Parkinson

Parkinson’s Diseases
Author
Robert A Hauser, MD, MBA Professor of Neurology, Molecular Pharmacology
and Physiology, Director, USF Parkinson's Disease and Movement Disorders
Center, National Parkinson Foundation Center of Excellence, Byrd Institute,
Clinical Chair, Signature Interdisciplinary Program in Neuroscience, University of
South Florida College of Medicine
Robert A Hauser, MD, MBA is a member of the following medical

societies: American Academy of Neurology, American Medical
Association, American Society of Neuroimaging, International Parkinson and
Movement Disorder Society
Disclosure: Received consulting fee from Cerecor for consulting; Received

consulting fee from L&M Healthcare for consulting; Received consulting fee from
Cleveland Clinic for consulting; Received consulting fee from Heptares for
consulting; Received consulting fee from Gerrson Lehrman Group for consulting;
Received consulting fee from Indus for consulting; Received consulting fee from
University of Houston for consulting; Received consulting fee from AbbVie for
consulting; Received consulting fee from Adama.
Coauthor(s)
Kelly E Lyons, PhD Research Professor of Neurology, Director of Research and
Education, Parkinson’s Disease and Movement Disorder Center, University of
Kansas Medical Center
Kelly E Lyons, PhD is a member of the following medical societies: American

Academy of Neurology, International Parkinson and Movement Disorder Society
Disclosure: Received honoraria from Novartis for speaking and teaching;

Received honoraria from Teva Neuroscience for speaking and teaching;
Received honoraria from St Jude Medical for board membership.
Theresa A McClain, RN, MSN, ARNP-BC Advanced Registered Nurse

Practitioner and Investigator, Parkinson’s Disease and Movement Disorders
Center, University of South Florida College of Medicine
Theresa A McClain, RN, MSN, ARNP-BC is a member of the following medical

societies: Sigma Theta Tau International
Disclosure: Received consulting fee from Teva for consulting; Received
consulting fee from Schering Plough for consulting; Received consulting fee from
Biotie for consulting; Received consulting fee from Novartis for consulting.
Rajesh Pahwa, MD Professor of Neurology, Director, Parkinson Disease and

Movement Disorder Center, Department of Neurology, University of Kansas
Medical Center
Rajesh Pahwa, MD is a member of the following medical societies: American

Academy of Neurology, International Parkinson and Movement Disorder Society
Disclosure: Nothing to disclose.
Chief Editor
Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program,
Departments of Neurology and Neurosurgery, Tampa General Hospital,
University of South Florida Morsani College of Medicine
Selim R Benbadis, MD is a member of the following medical societies: American

Academy of Neurology, American Academy of Sleep Medicine, American Clinical
Neurophysiology Society, American Epilepsy Society, American Medical
Association
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant

or trustee for: Ceribell, Eisai, Greenwich, Growhealthy, LivaNova, Neuropace, SK
biopharmaceuticals, Sunovion<br/>Serve(d) as a speaker or a member of a
speakers bureau for: Eisai, Greenwich, LivaNova, Sunovion<br/>Received
research grant from: Cavion, LivaNova, Greenwich, Sunovion, SK
biopharmaceuticals, Takeda, UCB.
Acknowledgements
Ron L Alterman, MD Associate Professor of Neurosurgery, Mount Sinai School of
Medicine; Consulting Surgeon, Department of Neurosurgery, Mount Sinai School
of Medicine, Elmhurst Hospital, and Walter Reed Army Medical Center
Ron L Alterman, MD is a member of the following medical societies: Alpha

Omega Alpha, American Association of Neurological Surgeons, Congress of
Neurological Surgeons, Medical Society of the State of New York, and New York
County Medical Society

Heather S Anderson, MD Assistant Professor, Staff Neurologist, Department of
Neurology, Alzheimer and Memory Center, University of Kansas Medical Center
Heather S Anderson, MD is a member of the following medical

societies: American Academy of Neurology
Jeff Blackmer, MD, FRCP(C) Associate Professor, Medical Director, Neurospinal

Service, Division of Physical Medicine and Rehabilitation, The Rehabilitation
Centre, University of Ottawa Faculty of Medicine; Executive Director, Office of
Ethics, Canadian Medical Association
Jeff Blackmer, MD, FRCP(C) is a member of the following medical

societies: American Paraplegia Society, Canadian Association of Physical
Medicine and Rehabilitation, Canadian Medical Association, and Royal College
of Physicians and Surgeons of Canada
Thomas L Carroll, MD Assistant Professor, Department of Otolaryngology-Head

and Neck Surgery, Tufts University School of Medicine and Director, The Center
for Voice and Swallowing, Tufts Medical Center
Thomas L Carroll, MD is a member of the following medical societies: Alpha

Omega Alpha, American Academy of Otolaryngology-Head and Neck
Surgery, American Bronchoesophagological Association, American
Laryngological Association, and American Medical Association
Disclosure: Merz aesthetics inc. Consulting fee Speaking and teaching
Richard J Caselli, MD Professor, Department of Neurology, Mayo Medical

School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of
Scottsdale
Richard J Caselli, MD is a member of the following medical societies: American

Academy of Neurology, American Association of Neuromuscular and
Electrodiagnostic Medicine, American Medical Association, American
Neurological Association, and Sigma Xi

Arif I Dalvi, MD Director, Movement Disorders Center, NorthShore University
HealthSystem, Clinical Associate Professor of Neurology, University of Chicago
Pritzker Medical School
Arif I Dalvi, MD is a member of the following medical societies: European

Neurological Society and Movement Disorders Society
Nestor Galvez-Jimenez, MD, MSc, MHA Chairman, Department of Neurology,

Program Director, Movement Disorders, Department of Neurology, Division of
Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical

societies: American Academy of Neurology, American College of Physicians,
and Movement Disorders Society
Stephen T Gancher, MD Adjunct Associate Professor, Department of Neurology,

Oregon Health Sciences University
Stephen T Gancher, MD is a member of the following medical

societies: American Academy of Neurology, American Neurological Association,
and Movement Disorders Society
Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, FAHA Professor of Neurology,

University of Central Florida College of Medicine; Director of Cognitive
Neurology, Director of Stroke Program, James A Haley Veterans Affairs Hospital
Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, FAHA is a member of the

following medical societies: American Academy of Neurology, American
Headache Society, American Heart Association, and American Society of
Neuroimaging
Daniel H Jacobs MD, FAAN, Associate Professor of Neurology, University of

Florida College of Medicine; Director for Stroke Services, Orlando Regional
Medical Center
Daniel H Jacobs is a member of the following medical societies: American
Academy of Neurology, American Society of Neurorehabilitation, and Society for
Neuroscience
Disclosure: Teva Pharmaceutical Grant/research funds Consulting; Biogen Idex

Grant/research funds Independent contractor; Serono EMD Royalty Speaking
and teaching; Pfizer Royalty Speaking and teaching; Berlex Royalty Speaking
and teaching
Robert M Kellman, MD Professor and Chair, Department of Otolaryngology and

Communication Sciences, State University of New York Upstate Medical
University
Robert M Kellman, MD is a member of the following medical societies: American

Academy of Facial Plastic and Reconstructive Surgery, American Academy of
Otolaryngology-Head and Neck Surgery, American College of
Surgeons, American Medical Association, American Neurotology
Society, American Rhinologic Society, American Society for Head and Neck
Surgery, Medical Society of the State of New York, and Triological Society
Disclosure: GE Healthcare Honoraria Review panel membership; Revent Medical

Honoraria Review panel membership
Milton J Klein, DO, MBA Consulting Physiatrist, Heritage Valley Health System-
Sewickley Hospital and Ohio Valley General Hospital
Milton J Klein, DO, MBA is a member of the following medical

societies: American Academy of Disability Evaluating Physicians, American
Academy of Medical Acupuncture, American Academy of Osteopathy, American
Academy of Physical Medicine and Rehabilitation, American Medical
Association, American Osteopathic Association, American Osteopathic College
of Physical Medicine and Rehabilitation, American Pain Society,
and Pennsylvania Medical Society
Kat Kolaski, MD Assistant Professor, Departments of Orthopedic Surgery and

Pediatrics, Wake Forest University School of Medicine
Kat Kolaski, MD is a member of the following medical societies: American

Academy for Cerebral Palsy and Developmental Medicine and American
Academy of Physical Medicine and Rehabilitation
Jose G Merino, MD Medical Director, Suburban Hospital Stroke Program
Jose G Merino, MD is a member of the following medical societies: American

Heart Association and American Stroke Association
Arlen D Meyers, MD, MBA Professor, Department of Otolaryngology-Head and

Neck Surgery, University of Colorado School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical

societies: American Academy of Facial Plastic and Reconstructive
Surgery, American Academy of Otolaryngology-Head and Neck Surgery,
and American Head and Neck Society
Disclosure: Covidien Corp Consulting fee Consulting; US Tobacco Corporation

Unrestricted gift Unknown; Axis Three Corporation Ownership interest
Consulting; Omni Biosciences Ownership interest Consulting; Sentegra
Ownership interest Board membership; Syndicom Ownership interest Consulting;
Oxlo Consulting; Medvoy Ownership interest Management position; Cerescan
Imaging Honoraria Consulting; GYRUS ACMI Honoraria Consulting
Lorraine Ramig, PhD Professor, Department of Speech Language Hearing

Sciences, University of Colorado at Boulder; Senior Scientist, National Center for
Voice and Speech (NCVS); Adjunct Professor, Department of Biobehavior,
Columbia University Teacher's College
Alan D Schmetzer, MD Professor Emeritus, Interim Chairman, Vice-Chair for

Education, Associate Residency Training Director in General Psychiatry,
Fellowship Training Director in Addiction Psychiatry, Department of Psychiatry,
Indiana University School of Medicine; Addiction Psychiatrist, Midtown Mental
Health Cener at Wishard Health Services
Alan D Schmetzer, MD is a member of the following medical societies: American

Academy of Addiction Psychiatry, American Academy of Clinical
Psychiatrists, American Academy of Psychiatry and the Law, American College
of Physician Executives, American Medical Association, American
Neuropsychiatric Association, American Psychiatric Association, and Association
for Convulsive Therapy
Disclosure: Eli Lilly & Co. Grant/research funds Other
Roy Sucholeiki, MD Director, Comprehensive Seizure and Epilepsy Program,

The Neurosciences Institute at Central DuPage Hospital
Roy Sucholeiki, MD is a member of the following medical societies: American

Academy of Neurology, American Epilepsy Society, and American
Neuropsychiatric Association
Margaret M Swanberg, DO Assistant Professor of Neurology, Uniformed

Services University; Chief of Neurobehavior Service, Walter Reed Army Medical
Center; Assistant Chief, Department of Neurology, Walter Reed Army Medical
Center
Margaret M Swanberg, DO is a member of the following medical

societies: American Academy of Neurology and American Neuropsychiatric
Association
Michele Tagliati, MD Associate Professor, Department of Neurology, Mount Sinai

School of Medicine; Division Chief of Movement Disorders, Mount Sinai Medical
Center
Michele Tagliati, MD is a member of the following medical societies: American

Academy of Neurology, American Medical Association, and Movement Disorders
Society
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of

Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug
Reference
Disclosure: Medscape Salary Employment
B Viswanatha, MBBS, MS, DLO Professor of Otolaryngology (ENT), Chief of

ENT III Unit, Sri Venkateshwara ENT Institute, Victoria Hospital, Bangalore
Medical College and Research Institute; PG and UG Examiner, Manipal
University, India and Annamalai University, India
B Viswanatha, MBBS, MS, DLO is a member of the following medical
societies: Association of Otolaryngologists of India, Indian Medical Association,
and Indian Society of Otology
Practice Essentials
Parkinson disease (PD) is one of the most common neurologic disorders,
affecting approximately 1% of individuals older than 60 years and causing
progressive disability that can be slowed, but not halted, by treatment. The 2
major neuropathologic findings in Parkinson disease are loss of pigmented
dopaminergic neurons of the substantia nigra pars compacta and the
presence of Lewy bodies and Lewy neurites. See the images below.
Lewy bodies are intracytoplasmic

eosinophilic inclusions, often with halos, that are easily seen in pigmented
neurons, as shown in this histologic slide. They contain polymerized alpha-
synuclein; therefore, Parkinson disease is a synucleinopathy.
View Media Gallery
Stages in the development of
Parkinson disease (PD)-related pathology (path.). Adapted from Braak H,
Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development
of Parkinson's disease-related pathology. Cell Tissue Res. 2004
Oct;318(1):121-34.
View Media Gallery
Signs and symptoms
Initial clinical symptoms of Parkinson disease include the following:
 Tremor
 Subtle decrease in dexterity
 Decreased arm swing on the first-involved side
 Soft voice
 Decreased facial expression
 Sleep disturbances
 Rapid eye movement (REM) behavior disorder (RBD; a loss of normal
atonia during REM sleep)
 Decreased sense of smell
 Symptoms of autonomic dysfunction (eg, constipation, sweating
abnormalities, sexual dysfunction, seborrheic dermatitis)
 A general feeling of weakness, malaise, or lassitude
 Depression or anhedonia
 Slowness in thinking
Onset of motor signs include the following:
 Typically asymmetric
 The most common initial finding is a resting tremor in an upper extremity
 Over time, patients experience progressive bradykinesia, rigidity, and gait
difficulty
 Axial posture becomes progressively flexed and strides become shorter
 Postural instability (balance impairment) is a late phenomenon
Nonmotor symptoms
Nonmotor symptoms are common in early Parkinson disease. Recognition of
the combination of nonmotor and motor symptoms can promote early
diagnosis and thus early intervention, which often results in a better quality of
life.
See Clinical Presentation for more detail.
Diagnosis
Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for
the condition, and findings on routine magnetic resonance imaging and
computed tomography scans are unremarkable.
Clinical diagnosis requires the presence of 2 of 3 cardinal signs:
 Resting tremor
 Rigidity
 Bradykinesia
See Workup for more detail.
Management
The goal of medical management of Parkinson disease is to provide control of
signs and symptoms for as long as possible while minimizing adverse effects.
Symptomatic drug therapy
 Usually provides good control of motor signs of Parkinson disease for 4-6
years
 Levodopa/carbidopa: The gold standard of symptomatic treatment
 Monoamine oxidase (MAO)–B inhibitors: Can be considered for initial
treatment of early disease
 Other dopamine agonists (eg, ropinirole, pramipexole): Monotherapy in
early disease and adjunctive therapy in moderate to advanced disease
 Anticholinergic agents (eg, trihexyphenidyl, benztropine): Second-line
drugs for tremor only
Treatment for nonmotor symptoms
 Sildenafil citrate (Viagra): For erectile dysfunction
 Polyethylene glycol: For constipation
 Modafinil: For excessive daytime somnolence
 Methylphenidate: For fatigue (potential for abuse and addiction)
Deep brain stimulation
 Surgical procedure of choice for Parkinson disease
 Does not involve destruction of brain tissue
 Reversible
 Can be adjusted as the disease progresses or adverse events occur
 Bilateral procedures can be performed without a significant increase in
adverse events
See Treatment and Medication for more detail.
Background
Parkinson disease is recognized as one of the most common neurologic
disorders, affecting approximately 1% of individuals older than 60 years.
There are 2 major neuropathologic findings: the loss of pigmented
dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the
presence of Lewy bodies (see the following image). Most cases of Parkinson
disease (idiopathic Parkinson disease [IPD]) are hypothesized to be due to a
combination of genetic and environmental factors. However, no environmental
cause of Parkinson disease has yet been proven. A known genetic cause can
be identified in approximately 10% of cases, and these are more common in
younger-onset patients.
Gross comparison of the

appearance of the substantia nigra between a normal brain and a brain
affected by Parkinson disease. Note the well-pigmented substantia nigra in
the normal brain specimen on the left. In the brain of a Parkinson disease
patient on the right, loss of pigmented substantia nigra due to depopulation of
pigmented neurons is observed.
View Media Gallery
The classic motor features of Parkinson disease typically start insidiously and
emerge slowly over weeks or months, with tremor being the most common
initial symptom. The 3 cardinal signs of Parkinson disease are resting tremor,
rigidity, and bradykinesia. Postural instability (balance impairment) is
sometimes listed as the fourth cardinal feature. However, balance impairment
in Parkinson disease is a late phenomenon, and in fact, prominent balance
impairment in the first few years suggests that Parkinson disease is not the
correct diagnosis. (See Presentation.)
When a patient presents with tremor, the clinician evaluates the patient's
history and physical examination findings to differentiate Parkinson disease
tremor from other types of tremor. In patients with parkinsonism, careful
attention to the history is necessary to exclude causes such as drugs, toxins,
or trauma. (See Differential Diagnosis.) Other common causes of tremor
include essential tremor, physiologic tremor, and dystonic tremor.
No laboratory or imaging study is required in patients with a typical
presentation of Parkinson disease. Such patients are aged 55 years or older
and have a slowly progressive and asymmetric parkinsonism with resting
tremor and bradykinesia or rigidity. There are no red flags such as prominent
autonomic dysfunction, balance impairment, dementia, or eye-movement
abnormalities. In such cases, the diagnosis is ultimately considered confirmed
once the patient goes on dopaminergic therapy (levodopa or a dopamine
agonist) as needed for motor symptom control and exhibits a robust and
sustained benefit. (See Workup.)
Imaging studies can be considered, depending on the differential diagnosis.
Magnetic resonance imaging (MRI) of the brain can be considered to evaluate
possible cerebrovascular disease (including multi-infarct state), space-
occupying lesions, normal-pressure hydrocephalus, and other disorders.
Iodine-123–labeled fluoropropyl-2beta-carbomethoxy-3beta-4-iodophenyl-
nortroptane (FP-CIT I123) (Ioflupane, DaTscan) single-photon emission
computed tomography (SPECT) can be considered in cases of uncertain
parkinsonism to help differentiate disorders associated with a loss of
dopamine neurons (Parkinson disease and atypical parkinsonisms, including
multiple system atrophy [MSA] and progressive supranuclear palsy [PSP])
from those disorders not associated with a loss of dopamine neurons (eg,
essential tremor, dystonic tremor, vascular parkinsonism, medication-induced
parkinsonism or tremor, psychogenic conditions). [1]
Levodopa coupled with a peripheral decarboxylase inhibitor (PDI), such as
carbidopa, remains the gold standard of symptomatic treatment of motor
features of Parkinson disease. It provides the greatest antiparkinsonian
benefit with the fewest adverse effects in the short term. However, its long-
term use is associated with the development of fluctuations and dyskinesias.
Moreover, the disease continues to progress, and patients accumulate long-
term disability. (See Treatment.)
Dopamine agonists such as pramipexole (Mirapex) and ropinirole (Requip)
can be used as monotherapy to improve symptoms in early Parkinson disease
or as adjuncts to levodopa in patients who are experiencing motor
fluctuations. Monoamine oxidase (MAO)-B inhibitors, such as selegiline
(Eldepryl) and rasagiline (Azilect) provide mild benefit as monotherapy in early
disease and as adjuncts to levodopa in patients with motor fluctuations. (See
Medication.) Entacapone (Comtan), a catechol-o-methyltransferase (COMT)
inhibitor, reduces the peripheral metabolism of levodopa, thereby making
more levodopa available to enter the brain over a longer period; this agent is
used as an adjunct to levodopa in patients with motor fluctuations.
Anatomy
Parkinson disease is predominantly a disorder of the basal ganglia, which are
a group of nuclei situated at the base of the forebrain. The striatum,
composed of the caudate and putamen, is the largest nuclear complex of the
basal ganglia. The striatum receives excitatory input from several areas of the
cerebral cortex, as well as inhibitory and excitatory input from the
dopaminergic cells of the substantia nigra pars compacta (SNc). These
cortical and nigral inputs are received by the spiny projection neurons, which
are of 2 types: those that project directly to the internal segment of the globus
pallidus (GPi), the major output site of the basal ganglia; and those that
project to the external segment of the globus pallidus (GPe), establishing an
indirect pathway to the GPi via the subthalamic nucleus (STN).
For an illustration of the subthalamic nucleus, see the image below.
Sagittal section, 12 mm lateral

