IAL Hemanta Kumar Kar

IAL TEXTBOOK OF
LEPROSY
Leprosy work is not merely medical relief; it is transforming frustration
of life into joy of dedication, personal ambition into selfless service.
Mahatma Gandhi
Mahatma Gandhi serving Pandit Parchure Shashtri (a renowned

scholar of Sanskrit) suffering from leprosy at Sevagram, Wardha in
1939. Shastri was disowned by his family after he contracted the
disease. Gandhi kept him at his ashram at Sevagram (against the
opposition from inmates), used to nurse his wounds personally and
massage his limbs. The same picture was used later in an India
postage stamp with words “Leprosy is Curable”. Photo courtesy: Kanu
Gandhi
IAL TEXTBOOK OF
LEPROSY
Editors
Hemanta Kumar Kar
Professor and Head
Department of Dermatology, STD and Leprosy
PGIMER, Dr Ram Manohar Lohia Hospital, New Delhi, India
Bhushan Kumar
Former Professor and Head
PGIMER (Chandigarh)
House No. 81, Sector-16/A
Chandigarh, India
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IAL Textbook of LEPROSY
© 2010, Jaypee Brothers Medical Publishers (P) Ltd.
All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means:
electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the editors and the publisher.
This book has been published in good faith that the material provided by contributors is original. Every effort is made to ensure accuracy
of material, but the publisher, printer and editors will not be held responsible for any inadvertent error (s). In case of any dispute, all legal
matters are to be settled under Delhi jurisdiction only.
First Edition: 2010
ISBN 978-81-8448-852-4
Typeset at JPBMP typesetting unit
Printed at Ajanta Offset

