primate striatum. J Neurosci 23: 43784385.
Critchley EM, Clark DB, Wikler A (1968). Acanthocytosis
and neurological disorder without betalipoproteinemia.
Arch Neurol 18: 134140.
Crompton DE, Chinnery PF, Bates D et al. (2004). Spectrum
of movement disorders in neuroferritinopathy. Mov
Disord 20: 9599.
Curtis AR, Fey C, Morris CM et al. (2001). Mutation in
the gene encoding ferritin light polypeptide causes domi-
nant adult-onset basal ganglia disease. Nat Genet 28:
350354.
Danek A, Hegele RA (2004). Compound heterozygous
PANK2 mutations confirm HARP and Hallervorden-Spatz
syndromes are allelic. Neurology. On-line correspondence
http://www.neurology.org/cgi/eletters/61/10/1423.
Danek A, Rubio JP, Rampoldi L et al. (2001). McLeod
neuroacanthocytosis: Genotype and phenotype. Ann
Neurol 50: 755764.
Davous P, Rondot P (1983). Homocystinuria and dystonia.
J Neurol Neurosurg Psychiatry 46: 283286.
de Carvalho AP, Sweadner KJ, Penniston JT et al. (2004).
Mutations in the Na/K-ATPase alpha3 gene ATP1A3
are associated with rapid-onset dystonia parkinsonism.
Neuron 43: 169175.
DeLong MR (1990). Primate models of movement disorders
of basal ganglia origin. Trends Neurosci 13: 281285.
 PARKINSONISM AND DYSTONIA
Djaldetti R, Mosberg-Galili R, Sroka H et al. (1999). Cam-
ptocormia (bent spine) in patients with Parkinsons
diseasecharacterization and possible pathogenesis of an
unusual phenomenon. Mov Disord 14: 443447.
Dobson-Stone C, Velayos-Baeza A, Filippone LA et al.
(2004). Chorein detection for the diagnosis of chorea-
acanthocytosis. Ann Neurol 56: 299302.
Edwards-Lee T, Ringman JM, Chung J et al. (2005). An African
American family with early-onset Alzheimer disease and an
APP (T714I) mutation. Neurology 64: 377379.
Eidelberg D (1998). Abnormal brain networks in DYT1 dys-
tonia. Adv Neurol 78: 127133.
Eidelberg D, Moeller JR, Dhawan V et al. (1990). The meta-
bolic anatomy of Parkinsons disease: complementary
fluorodeoxyglucose and fluorodopa positron emission
tomographic studies. Mov Disord 5: 203213.
Eidelberg D, Moeller JR, Isikawa T et al. (1995). Assessment
of disease severity in parkinsonism with fluorine-18-fluor-
odeoxyglucose and PET. J Nucl Med 36: 378383.
Eidelberg D, Moeller JR, Ishikawa T et al. (1996). Regional
metabolic correlates of surgical outcome following unilat-
eral pallidotomy for Parkinsons disease. Ann Neurol 39:
450459.
Eidelberg D, Moeller JR, Kazumata K et al. (1997). Meta-
bolic correlates of pallidal neuronal activity in Parkinsons
disease. Brain 120: 13151324.
Ekinci B, Apaydin H, Vural M et al. (2004). Two siblings
with homocystinuria presenting with dystonia and parkin-
sonism. Mov Disord 19: 962964.
Eltahawy HA, Saint-Cyr J, Giladi N et al. (2004). Primary
dystonia is more responsive than secondary dystonia to
pallidal interventions: Outcome after pallidotomy or palli-
dal deep brain stimulation. Neurosurgery 54: 613619.
Elwes R, Saunders M (1986). Generalized dystonia, whisper-
ing dysphonia and Wilsons disease in members of the same
family [letter]. J Neurol Neurosurg Psychiatry 49: 107.
Evidente VG (2002). Zolpidem improves dystonia in
Lubag or X-linked dystonia-parkinsonism syndrome.
Neurology 58: 662663.
Evidente VG, Gwinn KA, Caviness JN et al. (1998). Early
cinematographic cases of postencephalitic parkinsonism
and other movement disorders [see comments]. Mov Dis-
ord 13: 167169.
Evidente VG, Advincula J, Esteban R et al. (2002). Phenom-
enology of Lubag or X-linked dystonia-parkinsonism.
Mov Disord 17: 12711277.
Evidente VG, Nolte D, Niemann S et al. (2004). Phenotypic
and molecular analyses of X-linked dystonia-parkinsonism
(lubag) in women. Arch Neurol 61: 19561959.
Fabbrini G, Brancati F, Vacca L et al. (2005). A novel family
with an unusual early-onset generalized dystonia. Mov
Disord 20: 8186.
Fahn S, Bressman SB, Marsden CD (1998). Classification of
dystonia. Adv Neurol 78: 110.
Flores-Hernandez J, Cepeda C, Hernandez-Echeagaray
E et al. (2002). Dopamine enhancement of NMDA currents
in dissociated medium-sized striatal neurons: role of D1
receptors and DARPP-32. J Neurophysiol 88: 30103020.
525
Ford B, Greene P, Louis ED et al. (1996). Use of intrathecal
baclofen in the treatment of patients with dystonia. Arch
Neurol 53: 12411246.
Fukuda M, Mentis MJ, Ma Y et al. (2001). Networks mediat-
ing the clinical effects of pallidal brain stimulation for
Parkinsons diseasea PET study of resting-state glucose
metabolism. Brain 124: 16011609.
Furtado S, Payami H, Lockhart PJ et al. (2004). Profile of
families with parkinsonism-predominant spinocerebellar
ataxia type 2 (SCA2). Mov Disord 19: 622629.
Furukawa Y, Lang AE, Trugman JM et al. (1998). Gender-
related penetrance and de novo GTP-cyclohydrolase I
gene mutations in dopa-responsive dystonia [see com-
ments]. Neurology 50: 10151020.
Gascon GG, Ozand PT, Brismar J (1994). Movement dis-
orders in childhood organic acidurias. Clinical, neuroima-
ging, and biochemical correlations. Brain Dev 16 (Suppl):
94103.
Gerardin E, Lehericy S, Pochon JB et al. (2003). Foot, hand,
face and eye representation in the human striatum. Cereb
Cortex 13: 162169.
Geschwind DH, Loginov M, Stern JM (1999). Identification
of a locus on chromosome 14q for idiopathic basal ganglia
calcification (Fahr disease). Am J Hum Genet 65:
764772.
Geser F, Prokop S, Glatzel M et al. (2006). The neuropathol-
ogy of McLeod syndrome: a case study. Mov Disord
21 (Suppl 14): S357.
Goker-Alpan O, Schiffmann R, LaMarca ME et al. (2004).
Parkinsonism among Gaucher disease carriers. J Med
Genet 41: 937940.
Goldman JE, Katz D, Rapin I et al. (1981). Chronic GM1
gangliosidosis presenting as dystonia: I. Clinical and
pathological features. Ann Neurol 9: 465475.
Goto S, Lee LV, Munoz EL et al. (2005). Functional anat-
omy of the basal ganglia in X-linked recessive dystonia-
parkinsonism. Ann Neurol 58: 717.
Graybiel AM, Canales JJ, Capper-Loup C (2000). Levodopa-
induced dyskinesias and dopamine-dependent stereoty-
pies: a new hypothesis. Trends Neurosci 23: S71S77.
Grotzsch H, Pizzolato GP, Ghika J et al. (2002). Neuro-
pathology of a case of dopa-responsive dystonia asso-
ciated with a new genetic locus, DYT14. Neurology 58:
18391842.
Hagberg B, Hambraeus L, Bensch K (1970). A case of
homocystinuria with a dystonia neurological syndrome.
Neuropadiatrie 1: 337343.
Hallett M (2003). Parkinson revisited: Pathophysiology of
motor signs. Parkinsons disease Adv Neurol 91: 1928.
Hardie RJ, Young EP, Morgan-Hughes JA (1988). Hexosami-
nidase A deficiency presenting as juvenile progressive
dystonia [letter]. J Neurol Neurosurg Psychiatry 51:
446447.
Hardie RJ, Pullon HW, Harding AE et al. (1991). Neuroa-
canthocytosis. A clinical, haematological and pathological
study of 19 cases. Brain 114: 1349.
Hartig MB, Hortnagel K, Garavaglia B et al. (2006). Genoty-
pic and phenotypic spectrum of PANK2 mutations in
526 R. H. WALKER
patients with neurodegeneration with brain iron accumula-
tion. Ann Neurol 59: 248256.
Hayflick SJ, Westaway SK, Levinson B et al. (2003). Genet-
ic, clinical, and radiographic delineation of Hallervorden-
Spatz syndrome. N Engl J Med 348: 3340.
Heiman GA, Ottman R, Saunders-Pullman RJ et al.
(2004). Increased risk for recurrent major depression in
DYT1 dystonia mutation carriers. Neurology 63: 631637.
Ho M, Chelly J, Carter N et al. (1994). Isolation of the gene
for McLeod syndrome that encodes a novel membrane
transport protein. Cell 77: 869880.
Hoffmann GF, Assmann B, Brautigam C et al. (2003). Tyro-
sine hydroxylase deficiency causes progressive encephalo-
pathy and dopa-nonresponsive dystonia. Ann Neurol
54 (Suppl 6): S56S65.
Holmes SE, OHearn E, Rosenblatt A et al. (2001). A repeat
expansion in the gene encoding junctophilin-3 is asso-
ciated with Huntington disease-like 2. Nat Genet 29:
377378.
Houlden H, Lincoln S, Farrer M et al. (2003). Compound
heterozygous PANK2 mutations confirm HARP and Hal-
lervorden-Spatz syndromes are allelic. Neurology 61:
14231426.
Hutton M, Lendon CL, Rizzu P et al. (1998). Association of
missense and 50 -splice-site mutations in tau with the inher-
ited dementia FTDP-17. Nature 393: 702705.
Ichinose H, Suzuki T, Inagaki H et al. (1999). Molecular
genetics of dopa-responsive dystonia. Biol Chem 380:
13551364.
Ikoma K, Samii A, Mercuri B et al. (1996). Abnormal cortical
motor excitability in dystonia. Neurology 46: 13711376.
Inzelberg R, Korczyn AD (1994). Parkinsonism in adult-
onset GM2 gangliosidosis. Mov Disord 9: 375377.
Jahanshahi M, Jenkins IH, Brown RG et al. (1995). Self-
initiated versus externally triggered movements I. An
investigation using measurement of regional cerebral
blood flow with PET and movement-related potentials in
normal and Parkinsons disease subjects [see comments].
Brain 118: 913933.
Jenkins IH, Fernandez W, Playford ED et al. (1992).
Impaired activation of the supplementary motor area in
Parkinsons disease is reversed when akinesia is treated
with apomorphine. Ann Neurol 32: 749757.
Jung HH, Hergersberg M, Kneifel S et al. (2001a). McLeod
syndrome: a novel mutation, predominant psychiatric
manifestations, and distinct striatal imaging findings.
Ann Neurol 49: 384392.
Jung HH, Russo D, Redman C et al. (2001b). Kell and XK
immunohistochemistry in McLeod myopathy. Muscle
Nerve 24: 13461351.
Jung HH, Hergersberg M, Vogt M et al. (2003). McLeod
phenotype associated with a XK missense mutation with-
out hematologic, neuromuscular, or cerebral involvement.
Transfusion 43: 928938.
Juranyi Z, Zigmond MJ, Harsing LG Jr (2003). [3H] Dopa-
mine release in striatum in response to cortical stimulation
in a corticostriatal slice preparation. J Neurosci Methods
126: 5767.
Kaji R (2001). Basal ganglia as a sensory gating devise for
motor control. J Med Invest 48: 142146.
Katchen M, Duvoisin RC (1986). Parkinsonism following
dystonia in three patients. Mov Disord 1: 151157.
Kawakami T, Takiyama Y, Sakoe K et al. (1999). A case of
McLeod syndrome with unusually severe myopathy. J
Neurol Sci 166: 3639.
Kempster PA, Brenton DP, Gale AN et al. (1988). Dystonia
in homocystinuria. J Neurol Neurosurg Psychiatry 51:
859862.
Keskin S, Yurdakul F (1996). Parkinsonian manifestations
in a patient with homocystinuria. J Child Neurol 11:
235236.
Khan NL, Graham E, Critchley P et al. (2003). Parkin dis-
ease: a phenotypic study of a large case series. Brain
126: 12791292.
Kitai ST, Kita H (1987). Anatomy and physiology of the
subthalamic nucleus: a driving force of the basal ganglia.
In: MB Carpenter, A Jayaraman (Eds.), The Basal Ganglia
IIStructure and Function: Current Concepts, Advances
in Behavioral Biology. Plenum Press, New York, pp.
357373.
Kremer B, Weber B, Hayden MR (1992). New insights into
the clinical features, pathogenesis and molecular genetics
of Huntington disease. Brain Pathol 2: 321335.
Kwak YT, Han IW, Baik J et al. (2000). Relation between cho-
linesterase inhibitor and Pisa syndrome. Lancet 355: 2222.
Le Ber I, Camuzat A, Castelnovo G et al. (2003). Prevalence
of dentatorubral-pallidoluysian atrophy in a large series of
white patients with cerebellar ataxia. Arch Neurol 60:
10971099.
Lee LV, Pascasio FM, Fuentes FD et al. (1976). Torsion dys-
tonia in Panay, Philippines. Adv Neurol 14: 137151.
Lenz FA, Jaeger CJ, Seike MS et al. (1999). Thalamic single
neuron activity in patients with dystonia: Dystonia-related
activity and somatic sensory reorganization. J Neurophy-
siol 82: 23722392.
Levine IM, Yettra M, Stefanini M (1960). A hereditary
neurological disorder with acanthocytosis. Neurology 10:
425.
Levy LM, Hallett M (2002). Impaired brain GABA in focal
dystonia. Ann Neurol 51: 93101.
LeWitt PA, Burns RS, Newman RP (1986). Dystonia in
untreated parkinsonism. Clin Neuropharmacol 9: 293297.
Lohmann E, Periquet M, Bonifati V et al. (2003). How much
phenotypic variation can be attributed to parkin genotype?
Ann Neurol 54: 176185.
Low PA, Allsop JL (1973). Huntingtons choreathe rigid
form (Westphal variant) treated with L-DOPA: a case
report. Proc Aust Assoc Neurol 10: 4546.
Magalhaes AC, Caramelli P, Menezes JR et al. (1994). Wil-
sons disease: MRI with clinical correlation. Neuroradiol-
ogy 36: 97100.
Magnuson TM, Roccaforte WH, Wengel SP et al. (2000).
Medication-induced dystonias in nine patients with
dementia. J Neuropsychiatry Clin Neurosci 12: 219225.
Malandrini A, Cesaretti S, Mulinari M et al. (1996). Acantho-
cytosis, retinitis pigmentosa, pallidal degeneration. Report
 PARKINSONISM AND DYSTONIA
of two cases without serum lipid abnormalities. J Neurol
Sci 140: 129131.
Margolis RL, OHearn E, Rosenblatt A et al. (2001). A dis-
order similar to Huntingtons disease is associated with a
novel CAG repeat expansion. Ann Neurol 50: 373380.
Margolis RL, Holmes SE, Rosenblatt A et al. (2004). Hun-
tingtons disease-like 2 (HDL2) in North America and
Japan. Ann Neurol 56: 670674.
Martins S, Matama T, Guimaraes L et al. (2003). Portuguese
families with dentatorubropallidoluysian atrophy (DRPLA)
share a common haplotype of Asian origin. Eur J Hum
Genet 11: 808811.
Meek D, Wolfe LS, Andermann E et al. (1984). Juvenile
progressive dystonia: a new phenotype of GM2 gangliosi-
dosis. Ann Neurol 15: 348352.
Meunier S, Garnero L, Ducorps A et al. (2001). Human
brain mapping in dystonia reveals both endophenotypic
traits and adaptive reorganization. Ann Neurol 50:
521527.
Mink JW (1996). The basal ganglia: focused selection and
inhibition of competing motor programs. Prog Neurobiol
50: 381425.
Mink JW (2003). The basal ganglia and involuntary move-
mentsimpaired inhibition of competing motor patterns.
Arch Neurol 60: 13651368.
Mir P, Edwards MJ, Curtis AR et al. (2004). Adult-onset
generalized dystonia due to a mutation in the neuroferriti-
nopathy gene. Mov Disord 20: 243245.
Miyajima H (2003). Aceruloplasminemia, an iron metabolic
disorder. Neuropathology 23: 345350.
Miyaoka T, Seno H, Yamamori C et al. (2001). Pisa syn-
drome due to a cholinesterase inhibitor (donepezil): a case
report. J Clin Psychiatry 62: 573574.
Mole SE (2004). The genetic spectrum of human neuronal
ceroid-lipofuscinoses. Brain Pathol 14: 7076.
Moro E, Lang AE, Strafella AP et al. (2004). Bilateral globus
pallidus stimulation for Huntingtons disease. Ann Neurol
56: 290294.
Morrison PJ, Patterson VH (1992). Cranial dystonia (Meige
syndrome) in postencephalitic parkinsonism. Mov Disord
7: 9091.
Murgod UA, Muthane UB, Ravi V et al. (2001). Persistent
movement disorders following Japanese encephalitis. Neu-
rology 57: 23132315.
Muthane U, Chickabasaviah Y, Kaneski C et al. (2004). Clin-
ical features of adult GM1 gangliosidosis: Report of three
Indian patients and review of 40 cases. Mov Disord 19:
13341341.
Nardocci N, Bertagnolio B, Rumi V et al. (1992). Progressive
dystonia symptomatic of juvenile GM2 gangliosidosis [see
comments]. Mov Disord 7: 6467.
Nicholl DJ, Sutton I, Dotti MT et al. (2004). White matter
abnormalities on MRI in neuroacanthocytosis. J Neurol
Neurosurg Psychiatry 75: 12001201.
Nijssen PC, Brusse E, Leyten AC et al. (2002). Autosomal
dominant adult neuronal ceroid lipofuscinosis: Parkin-
sonism due to both striatal and nigral dysfunction. Mov
Disord 17: 482487.
527
Nolte D, Niemann S, Muller U (2003). Specific sequence
changes in multiple transcript system DYT3 are associated
with X-linked dystonia parkinsonism. Proc Natl Acad Sci
USA 100: 1034710352.
Nygaard TG, Wilhelmsen KC, Risch NJ et al. (1993). Link-
age mapping of dopa-responsive dystonia (DRD) to chro-
mosome 14q. Nat Genet 5: 386391.
Nygaard TG, Waran SP, Levine RA et al. (1994). Dopa-
responsive dystonia simulating cerebral palsy. Pediatr
Neurol 11: 236240.
Oide T, Ohara S, Yazawa M et al. (2002). Progressive supra-
nuclear palsy with asymmetric tau pathology presenting
with unilateral limb dystonia. Acta Neuropathol (Berl)
104: 209214.
Oliveira JR, Spiteri E, Sobrido MJ et al. (2004). Genetic het-
erogeneity in familial idiopathic basal ganglia calcifica-
tion (Fahr disease). Neurology 63: 21652167.
Orrell RW, Amrolia PJ, Heald A et al. (1995). Acantho-
cytosis, retinitis pigmentosa, and pallidal degeneration:
a report of three patients, including the second reported
case with hypoprebetalipoproteinemia (HARP syndrome).
Neurology 45: 487492.
Owens WE, Okun MS (2004). Dystonia, tremor, and par-
kinsonism in a 54 year old man with 2-hydroxyglutaric
aciduria. J Neurol Neurosurg Psychiatry 75: 13621363.
Oyanagi K, Takeda S, Takahashi H et al. (1989). A quantita-
tive investigation of the substantia nigra in Huntingtons
disease. Ann Neurol 26: 1319.
Ozand PT, Gascon GG, Al Essa M et al. (1998). Biotin-
responsive basal ganglia disease: A novel entity. Brain
121: 12671279.
Page RA, Davie CA, Macmanus D et al. (2004). Clinical cor-
relation of brain MRI and MRS abnormalities in patients
with Wilson disease. Neurology 63: 638643.
Partridge JG, Apparsundaram S, Gerhardt GA et al. (2002).
Nicotinic acetylcholine receptors interact with dopamine
in induction of striatal long-term depression. J Neurosci
22: 25412549.
Penney JB, Young AB, Shoulson I et al. (1990). Huntingtons
disease in Venezuela: 7 years of follow-up on sympto-
matic and asymptomatic individuals. Mov Disord 5:
9399.
Perlmutter JS, Tempel LW, Black KJ et al. (1997). MPTP
induces dystonia and parkinsonismclues to the patho-
physiology of dystonia. Neurology 49: 14321438.
Perlmutter JS, Stambuk MK, Markham J et al. (1998).
Decreased [18F]spiperone binding in putamen in dystonia.
Adv Neurol 78: 161168.
Pittock SJ, Joyce C, OKeane V et al. (2000). Rapid-onset
dystonia-parkinsonismA clinical and genetic analysis
of a new kindred. Neurology 55: 991995.
Playford ED, Jenkins IH, Passingham RE et al. (1992).
Impaired mesial frontal and putamen activation in Parkin-
sons disease: A positron emission tomography study. Ann
Neurol 32: 151161.
Poewe WH, Lees AJ, Stern GM (1988). Dystonia in Parkin-
sons disease: Clinical and pharmacological features. Ann
Neurol 23: 7378.
528 R. H. WALKER
Polymeropoulos MH, Lavedan C, Leroy E et al. (1997).
Mutation in the alpha-synuclein gene identified in families
with Parkinsons disease. Science 276: 20452047.
Quartarone A, Bagnato S, Rizzo V et al. (2003). Abnormal
associative plasticity of the human motor cortex in wri-
ters cramp. Brain 126: 25862596.
Quinn N, Critchley P, Marsden CD (1987). Young onset
Parkinsons disease. Mov Disord 2: 7391.
Rampoldi L, Danek A, Monaco AP (2002). Clinical features
and molecular bases of neuroacanthocytosis. J Mol Med
80: 475491.
Reske-Nielsen E, Jensen PK, Hein-Sorensen O et al. (1988).
Calcification of the central nervous system in a new her-
editary neurological syndrome. Acta Neuropathol (Berl)
75: 590596.
Reuter I, Hu MT, Andrews TC et al. (2000). Late onset levo-
dopa responsive Huntingtons disease with minimal
chorea masquerading as Parkinson plus syndrome. J Neu-
rol Neurosurg Psychiatry 68: 238241.
Rice ME, Cragg SJ (2004). Nicotine amplifies reward-related
dopamine signals in striatum. Nat Neurosci 7: 583584.
Ridding MC, Sheean G, Rothwell JC et al. (1995). Changes
in the balance between motor cortical excitation and inhi-
bition in focal, task specific dystonia. J Neurol Neurosurg
Psychiatry 59: 493498.
Rinne JO, Daniel SE, Scaravilli F et al. (1994). Nigral degen-
eration in neuroacanthocytosis. Neurology 44: 16291632.
Rinne JO, Iivanainen M, Metsahonkala L et al. (2004). Stri-
atal dopaminergic system in dopa-responsive dystonia: a
multi-tracer PET study shows increased D2 receptors. J
Neural Transm 111: 5967.
Risvoll H, Kerty E (2001). To test or not? The value of diag-
nostic tests in cervical dystonia. Mov Disord 16: 286289.
Rodriguez MC, Guridi OJ, Alvarez L et al. (1998). The sub-
thalamic nucleus and tremor in Parkinsons disease. Mov
Disord 13: 111118.
Rostasy K, Augood SJ, Hewett JW et al. (2003). TorsinA
protein and neuropathology in early onset generalized dys-
tonia with GAG deletion. Neurobiol Dis 12: 1124.
Rovito AD, Pirone FJ (1963). Acanthrocytosis associated
with schizophrenia. Am J Psychiatry 120: 182185.
Rubio JP, Levy ER, Dobson-Stone C et al. (1999). Genomic
organization of the human galpha14 and Galphaq genes
and mutation analysis in chorea-acanthocytosis (CHAC).
Genomics 57: 8493.
Russo D, Redman C, Lee S (1998). Association of XK and
Kell blood group proteins. J Biol Chem 273: 1395013956.
Russo D, Wu X, Redman CM et al. (2000). Expression of
Kell blood group protein in nonerythroid tissues. Blood
96: 340346.
Saiki S, Sakai K, Kitagawa Y et al. (2003). Mutation in the
CHAC gene in a family of autosomal dominant chorea-
acanthocytosis. Neurology 61: 16141616.
Saiki S, Hirose G, Sakai K et al. (2004). Chorea-acanthocyto-
sis associated with Tourettism. Mov Disord 19: 833836.
Saka E, Iadarola M, Fitzgerald DJ et al. (2002). Local circuit
neurons in the striatum regulate neural and behavioral
responses to dopaminergic stimulation. Proc Natl Acad
Sci USA 99: 90049009.
Segawa M, Nomura Y (1993). Hereditary progressive dysto-
nia with marked diurnal fluctuation. Pathophysiological
importance of the age of onset. Adv Neurol 60: 568576.
Sener RN (2003). Diffusion MR imaging changes associated
with Wilson disease. AJNR Am J Neuroradiol 24: 965967.
Shan DE, Soong BW, Sun CM et al. (2001). Spinocerebellar
ataxia type 2 presenting as familial levodopa-responsive
parkinsonism. Ann Neurol 50: 812815.
Shashidharan P, Sandu D, Walker RH (2002). Expression of
mutant torsinA in transgenic mice interferes with dop-
aminergic system. Soc Neurosci Abstr. Abstract/Itinerary
Planner CD-ROM: 523.11.
Shashidharan P, Sandu D, Potla U et al. (2005). Transgenic
mouse model of early-onset DYT1 dystonia. Hum Mol
Genet 14: 125133.
Silberstein P, Kuhn AA, Kupsch A et al. (2003). Patterning
of globus pallidus local field potentials differs between
Parkinsons disease and dystonia. Brain 126: 25972608.
Simonati A, Santorum E, Tessa A et al. (2000). A CLN2 gene
nonsense mutation is associated with severe caudate atro-
phy and dystonia in LINCL. Neuropediatrics 31: 199201.
Singleton A (2004). What does PINK1 mean for Parkinson
diseases? Neurology 63: 13501351.
Singleton A, Hague S, Hernandez D (2004). X-linked reces-
sive dystonia parkinsonism (XDP; Lubag; DYT3). Adv
Neurol 94: 139142.
Smith Y, Bennett BD, Bolam JP et al. (1994). Synaptic rela-
tionships between dopaminergic afferents and cortical or
thalamic input in the sensorimotor territory of the striatum
in monkey. J Comp Neurol 344: 119.
Sohn YH, Hallett M (2004). Disturbed surround inhibition in
focal hand dystonia. Ann Neurol 56: 595599.
Specola N, Vanier MT, Goutieres F et al. (1990). The juve-
nile and chronic forms of GM2 gangliosidosis: clinical
and enzymatic heterogeneity. Neurology 40: 145150.
Stevanin G, Camuzat A, Holmes SE et al. (2002). CAG/CTG
repeat expansions at the Huntingtons disease-like 2 locus
are rare in Huntingtons disease patients. Neurology 58:
965967.
Stevanin G, Fujigasaki H, Lebre AS et al. (2003). Hunting-
tons disease-like phenotype due to trinucleotide repeat
expansions in the TBP and JPH3 genes. Brain 126:
15991603.
Symmans WA, Shepherd CS, Marsh WL et al. (1979).
Hereditary acanthocytosis associated with the McLeod
phenotype of the Kell blood group system. Br J Haematol
42: 575583.
Takahashi-Fujigasaki J (2003). Neuronal intranuclear hya-
line inclusion disease. Neuropathology 23: 351359.
Takashima H, Sakai T, Iwashita H et al. (1994). A family of
McLeod syndrome, masquerading as chorea-acanthocyto-
sis. J Neurol Sci 124: 5660.
Tan EK, Chan LL, Wong MC (2003a). Levodopa-induced
oromandibular dystonia in progressive supranuclear palsy.
Clin Neurol Neurosurg 105: 132134.
 PARKINSONISM AND DYSTONIA
Tan LC, Tanner CM, Chen R et al. (2003b). Marked variation
in clinical presentation and age of onset in a family with a
heterozygous parkin mutation. Mov Disord 18: 758763.
Taniguchi S, McDonagh AM, Pickering-Brown SM et al.
(2004). The neuropathology of frontotemporal lobar
degeneration with respect to the cytological and biochem-
ical characteristics of tau protein. Neuropathol Appl Neu-
robiol 30: 118.
Tassin J, Durr A, Bonnet AM et al. (2000). Levodopa-
responsive dystonia. GTP cyclohydrolase I or parkin mut-
ations? Brain 123: 11121121.
Tayebi N, Walker J, Stubblefield B et al. (2003). Gaucher
disease with parkinsonian manifestations: does glucocer-
ebrosidase deficiency contribute to a vulnerability to par-
kinsonism? Mol Genet Metab 79: 104109.
Toda H, Hamani C, Lozano A (2004). Deep brain stimula-
tion in the treatment of dyskinesia and dystonia. Neuro-
surg Focus 17: E2.
Trottenberg T, Volkmann J, Deuschl G et al. (2005). Treat-
ment of severe tardive dystonia with pallidal deep brain
stimulation. Neurology 64: 344346.
Ueno S, Maruki Y, Nakamura M et al. (2001). The gene
encoding a newly discovered protein, chorein, is mutated
in chorea-acanthocytosis. Nat Genet 28: 121122.
Ueyama H, Kumamoto T, Nagao S et al. (2000). A novel
mutation of the McLeod syndrome gene in a Japanese
family. J Neurol Sci 176: 151154.
Umemura A, Jaggi JL, Dolinskas CA et al. (2004). Pallidal
deep brain stimulation for longstanding severe generalized
dystonia in Hallervorden-Spatz syndrome. Case report. J
Neurosurg 100: 706709.
Uyama E, Terasaki T, Watanabe S et al. (1992). Type-3
GM1 gangliosidosis-characteristic MRI findings corre-
lated with dystonia. Acta Neurol Scand 86: 609615.
Valente EM, Abou-Sleiman PM, Caputo V et al. (2004). Her-
editary early-onset Parkinsons disease caused by muta-
tions in PINK1. Science 304: 11581160.
Velayos-Baeza A, Vettori A, Copley RR et al. (2004). Analy-
sis of the human VPS13 gene family. Genomics 84:
536549.
Vidailhet M, Vercueil L, Houeto JL et al. (2005). Bilateral
deep-brain stimulation of the globus pallidus in primary
generalized dystonia. N Engl J Med 352: 459467.
Vitek JL, Zhang J, Evatt M et al. (1998). GPi pallidotomy for
dystonia: Clinical outcome and neuronal activity. Adv
Neurol 78: 211219.
Vitek JL, Chockkan V, Zhang JY et al. (1999). Neuronal
activity in the basal ganglia in patients with generalized
dystonia and hemiballismus. Ann Neurol 46: 2235.
Walker RH, Danisi FO, Swope DM et al. (2000). Intrathecal
baclofen for dystonia: Benefits and complications during
six years experience. Mov Disord 15: 12421247.
Walker RH, Friedman J, Wiener J et al. (2002a). A family
with a tau P301L mutation presenting with parkinsonism.
Parkinsonism Relat Disord 9: 121123.
Walker RH, Morgello S, Davidoff-Feldman B et al.
(2002b). Autosomal dominant chorea-acanthocytosis with
529
polyglutamine-containing neuronal inclusions. Neurology
58: 10311037.
Walker RH, Jankovic J, OHearn E et al. (2003a). Phenoty-
pic features of Huntington disease-like 2. Mov Disord 18:
15271530.
Walker RH, Rasmussen A, Rudnicki D et al. (2003b). Hun-
tingtons disease-like 2 can present as chorea-acanthocyto-
sis. Neurology 61: 10021004.
Walker RH, Danek A, Jung HH et al. (2005). McLeod syndrome
presenting with hepatic disease. Mov Disord 20: S6S7.
Walker RH, Danek A, Uttner I et al. McLeod phenotype
without the McLeod syndrome. Transfusion (in press).
Waters CH, Faust PL, Powers J et al. (1993a). Neuropath-
ology of lubag (X-Linked dystonia parkinsonism). Mov
Disord 8: 387390.
Waters CH, Takahashi H, Wilhelmsen KC et al. (1993b).
Phenotypic expression of X-linked dystonia-parkinsonism
(Lubag) in two women. Neurology 43: 15551558.
Wichmann T, Bergman H, DeLong MR (1994). The primate
subthalamic nucleus. III. Changes in motor behavior and
neuronal activity in the internal pallidum induced by sub-
thalamic inactivation in the MPTP model of parkinsonism.
J Neurophysiol 72: 521530.
Wihl G, Volkmann J, Allert N et al. (2001). Deep brain stimula-
tion of the internal pallidum did not improve chorea in a
patient with neuro-acanthocytosis. Mov Disord 16: 572575.
Wills AJ, Sawle GV, Guilbert PR et al. (2002). Palatal tre-
mor and cognitive decline in neuroferritinopathy. J Neurol
Neurosurg Psychiatry 73: 9192.
Wohrle JC, Weigel R, Grips E et al. (2003). Risperidone-
responsive segmental dystonia and pallidal deep brain sti-
mulation. Neurology 61: 546548.
Xu X, Pin S, Gathinji M et al. (2004). Aceruloplasminemia:
an inherited neurodegenerative disease with impairment of
iron homeostasis. Ann NY Acad Sci 1012: 299305.
Yoshida K, Ikeda S, Kawaguchi K et al. (1994). Adult GM1
gangliosidosis: immunohistochemical and ultrastructural
findings in an autopsy case. Neurology 44: 23762382.
Yoshioka A, Saiki S, Yamaya Y et al. (1999). [A 54-year-old
man with action myoclonus, parkinsonism and epilepsy].
No To Shinkei Brain Nerve 51: 9991007.
Younes-Mhenni S, Thobois S, Streichenberger N et al.
(2002). [Mitochondrial encephalomyopathy, lactic acido-
sis and stroke-like episodes (Melas) associated with a Fahr
disease and cerebellar calcifications]. Rev Med Interne 23:
10271029.
Zhou B, Westaway SK, Levinson B et al. (2001). A novel
pantothenate kinase gene (PANK2) is defective in Haller-
vorden-Spatz syndrome. Nat Genet 28: 345349.
Zimprich A, Muller-Myhsok B, Farrer M et al. (2004). The
PARK8 locus in autosomal dominant parkinsonism:
confirmation of linkage and further delineation of the
disease-containing interval. Am J Hum Genet 74: 1119.
Zuhlke C, Gehlken U, Hellenbroich Y et al. ((2003)). Pheno-
typical variability of expanded alleles in the TATA-bind-
ing protein gene. Reduced penetrance in SCA17?
J Neurol 250: 161163.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 60