of the midline, demonstrating the subthalamic nucleus (STN) (lavender). The
STN is one of the preferred surgical targets for deep brain stimulation to treat
symptoms of advanced Parkinson disease.
View Media Gallery
The actions of the direct and indirect pathways regulate the neuronal output
from the GPi, which provides tonic inhibitory input to the thalamic nuclei that
project to the primary and supplementary motor areas.
Pathophysiology
No specific, standard criteria exist for the neuropathologic diagnosis of
Parkinson disease, as the specificity and sensitivity of its characteristic
findings have not been clearly established. However, the following are the 2
major neuropathologic findings in Parkinson disease:
 Loss of pigmented dopaminergic neurons of the substantia nigra pars
compacta
 The presence of Lewy bodies and Lewy neurites
The loss of dopamine neurons occurs most prominently in the ventral lateral
substantia nigra. Approximately 60-80% of dopaminergic neurons are lost
before the motor signs of Parkinson disease emerge.
Some individuals who were thought to be normal neurologically at the time of
their deaths are found to have Lewy bodies on autopsy examination. These
incidental Lewy bodies have been hypothesized to represent the
presymptomatic phase of Parkinson disease. The prevalence of incidental
Lewy bodies increases with age. Note that Lewy bodies are not specific to
Parkinson disease, as they are found in some cases of atypical
parkinsonism, Hallervorden-Spatz disease, and other disorders. Nonetheless,
they are a characteristic pathology finding of Parkinson disease.
Motor circuit in Parkinson disease
The basal ganglia motor circuit modulates the cortical output necessary for
normal movement (see the following image).
Schematic representation of the basal ganglia