DEDICATION
This book is dedicated to all those who served the cause of leprosy in whatever capacity and
whatever form, to mitigate the sufferings of the unfortunate patients by giving them the most precious
gift of time. Looking back, the times were very difficult, experiences harrowing and there was
hardly any tool to fight this scourge. They were destined to suffer this in misery and isolation. The
only hope in their expectant eyes was the mere thought of arrival of these ‘angels’ who would
touch them, listen to their woes and tried to lift them from despair and fill the void in their hearts.
We dedicate this book to all those who fearlessly fought the disease and the stigma and have
made the world more livable with the eradication of the disease in sight.
May the flock of the devoted grow and so also the compassion for needs of the suffering humanity.
Foreword
It is indeed an honor and pleasure for me to write a foreword to this comprehensive textbook on leprosy brought out by
the Indian Association of Leprologists (IAL) at a time when there are apprehensions that the interest in leprosy as a
clinical and scientific challenge is diminishing.
Leprosy is an extremely fascinating subject whether from the point of view of basic sciences such as molecular
biology, clinical sciences such as nerve damage, public health sciences such as epidemiology, rehabilitation sciences
such as reconstructive surgery or social sciences such as stigmatization. The specializations in these areas have
continued to flourish over the years irrespective of the size of the problem getting reduced in numerical terms in
different parts of the world and in India.
The initiative taken by IAL to bring out this textbook is timely at a juncture when such updated scientific works are
not available for the purpose of training of leprosy scientists. In addition, I firmly believe that this work will be able to
serve as an important reference material to those whose interest in leprosy is confined to only certain areas.
A great deal of time and effort has gone into this book as one could see while going through it and compiling and
editing a multiauthor book with all the updated material, covering all aspects of leprosy is no mean task.
I sincerely hope that this important textbook reaches not only the members of IAL but also all the dermatologists,
libraries and postgraduate students with a strong interest in leprosy. The publication of this textbook by the sixty-year
old IAL is indeed a signal achievement made possible through the efforts of several interested persons lead by
Prof Hemanta Kumar Kar. My hearty congratulations to all the people involved in the publication of this textbook.
SK Noordeen
Former Chief Medical Officer
WHO Global Leprosy Program
South-East Asia Region
Preface
We must justify the addition of another book on leprosy when many good books are already available on the subject.
It is not that the Indian leprologists should also publish a book when everyone else has–because knowledge is
universal, to be shared and its spread a pious academic act.
However, in the last conference of the Indian Association of Leprologists (IAL) in September 2007 at Kanpur, it was
felt that because of various logistic and financial reasons coupled with the dwindling number of leprosy patients all over
the globe, revisions of the existing books on the subject were not forthcoming in the post-leprosy elimination era. It was
also felt that despite the reduced number of new leprosy patients being detected, changing classification systems,
modifications of traditional multidrug therapy schedules, changing profile of disease presentation, shortage of expertise
and shrinking of control program activities, the need was for more up-to-date knowledge and sharper skills to diagnose
the patients more confidently and to manage them better to reduce the incidence of complications and deformities; and
above all, to understand the patient with leprosy–better. More fundamental change is that management of leprosy now
has become an integral part of general health care. Therefore, all physicians and new medical graduates/postgraduates
are to be equipped as best as is possible with the basic but essential knowledge about the disease than ever before,
further justifying the need for a textbook to strengthen still more their basics in the field.
It was in their utmost wisdom that the members of the IAL expressed the need and the desire to have an updated
book on leprosy encompassing all aspects of the disease. We would remain eternally grateful to the IAL for choosing
us to take on this onerous task in the presence of so many stalwarts who had more experience collected over their life
time devoted to leprosy.
It was decided to be a multiauthor book because it is impossible for any single author to cover the entire gamut of
epidemiology, immunology, immunogenetics, pathology, clinical aspects, management (medical and surgical) and
finally the social, legal aspects and rehabilitation and then give you an insight into the brighter prospects beyond 2010
and future research. Moreover, it was felt that a collection from experts from all over the country will give the book a
pleasant hue and the most updated scientific content in their respective areas.
While going through the chapters from renowned leprologists, we did realize that there had been many important
and exciting newer advances in the field of diagnostics and therapy. With the rich contributions from the experts, the
book is hopefully the most up-to-date collection of the material available in the field which has recently been added to
the literature. The number of new drugs, treatment regimens, approaches to management and diagnostics have continued
to evolve and are being regularly added giving us more options. We are probably near the top or close to it, if the best
has still to come.
We would sincerely believe that the book helps to produce excellent clinicians, educators and researchers not
excluding the medical students who should have a better feel of the Indian scenario in relation to other leprosy affected
nations. The final decision about the product obviously has to come from the readers–happy reading.
However, we would frankly accept that this textbook is not perfect and in many places may not have the expected
details. Because of certain constraints, we could not do better than this–our sincere apologies especially to the
luminaries in the field who naturally expected more. We sincerely hope, the next attempt would be more organized and
certainly better.
Writing a textbook of this size would be impossible without the very willing cooperation of the contributors and
assistance and support of many other people. Although it is not possible to enumerate all–the editors most heartily
thank the most experienced and celebrated authors in the field and other colleagues who contributed illustrations and
photographs, gave suggestions and most of all, the reviewers who made substantive suggestions to improve the
contents and to all those who encouraged us to carry on.
This compilation entailed a tremendous amount of work but the experience gained and the rewards are priceless.
Hemanta Kumar Kar

Bhushan Kumar
Acknowledgments
Members of the Advisory Board
VM Katoch, Kiran Katoch
BK Girdhar, G N Malaviya and
D Porichha
The editors gratefully acknowledge the advice, constructive criticism and most importantly the very willing support
provided by all the esteemed members of the advisory team to make this dream project evolve into a reality and that
too as an up-to-date and readable manuscript. The IAL Textbook of Leprosy is the result of their personal commitment
to the cause and a desire to leave behind a legacy. We are sure that all those who read this book will agree with us and
join us in complimenting the Advisory Board.
We would always look forward to another occasion to be the beneficiaries of their vast experience and friendly
advice. We once again express our special thanks to the IAL for entrusting us to deliver.
Special thanks are also due to Shri Jitendar P Vij (CEO), Mr Tarun Duneja (Director-Publishing), Mr KK Raman
(Production Manager), Mr Subrata Adhikary (Author’s Coordinator), Ms Samina (PA to Director),
Mr Akhilesh Kumar Dubey (Proofreader), Mr Durgesh Verma (Typesetter) and Mr Manoj Pahuja (Designer) of Jaypee
Brothers Medical Publishers (P) Ltd for their patience and wholehearted cooperation.
Finally, we would be failing in our duty if we do not make a mention of the special help of our editorial associate
Dr Pankaj Sharma. We sincerely believe that his personal efforts and involvement to the soul were instrumental in
bringing this book to the present shape.
Hemanta Kumar Kar