Dementia with Lewy bodies

IAN MCKEITH*

Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK

60.1. Introduction 75 years in most studies) than for Parkinsons disease

Dementia with Lewy bodies (DLB) is the preferred
term (McKeith et al., 1996) for a clinicopathological
syndrome that has been variously labeled over the last
40 years as diffuse Lewy body disease (DLBD)
(Kosaka et al., 1984; Dickson et al., 1987; Lennox
et al., 1989a), dementia associated with cortical Lewy
bodies (DCLB) (Byrne et al., 1991), the Lewy body
variant of Alzheimers disease (LBVAD) (Hansen
et al., 1990; Forstl et al., 1993), senile dementia of
Lewy body type (SDLT) (Perry et al., 1989a, b, 1990)
and Lewy body dementia (LBD) (Gibb et al., 1987).
Initially regarded as uncommon, DLB is now thought
to account for up to 20% of all elderly cases of dementia
reaching autopsy (Jellinger, 1996), with a clinical pre-
sentation primarily characterized by cognitive decline
leading to dementia, accompanied in the majority of
cases (
75%) by extrapyramidal motor features and
additional neuropsychiatric features.
60.1.1. Prevalence and incidence
There is very little systematically collected informa-
tion about the prevalence, incidence and associated
risk factors for DLB (McKeith et al., 2004a). A com-
munity study of 85-year-olds in Finland found that
5.0% met clinical diagnostic criteria for DLB, repre-
senting 22% of all demented cases (Rahkonen et al.,
2003). This is similar to other clinical estimates (Shergill
et al., 1994; Stevens et al., 2002) and consistent with
estimates of Lewy body (LB) prevalence (15%) in a
dementia case register followed to autopsy (Holmes
et al., 1999). Little is known about risk factors for
LB disease except for male sex and age of onset,
which is on average 10 years greater for DLB (mean
(PD).
60.1.2. Dementia with Lewy bodies and dementia
in Parkinsons disease
At autopsy DLB is neuropathologically indistinguish-
able from dementia occurring late in the course of
PD (PDD). This has led to a continuing debate about
the relationship between these two clinically defined
syndromes. Most clinicians find it helpful to make a
distinction between DLB and PDD based on the tem-
poral sequence in which symptoms appear. This
approach is (understandably) not generally favored
by some contemporary neuroscience researchers, who
regard the different clinical presentations as simply
representing different points on a common spectrum
of LB disease with shared abnormalities in a-synuclein
metabolism. This unified approach to classification is
probably preferable for molecular and genetic studies
and for developing therapeutic agents.
The extent to which PD, PDD and DLB are similar
remains to be investigated in further depth. For exam-
ple, a proposal to stage LB pathology in the brain has
relatively recently been proposed for PD (Braak et al.,
2003). This postulates a progressive spread from the
medulla oblongata and olfactory bulb (presymptomatic
stages 1 and 2) through the substantia nigra and other
midbrain nuclei and basal forebrain (symptomatic
stages 3 and 4), eventually encroaching upon the tele-
ncephalic cortex in end-stages 5 and 6. It has been sug-
gested that in DLB the burden of pathology is
differently distributed, with greater emphasis on the
cortex (Kosaka et al., 1996). The validity of the Braak
staging scheme and its relevance to DLB remain to be
determined. The remainder of the chapter will focus on

*Correspondence to: Professor Ian McKeith, Institute for Ageing and Health, Newcastle General Hospital, Westgate Road,
Newcastle upon Tyne NE4 6BE, UK. E-mail: i.g.mckeith@ncl.ac.uk, Tel: 44-(0)191-256-3018, Fax: 44-(0)191-219-5071.
532 I. MCKEITH
clinical, pathological and management aspects of
DLB. PDD is covered in detail in Chapter 18.
60.1.3. Clinical significance of dementia with Lewy
bodies
Until the last decade DLB was not widely recognized as
a common form of dementia in older people and the
majority of cases were probably incorrectly diagnosed
in the clinic as Alzheimers disease (AD) or vascular
dementia (McKeith et al., 1994). Although case reports
describing dementia in association with LB pathology
had been published intermittently during the previous
30 years (Okazaki et al., 1961; Kosaka et al., 1984), it
was the advent of antiubiquitin immunocytochemical
staining (Lennox et al., 1989a, b) that prompted wide-
spread recognition that LB pathology was common in
patients with dementia. It was only after this that oper-
ationalized criteria for DLB started to be developed.
The history of these developments has been reviewed
elsewhere (McKeith, 2005a) and a Consortium on
DLB was established in 1985 to set internationally
agreed standards for clinical and pathological diagnosis
(McKeith et al., 2005). The importance of recognizing
DLB relates particularly to its pharmacological man-
agement, with reports of good responsiveness to choli-
nesterase inhibitors (ChEIs) (McKeith et al., 2000;
Aarsland et al., 2004), extreme sensitivity to the side-
effects of neuroleptics (McKeith et al., 1992a; Ballard
et al., 1998a) and limited responsiveness to levodopa
(Bonelli et al., 2004; Molloy et al., 2005).
60.2. Clinical features
The central characteristic of DLB is a progressive
dementia with marked impairments in visuoperceptual,
attentional and executive functions reflecting a combi-
nation of cortical and subcortical damage. The clinical
picture does not always conform to the classic descrip-
tion of a dementia syndrome, e.g. as described in Diag-
nostic and Statistical Manual of Mental Disorders
(DSM-IVR), which requires a combination of decline
in memory and at least one other cognitive function, in
the context of unimpaired consciousness. In DLB distur-
bances in the patients level of alertness and attention are
usually apparent and often severe, and the cognitive def-
icits do not always include severe memory loss. Fluctuat-
ing cognition, recurrent visual hallucinations (VHs) and
extrapyramidal motor symptoms are the core features
by which DLB is recognized clinically (McKeith et al.,
1996), although these features are now known to be
absent in a significant minority of cases, particularly
those with significant additional Alzheimer pathology
(Merdes et al., 2003). The onset tends to be insidious,
although reports of a period of increased confusion or
prominent hallucinations may give the impression of a
sudden onset. In the first instance the patient may be
considered to have a delirium rather than a dementia
syndrome. The course is almost invariably progressive,
with cognitive function scores declining about 10% per
annum. In one study over 1 year, subjects with DLB,
AD and vascular dementia had similar rates of overall
cognitive decline, approximately 45 points on Mini-
Mental State Examination (MMSE) and 1214 points
on Cambridge Cognitive Examination (CAMCOG)
(Ballard et al., 2001). Survival times from onset until
death are also similar to AD (Walker et al., 2000a),
although a minority of DLB patients have a very rapid
disease course (Armstrong et al., 1991; Lopez et al.,
2000; Collerton et al., 2003).
60.2.1. Cognition
The profile of neuropsychological impairments in
patients with DLB differs from that of AD and other
dementia syndromes (Collerton et al., 2003), reflecting
the combined involvement of cortical and subcortical
pathways and relative sparing of the hippocampus. Epi-
sodic recall and recognition (Calderon et al., 2001; Col-
lerton et al., 2003) can be relatively preserved in the
early stages, in contrast to AD, in which memory failure
is often the presenting complaint. Patients with DLB per-
form better than those with AD on tests of verbal mem-
ory (McKeith et al., 1992b) but worse on visuospatial
performance tasks (Walker et al., 1997) and tests of
attention (Sahgal et al., 1992). This profile may be harder
to recognize later in the disease when global cognitive
difficulties obscure the picture. It has been suggested that
this double discrimination can help differentiate DLB
from AD, with relative preservation of confrontation
naming, short- and medium-term recall as well as recog-
nition, and greater impairment on verbal fluency, visual
perception and performance tasks (Walker et al., 1997;
Connor et al., 1998; Ferman et al., 1999; Collerton
et al., 2003; Mormont et al., 2003). Despite these selec-
tive patterns of impairment, composite global cognitive
assessment tools such as MMSE cannot be relied upon
to distinguish DLB from other common dementia syn-
dromes (Ala et al., 2004) and detailed neuropsychologi-
cal assessment is often required. Computer-based test
systems may be particularly useful to capture elements
of attentional (Wesnes et al., 2002) and visuoperceptual
performance (Mosimann et al., 2004) in DLB.
60.2.2. Cognitive fluctuation
Fluctuations in cognitive function, which may vary
over minutes, hours or days, occur in 5075% of
 DEMENTIA WITH LEWY BODIES
patients and are associated with shifting levels of
attention and alertness. Cognitive fluctuations may
contribute to large variability in repeated test scores,
e.g. 5 MMSE points difference over the course of a
few days or weeks (Mega et al., 1996), making it dif-
ficult to be sure of the severity of cognitive impair-
ment by a single examination. The assessment of
fluctuating cognitive impairment poses considerable
difficulty to many clinicians and has been repeatedly
cited as a reason for low clinical ascertainment of
DLB (Mega et al., 1996; Litvan et al., 1998). Newly
proposed care-giver and observer-rated scales may be
particularly helpful in this regard (Walker et al.,
2000b). Questions such as are there episodes when
his/her thinking seems quite clear and then becomes
muddled? were originally thought to be useful probes
(Ballard et al., 1993), although two recent studies
found most carers responded positively to such ques-
tions regardless of diagnostic subtype (Bradshaw
et al., 2004; Ferman et al., 2004). These investigators
also established that more reliable predictors of DLB
diagnosis are objective questions about daytime sleepi-
ness, episodes of staring blankly or incoherent speech
and qualitative assessment of the range of fluctuation,
e.g. best versus worst. Recording variation in atten-
tional performance using a computer-based test system
offers an independent method of measuring fluctuation
which is also sensitive to drug treatment effects
(Wesnes et al., 2002).
60.2.3. Recurrent visual hallucinations
Recurrent VHs are the most characteristic neuropsy-
chiatric feature of DLB, occurring in up to 80% of
cases, and they are often the symptom which first
alerts the clinician to a DLB diagnosis. Their presence
early in the course of illness (Ballard et al., 1999) and
their persistence throughout (McShane et al., 1998)
help to distinguish them from the transient perceptual
disturbances that may occasionally occur in dementias
of other etiology or during delirium. Well-formed,
detailed and animate figures are experienced, provok-
ing emotional responses varying through fear, amuse-
ment or indifference, usually with some insight into
the unreality of the episode once it is over. Why VH
and other visual symptoms such as illusions and misi-
dentifications are so common in DLB (Ballard et al.,
1999; Mosimann et al., 2006) is not known but it
seems probable that they are closely related to the pro-
nounced visuoperceptual and attentional deficits.
Meta-analysis of neuropschological studies in different
neurogenerative disorders reveals a significant and
positive association between the severity of visuoper-
ceptual impairments and the frequency of VH, DLB
533
having the highest of all (Collerton et al., 2003). A
novel perception and attention deficit model for recur-
rent complex VH suggests that a combination of
impaired attentional binding and poor sensory activa-
tion of a correct proto-object, in conjunction with a
relatively intact scene representation, bias perception
to allow the intrusion of a hallucinatory proto-object
into a scene perception. Incorporation of this image
into a context-specific hallucinatory scene representa-
tion accounts for repetitive hallucinations (Collerton
et al., 2005). These impairments, which are under-
pinned by disturbances in a lateral frontal cortex-
ventral visual stream system, are consistent with the
known distribution of neurochemical and pathological
deficits of DLB, as discussed later in this chapter.
60.2.4. Other neuropsychiatric features
Neuropsychiatric features other than VH are common
in DLB (Del-Ser et al., 2000), but none is quite so
characteristic and most are also equally prevalent in
other dementing disorders. Auditory hallucinations
occur in about 20% of DLB cases and, together with
olfactory and tactile hallucinations, may lead to initial
diagnoses of late-onset psychosis (Birkett et al., 1992)
or temporal lobe epilepsy (McKeith et al., 1992b), the
latter particularly when they are associated with appar-
ent disturbances of consciousness. Delusions are com-
mon in DLB, occurring in over half and usually being
based on recollections of hallucinations and perceptual
disturbances. They consequently have a fixed, com-
plex and bizarre content that contrasts with the mun-
dane and often poorly formed persecutory ideas
encountered in AD patients that are usually based
upon forgetfulness and confabulation. The assessment
of depression, which is also frequently encountered
in DLB (McKeith et al., 1992b), is complicated not
only by apathy and attentional deficits, but by extra-
pyramidal motor dysfunction, including facial and
body bradykinesia (Klatka et al., 1996). Apathy is
another common feature of DLB and may mimic
depression or excessive daytime somnolence. Anxiety,
agitation and behavioral disturbances are frequently
secondary to fluctuating confusion and hallucinations
and may improve when these are treated.
60.2.5. Sleep disorders
Sleep disorders have recently been recognized as com-
mon in DLB, with daytime somnolence and nocturnal
restlessness (Boeve et al., 1998; Grace et al., 1998)
sometimes as a prodromal feature. Rapid-eye move-
ment (REM) sleepwakefulness dissociations may
explain several features of DLB that are characteristic
534 I. MCKEITH
of narcolepsy (REM sleep behavior disorder (RBD),
daytime hypersomnolence, VHs and cataplexy)
(Boeve et al., 2001). RBD is manifested by vivid and
often frightening dreams during REM sleep, but with-
out the normal muscle atonia typical of REM sleep.
Patients therefore appear to act out their dreams,
vocalizing, flailing limbs and moving around the bed,
sometimes violently. Vivid visual images are often
reported, although the patient may have little recall
of these episodes. The history is obtained from the
bed-partner who may report many years of this sleep
disorder prior to the onset of dementia and parkinson-
ism (Boeve et al., 2004). RBD is frequently associated
with LB disease and only rarely with other neurode-
generative disorders (Boeve et al., 2003). Sleep disor-
ders may contribute to the fluctuations typical of DLB
and their treatment may improve fluctuations and
quality of life (Boeve et al., 2003).
60.2.6. Motor parkinsonism
Extrapyramidal signs (EPS) are reported in 2550% of
DLB cases at diagnosis and 7580% develop some
EPS during the natural course. This means that up to
25% of patients with pathologically confirmed LB dis-
ease will have no clinical history of parkinsonism and
clinicians must be prepared to consider and diagnose
DLB in its absence. Originally said to be mild and
to appear late in the clinical course, the profile of
EPS in DLB is now generally thought to be similar
to that in age-matched non-demented PD patients with
regard to overall severity (Aarsland et al., 2001b).
There is however greater symmetry and axial ten-
dency, postural instability and facial impassivity but
less tremor (Burn et al., 2003). The rate of motor dete-
rioration on the Unified Parkinsons Disease Rating
Scale (UPDRS) (Fahn and Elton, 1987) is about 10%
per annum, similar to PD (Ballard et al., 2000a). Levo-
dopa-responsiveness is reduced in DLB compared with
PD (Bonelli et al., 2004; Molloy et al., 2005), possibly
due to additional intrinsic striatal pathology and dys-
function (Duda et al., 2002) and the fact that some
of the parkinsonian features are non-dopaminergic in
origin (Burn and McKeith, 2004).
60.2.7. Autonomic dysfunction
Severe autonomic dysfunction may occur early in the
clinical course, producing orthostatic hypotension,
neurocardiovascular instability, urinary incontinence,
constipation and impotence as well as eating and swal-
lowing difficulties (Kuzuhara and Yoshimura, 1993;
Del-Ser et al., 1996; Horimoto et al., 2003; McKeith,
2003). Autonomic dysfunction may also contribute to
repeated falls and syncope and the transient losses of
consciousness that are seen in some DLB patients
(Ballard et al., 1998b).
60.3. Clinical diagnostic criteria for dementia
with Lewy bodies
Following the recognition of LB pathology in neuro-
pathological autopsy series of elderly patients with
dementia, several preliminary attempts were made to
describe the clinical course and characteristics by which
these patients could be identified antemortem (Okazaki
et al., 1961; Kosaka, 1978; Kosaka et al., 1984; Byrne
et al., 1989; Gibb et al., 1989; Crystal et al., 1990; Han-
sen et al., 1990; Perry et al., 1990; Forstl and Levy,
1991; Kuzuhara and Yoshimura, 1993).
60.3.1. Early diagnostic criteria
Based upon these observations, attempts were made to
describe the typical course of illness (Burkhardt et al.,
1988; Crystal et al., 1990; McKeith et al., 1992b) and the
first formal clinical diagnostic criteria were proposed.
The Nottingham (UK) group based their proposed
system upon the clinical characteristics of 15 personal
cases, the largest individual series published at that time
(Byrne et al., 1989). Seven were men, the mean age at
onset was 72 years and the mean duration of illness
was 5.5 years. A total of 40% presented with symptoms
and signs of idiopathic PD, with cognitive impairment
occurring 14 years later. A further 20% had parkinson-
ism and mild cognitive impairment at presentation and
the remaining 40% showed motor features later in their
illnesses, gait disturbance and postural abnormalities
being most common. These latter cases presented with
neuropsychiatric features only, in various combinations
of cognitive impairment, paranoid delusions and visual
or auditory hallucinations. Fourteen of the 15 were
demented before death, the exception presenting with
classic PD and later becoming depressed, irritable and
mildly forgetful with frequent falls. Fluctuating cogni-
tion with episodic confusion, for which no adequate
underlying cause could be found, was observed in 80%
of the Nottingham cases. Byrne et al. (1991) also drew
attention to the frequent occurrence of depression
(20%) and psychosis (33%). This led to the first formal
proposal of operational criteria for DCLB.
The presence of extrapyramidal features was man-
datory, although these could be mild and occur late
in the course of the illness. Since at least 25% of
DLB cases reported in the whole literature (Kosaka
and Iseki, 1998; Papka et al., 1998) never have motor
parkinsonism, the sensitivity of the Nottingham cri-
teria was inevitably restricted by this requirement,
 DEMENTIA WITH LEWY BODIES
which may have been influenced by the inclusion in
their sample of 5 cases who had motor-only PD diag-
nosed for at least 12 months before neuropsychiatric
features developed. According to current criteria these
cases would be regarded as having PDD and not a
primary diagnosis of DLB.
The Newcastle upon Tyne (UK) criteria which were
formulated at about the same time, based upon a series
of 21 autopsy cases sampled from a geriatric psychia-
try service, stipulated the presence of fluctuating cog-
nitive impairment plus two of the following three
items: (1) visual and/or auditory hallucinations, which
are usually accompanied by secondary paranoid delu-
sions; (2) mild spontaneous extrapyramidal features
or neuroleptic sensitivity syndrome, i.e. exaggerated
adverse responses to standard doses of neuroleptic
medication; and (3) repeated unexplained falls and/or
transient clouding or loss of consciousness.
Applied retrospectively to a sample of autopsy-
confirmed cases, these criteria identified 71% of LB
pathology cases on initial presentation and 86% between
presentation and death. Although some of the cases also
met clinical criteria for AD, no AD cases met the pro-
posed LB criteria, indicating that the core features
selected have good specificity.
Applied to another independent sample of DLB,
AD and vascular dementia patients, the Newcastle cri-
teria yielded a 74% sensitivity rate, averaged across
four raters, and a specificity of 95%. Inter-rater agree-
ment was highest and diagnosis most accurate (90%
versus 55% sensitivity) among more experienced clin-
icians. The most common errors among less experi-
enced clinicians were failure to recognize cognitive
fluctuations unique to DLB patients, and a tendency
to overvalue comorbid disease as responsible for the
clinical presentation (McKeith et al., 1994).
The clinical narrative that accompanied these cri-
teria described the evolution of the disease in three
stages (McKeith et al., 1992b):
The first stage is often recognised only in retro-
spect and may extend back one to three years
pre-presentation with occasional minor episodes
of forgetfulness, sometimes described as lapses
of concentration or switching off. A brief per-
iod of delirium is sometimes noted for the first
time, often associated with genuine physical ill-
ness and/or surgical procedures. Disturbed
sleep, nightmares and daytime drowsiness often
persist after recovery.
Progression to the second stage frequently
prompts psychiatric or medical referral. A more
sustained cognitive impairment is established,
albeit with marked fluctuations in severity.
535
Recurrent confusional episodes are accompanied
by vivid hallucinatory experiences, visual misi-
dentification syndromes and topographical disor-
ientation. Extensive medical screening is usually
negative. Attentional deficits are apparent as
apathy, and daytime somnolence and sleep beha-
viour disorder may be severe. Gait disorder and
bradykinesia are often overlooked, particularly
in elderly subjects. Frequent falls occur due
either to postural instability or syncope.
The third and final stage often begins with a sud-
den increase in behavioural disturbance leading
to requests for sedation or hospital admission by
perplexed and exhausted carers. The natural
course from this point is variable and obscured
by the high incidence of adverse reactions to
neuroleptic medication. For patients not receiv-
ing, or tolerating neuroleptics, a progressive
decline into severe dementia with dysphasia
and dyspraxia occurs over months or years, with
death usually due to cardiac or pulmonary dis-
ease. During this terminal phase patients show
continuing behavioural disturbance including
vocal and motor responses to hallucinatory phe-
nomena. Lucid intervals with some retention of
recent memory function and insight may still be
apparent. Neurological disability is often pro-
found with fixed flexion deformities of the neck
and trunk and severe gait impairment.
60.3.2. The dementia with Lewy bodies Consortium
Consensus Criteria
By the early 1990s it was becoming apparent that DLB
was a relatively common dementia subtype and that
the several research groups investigating it were adopt-
ing different terminologies for what were essentially
the same patients. The Consortium on DLB therefore
met in October 1995 in Newcastle upon Tyne to agree
common clinical and pathological methods and
nomenclature. The Consensus Criteria (McKeith
et al., 1996) which resulted were largely based on the
symptom content of the earlier Newcastle and Notting-
ham schemes and followed the general structure of
operationalized criteria already in use for AD
(McKhann et al., 1984), assigning levels of possible
and probable clinical diagnosis.
The particular characteristics of the cognitive impair-
ments of DLB were described in some detail as differ-
ing from the dementia syndrome of AD. Probable
DLB is diagnosed when two of the three key symptoms
in Table 60.1 are present, namely fluctuation, VHs or
536 I. MCKEITH
Table 60.1
Consensus guidelines for the clinical diagnosis of probable
and possible dementia with Lewy bodies (DLB)
1. Central feature
Progressive cognitive decline of sufficient magnitude to
interfere with normal social and occupational function.
Prominent or persistent memory impairment may not
necessarily occur in the early stages but is usually
evident with progression. Deficits on tests of attention
and of frontal subcortical skills and visuospatial ability
may be especially prominent
2. Core features (two core features essential for a diagnosis
of probable, one for possible DLB)
Fluctuating cognition with pronounced variations in
attention and alertness
Recurrent visual hallucinations that are typically well
formed and detailed
Spontaneous features of parkinsonism
3. Supportive features
Repeated falls
Syncope
Transient loss of consciousness
Neuroleptic sensitivity
Systematized delusions
Hallucinations in other modalities
Rapid-eye movement sleep behavior disorder
Depression
4. Features less likely to be present
History of stroke
Any other physical illness or brain disorder sufficient
enough to interfere with cognitive performance
Reproduced from McKeith et al. (1996) with permission from Lip-
pincott/Williams & Wilkins.
spontaneous motor features of parkinsonism and
possible DLB if only one is present.
Several retrospective and two prospective studies
subsequently examined the predictive accuracy of Con-
sensus clinical criteria for probable DLB (Litvan et al.,
2003). These suggested that sensitivity of case detection
was variable and, although high in one prospective study
(McKeith et al., 2000b), was unacceptably low in several
others. In contrast, specificity was generally found to be
high. The main criticism of the Consensus criteria was
lack of operationalization of the core feature items,
fluctuation in particular (Mega et al., 1996). Modified
versions of the criteria were proposed which essentially
traded increased sensitivity against reduced diagnostic
specificity (Luis et al., 1999; Litvan et al., 2003). How-
ever, a later series of neuropathological autopsy studies
revealed a further reason for the failure of the clinical cri-
teria to detect demented cases with LB. These studies
suggested that DLB patients with additional neocortical
tangle (Alzheimer) pathology often lacked the typical
DLB cognitive profile, showing pronounced memory
deficits and a clinical presentation more characteristic
of AD. Fluctuation, VHs and parkinsonism were gener-
ally absent in such cases or if present were masked by
the Alzheimer-like clinical picture. The Consensus cri-
teria are then able to detect DLB cases with a high posi-
tive predictive value, but even when used in conjunction
with optimal clinical assessment tools for core features,
will inevitably fail to detect a significant proportion of
DLB cases in whom those features are absent.
60.3.3. Revised consensus criteria for the clinical
diagnosis of dementia with Lewy bodies
In order to address the perceived shortcomings of the
original diagnostic criteria, the DLB Consortium met
again in 2003 to resolve improved methods of identify-
ing cases antemortem (McKeith et al., 2005). No major
amendments to the three core features of DLB were
proposed, but better methods for their clinical assess-
ment (Table 60.2) were recommended for use in
diagnosis and for measurement of symptom severity.
A new category of features suggestive of DLB was
described, comprising RBD, severe neuroleptic sens-
itivity or abnormal dopamine transporter (DAT) neuroi-
maging. If one or more of these suggestive features is
present, in addition to one or more core features, a diag-
nosis of probable DLB is made. Possible DLB can be
diagnosed if one or more is present in a patient with
dementia even in the absence of any core features. Sug-
gestive features therefore have a similar diagnostic
weighting as core clinical features but are not consid-
ered sufficient, even in combination, to warrant a diag-
nosis of probable DLB if all three core features are
absent.
The revised criteria are also more explicit about the
importance to be attached to clinical and radiological
evidence of cerebrovascular disease (McKeith et al.,
2005) since pathological and imaging studies suggest
that white-matter lesions (periventricular and deep
white matter), microvascular changes and lacunes
may be present in up to 30% of DLB cases (McKeith,
et al., 2000b; Jellinger, 2003).
60.4. Differential diagnosis
The main differential diagnoses of DLB are AD, vascular
dementia, PDD, atypical parkinsonian syndromes such as
progressive supranuclear palsy (PSP), MSA, corticobasal
degeneration (CBD) and also CreutzfeldtJakob
disease (CJD) (McKeith et al., 1996). The mainstay of
differential diagnosis remains careful evaluation by a
specialist clinician familiar with these disorders and
 DEMENTIA WITH LEWY BODIES 537
Table 60.2
Revised criteria for the clinical diagnosis of dementia with Lewy bodies (DLB)