- thalamocortical motor circuit and its neurotransmitters in the normal state.
From Vitek J. Stereotaxic surgery and deep brain stimulation for Parkinson
disease and movement disorders. In: Watts RL, Koller WC, eds. Movement
Disorders: Neurologic Principles and Practice. New York: McGraw-Hill,
1997:240. Copyright, McGraw-Hill Companies, Inc. Used with permission.
View Media Gallery
Signals from the cerebral cortex are processed through the basal ganglia-
thalamocortical motor circuit and return to the same area via a feedback
pathway. Output from the motor circuit is directed through the internal
segment of the globus pallidus (GPi) and the substantia nigra pars reticulata
(SNr). This inhibitory output is directed to the thalamocortical pathway and
suppresses movement.
Two pathways exist within the basal ganglia circuit, the direct and indirect
pathways, as follows:
 In the direct pathway, outflow from the striatum directly inhibits the GPi
and SNr; striatal neurons containing D1 receptors constitute the direct
pathway and project to the GPi/SNr
 The indirect pathway contains inhibitory connections between the
striatum and the external segment of the globus pallidus (GPe) and
between the GPe and the subthalamic nucleus (STN); striatal neurons
with D2 receptors are part of the indirect pathway and project to the GPe
The STN exerts an excitatory influence on the GPi and SNr. The GPi/SNr
sends inhibitory output to the ventral lateral nucleus (VL) of the thalamus.
Dopamine is released from nigrostriatal (substantia nigra pars compacta
[SNpc]) neurons to activate the direct pathway and inhibit the indirect
pathway. In Parkinson disease, decreased striatal dopamine causes
increased inhibitory output from the GPi/SNr via both the direct and indirect
pathways (see the following image).
Schematic representation of the
basal ganglia - thalamocortical motor circuit and the relative change in
neuronal activity in Parkinson disease. From Vitek J. Stereotaxic surgery and
deep brain stimulation for Parkinson disease and movement disorders. In:
Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and
Practice. New York: McGraw-Hill, 1997:241. Used with kind permission.
Copyright, McGraw-Hill Companies, Inc.
View Media Gallery
The increased inhibition of the thalamocortical pathway suppresses
movement. Via the direct pathway, decreased striatal dopamine stimulation
causes decreased inhibition of the GPi/SNr. Via the indirect pathway,
decreased dopamine inhibition causes increased inhibition of the GPe,
resulting in disinhibition of the STN. Increased STN output increases GPi/SNr
inhibitory output to the thalamus.
Etiology
Although the etiology of Parkinson disease is still unclear, most cases are
hypothesized to be due to a combination of genetic and environmental factors.
Currently known genetic causes of Parkinson disease account for
approximately 10% of cases.
Environmental causes
Environmental risk factors commonly associated with the development of
Parkinson disease include use of pesticides, living in a rural environment,
consumption of well water, exposure to herbicides, and proximity to industrial
plants or quarries. [2]
A meta-analysis of 89 studies, including 6 prospective and 83 case-control
studies, found that exposure to pesticides may increase the risk for PD by as
much as 80%. [3, 4] Exposure to the weed killer paraquat or to the fungicides
maneb or mancozeb is particularly toxic, increasing the risk for PD about 2-
fold. Many of the agents studied are no longer used in the United States and
Europe; however, some are still found in developing parts of the world. [3, 4]
In case-control studies, PD was associated with exposure to any type of
pesticide, herbicide, insecticide, and solvent, with risks ranging from 33% to
80%. [3, 4] Increased PD risk was also associated with proxy conditions of
exposure to organic pollutants, such as farming, well-water drinking, and rural
living. In addition, risk seemed to increase with length of exposure. [3, 4]
The National Institutes of Health-AARP Diet and Health Study, as well as a
meta-analysis of prospective studies, found that higher caffeine intake was
associated with lower risk of Parkinson disease in both men and women. A
similar association was found for smoking and Parkinson disease risk. [5] The
biological mechanisms underlying the inverse relationship between caffeine or
smoking and Parkinson disease risk are not well elucidated.
MPTP interference with mitochondrial function
Several individuals were identified who developed parkinsonism after self-
injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These
patients developed bradykinesia, rigidity, and tremor, which progressed over
several weeks and improved with dopamine replacement therapy. MPTP
crosses the blood-brain barrier and is oxidized to 1-methyl-4-phenylpyridinium
(MPP+) by monoamine oxidase (MAO)-B. [6]
MPP+ accumulates in mitochondria and interferes with the function of
complex I of the respiratory chain. A chemical resemblance between MPTP
and some herbicides and pesticides suggested that an MPTP-like
environmental toxin might be a cause of Parkinson disease, but no specific
agent has been identified. Nonetheless, mitochondrial complex I activity is
reduced in Parkinson disease, suggesting a common pathway with MPTP-
induced parkinsonism.
Oxidation hypothesis
The oxidation hypothesis suggests that free radical damage, resulting from
dopamine's oxidative metabolism, plays a role in the development or
progression of Parkinson disease. The oxidative metabolism of dopamine by
MAO leads to the formation of hydrogen peroxide. Normally, hydrogen
peroxide is cleared rapidly by glutathione, but if hydrogen peroxide is not
cleared adequately, it may lead to the formation of highly reactive hydroxyl
radicals that can react with cell membrane lipids to cause lipid peroxidation
and cell damage. In Parkinson disease, levels of reduced glutathione are
decreased, suggesting a loss of protection against formation of free radicals.
Iron is increased in the substantia nigra and may serve as a source of donor
electrons, thereby promoting the formation of free radicals.
Parkinson disease is associated with increased dopamine turnover,
decreased protective mechanisms (glutathione), increased iron (a pro-
oxidation molecule), and evidence of increased lipid peroxidation. This
hypothesis has raised concern that increased dopamine turnover due to
levodopa administration could increase oxidative damage and accelerate loss
of dopamine neurons. However, there is no clear evidence that levodopa
accelerates disease progression.
Genetic factors
If genetic factors are important in a particular disease, concordance in
genetically identical monozygotic (MZ) twins will be greater than in dizygotic
(DZ) twins, who share only about 50% of genes. Early Parkinson disease twin
studies generally found low and similar concordance rates for MZ and DZ
pairs.
However, genetic factors in Parkinson disease appear to be very important
when the disease begins at or before age 50 years. In a study of 193 twins,
overall concordance for MZ and DZ pairs was similar, but in 16 pairs of twins
in whom Parkinson disease was diagnosed at or before age 50 years, all 4
MZ pairs, but only 2 of 12 DZ pairs, were concordant. [7]
The identification of a few families with familial Parkinson disease sparked
further interest in the genetics of the disease. In one large family in Salerno,
Italy, 50 of 592 members had Parkinson disease; linkage analysis
incriminated a region in bands 4q21-23, and sequencing revealed an A-for-G
substitution at base 209 of the alpha-synuclein gene. [8] Termed PD-1, this
mutation codes for a substitution of threonine for alanine at amino acid 53.
These individuals were characterized by early age of disease onset (mean
age, 47.5 years), rapid progression (mean age at death, 56.1 years), lack of
tremor, and good response to levodopa therapy. [8] Five small Greek kindreds
were also found to have the PD-1 mutation.
In a German family, a different point mutation in the alpha-synuclein gene (a
substitution of C for G at base 88, producing a substitution of proline for
alanine at amino acid 30) confirmed that mutations in the alpha-synuclein
gene can cause Parkinson disease. [9] A few additional familial mutations in
the alpha-synuclein gene have been identified and are collectively
called PARK1. It is now clear that these mutations are an exceedingly rare
cause of Parkinson disease.
A total of 18 loci in various genes have now been proposed for Parkinson
disease. Mutations within 6 of these loci (SNCA, LRRK2, PRKN, DJ1, PINK1,
and ATP 13A2) are well-validated causes of familial
parkinsonism. [10] Inheritance is autosomal dominant
for SNCA and LRRK2 (although LRRK2 mutations exhibit variable
penetrance). Inheritance is autosomal recessive for PRKN, DJ1, PINK1,
and ATP13A2. In addition, polymorphisms within SNCA and LRRK2, as well
as variations in MAPT and GBA, are risk factors for Parkinson disease. [10]
(For more information on genes/loci underlying monogenic parkinsonism and
susceptibility genes/loci for Parkinson disease, see Tables 1 and 2,
respectively, in The Genetics of Parkinson Disease. [10] )
In one study of 953 patients with Parkinson disease with age at onset of 50
years or younger, 64 patients (6.7%) had a PRKN mutation, 1 patient (0.2%)
had a DJ1 mutation, 35 patients (3.6%) had an LRRK2 mutation, and 64
patients (6.7%) had a GBA mutation. [11] . Mutations were more common in
patients with age at onset of 30 years or younger (40.6%) than in those with
age at onset between 31 and 50 years (14.6%); more common in patients of
Jewish ancestry (32.4%) than in non-Jewish patients (13.7%); and more
common in patients reporting a first-degree family history of Parkinson
disease (23.9%) than in those without such a family history (15.1%). [11]
Although the mechanisms by which genetic mutations cause Parkinson
disease is not known, evidence to date converges on mechanisms related to
abnormal protein aggregation, defective ubiquitin-mediated protein
degradation, mitochondrial dysfunction, and oxidative damage.
Alpha-synuclein conformational changes and aggregation
Abnormally aggregated alpha-synuclein is the major component of Lewy
bodies and Lewy neurites, which are characteristic pathologic findings in
Parkinson disease. Missense mutations and multiplications in the SNCA gene
that encodes alpha-synuclein, although rare, cause autosomal dominant
Parkinson disease. However, genome-wide association studies have also
demonstrated a link between SNCA and sporadic Parkinson disease.
Dysfunction of alpha-synuclein appears to play a central role in the
pathogenesis of Parkinson disease, and understanding its relationship to the
disease process holds major promise for the development of a cure.
Alpha-synuclein is a 140-amino-acid protein that is unfolded at neutral pH.
However, when bound to membranes or vesicles containing acidic
phospholipids, it takes on an alpha-helical structure. Normally, alpha-
synuclein is found mainly in neuronal presynaptic terminals and may play a
role in assembly and function of SNARE (soluble N-ethylmaleimide-sensitive
factor activating protein receptor) proteins that are involved in
neurotransmitter release.
Under certain conditions, alpha-synuclein aggregates into oligomers that are
gradually converted to the beta–sheet-rich fibrillary structures that form Lewy
bodies and neurites in Parkinson disease. Most evidence currently suggests
that it is the intermediate soluble oligomers that are toxic to neurons.
Multiple mechanisms have been suggested as to how abnormally aggregated
alpha-synuclein could exert neurotoxicity. [12] One hypothesis suggests that
oligomeric alpha-synuclein can promote formation of ion-permeable pores on
neuronal membranes, leading to increased calcium influx. Aberrant pore
formation could also lead to neurotransmitter leaks from synaptic vesicles into
the cytosol. In addition, overexpression of alpha-synuclein has been
demonstrated to impair mitochondrial complex I activity, and oligomeric alpha-
synuclein may have a direct effect on mitochondrial membranes. Other lines
of evidence suggest that oligomerization of alpha-synuclein could cause
cytoskeletal disruption, possibly by an effect on the microtubule-stabilizing
protein, tau. [13]
Elevated levels of alpha-synuclein promote abnormal aggregation. levels are
normally regulated by a balance between synthesis and
degradation. SNCA multiplications lead to increased synthesis of alpha-
synuclein and can cause Parkinson disease. Alpha-synuclein appears to be
degraded by the ubiquitin proteasome system and the autophagy-lysosome
pathway. Several genetic mutations associated with Parkinson disease may
lead to decreased alpha-synuclein degradation. For example, increased risk
of Parkinson disease in carriers of GBA (beta-glucocerebrosidase gene)
mutations, which encode for the lysosomal enzyme glucocerebrosidase, may
be due to lysosomal dysfunction and consequent alpha-synuclein
accumulation and oligomerization.
How the Parkinson disease process begins is not known. Once it is initiated,
however, it may propagate by a prionlike process in which misconformed
proteins induce the templated misfolding of other protein molecules. In
Parkinson disease, synuclein pathology begins in the lower brainstem and
olfactory bulb, ascends up the midbrain, and eventually affects the neocortex.
One set of observations in support of a prionlike process comes from
experience with fetal dopaminergic grafts transplanted into the striata of
patients with Parkinson disease, because these grafts develop Lewy bodies,
suggesting host-graft transmission of disease. [14]
Preventing the propagation of abnormal alpha-synuclein aggregation may be
the key to slowing or stopping Parkinson disease progression.
Melanoma
For years, there has been speculation about a relationship between PD and
melanoma. Initially, it was theorized that the drug levodopa led to an
increased risk of skin cancer, but studies did not confirm this. However,
subsequent trials have since found an increased risk for melanoma in patients
with PD. One particular study conducted in 2017 found that Parkinson patients
have about a 4-fold increased risk of having preexisting
melanoma. [15, 16] Another study found the risk to be 7-fold. [17]
Diabetes
In a large cohort study, researchers found that individuals with type 2 diabetes
had a 32% increased risk of developing later Parkinson's disease than those
without diabetes. The study involved 2 million people with type 2 diabetes and
compared them to a reference cohort of 6,173,208 people without diabetes
and results showed significantly elevated rates of Parkinson's disease in the
type 2 diabetes cohort (hazard ratio [HR], 1.32, 95% confidence interval [CI],
1.29 - 1.35; P < .001). The relative increase was greater in patients with
diabetic complications and in younger individuals with type 2 diabetes aged 25
to 44 years. [18]
Epidemiology
Parkinson disease is recognized as one of the most common neurologic
disorders, affecting approximately 1% of individuals older than 60 years. The
incidence of Parkinson disease has been estimated to be 4.5-21 cases per
100,000 population per year, and estimates of prevalence range from 18 to
328 cases per 100,000 population, with most studies yielding a prevalence of
approximately 120 cases per 100,000 population. The wide variation in
reported global incidence and prevalence estimates may be the result of a
number of factors, including the way data are collected, differences in
population structures and patient survival, case ascertainment, and the
methodology used to define cases. [19]
The incidence and prevalence of Parkinson disease increase with age, and
the average age of onset is approximately 60 years. Onset in persons
younger than 40 years is relatively uncommon. Parkinson disease is about 1.5
times more common in men than in women.
Prognosis
Before the introduction of levodopa, Parkinson disease caused severe
disability or death in 25% of patients within 5 years of onset, 65% within 10
years, and 89% within 15 years. The mortality rate from Parkinson disease
was 3 times that of the general population matched for age, sex, and racial
origin. With the introduction of levodopa, the mortality rate dropped
approximately 50%, and longevity was extended by many years. This is
thought to be due to the symptomatic effects of levodopa, as no clear
evidence suggests that levodopa stems the progressive nature of the
disease. [20, 21]
The American Academy of Neurology notes that the following clinical features
may help predict the rate of progression of Parkinson disease [22] :
 Older age at onset and initial rigidity/hypokinesia can be used to predict
(1) a more rapid rate of motor progression in those with newly diagnosed
Parkinson disease and (2) earlier development of cognitive decline and
dementia; however, initially presenting with tremor may predict a more
benign disease course and longer therapeutic benefit from levodopa
 A faster rate of motor progression may also be predicted if the patient is
male, has associated comorbidities, and has postural instability/gait
difficulty (PIGD)
 Older age at onset, dementia, and decreased responsiveness to
dopaminergic therapy may predict earlier nursing home placement and
decreased survival
Patient Education
Patients with Parkinson disease should be encouraged to participate in
decision making regarding their condition. [23] In addition, individuals and their
caregivers should be provided with information that is appropriate for their
disease state and expected or ongoing challenges. [21] Psychosocial support
and concerns should be addressed and/or referred to a social worker or
psychologist as needed.
Prevention of falls should be discussed. The UK National Institute for Health
and Clinical Excellence has several guidance documents including those for
patients and caregivers.
Other issues that commonly need to be addressed at appropriate times in the
disease course include cognitive decline, personality changes, depression,
dysphagia, sleepiness and fatigue, and impulse control disorders. Additional
information is also often needed for financial planning, insurance issues,
disability application, and placement (assisted living facility, nursing home).
For patient education information, see the Brain & Nervous System Center, as
well as Parkinson's Disease Dementia.
History
Onset of motor signs in Parkinson disease is typically asymmetric, with the
most common initial finding being an asymmetric resting tremor in an upper
extremity. Over time, patients notice symptoms related to progressive
bradykinesia, rigidity, and gait difficulty. The first affected arm may not swing
fully when walking, and the foot on the same side may scrape the floor. Over
time, axial posture becomes progressively flexed and strides become shorter.
Some nonmotor symptoms commonly precede motor signs in Parkinson
disease. Most Parkinson disease patients have a substantial reduction in
olfactory function (smell) by the time motor signs emerge. However, either this
is not noticed by the patients or patients may not realize that it is part of the
disease. Another common premotor symptom is rapid eye movement (REM)
behavior disorder (RBD). In this condition, individuals exhibit movements
during REM sleep that are often described as hitting or kicking motions. There
are also a number of midlife risk factors for the later development of Parkinson
disease. These include constipation and excessive daytime sleepiness,
although they are far from specific for Parkinson disease.
In a British study, the frequency of nonmotor symptoms in 159 patients with
newly diagnosed Parkinson’s disease was found to be significantly greater
than that in 99 healthy age-matched control patients (mean, 8.4 vs
2.8). [24] The most commonly experienced nonmotor symptoms in patients with
early Parkinson disease in this study included the following [25] :
 Excessive saliva
 Forgetfulness
 Urinary urgency
 Hyposmia
 Constipation
Initial clinical symptoms in Parkinson disease include the following:
 Tremor
 A subtle decrease in dexterity; for example, a lack of coordination with
activities such as playing golf or dressing (about 20% of patients first
experience clumsiness in one hand)
 Decreased arm swing on the first-involved side
 Soft voice
 Decreased facial expression
 Sleep disturbances
 RBD, in which there is a loss of normal atonia during REM sleep: In one
study, 38% of 50-year-old men with RBD and no neurologic signs went
on to develop parkinsonism [26] ; patients “act out their dreams” and may
kick, hit, talk, or cry out in their sleep
 Decreased sense of smell
 Symptoms of autonomic dysfunction, including constipation, sweating
abnormalities, sexual dysfunction, and seborrheic dermatitis
 A general feeling of weakness, malaise, or lassitude
 Depression or anhedonia
 Slowness in thinking
Common early motor signs of Parkinson disease include tremor, bradykinesia,
rigidity, and dystonia.
Tremor
Although tremor is the most common initial symptom in Parkinson disease,
occurring in approximately 70% of patients, it does not have to be present to
make the diagnosis. Tremor is most often described by patients as shakiness
or nervousness and usually begins in one upper extremity and initially may be
intermittent. Upper extremity tremor generally begins in the fingers or thumb,
but it can also start in the forearm or wrist. After several months or years, the
tremor may spread to the ipsilateral lower extremity or the contralateral upper
extremity before becoming more generalized; however, asymmetry is usually
maintained.
Tremor can vary considerably, emerging only with stress, anxiety, or fatigue.
Classically, the tremor of Parkinson disease is a resting tremor (occurring with
the limb in a resting position) and disappears with action or use of the limb,
but this is not seen in all patients. Initially, the tremor may be noticed during
activities such as eating or reading a newspaper. Although Parkinson disease
is a rare cause of tremor affecting the head or neck, tremors of the chin, lip, or
tongue are not uncommon. As with other tremors, the amplitude increases
with stress and resolves during sleep.
Bradykinesia
Bradykinesia refers to slowness of movement. Symptoms of bradykinesia are
varied and can be described by patients in different ways. These may include
a subjective sense of weakness, without true weakness on physical
examination; loss of dexterity, sometimes described by patients as the
"message not getting to the limb"; fatigability; or achiness when performing
repeated actions.
Facial bradykinesia is characterized by decreased blink rate and facial
expression. Speech may become softer, less distinct, or more monotonal. In
more advanced cases, speech is slurred, poorly articulated, and difficult to
understand. Drooling is an uncommon initial symptom in isolation but is
reported commonly (especially nighttime drooling) later in the disease course.
Truncal bradykinesia results in slowness or difficulty in rising from a chair,
turning in bed, or walking. If walking is affected, patients may take smaller
steps and gait cadence is reduced. Some patients experience a transient
inability to walk, as though their feet are frozen to the floor. This "freezing" is
seen commonly in patients with more advanced disease; it is more prominent
as patients attempt to navigate doorways or narrow areas and can result in
patients getting trapped behind furniture or being unable to cross a door
threshold easily.
In the upper extremities, bradykinesia can cause small, effortful handwriting
(ie, micrographia) and difficulty using the hand for fine dexterous activities
such as using a key or kitchen utensils. In the lower extremities, unilateral
bradykinesia commonly causes scuffing of that foot on the ground, as it is not
picked up during leg swing. This may also be described as dragging of one
leg.
Rigidity
Some patients may describe stiffness in the limbs, but this may reflect
bradykinesia more than rigidity. Occasionally, individuals may describe a
feeling of ratchety stiffness when moving a limb, which may be a
manifestation of cogwheel rigidity.
Dystonia
Dystonia is a common initial symptom in young-onset Parkinson disease,
which is defined as symptom onset before age 40 years. Dystonia in
Parkinson disease commonly consists of a foot involuntary turning in
(inversion) or down (plantar flexion), often associated with cramping or aching
in the leg. Dorsiflexion of the big toe may also occur. Another common
dystonia in Parkinson disease is adduction of the arm and elbow, causing the
hand to rest in front of the abdomen or chest. Dystonic postures can wax and
wane, occurring with fatigue or exertion.
Whether stooped posture is due to truncal dystonia is a matter of debate. One
study suggests that the stooped posture may be due to vertebral fractures
resulting from vitamin D deficiency with compensatory
hyperparathyroidism. [27] Vitamin D supplementation may reduce the risk for
stooped posture.
Physical Examination
There are 4 cardinal signs of Parkinson disease, with 2 of the first 3 listed
below required to make the clinical diagnosis. The fourth cardinal sign,
postural instability (balance difficulty), emerges late in the disease, usually
after 8 years or more.
 Resting tremor
 Rigidity
 Bradykinesia
 Postural instability
Resting tremor
Resting tremor is assessed by having patients relax their arms in their lap
while in a seated position. Having patients count aloud backward from 10 may
help bring out the tremor. The arms should also be observed in an
outstretched position to assess postural tremor, and kinetic tremor (tremor
with voluntary movement) can be observed during the finger-to-nose test.
Although a resting tremor is the tremor characteristic of Parkinson disease,
many Parkinson disease patients also have some postural and/or kinetic
tremor.
Rigidity
Rigidity refers to an increase in resistance to passive movement about a joint.
The resistance can be either smooth (lead pipe) or oscillating (cogwheeling).
Cogwheeling is thought to reflect tremor rather than rigidity and may be
present with tremors not associated with an increase in tone (ie, essential
tremor). Rigidity is usually tested by flexing and extending the patient's
relaxed wrist and can be made more obvious by having the patient perform
voluntary movements, such as tapping, with the contralateral limb.
Bradykinesia
Bradykinesia refers to slowness of movement but also includes reduced
spontaneous movements and decreased amplitude of movement.
Bradykinesia is also expressed as micrographia (small handwriting),
hypomimia (decreased facial expression), decreased blink rate, and
hypophonia (soft speech). Thus, the patient’s blink rate and facial expression
should be observed.
In addition, speed and amplitude of movements are assessed by having the
patient open his or her hand (each limb is assessed individually) and tap his
or her thumb and index finger repetitively, trying to perform the movement as
big and as fast as possible. Similarly, the patient should be asked to tap the
toes of each foot as big and as fast as possible. Finally, the patient should be
asked to arise from a seated position with the arms crossed to assess the
ability to arise from a chair. The patient is then observed while walking to
assess stride length and speed, as well as arm swing.
Postural instability
Postural instability refers to imbalance and loss of righting reflexes. Its
emergence in a patient with Parkinson disease is an important milestone,
because it is poorly amenable to treatment and a common source of disability
in late disease. Postural stability is typically assessed by having patients stand
with their eyes open and then pulling their shoulders back toward the
examiner. Patients are told to be ready for the displacement and to regain
their balance as quickly as possible. Taking 1 or 2 steps backward to regain
balance is considered normal. The examiner should be ready to catch patients
if they are unable to regain balance.
Laryngeal dysfunction and dysphagia
As the patient is speaking, the vocal loudness, intonation, and quality,
including fluidity of speech and articulation, should be assessed. Sustaining
vowel phonation (eg, "ah") for maximum duration, counting to 50, and reading
a passage that tests articulation (eg, the rainbow passage) provide
reasonable speech samples. Closely listening for reduced or diminishing
loudness and intonation and increasing breathiness and hoarseness helps
differentiate Parkinson disease from hyperkinetic disorders such as
spasmodic dysphonia. [28]
A soft, monotone voice, vocal tremor, poor articulation, variable speech rate,
trouble with the initiation of speech, and stuttering-like qualities are all
characteristics of Parkinson disease. Perhaps the most telling vocal symptom
is the marked contrast between habitual vocal volume (soft and diminishing)
and the patient's response to a request to increase loudness. A request to
"say that again, twice as loud" often results in increased loudness, improved
voice quality, and a dramatic improvement in speech intelligibility.
Dysphagia is common, especially in advanced Parkinson disease.
Manifestations may range from drooling to aspiration.
An otolaryngologist can perform a more detailed assessment of laryngeal
dysfunction in patients with Parkinson disease, using neurolaryngeal
examination and stroboscopy. Because distortion can occur when the tongue
is held forward during rigid stroboscopy, the neurolaryngeal examination is
best performed by viewing the larynx with a flexible laryngoscope. The larynx
is evaluated for vocal fold mobility, paresis or paralysis, coordination of
movement, agility, fatigability, flexibility, and use of accessory muscles during
phonation while the patient says various phrases and syllables.
Hyperfunctional and hypofunctional disorders can often be differentiated by
isolating the abductor and adductor muscle groups. The larynx is also
visualized at rest.
Rigid stroboscopy plays a key role in the assessment of the vibratory
characteristics of the vocal folds, including the presence of masses, lesions,
or scar and glottic configuration abnormalities, including an elliptical closure
pattern, phase asymmetry, and abnormal phase closure. Stroboscopy and
neurolaryngeal examination are complementary in the evaluation of the
patient with Parkinson disease. Common stroboscopy findings in Parkinson
disease include true vocal fold atrophy or other evidence of glottal
incompetence, including a chasing wave or a shorter closed phase.
Pooling of secretions, decreased sensation, and aspiration are also
characterizations of the Parkinson disease larynx. A paralyzed vocal fold
suggests Parkinson-plus syndrome (PPS) as the etiology for the parkinsonism
if other aspects of the diagnosis are present.
Perez et al found that vocal tremor is present in 55% of patients with
Parkinson disease. [29] Interestingly, only 35% of patients with Parkinson
disease exhibited a resting vocal cord tremor, whereas the remainder
exhibited kinetic tremor. The tremor is primarily a vertical laryngeal movement.
PPS was found to carry a higher incidence of vocal tremor (64%), with most
tremors located in the arytenoids. The authors found no vertical laryngeal
tremor in patients with PPS. [29]
Autonomic dysfunction
Autonomic dysfunction is common in patients with Parkinson disease.
Orthostatic hypotension often becomes a concern in late disease, and
impaired intestinal motility can lead to constipation and, sometimes, vomiting
or impaired absorption. Urinary symptoms, retention, and bladder infection
can occur, and erectile dysfunction is not uncommon. In addition, many
patients note episodes of sweating.
Prominent autonomic dysfunction, especially frank urinary incontinence or
profound orthostatic hypotension, may suggest multiple system atrophy (MSA)
rather than Parkinson disease.
Cardiopulmonary impairment
The flexed posture of patients with Parkinson disease can lead to kyphosis,
cause a reduction in pulmonary capacity, and produce a restrictive lung
disease pattern.
Staging
Investigators have proposed a staging system to improve the assessment of
overall Parkinson disease severity. In an observational, cross-sectional study
of 933 patients with Parkinson disease, Ray Chaudhuri and colleagues found
a wide discrepancy between the severity of nonmotor symptoms as measured
by the NonMotor Symptoms Scale (NMSS) and motor symptoms as
measured by the Hoehn and Yahr scale. [30, 31] The investigators proposed a
staging system for nonmotor symptom burden based on NMSS scores, which
was correlated with measures of disability and quality of life. The staging
system rates nonmotor symptom burden (NMSB) on a scale of 0 (no NMSB)
to 4 (very severe NMSB). [30, 31]
Depression
Given the high prevalence of mood disorders in Parkinson disease, these
patients should be screened regularly for depression. However, assessment
of depression in patients with Parkinson disease is complicated by the fact
that some symptoms of Parkinson disease overlap with those of depression
(eg, masklike facies, insomnia, psychomotor slowing, difficulty concentrating,
fatigue). Guilt and self-reproach are less prominent in depression in patients
with Parkinson disease, whereas anxiety and pessimism are more prominent.
Dementia
Hoops et al found that in Parkinson disease, the Montreal Cognitive
Assessment (MoCA) is superior to the Mini-Mental State Examination (MMSE)
for screening for mild cognitive impairment or dementia. [32] MoCA and MMSE
demonstrated similar overall discriminant validity for detection of any cognitive
disorder, but as a screening instrument, MoCA was better than MMSE (64%
vs 54% correct diagnoses). [32]
The prevalence of dementia in Parkinson disease ranges from 20-40%, with
the disease conferring a 2- to 6-fold increased risk compared with control
populations. [33] Many patients with Parkinson disease have some executive
function impairment, even early in the disease. [33] Substantial cognitive
impairment and dementia typically occur 8 years or more after the onset of
motor features.
Dementia generally occurs late in Parkinson disease; substantial cognitive
dysfunction within 1 year of onset of motor features suggests a diagnosis
of Lewy body disease, a disease closely related to Parkinson disease and
marked by the presence of cortical Lewy bodies. In the affected age group,
comorbidity with other neurodegenerative disorders, particularly Alzheimer
disease and cerebrovascular disease, is common. The relatively high
prevalence of depression in patients with Parkinson disease is another
confounder in the diagnosis of Parkinson disease dementia.
Executive function, short-term memory, and visuospatial ability may be
impaired in patients with Parkinson disease dementia, but aphasia is not
present. In a long-term Australian study that compared neuropsychologic
measures between patients with Parkinson disease who had early dementia
(< 10 years of disease onset) and those with late dementia, investigators
reported that dementia in parkinsonism appears to occur at about age 70
years regardless of the time of onset of Parkinson disease. [34] However,
although early and late dementia had similar effects in cognitive domains,
individuals with early onset of parkinsonism had a preserved linguistic ability
before the onset of dementia. [34]
Atypical Parkinsonisms
Atypical parkinsonisms, or Parkinson-plus syndromes, are primary
neurodegenerative disorders that have parkinsonian features and are
associated with complex clinical presentations that reflect degeneration in
various neuronal systems. Patients with atypical parkinsonisms typically have
a worse prognosis than those with Parkinson disease, and atypical
parkinsonisms respond poorly to standard anti-Parkinson disease treatments.
(For more information, see Parkinson-Plus Syndromes for detailed information
regarding clinical clues, workup, differential diagnosis, and treatment of
atypical parkinsonisms, including multiple system atrophy, progressive
supranuclear palsy, parkinsonism-dementia-amyotrophic lateral
sclerosis complex, corticobasal ganglionic degeneration, and diffuse Lewy
body disease.)
Diagnostic Considerations
The most common tremor disorders are Parkinson disease and essential tremor. When
a patient presents with tremor, the clinician should pay particular attention to the body
parts involved, positions/conditions in which the tremor occurs (ie, resting, postural,
kinetic, intention), and the frequency of the tremor. It is also critical to look for potential
associated signs. The patient should be examined for evidence of parkinsonism
(bradykinesia, rigidity, postural instability), dystonia, and other neurologic signs.
An 8-12 Hz action (postural/kinetic) tremor of the upper extremities that is temporarily
relieved by drinking alcohol is characteristic of essential tremor, whereas the presence
of a pill-rolling rest tremor, bradykinesia, and rigidity is consistent with Parkinson
disease and argues against essential tremor.
In patients with parkinsonism, careful attention to the history is necessary to exclude
secondary causes such as medications, toxins, or trauma. Medications that block
striatal dopamine receptors, such as metoclopramide and neuroleptics, can cause drug-
induced parkinsonism. Certain toxins such as MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine) and manganese (at high levels of exposure) can also cause
parkinsonism.
Consider evaluating patients with parkinsonism for osteoporosis and osteopenia. In a
meta-analysis of 23 studies, Tornsey and colleagues found evidence that individuals
with Parkinson disease have an increased risk for osteoporosis and osteopenia. [35, 36] A
pooled analysis of 2 of the studies, for example, indicated that in patients with Parkinson
disease, the odds ratio for developing osteoporosis, when compared with healthy
controls, was 2.61, although the increase was lower in men than in women.
Analysis of 14 studies found bone mineral densities in patients with Parkinson disease
to be significantly lower at the hip, lumbar spine, and femoral neck, whereas, after an
examination of 9 studies, the investigators estimated that bone fracture risk is doubled
in Parkinson patients. [35, 36]
Early clinical features that suggest an atypical parkinsonism rather than Parkinson
disease include the following [22] :
 Falls at presentation or early in the disease
 Poor response to levodopa
 Symmetry at disease onset
 Rapid disease progression
 No tremor
 Dysautonomia (eg, urinary incontinence, fecal incontinence, catheterization for
urinary retention, persistent erectile failure, prominent symptomatic orthostatic
hypotension)
The atypical parkinsonisms are usually associated with little or no tremor, relatively
early speech and balance difficulty, and little or no response to dopaminergic
medications. Multiple system atrophy (MSA) is relatively symmetric and characterized
by parkinsonism, often with some combination of autonomic, corticospinal, and
cerebellar dysfunction. Progressive supranuclear palsy (PSP) is relatively symmetric
and characterized by parkinsonism with early falls (often in the first year) and a
supranuclear gaze palsy in which the patient has difficulty with voluntary down-gaze.
Corticobasal ganglionic degeneration (CBD) is typically very asymmetric and
characterized by both cortical (difficulty identifying objects, apraxias) and basal
ganglionic (usually marked rigidity in an arm) features.
Lewy body disease is characterized by substantial cognitive dysfunction within 1 year of
onset of parkinsonism. Hallucinations are common.
Patients with onset of parkinsonism before age 40 years should be tested for Wilson
disease, starting with serum ceruloplasmin measurement and ophthalmologic
evaluation for Kayser-Fleischer rings.
Differential Diagnoses
 Alzheimer Disease
 Cardioembolic Stroke
 Chorea in Adults
 Cortical Basal Ganglionic Degeneration
 Lewy Body Dementia
 Dopamine-Responsive Dystonia
 Essential Tremor
 Pantothenate Kinase-Associated Neurodegeneration (PKAN)
 Huntington Disease
 Lacunar Syndrome
 Multiple System Atrophy
 Neuroacanthocytosis
 Neurological Manifestations of Vascular Dementia
 Normal Pressure Hydrocephalus
 Olivopontocerebellar Atrophy
 Parkinson-Plus Syndromes
 Progressive Supranuclear Palsy
 Striatonigral Degeneration
Approach Considerations
Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for
the condition, and findings on routine magnetic resonance imaging (MRI) and
computed tomography (CT) scan are unremarkable. Positron emission
tomography (PET) and single-photon emission CT (SPECT) may show
findings consistent with Parkinson disease, and olfactory testing may provide
evidence pointing toward Parkinson disease, but these studies are not
routinely needed. (Olfactory testing can reveal hyposmia, which may precede
the motor signs of Parkinson disease by several years. [37] However, olfactory
loss is not specific and can also occur in Alzheimer disease.)
No laboratory or imaging study is required in patients with a typical
presentation. Such patients are aged 55 years or older and have a slowly
progressive and asymmetric parkinsonism with resting tremor and
bradykinesia or rigidity. Patients who do not have tremor should generally be
considered for MRI evaluation to exclude brain lesions such as stroke, tumor,
or demyelination.
In patients with an unusual presentation, diagnostic testing may be indicated
to exclude other disorders in the differential diagnosis. Such tests may include
serum ceruloplasmin, sphincter electromyography, or lumbar puncture.
Serum ceruloplasmin concentration is obtained as a screening test for Wilson
disease in patients younger than 40 years who present with parkinsonian
signs. If the ceruloplasmin level is low, measurement of 24-hour urinary
copper excretion and slit-lamp examination for Kayser-Fleischer rings must be
performed. Abnormal results on urinary sphincter electromyography have
been noted in patients with multiple system atrophy (MSA).
A substantial and sustained response to dopamine medications (dopamine
agonists or levodopa) helps confirm a diagnosis of Parkinson disease. It is
unclear whether acute levodopa or apomorphine challenge has any
advantage over clinical diagnostic criteria. [22] Over time, diagnostic accuracy
improves as the progression of signs and symptoms and response to
medications unfolds.
In the general community, there is a high diagnosis error rate between
Parkinson disease and essential tremor. For movement disorder neurologists,
when an erroneous diagnosis of Parkinson disease is made, the most likely
correct diagnoses are the atypical parkinsonisms (MSA, progressive
supranuclear palsy [PSP], corticobasal ganglionic degeneration [CBD]). Early
in the disease course, it may be very difficult to distinguish between Parkinson
disease and the atypical parkinsonisms. These disorders also do not have
laboratory biomarkers, and, therefore, distinguishing among them is based on
clinical criteria. Olfactory testing may help differentiate Parkinson disease from
PSP and CBD, but olfaction is also reduced in MSA.
Radiologic Studies
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is useful to exclude strokes, tumors, multi-
infarct state, hydrocephalus, and the lesions of Wilson disease. MRI should be
obtained in patients whose clinical presentation does not allow a high degree
of diagnostic certainty, including those who lack tremor, have an acute or
stepwise progression, or are younger than 55 years.
The following MRI indicates where a thalamic stimulator is typically placed.
Axial, fast spin-echo inversion
recovery magnetic resonance image at the level of the posterior commissure.
The typical target for placing a thalamic stimulator is demonstrated (cross-
hairs).
View Media Gallery
Below is a coronal MRI following bilateral subthalamic nuclei deep brain
stimulation.
Postoperative coronal
magnetic resonance image (MRI) demonstrating desired placement of
bilateral subthalamic nuclei-deep brain stimulation (STN-DBS) leads.
View Media Gallery
PET and SPECT scanning
Positron emission tomography (PET) and single-photon emission computed
tomography (SPECT) scanning are useful diagnostic imaging studies, but
these are not routinely required. Different radioligands permit imaging of
different components or abnormalities within the brain.
At the onset of motor signs, patients with Parkinson disease show an
approximately 30% decrease in18 F-dopa (fluorodopa) uptake on PET imaging
in the contralateral putamen.18 F-Dopa is taken up by the terminals of
dopamine neurons and converted to18 F-dopamine. The rate of striatal18 F
accumulation reflects transport of18 F-dopa into dopamine neurons and its
decarboxylation to18 F-dopamine, which is stored in dopamine nerve terminals
in the striatum. Thus,18 F-dopa PET imaging provides an index of remaining
dopamine neurons. However, this study is not widely available, is usually not
covered by insurance, and is currently generally considered a research tool.
Carbon-11 (11 C)-nomifensine and cocaine analogues such as123 I-beta-CIT
(iodine-123-labeled carboxymethoxy-3beta-4-iodophenyl-nortropane) and123 I-
FP-CIT (fluoropropyl-CIT) bind to dopamine reuptake sites on nigrostriatal
terminals and provide an index of the remaining dopamine neurons. Ioflupane
(123 I) (DaTscan) is a radiopharmaceutical agent that is indicated for striatal
dopamine transporter visualization using SPECT brain imaging to assist in the
evaluation of adults with suspected Parkinsonian syndromes (PSs). This
agent may be used to help differentiate essential tremor from tremor due to
PSs (idiopathic Parkinson disease [IPD] and Parkinson-plus syndromes
[PPS]). [1] Analysis of data from 2 clinical trials demonstrated that the use of
ioflupane with iodine-123 and single-photon emission computed tomography
(SPECT) scanning to diagnose early-stage Parkinson's disease performed as
well as clinical assessment at 1-year follow-up. [38, 39]
Deficits on123 I SPECT scans indicate a dopamine deficiency syndrome but do
not differentiate Parkinson disease from atypical parkinsonisms,
including multiple system atrophy (MSA) and progressive supranuclear
palsy (PSP). Ioflupane SPECT imaging reveals a dopamine deficiency in
Parkinson disease, MSA, PSP, corticobasal ganglionic degeneration, and
Lewy body disease. This study is normal in essential tremor, dystonic tremor,
medication-induced parkinsonism or tremor, psychogenic disorders, and in
normal individuals.
Histologic Findings
Classic pathologic findings in Parkinson disease include degeneration of the
neurons containing neuromelanin, especially in the substantia nigra and the
locus ceruleus. Surviving neurons often contain eosinophilic cytoplasmic
inclusions called Lewy bodies (see the following image). The primary
biochemical defects are loss of striatal dopamine, which results from
degeneration of dopamine-producing cells in the substantia nigra, as well as
hyperactivity of the cholinergic neurons in the caudate nucleus.
Lewy bodies are intracytoplasmic