Bhushan Kumar
Contributors
Aparna Palit MD Charles K Job BSc, MD, FAMS, FRCP (Path), FICPath
Associate Professor Consultant Pathologist
Department of Dermatology, STD and Leprosy St Thomas Hospital, and Leprosy Centre
SBPM Medical College, Ashram Road TS Dist Chettupattu 606801, Tamil Nadu
Bijapur-586103, Karnataka e-mail: sthlcchet@hotmail.com
e-mail: aparnapalit@rediimail.com
D Kamaraj MSc, CDS
Archana Singal MD, MNAMS WHO Consultant (Rehabilitation)
Professor and HOD H No 300, C Block, Vikas Puri, New Delhi-110018
Department of Dermatology, STD and Leprosy Tel Work: 011-42595600, Mobile: 0-9717727823
University College of Medical Sciences and associated e-mail: devapitchaik@searo.who.int,
GTB Hospital, Delhi-110092 kamaraj_95@yahoo.co.in
e-mail: archanasingal@hotmail.com
Dhaval M Thorat MD (PSM)
Arun C Inamdar MD, DVD ADG, Central Leprosy Division, DGHS
Professor and HOD Nirman Bhawan, A-Block, New Delhi-110001
Department of Dermatology, STD and Leprosy e-mail: adglep@yahoo.co.in
SBPM Medical College, Ashram road
Bijapur 586103, Karnataka Devinder Mohan Thappa MD, DHA, MNAMS
e-mail: aruninamadar@rediffmail.com Professor and Head
Atul Shah MS (Gen Surgery), MS (Plastic Surgery) JIPMER, Pondicherry - 605006
MNAMS (Plastic Surgery) e-mail: dmthappa@satyam.net.in
Honorary Professor of Plastic Surgery
Grant Medical College and Sir JJ Group of Hospitals Dullobho Porichha MD
Mumbai 400058, Maharashtra Medical Coordinator, LEPRA Health in action
e-mail: clcp@vsnl.com Formerly Consultant Pathologist
Medical Center, Parliament House Annexe
Balaraman Sekar MD (Microbiology) N-1/89, IRC village, Bhubhneshwar-751015, Orissa
Joint Director, CLTRI, Chingleput e-mail: d_porichha@yahoo.com
Tamil Nadu-600001
e-mail: drbsekar@yahoo.com Govind Narain Malaviya MS (Ortho), DHRM
Senior Deputy Director
BK Girdhar MD National JALMA Institute for Leprosy and other
Consultant Dermatologist, Shanti Manglick Hospital, Agra Mycobacterial diseases
Formerly Head Clinical Division Post Box No. 101, Taj Ganj, Agra - 282001 (UP)
National JALMA Institute for Leprosy and other e-mail: govindmalaviya@rediffmail.com
Mycobacterial Diseases
PB No 31, Tajganj, Agra-282001, (UP) Govind Srivastava MD
e-mail: girdharbk@yahoo.com Behl’s Skin Institute and Research center
Greater Kailash, New Delhi - 110024
Bhushan Kumar MD, MNAMS
Former Professor and Head Gurmohan Singh MD, FAMS, FRCP (Edin.)
Department of Dermatology, STD and Leprosy (Former Professor, BHU), Consultant Dermatologist
PGIMER (Chandigarh) The Skin Institute, Laxmi Complex
House No. 81, Sector- 16/A, Chandigarh-160015 Mehmoorganj, Varanasi – 221010, (UP)
e-mail: kumarbhushan@hotmail.com e-mail: drgurmohan@gmail.com
xiv IAL Textbook of Leprosy
Hemanta Kumar Kar MD, MNAMS Mehervani Chaduvula MD