1. Central feature (essential for a diagnosis of possible or probable DLB)

Dementia defined as progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational
function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident
with progression. Deficits on tests of attention, executive function and visuospatial ability may be especially prominent
2. Core features (two core features are sufficient for a diagnosis of probable DLB, one for possible DLB)
Fluctuating cognition with pronounced variations in attention and alertness
Recurrent visual hallucinations that are typically well formed and detailed
Spontaneous features of parkinsonism
3. Suggestive features (if one or more of these is present in the presence of one or more core features, a diagnosis of probable
DLB can be made. In the absence of any core features, one or more suggestive features is sufficient for possible DLB.
Probable DLB should not be diagnosed on the basis of suggestive features alone)
Rapid-eye movement sleep behavior disorder
Severe neuroleptic sensitivity
Low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging
4. Supportive features (commonly present but not proven to have diagnostic specificity)
Repeated falls and syncope
Transient, unexplained loss of consciousness
Severe autonomic dysfunction, e.g. orthostatic hypotension, urinary incontinence
Hallucinations in other modalities
Systematized delusions
Depression
Relative preservation of medial temporal lobe structures on CT/MRI scan
Generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity
Abnormal (low-uptake) MIBG myocardial scintigraphy
Prominent slow-wave activity on EEG with temporal lobe transient sharp waves
5. A diagnosis of DLB is less likely
In the presence of cerebrovascular disease evident as focal neurological signs or on brain imaging
In the presence of any other physical illness or brain disorder sufficient to account in part or in total for the clinical picture
If parkinsonism only appears for the first time at a stage of severe dementia
6. Temporal sequence of symptoms
DLB should be diagnosed when dementia occurs before or concurrently with parkinsonism (if it is present). The term
Parkinsons disease dementia (PDD) should be used to describe dementia that occurs in the context of well-established
Parkinsons disease. In a practice setting the term that is most appropriate to the clinical situation should be used and
generic terms such as Lewy body disease are often helpful. In research studies in which distinction needs to be made
between DLB and PDD, the existing 1-year rule between the onset of dementia and parkinsonism DLB continues to be
recommended. Adoption of other time periods will simply confound data pooling or comparison between studies. In other
research settings that may include clinicopathologic studies and clinical trials, both clinical phenotypes may be considered
collectively under categories such as Lewy body disease or a-synucleinopathy.

Reproduced from McKeith et al. (2005) with permission from Lippincott/Williams & Wilkins.
SPECT, single-photon emission computed tomography; PET, positron emission tomography; CT, computed tomography; MRI, magnetic
resonance imaging; MIBG, 123I-metaiodobenzylguanadine; EEG, electroencephalogram.