eosinophilic inclusions, often with halos, that are easily seen in pigmented
neurons, as shown in this histologic slide. They contain polymerized alpha-
synuclein; therefore, Parkinson disease is a synucleinopathy.
View Media Gallery
Lewy bodies in the locus

coeruleus from a patient with Parkinson disease.
View Media Gallery
Alpha-synuclein is a major structural component of Lewy bodies; all Lewy
bodies stain for alpha-synuclein, and most also stain for ubiquitin. Lewy
bodies are concentric, eosinophilic, cytoplasmic inclusions with peripheral
halos and dense cores. The presence of Lewy bodies within pigmented
neurons of the substantia nigra is characteristic, but not pathognomonic, of
Parkinson disease. Lewy bodies are also found in the cortex, nucleus basalis,
locus ceruleus, intermediolateral column of the spinal cord, and other areas.
According to the Braak hypothesis, Lewy body pathology in the brain begins in
the olfactory bulb and lower brainstem and slowly ascends to affect dopamine
neurons in the substantia nigra and, ultimately, the cerebral cortex. [40] Lewy
body pathology is also observed in autonomic nerves of the gut and heart.
Lumbar Puncture
Lumbar puncture should be considered if signs of normal-pressure
hydrocephalus (NPH) are observed (eg, incontinence, ataxia, dementia). In
NPH, clinical signs characteristically improve after removal of about 20 mL of
cerebrospinal fluid.
Dopa-responsive dystonia should be considered in patients with juvenile-
onset dystonia and parkinsonism, particularly with diurnal fluctuations in
symptoms. In such patients, a trial of levodopa is critical. Additional tests for
this condition include measurement of CSF concentrations of biopterin,
neopterin, and the neurotransmitter metabolites homovanillic acid (HVA), 5-
hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol
(MHPG). In both forms of dopa-responsive dystonia, an altered pattern of
decreases in these compounds is observed.
In the "Parkinson's Progression Markers Initiative" cross-sectional study of 63
drug-naive patients with early-stage PD and 39 healthy controls, CSF levels of
the Alzheimer's biomarkers β-amyloid 1-42 (Aβ1-42), total tau (T-tau), tau
phosphorylated at threonine 181 (P-tau181), and α-synuclein were lower in
the PD patients than in the controls. Aβ1-42 and P-tau181 were significant
predictors of Parkinson's disease, and T-tau and α-synuclein were associated
with the severity of motor dysfunction. In particular, lower Aβ1-42 and P-
tau181 concentrations were associated with the postural instability–gait
disturbance–dominant PD phenotype, but were not associated with the
tremor-dominant or intermediate phenotypes. [41, 42]
See Lumbar Puncture for detailed information on indications for the
procedure, contraindications, and a step-by-step discussion containing
images and video on how to perform the procedure.
Approach Considerations
The goal of medical management of Parkinson disease is to provide control of
signs and symptoms for as long as possible while minimizing adverse effects.
Studies demonstrate that a patient's quality of life deteriorates quickly if
treatment is not instituted at or shortly after diagnosis. [43]
Symptomatic and neuroprotective therapy
Pharmacologic treatment of Parkinson disease can be divided into
symptomatic and neuroprotective (disease modifying) therapy. At this time,
there is no proven neuroprotective or disease-modifying therapy.
Levodopa, coupled with carbidopa, a peripheral decarboxylase inhibitor (PDI),
remains the gold standard of symptomatic treatment for Parkinson disease.
Carbidopa inhibits the decarboxylation of levodopa to dopamine in the
systemic circulation, allowing for greater levodopa distribution into the central
nervous system. Levodopa provides the greatest antiparkinsonian benefit for
motor signs and symptoms, with the fewest adverse effects in the short term;
however, its long-term use is associated with the development of motor
fluctuations (“wearing-off”) and dyskinesias. Once fluctuations and
dyskinesias become problematic, they are difficult to resolve.
Monoamine oxidase (MAO)-B inhibitors can be considered for initial treatment
of early disease. These drugs provide mild symptomatic benefit, have
excellent adverse effect profiles, and, according to a Cochrane review, have
improved long-term outcomes in quality-of-life indicators by 20-25%. [44]
Dopamine agonists (ropinirole, pramipexole) provide moderate symptomatic
benefit and delay the development of dyskinesia compared with levodopa.
Proactively screen patients receiving oral dopamine agonists for adverse
events. A review of the Cochrane and PubMed databases from 1990 to 2008
found that these agents caused a 15% increase in adverse events such as
somnolence, sudden-onset sleep, hallucinations, edema, and impulse control
disorders (eg, pathologic gambling, shopping, and Internet use;
hypersexuality; and hoarding). [45] Note that patients may be reluctant to
mention these events or may not attribute them to their treatment.
Symptomatic anti-Parkinson disease medications usually provide good control
of motor signs of Parkinson disease for 4-6 years. After this, disability often
progresses despite best medical management, and many patients develop
long-term motor complications, including fluctuations and dyskinesias.
Additional causes of disability in late disease include postural instability
(balance difficulty) and dementia. Thus, symptomatic therapy for late disease
requires different strategies.
Neuroprotective therapy aims to slow, block, or reverse disease progression;
such therapies are defined as those that slow underlying loss of dopamine
neurons. Although no therapy has been proven to be neuroprotective, there
remains interest in the long-term effects of MAO-B inhibitors. Other agents
currently under investigation include creatine and isradipine.
The younger the patient, the more emphasis the authors place on long-term
considerations to guide early treatment. Young patients have a longer life
expectancy and are more likely to develop motor fluctuations and dyskinesias.
For older patients and those with cognitive impairment, less emphasis is
placed on long-term considerations; instead, the focus is on providing
adequate symptomatic benefit in the near term, with as few adverse effects as
possible.
For patients who have motor fluctuations and dyskinesias that cannot be
adequately managed with medication manipulation, surgery is considered.
The principal surgical option is deep brain stimulation (DBS), which has
largely replaced neuroablative lesion surgeries. Levodopa/carbidopa intestinal
gel infusion is available in some countries and is in clinical trials in others,
including the United States. [12]
Nonmotor symptoms
It is now recognized that in Parkinson disease, nonmotor symptoms may be
as troublesome as, or more troublesome than, motor symptoms. Nonmotor
symptoms can be categorized as autonomic, cognitive/psychiatric, and
sensory [46] and may include depression, dementia, hallucinations, rapid eye
movement (REM) sleep behavior disorder (RMD), orthostatic hypotension,
and constipation. Nonmotor symptoms can also fluctuate, especially
depression, pain, numbness, paresthesia/dysesthesia, akathisia, and restless-
legs syndrome. Recognition of nonmotor symptoms of Parkinson disease is
essential for appropriate management. [46]
Screen Parkinson disease patients for depression, and treat it when present.
An evidence-based guideline from the American Academy of Neurology
(AAN) reports that physician recognition of depression is low in Parkinson
disease, at less than 30% of clinically proven cases. There are many factors
that confound its diagnosis in these patients; and depression has the single
largest effect on the quality of life of patients with Parkinson disease. [26, 47]
In 2010, the AAN released guidelines on the treatment of nonmotor symptoms
of Parkinson disease. Recommendations included the following [48] :
 Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction
 Polyethylene glycol may be considered to treat constipation
 Modafinil should be considered for patients who subjectively experience
excessive daytime somnolence
 For insomnia, evidence is insufficient to support or refute the use of
levodopa to improve objective sleep parameters that are not affected by
motor symptoms; evidence is also insufficient to support or refute the use
of melatonin for poor sleep quality
 Levodopa/carbidopa should be considered to treat periodic limb
movements of sleep in Parkinson disease, but there are insufficient data
to support or refute the use of nonergot dopamine agonists to treat this
condition or that of restless-legs syndrome
 Methylphenidate may be considered for fatigue (note: methylphenidate
has the potential for abuse and addiction)
 Evidence is insufficient to support or refute specific treatments of
orthostatic hypotension, urinary incontinence, anxiety, and RMD
Symptomatic Therapy, Early Disease
Medications commonly used for symptomatic benefit of motor symptoms in
early Parkinson disease include levodopa, monoamine oxidase (MAO)-B
inhibitors, and dopamine agonists.
Levodopa
Levodopa, coupled with a peripheral dopa decarboxylase inhibitor such as
carbidopa, remains the standard of symptomatic treatment for Parkinson
disease. It provides the greatest antiparkinsonian benefit with the fewest
adverse effects in the short term. However, long-term use of levodopa is
associated with the development of fluctuations and dyskinesias. Once
fluctuations and dyskinesias become problematic, they are difficult to resolve.
These adverse effects are the reason to consider delaying the initiation of
levodopa if other alternatives are able to control symptoms.
Levodopa/carbidopa is introduced at a low dose and escalated slowly.
Carbidopa inhibits the decarboxylation of levodopa to dopamine in the
systemic circulation, allowing for greater levodopa delivery into the central
nervous system.
Currently available levodopa preparations in the United States include
levodopa/carbidopa immediate-release (IR) tablets (Sinemet),
levodopa/carbidopa controlled-release (CR) tablets (Sinemet CR), and
levodopa/carbidopa orally disintegrating tablets (Parcopa). The orally
disintegrating tablet is bioequivalent to oral levodopa/carbidopa IR, but it
dissolves on the tongue without the need to swallow it with water. The orally
disintegrating tablet is not absorbed in the mouth but travels in the saliva to
absorption sites in the proximal small bowel (where other levodopa
preparations are also absorbed).
Levodopa/carbidopa is also available in combination with entacapone, a
catechol-O-methyltransferase (COMT) inhibitor. When entacapone is given in
conjunction with levodopa and carbidopa, plasma levels of levodopa are
higher and more sustained than after administration of levodopa and
carbidopa alone. Levodopa/carbidopa/entacapone is useful in advanced
Parkinson disease in patients with motor fluctuations. In the STRIDE-PD
(STalevo Reduction In Dyskinesia Evaluation) study, patients with early
Parkinson disease treated with levodopa/carbidopa/entacapone (Stalevo)
developed more dyskinesia than patients treated with levodopa/carbidopa;
therefore, levodopa/carbidopa/entacapone is not recommended for treatment
of early disease. [49]
Levodopa in combination with a dopa decarboxylase inhibitor is started at a
low dose and slowly titrated to control clinical symptoms. Most patients
experience a good response on a daily levodopa dosage of 300–600 mg/day
(usually divided 3 or 4 times daily) for 3–5 years or longer. Doses higher than
those necessary to control symptoms adequately should be avoided, because
higher doses increase the risk for the development of dyskinesia. [50] If nausea
occurs, the levodopa dose can be taken immediately following a meal.
Additional measures to alleviate nausea include adding extra carbidopa or
introducing domperidone (available outside the United States). Other side
effects include dizziness and headache. In elderly patients, confusion,
delusions, agitation, hallucinations, and psychosis may be more commonly
seen.
MAO-B inhibitors
MAO-B inhibitors, such as selegiline and rasagiline, may be used for early
symptomatic treatment of Parkinson disease. These medications provide mild
symptomatic benefit, have excellent adverse effect profiles, and may improve
long-term outcomes. These characteristics make MAO-B inhibitors a good
choice as initial treatment for many patients. When the MAO-B inhibitor alone
is not sufficient to provide good control of motor symptoms, another
medication (eg, a dopamine agonist or levodopa) can be added.
Selegiline is indicated as adjunctive therapy (5 mg every morning; maximum,
10 mg/day) in the treatment of Parkinson disease in patients being treated
with levodopa/carbidopa. Rasagiline is indicated for the treatment of the signs
and symptoms of Parkinson disease as initial monotherapy (1 mg/day) and as
adjunctive therapy (0.5-1.0 mg/day) to levodopa. Potential side effects include
nausea, headaches, and dizziness.
Dopamine agonists
Initial treatment with a dopamine agonist, to which levodopa can be added as
necessary, is associated with fewer motor fluctuations and dyskinesias than
levodopa alone in prospective, double-blind studies. Subsequent analyses of
these studies indicate that the benefit of dopamine agonists in delaying motor
symptoms is due to their ability to delay the need for
levodopa/carbidopa. [51, 52] Commonly used dopamine agonists include
pramipexole and ropinirole.
Dopamine agonists provide symptomatic benefit that is comparable to that
with levodopa/carbidopa in early disease, but these agents lack sufficient
efficacy to control signs and symptoms by themselves in more advanced
disease. Dopamine agonists provide moderate symptomatic benefit and rarely
cause fluctuations and dyskinesias by themselves, but they have more
adverse effects than levodopa, including sleepiness, hallucinations, edema,
and impulse control disorders. However, these adverse effects resolve upon
lowering the dose or discontinuing the medication.
Dopamine agonists are commonly reserved for younger individuals (< 65-70
years) who are cognitively intact. When the dopamine agonist (with or without
an MAO-B inhibitor) no longer provides good control of motor symptoms,
levodopa can be added. However, dopamine agonists may provide good
symptom control for several years before levodopa is required.
For patients aged 65-70 years, the authors make a judgment based on
general health and cognitive status. The more robust and cognitively intact the
patient, the more likely the authors are to treat with a dopamine agonist before
levodopa and add levodopa/carbidopa when necessary. For patients with
cognitive impairment and those older than 70 years—who may be prone to
adverse effects, such as hallucinations, from dopamine agonists—and for
those likely to require treatment for only a few years, the authors may elect
not to use a dopamine agonist and instead depend on levodopa/PDI
(peripheral decarboxylase inhibitor) as primary symptomatic therapy.
When introducing a dopamine agonist, it is important to start at a low dose
and escalate slowly. The dose should be titrated upward until symptoms are
controlled, the maximum dose is reached, or adverse effects emerge.
The most common adverse effects of dopamine agonists are nausea,
orthostatic hypotension, hallucinations, somnolence, and impulse control
disorders. Nausea can usually be reduced by having the patient take the
medication after meals. Domperidone, a peripheral dopamine agonist
available outside the United States, is very helpful in relieving refractory
nausea.
Patients on dopamine agonists should be routinely asked about sleepiness,
sudden onset of sleep, and impulse control disorders such as pathologic
gambling, shopping, internet use, and sexual activity. These adverse effects
typically resolve with reduction in dose or discontinuation of the medication.
Patients should be warned not to drive if they are experiencing undue
sleepiness. They should also be warned about the possibility of impulse
control disorders and the need to let their physician know if such an effect
occurs.
Anticholinergic agents
Anticholinergic agents can be used for patients who have disability due to
tremor that is not adequately controlled with dopaminergic medication, but
these are not first-line drugs, because of their limited efficacy and the
possibility of neuropsychiatric side effects. Anticholinergic medications provide
good tremor relief in approximately 50% of patients but do not meaningfully
improve bradykinesia or rigidity. Because tremor may respond to one
anticholinergic medication but not another, a second anticholinergic agent
usually can be tried if the first is not successful. These medications should be
introduced at a low dose and escalated slowly to minimize adverse effects,
which include memory difficulty, confusion, and hallucinations. Adverse
cognitive effects are relatively common, especially in elderly persons.
One of the most commonly used anticholinergic is trihexyphenidyl. The initial
dose of trihexyphenidyl should be low and gradually increased. It is
recommended to begin therapy with a single 1-mg dose. Dosage can be
titrated by 1 mg each week or so, until a total of 4-6 mg is given daily or until
satisfactory control is achieved. Some patients may require higher doses.
Benztropine (Cogentin) is also commonly used, with an initial dose of 0.5-1
mg daily at bedtime. Dose can be titrated at weekly intervals in increments of
0.5 mg to a maximum of 6 mg/day.
Amantadine
Amantadine is an antiviral agent that has antiparkinsonian activity. Its
mechanism of action is not fully understood, but amantadine appears to
potentiate CNS dopaminergic responses. It may release dopamine and
norepinephrine from storage sites and inhibit the reuptake of dopamine and
norepinephrine. Amantadine may offer additional benefit in patients
experiencing maximal or waning effects from levodopa.
Amantadine is commonly introduced at a dose of 100 mg per day and slowly
increased to an initial maintenance dose of 100 mg 2 or 3 times daily. The
most concerning potential side effects of amantadine are confusion and
hallucinations. Common side effects include nausea, headache, dizziness,
and insomnia. Less frequently reported side effects include anxiety and
irritability, ataxia, livedo reticularis, peripheral edema, and orthostatic
hypotension.
In a small, double-blind crossover study, amantadine was found to ameliorate
pathologic gambling associated with Parkinson disease. [53] However, in a
large cross-sectional study, amantadine was associated with a higher
prevalence of impulse control disorders, including gambling. [54] Thus, further
research is needed to understand the role of amantadine as a treatment or
cause of impulse control disorders in patients with Parkinson disease.
Symptomatic Therapy, Advanced Disease
Motor fluctuations
Patients initially experience stable, sustained benefit through the day in
response to levodopa. However, after several months to years, many patients
notice that the benefit from immediate-release (IR) levodopa/carbidopa wears
off after 4-5 hours. Over time, this shortened duration of response becomes
more fleeting, and clinical status fluctuates more and more closely in concert
with peripheral levodopa concentration. Ultimately, benefit lasts only about 2
hours. The time when medication is providing benefit for bradykinesia, rigidity,
and tremor is called "on" time, and the time when medication is not providing
benefit is called "off" time.
Treating motor fluctuations in the absence of peak-dose dyskinesia is
relatively easy. Several different strategies, either alone or in combination, can
be used to provide more sustained dopaminergic therapy. Possible strategies
include the following:
 Adding a dopamine agonist, catechol-O -methyltransferase (COMT)
inhibitor, monoamine oxidase (MAO)-B inhibitor, or selective adenosine
antagonist
 Dosing levodopa more frequently
 Increasing the levodopa dose
 Adding intermittent levodopa inhaled doses
 Switching from immediate-release (IR) to sustained-release (CR)
levodopa/carbidopa or levodopa/carbidopa/entacapone
 Continuous intrajejunal infusion of a carbidopa/levodopa enteral
suspension [55]
In January 2015, the FDA approved a carbidopa/levodopa enteral suspension
(Duopa) that is infused into the jejunum by a portable pump. The efficacy of
the enteral suspension to decrease off-time and increase on-time was shown
in a multicenter, international study. From baseline to 12 weeks, mean off-time
decreased by 4.04 hours for 35 patients allocated to the levodopa/carbidopa
intestinal group compared with a decrease of 2.14 hours for 31 patients
allocated to immediate-release oral levodopa/carbidopa (p=0.0015). Mean on-
time without troublesome dyskinesia increased by 4.11 hours in the intestinal
gel group and 2.24 hours in the immediate-release oral group (p=0.0059). [55]
Safinamide (Xadago), a MAO-B inhibitor, was approved by the FDA in March
2017 as add-on treatment for patients with Parkinson disease who are
currently taking levodopa/carbidopa and experiencing “off” episodes. It is the
first new chemical entity approved in the United States in more than 10 years.
Approval was based on 2 phase-III trials that included nearly 1200 patients
who had PD with motor fluctuations. Results showed that safinamide as add-
on treatment to levodopa/carbidopa provided a significant reduction in off-time
and a significant increase in on-time without troublesome dyskinesia in
patients experiencing motor fluctuations. [56, 57]
Levodopa inhaled (Inbrija), a dopamine agonist, was approved in December
2018 for intermittent treatment of "off" episodes in patients who are already
treated with oral carbidopa/levodopa. The inhaled dosage form bypasses the
digestive system, thereby providing a quick onset of action as soon as 10
minutes. Approval was based on the phase 3 SPAN-PD trial (N = 339). The
change at week 12 in UPDRS III score was -9.83 for patients receiving the 84-
mg dose compared with -5.91 for the group taking placebo (P = 0.009). [58]
Istradefylline (Nourianz), a selective adenosine A2A antagonist, was approved
by the FDA in August 2019 as adjunctive treatment to levodopa/carbidopa in
adults with PD experiencing “off” episodes. Approval was based on four
randomized, placebo-controlled trials (n=1143) in patients stabilized on
levodopa/carbidopa with or without other medications for their Parkinson
disease. Results showed statistically significant decreases in OFF time in the
istradefylline treatment groups compared with placebo. [59, 60, 61]
Unless limited by the emergence of peak-dose symptoms such as dyskinesia
or hallucinations, dopaminergic therapy should be increased until off-time is
eliminated. Once-daily formulations of the dopamine agonists ropinirole and
pramipexole are now available. These medications appear to provide efficacy
and safety similar to the IR formulations that are administered 3 times daily. [62]
Dyskinesia
By several months to years after the introduction of levodopa, many patients
develop peak-dose dyskinesia consisting of choreiform, which is
twisting/turning movements that occur when levodopa-derived dopamine
levels are peaking. At this point, increasing dopamine stimulation is likely to
worsen peak-dose dyskinesias, and decreasing dopamine stimulation may
worsen Parkinson disease motor signs and increase off time. The therapeutic
window lies above the threshold required to improve symptoms (on threshold)
and below the threshold for peak-dose dyskinesia (dyskinesia threshold). The
therapeutic window narrows over time because of a progressive decrease in
the threshold for peak-dose dyskinesia.
Although many patients prefer mild dyskinesia to off time, the clinician should
recognize that dyskinesias can be sufficiently severe to be troublesome to the
patient, either by interfering with activities or because of discomfort. Asking
patients how they feel during both off time and time with dyskinesia is
important in titrating medication optimally. Having patients fill out a diary may
be helpful; the diary should be divided into half-hour time periods on which the
patient denotes whether they are off; on without dyskinesia; on with non-
troublesome dyskinesia; or on with troublesome dyskinesia (see the following
image). The goal of medical management is to minimize off time and time on
with troublesome dyskinesia. Stated another way, the goal is to maximize on
time without troublesome dyskinesia.
Parkinson disease diary. The