Professor and HOD Blue Peter Research Centre (LEPRA)
Department of Dermatology, STD and Leprosy Near TEC Building, Cherlapally
PGIMER, Dr RML Hospital, New Delhi –110001 Hyderabad–501301, Andhra Pradesh
e-mail: hkkar_2000@yahoo.com
Mohan Natrajan MBBS, DD, PhD
Indira Nath MD, FRCPath, DSc (hc, Paris 6) Deputy Director (SG)
Padmashri (India) Department of Histopathology
Chevalier, Ordre National du Merite (France) National JALMA Institute for Leprosy and other
Emeritus Professor, Institute of Pathology (ICMR) Mycobacterial diseases (ICMR)
Safdarjang Hospital Campus, New Delhi 110029
Taj Ganj, Agra - 282001 (UP)
e-mail: indiranath38@hotmail
e-mail: mohunpath@rediffmail.com
Joginder Kumar MD
Nand Lal Sharma MD
Department of Dermatology, Venereology and Leprosy
Professor and Head
Safdarjang Hospital and Vardhman Mahavir Medical College
New Delhi 110029
e-mail: jogikataria@gmail.com Dr RP Govt. Medical College, Kangra (Tanda) - 176001 (HP)
e-mail: nandlals@hotmail.com
Joyce Ponnaiya MD (Path)
Consultant Pathologist Neela Shah MSc, DHM
Schieffelin Institute of Health - Research and Leprosy Centre Managing Director
Karigiri – 632 106, Tamil Nadu Novartis Comprehensive Leprosy Care Association
Formerly Director, Christian Medical College Hospital Remi Bizcourt, GR-01, Veera Desai Road, Andheri West
e-mail: Vellore – 632 004, Tamil Nadu, India Mumbai 400058, Maharashtra
e-mail: clcp@vsnl.com
Kiran Katoch MD
Senior Deputy Director, Neena Khanna MD
National JALMA Institute for Leprosy and other Professor, Department of Dermatology, STD and Leprosy
Mycobacterial diseases, All India Institute of Medical Sciences
Post Box No. 101, Taj Ganj, Agra 282001 (UP) New Delhi-110029
e-mail: kirankatoch@rediffmail.com e-mail: neena_aiims@yahoo.co.in
Krishnamurthy Venkatesan MSc, PhD Nirmala Deo MSc, PhD