incorporating a history from an independent informant.
Enquiry should be made not only about cognitive, psy-
chiatric and motor features, but also about other symptom
domains such as sleep or autonomic dysfunction.
60.4.1. Role of investigations
There are as yet no clinically applicable electrophysio-
logical, genotypic or cerebrospinal fluid markers to
support a DLB diagnosis (McKeith et al., 2004a) but
neuroimaging investigations may be helpful. Changes
associated with DLB include preservation of hippocam-
pal and medial temporal lobe volume on magnetic reso-
nance imaging (Barber et al., 1999, 2000a) (Fig. 60.1)
and occipital hypoperfusion on single-photon emission
computed tomography (SPECT) (Lobotesis et al., 2001;
Colloby et al., 2002). Other features, such as general-
ized atrophy (Barber et al., 2000a), white-matter
changes (Barber et al., 2000b) and rates of progression
of whole-brain atrophy (OBrien et al., 2001), appear to
538 I. MCKEITH
Fig. 60.1. Coronal magnetic resonance imaging (MRI) scan
of patients with Alzheimers disease (AD) and dementia with
Lewy bodies (DLB) matched for clinical severity of dementia.
Medial temporal lobe (particularly hippocampal) atrophy is less
pronounced in DLB, consistent with autopsy findings. Courtesy
of Dr. Emma Burton. Reproduced from McKeith et al. (2004a),
The Lancet Neurology, with permission from Elsevier.
be unhelpful in differential diagnosis. Functional ima-
ging of the DAT defines integrity of the nigrostriatal
dopaminergic system and currently has its main clinical
application in assisting diagnosis of patients with tre-
mor of uncertain etiology (Marshall and Grosset,
2003). Imaging with specific SPECT ligands for DAT
provides a marker for presynaptic neuronal degenera-
tion. DAT imaging is abnormal in idiopathic PD, multi-
ple system atrophy (MSA) and PSP and does not
distinguish between these disorders. Low striatal uptake
has also been reported in DLB but is normal in AD (Pig-
gott et al., 1999), making DAT scanning particularly use-
ful in distinguishing between the two disorders (OBrien
et al., 2004; Walker et al., 2004) (Fig. 60.2). Scintigraphy
with MIBG (Yoshita et al., 2001) enables the quantifica-
tion of postganglionic sympathetic cardiac innervation
and has also been suggested to have high sensitivity and
specificity in the differential diagnosis of DLB from AD
(Taki et al., 2004).
Fig. 60.2. For full color figure, see plate section. Single-
photon emission computed tomography (SPECT) images of
the dopamine transporter at the level of the striatum using
fluoropropyl (FP)-CIT show marked reduction of activity in
dementia with Lewy bodies (DLB) compared with normal
activity in Alzheimers disease (AD) and normal aging. Cour-
tesy of Professor JT OBrien. Reproduced from McKeith et al.
(2004a), The Lancet Neurology, with permission from Elsevier.
60.4.2. Distinguishing between dementia with Lewy
bodies and Parkinsons disease dementia
An issue, already alluded to in section 60.1.1 , which
repeatedly causes difficulty in diagnosing DLB, is
uncertainty about its relationship with PDD. PDD is
similar to DLB (Aarsland et al., 2003; Emre, 2003)
with respect to fluctuating neuropsychological func-
tion (Ballard et al., 2002), neuropsychiatric features
(Aarsland et al., 2001a) and extrapyramidal motor fea-
tures (Aarsland et al., 2001b). The findings at autopsy
are also similar in DLB and PDD and the clinical his-
tory cannot be extrapolated from the neuropathological
findings. The 1996 Consensus statement recommended
an arbitrary 1-year rule that proposes that the onset
of dementia within 12 months of parkinsonism quali-
fies as DLB and more than 12 months of parkinsonism
before dementia qualifies as PDD. As previously sta-
ted, this distinction between DLB and PDD as two dis-
tinct clinical phenotypes, based solely on the temporal
sequence of appearance of symptoms, has been criti-
cized by those who regard the different clinical presen-
tations as simply representing different points on a
common spectrum of LB disease (Hardy, 2003). This
approach to classification may be preferable for mole-
cular and genetic studies and for developing therapeu-
tics. Clinicians on the other hand prefer diagnostic
labels that describe the symptoms as patients present
to them and this will often include consideration of
the temporal course. The revised Consensus statement
recommends that, for clinical, operational definitions,
DLB should be diagnosed when dementia occurs
before or concurrently with parkinsonism and PDD
should be used to describe dementia that occurs in
the context of well-established PD. In a practice set-
ting the term that is most appropriate to the clinical
situation should be used and generic terms such as
LB disease are often more helpful. In research studies
in which distinction is made between DLB and PDD,
the 1-year rule between the onset of dementia and
parkinsonism for DLB continues to be recommended.
Further research efforts which lead to better understand-
ing of the molecular basis for these disorders may lead to
modifications in these temporal considerations.
60.4.3. Pathology and etiology
The original delineation of DLB from other dementing
disorders was made on the basis of neuropathological
findings, i.e. the presence of cortical LB at autopsy.
It is generally accepted that most DLB cases show a-
synuclein-positive LB and Lewy neurites (LN)
together (Fig. 60.3) with abundant Alzheimer-type
pathology, predominantly in the form of amyloid
 DEMENTIA WITH LEWY BODIES
Fig. 60.3. For full color figure, see plate section. Neuro-
pathology of dementia with Lewy bodies (DLB). Pathological
a-synuclein aggregates assume many forms in DLB, including
typical classical Lewy bodies (LBs) in the pigmented nuclei of
the brainstem (A, B), cortical LBs in the neocortex (C) and
amygdala, dystrophic or Lewy neurites (LNs) in the CA 2/3
subfield of Ammons horn (D) and neuroaxonal spheroids
(E). The burden of a-synuclein aggregates in the neocortex
(F) can be extreme with cortical LBs in the deeper layers
(top left) and LNs throughout the cortical mantle to the pial
surface (bottom right). The striatum is also affected (G) with
primarily LNs (H) and dot-like aggregates (I). LNs tend to
cluster around -amyloid plaques (J), which are also common
in DLB, and are primarily axonal in location (K). (Antibodies:
a-synuclein in A, CI, and J, K (green); tyrosine hydroxylase
in B; -amyloid in J (red); neurofilaments light chain in K
(red).) Courtesy of Dr. John E Duda. Reproduced from
McKeith et al. (2004a), The Lancet Neurology, with permis-
sion from Elsevier.
plaques. Tau-positive inclusions and neocortical neu-
rofibrillary tangles sufficient to meet Braak stages V
or VI (sufficient to qualify for a diagnosis of concomi-
tant AD) occur in only a minority (1025%) of cases.
Alzheimer pathology of any type is not a prerequisite
for the existence of dementia, however, since older
patients with pure LB disease (no plaques or tangles)
may present clinically with cognitive impairment and
other neuropsychiatric features.
60.4.4. Lewy bodies and Lewy-related pathologies
Immunohistochemical and protein chemical studies
indicate that LBs and LNs are pathological aggrega-
tions of a-synuclein, DLB being a member of the
family of a-synucleinopathies (Jellinger, 2003) which
also includes PD and MSA. LBs and LNs are asso-
ciated with intermediate filaments, chaperone proteins
539
and elements of the ubiquitin-proteasome system, indi-
cating a role of the aggresomal response, but these fea-
tures are not specific for LBs and are found in other
neuronal inclusions (McNaught et al., 2002; Tanaka
et al., 2004).
Cortical LB density is not robustly correlated
with either the severity or duration of dementia
(Gomez-Tortosa et al., 1999; Harding and Halliday,
2001), although associations have been reported with
LB and plaque density in mid frontal cortex (Samuel
et al., 1996). LNs and neurotransmitter deficits are bet-
ter correlates of clinical symptoms (Gomez-Tortosa
et al., 1999; Perry et al., 2003c).
Formal criteria for the pathological diagnosis of
DLB have not yet been established in the way that
they have for other neurodegenerative disorders. The
original 1996 Consensus paper provided guidelines
for sampling procedures and recommendations about
staining and counting methods (McKeith et al.,
1996), but these have had two subsequent revisions
(McKeith et al., 1999, 2005). For the purposes of
assessing Lewy-related pathology, the latest recom-
mendation is to use a-synuclein immunohistochemis-
try and a semiquantitative grading of lesion density
rather than the counting methods previously proposed.
LB-type pathology is assigned according to the guide-
lines in the original Consensus report. Semiquantitative
grading of LB severity is adopted rather than counting
LB in various brain regions. The pattern of regional
involvement is more important than total LB count.
60.4.5. Alzheimer-type pathology
The guidelines have also been modified to address the
issue of concomitant Alzheimer-type pathology, taking
account of the pathoplastic effect that this has upon the
clinical presentation. Cases are assigned a likelihood
that the dementia can be attributed to AD pathology
using the NIAReagan criteria (NIA, National Institute
on Aging), which employs the Consortium to Establish
a Registry for Alzheimers Disease (CERAD) method
for assessing neuritic plaques (Mirra et al., 1991) and
a topographic staging method for neurofibrillary degen-
eration (Harding et al., 2000). This approach allows the
reporting pathologist not only to give a detailed semi-
quantitative description of the pathological findings in
an individual case, but also to estimate the probability
(low, intermediate or high) of the patient having had
the characteristic DLB clinical syndrome.
60.4.6. Synuclein pathology in Alzheimers disease
a-Synuclein immunoreactive deposits with many of
the characteristics of LB have also been reported in
540 I. MCKEITH
60% of AD cases, particularly in the amygdalae
(Hamilton, 2000) but seldom involving other brain
regions to any significant extent. This distribution
probably represents an end-stage phenomenon, with a
secondary accumulation of aggregated synuclein in
severely dysfunctional neurons that are already heavily
burdened by plaque and tangle pathology (Lippa and
McKeith, 2003). Such cases with amydalae-only LB
are highly unlikely to be associated with the DLB clin-
ical syndrome and their inclusion in a clinicopatholo-
gical series serves to underestimate the diagnostic
sensitivity of clinical criteria.
60.4.7. Genetics of dementia with Lewy bodies
There are few reports to date of autosomal-dominant
DLB families. This may partly be due to the relatively
late onset of DLB but also to a failure to recognize the
relationship of DLB with other phenotypes, including
PD and autonomic dysfunction. The identification of
mutations in the a-synuclein gene in familial PD
(Polymeropoulos et al., 1997) has not been followed
by similar findings in sporadic PD and DLB. Nor have
associations been found with DLB with polymorph-
isms in the genes for presenilin 1, presenilin 2, and
a1 antichymotrypsin. These genes are therefore unli-
kely to have a major influence on the pathogenesis of
DLB.
Because of the association of the 4 allele of the apo-
lipoprotein E (APO E) gene on chromosome 19 and
AD, and the presence of b-amyloid in DLB, several
groups have reported genotyping studies. In DLB, the
e4 allele frequency is elevated in a manner analogous
to that found in AD (Benjamin et al., 1994). In PD
no association is observed with APO E e4. There are,
however, subtle differences in the APO E allele fre-
quencies between AD and DLB, with a higher e2 allele
frequency and a reduced frequency of the e4/4 geno-
type in DLB (Morris et al., 1996). Differences in the
APO E frequencies may account for some of the dif-
ferences between the two diseases in terms of clinical
presentation and pathology, but it is unlikely that one
single genetic determinant accounts for the differences
between DLB and AD. Polymorphisms in other puta-
tive risk genes for DLB, which have not been reliably
replicated, include the butyrylcholinesterase gene K
variant (BCHE K), the cytochrome P-450 gene
CYP2D6 (debrisoquine 4-hydroxylase) and N-acetyl-
transferase 2 gene locus. Butyrylcholinesterase gene
K/K and atypical variants do however appear to have
a role in modifying the level of cognitive impairment
and responsiveness to ChEI responsiveness in DLB
(OBrien et al., 2003) and may also influence rate of
progression of untreated disease (Perry et al., 2003a).
There are recent reports that triplication of the
a-synuclein gene (SNCA) can cause DLB, PD and
PDD whereas gene duplication is only associated with
motor PD, suggesting a gene dose effect (Singleton
and Gwinn-Hardy, 2004). However, SCNA multiplica-
tion is not found in most LB disease patients (Johnson
et al., 2004).
60.4.8. Neurochemical pathology of dementia with
Lewy bodies
DLB is a disorder in which functional deficits might
reasonably be postulated to be related to perturbations
in neurotransmitter function, given the fluctuating
nature of the clinical syndrome and the relative lack
of major structural disruption of the cortex compared
with AD. Neurochemical studies of transmitter and
receptor function in frozen autopsy tissue lend some
support to such a model. Neurotransmitter replacement
treatments in DLB which are based on these obser-
vations have produced mixed results, with good
response experienced by some patients receiving choli-
nergic, but a generally poor response to dopaminergic,
treatments.
60.4.8.1. Dopaminergic system
Although neuronal loss within the substantia nigra
may be less in DLB than in PD, striatal dopamine
concentrations are reduced to an equivalent level
(Piggott et al., 1999). Within the striatum, dopamine
D2-receptor levels are elevated in PD and this compen-
satory upregulation is maintained for several years. In
contrast, D2-receptors are modestly reduced in DLB,
particularly in the putamen (Piggott et al., 1999), con-
tributing to severe neuroleptic sensitivity. Extrastriatal
dopaminergic systems are also affected in PD and
DLB. Mesocortical projections to the frontal cortex
are implicated in working memory performance, and
dopamine receptors are also expressed in temporal cor-
tex (Farde et al., 1997). Investigations in PD have
shown no change in early disease in cortical D1-receptors
(Gnanalingham et al., 1993), whereas in advanced PD,
functional imaging studies have indicated D2-receptors
to be reduced by 40% in frontal cortex (Kaasinen et al.,
2000).
60.4.8.2. Cholinergic system
Cholinergic deficits are more marked in PD patients
with dementia compared to those without, as evi-
denced by greater neuronal loss in the nucleus basalis
of Meynert (Jellinger and Bancher, 1995). Further-
more, using [123I] iodobenzovasamicol (a marker of
vesicular acetylcholine transporter) and SPECT brain
 DEMENTIA WITH LEWY BODIES
imaging, PDD cases demonstrate extensive cortical
binding decreases similar to early-onset (age at onset
< 64 years) AD (Kuhl et al., 1996). Not only are neo-
cortical presynaptic cholinergic inputs reduced in DLB
to a greater extent than in AD (Tiraboschi et al., 2000;
Shinotoh et al., 2001), but there are also losses in
the striatum and pedunculopontine pathway projecting
to areas including the thalamus. Cortical choline acet-
yltransferase reductions in DLB correlate with cogni-
tive impairment and VH. The cortical cholinergic
deficit in DLB is, however, independent of the extent
of Alzheimer-type pathology, although this pathology
is associated with more severe cognitive impairment
(Samuel et al., 1997). Nicotinic receptor density, mea-
sured using a-bungarotoxin binding (a7 subunit) is
reported to be lower in hallucinating compared with
non-hallucinating DLB patients (Court et al., 2001).
In PDD and DLB, muscarinic M1-receptor binding
is elevated. In DLB patients at least, this elevation is
greater in individuals with delusions than those with-
out (Ballard et al., 2000b), suggesting that this psycho-
tic feature may be associated with a greater loss of
presynaptic cholinergic activity and a consequent
upregulation in the M1-receptor subtype. It is not yet
established whether loss of cholinergic activity in the
thalamic reticular formation, reflecting loss of peduncu-
lopontine neurons, correlates with fluctuating attention
and cognition.
In summary, in both DLB and PDD, extrastriatal
dopaminergic and particularly cholinergic deficits play
a central role in mediating dementia.
60.5. Clinical management
The pharmacological management of DLB can
be one of the most challenging issues facing neurolo-
gists, psychiatrists, geriatricians, primary care
physicians or others caring for older people. Poly-
pharmacy is the norm, with multiple pharmacological
treatment targets including motor parkinsonism, cog-
nitive failure, psychiatric symptoms and autonomic
dysfunction. The positive effects of ChEIs seen in
many DLB patients contrast with the severe, some-
times fatal, neuroleptic sensitivity reactions that are
seen in up to 50% of patients exposed to such agents
(McKeith et al., 1992a; Aarsland et al., 2005). There
is an intermediate responsiveness to antiparkinsonian
agents (Bonelli et al., 2004; Molloy et al., 2005).
Since there are no treatments currently licenced for
DLB, all prescribing to this group of patients is
essentially off-license. In addition to the medicole-
gal and liability issues that this can pose for prescri-
bers, health care providers may be reluctant to
reimburse drug costs for DLB patients.
541
60.5.1. A problem-oriented approach to
management
It is helpful first to draw up a problem list of cognitive,
psychiatric and motor disabilities and ask the patient
and carer to identify the symptoms that they find most
disabling or distressing and which carry highest prior-
ity for treatment (McKeith, 2005b). The clinician
should explain, before any drugs are prescribed, that
treatment gains in a target symptom may be associated
with worsening of symptoms in other domains. The
specific risks of neuroleptic sensitivity reactions
should be mentioned in all cases and it is prudent to
mark patient case notes and records with an alert to
reduce the possibility of inadvertent neuroleptic pre-
scribing, particularly in primary care or emergency
room settings.
Non-pharmacologic strategies for cognitive symp-
toms, including explanation, education, reassurance,
orientation and memory prompts, attentional cues and
targeted behavioral interventions are an integral part
of the management of DLB and pharmacological treat-
ment is most successful when prescribed as part of a
comprehensive management approach (Cohen-Mans-
field, 2006). Similarly, if a patient with DLB has
become acutely confused and psychotic, intercurrent
infection and subdural hematoma, in particular, should
be actively excluded (McKeith et al., 1996). It cannot
always be assumed that worsening of symptoms is
simply part of the natural fluctuating history of DLB.
Non-essential medications capable of causing confu-
sion should be discontinued.
60.5.2. Antiparkinsonian agents
Levodopa monotherapy is generally accepted as the
preferred option in DLB. Medication should generally
be introduced at low doses and slowly increased to the
least dose required to minimize disability. Levodopa-
responsiveness is of the order of 50% in DLB (Bonelli
et al., 2004; Molloy et al., 2005), considerably less
than in uncomplicated PD but reminiscent of the loss
in treatment sensitivity which comes later in the course
of PD, especially as cognitive decline and dementia
intervene. Although the reasons for this reduced
response to treatment are unclear, it may be partially
related to the development of synuclein-positive striatal
pathology and associated neuronal dysfunction (Duda
et al., 2002) which is no longer amenable to neurotrans-
mitter replacement. Patients and carers will usually
indicate when they feel that the lower acceptable limit
of antiparkinsonian treatment has been reached. It is
not uncommon to find that confusional and psychotic
symptoms are not significantly ameliorated by dose
542 I. MCKEITH
reductions in antiparkinsonians, nor is motor disability
substantially aggravated. This suggests that non-dopa-
minergic mechanisms may be playing a major role in
symptom formation.
Other antiparkinsonian medications, including sele-
geline, amantadine, catechol-O-methyltransferase inhi-
bitors and dopamine agonists are contraindicated in
DLB in view of concerns about inducing confusion
and psychosis (visual illusions, hallucinations and
delusions). Anticholinergics should also be avoided
in both DLB and PDD, because they may cause mental
clouding, impaired cognition and induce or aggravate
hallucinations. There is evidence that their long-term
use in PD may be associated with dementia (Pondal
et al., 1996) and the accumulation of a higher density
of plaque and tangle pathology (Perry et al., 2003b).
60.5.3. Cholinesterase inhibitors
ChEIs appear to be effective and relatively safe in the
treatment of neuropsychiatric and cognitive symptoms
in DLB (Aarsland et al., 2004), but the number of
patients studied is relatively small and larger trials
are still needed. Apathy, anxiety, impaired attention,
hallucinations, delusions, sleep disturbance and cogni-
tive changes are the most frequently cited treatment-
responsive symptoms. Improvements are generally
reported as greater than those achieved in AD (Samuel
et al., 2000).
The first report of benefit with ChEIs was with
tacrine, which was administered in an open-label trial
to 7 PDD patients. Mean age at the time of treatment
was 74 years and the duration of PD before the onset
of dementia was 7.6 years. In all cases there was a
greatly reduced frequency of VH (Hutchinson and
Fazzini, 1996). Both MMSE scores and UPDRS motor
scores improved significantly after treatment, suggest-
ing that not only did cognitive and neuropsychiatric
features improve with tacrine, but so did extrapyrami-
dal motor function. This latter finding was unexpected
since theoretical predictions would anticipate motor
worsening. Subsequent studies in PDD and DLB have
found no evidence for significant motor deterioration,
although a minority of patients do experience dose-
dependent worsening of their tremor. If troublesome,
this can be managed in most cases by ChEI dose
reduction or increase in levodopa.
The ChEI generally available at present are rivas-
tigmine, donepezil and galantamine; all three prevent
the inactivation of acetylcholine after its release from
the neurone. Rivastigmine is a dual inhibitor of acetyl-
cholinesterase and butyrylcholinesterase, whereas
donepezil and galantamine are acetylcholinesterase-
selective. Galantamine, the most recently licenced
ChEI, is additionally an allosteric modulator of nicoti-
nic receptors. The outcomes of ChEI treatment of DLB
and PDD have been comprehensively reviewed (Aars-
land et al., 2004). Placebo-controlled randomized con-
trolled trials of rivastigmine have shown benefits in
DLB (McKeith et al., 2000a) and PDD (Emre et al.,
2004), in addition to which there is some short-term
(Maclean et al., 2001; Reading et al., 2001) and long-
term open-label data (Grace et al., 2001). In the latter
study MMSE and Neuropsychiatric Inventory (NPI)
scores remained stable over the first 12 months of treat-
ment, then gradually worsened, although not statisti-
cally significantly so even 2 years after baseline.
Motor UPDRS scores tended to improve, probably
because antiparkinsonian treatment was initiated over
that time. With donepezil there is a double-blind
cross-over study in PDD (Aarsland et al., 2002) and a
series of open-label studies in DLB (Kaufer et al.,
1998; Shea et al., 1998), including one reporting a
rebound worsening of neuropsychiatric symptoms,
when treatment was stopped abruptly (Minett et al.,
2003). Although reinstatement of treatment may reverse
such deterioration, it is recommended that DLB patients
who are assessed as responding to ChEIs are maintained
on treatment long-term. Attempts at switching from one
ChEI to another were similarly associated with clini-
cally significant withdrawal effects and the authors did
not recommended this treatment strategy (Bhanji and
Gauthier, 2003). With galantamine there are as yet only
preliminary open-label data (Aarsland and Hutchinson,
2003; Edwards et al., 2004).
Taken overall, the effects of the three available
ChEIs appear similar, with doses in the same range
as used in AD. Parkinsonian signs do not generally
worsen on treatment. Predominant adverse effects are
cholinergic in nature (nausea, vomiting, anorexia and
somnolence) and are generally rated as mild or moder-
ate. Hypersalivation, rhinorrhea and lacrimation were
recorded in approximately 15% of DLB and PDD
patients treated with donepezil (Thomas et al., 2005)
and postural hypotension, falls and syncope are possi-
bly also increased. This latter side-effect profile is con-
sistent with the known pre-existing autonomic
dysfunction in DLB and such symptoms are likely to
occur with all procholinergic agents.
The presence of VH in DLB predicted a good
response to rivastigmine in DLB assessed using a com-
puter-based system measuring attentional speed and
accuracy (McKeith et al., 2004b). Cognitive reaction
time, calculated by subtracting simple from choice reac-
tion times, was however not improved by rivastigmine.
This suggests that this cognitive component may be
dopaminergically mediated, and the marked reductions
that are seen in cognitive reaction time in DLB and
 DEMENTIA WITH LEWY BODIES
PDD but not in AD (Ballard et al., 2002; Wesnes et al.,
2002) are related to a loss of mesocortical dopaminergic
projections.
60.5.4. Antipsychotic agents
Since hallucinations, delusions and associated beha-
vioral disturbances are so frequent in DLB, a very
common clinical scenario is for the clinician to con-
sider using antipsychotic medication. Traditional
agents with potent D2-receptor antagonism are asso-
ciated with severe neuroleptic sensitivity reactions in
up to 50% of DLB patients, leading to substantial mor-
bidity and a two- to threefold increased mortality risk
(McKeith et al., 1992a; Aarsland et al., 2005). These
reactions are generally evident within the first few
doses or after increase from a previously tolerated
dose. Sensitivity reactions have also been reported
for second-generation antipsychotic agents such as ris-
peridone and olanzapine (McKeith et al., 1995; Walker
et al., 1999). Newer atypicals with potentially more
favorable pharmacological properties, such as quetia-
pine, clozapine and aripiprazole, have theoretical
advantages in LB disease (Fernandez et al., 2003; Terao
et al., 2003) but controlled clinical trial data are lacking
and clinicians should remain vigilant to the possibility
of adverse side-effects. If acute deterioration occurs
in a confused elderly patient following neuroleptic
administration, DLB should always be considered as
part of the differential diagnosis. However, since up to
50% of DLB patients receiving typical or atypical anti-
psychotic agents do not react adversely, a history of
neuroleptic tolerance does not therefore rule out a diag-
nosis of DLB and deliberate neuroleptic challenge is
neither a safe nor a reliable diagnostic procedure.
60.5.5. Other pharmacological agents for
symptomatic treatment
Depression is common in DLB but there have been no
systematic studies of its management. At the present
time selective serotonin reuptake inhibitors and sero-
tonin-norepinephrine reuptake inhibitors (SNRIs) are
probably the preferred pharmacological treatments.
Tricylic antidepressants and those with anticholinergic
properties should be avoided. Apathy is a common
feature which may mimic depression or excessive day-
time somnolence and which may improve with ChEIs.
Anxiety is frequently secondary to fluctuating confu-
sion and hallucinations and improves when these are
treated. Small doses of benzodiazepines may offer
short-term symptomatic relief but at the expense of wor-
sening amnesia, alertness and motor function, with
increased risk of falls. Sleep disorders are also
543
frequently seen in LB disease and may be an early feature.
RBD can be treated with clonazepam 0.25 mg at bedtime,
melatonin 3 mg at bedtime or quetiapine 12.5 mg at bed-
time and titrated slowly, monitoring for both efficacy
and side-effects (McKeith et al., 2005). ChEIs may also
be helpful for disturbed sleep (Reading et al., 2001).
The frequent occurrence of electroencephalographic
(EEG) abnormalities in DLB, incuding transient tem-
poral slow waves, has prompted the use of carbamaze-
pine and sodium valproate, usually for agitation or
insomnia. No systematic reports of efficacy or side-
effects are available. The 5-HT3 antagonist ondansetron
was reported as having antipsychotic effects in halluci-
nated PD patients but this has not been independently
replicated and the high doses required make the cost
prohibitive for routine practice (Harrison and McKeith,
1995).
60.5.6. Disease-modifying agents
There are no disease-modifying pharmacological
therapies for DLB. Better understanding of the neuro-
biology of synuclein may lead to the development of
novel therapeutic interventions applicable to a diverse
group of neurodegenerative disorders, including DLB,
PD and MSA, but until then the clinician has only
symptomatic treatments available. Clinical trial data
suggest that ChEIs may potentially slow disease pro-
gression in AD, and similar effects could be antici-
pated in DLB.
60.6. Summary
DLB is now established as a relatively common form
of dementia in older people and is part of a larger
spectrum of LB disease which has diverse clinical pre-
sentations, including PD, primary autonomic failure
and RBD. Recent modifications to clinical and patho-
logical guidelines for the assessment and diagnosis of
DLB have been made (McKeith et al., 2005) and these
will require independent validation in a variety of set-
tings. Suspicion of a DLB diagnosis should be raised
in the presence of any one of the proposed core or sug-
gestive features and may be supported by the use of
specifically designed assessment scales and appropri-
ate neuroimaging techniques. ChEIs offer the greatest
hope for symptomatic improvement in both psychotic
and cognitive features of DLB and seem to offer these
benefits without significant compromise of motor
function. Ongoing multicenter, double-blind, placebo-
controlled studies will hopefully clarify these issues,
whereas long-term studies are required to assess the
duration of benefit. Antipsychotic drugs need to be
544 I. MCKEITH
used sparingly and only when other pharmacological
and non-pharmacological approaches fail to prevent
severe distress or injurious behavior to self or others.
Clinicians should be vigilant for severe neuroleptic
sensitivity reactions. Clonazepam may have a particu-
lar role in the management of sleep disorders but the
role of other sedatives and anticonvulsants is unpro-
ven. New-generation antidepressants may be helpful
for persistent depressive symptoms. Disease-modifying
treatments are urgently required. Better understanding
of the pathobiological processing of synuclein proteins
could ultimately lead to the development of novel
therapeutic interventions for DLB.
References
Aarsland D, Hutchinson M (2003). Galantamine for Parkin-
sons disease with dementia. Int Psychogeriatr 15: 243.
Aarsland D, Ballard C, Larsen JP et al. (2001a). A compara-
tive study of psychiatric symptoms in dementia with Lewy
bodies and Parkinsons disease with and without dementia.
Int J Geriatr Psychiatry 16: 528536.
Aarsland D, Ballard C, McKeith I et al. (2001b). Comparison
of extrapyramidal signs in dementia with Lewy bodies and
Parkinsons disease. J Neuropsychiatry Clin Neurosci 13:
374379.
Aarsland D, Laake K, Larsen JP et al. (2002). Donepezil for cog-
nitive impairment in Parkinsons disease: a randomised con-
trolled study. J Neurol Neurosurg Psychiatry 72 (6): 708712.
Aarsland D, Andersen K, Larsen JP et al. (2003). Prevalence
and characteristics of dementia in Parkinson disease: an
8-year prospective study. Arch Neurol 60 (3): 387392.
Aarsland D, Mosimann UP, McKeith IG (2004). Role of
cholinesterase inhibitors in Parkinsons disease and
dementia with Lewy bodies. J Geriatr Psychiatry Neurol
17 (3): 164171.
Aarsland D, Ballard C, Larsen JP et al. (2005). Marked
neuroleptic sensitivity in dementia with Lewy bodies and
Parkinsons disease. J Clin Psychiatry 66 (5): 633637.
Ala T, Hughes LF, Kyrouac GA et al. (2004). Use of MMSE
to differentiate Alzheimers disease from dementia with
Lewy bodiesresponse to Larner The Mini-Mental State
exam may help in the differentiation of dementia with
Lewy bodies and Alzheimers disease. Int J Geriatr
Psychiatry 19 (12): 1209; author reply 12091210.
Armstrong TP, Hansen LA, Salmon DP et al. (1991). Rapidly
progressive dementia in a patient with the Lewy body
variant of Alzheimers disease. Neurology 41: 11781180.
Ballard CG, Mohan RNC, Patel A et al. (1993). Idiopathic
clouding of consciousnessdo the patients have cortical
Lewy body disease? Int J Geriatr Psychiatry 8: 571576.
Ballard C, Grace J, McKeith I et al. (1998a). Neuroleptic
sensitivity in dementia with Lewy bodies and Alzheimers
disease. Lancet 351: 10321033.
Ballard C, Shaw F, McKeith I et al. (1998b). High prevalence
of neurovascular instability in neurodegenerative demen-
tias. Neurology 51: 17601762.
Ballard C, Holmes C, McKeith I et al. (1999). Psychiatric
morbidity in dementia with Lewy bodies: a prospective
clinical and neuropathological comparative study with
Alzheimers disease. Am J Psychiatry 156 (7): 10391045.
Ballard C, OBrien J, Swann A et al. (2000a). One year fol-
low-up of parkinsonism in dementia with Lewy bodies.
Dement Geriatr Cogn Disord 11: 219222.
Ballard C, Piggott M, Johnson M et al. (2000b). Delusions
associated with elevated muscarinic binding in dementia
with Lewy bodies. Ann Neurol 48: 868876.
Ballard C, OBrien J, Morris CM et al. (2001). The progres-
sion of cognitive impairment in dementia with Lewy
bodies, vascular dementia and Alzheimers disease. Int
J Geriatr Psychiatry 16 (5): 499503.
Ballard CG, Aarsland D, McKeith IG et al. (2002). Fluctua-
tions in attentionPD dementia vs DLB with parkinson-
ism. Neurology 59 (11): 17141720.
Barber R, Gholkar A, Scheltens P et al. (1999). Medial tem-
poral lobe atrophy on MRI in dementia with Lewy bodies.
Neurology 52: 11531158.
Barber R, Ballard C, McKeith IG et al. (2000a). MRI volu-
metric study of dementia with Lewy bodies. A comparison
with AD and vascular dementia. Neurology 54: 13041309.
Barber R, Gholkar A, Scheltens P et al. (2000b). MRI
volumetric correlates of white matter lesions in dementia
with Lewy bodies and Alzheimers disease. Int J Geriatr
Psychiatry 15: 911916.
Benjamin R, Leake A, Edwardson JA et al. (1994). Apolipo-
protein E genes in Lewy body and Parkinsons disease.
Lancet 343: 1565.
Bhanji NH, Gauthier S (2003). Dementia with Lewy bodies:
preliminary observations on cholinesterase inhibitor
switching. Int Psychogeriatr 15: 179.
Birkett DP, Desouky A, Han L et al. (1992). Lewy bodies in
psychiatric patients. Int J Geriatr Psychiatry 7: 235240.
Boeve BF, Silber MH, Ferman TJ et al. (1998). REM sleep
behaviour disorder and degenerative dementia. An associa-
tion likely reflecting Lewy body disease. Neurology 51:
363370.
Boeve BF, Silber MH, Ferman TJ et al. (2001). Association of
REM sleep behavior disorder and neurodegenerative disease
may reflect an underlying synucleinopathy. Mov Disord 16:
622630.
Boeve BF, Silber MH, Parisi JE et al. (2003). Synucleinopa-
thy pathology and REM sleep behavior disorder plus
dementia or parkinsonism. Neurology 61: 4045.
Boeve BF, Silber MH, Ferman TJ (2004). REM sleep
behavior disorder in Parkinsons disease and dementia with
Lewy bodies. J Geriatr Psychiatry Neurol 17 (3): 146157.
Bonelli SB, Ransmayr G, Steffelbauer M et al. (2004). L-dopa
responsiveness in dementia with Lewy bodies, Parkinson dis-
ease with and without dementia. Neurology 63 (2): 376378.
Braak H, Del Tredici K, Rub U et al. (2003). Staging of brain
pathology related to sporadic Parkinsons disease. Neuro-
biol Aging 24 (2): 197211.
Bradshaw J, Saling M, Hopwood M et al. (2004). Fluctuating
cognition in dementia with Lewy bodies and Alzheimers
disease is qualitatively distinct. J Neurol Neurosurg
Psychiatry 75: 382387.
 DEMENTIA WITH LEWY BODIES
Burkhardt CR, Filley CM, Kleinschmidt-DeMasters BK et al.
(1988). Diffuse Lewy body disease and progressive demen-
tia. Neurology 38: 15201528.
Burn DJ, McKeith IG (2004). Update on treatment strategies for
dementia with Lewy bodies. World J Biol Psychiatry 5 (1): 78.
Burn DJ, Rowan EN, Minett T et al. (2003). Extrapyramidal
features in Parkinsons disease with and without dementia
and dementia with Lewy bodies: a cross-sectional com-
parative study. Mov Disord 18 (8): 884889.
Byrne EJ, Lennox G, Lowe J et al. (1989). Diffuse Lewy
body disease: clinical features in 15 cases. J Neurol Neu-
rosurg Psychiatry 52: 709717.
Byrne EJ, Lennox G, Godwin-Austen RB et al.
(1991). Dementia associated with cortical Lewy bodies.
Proposed diagnostic criteria. Dementia 2: 283284.
Calderon J, Perry RJ, Erzinclioglu SW et al. (2001). Perception,
attention, and working memory are disproportionately
impaired in dementia with Lewy bodies compared with Alzhei-
mers disease. J Neurol Neurosurg Psychiatry 70 (2): 157164.
Cohen-Mansfield J (2006). Non-pharmacological manage-
ment of DLB. In: JT OBrien, I McKeith, D Ames, E
Chiu (Eds.), Dementia with Lewy Bodies. Dunitz, New
York, pp. 193206.
Collerton D, Burn D, McKeith I et al. (2003). Systematic
review and meta-analysis show that dementia with Lewy
bodies is a visual-perceptual and attentional-executive
dementia. Dement Geriatr Cogn Disord 16 (4): 229237.
Collerton D, Perry E, McKeith I (2005). Why people see
things that are not there: a novel Perception and Attention
Deficit model for recurrent complex visual hallucinations.
Behav Brain Sci 28: 737757.
Colloby SJ, Fenwick JD, Williams ED et al. (2002). A com-
parison of 99mTc-HMPAO SPECT changes in dementia
with Lewy bodies and Alzheimers disease using statisti-
cal parametric mapping. Eur J Nucl Med 29 (5): 615622.
Connor DJ, Salmon DP, Sandy TJ et al. (1998). Cognitive
profiles of autopsy-confirmed Lewy body variant vs pure
Alzheimer disease. Arch Neurol 55 (7): 9941000.
Court JA, Ballard CG, Piggott MA et al. (2001). Visual
hallucinations are associated with lower a-bungarotoxin
binding in dementia with Lewy bodies. Pharmacol Biochem
Behav 70: 571579.
Crystal HA, Dickson DW, Lizardi JE et al. (1990). Antemor-
tem diagnosis of diffuse Lewy body disease. Neurology 40:
15231528.
Del-Ser T, Munoz DG, Hachinski V (1996). Temporal pat-
tern of cognitive decline and incontinence is different in
Alzheimers disease and diffuse Lewy body disease. Neu-
rology 46: 682686.
Del-Ser T, McKeith I, Anand R et al. (2000). Dementia with
Lewy bodies: findings from an international multicentre
study. Int J Geriatr Psychiatry 15: 10341045.
Dickson DW, Davies P, Mayeux R et al. (1987). Diffuse
Lewy body disease. Neuropathological and biochemical
studies of six patients. Acta Neuropathol (Berl) 75: 815.
Duda JE, Giasson BI, Mabon ME et al. (2002). Novel anti-
bodies to synuclein show abundant striatal pathology in
Lewy body diseases. Ann Neurol 52 (2): 205210.
545
Edwards KR, Hershey L, Wray L et al. (2004). Efficacy and
safety of galantamine in patients with dementia with Lewy
bodies: a 12-week interim analysis. Dement Geriatr Cogn
Disord S1: 4048.
Emre M (2003). Dementia associated with Parkinsons dis-
ease. Lancet Neurol 2 (4): 229237.
Emre M, Aarsland D, Albanese A et al. (2004). Rivastigmine
for dementia associated with Parkinsons disease. N Engl J
Med 351 (24): 25092518.
Fahn S, Elton RL (1987). Unified Parkinsons disease rating
scale. In: S Fahn, CD Marsden, M Goldstein, DB Calne
(Eds.), Recent Developments in Parkinsons Disease.
McMillan, New York, pp. 153163.
Farde L, Suhara T, Nyberg S et al. (1997). A PET study of
[11C]FLB 457 binding to extrastriatal D2-dopamine recep-
tors in healthy subjects and antipsychotic drug-treated
patients. Psychopharmacology (Berl) 133: 396404.
Ferman TJ, Boeve BF, Smith GE et al. (1999). REM sleep
behaviour disorder and dementia. Cognitive differences
when compared with AD. Neurology 52: 951957.
Ferman TJ, Smith GE, Boeve BF et al. (2004). DLB fluctua-
tions: specific features that reliably differentiate from AD
and normal aging. Neurology 62 (2): 181187.
Fernandez HH, Wu CK, Ott BR (2003). Pharmacotherapy of
dementia with Lewy bodies. Expert Opin Pharmacother
4 (11): 20272037.
Forstl H, Levy R (1991). FH Lewy on Lewy bodies, par-
kinsonism and dementia. Int J Geriatr Psychiatry 6:
757766.
Forstl H, Burns A, Luthert P et al. (1993). The Lewy-body
variant of Alzheimers disease. Clinical and pathological
findings. Br J Psychiatry 162: 385392.
Gibb WRG, Esiri MM, Lees AJ (1987). Clinical and patho-
logical features of diffuse cortical Lewy body disease
(Lewy body dementia). Brain 110: 11311153.
Gibb WRG, Luthert PJ, Janota I et al. (1989). Cortical Lewy
body dementia: clinical features and classification. J Neu-
rol Neurosurg Psychiatry 52: 185192.
Gnanalingham KK, Smith LA, Hunter AJ et al. (1993). Altera-
tions in striatal and extrastriatal D-1 and D-2 dopamine
receptors in the MPTP-treated common marmoset: an
autoradiographic study. Synapse 14: 184194.
Gomez-Tortosa E, Newell K, Irizarry MC et al. (1999). Clini-
cal and quantitative pathological correlates of dementia
with Lewy bodies. Neurology 53: 12841291.
Grace J, Daniel S, Stevens T et al. (2001). Long-term use of
rivastigmine in patients with dementia with Lewy bodies:
an open-label trial. Int Psychogeriatr 13 (2): 199205.
Hamilton RL (2000). Lewy bodies in Alzheimers disease:
a neuropathological review of 145 cases using alpha-
synuclein immunohistochemistry. Brain Pathol 10:
378384.
Hansen L, Salmon D, Galasko D et al. (1990). The Lewy
body variant of Alzheimers disease: a clinical and patho-
logic entity. Neurology 40: 18.
Harding AJ, Halliday GM (2001). Cortical Lewy body
pathology in the diagnosis of dementia. Acta Neuropathol
(Berl) 102: 355363.
546 I. MCKEITH
Harding AJ, Kril JJ, Halliday GM (2000). Practical mea-
sures to simplify the Braak tangle staging method for
routine pathological screening. Acta Neuropathol (Berl)
99 (2): 199208.
Hardy J (2003). The relationship between Lewy body dis-
ease, Parkinsons disease, and Alzheimers disease. Ann
NY Acad Sci 991: 167170.
Harrison RH, McKeith IG (1995). Senile dementia of Lewy
body typea review of clinical and pathological features:
implications for treatment. Int J Geriatr Psychiatry 10:
919926.
Holmes C, Cairns N, Lantos P et al. (1999). Validity of current
clinical criteria for Alzheimers disease, vascular dementia
and dementia with Lewy bodies. Br J Psychiatry 174: 4550.
Horimoto Y, Matsumoto M, Akatsu H et al. (2003). Auto-
nomic dysfunctions in dementia with Lewy bodies. J Neu-
rol 250 (5): 530533.
Hutchinson M, Fazzini E (1996). Cholinesterase inhibitors in
Parkinsons disease. J Neurol Neurosurg Psychiatry 61:
324325.
Jellinger KA (1996). Structural basis of dementia in neurode-
generative disorders. J Neural Transm 47: 129.
Jellinger KA (2003). Neuropathological spectrum of synu-
cleinopathies. Mov Disord 18 (Suppl 6): S2S12.
Jellinger KA, Bancher CH (1995). Structural basis of mental
impairment in Parkinsons disease. Neuropsychiatrie 9:
914.
Johnson J, Hague SM, Hanson M et al. (2004). SNCA multi-
plication is not a common cause of Parkinson disease or
dementia with Lewy bodies. Neurology 63 (3): 554556.
Kaasinen V, Nagren K, Hietala J et al. (2000). Extrastriatal
dopamine D2 and D3 receptors in early and advanced Par-
kinsons disease. Neurology 54: 14821487.
Kaufer DI, Catt KE, Lopez OL et al. (1998). Dementia with
Lewy bodies: response of delirium-like features to done-
pezil. Neurology 51: 1512.
Klatka LA, Louis ED, Schiffer RB (1996). Psychiatric fea-
tures in diffuse Lewy body disease: findings in 28 patholo-
gically diagnosed cases. Neurology 46: A180.
Kosaka K (1978). Lewy bodies in cerebral cortex, report of
three cases. Acta Neuropathol (Berl) 42: 127134.
Kosaka K, Iseki E (1998). Recent advances in dementia
research in Japan: non-Alzheimer type degenerative
dementias. Psychiatry Clin Neurosci 52: 367373.
Kosaka K, Yoshimura M, Ikeda K et al. (1984). Diffuse type
of Lewy body disease: progressive dementia with abun-
dant cortical Lewy bodies and senile changes of varying
degreea new disease? Clin Neuropathol 3 (5): 185192.
Kosaka K, Iseki E, Odawara T et al. (1996). Cerebral type of
Lewy body disease. Neuropathology 16: 3235.
Kuhl DE, Minoshima S et al. (1996). In vivo mapping of
cholinergic terminals in normal aging, Alzheimers dis-
ease, and Parkinsons disease. Ann Neurol 40: 399410.
Kuzuhara S, Yoshimura M (1993). Clinical and neuropatho-
logical aspects of diffuse Lewy body disease in the
elderly. Adv Neurol 60: 464469.
Lennox G, Lowe J, Byrne EJ et al. (1989a). Diffuse Lewy
body disease. Lancet 1 (8633): 323324.
Lennox G, Lowe J, Landon M et al. (1989b). Diffuse Lewy
body disease: correlative neuropathology using anti-ubi-
quitin immunocytochemistry. J Neurol Neurosurg Psy-
chiatry 52: 12361247.
Lippa CF, McKeith I (2003). Dementia with Lewy bodies
improving diagnostic criteria. Neurology 60: 15711572.
Litvan I, MacIntyre A, Goetz CG et al. (1998). Accuracy
of the clinical diagnoses of Lewy body disease, Parkin-
sons disease, and dementia with Lewy bodies. Arch
Neurol 55: 969978.
Litvan I, Bhatia KP, Burn DJ et al. (2003). SIC Task Force
appraisal of clinical diagnostic criteria for parkinsonian
disorders. Mov Disord 18 (5): 467486.
Lobotesis K, Fenwick JD, Phipps A et al. (2001). Occipital
hypoperfusion on SPECT in dementia with Lewy bodies
but not AD. Neurology 56: 643649.
Lopez OL, Wisniewski S, Hamilton RL et al. (2000). Predic-
tors of progression in patients with AD and Lewy bodies.
Neurology 54 (9): 17741779.
Luis CA, Barker WW, Gajaraj K et al. (1999). Sensitivity
and specificity of three clinical criteria for dementia with
Lewy bodies in an autopsy-verified sample. Int J Geriatr
Psychiatry 14: 526533.
Maclean LE, Collins CC, Byrne EJ (2001). Dementia with
Lewy bodies treated with rivastigmine: effects on cogni-
tion, neuropsychiatric symptoms, and sleep. Int Psycho-
geriatr 13: 277288.
Marshall V, Grosset D (2003). Role of dopamine transporter
imaging in routine clinical practice. Mov Disord 18 (12):
14151423.
McKeith I (2005a). Dementia with Lewy bodies: a clinical
overview. In: A Burns, JT OBrien, D Ames (Eds.),
Dementia. Arnold, London.
McKeith I (2005b). Pharmacological management of DLB.
In: JT OBrien, I McKeith, D Ames, E Chiu (Eds.),
Dementia with Lewy Bodies. Dunitz, New York, pp.
183192.
McKeith I, Fairbairn A, Perry R et al. (1992a). Neuroleptic
sensitivity in patients with senile dementia of Lewy body
type. BMJ 305: 673678.
McKeith I, Del-Ser T, Spano PF et al. (2000a). Efficacy of
rivastigmine in dementia with Lewy bodies: a randomised,
double-blind, placebo-controlled international study.
Lancet 356: 20312036.
McKeith I, Mintzer J, Aarsland D et al. (2004a). Dementia
with Lewy bodies. Lancet Neurol 3: 1928.
McKeith I, Dickson D, Emre M et al. (2005). Dementia with
Lewy bodies: diagnosis and management: Third Report of
the DLB Consortium. Neurology 65 (12): 18631872.
McKeith IG (2003). The clinical spectrum of Lewy body dis-
ease. The Third Kuopio Alzheimer Symposium, Vol. 3,
Kuopio, Finland. p. 25.
McKeith IG, Perry RH, Fairbairn AF, et al. (1992b). Opera-
tional criteria for senile dementia of Lewy body type
(SDLT). Psychol Med 22: 911922.
McKeith IG, Fairbairn AF, Perry RH et al. (1994). The
clinical diagnosis and misdiagnosis of senile dementia of
Lewy body type (SDLT). Br J Psychiatry 165: 324332.
 DEMENTIA WITH LEWY BODIES
McKeith IG, Ballard CG, Harrison RWS (1995). Neuroleptic
sensitivity to risperidone in Lewy body dementia. Lancet
346: 699.
McKeith IG, Galasko D, Kosaka K et al. (1996). Consensus
guidelines for the clinical and pathologic diagnosis of demen-
tia with Lewy bodies (DLB): report of the consortium on
DLB international workshop. Neurology 47: 11131124.
McKeith IG, Perry EK, Perry RH (1999). Report of the sec-
ond dementia with Lewy body international workshop:
diagnosis and treatment. Consortium on dementia with
Lewy bodies. Neurology 53 (5): 902905.
McKeith IG, Ballard CG, Perry RH et al. (2000b). Pros-
pective validation of consensus criteria for the diagnosis
of dementia with Lewy bodies. Neurology 54: 10501058.
McKeith IG, Wesnes KA, Perry E et al. (2004b). Hallucina-
tions predict attentional improvements with rivastigmine
in dementia with Lewy bodies. Dement Geriatr Cogn Disord
18: 94100.
McKhann G, Drachman D, Folstein M et al. (1984). Clinical
diagnosis of Alzheimers diseasereport of the NINCDS-
ADRDA Work Group under the auspices of Department
of Health and Human Services Task Force on Alzheimers
disease. Neurology 34 (7): 939944.
McNaught KS, Shashidharan P, Perl DP et al. (2002). Aggre-
some-related biogenesis of Lewy bodies. Eur J Neurosci
16 (11): 21362148.
McShane RH, Esiri MM, Joachim C et al. (1998). Prospective
evaluation of diagnostic criteria for dementia with Lewy
bodies. Neurobiol Aging 19 (4S): S204.
Mega MS, Masterman DL, Benson F et al. (1996). Dementia
with Lewy bodies: reliability and validity of clinical and
pathologic criteria. Neurology 47: 14031409.
Merdes AR, Hansen LA, Jeste DV et al. (2003). Influence of
Alzheimer pathology on clinical diagnostic accuracy in
dementia with Lewy bodies. Neurology 60 (10): 15861590.
Minett TSC, Thomas A, Wilkinson LM et al. (2003). What
happens when donepezil is suddenly withdrawn? An open
label trial in dementia with Lewy bodies and Parkinsons
disease with dementia. Int J Geriatr Psychiatry 18: 988993.
Mirra SS, Heyman A, McKeel D et al. (1991). The Consortium
to Establish a Registry for Alzheimers Disease (CERAD) II.
Standardisation of the neuropathological assessment of
Alzheimers disease. Neurology 41: 479486.
Molloy S, McKeith I, OBrien JT et al. (2005). The role of
levodopa in the management of dementia with Lewy
bodies. J Neurol Neurosurg Psychiatry 76 (9): 12001203.
Mormont E, Grymonprez LL, Baisset-Mouly C et al. (2003).
The profile of memory disturbance in early Lewy body
dementia differs from that in Alzheimers disease. Rev
Neurol (Paris) 159 (89): 762766.
Morris CM, Massey HM, Benjamin R et al. (1996). Molecular
biology of APO E alleles in Alzheimers and non-Alzheimers
dementias. J Neural Transm 47: 205218.
Mosimann UP, Mather G, Wesnes K et al. (2004). Visual
perception in Parkinson disease dementia and dementia
with Lewy bodies. Neurology 63 (11): 20912096.
Mosimann UP, Rowan EN, Partington CE, et al. (2006).
Characteristics of visual hallucinations in Parkinsons
547
disease dementia and dementia with Lewy bodies. Am J
Geriatr Psychiatry 14: 153160.
OBrien JT, Paling S, Barber R et al. (2001). Progressive
brain atrophy on serial MRI in dementia with Lewy
bodies, AD, and vascular dementia. Neurology 56 (10):
13861388.
OBrien JT, Colloby SJ, Fenwick J et al. (2004). Dopamine
transporter loss visualised with FP-CIT SPECT in demen-
tia with Lewy bodies. Arch Neurol 61 (6): 919925.
OBrien KK, Saxby BK, Ballard CG et al. (2003). Regulation
of attention and response to therapy in dementia by
butyrylcholinesterase. Pharmacogenetics 13: 231239.
Okazaki H, Lipkin LE, Aronson SM (1961). Diffuse intracyto-
plasmic ganglionic inclusions (Lewy type) associated with
progressive dementia and quadriparesis in flexion. J Neuro-
pathol Exp Neurol 20: 237244.
Papka M, Rubio A, Schiffer RB (1998). A review of Lewy
body disease, an emerging concept of cortical dementia.
J Neuropsychiatry Clin Neurosci 10: 267279.
Perry E, McKeith I, Ballard C (2003a). Butyrylcholinesterase
and progression of cognitive deficits in dementia with
Lewy bodies. Neurology 60 (11): 18521853.
Perry EK, Kilford L, Lees AJ et al. (2003b). Increased
Alzheimer pathology in Parkinsons disease related to
antimuscarinic drugs. Ann Neurol 54 (2): 235238.
Perry EK, Piggott MA, Johnson M et al. (2003c). Neuro-
transmitter correlates of neuropsychiatric symptoms in
dementia with Lewy bodies. In: MA Bedard, Y Agid, S
Chouinard et al. (Eds.), Mental and Behavioral Dysfunc-
tion in Movement Disorders. Humana Press Inc, Totowa,
NJ, pp. 285294.
Perry RH, Irving D, Blessed G et al. (1989a). Clinically and
neuropathologically distinct form of dementia in the
elderly. Lancet 1 (8630): 166.
Perry RH, Irving D, Blessed G et al. (1989b). Senile demen-
tia of Lewy body type and spectrum of Lewy body
disease. Lancet 1 (8646): 1088.
Perry RH, Irving D, Blessed G et al. (1990). Senile dementia
of Lewy body type. A clinically and neuropathologically
distinct form of Lewy body dementia in the elderly.
J Neurol Sci 95: 119139.
Piggott MA, Marshall EF, Thomas N et al. (1999). Striatal
dopaminergic markers in dementia with Lewy bodies,
Alzheimers and Parkinsons diseases: rostrocaudal distri-
bution. Brain 122: 14491468.
Polymeropoulos MH, Lavedan C, Leroy E et al. (1997). Muta-
tion in the alpha-synuclein gene identified in families with
Parkinsons disease. Science 276 (5321): 20452047.
Pondal M, DelSer T, Bermejo F (1996). Anticholinergic ther-
apy and dementia in patients with Parkinsons disease.
J Neurol 243 (7): 543546.
Rahkonen T, Eloniemi-Sulkava U, Rissanen S et al. (2003).
Dementia with Lewy bodies according to the consensus
criteria in a general population aged 75 years or older.
J Neurol Neurosurg Psychiatry 74 (6): 720724.
Reading PJ, Luce AK, McKeith IG (2001). Rivastigmine in
the treatment of parkinsonian psychosis and cognitive
impairment. Mov Disord 16 (6): 11711174.
548 I. MCKEITH
Sahgal A, Galloway PH, McKeith IG et al. (1992). A com-
parative study of attentional deficits in senile dementias
of Alzheimer and Lewy body types. Dementia 3: 350354.
Samuel W, Galasko D, Masliah E et al. (1996). Neocortical
Lewy body counts correlate with dementia in the Lewy
body variant of Alzheimers disease. J Neuropathol Exp
Neurol 55 (1): 4452.
Samuel W, Alford M, Hofstetter CR et al. (1997). Dementia
with Lewy bodies versus pure Alzheimer disease: differ-
ences in cognition, neuropathology, cholinergic dysfunc-
tion, and synapse density. J Neuropathol Exp Neurol 56:
499508.
Samuel W, Caligiuri M, Galasko D et al. (2000). Better cogni-
tive and psychopathologic response to donepezil in patients
prospectively diagnosed as dementia with Lewy bodies: a
preliminary study. Int J Geriatr Psychiatry 15 (9): 794802.
Shea C, MacKnight C, Rockwood K (1998). Donepezil for
treatment of dementia with Lewy bodies: a case series of
nine patients. Int Psychogeriatr 10 (3): 229238.
Shergill S, Mullan E, Dath P et al. (1994). What is the clin-
ical prevalence of Lewy body dementia? Int J Geriatr Psy-
chiatry 9: 907912.
Shinotoh H, Aotsuka A, Ota T et al. (2001). Brain cholinergic
function in dementia with Lewy bodies and Alzheimers
disease measured by PET. In: Abstracts. Proceedings of
5th International Conference on Progress in PD and AD: 74.
Singleton A, Gwinn-Hardy K (2004). Parkinsons disease
and dementia with Lewy bodies: a difference in dose?
Lancet 364 (9440): 11051107.
Stevens T, Livingston G, Kitchen G et al. (2002). Islington
study of dementia subtypes in the community. Br J Psy-
chiatry 180: 270276.
Taki J, Yoshita M, Yamada M et al. (2004). Significance of
I-123-MIBG scintigraphy as a pathophysiological indica-
tor in the assessment of Parkinsons disease and related
disorders: it can be a specific marker for Lewy body dis-
ease. Ann Nucl Med 18 (6): 453461.
Tanaka M, Kim YM, Lee G et al. (2004). Aggresomes
formed by alpha-synuclein and synphilin-1 are cytoprotec-
tive. J Biol Chem 279 (6): 46254631.
Terao T, Shimomura T, Izumi Y et al. (2003). Two cases of
quetiapine augmentation for donepezil-refractory visual
hallucinations in dementia with Lewy bodies. J Clin
Psychiatry 64 (12): 15201521.
Thomas AJ, Burn DJ, Rowan EN et al. (2005). A comparison
of the efficacy of donepezil in Parkinsons disease with
dementia and dementia with Lewy bodies. Int J Geriatr
Psychiatry 20: 938944.
Tiraboschi P, Hansen LA, Alford M et al. (2000). Cholinergic
dysfunction in diseases with Lewy bodies. Neurology 54:
407411.
Walker MP, Ayre GA, Cummings JL et al. (2000a). The
Clinician Assessment of Fluctuation and the One Day
Fluctuation Assessment Scale. Two methods to assess
fluctuating confusion in dementia. Br J Psychiatry 177:
252256.
Walker Z, Allan RL, Shergill S et al. (1997). Neuropsycholo-
gical performance in Lewy body dementia and Alzhei-
mers disease. Br J Psychiatry 170: 156158.
Walker Z, Grace J, Overshot R et al. (1999). Olanzapine in
dementia with Lewy bodies: a clinical study. Int J Geriatr
Psychiatry 14 (6): 459466.
Walker Z, Allen RL, Shergill S et al. (2000b). Three years
survival in patients with a clinical diagnosis of dementia
with Lewy bodies. Int J Geriatr Psychiatry 15: 267273.
Walker Z, Costa DC, Walker RWH et al. (2004). Striatal
dopamine transporter in dementia with Lewy bodies and
Parkinson disease: a comparison. Neurology 62 (9):
15681572.
Wesnes KA, McKeith IG, Ferrara R et al. (2002). Effects of
rivastigmine on cognitive function in dementia with Lewy
bodies: a randomised placebo-controlled international study
using the Cognitive Drug Research computerised assess-
ment system. Dement Geriatr Cogn Disord 13 (3):
183192.
Yoshita M, Taki J, Yamada M (2001). A clinical role for
I-123 MIBG myocardial scintigraphy in the distinction
between dementia of the Alzheimers-type and dementia
with Lewy bodies. J Neurol Neurosurg Psychiatry 71 (5):
583588.
Handbook of Clinical Neurology, Vol. 84 (3rd series)
Parkinsons disease and related disorders, Part II
W. C. Koller, E. Melamed, Editors
# 2007 Elsevier B. V. All rights reserved