patient or caregiver should place 1 check mark in each half-hour time slot to
indicate the patient's predominant response during most of that period. The
goal of therapeutic management is to minimize off time and on time with
troublesome dyskinesia. Copyright Robert Hauser, 1996. Used with
permission.
View Media Gallery
Treatment of motor fluctuations with dyskinesia
The treatment of patients with both motor fluctuations and troublesome peak-
dose dyskinesia can be difficult. The goal of treatment in this situation is to
provide as much functional time throughout the day as possible. This is
accomplished by maximizing on time without troublesome dyskinesia. An
attempt is made to reduce both off time and time with troublesome or
disabling dyskinesia. Unfortunately, a decrease in dopaminergic therapy may
increase off time, and an increase in dopaminergic therapy may worsen peak-
dose dyskinesia.
For patients on the levodopa/carbidopa CR formulation, switching to
levodopa/carbidopa IR often provides a more consistent and predictable
dosing cycle and allows finer titration. In general, smaller levodopa doses are
administered more frequently. A dose should be sought that is sufficient to
provide benefit without causing troublesome dyskinesia. The time to wearing-
off then determines the appropriate interdose interval. The extreme of this
strategy is using liquid levodopa, a solution with which the dose can be titrated
finely and administered every hour.
COMT inhibitors inhibit the peripheral metabolism of levodopa to 3-O -
methyldopa (3-OMD), thereby prolonging the levodopa half-life and making
more levodopa available for transport across the blood-brain barrier over a
longer period. Because of the potential risk of hepatotoxicity with tolcapone
(Tasmar), liver function test monitoring is required, and this medication should
be used only in patients who are experiencing motor fluctuations on levodopa
that cannot be adequately controlled with other medications. If dyskinesia
occurs, the levodopa dose should be reduced. In patients who already have
dyskinesia, the levodopa dose often is reduced by 30-50% at the time
tolcapone is introduced.
Entacapone (Comtan) is a COMT inhibitor that does not cause hepatotoxicity;
liver function tests are not required with this medication.
Levodopa/carbidopa/entacapone (Stalevo) is currently available as a drug
combination for Parkinson disease.
Similarly, dopamine agonists can be added to levodopa to try to smooth the
response. If the patient has both fluctuations and dyskinesias on levodopa,
adding a dopamine agonist is likely to decrease the disease severity and
could delay dyskinesias and motor fluctuations; then, an attempt can be made
to lower the levodopa dose.
The FDA approved amantadine (Gocovri) extended-release (ER) capsules for
the treatment of dyskinesia in Parkinson disease patients receiving levodopa-
based therapy, with or without concomitant dopaminergic medications.
Amantadine ER, previously known as ADS-5102, is the first drug FDA-
approved for this indication.
The safety and efficacy of amantadine ER was seen in two Phase 3 controlled
trials in Parkinson disease patients with dyskinesia. In the Easy LID trial,
amantadine ER-treated patients had statistically significant and clinically
relevant reductions in dyskinesia as per the Unified Dyskinesia Rating Scale
(UDysRS) total score vs. placebo at Week 12 (37% vs. 12%). In the Easy LID
2 trial, amantadine ER-treated patients had a 46% reduction in UDysRS
compared with 16% in the placebo arm. For both studies, treatment with
amantadine ER increased functional time daily (ON time without troublesome
dyskinesia) for patients at Week 12 (3.6 hours and 4.0 hours, respectively) vs.
placebo (0.8 hour and 2.1 hours, respectively). [63, 64]
This should be considered for patients who have clinically relevant dyskinesia
and who appear likely to be able to tolerate this medication. Results from the
3-month, parallel-group, washout AMANDYSK (AMANtadine for DYSKinesia)
study showed that amantadine treatment maintained its antidyskinetic effect
over several years in patients with Parkinson disease and levodopa-induced
dyskinesia. [65, 66]
The principal side effects of amantadine are hallucinations and confusion, so
the drug is usually not appropriate for patients with preexisting cognitive
dysfunction.
For patients who have motor fluctuations and dyskinesia that cannot be
adequately managed with medication manipulation, surgery is considered.
Tremor
Levodopa/carbidopa, dopamine agonists, and anticholinergics each provide
good benefit for tremor in approximately 50-60% of patients. If a patient is
experiencing troublesome tremor and if symptoms are not controlled
adequately with one medication, another should be tried. If the tremor is not
controlled adequately with medication, surgical therapy may be considered at
any time during the disease.
Bradykinesia
A study published in Neurology found that laser shoes can improve freezing
episodes in patients with PD. The shoes are specially designed to emit a laser
beam on the ground ahead, providing a visual cue to the patient and a target
to aim for. In the study, the shoes cut freezing episodes and their overall
duration by 49.5% when patients were off medication and 37.7% when
patients were on medication. [67]
Putative Neuroprotective Therapy
Neuroprotective therapies are defined as those that slow underlying loss of
neurons. Currently, no proven neuroprotective therapies exist for Parkinson
disease. If a neuroprotective therapy were available for Parkinson disease, it
would be administered from the time of diagnosis onward. At the current time,
the greatest interest in possible neuroprotection resides with the monoamine
oxidase (MAO)-B inhibitors, selegiline, and rasagiline. Other agents of interest
include creatine and isradipine. Clinical trials have not provided support for
neuroprotective effects for vitamin E or coenzyme Q10.
Selegiline
Selegiline (Eldepryl, Zelapar) is an irreversible inhibitor of MAO-B. In humans,
brain dopamine is metabolized by MAO-B, and the blockade of this enzyme
will reduce the metabolism of dopamine. Selegiline was shown conclusively to
delay the need for levodopa therapy in early Parkinson disease, in the
DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism)
study. [68, 69] The Parkinson Study Group evaluated the ability of selegiline and
tocopherol to delay progression of clinical disability in early Parkinson disease
by randomizing 800 patients to receive selegiline (10 mg/day) or placebo and
tocopherol (2000 IU/day) or placebo. Patients who received selegiline, with
placebo or with tocopherol, experienced a significant delay in the need for
levodopa therapy. Patients who received placebo required levodopa at a
projected median of 15 months from enrollment, whereas those who received
selegiline required levodopa
ataprojectedmedianof24monthsafterenrollment.Tocopherolhadnoeffectonprogr
ession of disability. [68, 69]
Because selegiline was observed to provide a small but statistically significant
symptomatic (early) benefit, it is not possible to determine whether a
neuroprotective effect contributed to the delay in need for levodopa in the
DATATOP study. [68, 69]
In another study, patients with early Parkinson disease who received
selegiline over a 7-year period experienced less clinical progression and
required less levodopa than patients receiving placebo. [70] In this study,
patients with early Parkinson disease were randomized to selegiline or
placebo, and levodopa was added as needed. After 5 years, patients who
were treated with placebo had Unified Parkinson Disease Rating Scale
(UPDRS) scores that were 35% higher (worse) than those treated with
selegiline, even as they were receiving 19% higher doses of levodopa. [70] This
is a striking finding, considering that as monotherapy in early disease,
selegiline provides only modest symptomatic improvement.
Selegiline is the medication that first garnered wide interest as a possible
neuroprotective agent for Parkinson disease. Laboratory investigations
continue to provide evidence that selegiline affords a neuroprotective effect for
dopamine neurons independent of MAO-B inhibition. Selegiline was reported
to protect dopamine cells in mice from MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine) toxicity, even when the agent was administered after a
delay sufficient to allow the oxidation of MPTP to MPP+ (1-methyl-4-
phenylpyridinium), [71] an effect that cannot be attributed to MAO-B inhibition.
In cell-culture systems, selegiline's neuroprotective effect is mediated by new
protein synthesis. Selegiline induces transcriptional events that result in
increased synthesis of antioxidant and antiapoptotic proteins. Evidence
indicates that one of selegiline's metabolites, desmethylselegiline, is the active
agent for neuroprotection. It is possible that selegiline's amphetamine
metabolites may interfere with its neuroprotective actions.
Rasagiline
Rasagiline (Azilect) is also an MAO-B inhibitor that exhibits neuroprotective
effects in cell culture and animal models. Possible disease-modifying effects
of rasagiline were studied in 2 large, delayed-start studies. In such studies,
subjects are randomized to treatment with active study medication or to
placebo followed by active study medication. This creates 2 phases within the
study. In phase I, one group is on placebo, and the other is on active study
medication; in phase II, both groups are receiving active study medication. If
phase II is long enough to allow full wash-in of symptomatic effects, any
differences between the groups at the end of the study should be due to
enduring benefits (ie, disease modification) that accrue only to the group that
received active study medication during phase I.
Stated another way, in a delayed-start design, half of the subjects in the study
take the trial drug from day 1 and the other half take placebo. However,
halfway through the study, the placebo group is switched from placebo to the
trial drug. If the drug is truly beneficial in slowing progression of the disease,
those that started the trial on placebo should never catch up, in terms of
disease progression, to those who were given the trial drug from the
beginning of the study.
ADAGIO and TEMPO studies
In October 2011, the US Food and Drug Administration’s (FDA’s) Peripheral
and Central Nervous System Drugs Advisory Committee voted against
approval of an indication for disease-modifying effects for rasagiline. The
advisory committee determined that the 2 delayed-start rasagiline studies did
not provide compelling evidence that rasagiline slows progression of
Parkinson disease. These trials were the ADAGIO (Attenuation of Disease
progression with Azilect Given Once-daily) [72, 73] and TEMPO (Rasagiline in
Early Monotherapy for Parkinson's Disease Outpatients) [74, 75] studies, which
are discussed below.
In the TEMPO study, patients were randomized to treatment with rasagiline 1
mg/day for 12 months; rasagiline 2 mg/day for 12 months; or placebo for 6
months, followed by rasagiline 2 mg/day for 6 months. [74] Rasagiline
administered at a dosage of 1 or 2 mg/day for the first 6 months resulted in
improved Unified Parkinson Disease Rating Scale (UPDRS) scores relative to
placebo; there was also a higher proportion of patients with treatment
responses in the active treatment groups than in the placebo group. [74] In
addition, both of the rasagiline groups showed significant differences,
compared with the placebo group, in the motor and activities of daily living
(ADL) subscales of the UPDRS and in the Parkinson Disease Quality of Life
(PDQUALIF) scale. [74]
Over the 12 months of the TEMPO study, patients who were initially treated
with placebo had a greater progression in clinical symptomatology as
assessed by UPDRS scores than did patients who were treated with
rasagiline for the full 12 months. This finding suggested that there was an
effect over and above a simple symptomatic effect and potentially consistent
with a disease-modifying effect. [76] When the TEMPO investigators looked at
the long-term (6.5-year follow-up period) outcome of early rasagiline therapy
relative to late therapy in early Parkinson disease, patients in the early
rasagiline treatment group—who received the drug from the beginning of the
TEMPO study—had significantly less worsening of their total UPDRS scores
than patients in the delayed-start group, even as investigators added other
antiparkinson medications as needed. [75]
In the large and rigorous delayed-start study called ADAGIO, patients with
early Parkinson disease were randomized to rasagiline 1 mg/day for 18
months; rasagiline 2 mg/day for 18 months; placebo for 9 months, followed by
rasagiline 1 mg/day for 9 months; or placebo for 9 months, followed by
rasagiline 2 mg/day for 9 months. Results demonstrated that rasagiline at 1 or
2 mg/day was associated with a slower rate of worsening in the active drug
groups, relative to the placebo groups. [73] Over 18 months, rasagiline 1
mg/day started early resulted in less worsening in mean total UPDRS score
than when it was started late. However, for the groups that received rasagiline
2 mg/day, there was no difference at 18 months between the early-start and
delayed-start groups. [73]
Based on their findings, the ADAGIO investigators concluded that early
treatment with rasagiline at a dose of 1 mg/day provided benefits that were
consistent with a possible disease-modifying effect, but early treatment with
rasagiline at a dose of 2 mg/day did not. [73] They speculated that the effect of
the 2-mg dose on symptoms may have masked any disease-modifying effects
in patients with mild Parkinson disease; they also noted that it was possible
that results with 1 mg/day were false positive, rather than the results with 2
mg/day being false negative. [73]
Thus, there remains interest as to whether selegiline and rasagiline improve
long-term outcome for Parkinson disease patients, but this is not definitively
proven, and the mechanism is unclear.
Levodopa
Clinical trial data suggest that levodopa therapy in early Parkinson disease
can potentially slow progression or has a prolonged effect on the symptoms of
the disease. [77] However, neuroimaging studies also indicate that loss of
nigrostriatal dopamine nerve terminals may be accelerated or the dopamine
terminals may be modified with use of levodopa. [77] In a study by Parkkinen et
al that evaluated whether chronic levodopa use accelerates pathologic
cerebral processes in parkinsonism, the investigators did not find such a
progression based on nigral neuronal count and Lewy body
pathology. [78] Nonetheless, the lowest dose that is necessary to maintain good
function should be used to avoid motor complications. [23] Additional research
is needed to determine whether levodopa accelerates, slows, or has no effect
on disease progression.
Dopamine agonists
Dopamine agonists have been used to provide symptomatic relief in early
Parkinson disease. In vivo experiments have demonstrated that the ergot and
nonergot dopamine agonists protect cultured cells from death due to oxidative
damage. Clinical data in patients with early Parkinson disease provide
neuroimaging results that suggest a possible neuroprotective
effect. [77, 79] Various studies have been conducted with ropinirole and
pramipexole; however, definitive neuroprotection cannot be confirmed on the
basis of these studies. [80, 81]
Deep Brain Stimulation
Deep brain stimulation (DBS) has become the surgical procedure of choice for
Parkinson disease for the following reasons:
 It does not involve destruction of brain tissue
 It is reversible
 It can be adjusted as the disease progresses or adverse events occur
 Bilateral procedures can be performed without a significant increase in
adverse events
Deep brain stimulation, a form of stereotactic surgery, has made a resurgence
in the treatment of Parkinson disease largely because long-term complications
of levodopa therapy result in significant disability over time. A better
understanding of basal ganglia physiology and circuitry and improvements in
surgical techniques, neuroimaging, and electrophysiologic recording have
allowed surgical procedures to be performed more accurately and with lower
morbidity.
Surgery for movement disorders previously involved predominantly
destructive lesioning of abnormally hyperactive deep brain nuclei; however,
the observation that high-frequency electrostimulation in the ventral lateral
nucleus (VL) of the thalamus eliminates tremors in patients undergoing
thalamotomy led to investigation of long-term DBS as a reversible alternative
to lesioning procedures.
Continued refinement of the knowledge of basal ganglia circuitry and
Parkinson disease pathophysiology has narrowed the focus of movement
disorder surgery to 3 key gray-matter structures: the thalamus, the globus
pallidus, and the subthalamic nucleus (STN). Currently, the STN is the most
commonly targeted site for Parkinson disease. (See the following image.)
Sagittal section, 12 mm lateral
of the midline, demonstrating the subthalamic nucleus (STN) (lavender). The
STN is one of the preferred surgical targets for deep brain stimulation to treat
symptoms of advanced Parkinson disease.
View Media Gallery
DBS surgery includes subthalamic nucleus (STN) stimulation, globus pallidus
interna (GPi) stimulation, and thalamic deep brain stimulation (see the
following images). The UK National Collaborating Centre for Chronic
Conditions notes the following indications for STN and GPi in patients with
Parkinson disease [23] :
 The presence of motor complications refractory to medical therapy
 The absence of significant comorbidities in a biologically fit individual
 The absence of significant mental health problems (eg, depression,
dementia)
 Response to levodopa
A key to patient selection is that appropriate patients still experience a good
response to levodopa, but that response cannot be adequately maintained
through the day or is complicated by excessive dyskinesia.
The deep brain stimulating
lead is equipped with 4 electrode contacts, each of which may be used, alone
or in combination, for therapeutic stimulation.
View Media Gallery
Implantation of the deep brain