Scientist F/Deputy Director (Sr Grade) Research Assistant, Department of Biochemistry
Department of Biochemistry National JALMA Institute for Leprosy and Other
National JALMA Institute for Leprosy and Other Mycobacterial Diseases (ICMR)
Mycobacterial Diseases (ICMR) Taj ganj, Agra-282001 (UP)
Taj Ganj, Agra -282001 (UP)
e-mail: nirmaladeo2000@yahoo.com
e-mail: venkatesan_52@rediffmail.com
Pankaj Sharma MBBS, DVD
Manav Deep Singh MS
Senior Research Officer
Assistant Professor, Senior Eye Specialist
Department of Ophthalmology, PGIMER
PGIMER and Dr Ram Manohar Lohia Hospital
Dr Ram Manohar Lohia Hospital, New Delhi-110001
e-mail: singh_md@yahoo.com Baba Khadak Singh Marg
New Delhi -110001
Manimozhi Natarajan MBBS, DHE e-mail: pankajsharma60@gmail.com
Cert. (Epidemiology) John Hopkins
Medical Coordinator, AIFO India P K Gopal MA, PhD
No. 58, 4th Cross, Kavery Lay out, Thavarekere Main Road IDEA India, 113, Selvam Nagar, Collectorate PO
Bangalore 560 029 Erode- 638011, Tamilnadu
e-mail: aifomm@gmail.com e-mail: ideaind@sancharnet.in
Contributors xv
P L Joshi MD, FAMS Raghuram Rao MBBS, DPH
Dy. Director General (Leprosy), DGHS Former Assistant Director
Government of India, Ministry of Health and Family Welfare Bombay Leprosy Project (BLP), Vidnyan Bhavan,
Room No. 342, A-wing, Nirman Bhavan, New Delhi 110011 V.N. Purav Marg, Sion-Chunabhatti
e-mail: doctorjoshi@yahoo.com Mumbai-400022, Maharashtra
e-mail: bombayleprosy@mtnl.net.in
P Narasimha Rao MD, DD, PhD
Professor and HOD Rajni Rani PhD
Department of Dermatology, STD and Leprosy Staff Scientist VI, Molecular Immunogenetics Group
Bhaskar Medical College Hyderabad and National Institute of Immunology, JNU Campus
Clinical Consultant, Blue Peter Research Centre New Delhi-110067
LEPRA Society e-mail: rajnirani@yahoo.com
Near TEC Building, Cherlapally
Hyderabad - 501301, Andhra Pradesh Ramaswami Ganapati MBBS, DDV
e-mail: dermarao@gmail.com Director Emeritus, Bombay Leprosy project
11, V N Purav Marg, Chunabhatti, Sion (E)
Prafulla Kumar Sharma MD Mumbai-400022, Maharashtra
Associate Professor, Senior Dermatologist e-mail: rganapati@yahoo.com
PGIMER, Dr RML Hospital, New Delhi- 110001 Shubhada S Pandya MBBS, PhD
e-mail: prafulla21@gmail.com Acworth Leprosy Hospital
Society for Research, Rehabilitation and Education in Leprosy
Pratap Rai Manglani MBBS Wadala, Mumbai - 400031, Maharashtra
National Consultant (DPMR) e-mail: shunil3@gmail.com
Central Leprosy Division, DGHS
Nirman Bhawan, 3rd Floor, A-Block, New Delhi- 110011 Soumya Kaimal MD
e-mail: manglanipr@rediffmail.com Former Resident
PSS Sunder Rao MA, MPH JIPMER, Pondicherry - 605006
Research Coordinator, TLM India
CNI Bhavan, 16, Pandit Pant Marg, New Delhi 110001 Sujai K Suneetha MBBS, DCP, PhD
e-mail: psssrao2002@yahoo.co.in/psssrao@tlmindia.org Director Nireekshana ACET
3-5-48 Raj Mohalla
Rajeshwar Dayal MD, FIAP FAMS, DN, DCH (London) Hyderabad 500029, Andhra Pradesh
Professor and HOD e-mail: drsujai@rediffmail.com
Department of Pediatrics, SN Medical College
Agra-282002 (UP) Sunil Dogra MD, DNB, MNAMS
e-mail: r_dayal123@rediffmail.com Assistant Professor
Radhey Shyam Mishra MD, DD PGIMER, Chandigarh - 160012
Senior Consultant Dermato-cosmetologist and Leprologist e-mail: sundogra@hotmail.com
Skin Care and Cosmetology Centre and
Sir Ganga Ram Hospital Sunil Sanghi MD
Rajinder Nagar, New Delhi - 110005 Classified Specialist, (Dermatology and Venereology)
e-mail: drrsm1@yahoo.com Skin Center, Command Hospital
Pune - 411040, Maharashtra
Ragunatha S MD e-mail: sunilsanghi@yahoo.com
Assistant Professor
Department of Dermatology, STD and Leprosy Swapan Kumar Samanta MS
BLDEA’s SBMP Medical College Hospital Assistant Professor
and Research Centre Department of Ophthalmology,
Bijapur-586103, Karnataka R G Kar Medical College, 1, RG Kar road, Kolkata- 700004.
e-mail: drragus@yahoo.co.in e-mail: swapan_samanta@hotmail.com
xvi IAL Textbook of Leprosy
Thomas Abraham BSc, MD, DVD Vijay Kumar V Dongre GFAM, LMP, MBBS, DVD, DHA
Dy. Director and Medical Advisor, GLRA/ Swiss Emmaus India Consultant, LEAP, ALERT-India, Mumbai
18, Railway Colony, 4th Street, Aminjikarai 19, HEPT Building, Ranade Road
Chennai- 600029 (TN) Dadar (West), Mumbai- 400028, Maharashtra
e-mail: thambu49@gmail.com e-mail: alert@bom5.vsnl.net.in
Utpal Sengupta PhD, FNASc, FAMS Vikram Mahajan MD