Chapter 61

Myoclonus and parkinsonism

DANIEL D. TRUONG1* AND ROONGROJ BHIDAYASIRI1,2,3

1
The Parkinsons and Movement Disorder Institute, Fountain Valley, CA, USA
2
Movement Disorders Group, Division of Neurology, Chulalongkorn University Hospital, Bangkok, Thailand
3
Department of Neurology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

61.1. Introduction mental status abnormalities) guide the physicians to

Myoclonus is defined as sudden, brief, shock-like,
involuntary movements caused by muscular contrac-
tions (positive myoclonus) or inhibitions (negative
myoclonus) (Fahn et al., 1986). Myoclonus is not a
diagnosis but rather a descriptive term denoting symp-
toms or signs that are non-specific in relation to their
neuroanatomical source and pathogenesis. Despite its
non-specific nature, myoclonus has been described in
various conditions and has strong implications for the
diagnosis, prognosis and treatment of the underlying
disorder.
Myoclonus has been classified according to clinical
presentation, etiology, pathophysiology, pharmacologi-
cal and biochemical pathology, with an attempt to
establish the relationship between semiology, physiol-
ogy and etiology (Marsden et al., 1981). Of these, the
etiological classification is considered the most helpful
and appropriate in clinical practice and includes
physiological myoclonus, a normal manifestation in
healthy people; essential myoclonus, where no other
neurological deficit is present and can be sporadic or
inherited; epileptic myoclonus, where epilepsy domi-
nates the clinical picture and myoclonus is considered
as an epileptic phenomenon; and symptomatic myoclo-
nus, in the setting of an identifiable underlying disorder
(Fahn et al., 1986). In a study conducted by Caviness
(2002), symptomatic myoclonus was found to be the
most common (72%), followed by epileptic myoclonus
(17%) and essential myoclonus (11%).
In symptomatic myoclonus, the features of myoclo-
nus may not be distinctive. Instead, the history and
associated clinical signs (such as seizures, ataxia and
the appropriate diagnosis and relevant investigations.
Often, there is clinical and pathological evidence of
diffuse nervous system involvement. Within the symp-
tomatic group, posthypoxic syndrome and neurodegen-
erative disorders (particularly Alzheimers disease
(AD) and CreutzfeldtJakob disease (CJD)), account
for most of the cases (Caviness, 2002). Most myoclo-
nus in neurodegenerative disease is classified as corti-
cal, consistent with the well-known cortical pathology
in AD and CJD. In AD, myoclonus is more likely to
occur at a late stage when dementia is severe and tends
to be multifocal, affecting distal muscles, both sponta-
neously and in response to various stimuli (Hauser
et al., 1986). On the other hand, myoclonus is much
more frequent and more likely to be generalized in
CJD, although focal jerking in the face and limb can
be seen initially (Van Everbroeck et al., 2004). The
rapidly progressive dementia, associated neurological
signs, including cortical blindness, cerebellar, parkin-
sonism and typical electroencephalographic (EEG)
discharges, help distinguish CJD from the more com-
mon AD (Wojcieszek et al., 1994; Tschampa et al.,
2001). When the disease is of longer duration, asso-
ciated with myoclonus and rigidity, AD should be
considered (Tschampa et al., 2001).
Myoclonus is a recognized feature of many basal
ganglia disorders where parkinsonian signs predomi-
nate. Although tremor is frequently observed in
patients with idiopathic Parkinsons disease (PD),
myoclonus is much less common than tremor in par-
kinsonian syndromes and the presence of myoclonus
usually suggests a less common cause of parkinsonism
(Caviness et al., 2002a). Klawans et al. (1986) were

*Correspondence to: Daniel D. Truong, The Parkinsons and Movement Disorder Institute, 9940 Talbert Ave, Fountain Valley,
CA 92708, USA. E-mail: dtruong@pmdi.org, Tel: 714-378-5062, Fax: 714-378-5061.
550 D. D. TRUONG AND R. BHIDAYASIRI
Table 61.1
Common causes of myoclonus and parkinsonism
Idiopathic Parkinsons disease
Related to medications, including levodopa, dopamine
agonists, amantadine
Unrelated to medications
Diffuse Lewy body disease
Corticobasal degeneration
Multiple system atrophy
Encephalitis lethargica
Juvenile-onset Huntingtons disease
Dentatorubral-pallidoluysian atrophy
Frontotemporal dementia with parkinsonism
Chronic manganese poisoning
the first to report that myoclonus and parkinsonism
occurred simultaneously in three conditions: (1) PD
where patients are treated chronically with levodopa;
(2) von Economos encephalitis; and (3) acutely in 1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
intoxication. Since then, the association between myo-
clonus and parkinsonism has been described in other
parkinsonian disorders, including multiple system
atrophy (MSA), corticobasal degeneration (CBD),
diffuse Lewy body disease (DLB), postencephalitic
parkinsonism and frontotemporal dementia with
parkinsonism (FTD) (Table 61.1) (Howard and Lees,
1987; Chen et al., 1992; Thompson et al., 1994b; Wen-
ning et al., 1994; Louis et al., 1997; Caviness and
Wszolek, 2002). In addition, myoclonus has been
recognized in other neurological conditions in which
parkinsonism may occur but is less prominent, such
as cerebellar degenerations, Huntingtons disease
(HD), dentatorubral-pallidoluysian atrophy (DRPLA)
or even chronic manganese poisoning (Rodriguez
et al., 1994; Thompson et al., 1994a; Thompson and
Shibasaki, 2000; Ono et al., 2002).
Although myoclonus has been reported in various
parkinsonian syndromes, particularly cortical myoclo-
nus in all Lewy body disorders, the mechanism of
myoclonus is not identical across these different par-
kinsonian syndromes and different types of myoclonus
may coexist in the same syndrome (Caviness et al.,
2002a, b). Hence, electrophysiological studies play a
crucial role in the evaluation of myoclonus in these
parkinsonian disorders, not only for differential
diagnosis, but also for better understanding of the phy-
siological mechanism underlying each type of myoclo-
nus. Indeed, certain patterns have some etiological
specificity. The specific methods used in the neuro-
physiological study of myoclonus usually include,
but are not limited to, multichannel surface electro-
myography (EMG) recording with testing for long-
latency EMG responses to nerve stimulation, EEG,
EEG-EMG polygraphy with back-averaging and
somatosensory evoked potentials (SEPs). Since the
majority of myoclonic jerks are caused by hyperexcit-
ability of groups of neurons in certain brain structures,
the relationship of myoclonic jerks to EEG activities is
of primary importance in the study of myoclonus
(Shibasaki, 2000). Jerk-locked back-averaging is an
extension of the EEG-EMG polygraph and its princi-
ple is to back-average the simultaneously recorded
EEGs with respect to myoclonus. SEPs record EEG
potentials time-locked to EMG events such as a
myoclonus EMG discharge.
A good example of the utility of electrophysiologi-
cal studies is the differentiation between myoclonus
in MSA and CBD (Table 61.2). Myoclonus in MSA
has been reported to be typical of cortical reflex myo-
clonus, with enlarged SEPs, exaggerated long-latency
EMG responses to median nerve stimulation and
back-averaged EEG transients (Obeso et al., 1985). In
contrast to MSA, there is no preceding cortical dis-
charge time-locked to action myoclonus in CBD, SEPs
are not enlarged and latency on stimulation of median
nerve at the wrist is shorter (40 versus 50 ms)
(Thompson et al., 1994b).
61.2. Myoclonus in idiopathic Parkinsons
disease
Unilateral resting tremor in the distal limb is usually
the first motor manifestation in the majority of patients
with PD. While tremor, either at rest or during muscle
activation, is common in PD, myoclonus is much less
prevalent and was originally described as a conse-
quence of levodopa therapy. In a study of 12 PD
patients who developed myoclonus after taking levo-
dopa for 12 months, abnormal movements consisted
of single, abrupt jerks of the extremities, which were
bilateral and symmetrical or occasionally in an arm
or leg on the same side (Klawans et al., 1975). In gen-
eral, the trunk and limbs are most commonly affected,
whereas facial muscle involvement is unusual. Myo-
clonus can occur during sleep, fatigue, dozing or even
wakefulness, but abates with levodopa cessation.
Luquin et al. (1992) reported spontaneous and action
myoclonus with multifocal distribution in only 6 out
of 168 patients with levodopa-induced dyskinesias,
whereas Marconi et al. (1994) observed sporadic myo-
clonic jerks in most patients (10 out of 15 patients)
during the 1020 minutes following absorption of
levodopa. Methylsergide, a serotonin-specific antago-
nist, has been reported to improve levodopa-induced
 MYOCLONUS AND PARKINSONISM 551
Table 61.2
Electrophysiological findings in various subtypes of myoclonus

Back-averaged
Types EEG findings EMG EEG transients SEPs Reflex responses

Cortical Variable, may show Bursts typically Variable but focal Enlarged  C reflex at rest
epileptiform less than 75 ms sharp-wave 1040 cortical
discharges and ms before jerks component
slow waves
Cortical Generalized spike Bursts < 100 ms Time-locked Enlarged  C reflex at rest
subcortical and wave association cortical
component
possible
Subcortical No consistent Variable burst No correlate Normal Sometimes reflex
supraspinal abnormalities properties response to
sound
Spinal Normal Bursts > 100 ms No correlate Normal Variable but can
and  rhythmic be very short in
latency
Peripheral Normal Variable burst, No correlate Normal Normal
may be
denervation

EEG, electroencephalogram; EMG, electromyogram; SEPs, somatosensory evoked potentials.