stimulation (DBS) lead.
View Media Gallery
Insertion of an electrode during deep brain
stimulation for Parkinson disease.
View Media Gallery
Thalamic DBS has been used in patients with predominantly severe and
disabling tremor. [23] However, this surgery is now rarely used in patients with
Parkinson disease, because it has been shown that other symptoms continue
to progress, causing significant disability that is not controlled by thalamic
DBS.
Recent landmark studies have demonstrated the effectiveness of STN and
GPi DBS for appropriate Parkinson disease patients. [82] In a randomized,
controlled trial of 255 patients enrolled in the Veterans Affairs (VA)
Cooperative Studies Program (CSP) trial for patients with advanced Parkinson
disease, bilateral DBS (STN and GPi) was more effective than best medical
therapy in improving on time without troublesome dyskinesia, motor function,
and quality of life at 6 months; however, DBS was associated with an
increased risk of serious adverse events. [83] In the same study, when the 2-
year outcomes of 147 patients who received STN DBS and 152 patients who
received GPi DBS were compared, motor function and adverse events were
not significantly different between the 2 sites. [84] However, those who received
STN DBS had a greater reduction in dopaminergic medications, and
individuals who received GPi DBS had significantly less depression. [84]
Investigators from the EARLYSTIM Study Group reported that relative to
medical therapy alone, STN DBS in conjunction with medical therapy offers
benefits earlier in the course of PD, before the appearance of severe disabling
motor complications. [85, 86] Moreover, subthalamic stimulation plus medical
therapy was superior to medical therapy alone on several key measures of
quality of life and motor function. However, 54.8% of the patients in the DBS
group suffered serious adverse events, compared to 44.1% of those in the
medical-therapy group [85, 86] ; 17.7% of patients suffered serious adverse
events related to surgical implantation or the neurostimulation device.
A study by Foltynie assessed 79 consecutive patients who underwent bilateral
subthalamic nucleus DBS at the National Hospital for Neurology and
Neurosurgery using an MRI-guided surgical technique without microelectrode
recording. [87] At a median follow-up period of 12-14 months, a mean
improvement of 27.7 points (standard deviation, 13.8) was noted in the off-
medication motor part of the Unified Parkinson Disease Rating Scale (UPDRS
III), equivalent to a mean improvement of 52%. Significant improvements in
dyskinesia duration, disability, and pain were noted. This suggests that in well-
selected patients with Parkinson disease, image-guided STN DBS without
microelectrode recording can lead to substantial improvements in motor
disability and improvements in quality of life, with very low morbidity.
A randomized trial by Moreau et al assessed the effectiveness of the drug
methylphenidate in improving gait disorders and freezing of gait in patients
with advanced Parkinson disease without dementia who also received
subthalamic nucleus stimulation (STN). Eighty-one patients from 13
movement disorders departments in France were randomly assigned to
methylphenidate or placebo for 90 days. Compared with patients in the
placebo group, patients in the methylphenidate group used fewer steps at 90
days. These results suggest methylphenidate may improve gait hypokinesia
and freezing although further study is needed to determine long-term risks. [88]
There is evidence that long-term motor improvement from STN DBS is
sustained overall. However, axial signs progressively decline over time and
contribute to a waning of the initial benefit of this procedure. [89]
Although not specifically approved by the Food and Drug Administration
(FDA) for pain, STN DBS may be effective in improving specific types of pain
related to Parkinson disease, [90, 91] such as musculoskeletal pain [90, 92] and
dystonic pain. However, there is a risk of postoperative deterioration of
somatic pain exacerbated by Parkinson disease and radicular/peripheral
neuropathic pain due to lumbar spine diseases. Patients with central pain
have had a poor response to STN DBS. [90]
STN DBS may result in either a favorable or an unfavorable outcome in
patients with Parkinson disease and impulse control and related
disorders. [93] Although there may be resolution or improvement of impulse
control disorders following STN DBS, the procedure may also induce,
exacerbate, reveal, or have no effect on these conditions. [93]
In 2017, the FDA approved the Vercise DBS system to treat symptoms of
Parkinson disease. The device is a rechargeable implantable pulse generator
with a potential battery life of 15 years. It has been available in Europe since
2012. [94]
(See Deep Brain Stimulation forParkinson Disease for a more extensive
discussion of deep brain stimulation in this setting, including mechanisms of
action, advantages and disadvantages, and stages of the procedure.)
Neuroablative Lesion Surgeries
Lesion surgeries involve the destruction of targeted areas of the brain to
control the symptoms of Parkinson disease. Lesion surgeries for Parkinson
disease have largely been replaced by deep brain stimulation (DBS). During
neuroablation, a specific deep brain target is destroyed by thermocoagulation.
A radiofrequency generator is used most commonly to heat the lesioning
electrode tip to the prescribed temperature in a controlled fashion.
Thalamotomy and pallidotomy
Thalamotomy involves destruction of a part of the thalamus, generally the
ventralis intermedius (VIM), to relieve tremor. The VIM nucleus is considered
the best target for tremor suppression, with excellent short- and long-term
tremor suppression in 80-90% of patients with Parkinson disease.
Thalamotomy has little effect on bradykinesia, rigidity, motor fluctuations, or
dyskinesia. When rigidity and akinesia are prominent, other targets, including
the globus pallidus interna (GPi) and subthalamic nucleus (STN), are
preferred.
Svenillson and Leksell described ventral posterior pallidotomy in the
1960s [95] ; however, their report was largely overlooked. The original
pallidotomy target was in the medial and anterodorsal part of the nucleus. This
so-called medial pallidotomy effectively relieved rigidity but inconsistently
improved tremor. Leksell subsequently moved the target to the posteroventral
and lateral GPi, resulting in sustained improvement in as many as 96% of
patients. In 1992, Laitinen et al reported reduced tremor, rigidity, akinesia, and
levodopa-induced dyskinesia in 38 patients treated with pallidotomy,
prompting a reappraisal of the procedure performed with more modern
techniques. [96]
Pallidotomy involves destruction of a part of the GPi. Pallidotomy studies have
demonstrated significant improvements in each of the cardinal symptoms of
Parkinson disease (tremor, rigidity, bradykinesia), as well as a significant
reduction in dyskinesia.
The most serious and frequent (3.6%) adverse effect of pallidotomy is a
scotoma in the contralateral lower-central visual field. This complication
occurs when the GPi lesion extends into the optic tract, which lies immediately
below the GPi. The risk of visual-field deficit is reduced greatly by accurate
delineation of the ventral GPi border by microelectrode recording. Less
frequent complications (< 5%) include injury to the internal capsule, facial
paresis, and intracerebral hemorrhage (1-2%). Abnormalities of speech,
swallowing, and cognition may also be observed.
Bilateral pallidotomy is not recommended because complications are relatively
common and include speech difficulties, dysphagia, and cognitive impairment.
Subthalamotomy
Hyperactivity of the excitatory STN projections to the GPi is a crucial
physiologic feature of Parkinson disease. Subthalamotomy involves
destruction of a part of the STN. Although lesioning the STN usually has been
avoided because of the concern about producing hemiballismus, results
obtained by experimental lesions of the STN in animals and humans suggest
that subthalamotomy may be performed safely and may reverse parkinsonism
dramatically. Subthalamotomy studies have shown significant improvements
in the cardinal features of Parkinson disease, as well as the reduction of motor
fluctuations and dyskinesia.
Preoperative Evaluation
Good surgical outcomes begin with careful patient selection and end with
attentive, detail-oriented postoperative care. The authors believe that this level
of care is best provided by a multidisciplinary team that includes a movement
disorder neurologist, a neurosurgeon who is well-versed in stereotactic
technique, a neurophysiologist, a psychiatrist, and a neuropsychologist.
Additional support from neuroradiology and rehabilitation medicine is
essential.
First, a neurologist with expertise in movement disorders evaluates the
patient. Patient selection is particularly important for successful subthalamic
nucleus (STN) deep brain stimulation (DBS), because a number of factors
determine positive surgical outcome. [97, 98] These can be summarized as
follows:
 A diagnosis of Parkinson disease
 Positive response to levodopa
 Absence of atypical parkinsonian features
 Advanced disease, virtually unmanageable with dopaminergic
medications
 Relatively young age; however, advanced age (>75 years) is not an
absolute contraindication to surgery (if a patient otherwise meets the
selection criteria for a procedure and the quality of life is predicted to
improve substantially, surgery should be offered)
 No significant cognitive impairment
 Absence of active psychiatric disease
 Good social support and access to programming
Potential surgical candidates are then evaluated by the neurosurgeon, who
determines whether the patient is indeed a surgical candidate and decides
which procedure(s) would benefit the patient most. Close collaboration
between the neurologist and the neurosurgeon aids the decision-making
process, minimizing patient confusion and stress. If the neurologist and
neurosurgeon agree that the patient is a good surgical candidate, further
workup includes the following:
 Brain magnetic resonance imaging (MRI) to rule out comorbid conditions
and to assess the degree of brain atrophy; significant atrophy may
increase the risk of perioperative hemorrhage
 Detailed neuropsychological testing to rule out cognitive impairment,
which can be worsened by the surgical procedure
A psychiatrist with expertise in psychiatric complications of movement
disorders may be consulted to rule out active psychiatric disease and screen
for relevant past psychiatric history that may pose a contraindication to
surgery (eg, major depression, suicidality).
A fluorodopa positron emission tomography (PET) scan may be performed in
the unusual circumstance of diagnostic uncertainty. A medical evaluation is
performed to determine the patient's general fitness for surgery.
Surgery is reserved for patients with disabling motor fluctuations and
dyskinesia or disabling tremor that cannot be adequately controlled with
medications. Key points to consider are as follows:
 Ablative surgery such as thalamotomy, pallidotomy, and subthalamotomy
have largely been replaced by DBS
 Thalamic DBS is offered to the minority of patients with Parkinson
disease who have predominant and disabling tremor (more commonly,
this procedure is performed on patients with disabling essential tremor)
 Bilateral STN DBS (or globus pallidus interna [GPi] DBS) is offered to
patients with advanced Parkinson disease with disabling motor
fluctuations and/or dyskinesia or disabling tremor that cannot be
adequately controlled by medications; outcomes have been shown to be
similar after STN and GPi DBS
 Before surgery, the patient should be informed that these procedures do
not cure Parkinson disease and that progression is expected
Neural Transplantation
Neural transplantation is a potential treatment for Parkinson disease, because
the most significant neuronal degeneration is site and type specific (ie,
dopaminergic); the target area is well defined (ie, striatum); postsynaptic
receptors are relatively intact; and the neurons provide tonic stimulation of the
receptors and appear to serve a modulatory function.
Transplantation of autologous adrenal medullary cells and fetal porcine cells
has not been found to be effective in double-blind studies and has been
abandoned. Although open-label studies of fetal dopaminergic cell
transplantation yielded promising results, 3 randomized, double-blind, sham-
surgery–controlled studies found no net benefit. In addition, some patients
receiving these transplants developed a potentially disabling form of
dyskinesia that persisted even after withdrawal of levodopa. Features such as
gait dysfunction, freezing, falling, and dementia are likely due to
nondopaminergic pathology and hence are unlikely to respond to
dopaminergic grafts. [99]
Lewy body–like inclusions have been found in grafted nigral neurons in long-
term transplant recipients; these inclusions stained positively for alpha-
synuclein and ubiquitin and had reduced immunostaining for dopamine
transporter, suggesting that Parkinson disease may affect grafted cells. [14]
Human retinal pigment epithelial cells produce levodopa, and retinal pigment
epithelial cells in gelatin microcarriers have been implanted into the putamen
in preliminary studies. A phase II double-blind, randomized, multicenter,
sham-surgery–controlled study of this technique has been
completed. [100, 101] Parkinson disease patients received no benefit from this
procedure compared to sham surgery. In addition, in one case study,
postmortem examination in a patient who died 6 months after surgical
implantation of 325,000 retinal pigment epithelial cells found only 118
surviving cells. [102]
Gene Therapy
Several studies have demonstrated the safety of gene therapy as a treatment
for Parkinson disease, and larger studies have been initiated to examine the
efficacy of this procedure. Three investigational strategies that use gene
transfer for targeted protein expression are as follows [103] :
 Improving dopamine availability to the striatum using more continuous
delivery,
 Reducing STN activity with local induction of gamma-aminobutryic acid
(GABA) expression
 Protection/restoration of nigrostriatal neuronal function with trophic factor
expression
A double-blind, phase II, randomized, controlled trial of gene delivery of the
trophic factor neurturin via an adeno-associated type-2 vector (AAV2) in
Parkinson patients aged 30-75 years suggested mild efficacy. Further studies
are ongoing. [104]
Management of Psychiatric Comorbidities
Dementia
Although no specific therapy exists for dementia, the American Academy of
Neurology evaluated the evidence regarding the use of cholinesterase
inhibitors in Parkinson disease dementia. [105] Based on their review, they
suggested that rivastigmine (Exelon) and donepezil (Aricept) are probably
effective in treating Parkinson disease dementia. Anticholinergic drugs used
for the treatment of motor symptoms of Parkinson disease may exacerbate
memory impairment. When possible, avoid these medications.
Depression
Depression is one of the most common nonmotor symptoms of Parkinson
disease, occurring in approximately 35% of patients. [106, 107] This condition is
more common in patients with Parkinson disease than in the general elderly
population and in those with chronic conditions such as osteoarthritis.
Depression in Parkinson disease has a profound impact on quality of life and
is associated with reduced function, cognitive impairment, and increased
caregiver stress.
A systematic review of prevalence studies of depression in Parkinson disease
found that 17% of patients present with major depression, 22% with minor
depression, and 13% with dysthymia [108] Moreover, multiple studies have
found that a history of depression is a risk factor for the subsequent
development of Parkinson disease. [109]
Imaging, cerebrospinal fluid, and autopsy studies indicate that depression in
Parkinson disease is associated with dysfunction of basal ganglia
dopaminergic circuits that project to the frontal lobes, as well as noradrenergic
limbic and brainstem structures. [107] Whether serotonin (5-HT) dysfunction
plays a role in depression in PD is unclear.
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used
medications to treat depression in Parkinson disease in clinical practice.
However, several randomized controlled trials, systematic reviews, and meta-
analyses have suggested that SSRIs may be no more effective than placebo
in this situation. [47, 107, 110]
Positive results in randomized clinical trials have been demonstrated for
nortriptyline (a tricyclic antidepressant [TCA] with serotoninergic and
adrenergic activity), desipramine (a predominantly noradrenergic reuptake
inhibitor TCA), venlafaxine (a serotonin-noradrenaline uptake inhibitor),
citalopram (an SSRI), and paroxetine (an SSRI). [107] For example, in
Parkinson disease patients that were diagnosed with depressive disorder or
operationally-defined subsyndromal depression, venlafaxine extended release
or paroxetine significantly reduced scores on the Hamilton Rating Scale for
Depression compared to placebo. Both venlafaxine and paroxetine were well
tolerated and did not worsen motor function. [111]
There is a suggestion that noradrenergic or dual action
(noradrenergic/serotoninergic) antidepressants may be more effective for
treating depression in Parkinson disease than SSRIs. However, whether this
is an artifact of clinical-trials methodology is not yet clear, and more research
is necessary.
Antiparkinsonian medications can also exert an antidepressant effect. In a
large, randomized trial, pramipexole (mean daily dose, 2.18 mg) significantly
reduced depression scores relative to placebo. [112] The monoamine oxidase
(MAO)-B inhibitor selegiline was also demonstrated to provide an
antidepressant effect in patients with early Parkinson disease who were not
clinically depressed. [113]
Preliminary studies suggest that repetitive transcranial magnetic stimulation
(rTMS) may be effective for depression in Parkinson disease, but more
research is required. Electroconvulsive therapy (ECT) can be considered for
refractory moderate to severe depression.
Psychotic symptoms (hallucinations or delusions)
Antiparkinsonian drugs can trigger psychosis in patients with Parkinson
disease. In Parkinson disease patients with psychosis, antiparkinsonian
medications other than levodopa should be withdrawn in an effort to resolve
psychosis while maintaining motor control with levodopa. In individuals with
only mild hallucinations that are well tolerated, active antipsychotic treatment
may not be necessary.
Pimavanserin (Nuplazid) was approved in April 2016 for treatment of
hallucinations and delusions associated with Parkinson disease psychosis. It
is the first drug to be approved for this condition. It is a selective serotonin
inverse agonists (SSIA). It not only preferentially targets 5-HT2A receptors,
but also avoids activity at dopamine and other receptors commonly targeted
by antipsychotics. Efficacy was shown in a 6-week clinical trial (n=199), where
it was shown to be superior to placebo in decreasing the frequency and/or
severity of hallucinations and delusions without worsening the primary motor
Parkinson disease symptoms (p=0.001). [114]
Use of some other typical antipsychotics can exacerbate motor symptoms of
Parkinson disease and should be avoided. [23]
Quetiapine is the atypical neuroleptic agent most commonly used by
movement-disorder experts, because it rarely exacerbates motor symptoms
and blood monitoring is not required. However, its efficacy has not been
confirmed in clinical trials. Quetiapine is used in Parkinson disease at doses
much lower than those used in schizophrenia. It is usually introduced at a
dose of 25 mg at bedtime and can be increased to 50 mg or more at bedtime
as necessary.
Clozapine can also be used, but blood monitoring is required due to its
potential for agranulocytosis and other severe side effects. [23, 115] For this
reason, clozapine is usually reserved for patients who are not adequately
controlled with quetiapine. Other atypical neuroleptics generally have more
potential to worsen Parkinson disease motor symptoms than quetiapine and
clozapine.
Anxiety
The 2010 American Academy of Neurology (AAN) practice parameter on the
treatment of nonmotor symptoms in Parkinson disease found insufficient
evidence to support or refute the treatment of anxiety in Parkinson disease
with levodopa. [48] However, SSRIs and venlafaxine (Effexor, Effexor XR) may
be beneficial. Buspirone is well tolerated but has not been studied in this
population. Benzodiazepines can be considered, but adverse effects such as
cognitive impairment, somnolence, and balance problems may be concerning.
Behavior modification techniques can play an important role in the treatment
of anxiety. [116]
Impulse behaviors
Cognitive-behavioral therapy (CBT) can help control impulse behaviors in PD.
In a study of 45 patients with idiopathic PD and associated impulse control
behaviors that had not responded to standard treatment, CBT significantly
improved symptom severity, neuropsychiatric disturbances, and depression
and anxiety levels. Of the 45 patients, 17 were randomly assigned to a 6-
month wait list for CBT along with standard medical care and 28 were
randomized to CBT starting immediately. Among the 28 patients in the
treatment group, 58% completed all 12 sessions of CBT and 88% completed
at least 6. Three-quarters of those receiving the treatment had improved
symptom severity compared with only about a third of those who did not
receive the therapy. [117, 118]
In a placebo-controlled pilot study of 50 patients with idiopathic PD who
developed impulse control disorder (ICD) symptoms while receiving dopamine
agonist treatment, Papay and colleagues found that the opioid antagonist
naltrexone improved ICD symptoms, as measured on a PD-specific rating
scale. [119, 120]
Naltrexone was administered at 50 mg daily for 4 weeks and then increased
to 100 mg daily for 4 weeks in nonresponders. The difference in response rate
on the Clinical Global Impression-Change (CGI-C) scale between the
naltrexone (54.5%) and placebo (34.8%) groups was not significant (P =
0.23). Estimated changes on the patient-completed Questionnaire for
Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-
RS) from baseline to week 8, however, significantly favored naltrexone: a
change of 14.9 points for naltrexone vs 7.5 points for placebo (P = 0.04).
Nausea and headache were the most common side effects of naltrexone
treatment. [119, 120]
Sleep disturbances
Benzodiazepines can be helpful in the treatment of rapid eye movement
(REM) sleep behavior disorder (RBD), and obstructive sleep apnea (OSA) can
be treated with positive airway pressure with either continuous pressure or
bilevel pressure. Sleep hygiene techniques include avoiding stimulants/fluids
near bedtime, avoiding heavy late-night meals, and following a regular sleep
schedule. [116, 121] It is advised that patients with Parkinson disease and
sudden-onset sleep avoid driving and take precautions against potential
occupational hazards. [23]
The 2010 AAN practice parameter found insufficient evidence to support or
refute beneficial effects from the treatment of RBD in Parkinson disease.
Other sleep disorders may benefit from treatment. Levodopa/carbidopa should
be considered to treat periodic limb movements of sleep. Modafinil may
improve patients’ subjective perceptions of excessive daytime somnolence
(EDS), and methylphenidate may be considered in patients with fatigue. [48]
Exercise and Physical Therapy
Exercise therapy in patients with Parkinson disease using a variety of
physiotherapy interventions may play a role in improving gait, balance and
flexibility, aerobic capacity, initiation of movement, and functional
independence. Studies generally have suggested improvement in functional
outcomes, but the observed benefits were small in magnitude and were not
sustained following discontinuation of the exercise. [81]
A systematic review of 33 randomized trials involving 1518 patients evaluated
various physiotherapy interventions, including general physiotherapy,
exercise, treadmill training, cueing, dance and martial arts. There were
significant improvements for walking speed, walking endurance and step
length, mobility (the Timed Up & Go test), and balance. Unified Parkinson’s
Disease Rating Scale (UPDRS) scores were also improved with
physiotherapy. There was no benefit observed for falls or patient-rated quality
of life, and there was no evidence that one type of physiotherapy was superior
to others. [122]
There has been a resurgence of interest in the potential benefit of exercise in
Parkinson disease, including a possible neuroprotective effect. [123] Vigorous
exercise in mid-life is associated with a reduced risk of subsequent Parkinson
disease. In animal models, vigorous exercise provides a protective effect
against a variety of toxins that cause parkinsonism. In addition, in healthy
people, serum brain-derived neurotrophic factor (BDNF) increases after
exercise, in proportion to the intensity of the activity. In Parkinson disease,
BDNF levels in the substantia nigra are reduced, and in animal models of
Parkinson disease, BDNF provides a neuroprotective effect. This is an area of
active research.
Speech Therapy
The laryngeal manifestations of Parkinson disease often lead to decreased
participation in the activities of daily living because of an inability to
communicate effectively. During the course of the disease, 45-89% of patients
report speech problems, and more than 30% find speech problems to be the
most debilitating part of the disease.
Medications and surgery cannot effectively treat the laryngeal manifestations
of Parkinson disease. For this reason, speech therapy plays a key role in the
disease's vocal treatment regimen. Speech therapy is effective in treating the
laryngeal manifestations of Parkinson disease, but despite the significant
number of patients with vocal symptoms, only an estimated 3-4% of patients
with Parkinson disease undergo speech therapy.
The Lee Silverman Voice Treatment (LSVT) is a program designed to
increase vocal intensity in patients with Parkinson disease. The treatment
focuses on a simple set of tasks that are practiced intensively, 4 sessions per
week during a 4-week period, resulting in maximization of phonatory and
respiratory functions. The goal of LSVT is to improve vocal performance for 6-
24 months without interval intervention. LSVT focuses on maximizing vocal
effort ("think loud, think shout") and maximizing sensory perception of vocal
effort and loudness by therapists. Therapists who quantify results give
constant feedback to patients during sessions and encourage patients to self-
monitor and internally calibrate their loudness. After LSVT, patients with
Parkinson disease speak at a normal volume and with a healthy voice quality
despite the need to "think loud, think shout."
In studies with a 2-year follow-up, patients who received LSVT maintained or
improved vocal intensity compared with pretreatment levels. Glottal
incompetence and swallowing ability both improved after LSVT, without any
significant change in supraglottal hyperfunction. Preliminary positron emission
tomography (PET) scans after LSVT training in patients with Parkinson
disease show reduced activity in the globus pallidus, an effect similar to
pallidotomy. LSVT may also stimulate coordination of motor output beyond the
phonatory system in the form of increased orofacial expression.
Other therapies have been suggested for the treatment of the vocal symptoms
in Parkinson disease, but most data so far support LSVT as the most
promising therapy for Parkinson disease laryngeal symptoms. Alternative
methods of delivering therapy that do not involve 16 face-to-face sessions
with a therapist are currently being studied. These methods incorporate
webcam delivery of LSVT (eLOUD) and software programs that patients can
perform at home. These technologically enhanced methods, when used to
replace half of the face-to-face sessions, have documented outcomes that are
equivalent to classic LSVT. The hope is that such alternatives will be
implemented to allow a less transportation-intensive therapy course for the
patient and to allow follow-up review of the LSVT techniques as needed.
A systematic review of clinical trials of speech and language therapy in
Parkinson disease identified 3 randomized controlled trials that included 61
patients. The authors concluded that although improvements were noted, they
were not able to conclusively confirm or refute the benefit of speech and
language therapy in Parkinson disease due to the small number of patients in
these trials, methodologic limitations, and possible publication bias. [124]
Dietary Considerations
Proper nutritional support is essential for patients with Parkinson disease,
including adequate dietary fiber to prevent the common problem of
constipation. Patients recently diagnosed with Parkinson disease are often
confused regarding dietary protein, because they receive conflicting
information.
Levodopa is absorbed via a large neutral amino acid active carrier system and
therefore competes with dietary proteins for absorption; this effect is generally
relatively small and is not clinically important for most patients, especially
those with early or moderate disease. However, as the disease progresses
and patients become more and more sensitive to maintaining relatively narrow
therapeutic serum concentrations of levodopa, this effect can become
clinically relevant. These patients usually have significant motor fluctuations.
Some report that when they are "on" and they eat a meal including protein,
they turn "off." Others find that if they eat a protein meal, their next levodopa
dose does not kick in. These patients may benefit from a low protein or a
protein redistributed diet.
In a low-protein diet, the total daily protein intake is spread more or less
equally over the day. In a protein-redistributed diet, individuals only consume
food very low in protein during the day and then eat a high-protein meal in the
evening. Unfortunately, these diets are difficult to follow; dietary consultation
may be beneficial for patients in whom such diets are considered.
For patients with early and moderate Parkinson disease, the considerations
are quite different. As with patients with more advanced Parkinson disease,
patients with early and moderate Parkinson disease will get the most
complete and consistent absorption of levodopa by taking their levodopa
doses a half hour or more before meals or 1 hour or more after meals.
However, most patients with early or moderate disease will not notice a
difference in clinical benefit, whether they take their levodopa with meals or
apart from meals.
Even if there is some reduction in clinical benefit when levodopa is taken with
meals, this can be mitigated by increasing the levodopa dose, if necessary. In
patients with early disease, the primary concern regarding levodopa is
typically nausea, which is less likely to occur if they take their levodopa dose
at the completion of meals. Therefore, in early Parkinson disease, it is
common to instruct patients to take their levodopa after meals to reduce the
likelihood of nausea as the dose is titrated to clinical effect.
Some studies have shown mild motor benefit with Mucuna pruriens (cowhage,
velvet bean), which contain levodopa, and Vicia faba (broad or fava bean)
may have short-term benefits. [81] However, additional studies are needed.
Vitamin E and coenzyme Q10 have not been shown to have a neuroprotective
effect in Parkinson disease, [68, 125] and they are not currently recommended as
dietary supplements for this condition.
Consultations
Generally, patients with Parkinson disease are best treated and monitored by
a neurologist or movement disorder specialist. Depending on the patient,
consultations may include the following:
 Neurosurgeon
 Psychiatrist
 Urologist
 Physiatrist
 Nutritionist
 Otolaryngologist
 Gastroenterologist
 Speech therapist
Neurosurgical consultation may be appropriate in patients with tremor,
dyskinesias, motor fluctuations, or dystonia refractory to medical treatment.
However, patients with dementia or significant psychiatric or behavioral
problems are not candidates for current neurosurgical treatments for
Parkinson disease.
Psychiatric consultation may be required to control mood disorders and
psychiatric symptoms, especially in patients with refractory depression or
psychosis.
A urologist is consulted for evaluation and treatment of urinary frequency,
urgency, incontinence, or erectile dysfunction.
A physiatrist, physical therapist, or occupational therapist may be able to
improve the patient's ability to perform activities of daily living, reduce pain,
and avoid fractures and compression neuropathies from falls. Botulinum
injections for limb dystonia can be very helpful and are administered by
specially trained physiatrists or neurologists.
A nutritionist can help ensure adequate energy intake, particularly when low-
protein diets are needed to avoid adverse effects of levodopa.
An otolaryngologist can offer vocal fold bulking procedures in the form of vocal
fold injection or Gore-Tex thyroplasty as a possibility in treating refractory true
vocal fold bowing. Bilateral injections to medialize the vocal fold can offer
improvement, unless the patient is already aphonic due to advanced disease.
Bilateral collagen, gel, fat, and hydroxyapatite injections have been used for
this purpose. [126] Articulatory problems can persist, and the result of surgery
can be disappointing.
A gastroenterologist and a speech therapist may be needed to evaluate
dysphagia, a common complication in patients with more advanced Parkinson
disease. Excessive sialorrhea can be treated with botulinum toxin injections
into the salivary glands, usually administered by neurologists or
otolaryngologists. In some patients, a gastrostomy may be needed to maintain
adequate nutrition.
Long-Term Monitoring
Patients with Parkinson disease must have regular follow-up care to ensure
adequate treatment of motor and behavioral abnormalities. Once patients are
stable on a medication regimen, provide follow-up care at least every 3-6
months, and periodically adjust medication dosages as necessary. Patients
also need to be monitored for adverse events, including somnolence, sudden-
onset sleep, impulse control disorders, and psychosis. In addition, patients
should be evaluated and treated for emergence of clinically relevant nonmotor
symptoms, including dementia, psychosis, sleep disorders, and mood
disorders.
Future Treatments for Parkinson Disease
Future treatments for Parkinson disease are covered in Future Treatments for
Parkinson’s Disease: Surfing the PD Pipeline. This article provides a
discussion of new therapies in clinical development that may alleviate motor
features or slow disease progression, including A2a antagonists, levodopa
formulations, other antiparkinsonian medications, antidyskinesia medications,
and gene therapy. [127]
Guidelines Summary
American Academy of Neurology (AAN)
In 2010, the AAN released guidelines on the treatment of nonmotor symptoms
of Parkinson disease. Recommendations included the following [48] :
 Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction
 Polyethylene glycol may be considered to treat constipation
 Modafinil should be considered for patients who subjectively experience
excessive daytime somnolence
 For insomnia, evidence is insufficient to support or refute the use of
levodopa to improve objective sleep parameters that are not affected by
motor symptoms; evidence is also insufficient to support or refute the use
of melatonin for poor sleep quality
 Levodopa/carbidopa should be considered to treat periodic limb
movements of sleep in Parkinson disease, but there are insufficient data
to support or refute the use of nonergot dopamine agonists to treat this
condition or that of restless-legs syndrome
 Methylphenidate may be considered for fatigue (note: methylphenidate
has the potential for abuse and addiction)
 Evidence is insufficient to support or refute specific treatments of
orthostatic hypotension, urinary incontinence, anxiety, and RMD
Medication Summary
The cornerstone of symptomatic treatment for Parkinson disease (PD) is
dopamine replacement therapy. The criterion standard of symptomatic
therapy is levodopa (L-dopa), the metabolic precursor of dopamine, in
combination with carbidopa, a peripheral decarboxylase inhibitor (PDI). This
combination provides the greatest symptomatic benefit with the fewest short-
term adverse effects.
Dopamine agonists such as pramipexole and ropinirole can be used as
monotherapy to improve symptoms in early disease or as adjuncts to
levodopa in patients whose response to levodopa is deteriorating and in those
who are experiencing fluctuations in their response to levodopa.
Monoamine oxidase (MAO)-B inhibitors (eg, rasagiline, safinamide, selegiline)
provide symptomatic benefit as monotherapy in early disease and as adjuncts
to levodopa in patients experiencing motor fluctuations.
Catechol-O -methyl transferase (COMT) inhibitors inhibitors such as
entacapone and tolcapone may be used to increase the peripheral half-life of
levodopa, thereby delivering more levodopa to the brain over a longer time.
Anticholinergic medications can be used for the treatment of resting tremor.
However, they are not particularly effective for bradykinesia, rigidity, gait
disturbance, or other features of advanced Parkinson disease; and cognitive
side effects are common. Therefore anticholinergics are usually reserved for
the treatment of tremor that is not adequately controlled with dopaminergic
medications.
Pimavanserin is the first medication approved by the FDA for hallucinations
and delusions associated with PD. It is a selective serotonin inverse agonists
(SSIA) which preferentially targets 5-HT2A receptors and avoids activity at
dopamine and other receptors commonly targeted by antipsychotics.
Dopamine Agonists
Class Summary
Dopamine agonists are effective as monotherapy in early PD and as adjuncts
to levodopa/PDI (peripheral decarboxylase inhibitor) in moderate to advanced
disease. Dopamine agonists directly stimulate postsynaptic dopamine
receptors to provide antiparkinsonian benefit. All available dopamine agonists
stimulate D2 receptors, an action that is thought to be clinically beneficial. The
role of other dopamine receptors is currently unclear.
Dopamine agonists are effective to treat motor features of early PD, and they
cause less development of motor fluctuations and dyskinesia than levodopa.
For patients with motor fluctuations on levodopa/PDI, the addition of a
dopamine agonist reduces off time, improves motor function, and allows lower
levodopa doses.
Carbidopa/levodopa (Sinemet, Sinemet CR, Rytary,