Reproduced from Caviness and Brown (2004), The Lancet Neurology, with permission from Elsevier.

myoclonus, without worsening levodopa-induced
dyskinesias (Klawans et al., 1975).
In addition to levodopa, other medications have
been shown to induce myoclonus in PD. The dopa-
mine agonist bromocriptine was reported to induce
nocturnal myoclonus in 6 PD patients after the levo-
dopa was discontinued (Vardi et al., 1978). Another
patient with generalized dystonia from anoxic brain
injury also developed myoclonus affecting the proxi-
mal arms and axial muscles following the increasing
doses of bromocriptine (Buchman et al., 1987). When
bromocriptine was discontinued, the myoclonus
improved but the dystonia worsened. Amantadine, a
dopamine-reuptake inhibitor, a dopamine agonist and
an N-methyl-D-aspartate (NMDA) receptor agonist,
can also cause myoclonus and delirium. It was impli-
cated as a cause of vocal myoclonus affecting the
larynx, pharynx and face in a PD patient who was on
concomitant levodopa (Pfeiffer, 1996). The myoclonus
resolved after discontinuation of amantadine. In addi-
tion, amantadine has also been reported to induce
delirium and multifocal myoclonic jerks in all extremi-
ties, neck, tongue and face in another 2 PD patients
(Matsunaga et al., 2001). One patient also had renal
impairment with toxic levels of amantadine.
Recently, the occurrence of myoclonus unrelated to
medication has been recognized, with the incidence of
approximately 5% in non-demented PD patients in a
tertiary care center (Caviness et al., 1998, 2002b). The
myoclonus in PD in this category is typically of small
amplitude, occurring during muscle activation, and
may seem repetitive and rhythmic enough to resemble
action tremor. However, the movement is irregular in
both timing and amplitude and thus deserves the term
myoclonus. In a few cases, frequent (> 6 Hz) repetitive
rhythmic trains of EMG discharges coincided with a
movement that could overlap with a tremor phenotype.
The myoclonus is rarely present at rest and reflex
myoclonus cannot be demonstrated to touch, stretch or
tendon reflexes. The amplitude is often greater on one
side, but not always the same side as the more prominent
parkinsonian signs.
This myoclonus is very different from the levodopa-
induced myoclonus reported by Klawans et al. (1975)
because the latter usually occurs at rest, often during
sleep or drowsiness, and is sensitive to levodopa dosage.
In addition, this small-amplitude myoclonus was present
even before levodopa therapy in 1 of the 2 patients with
levodopa-responsive parkinsonism (Caviness et al.,
1998). Because this type of myoclonus can be observed
in early and moderate stages of non-demented PD
patients, advanced parkinsonism or dementia is gener-
ally not considered as a requirement. This is in contrast
to asterixis observed in PD, which is associated with
signs of chronic drug toxicity, dementia and its reversal
following drug withdrawal (Glantz et al., 1982).
552 D. D. TRUONG AND R. BHIDAYASIRI
Electrophysiological studies of myoclonus in PD
reported by Caviness et al. (2002b) are quite different
from the cortical reflex myoclonus physiology. EMG
recording during muscle activation showed irregular,
multifocal, brief (< 50 ms) myoclonic EMG dis-
charges. Back-averaging consistently showed a focal,
short-latency, EEG transient prior to the myoclonic
EMG discharges. Furthermore, cortical SEPs were
not enlarged and long-latency EMG responses at rest
were not present. Corticomuscular coherence is also
increased in PD patients with small-amplitude myoclo-
nus (Caviness et al., 2003b). Indeed, these electrophy-
siological findings distinguish myoclonus in PD from
the myoclonus seen in MSA, CBD, AD, minipolymyo-
clonus and cortical tremor. The mechanisms for the
cortical myoclonus in PD are probably secondary to
the lack of inhibitory influences or excessive excita-
tion of the sensorimotor cortex produced by the neuro-
degeneration locally around the sensorimotor cortical
region (Caviness et al., 2002b).
61.3. Myoclonus in diffuse Lewy body disease
Myoclonus in DLB is similar to myoclonus in PD,
although the former is more clinically impressive, with
larger amplitude, and is much more likely to occur at
rest (Fig. 61.1) (Caviness, 2002, 2003). Myoclonus
in DLB is also more common, occurring in about
1520% of cases (Burkhardt et al., 1988; Louis et al.,
LEFT DELT
LEFT BICEP
0.00 0.25 0.50 0.75
Fig. 61.1. Rectified surface electromyogram (EMG) of left deltoid and left biceps during the finger-to-nose maneuver in a
patient with dementia with Lewy bodies. The EMG burst in the center of the figure produced a myoclonic jerk. Courtesy of
Dr. John Caviness, Mayo Clinic, Scottsdale, AZ.
1997). The source of myoclonus in DLB is cortical
and previously published series of myoclonus in PD
showed electrophysiological characteristics that are
indistinguishable from the DLB series, even though
myoclonus in DLB is clinically more severe (Caviness
et al., 2002b, 2003a). In addition, myoclonus seen in
PD and DLB also showed many properties in common
with the myoclonus that was previously reported in
individuals with hereditary DLB (Caviness et al.,
2000). However, the electrophysiological properties
of myoclonus in Lewy body disorders differ from
those of myoclonus in AD.
The fact that cortical myoclonus shares similar phy-
siological properties across a spectrum of Lewy body
disorders suggests that a unifying mechanism may be
responsible for its occurrence. It is at present unclear
if the abnormal basal ganglia output to the cortex, cor-
tical pathology itself (either within the sensorimotor
region or more diffusely in the motor circuits in the
frontal and parietal lobes) or both in some way facili-
tate cortical myoclonus. Compared to the pathology
in PD, there is more widespread cortical pathology in
DLB, which may explain why myoclonus in DLB is
more severe. However, the neuropathological examina-
tion of previously reported cases only showed occa-
sional Lewy bodies in the pre- and postcentral gyri
as well as parietal, cingulate and entorhinal cortex
(Caviness et al., 1998). Furthermore, there is no correla-
tion between cortical myoclonus and the severity of
20.00 mV
1.00 1.25 1.50 1.75 2.00
S
 MYOCLONUS AND PARKINSONISM
RFCU
850 mV
RFDI
Fig. 61.2. Polygram in a patient with corticobasal degeneration demonstrating spontaneous myoclonus. Two bipolar surface
electromyogram channels are shown. RFCU, right flexor carpi ulnaris; RFDI, right first dorsal interosseous. Courtesy of
Dr. Zoltan Mari, Human Motor Control Section, NINDS.
parkinsonism in DLB. It is unclear if cortical myoclonus
is a marker for cortical dysfunction in DLB and is related
to the presence of cognitive dysfunction. It is possible
that cortical pathology in DLB exerts some influence
on the abnormal basal ganglia output to the cortex.
61.4. Myoclonus in corticobasal degeneration
The most frequent clinical presentation in CBD is a pro-
gressive levodopa-unresponsive akinetic-rigid syn-
drome associated with both cortical and basal ganglia
dysfunction (Kompoliti et al., 1998). A clinical diagnos-
tic criterion has been proposed to include manifestations
reflecting dysfunction of the cortex (corticosensory loss,
apraxia, frontal lobe reflexes, hyperreflexia, Babinskis
sign) and basal ganglia (akinesia, rigidity, limb dysto-
nia, postural instability) (Riley and Lang, 2000). When
specific signs are absent, the evolution of asymmetric
rigid dystonia and reflex myoclonus is highly sugges-
tive of CBD. At the time of presentation, myoclonus
of one limb has been reported in one-third of cases
and usually evolves in a further 20% over the following
2 years as the disease progresses (Rinne et al., 1994).
Overall, approximately 50% of patients with CBD
develop myoclonus during the course of illness (Rinne
et al., 1994). The tremor in CBD is usually of 68 Hz
action postural and action tremor, more irregular and
also jerky (Stover et al., 2004). A jerky tremor may pre-
cede the appearance of myoclonus in the limb early in
the condition (Brunt et al., 1995).
Myoclonus is best demonstrated during action or
maintenance of a posture in distal muscles; it is also
stimulus-sensitive in most cases, easily elicited by
553
100 ms
cutaneous stimuli (Fig. 61.2). However, it may be
masked by increased muscle tone. Action and reflex
myoclonus are characteristic (Thompson and Shibasaki,
2000). The presence of spontaneous myoclonus is diffi-
cult to judge because of the action myoclonus in the
setting of rigidity and alien-limb movements, which
interfere with the ability to complete relaxation.
Attempts to move the limb voluntarily are interrupted
by trains of repetitive-action myoclonus.
The myoclonus in CBD is focal in distribution and
predominantly distal. They are stimulus-sensitive and
closely resemble those of cortical reflex myoclonus
(Fig. 61.3) (Riley et al., 1990; Chen et al., 1992;
Thompson et al., 1994b; Carella et al., 1997). Thompson
et al. (1994b) studied the clinical and physiological
characteristics of myoclonus in 14 patients with
CBD, compared to 13 patients with epilepsia partialis
continua and progressive myoclonic ataxia. Although
hypersynchronous short-duration bursts of muscle
activity are common to both (often comprising runs
of 24 discharges with an interburst interval of
6080 ms), major differences between myoclonus
in CBD and typical cortical reflex myoclonus
exist (Thompson and Shibasaki, 2000). First of all,
myoclonus in CBD is not generally associated with
enlarged or giant SEPs, in contrast to typical cor-
tical reflex myoclonus. Secondly, cortical potentials
of myoclonus in CBD do not precede each myoclonic
jerk on back-averaged EEG. In addition, the latency
of reflex myoclonic jerks is shorter, about 40 ms in
CBD, in contrast to 5060 ms in typical cortical
reflex myoclonus. Lastly, the estimates of the cortical
delay for generation of myoclonic activity in typical
554 D. D. TRUONG AND R. BHIDAYASIRI

Lt biceps br.

triceps br.

rhomboid

Rt biceps br.

triceps br.

rhomboid

500 mV
1 sec
Fig. 61.3. Electromyogram polygraph obtained from a patient with clinical diagnosis of corticobasal ganglionic degeneration.
Repetitive spontaneous discharges are seen in the right biceps and triceps muscles almost synchronously at an approximate rate
of 78 Hz. Courtesy of Dr. Hiroshi Shibasaki, Kyoto University, Kyoto, Japan, reprinted with permission from Elsevier.

cortical reflex myoclonus associated with giant SEPs
(6.9  3.7 ms) are significantly longer than those of myo-
clonus in CBD (1.4  0.8 ms) (Thompson et al., 1994b).
Different patterns of abnormality in cortical reflex myo-
clonus may be explained by the differences in the proces-
sing and relay of sensory information in thalamocortical
pathways. In addition, other factors, such as fatigue, if
present, may influence the occurrence of periodic
discharges in the cortex and muscles in patients with
CBD (Manto et al., 2000).
The combination of focal, predominantly distal,
hypersynchronous jerks, evidence of enhanced cortical
excitability, together with the known pathology in
CBD suggests that the myoclonus in these patients
may be cortical in origin, despite the fact that back-
averaging fails to detect a cortical correlate to sponta-
neous or action-induced jerks and giant SEPs are
seldom found (Thompson et al., 1994b; Monza et al.,
2003). Furthermore, the study involving magnetoence-
phalogram also supported the role of precentral cortex
in generating spontaneous myoclonus (Mima et al.,
1998). Grosse et al. (2003) evaluated EEG-EMG and
EMG-EMG coherence and phase in 5 patients with
clinically probable CBD and unilateral, action-induced
stimulus-sensitive myoclonus. All patients exhibited
dramatic inflated EMG-EMG coherence in the absence
of any evidence of a pathological corticospinal drive
as determined by EEG-EMG coherence, raising the
possibility of involvement of subcortical motor sys-
tems in the myoclonus of CBD. Since the latency of
reflex myoclonus in CBD is only 12 ms longer than
the sum of afferent and efferent times to and from
the cortex, it is therefore possible that myoclonus in
CBD is due to the direct sensory input to motor corti-
cal areas that activate corticospinal tract output
(Thompson et al., 1994b). Alternatively, prominent
parietal involvement in CBD could result in a loss of
inhibitory input from the somatosensory area to the
motor cortex or thalamic pathology, possibly resulting
in a loss of thalamocortical recurrent inhibition (Shafiq
and Lang, 2002).
Shafiq and Lang (2002) provided their personal
experience of evaluating 1 patient with CBD whose
reflex latencies were consistent with typical cortical
reflex myoclonus and other patients with a CBD phe-
notype whose reflex myoclonus also did not have
classical electrophysiological features of CBD,
described by Thompson et al. (1994b). Whether there
are electrophysiological features that are specific and
sensitive for the pathology of CBD in order to confirm
 MYOCLONUS AND PARKINSONISM
or exclude the diagnosis remains uncertain and more
studies are needed to address this issue.
61.5. Myoclonus in multiple system atrophy
MSA encompasses a wide spectrum of clinical presen-
tations with various combinations of extrapyramidal,
pyramidal, cerebellar and autonomic signs and symp-
toms (Quinn, 1989). Since a statement on the diagnosis
of MSA was published in 1998 (Gilman et al., 1998a, b),
definite MSA is restricted to patients with postmor-
tem pathological confirmation. A possible diagnosis
may be conferred in patients with either parkinsonism
with poor levodopa-responsiveness or cerebellar par-
kinsonism. A probable diagnosis applies to patients
presenting with autonomic failure, urinary dysfunc-
tion and poor levodopa-responsive parkinsonism or
cerebellar dysfunction. Although myoclonus is not
recognized as a feature in the diagnostic criteria, it
is increasingly recognized as a common manifestation
in MSA. Indeed, involuntary movements of the hands
and fingers during posture and action were described in
1 of the 3 original cases by Adams et al. (1964). Such
movements are usually referred to as jerky tremor
by some authors and at least two series have reported
an upper-extremity small-amplitude jerky postural tre-
mor in 20% and 55% of cases (Wenning et al., 1994;
Colosimo et al., 1995; Gouider-Khouja et al., 1995).
Myoclonus predominantly occurs in the parkinsonian-
type MSA (MSA-P), although stimulus-sensitive
myoclonus can also occur in cerebellar-type MSA
(MSA-C) and the literature is split as to whether this
stimulus-sensitive myoclonus is more prevalent in
MSA-P or MSA-C (Obeso et al., 1985; Rodriguez
et al., 1994; Wenning et al., 1994; Salazar et al.,
2000). Wenning et al. (1994) reported that myoclonus
was present in 37% of those with MSA-P and 6% of
those in MSA-C, whereas Obeso et al. (1985) found that
stimulus-sensitive myoclonus occurred more frequently
in patients with MSA-C. However, 92% of their
patients exhibited bradykinesia and 50% had rigidity.
Salazar et al. (2000) proposed the term minipolymyo-
clonus to describe jerky tremor in 82% of patients response to tapping the nose, consistent with exagger-
with MSA-P.
Clinical observation showed that patients with
MSA-P had abnormal involuntary movements predo-
minantly in the hands and fingers with maintenance
of a posture or at the beginning of an action. Clini-
cally, these movements were jerky, irregular and not
entirely rhythmic. Neurophysiological evidence also
favored these movements as a form of postural and
reflex myoclonus (Salazar et al., 2000). The EMG
activity recorded in the forearm and hand muscles
was not usually regular but made of synchronous burst
555
and silent periods of variable duration and amplitude
and electrical stimuli elicited synchronized reflex
response of the type observed in reflex myoclonus.
Despite the direct neurophysiological evidence of
reflex myoclonus in these patients, authors cannot
firmly conclude the cortical origin of the myoclonus,
since no EEG spikes and no cortical activity time-
locked to the EMG bursts were obtained (Salazar
et al., 2000). In a separate study, typical cortical reflex
myoclonus in the olivopontocerebellar form of MSA is
well recognized and characterized by stimulus-
sensitive myoclonus with enlargement of the P25-N33
component of the cortical SEPs (Rodriguez et al.,
1994). Photic cortical reflex myoclonus with general-
ized muscle jerks may also occur in both olivopontocer-
ebellar and striatonigral forms of MSA (MSA-C and
MSA-P, respectively) (Artieda and Obeso, 1993).
Electrophysiological studies recorded a large (36.9
mV) positive/negative wave maximum in the mid
frontal region following visual stimuli (3.8 ms later)
preceding the myoclonus in a time-locked fashion.
The myoclonus markedly improved following levodopa
and piracetam.
In addition to a cortical origin on various forms of
myoclonus in patients with MSA, Clouston et al.
(1996) evaluated 1 patient with non-dopa-responsive
parkinsonism who exhibited early autonomic symp-
toms, a marked sleep disturbance and myoclonus with
a brainstem origin that was both spontaneous and
induced by somatosensory stimuli. No giant SEPs
and no preceding EEG activity were recorded. In addi-
tion, reflex latencies were compatible with a brainstem
myoclonus and there was no evidence of photically
induced myoclonus following discontinuation of levo-
dopa. The mechanism of brainstem myoclonus is
thought to be disruption of the lower brainstem reticu-
lar formation, which may also explain abnormal sleep
architecture in this patient (Hallett et al., 1977).
Furthermore, hyperexcitability of the cortex and brain-
stem has been reported in a patient with MSA-P, who
exhibited postural and action myoclonus (Kofler et al.,
1998). Interestingly, facial and whole-body jerks in
ated startle response, indicating an underlying brainstem
dysfunction, were also observed. Although isolated
cortical reflex myoclonus is frequently encountered in
patients with MSA, the authors emphasize that exagger-
ated startle response secondary to brainstem hyperexcit-
ability can also occur in a case of definite MSA (Kofler
et al., 2000). The authors further hypothesized that
brainstem atrophy with loss of pontine nuclei and glial
cytoplasmic inclusion deposition in the reticular forma-
tion may be responsible for startle responses in their
case (Kofler et al., 2000).
556 D. D. TRUONG AND R. BHIDAYASIRI
61.6. Myoclonus in encephalitis lethargica
Encephalitis lethargica (von Economos encephalitis)
appeared suddenly in 19171918 and was pandemic
for the next 10 years (von Economo, 1931). Since
then, no further epidemics have occurred and the exact
etiology has never been identified. However, rare
cases resembling von Economos encephalitis contin-
ued to be reported (Howard and Lees, 1987; Blunt
et al., 1997). Although the manifestations were pro-
tean, three main clinical presentations have been
described (Howard and Lees, 1987). The commonest
variety, the somnolent-ophthalmoplegic form, started
with an influenza-like illness, which was followed by
increasing drowsiness and confusion, progression to
continuous sleep, stupor and finally coma. In addition
to external ophthalmoplegia, oculogyric crisis and nys-
tagmus, a smaller number of patients presented with
bradykinesia and mutism, whereas a third hyperkinetic
group developed extreme motor restlessness, dyskine-
sia and myoclonus. In fact, Klawans et al. (1986)
included von Economos encephalitis as one of the
three conditions in which myolonus and parkinsonism
occurred. They reported that adrenocorticotropic hor-
mone relieved all symptoms the first time it was given
and twice more brought about significant amelioration
of all symptoms, especially the myoclonus. In general,
myoclonic movements tended to occur at onset and
often subsided as the patient recovered (McAlpine,
1920). However, myoclonus persisted indefinitely in
some patients (Rail et al., 1981).
Although characterized at the time as a separate
entity, epidemic hiccup may have been another form
of myoclonus in encephalitis lethargica. Hiccups
occurred sporadically in small epidemics during the
1920s and were sometimes one of the first symptoms
hailing the onset of encephalitis lethargica (Loewe
and Strauss, 1919).
61.7. Myoclonus in Huntingtons disease
Myoclonus is uncommon in HD, but recognized in a
young-onset akinetic-rigid form when it is often accom-
panied by seizures (Gambardella et al., 2001; Thompson,
2002). Myoclonus and seizures may occur in the early
stages of juvenile HD and dominate its clinical picture.
The myoclonus is usually stimulus-sensitive and induced
by action (Thompson et al., 1994a). Thompson et al.
(1994a) studied 3 patients with young-onset HD who
were the offspring of an affected father. Neurophysiolo-
gical studies documented generalized and multifocal
action myoclonus of cortical origin that was strikingly
stimulus-sensitive, without enlargement of the cortical
SEPs. Furthermore, reflex myoclonus in hand muscles
following peripheral nerve stimulation had a latency of
approximately 40 ms, similar to CBD, and were unlike
typical cortical reflex myoclonus.
Caviness and Kurth (1997) reported the electrophy-
siological findings of myoclonus in a patient with HD
who was studied postoperatively following a bilateral
fetal cell transplant in the striatum. Incomplete transi-
ent improvement was seen in the myoclonus, followed
by gradual deterioration. The myoclonus itself was
consistent with typical cortical reflex myoclonus with
enlarged SEPs, unlike those reported by Thompson
et al. (1994a). The reason for the transient improvement
of the myoclonus is unclear, but this study raised the
possible role of basal ganglia in the modulation of
cortical myoclonic activity.
61.8. Myoclonus in dentatorubral-
pallidoluysian atrophy
DRPLA is a rare autosomal-dominant neurodegenera-
tive disorder, characterized by various combinations
of cerebellar ataxia, chorea, myoclonus, epilepsy, par-
kinsonism, dementia and psychiatric symptoms (Naito
and Oyanagi, 1982). After the gene was identified in
1994, DRPLA became known as one of the CAG
repeat expansion diseases, in which the responsible
gene is located on chromosome 12p, and its product
is called atrophin-1 with prominent anticipation
(Koide et al., 1994; Nagafuchi et al., 1994). The condition
has mainly been described in Japan (Kanazawa, 1998).
Myoclonus is a distinctive feature of some families with
myoclonus epilepsy phenotype of this condition,
although uncommon (Thompson, 2002). Although a
cortical source is likely for the myoclonus because of
the epileptiform activity on the EEG, a detailed electro-
physiological examination of the myoclonus has not been
reported.
61.9. Myoclonus in frontotemporal dementia
with parkinsonism
FTD, linked to chromosome 17 (FTD-17), is asso-
ciated with tau protein mutations (Foster et al.,
1997). Pallidopontonigral degeneration (PPND) is
one example of a FTD-17 syndrome (Wszolek et al.,
1992; Caviness and Wszolek, 2002). The clinical
manifestations include frontal lobe behavior, psychia-
tric problems and memory loss. Motor symptoms
associated with FTD-17 consist of akinetic-rigid par-
kinsonian features without resting tremor, dystonia,
spasticity and occasional amyotrophy. Most patients
harboring exon-10 missense and intronic mutations
in the tau gene develop a parkinsonian phenotype.
Myoclonus is rarely seen in FTD-17 kindreds but
 MYOCLONUS AND PARKINSONISM
has been reported with the N279K, P301S and
V337M tau mutations (Caviness and Wszolek, 2002;
Tsuboi et al., 2002).
Not all affected individuals with PPND develop
myoclonus. Myoclonus is invariably present in the
upper extremities of rather small, subtle and action-
induced, without detectable activation with rest or
stimuli (Caviness and Wszolek, 2002). Caviness and
Wszolek (2002) observed that clinical progression is
more advanced for the myoclonus cases than for those
without myoclonus, although the explanation is
unclear. Previous EMG studies reported muscle
activation tremor-like discharges in 3 subjects and
definite myoclonic discharges in 1 (Wszolek et al.,
1998). Further study demonstrated at least two dif-
ferent myoclonus physiological patterns in PPND,
associated with the N279K tau mutation (Caviness
et al., 2003c). The absence of a back-averaged
EEG transient characterized the myoclonus physiol-
ogy associated with disease progression, whereas
pre-myoclonus EEG transient was present in the
myoclonus that occurred in one of the individuals
with stage 0 (presymptomatic but gene-positive)
(Caviness et al., 2003c). However, the physiology
of myoclonus may change over the course of the
disorder, reflecting progressive cortical pathology
and other brain regions. So far, the exact physiology
of myoclonus in this disorder is still unclear, although
cortical origin has been proposed, based on the find-
ings of the cortical transient back-averaged to the
myoclonus in one of the at-risk individuals.
61.10. Myoclonus in chronic manganese
poisoning
Manganese is a paramagnetic heavy metal that is
widely distributed in the environment, in air, water
and food. It has long been appreciated that manganese
exposure can cause neurotoxicity and certain brain
areas, including globus pallidus and substantia nigra
pars reticulata, are preferentially affected (Yamada
et al., 1986). Substantia nigra pars compacta and stria-
tal dopamine are relatively spared. The most common
neurological manifestations of chronic manganese
poisoning are extrapyramidal syndromes, especially
parkinsonism, comprising bradykinesia, rigidity and
postural instability (Olanow, 2004). Magnetic reso-
nance imaging (MRI) studies in manganese-intoxi-
cated patients demonstrated a characteristic signal
abnormality on T1-weighted images that are not seen
in normal individuals or PD patients or other forms
of parkinsonism (Olanow, 2004).
In addition to parkinsonism, chorea, tremor and
myclonus have been described in patients with chronic
557
manganese poisoning (Pal et al., 1999; Ono et al.,
2002). Ono et al. (2002) reported a 17-year-old welder
with myoclonic involuntary movements involving the
right upper and lower extremities who showed ele-
vated levels of manganese in the blood and hair and
characteristic MRI abnormalities. Electrophysiological
studies indicated absence of giant SEPs or paroxys-
mal discharge in jerk-locked EEG averaging. Chelation
therapy with Ca-EDTA (EDTA, ethylene diamine tetra
acetic acid) improved the myoclonus and MRI abnor-
malities. Although the exact mechanism of myoclonus
in chronic manganese poisoning is uncertain, authors
proposed that subcortical neural circuits via globus
pallidus might have been involved (Ono et al., 2002).
Since Klawans et al. (1986) first reported 3
patients in whom the onset of parkinsonian signs
was clinically associated with myoclonic movements,
more conditions have been recognized to encompass
a variety of atypical parkinsonian syndromes as well
as recently identified neurodegenerative disorders.
In addition to clinical descriptions of myoclonus,
more advances have been made in electrophysiologi-
cal and molecular studies to understand better the
pathophysiology, etiology, neuroanatomy and possi-
ble therapeutic options of various subtypes of myo-
clonus. In the setting of patients with predominant
parkinsonian features, the occurrence of myoclonus
should alert physicians to the possibility of many dif-
ferent neurodegenerative disorders, not limited to PD.
Although the use of clinical neurophysiology helps in
defining the nature of the EMG discharges in such
disorders, the current ability of these techniques to
provide absolute specificity and sensitivity is still
lacking. Therefore, further studies in various parkin-
sonian disorders are needed to clarify neurochemical,
electrophysiology, molecular pathophysiology and
neural networks of myoclonus, which will hopefully
lead to the development of therapeutic targets in
these progressive disorders.
Acknowledgments
Roongroj Bhidayasiri (UK) is supported by the Lilian
Schorr Postdoctoral Fellowship of the Parkinsons Dis-
ease Foundation (PDF).
Daniel D. Truong is supported by the Parkinsons
and Movement Disorder Foundation and the Long
Beach Memorial Foundation.
References
Adams RD, Vanbogaert L, Vandereecken H (1964). Strao-
nigral degeneration. J Neuropathol Exp Neurol 23:
584608.
558 D. D. TRUONG AND R. BHIDAYASIRI
Artieda J, Obeso JA (1993). The pathophysiology and phar-
macology of photic cortical reflex myoclonus. Ann Neurol
34: 175184.
Blunt SB, Lane RJ, Turjanski N et al. (1997). Clinical fea-
tures and management of two cases of encephalitis
lethargica. Mov Disord 12: 354359.
Brunt ER, van Weerden TW, Pruim J et al. (1995). Unique
myoclonic pattern in corticobasal degeneration. Mov Disord
10: 132142.
Buchman AS, Bennett DA, Goetz CG (1987). Bromocrip-
tine-induced myoclonus. Neurology 37: 885.
Burkhardt CR, Filley CM, Kleinschmidt-DeMasters BK et al.
(1988). Diffuse Lewy body disease and progressive demen-
tia. Neurology 38: 15201528.
Carella F, Ciano C, Panzica F et al. (1997). Myoclonus in
corticobasal degeneration. Mov Disord 12: 598603.
Caviness JN (2002). Epidemiology of myoclonus. Adv Neurol
89: 1922.
Caviness JN (2003). Myoclonus and neurodegenerative
diseasewhats in a name? Parkinsonism Relat Disord
9: 185192.
Caviness JN, Brown P (2004). Myoclonus: current concepts
and recent advances. Lancet Neurol 3: 598607.
Caviness JN, Kurth M (1997). Cortical myoclonus in
Huntingtons disease associated with an enlarged
somatosensory evoked potential. Mov Disord 12:
10461051.
Caviness JN, Wszolek ZK (2002). Myoclonus in pallido-
ponto-nigral degeneration. Adv Neurol 89: 3539.
Caviness JN, Adler CH, Newman S et al. (1998). Cortical
myoclonus in levodopa-responsive parkinsonism. Mov
Disord 13: 540544.
Caviness JN, Gwinn-Hardy K, Adler CH et al. (2000). Elec-
trophysiological observations in hereditary parkinsonism-
dementia with Lewy body pathology. Mov Disord 15:
140145.
Caviness JN, Adler CH, Beach TG et al. (2002a). Myoclonus
in Lewy body disorders. Adv Neurol 89: 2330.
Caviness JN, Adler CH, Beach TG et al. (2002b). Small-
amplitude cortical myoclonus in Parkinsons disease:
physiology and clinical observations. Mov Disord 17:
657662.
Caviness JN, Adler CH, Caselli RJ et al. (2003a). Electro-
physiology of the myoclonus in dementia with Lewy
bodies. Neurology 60: 523524.
Caviness JN, Adler CH, Sabbagh MN et al. (2003b). Abnor-
mal corticomuscular coherence is associated with the
small amplitude cortical myoclonus in Parkinsons
disease. Mov Disord 18: 11571162.
Caviness JN, Tsuboi Y, Wszolek ZK (2003c). Clinical-
electrophysiological correlation of tremor and myoclonus
in a kindred with the N279K tau mutation. Parkinsonism
Relat Disord 9: 151157.
Chen R, Ashby P, Lang AE (1992). Stimulus-sensitive
myoclonus in akinetic-rigid syndromes. Brain 115 (6):
18751888.
Clouston PD, Lim CL, Fung V et al. (1996). Brainstem
myoclonus in a patient with non-dopa-responsive parkin-
sonism. Mov Disord 11: 404410.
Colosimo C, Albanese A, Hughes AJ et al. (1995). Some
specific clinical features differentiate multiple system
atrophy (striatonigral variety) from Parkinsons disease.
Arch Neurol 52: 294298.
Fahn S, Marsden CD, Van Woert MH (1986). Definition and
classification of myoclonus. Adv Neurol 43: 15.
Foster NL, Wilhelmsen K, Sima AA et al. (1997). Frontotem-
poral dementia and parkinsonism linked to chromosome
17: a consensus conference. Conference Participants.
Ann Neurol 41: 706715.
Gambardella A, Muglia M, Labate A et al. (2001). Juvenile
Huntingtons disease presenting as progressive myoclonic
epilepsy. Neurology 57: 708711.
Gilman S, Low P, Quinn N et al. (1998a). Consensus state-
ment on the diagnosis of multiple system atrophy. Ameri-
can Autonomic Society and American Academy of
Neurology. Clin Auton Res 8: 359362.
Gilman S, Low PA, Quinn N et al. (1998b). Consensus state-
ment on the diagnosis of multiple system atrophy. J Auton
Nerv Syst 74: 189192.
Glantz R, Weiner WJ, Goetz CG et al. (1982). Drug-induced
asterixis in Parkinson disease. Neurology 32: 553555.
Gouider-Khouja N, Vidailhet M, Bonnet AM et al. (1995).
Pure striatonigral degeneration and Parkinsons disease:
a comparative clinical study. Mov Disord 10: 288294.
Grosse P, Kuhn A, Cordivari C et al. (2003). Coherence
analysis in the myoclonus of corticobasal degeneration.
Mov Disord 18: 13451350.
Hallett M, Chadwick D, Adam J et al. (1977). Reticular
reflex myoclonus: a physiological type of human post-
hypoxic myoclonus. J Neurol Neurosurg Psychiatry 40:
253264.
Hauser WA, Morris ML, Heston LL et al. (1986). Seizures
and myoclonus in patients with Alzheimers disease.
Neurology 36: 12261230.
Howard RS, Lees AJ (1987). Encephalitis lethargica.
A report of four recent cases. Brain 110 (1): 1933.
Kanazawa I (1998). Dentatorubral-pallidoluysian atrophy or
Naito-Oyanagi disease. Neurogenetics 2: 117.
Klawans HL, Goetz C, Bergen D (1975). Levodopa-induced
myoclonus. Arch Neurol 32: 330334.
Klawans HL, Tanner CM, McDermott J (1986). Myoclonus
and parkinsonism. Clin Neuropharmacol 9: 202205.
Kofler M, Wenning GK, Poewe W (1998). Cortical and brain
stem hyperexcitability in striatonigral degeneration. Mov
Disord 13: 602607.
Kofler M, Wenning GK, Poewe W et al. (2000). Cortical
and brain stem hyperexcitability in a pathologically con-
firmed case of multiple system atrophy. Mov Disord 15:
362363.
Koide R, Ikeuchi T, Onodera O et al. (1994). Unstable
expansion of CAG repeat in hereditary dentatorubral-
pallidoluysian atrophy (DRPLA). Nat Genet 6: 913.
 MYOCLONUS AND PARKINSONISM
Kompoliti K, Goetz CG, Boeve BF et al. (1998). Clinical
presentation and pharmacological therapy in corticobasal
degeneration. Arch Neurol 55: 957961.
Loewe L, Strauss I (1919). Etiology of epidemic (lethargic)
encephalitis: Preliminary note. JAMA 73: 10561057.
Louis ED, Klatka LA, Liu Y et al. (1997). Comparison of
extrapyramidal features in 31 pathologically confirmed
cases of diffuse Lewy body disease and 34 pathologically
confirmed cases of Parkinsons disease. Neurology 48:
376380.
Luquin MR, Scipioni O, Vaamonde J et al. (1992). Levodopa-
induced dyskinesias in Parkinsons disease: clinical and
pharmacological classification. Mov Disord 7: 117124.
Manto MU, Jacquy J, Van Bogaert P et al. (2000). Rhythmic
cortical and muscle discharges induced by fatigue in cor-
ticobasal degeneration. Clin Neurophysiol 111: 496503.
Marconi R, Lefebvre-Caparros D, Bonnet AM et al. (1994).
Levodopa-induced dyskinesias in Parkinsons disease phe-
nomenology and pathophysiology. Mov Disord 9: 212.
Marsden CD, Hallett M, Fahn S (1981). The nosology and
pathophysiology of myoclonus. In: CD Marsden, S Fahn
(Eds.), Movement Disorders. Butterworth Scientific,
London, pp. 196248.
Matsunaga K, Uozumi T, Qingrui L et al. (2001). Amanta-
dine-induced cortical myoclonus. Neurology 56: 279280.
McAlpine D (1920). A case of myoclonic form of acute
epidemic encephalitis with recovery. Lancet 2: 353354.
Mima T, Nagamine T, Ikeda A et al. (1998). Pathogenesis of
cortical myoclonus studied by magnetoencephalography.
Ann Neurol 43: 598607.
Monza D, Ciano C, Scaioli V et al. (2003). Neurophysiolo-
gical features in relation to clinical signs in clinically
diagnosed corticobasal degeneration. Neurol Sci 24:
1623.
Nagafuchi S, Yanagisawa H, Sato K et al. (1994). Dentatoru-
bral and pallidoluysian atrophy expansion of an unstable
CAG trinucleotide on chromosome 12p. Nat Genet 6:
1418.
Naito H, Oyanagi S (1982). Familial myoclonus epilepsy and
choreoathetosis: hereditary dentatorubral-pallidoluysian
atrophy. Neurology 32: 798807.
Obeso JA, Rothwell JC, Marsden CD (1985). The spectrum
of cortical myoclonus. From focal reflex jerks to sponta-
neous motor epilepsy. Brain 108 (1): 193224.
Olanow CW (2004). Manganese-induced parkinsonism and
Parkinsons disease. Ann N Y Acad Sci 1012: 209223.
Ono K, Komai K, Yamada M (2002). Myoclonic involuntary
movement associated with chronic manganese poisoning.
J Neurol Sci 199: 9396.
Pal PK, Samii A, Calne DB (1999). Manganese neurotoxi-
city: a review of clinical features, imaging and pathology.
Neurotoxicology 20: 227238.
Pfeiffer RF (1996). Amantadine-induced vocal myoclonus.
Mov Disord 11: 104106.
559
Quinn N (1989). Multiple system atrophythe nature of the
beast. J Neurol Neurosurg Psychiatry (Suppl): 7889.
Rail D, Scholtz C, Swash M (1981). Post-encephalitic
Parkinsonism: Current experience. J Neurol Neurosurg
Psychiatry 44: 670676.
Riley DE, Lang AE (2000). Clinical diagnostic criteria. Adv
Neurol 82: 2934.
Riley DE, Lang AE, Lewis A et al. (1990). Cortical-basal
ganglionic degeneration. Neurology 40: 12031212.
Rinne JO, Lee MS, Thompson PD et al. (1994). Corticobasal
degeneration. A clinical study of 36 cases. Brain 117 (5):
11831196.
Rodriguez ME, Artieda J, Zubieta JL et al. (1994). Reflex
myoclonus in olivopontocerebellar atrophy. J Neurol Neu-
rosurg Psychiatry 57: 316319.
Salazar G, Valls-Sole J, Marti MJ et al. (2000). Postural and
action myoclonus in patients with parkinsonian type multi-
ple system atrophy. Mov Disord 15: 7783.
Shafiq M, Lang AE (2002). Myoclonus in parkinsonian dis-
orders. Adv Neurol 89: 7783.
Shibasaki H (2000). Electrophysiological studies of myoclo-
nus. Muscle Nerve 23: 321335.
Stover NP, Wainer BH, Watts RL (2004). Corticobasal
degeneration. In: RL Watts, WC Koller (Eds.), Movement
Disorders. McGraw-Hill Medical Publishing, New York,
pp. 763778.
Thompson PD (2002). Neurodegenerative causes of myoclo-
nus. Adv Neurol 89: 3134.
Thompson PD, Shibasaki H (2000). Myoclonus in corticoba-
sal degeneration and other neurodegenerations. Adv Neu-
rol 82: 6981.
Thompson PD, Bhatia KP, Brown P et al. (1994a). Cortical
myoclonus in Huntingtons disease. Mov Disord 9:
633641.
Thompson PD, Day BL, Rothwell JC et al. (1994b). The
myoclonus in corticobasal degeneration. Evidence for
two forms of cortical reflex myoclonus. Brain 117 (5):
11971207.
Tschampa HJ, Neumann M, Zerr I et al. (2001). Patients with
Alzheimers disease and dementia with Lewy bodies mis-
taken for Creutzfeldt-Jakob disease. J Neurol Neurosurg
Psychiatry 71: 3339.
Tsuboi Y, Baker M, Hutton ML et al. (2002). Clinical and
genetic studies of families with the tau N279K mutation
(FTDP-17). Neurology 59: 17911793.
Van Everbroeck B, Dobbeleir I, De Waele M et al. (2004).
Differential diagnosis of 201 possible Creutzfeldt-Jakob
disease patients. J Neurol 251: 298304.
Vardi J, Glaubman H, Rabey JM et al. (1978). Myoclonic
attacks induced by L-dopa and bromocryptin in Parkinson
patients: a sleep EEG study. J Neurol 218: 3542.
von Economo C (1931). Encephalitis Lethargica: Its Seque-
lae and Treatment. Oxford University Press, London.
Wenning GK, Ben Shlomo Y, Magalhaes M et al. (1994).
Clinical features and natural history of multiple system
560 D. D. TRUONG AND R. BHIDAYASIRI
atrophy. An analysis of 100 cases. Brain 117 (4):
835845.
Wojcieszek J, Lang AE, Jankovic J et al. (1994). What is
it? Case 1, 1994: rapidly progressive aphasia, apraxia,
dementia, myoclonus, and parkinsonism. Mov Disord 9:
358366.
Wszolek ZK, Lagerlund TD, Steg RE et al. (1998). Clinical
neurophysiologic findings in patients with rapidly
progressive familial parkinsonism and dementia with
pallido-ponto-nigral degeneration. Electroencephalogr
Clin Neurophysiol 107: 213222.
Wszolek ZK, Pfeiffer RF, Bhatt MH et al. (1992). Rapidly
progressive autosomal dominant parkinsonism and demen-
tia with pallido-ponto-nigral degeneration. Ann Neurol 32:
312320.
Yamada M, Ohno S, Okayasu I et al. (1986). Chronic manga-
nese poisoning: a neuropathological study with determina-
tion of manganese distribution in the brain. Acta
Neuropathol (Berl) 70: 273278.