Duopa)
 View full drug information
Carbidopa/levodopa is approved for the treatment of symptoms of idiopathic
PD, postencephalitic parkinsonism, and symptomatic parkinsonism that may
follow injury to the nervous system by carbon monoxide and/or manganese
intoxication. Levodopa, combined with a peripheral decarboxylase inhibitor
(PDI) such as carbidopa, is the criterion standard of symptomatic treatment for
PD; it provides the greatest antiparkinsonian efficacy in moderate to advanced
disease with the fewest acute adverse effects. When administered alone,
levodopa causes a high incidence of nausea and vomiting due to the
formation of dopamine in the peripheral circulation. Carbidopa inhibits the
decarboxylation of levodopa to dopamine in the peripheral circulation thereby
reducing nausea and allowing for greater levodopa distribution into the CNS.
Carbidopa does not cross the blood-brain barrier.
Sustained-release capsules (Rytary) may improve drug delivery for patients
unable to swallow effectively. The capsule may be either swallowed whole or
opened and sprinkled on a small amount of applesauce for immediate
consumption.
An enteral suspension (Duopa) is administered by a portable pump into the
jejunum over a 16-hr period to improve on-time and decrease off-time in
patients with motor fluctuations with advanced Parkinson disease.
Levodopa inhaled (Inbrija)
Powder for inhalation is systemically absorbed via lungs, and therefore
bypasses GI absorption, which may be variable in patients with PD.
Levodopa, the metabolic precursor of dopamine, crosses the blood-brain
barrier and is converted to dopamine in the brain. It is indicated for intermittent
treatment of "off" episodes in patients with Parkinson disease who are taking
oral carbidopa/levodopa.
Apomorphine (Apokyn)
Apomorphine is a nonergoline dopamine agonist indicated for the acute,
intermittent treatment of hypomobility "off" episodes ("end-of-dose wearing off"
and unpredictable "on/off" episodes) associated with advanced PD. It is
administered by a subcutaneous injection. Although the exact mechanism by
which apomorphine exerts its therapeutic effects in PD is unknown, it is
thought to occur via activation of postsynaptic D2 receptors in the striatum.
Pramipexole (Mirapex, Mirapex ER)