Page numbers in italic, e.g. 96, refer to figures. Page numbers in bold, e.g. 435, denote tables.
acetylcholine, 1023, 121, 128, 142,
335, 540, 542
acetylcholine esterase, 102, 141, 335,
522, 542
adenosine, 21, 142, 146, 1901
aging
eye movement, 434
gait abnormality, 432
motor
abnormalities, 435
slowing, 429
Parkinsons disease and, 4379
posture, 4312
tone change, 4301
tremor disorders, 4357
akathisia, 45, 169, 1734, 224, 226,
399400, 401, 402, 406,
40911
Alzheimers disease, 358
and Parkinsons disease, 439
dystonia and, 516, 522
Lewy bodies and, 404, 446
mixed movement disorders
in, 522
a-synuclein and, 53940
with parkinsonism, 364, 439, 516
aminoindane, 96, 107
amphetamine 1920, 96, 105, 107, 110,
139, 165, 228, 2801, 2959,
3889, 410, see also
methamphetamine
amyloid precursor protein, 106
amyotrophic lateral sclerosis-
parkinsonism dementia complex
of Guam, 336, 3923
antiapoptotic proteins, 105
anticholinergic drugs
in clinical practice, 1213, 142, 320,
401, 411, 419
effectiveness, 31819
side effects, 406
tremor and, 123
mechanism, 1212
antiglutamatergic drugs, 1278
amatadine, 12831
for motor complications, 1301
pharmacology, 1289
Index
antiglutamatergic drugs (Continued )
amatadine (Continued )
for prevention of disease
progression, 1301
side-effects, 131
for symptoms of parkinsonism, 129
budipine, 128, 1313
dextromethorphan, 128, 132, 143
memantine, 1278, 1312, 202
remacemide, 21, 128, 133
riluzole, 21, 128, 1334, 202
antioxidants for neuroprotection in
Parkinsons disease, 1922
apomorphine, see dopamine agonist(s):
apomorphine
apoptosis, 18, 22, 44, 103, 104, 105,
107, 127, 1389, 297, 382,
3901, 393, 409, 491
apraxia, 357
equilibrium, 462
gait, 4334, 434, 438, 4612
ideomotor, 3556, 461
kinetic, 356, 461, 474, 476
armantadine, 143
ballooned neuron (BN), 336, 352,
358, 358, 360, 361, 380, 445,
460, 465
basal ganglia
calcification
epidemiology, 47981
etiology, 480
history, 479
hypoparathyroidism and, 480,
480
pathophysiology, 4845
treatment, 485, 485
circuitry, 1923, 5089
neurophysiology, 1967
Bcl-2 family proteins
antiapoptotic (Bcl-2), 105
proapoptotic (Bad, Bax), 105
befloxatone, 94
beta-methylaminoalanine (BMAA),
3923, 392
BIA-3-202, 141
bilateral striopallidodentate calcinosis,
479, 480, 481, 4825, 483, 485
boxers encephalopathy, see
parkinsonism: posttraumatic:
repetitive head trauma
bradykinesia
in Alzheimers disease, 364, 406, 439
in corticobasal disease, 353, 356, 357
essential tremor and, 436
in Japanese B encephalitis, 379
MPTP-induced, 390
in mixed movement disorders, 515
myoclonus and, 5557
in old age with parkinsonism, 4289,
429, 432
in pallidonigroluysian degeneration,
450
in Parkinsons disease and
parkinsonism, 17, 77, 159,
243, 292, 310, 315, 330, 364,
385, 390, 393, 399, 401, 417,
4278, 430, 434, 462, 5013,
503
in progressive supranuclear palsy,
332, 343
measurement, 162, 404
mechanisms, 2434, 263, 422, 438
in posttraumatic parkinsonism, 493,
495
in Rett syndrome, 453
therapy, 7
treatment
deep brain stimulation, 267, 269
drug, 51, 101, 111, 112, 129,
1445
surgical, 249, 2502, 254
transplantation, 282, 287
in tuberculosis, 376
bradyphenia, 327
brofaromine, 94
burden of diseases, 1512
buspirone, 143
BW 137OU87, 94
cabergoline, 378, 48, 735, 74, 78,
7884, 80, 86, 137, 164, 191, 200
562
carbon monoxide, 3934, 419, 480
caroxazone, 94
catecholamines, 31, 34, 103, 315, 422,
437
catechol-O-methyltransferase inhibitors
(COMT)
clinical effects, 55, 56
inhibition, 54
entacapone, 548, 567, 75, 83,
98, 102, 112, 113, 1646, 437
tolcapone, 548, 567, 801, 102,
1645, 437
and MAO inhibitors, 1023
side-effects, 56, 568
Charcot, Jean-Martin, 31, 121, 327,
351, 487, 495
chlorpromazine, 399, 408, 521
choline acetyltransferase, 541
chorea acanthocytosis, 447, 44950,
51718
clorgyline, 94, 96
clozapine, 143
Cockaynes syndrome, 480
coenzyme A, 446, 520
corticobasal degeneration
history, 3513
diagnosis, 3534
cognitive and neuropsychiatric,
3567, 357
cortical symptoms, 3556, 357
differential, 364
motor symptoms, 3545, 357
electrophysiological studies, 3623
epidemiology, 353
imaging studies, 3612
laboratory studies, 363
myoclonus and, 550
parkinsonism and, 512
pathology
ballooned neurons in, 358, 360
macroscopic, 358, 361
microscopic, 358, 3589, 361
tau, 35960
tau mutations and ultrastructure,
3601, 361
therapy
for cognitive and
neuropsychiatric symptoms,
364
for gastrointestinal symptoms,
365
for motor symptoms, 363
for orthostatic hypotension, 365
for urinary symptoms, 365
Creutzfeldt-Jakob disease, 286, 332,
355, 380, 364, 535, 549
cystercercosis, 480
cytokines, 140, 374, 387, 491
INDEX
deep brain stimulation (DBS), 205
adverse effects, 26970
clinical efficacy, 266
comparison, 2689
pallidal, 266, 2667
subthalamic, 267, 267
thalamic, 266
magnetic resonance imaging, 263
methodology
safety issues, 265
surgical preparation, 2634
target location, 264, 2645
patient selection, 2702
advanced Parkinsons disease,
2712
tremor, 271
physiological mechanisms, 2613
systemic, 2623
thalamic, 262
dementia
aging and, 434
in corticobasal degeneration, 357
frontotemporal, 153, 364, 508, 512,
5567
chromosome 17 and, 332, 3389,
351, 353, 3567, 3601, 363,
381, 4456, 512, 513, 550, 556
parkinsonism and, 513, 550, 556
with Lewy bodies (DLB), 364
antiparkinsonian agents for, 541
antipsychotic agents for, 543
cholinergic system and, 540
cholinesterase inhibitors for, 542
clinical features, 5324
clinical significance of, 532
cognition and, 5323
diagnostic features, 5346,
5367
differential diagnosis, 53641
dopaminergic system and, 540
etiology, 5389
genetics of, 540
hallucinations in, 533
magnetic resonance imaging
of, 538
management, 541
motor parkinsonism and, 534
myoclonus and, 550
pathology, 53840, 53940
prevalence and incidence, 531
relationship to dementia in
Parkinsons disease, 531, 538
sleep disorders, 5334
deprenyl, 94
depression
in corticobasal degeneration, 357, 357
in dementia with Lewy bodies
536, 540
depression (Continued )
measurement scales for, 7, 111
in multiple system atrophy, 314
in Parkinsons disease, 10, 40, 45,
81, 86, 99103, 108, 114, 129,
169, 16970, 226, 26970,
331, 4034, 429, 502, 505,
511, 534
in progressive supranuclear palsy,
330, 340, 3412
non-parkinsonian, 81
therapy resistant, 100
as treatment side-effect, 229, 2312,
2701
treatment, 94, 945, 170
dextromethorphan, 143
diffuse Lewy body disease (DLBD), see
dementia: with Lewy bodies;
Lewy body disease
DJ-1, 336, 512, 512
DL-dopa, 31, 35
donepezil, 141, 341, 542
dopamine
agonists, see dopamine agonist(s)
antagonists, 2001, 400
biosynthesis, 32, 323
degradation, 32, 323
-enhancing agents, see catechol-O-
methyltransferase inhibitors
loss, 422, 430, 435, 439
monoamine oxidase-B inhibitors,
534
pharmacology, 313
metabolization, 323
synthesis and storage, 312
receptors, 24, 34, 42, 735, 82, 98,
128, 1613, 167, 188, 191,
203, 280, 400, 409, 422, 511,
522, 540
release, 3, 76, 146, 280, 294, 394
reuptake, 32, 121, 140, 341, 551
signaling, 382
structure, 34
transporters, 34, 24, 32, 50, 77, 98,
140, 298, 309, 340, 362, 390,
404, 420, 473, 492, 504, 510,
536, 537, 538
working memory and, 540
dopamine agonist(s), 37
apomorphine, 39, 47, 73, 74, 78, 80,
81, 83, 856, 134, 137,
1445, 162, 1678, 172,
174, 191, 198, 201, 2023,
280, 2923, 298, 320, 3412,
392, 474
bromocriptine, 74, 78, 80
cabergoline, see cabergoline
clinical trials with, 7682

dopamine agonist(s) (Continued )
clinical trials with (Continued )
levodopa-nave Parkinsons
patients, 769
motor complication prevention,
7980
non-motor complication
prevention, 81
dihydroergocryptine, 74, 78, 80
efficacy, 7380, 80, 856
as levodopa adjunct, 79
lisuride, 74, 78, 80
for neuroprotection in Parkinsons
disease, 256, 76
Parkinsons disease management
with, 846
pergolide, see pergolide
piribedil, 76, 78, 80
pharmacology, 73
pharmacodynamics, 756
pharmacokinetic properties, 73,
74
receptor sensitivity, 756
pramipexole, 74, 78, 80
receptor D2 agonists, 98
ropinirole, see ropinirole
safety issues, 82
synthesis, 98
type A adverse reactions
central, 823
peripheral, 82
type B adverse reactions, 834
dopaminergic
drugs, 40, 42, 59, 140, 145, 168,
1701, 187, 191, 196, 197,
198, 2034, 2056, 222, 228,
269, 399, 406, 420, 433, see
also dopamine agonist(s);
dopamine: antagonists
neurons, 21, 23, 26, 32, 40, 489, 96,
103, 140, 146, 159, 285, 291,
2956, 338, 374, 379, 385,
38792, 394, 417, 421, 491,
513, 515
systems, 3, 19, 36, 42, 74, 96, 127,
161, 174, 2001, 335, 386,
388, 394, 4034, 422, 448,
494, 507, 538, 540
Downs syndrome, 480
drug-induced movement disorders
(DIMD), 399400, 403, 4056,
40911
DU-127090, 141
dysarthria, 35, 24952, 269, 307, 313,
315, 319, 333, 340, 3526, 357,
364, 447, 451, 482, 495, 515,
51718, 519, 520
dyskinesia
antidyskinetic drugs, 1425
INDEX
dyskinesia (Continued )
antidyskinetic drugs (Continued )
glutamatergic, 1424, see also
glutamatergic: antagonists
biochemistry and molecular biology,
18894
dopaminergic receptors, 188
early genes, 191
GABA receptors, 191, 193
glutamatergic receptors, 188200
neuropeptides and adenosine
receptors, 1903
serotonergic receptors, 1934
choreic and dystonic movements, 186
deep brain stimulation (DBS), 205
diphasia, 45
diphasic, 186, 1867
dopamine agonists and, 81
entacapone, 57
incidence in Parkinsons disease, 48
levodopa-induced (LID), 445, 143,
160, 186, 205
clinical presentation, 1858
symptomatic drugs for, 143
surgery for, 2078
morphological basis, 1979
neurophysiology, 196, 1967
nocturnal myoclonus, 187
non-dopaminergic drugs for, 1457
noradrenergic drugs, 1445
adenosine receptors and, 146
serotonergic, 146
synaptic vesicular proteins and,
1467
off-period, 186, 1867
pathophysiology
classic model, 194
synaptic plasticity, 1956
surgery, 2048, 244
treatment
pharmacological, 199204
surgery, 2048, 244
without benefit, 187
dysphagia, 340, 357, 365
dystonia
ablative surgery for, 244
in cerebral toxoplasmosis, 378
chlorpromazine and, 399
classification, 5078
in corticobasal degeneration, 357
dopamine and, 507, 508, 511
dopa-responsive (Segawa disease),
515
genetically defined, 514
in HIV/AIDS, 378
lubag (DYT3), 51315
mixed movement disorder and 516,
see also mixed movement
disorders
563
dystonia (Continued )
neuronal intermediate filament
inclusion disease and, 513
Parkinsons disease and, 512, 51315
inherited, 512
postencephalitic, 51213
sporadic, 51112
pathophysiology, 50810
primary pallidal degeneration and,
513
progressive supranuclear palsy and,
513
rapid-onset (DYT12), 515
encephalitis lethargica, 327, 373,
376, 37980, 399, 513, 550,
556
Epstein-Barr virus (EBV), 373, 381
excitotoxicity, 17, 20, 24, 43, 76, 127,
1389, 385, 484
Fahrs disease, see basal ganglia:
calcification
fibroblast growth factors 107, 287, 294,
see also growth factors
fludrocortisones, 39, 320, 365
fluoxetine, 143
FTDP-17, see dementia:
frontotemporal: chromosome 17
and
frontotemporal dementia, see dementia:
frontotemporal
GABA, see gamma-aminobutyric acid
gait apraxia, 4334, 434, 438, 4612
gama-aminobutyric acid (GABA)
cells, 107, 130, 132, 18991, 194,
205, 243, 453, 509, 51011,
513
receptors, 48, 163, 191, 193, 514
genes immediate early (IEG), 409, 496
gene therapy for Parkinsons disease
drug development strategy, 292
glial-derived neurotrophic factor
(GDNF) delivery in, 2958,
299300
neurorestoration in
6-hydroxydopamine lesioning
and, 2978
MPTP and, 298
neuroturin, 299
therapeutic enzyme delivery in, 2924
trophic molecule delivery in, 2945
viral vectors
adeno-associated virus, 293
adenovirus, 293
564
gene therapy for Parkinsons disease
(Continued )
viral vectors (Continued )
herpes simplex virus, 293
lentivirus, 293, 299300
glial cell line-derived neurotrophic
factor (GDNF), 4, 234, 106,
107, 292, 293, 2949, 300, 301
glial cells, 4, 33, 49, 96, 287, 300, 337,
374, 382, 446
globus pallidus, 21, 48, 99, 127, 142,
163, 196, 229, 229, 243, 247,
2623, 296, 298, 315, 3346,
353, 360, 394, 418, 4467,
44951, 474, 476, 47980, 508,
509, 511, 513, 520, 557
glutamate
antagonists, see antiglutamatergic
drugs
neurotransmitter function, 21, 127
neuroprotection by, 21
receptors, 128, 163, 18891
release, 99, 133, 142, 294, 511, see
also antiglutamatergic drugs
toxicity, 21, 103, 127, 484
glutamatergic
antagonists, 142, 143, 202, see also
antiglutamatergic drugs
neurons, 21, 127, 196, 509
pathways, 127, 188, 194, 208, 509,
511
receptors, 1278, 18890, 196
see also glutamate
growth factors
fibroblast, 107, 287, 294
insulin-like, 287, 309
nerve, 26, 105, 107, 138, 134, 280,
391
Guam, amyotrophic lateral sclerosis-
parkinsonism dementia complex
of, 336, 3923
Hallervorden-Spatz syndrome, 446,
480
Helicobacter pylori, 374, 376,
3801
hemiparkinson-hemiatrophy (HPHA)
syndrome, 4489
HIV-AIDS, 2923, 3734, 3756,
3778, 407, 480
hippocampus, 1023, 163, 195, 352,
3578, 419, 463, 491, 532
Huntingtons disease, 21, 23, 355, 362,
405, 447, 450, 482, 504, 508,
515, 516, 550, 556
hydrocephalus
neurological features, 466, 4667
normal-pressure (NPH), 459
INDEX
hydrocephalus (Continued )
normal-pressure (NPH) (Continued )
clinical features, 4601, 461
cognitive changes in, 4623
drugs, 4701
history, 459
imaging, 4634, 4635, 467, 476
incontinence and, 462
mechanisms, 4657
shunting, 46970
treatment, 467, 4689
hydroxyaminoindane, 96
hyperhomocysteinemia, 434, 422
hyperreflexia, 31213, 315, 330, 353,
356, 357, 376, 4523, 4601,
466, 494, 517, 533
hypoparathyroidism, 479, 480, 480
hypotension, see orthostatic
hypotension
hypothyroidism, 480
idazoxan, 143
influenza A virus, 374, 375, 379
insulin-like growth factor, 287, 309, see
also growth factors
iproniazid, 94
iron
in Parkinsons disease, 18, 389
deposition, 31516, 409, 421, 4467,
484, 51718, 520
metabolism, 447, 520
neurodegeneration and, 44, 4468
oxidative stress and, 103
transport, 409
isocarboxazid, 94
istradefylline, 141, 146
Japanese B encephalitis virus, 374, 379
KF-17837, 141
lazabemide, 94
L-dopa, see levodopa
lead intoxication, 480
learning, 7, 265, 379
long-term potentiation and,
163, 195
memory and, 234
motor, 195
spatial, 102
testing, 232, 233, 252
leprosy, 381
lesions
basal ganglia, 419, 420
brainstem, 41819
globus, 474
lesions (Continued )
hemorrhagic, 418, 487
nigrostriatal, 61, 294, 37981, 406
striatum, 474
structural, in parkinsonism, 459, 471,
4746, 475, 504, 5078, 510
thalamic, 229, 251, 262, 265, 474,
476
white-matter, 394, 41920, 422, 464,
536
levodopa
cheese reaction and, 95
dopamine synthesis and, 98
aging and, 434
dopa-cecarboxylase inhibition and,
345
dyskinesias and, 448, 48, 186, 197
early versus late L-dopa
(ELLDOPA) studies, 35, 35
history of use, 31
motor complications, 45
clinical presentation, 468
effects, 37
fluctuations, 448
mechanisms, 468
prevalence, 47
onset, 46
in neuroprotection for Parkinsons
disease, 25
side-effects, 36, 38, 3944
hallucinations, 38, 3941
hyperhomocysteinemia, 43
impulse control deficits, 412
melanoma, 423
nausea, 36, 38
orthostatic hypotension, 389
sleep disturbances, 38
somnolence, 38
withdrawal rate for adverse
events, 38
therapy strategies
infusion, 512
oral formulations, 501
slow-release preparations, 523
tolerance, 3644
treatment of Parkinsons disease,
356, 445, 141
Lewy bodies
in Alzheimers disease, 404, 446
degeneration, 3940
dementia with, see dementia: with
Lewy bodies
in Parkinsons disease, 427
Lewy body disease, 81, 102, 114, 363,
427, 436, 4389, 531, 537, 550,
550, 552
locus ceruleus, 39, 96, 99, 101, 103,
307, 315, 352, 35860
lymphocytes, 373, 391, 447

manganese
parkinsonism induction by, 38990,
504, 550
poisoning, 550, 550, 557
melanoma, 423, 105, 112
melevodopa, 140, 141
mental changes from Parkinsons
disease treatment
drug-induced psychosis, 219, 220
with clear sensorium, 220
hallucinations, 2202, 221
with impaired sensorium/
dementia, 220
long-term outcome, 225
treatment, 2225
mood and anxiety fluctuations, 2256
repetitive/compulsive disorders,
2267
dopamine dysregulation
syndrome, 227
gambling, pathological, 228
punding, 228
surgery-induced, 229
adverse cognitive effects, 2324
anxiety, 232
apathy, 232
depression, 2312
executive function changes, 234
learning and memory disorders,
234
mania, 2301
neuropsychological tests for, 233
psychosis, 229
visuospatial function changes,
2345
methamphetamine, 96, 98, 1067, 110,
280, 410
methanol, parkinsonism induction
by, 393
methemoglobinopathies, 480
methotrexate, 480
midodrine, 39, 320, 365
milacemide, 94
mitochondria(l)
abnormalities, 17, 104
bioenergetics, 21
cell survival/death and, 105
complex
I, 48, 139, 338, 387, 3912, 394,
410
II, 392, 410
dysfunction, 21, 44, 127, 327, 337,
385
function, 212, 1045, 107, 139,
3857
genes and inheritance, 337, 517
membrane, 212, 1045, 107, 480
myopathies, 480
INDEX
mitochondria(l) (Continued )
see also oxidative stress
mixed movement disorders
in Alzheimers disease, 522, see also
Alzheimers disease
autosomal-dominant
Huntingtons disease, 515, 516
Huntingtons disease-like 2,
51516, 516
autosomal-recessive, 519
aceruloplasminemia, 51819
chorea acanthocytosis, 518
Gaucher disease type III, 5201
glutaric aciduria, 521
GM1 gangliosidosis, 520
Niemann-Pick type C, 520
pantothenate kinase-associated
neurodegeneration, 520
Wilsons disease, 518, 519
biotin-responsive basal ganglia
disease, 521
dentatorubropallidoluysian atrophy,
516, 517, 550, 556
drug-induced, 521
dystonia and, 516
Fahrs disease, 516, 517
homocystinuria, 521
neuroferritinopathy, 517
neuronal intranuclear hyaline
inclusion disease, 521
parkinsonism and, 516
spinocerebellar ataxia, 516, 51617
therapy, 522
X-linked recessive, 517
McLeod syndrome, 51718
moclobemide, 94, 95, 97
monoamine oxidase, 94
monoamine oxidase inhibitors, see
monoamine oxidase-A inhibitors;
monoamine oxidase-AB
inhibitors; monoamine oxidase-B
inhibitors
monoamine oxidase-A inhibitors
for depression, 94
discovery of, 935
distribution, 95, 97
irreversible, 94, 96
in Parkinsons disease, 99101
reversible, 94, 97
structure, 96
substrates, 97
tyramine metabolism inhibition
by, 95
tyrosine metabolism and, 98
see also specific drugs
monoamine oxidase-AB inhibitors
for depression, 94
irreversible, 94, 96, 102
565
monoamine oxidase-AB inhibitors
(Continued )
reversible, 94, 96, 142
structure, 96
substrates, 97
see also specific drugs
monoamine oxidase-B inhibitors
for depression, 94
discovery of, 935
distribution, 95, 97
irreversible, 94
for Parkinsons disease, 1922,
989, 10812
reversible, 94
structure, 94, 96
substrates, 97
tyramine metabolism inhibition
by, 95
tyrosine metabolism and, 98
see also specific drugs
motor fluctuations in Parkinsons
disease
epidemiology, 161
levodopa-induced, 15960, 160
dose-related, 160
dyskinesia, 160
motor blocks, 160
on-off fluctuations, 160
tachykinetic problems, 160
treatment, 1648
unpredictable sudden offs, 15960
pathophysiology, 1613
pharmacodynamics, 1623
pharmacokinetics, 1612
spontaneous, 161
see also non-motor fluctuations in
parkinsonism
MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyrodine)
-induced parkinsonism, 18, 391
lesions, 4, 23, 142, 144, 163, 173,
190, 294, 298, 300, 3901
toxicity, 18
-treated animals, 21, 48, 56, 102,
144, 188, 293, 391
multiple system atrophy
categories, 314
clinical features, 31014, 315
behavioral disorders, 314
cardiovascular dysfunction, 312
cerebellar dysfunction, 313
disordered sleep, 31314
dystonia, 310, 402, 4334, 508,
512, 513
gastrointestinal dysfunction, 312
genital dysfunction, 311
parkinsonism, 310
pyramidal dysfunction, 313
566
multiple system atrophy (Continued )
clinical features (Continued )
thermoregulatory dysfunction, 313
urinary dysfunction, 31112
consensus criteria, 314, 315
diagnosis
autonomic function tests, 317
differential, 364, 380, 438, 451
functional neuroimaging, 31617
neurophysiological testing, 31718
structural neuroimaging, 316
epidemiology
analytical, 3089
descriptive, 308
history, 3078
glial cytoplasmic inclusions, 316
myoclonus and, 550, 555
neuropathology
macroscopic, 31415, 421
microscopic, 315
parkinsonism and, 512
sonographic brain images, 421
treatment
of cardiovascular dysfunction,
31920
of gastrointestinal dysfunction,
320
of genital dysfunction, 319
of motor disorders, 31819
of urinary dysfunction, 319
myoclonus, 357
causes, 550
chronic manganese poisoning and,
557
classification, 549
corticobasal degeneration and, 553,
5535
dentatorubropallidoluysian atrophy
and, 556
in diffuse Lewy body disease,
5523, 552
electrophysiological findings, 551
encephalitis lethargica and, 556
frontotemporal dementia with
parkinsonism and, 5567
idiopathic Parkinsons disease and,
550
in multiple system atrophy, 555
nabilone, 143
naloxone, 143
nerve growth factor 26, 105, 107, 138,
139, 280, 391, see also growth
factors
neurodegeneration with brain iron
accumulation (NBIA), 4468,
517, 520
INDEX
neurofibromatosis, 480
neuronal death, 105, 139, 373, 484
mechanism, 104
models, 767
prevention, 104
propargylamines and, 104
see also neuroprotection in
Parkinsons disease
neuroprotection in Parkinsons disease
amyloid precursor protein and, 106
drugs
antiapoptotic agents, 212
antiexcitotoxic agents, 201
antioxidants, 1822
CEP-1347, 138
development status of, 138
dopamine agonists, 256, 1402
E-2007, 138
GPI-1485, 138
leteprinim, 138
levodopa 25, 140, see also
levodopa
liatermine, 138
MITO-4509, 138
monoamine oxidase-B inhibitors,
1822
ONO-2506, 138
PAN-408, 138
PYM-50028, 138
propargylamine, 106
rasagiline (Azilect, Agilect), 103,
106, 11012
selegiline, 103, 106, 109
sonic hedgehog protein agonist,
138
TCH-346, 138
V-10367, 138
zydis selegine, 110, 139, 165
mitochondrial modulation, 13940
antiapoptotic kinase inhibitors,
13940
minocycline, 140
neuroimmunophilin, 139
neurorescuing agents, 1038
physical activity and, 3
primate model, 297
restorative therapies and, 224
therapies, 13840
monoamine oxidase inhibitors,
1389, see also monoamine
oxidase-AB inhibitors:
irreversible; rasagiline; zydis
selegiline
therapeutic design, 17
neurotransplantation for Parkinsons
disease
adrenal medulla, 2812
age and, 285
neurotransplantation for Parkinsons
disease (Continued )
alternative tissue sources for, 286
donor neurons for, 2856
dopamine neurons and, 286
effects of, 283
experimental basis for, 27981
fluorodopa positron emission
tomography evaluation of, 283
human fetal dopamine cell, 2825
nialamide, 94
nitric oxide, 338, 374, 491, 511
Nocardia asteroides, 374, 380, 382
non-motor fluctuations in parkinsonism
autonomic symptoms, 1713
dysphagia, 172
dyspnea, 172
management, 173
orthostatic hypotension, 171
sphincter function, 172
thermoregulation, 171
classification, 168, 169
epidemiology, 169
neuropsychiatric, 16971
mood, 16970
psychotic symptoms, 1701
sensory, 173
akathisia, 173
dysthesia, 173
management, 174
pain, 173
noradrenaline, 95
NS-2330, 141
olanzapine, 143
1-methyl-4phenyl-1,2,3,6-
tetrahydropyridine, see MPTP
orthostatic hypotension, 34, 36, 38, 39,
812, 98, 169, 1712, 220, 225,
308, 31113, 315, 31720, 336,
365, 534, 537, 542
oxidative stress, 18, 44, 489, 76, 103,
107, 327, 3378, 342, 385, 387,
390, 392, 409
pallidonigroluysian degeneration,
4501
pallidopyramidal disease, 4512
palsy
progressive supranuclear, see
progressive supranuclear palsy
pseudobulbar, 341, 371, 393, 417,
419, 423
pargyline, 94
paralysis agitans, see Parkinsons
disease

parkin gene, 161, 250, 340, 448, 512,
512
Parkinson, James, 31, 351, 436, 487
Parkinsons disease
aging and
bradykinesia and, 42830
cogwheeling phenomenon,
4301, 431, 436, 503
eye movement, 434
gait abnormality, 4324, 434
motor slowing, 429
normal, 428
paratonia, 429, 430, 431
primitive reflexes, 4345
tone change, 430, 431
agricultural chemicals and
atrazine, 387, 388
maneb, 387, 388
organochlorine compounds, 388,
388
paraquat, 387, 388
rotenone, 3867, 387
Alzheimers disease and, 439
animal models, 13, 21, 133, 13940,
146, 1623, 185, 1889, 194,
1989, 262, 279, 293, 2945,
297, 386, 391, 394, 509
annonacin and, 393, 393
anticholinergic drugs, see
anticholinergic drugs
antiglutamatergics, see
antiglutamatergic drugs
atypical, 270, 30910, 318, 328,
3346, 351, 353, 355, 363,
421, 501, 536, 557
carbon monoxide poisoning and,
3934, 419, 480
cycad toxin and, 392, 3923
dementia and, 364, see also
dementia
drug-induced
6-hydroxydopamine, 3, 49, 75,
103, 185, 280, 292, 297, 386,
390, 392
methanol, 393
MPTP, see MPTP
6-OHDA, 34, 49, 103, 185,
18893, 1956, 1989, 201,
208, 2801, 285, 2929, 392
reserpine, 31, 75, 201, 399, 408, 411
see also parkinsonism: drug-
induced
environmental risk factors, 3856
excitoxicity and, see excitoxicity
freezing, 5, 17, 19, 45, 109, 160,
168, 401, 401, 41719, 420,
433, 437, 462, 520
strategies, 1013
INDEX
Parkinsons disease (Continued )
GDNF proteins receptors and
actions, 4, 23, 105, 139, 281,
287, 292, 293, 2945, 299
gene therapy, see gene therapy for
Parkinsons disease
hereditary factors, 385
history, see Charcot, Jean-Martin;
Parkinson, James
hypersexuality and, 42, 82, 167, 170,
227, 270
idiopathic, 251, 3801, 406, 488,
4956, 549, 550
imaging, 421
incidence, 385
infectious basis
animal studies, 3812
Epstein-Barr virus (EBV), 373,
381
Helicobacter pylori, 374, 376,
3801
HIV, 3746, 3756, 377, 407, 480
immunology, 3734
influenza A virus, 374, 375, 379
Japanese B encephalitis virus,
374, 379
leprosy, 381
Nocardia asteroides, 374, 3802
prion protein, 153, 337, 363, 374,
381
Toxoplasma gondii, 374, 376,
3778, 378, 407, 480
transmissible spongiform
encephalopathy, 3812
tuberculosis, 376, 377, 379, 480
isoquinoline derivatives and, 103,
338, 3912
iron and, see iron
metals and, 389
copper, 363, 38990, 518
iron, see iron
manganese, 38990, 504, 550
methanol and, 393
mood disorders, 170, 227, 230, 270
anxiety, 45, 108, 131, 153, 160,
169, 16970, 2257, 229, 232,
270, 357, 450, 505, 533, 5423
apathy, 10, 169, 229, 2312, 270,
314, 330, 333, 334, 357, 399,
450, 462, 533, 5423
depression, see depression: in
Parkinsons disease
mania, 45, 2278, 229, 2301, 270
motor fluctuations, see motor
fluctuations in Parkinsons
disease
MPTP
-induced parkinsonism, 18, 391
567
Parkinsons disease (Continued )
MPTP (Continued )
lesions, 4, 23, 142, 144, 163, 173,
190, 294, 298, 300, 3901
toxicity, 18
-treated animals, 21, 48, 56, 102,
144, 188, 293, 391
multiple system atrophy and, see
multiple system atrophy
myoclonus and, 550
neuroprotection in, see
neuroprotection in Parkinsons
disease
oxidative stress and, see oxidative
stress
patient advocacy groups (PAGs)
advocacy by, 154
collaboration and partnerships, 152
future, 155
policy and, 1534
research issues, 1525
responsible advocacy, 152
pesticide models
maneb, 386, 387, 388
paraquat, 386, 387, 388
rotenone, 21, 44, 3867, 387, 393
physical exercise and, 38
physical therapy for, see physical
therapy
postural reflexes, 431
progressive supranuclear palsy and,
see progressive supranuclear
palsy
risk factors, 408
alcohol, 2278, 309, 319, 408,
4367
coffee and caffeine, 17
gender, 83, 131, 401, 4067
head trauma, 461, 48891, 4967,
508
metals, see Parkinsons disease:
metals and
obesity, 1
pesticide exposure, see
Parkinsons disease: pesticide
models
smoking, 7, 17, 43, 108, 309,
386, 406, 488
sensory symptom(s), 169, 1734
selegiline monotherapy, 108
sleep disorders, 40, 222, 357, 5334,
5434
speech disorders, 138, 354
surgery, see also surgery: ablative
pallidotomy, 24850, 254
radio-, 253
subthalamotomy, 2524
thalamotomy, 2502, 254
568
Parkinsons disease (Continued )
symptoms, 17, 417, 427
transplantation for, see
neurotransplantation for
Parkinsons disease
trauma and
as risk factor, 48891
epidemiology, 489
posttraumatic parkinsonism, see
parkinsonism: posttraumatic
treatment
gene therapy, see gene therapy
for Parkinsons disease
with levodopa, 356, see also
levodopa
mental changes from, 21928,
see also mental changes from
Parkinsons disease treatment
parkinsonism
amytrophic lateral sclerosis-
parkinsonism dementia
complex of Guam, 336, 3923
Alzheimers and, 439
arteriovenous malformation and,
471
intracerebral hemorrhage, 471
midbrain cavernoma, 471, 472
brain imaging, 4201
dystonia and, see also dystonia
dopa-responsive (Segawa
disease), 515
lubag (DYT3), 51315
rapid-onset (DYT12), 515
drug-induced (DIP)
age/dementia and, 4056
cigarette smoking and, 406
cinnarizine, 4068, 408, 40910,
522
diagnosis, 4035
drugs causing/aggravating, 408
flunarizine, 40910
gender and, 406
genetics and, 406
history, 399400
HIV and, 407
magnetic resonance spectroscopy,
405
neuroleptics and, 409
pathology, 4034
pre-existing movement disorders
and, 406
prevalence, 4001
progression of, 4023
schizophrenia subtype and, 407
serotonin reuptake inhibitors
and, 410
symptoms, 401, 4012
ventricular/brain ratio, 407
INDEX
parkinsonism (Continued )
drug-induced (DIP) (Continued )
treatment, 41011
frontotemporal dementia and, see
dementia: frontotemporal
history, 417, 459
lesions, see lesions
mechanism for motor symptoms
bradykinesia, 2434
dyskinesia, 244
dystonia, 244
tremor, 244
myoclonus and, see myoclonus
postencephalitic, 512
posttraumatic, 491, 4934
central lesions, 491
peripheral lesions, 4956
repetitive head trauma, 4945,
497
single head trauma, 4912, 494
worsening of parkinsonism, 496
psychogenic
clinical manifestations, 5023
description, 501
diagnosis, 503, 5035
epidemiology, 5012
natural history, 501
prognosis, 505
treatment, 505
stroke and, 439
substantia nigra and, 459
symptomatic agents, 141
symptoms, 399, 417
tumors and, 4734
vascular
and Parkinsons disease, 4212
imaging methods, 421
history, 417
pergolide, 73, 74, 75, 7781, 78, 80,
834, 86, 164, 222, 228, 341, 363
phenelzine, 94
physical exercise
metabolic effects, 37
neuroprotective effects, 37
and Parkinsons disease, 810, 89
see also physical therapy
physical therapy
for advanced Parkinsons disease
discipline and, 10
freezing episodes, 1013
appendicular and axial stretch, 6,
89
attentional strategies, 56
compensation strategies, 1013
ambulation assistive devices, 13
freezing episodes, 1013
home environment modification, 13
sensory cues, 11
physical therapy (Continued )
long-term effects, 78
resistance training, 4
sensory cueing and, 56
training techniques, 4
treadmill training, 67
see also physical exercise
postencephalitic parkinsonism (PEP),
3278, 336, 382
clinical features, 380
epidemiology, 376, 379
pramipexole (Mirapex), 24, 378,
48, 49, 73, 74, 75, 7786,
78, 80, 164, 200, 222, 228,
341, 363
prion protein/disease, 153, 337, 363,
374, 381
progressive supranuclear palsy (PSP)
brain parenchyma sonography
(BPS), 335
cerebral fluid analysis, 334
clinical
features, 3301, 340
heterogeneity, 3323
diagnosis
criteria, 3312, 3323
differential, 364
epidemiology
age of onset, 329, 329
incidence, 328, 328
prevalence, 3289, 329
sex ratio, 329, 329
familial, 338
functional imaging, 3356
history, 3278
magnetic resonance imaging (MRI),
3345
management
adrenergic agents, 341
cholinergic agents, 341
dopaminergic agents, 341
neurotransmitter replacement
and, 340
non-pharmacological, 342
palliative treatments, 340
natural history, 331
neuropsychological assessment,
3334, 336
nortriptyline and, 341
pathology
molecular, 33840
neuro-, 336, 337
tau aggregation and cell death,
3378
parkinsonism and, 512
propargylamine, 1056
propranolol, 143
proteosome inhibition, 104

protein
kinase, 107, 390
synthesis, 1045
translation, 22, 342
pseudohypoparathyroidism, 480
psychogenic movement disorders
(PMD), 501, 503
quinpirole, 201
rasagiline, 20, 53, 94, 98, 1046
adverse effects, 111
developmental status, 141
effects
longterm, 112
shortterm, 94, 98104, 1046,
1078, 111, 113, 1389
efficacy, 113, 98, 165
structure, 96
see also monamine oxidase-B
inhibitors
reactive oxygen species (ROS), 385
Rett syndrome, 4524
reversible monoamine oxidase (MOA)-
A inhibitors
RIMA, 97, 99, 101, 114
moclobemide, 94, 945, 978,
99102, 108, 112, 114
ritanserin, 143
ropinirole (Requip)
dyskinesias, 48
metabolism, 74
pharmacological properties, 74
treatment, 245, 734, 7783, 78,
80, 856, 222, 228
effectiveness, 3738, 49, 75
rotenone, 21, 44, 3867, 387, 393
rotigotine, 73, 86, 141, 164
safanamide, 94, 96, 141, 142
sarizotan, 143
selegiline
as levodopa adjunct, 109
effects, 94, 1034, 1046, 109, 223,
433
neuroprotection, 109
in Parkinsons disease treatment,
1819, 94, 98103, 105,
1078, 1089, 165,
341, 438
structure, 96
serotonin (5-HT), 32, 93, 97, 100, 142,
143, 146, 170, 227, 232, 364,
382, 391, 400, 410, 453, 543, 550
SKF-82958, 191, 201
INDEX
SKF-39392, 201
sleep disorders, 40, 222, 357, 5334,
5434
SLV-308, 141, 142
somatostatin (SOM), 320, 363, 484
speech
in bilateral striopallidodentate
calcinosis, 4823
in chorea acanthocytosis, 449
in corticobasal degeneration, 352,
3546, 365
in dementia with Lewy body disease,
533
in GM2 gangliosidosis, 520
in pantothenate kinase-associated
neurodegeneration, 520
in Parkinsons disease, 3, 138, 229,
401, 429, 447
in progressive supranuclear palsy,
331, 340, 340
surgery and, 204, 224, 246, 2503,
269
SPD-473, 141
SR-57667, 141
Steele-Richardson-Olszewski
syndrome, see progressive
supranuclear palsy
substantia nigra pars compacta (SNc or
SNpc)
in corticobasal degeneration, 361
deep brain stimulation and, 2634,
270
degeneration, 17, 103, 107, 159, 280,
287, 307, 315, 352, 361, 390,
417, 427, 435, 445, 450,
4523, 492, 493, 495, 508, systemic lupus erythematosus, 418, 480
531, 540
dopamine synthesis and, 98
neurons, 96, 190, 192, 197, 243,
285, 291, 373, 385, 3889,
391
oxidative stress and, 48, 76
in Parkinsons disease, 18, 21, 99,
389, 421, 509, 531, see also
substantia nigra pars
compacta: degeneration
in progressive supranuclear palsy,
336, 337
subthalamic nucleus (STN)
deep brain stimulation and, 168,
2056, 229, 261, 2634, 267, transplantation for Parkinsons disease,
2678, 285, 449
Parkinson disease and, 20, 229, 243,
294
progressive supranuclear palsy and,
336, 337
surgery, 205
sumanirole, 141
569
surgery
ablative
microelectrode localization, 246
physiological localization, 245
radiological localization, 245
stereotactic lesioning techniques,
246
stereotactic surgical techniques,
245
for dyskinesia, 2048, 244
deep brain stimulation (DBS), 205
of globus pallidum, 204
subthalamic nucleus, 2047
for dystonia, 244
mental changes following, 229, 2325
for Parkinsons disease, see
Parkinsons disease: surgery
radio-, 253
speech impairment from, 204, 224,
246, 2503, 269
a-synuclein
abnormalities and mutations, 297,
340, 351, 512, 531, 540
Alzheimers disease and, 53940
degradation, 316
expression, 315
in glial cytoplasmic inclusions and
Lewy bodies, 307, 315, 316,
359, 374, 381, 385, 388,
5389, 539
metals and, 38990
neuroprotection and, 138
and synucleinopathies, 307, 313,
330, 340, 351, 357, 359, 363,
374, 491, 539
talipexole, 141
tau protein, 3334, 3389, 343, 360,
445, 513, 556
tolcapone, 57
toloxatone, 94
toxoplasmosis and Toxoplasma
gondii, 374, 376, 3778, 378,
407, 480
transcranial ultrasonography, 318, 336,
342, 405, 4201, 448
transmissible spongiform
encephalopathy, 3812
see neurotransplantation for
Parkinsons disease
tranylcypromine, 94
tremor
ablative surgery, 244
aging and, 434
in corticobasal degeneration, 357
570 INDEX
tremor (Continued ) tyrosine (Continued ) VR-2006, 141
essential, 250, 253, 4046, 4356, hydroxylase, 31, 32, 98, 101, 103,
496, 504 107, 286, 292, 293, 382, 388,
tone testing, 4301 514, 539 working memory, 540
tuberculosis, 376, 377, 379, potentiation of cardiovascular World Health Organization (WHO),
480 effects, 95 151, 155, 271
tuberous sclerosis, 480
tyrosine, 98
cheese reaction and, 95 UCHL-1, 309 zydis selegiline, 110, 139, 165