Pramipexole is approved as monotherapy in early disease and as adjunctive
therapy to levodopa/PDI in more advanced stages. The mechanism of action
of pramipexole as a treatment for PD is unknown, although it is believed to be
related to its ability to stimulate D2 dopamine receptors in the striatum. It is
available as an immediate-release and an extended-release tablet.
Ropinirole (Requip and Requip XL)

Ropinirole is approved as monotherapy in early disease and as adjunctive
therapy to levodopa/PDI in more advanced disease. Ropinirole is a nonergot
dopamine agonist that has high relative in vitro specificity and full intrinsic
activity at the D2 subfamily of dopamine receptors; it binds with higher affinity
to D3 than to D2 or D4 receptor subtypes. The mechanism of action of
ropinirole is stimulation of dopamine D2 receptors in striatum. It is available as
an immediate-release and an extended-release tablet.
Amantadine (Gocovri)
Amantadine is approved for the treatment of idiopathic PD, postencephalitic
parkinsonism, and symptomatic parkinsonism, which may follow injury to the
nervous system by carbon monoxide intoxication. The extended-release
capsule is indicated for dyskinesia in patients with PD. Amantadine is
available as a syrup, tablet, capsule, and an extended-release capsule. The
exact mechanism of amantadine for the treatment of PD and dyskinesia
associated with PD is unknown. Amantadine is a weak, noncompetitive N-
methyl-D-aspartate (NMDA) receptor antagonist.
Rotigotine (Neupro)
Dopamine agonist stimulating D3, D2, and D1 receptors. Improvement in
Parkinson-related symptoms thought to be its ability to stimulate D2 receptors
within the caudate putamen in the brain. Indicated for the treatment of the
signs and symptoms of idiopathic Parkinson disease (PD). Dosage ranges
differ for early-stage PD and advanced-stage PD. Available as transdermal
patch that provides continuous delivery for 24 h
Anticholinergic
Class Summary
Anticholinergics are commonly used as symptomatic treatment of PD, both as
monotherapy and as part of combination therapy. Anticholinergic agents
provide benefit for tremor in approximately 50% of patients but do not
substantially improve bradykinesia or rigidity. If one anticholinergic does not
work, try another.
Trihexyphenidyl
Trihexyphenidyl is indicated as an adjunct for all forms of parkinsonism
(postencephalitic, arteriosclerotic, and idiopathic). It is often useful as adjuvant
therapy when treating these forms of parkinsonism with levodopa.
It is a synthetic tertiary amine anticholinergic agent. It has a direct
antispasmodic action on smooth muscle and has weak mydriatic,
antisecretory, and positive chronotropic activities. In addition to suppressing
central cholinergic activity, trihexyphenidyl may also inhibit reuptake and
storage of dopamine at central dopamine receptors, thereby prolonging the
action of dopamine. It is commonly used in combination with other
antiparkinsonian agents. Generally, anticholinergic agents can help control
tremor but are less effective for treating bradykinesia or rigidity.
Benztropine mesylate (Cogentin)

Benztropine mesylate is approved for use as an adjunct in the therapy of all
forms of PD. It partially blocks striatal cholinergic receptors, and by blocking
muscarinic cholinergic receptors in the CNS, benztropine reduces the
excessive cholinergic activity present in parkinsonism and related states. It
can also block dopamine reuptake and storage in CNS cells. In general,
anticholinergic agents can help control tremor but are less effective for
treating bradykinesia or rigidity.
MAO-B inhibitors
Class Summary
MAO-B inhibitors inhibit the activity of MAO-B oxidases that are responsible
for inactivating dopamine.
Selegiline (Eldepryl, Zelapar)

Selegiline is approved as adjunctive therapy to levodopa/carbidopa in patients
who exhibit deterioration in response to that therapy. For patients who are
experiencing motor fluctuations on levodopa/carbidopa, the addition of
selegiline reduces off time, improves motor function, and allows levodopa
dose reductions. If a patient experiences an increase in troublesome
dyskinesia, reduce the levodopa dose. Selegiline blocks the breakdown of
dopamine and extends the duration of action of each dose of levodopa.
Rasagiline (Azilect)
Rasagiline is indicated for the treatment of the signs and symptoms of
idiopathic PD as initial monotherapy and as adjunctive therapy to levodopa.
Rasagiline is an irreversible MAO-B inhibitor that blocks dopamine
degradation. Rasagiline at a dosage of 1 mg once daily is given as
monotherapy. When it is given as adjunctive therapy, an initial dose of 0.5 mg
once daily is administered. Dosage adjustments are required if clinical
response is not seen.
Safinamide (Xadago)
Safinamide inhibits MAO-B activity, by blocking the catabolism of dopamine. It
is indicated as add-on treatment for patients with Parkinson disease who are
currently taking levodopa/carbidopa and experiencing “off” episodes.
Acetylcholinesterase Inhibitors, Central
Class Summary
Pathologic changes in dementia associated with PD involve cholinergic
neuronal pathways that project from the basal forebrain to the cerebral cortex
and hippocampus. These pathways may be involved in memory, attention,
learning, and other cognitive processes. Acetylcholinesterase inhibitors may
exert their therapeutic effect by enhancing cholinergic function through
inhibition of acetylcholinesterase.
Donepezil (Aricept)
Donepezil is a reversible inhibitor of ACh and exerts its beneficial effects by
enhancing cholinergic function. It is indicated for the treatment for dementia of
the Alzheimer type.
Rivastigmine (Exelon)
Rivastigmine is indicated for the treatment of mild to moderate dementia
associated with PD. In addition, it is also approved for the treatment of mild to
moderate dementia of the Alzheimer type.
Rivastigmine is a selective, competitive, and reversible acetylcholinesterase
(ACh) inhibitor. It may reversibly inhibit cholinesterase, which may, in turn,
increase concentrations of ACh available for synaptic transmission in CNS
and thereby enhance cholinergic function. The effect may lessen as the
disease process advances and fewer cholinergic neurons remain functionally
intact. It is available as a capsule and an extended-release transdermal.
Galantamine (Razadyne, Razadyne ER)

Galantamine is a competitive and reversible inhibitor of ACh. It is approved for
the treatment of mild to moderate dementia of the Alzheimer type.
NMDA Antagonists
Class Summary
Persistent activation of CNS N-methyl-D-aspartate (NMDA) receptors by the
excitatory amino acid glutamate has been hypothesized to contribute to the
symptomatology of dementia. Agents such as memantine, which is an NMDA
receptor antagonist, can prevent activation of the NMDA receptors.
Memantine (Namenda, Namenda XR)

Memantine is approved for the treatment of moderate to severe dementia in
Alzheimer disease. Initial dosage is 5 mg once daily for immediate-release
tablets and 7 mg once daily for extended-release tablets. Dosage titration may
be required based on clinical response.
Memantine is postulated to exert its therapeutic effect through its action as a
low- to moderate-affinity, uncompetitive NMDA receptor antagonist. Blockade
of NMDA receptors by memantine slows the intracellular calcium
accumulation and helps prevent further nerve damage.
COMT Inhibitors
Class Summary
Catechol-O -methyl transferase (COMT) inhibitors inhibit the peripheral
metabolism of levodopa, making more levodopa available for transport across
the blood-brain barrier over a longer time. For patients with motor fluctuations
on levodopa/carbidopa, the addition of a COMT inhibitor decreases off time,
improves motor function, and allows lower levodopa doses.
Tolcapone (Tasmar)
Tolcapone is an adjunct to levodopa/carbidopa therapy in PD in patients who
are experiencing motor fluctuations. Because of the risk of hepatotoxicity,
tolcapone is reserved for patients who have not responded adequately to, or
are not appropriate candidates for, other adjunctive medications. If
improvement is not apparent within 3 weeks, this medication should be
withdrawn.
Tolcapone is a selective and reversible inhibitor of COMT. In the presence of
a decarboxylase inhibitor such as carbidopa, COMT is the major degradation
pathway for levodopa. By inhibiting COMT, there are more sustained plasma
levels of levodopa, as well as enhanced central dopaminergic activity.
Entacapone (Comtan)
Entacapone is approved as an adjunct to levodopa/carbidopa for patients who
are experiencing signs and symptoms of end-of-dose "wearing-off." The
mechanism of action of entacapone is related to its ability to inhibit COMT and
alter plasma pharmacokinetics of levodopa. When given in conjunction with
levodopa and an aromatic amino acid decarboxylase inhibitor (eg, carbidopa),
plasma levels of levodopa are more sustained than after administration of
levodopa and an aromatic amino acid decarboxylase inhibitor alone. These
sustained plasma levels of levodopa may result in more constant
dopaminergic stimulation in the brain. This may lead to greater effects on
signs and symptoms of PD, as well as increased levodopa adverse effects
(which sometimes require a levodopa dose decrease).
Carbidopa, levodopa, and entacapone (Stalevo)

Carbidopa/levodopa/entacapone is indicated for the treatment of PD to
substitute (with equivalent strengths of each of the 3 components) for
immediate-release carbidopa/levodopa and entacapone previously
administered as individual products. It is also used to replace immediate-
release carbidopa/levodopa therapy (without entacapone) when patients
experience the signs and symptoms of end-of-dose "wearing-off" (only for
patients taking a total daily dose of levodopa of 600 mg or less and not
experiencing dyskinesias).
Carbidopa inhibits dopa decarboxylation, thereby allowing more complete
levodopa distribution to the CNS. Levodopa is a dopamine precursor capable
of crossing the blood-brain barrier, thereby increasing CNS dopamine
following conversion. Entacapone inhibits COMT, another enzyme that
metabolizes levodopa. COMT inhibition increases and sustains levodopa
plasma levels, enabling more blood-brain barrier penetration.
Selective Serotonin Inverse Agonists (SSIA)
Class Summary
SSIAs preferentially target 5-HT2A receptors, but does not affect activity of
dopamine and other receptors commonly targeted by antipsychotics.
Pimavanserin (Nuplazid)
Pimavanserin is an SSIA which preferentially targets 5-HT2A receptors and
avoids activity at dopamine and other receptors commonly targeted by
antipsychotics. It is indicated for hallucinations and delusions associated with
PD.
Adenosine Antagonists
Class Summary
Option for adjunctive use with levodopa/carbidopa to reduce Parkinson
disease OFF episodes.
Istradefylline (Nourianz)
Selective adenosine A2A receptor antagonist. Precise mechanism by which it
reduces OFF episodes is unknown. Istradefylline is indicated as adjunctive
treatment to levodopa/carbidopa in adults with PD experiencing OFF
episodes.
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Robert A Hauser, MD, MBA is a member of the following medical

Disclosure: Received consulting fee from Cerecor for consulting; Received

Kelly E Lyons, PhD is a member of the following medical societies: American

Disclosure: Received honoraria from Novartis for speaking and teaching;

Theresa A McClain, RN, MSN, ARNP-BC Advanced Registered Nurse

Theresa A McClain, RN, MSN, ARNP-BC is a member of the following medical

Rajesh Pahwa, MD Professor of Neurology, Director, Parkinson Disease and

Rajesh Pahwa, MD is a member of the following medical societies: American

Disclosure: Nothing to disclose.

Selim R Benbadis, MD is a member of the following medical societies: American

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant

Ron L Alterman, MD is a member of the following medical societies: Alpha

Disclosure: Nothing to disclose.

Heather S Anderson, MD is a member of the following medical

Disclosure: Nothing to disclose.

Jeff Blackmer, MD, FRCP(C) Associate Professor, Medical Director, Neurospinal

Jeff Blackmer, MD, FRCP(C) is a member of the following medical

Disclosure: Nothing to disclose.

Thomas L Carroll, MD Assistant Professor, Department of Otolaryngology-Head

Thomas L Carroll, MD is a member of the following medical societies: Alpha

Disclosure: Merz aesthetics inc. Consulting fee Speaking and teaching

Richard J Caselli, MD Professor, Department of Neurology, Mayo Medical

Richard J Caselli, MD is a member of the following medical societies: American

Disclosure: Nothing to disclose.

Arif I Dalvi, MD is a member of the following medical societies: European

Disclosure: Nothing to disclose.

Nestor Galvez-Jimenez, MD, MSc, MHA Chairman, Department of Neurology,

Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical

Disclosure: Nothing to disclose.

Stephen T Gancher, MD Adjunct Associate Professor, Department of Neurology,

Stephen T Gancher, MD is a member of the following medical

Disclosure: Nothing to disclose.

Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, FAHA Professor of Neurology,

Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, FAHA is a member of the

Disclosure: Nothing to disclose.

Daniel H Jacobs MD, FAAN, Associate Professor of Neurology, University of

Disclosure: Teva Pharmaceutical Grant/research funds Consulting; Biogen Idex

Robert M Kellman, MD Professor and Chair, Department of Otolaryngology and

Robert M Kellman, MD is a member of the following medical societies: American

Disclosure: GE Healthcare Honoraria Review panel membership; Revent Medical

Milton J Klein, DO, MBA is a member of the following medical

Disclosure: Nothing to disclose.

Kat Kolaski, MD Assistant Professor, Departments of Orthopedic Surgery and

Kat Kolaski, MD is a member of the following medical societies: American

Jose G Merino, MD Medical Director, Suburban Hospital Stroke Program

Jose G Merino, MD is a member of the following medical societies: American

Disclosure: Nothing to disclose.

Arlen D Meyers, MD, MBA Professor, Department of Otolaryngology-Head and

Arlen D Meyers, MD, MBA is a member of the following medical

Disclosure: Covidien Corp Consulting fee Consulting; US Tobacco Corporation

Lorraine Ramig, PhD Professor, Department of Speech Language Hearing

Disclosure: Nothing to disclose.

Alan D Schmetzer, MD Professor Emeritus, Interim Chairman, Vice-Chair for

Alan D Schmetzer, MD is a member of the following medical societies: American

Roy Sucholeiki, MD Director, Comprehensive Seizure and Epilepsy Program,

Roy Sucholeiki, MD is a member of the following medical societies: American

Disclosure: Nothing to disclose.

Margaret M Swanberg, DO Assistant Professor of Neurology, Uniformed

Margaret M Swanberg, DO is a member of the following medical

Disclosure: Nothing to disclose.

Michele Tagliati, MD Associate Professor, Department of Neurology, Mount Sinai

Michele Tagliati, MD is a member of the following medical societies: American