Lab Manager, IBBA Project Associate Professor
National Institute of Medical Statistics (ICMR) Department of Dermatology, STD and Leprosy
ICMR Complex, Ansari Nagar, New Delhi-110029 Dr. R. P. Government Medical College
Ex-Director, National JALMA Institute for Leprosy (ICMR) Kangra (Tanda) - 176001 (HP)
Taj Ganj, Agra 282001 (UP) e-mail: vkm1@rediffmail.com
e-mail: usengupta2002@yahoo.com
Vineet Kaur DNBE (Derm and Ven.), Dip GUM (UK), MAMS
Umesh D Gupta MSc, PhD
Vineet skin care institute, Laxmi Complex, Mehmoorganj
Deputy Director and Scientist E, Lab for Animal experiment
Varanasi –221005 (UP)
National JALMA Institute for Leprosy and other
e-mail: drvineet11@gmail.com
Mycobacterial diseases (ICMR)
Taj Ganj, Agra – 282001 (UP)
Virendra Nath Sehgal MD
e-mail: gdupg@yahoo.com
Former Director, Professor and Principal
Lady Hardinge Medical College
V Ramesh MD
Consultant and HOD and Shucheta Kriplani Hospital, New Delhi
Department of Dermatology, STD and Leprosy Consultant Dermatologist, A/6, Panchavati
Safdarjang Hospital and Vardhman Mahavir Medical Opposite Azadpur Subji Mandi
College New Delhi- 110033
New Delhi 110029 e-mail: drsehgal@ndf.vsnl.net.in
e-mail: weramesh@hotmail.com
Vishwa Mohan Katoch MD, FNASc, FAMS, FASc, FNA
Vanaja Prabhakar Shetty PhD Secretary
Deputy Director, The foundation for Medical Research, Department of Health Research
84-A R G Thadani Marg, Worli Ministry of Health and Family Welfare
Mumbai-400018, Maharashtra Director General, Indian Council of Medical Research
e-mail: frm@vsnl.net, fmr@fmrindia.org, Ansari Nagar, New Delhi-110029
fmrborn@hathway.com e-mail: vishwamohan_katoch@yahoo.co.in
Vijay K Pannikar Vivek V Pai MBBS, DVD, FCGP

Team Leader, Global Leprosy Programme Director, Bombay Leprosy Project (BLP)
SEARO-WHO, Indraprastha Estate, Ring Road Vidnyan Bhavan, V.N. Purav Marg,
New Delhi - 110002 Sion-Chunabhatti, Mumbai-400022, Maharashtra
e-mail: pannikarv@searo.who.int e-mail: bombayleprosy@mtnl.net.in
Contributors xvii
Contents
Section 1: The Disease History and Epidemiology
1. Historical Background ...................................................................................................................................... 3
Shubhada S Pandya
2. Epidemiology ................................................................................................................................................. 24
Dhaval M Thorat, Pankaj Sharma
3. Global Scenario ............................................................................................................................................. 32
Vijay K Pannikar
4. National Scenario, National Leprosy Eradication Program (NLEP) and New Paradigms.................................. 35
PL Joshi
Section 2: Basic Scientific Considerations and Pathology

5. Genetic Susceptibility and Immunogenetics .................................................................................................. 47
Rajni Rani
6. Immunological Aspects ................................................................................................................................. 60
Indira Nath, Mehervani Chaduvula
7. Bacteriological Aspects ................................................................................................................................. 74
Balaraman Sekar
8. Biochemical Aspects ..................................................................................................................................... 87
Krishnamurthy Venkatesan, Nirmala Deo
9. Pathological Aspects ....................................................................................................................................100
Dullobho Porichha, Mohan Natrajan
Section 3: Clinical and Laboratory Diagnosis

10. History Taking and Clinical Examination .......................................................................................................121
Aparna Palit, S Ragunatha, Arun C Inamadar
11. Classification ................................................................................................................................................144
Radhe Shyam Mishra, Joginder Kumar
12. Case Definition and Clinical Types ................................................................................................................152
Bhushan Kumar, Sunil Dogra
13. Histoid Leprosy ............................................................................................................................................167
Virendra Nath Sehgal, Govind Srivastava
14. Laboratory Diagnosis ....................................................................................................................................176
Charles K Job, Joyce Ponnaiya
15. Serological and Molecular Diagnosis ............................................................................................................189
Utpal Sengupta, Vishwa Mohan Katoch
xviii IAL Textbook of Leprosy
16. Differential Diagnosis of Dermatological Conditions ......................................................................................197

Nand Lal Sharma, Vikram Mahajan
17. Differential Diagnosis of Neurological and Other Conditions ..........................................................................211
Prafulla K Sharma, Pankaj Sharma
Section 4: Disease Complications (Nerve Involvement,

Neuritis and Reactions)
18. Structure and Electrophysiological Studies of Peripheral Nerve ....................................................................227
Sujai K Suneetha, P Narasimha Rao
19. Pathomechanisms of Nerve Damage ............................................................................................................237
Vanaja Prabhakar Shetty
20. Methods of Nerve Examination .....................................................................................................................248
BK Girdhar
21. Neuritis: Definition, Clinical Manifestations and Proforma to Record Nerve Impairment.................................253
P Narasimha Rao, Sujai K Suneetha
22. Leprosy Reactions ........................................................................................................................................269
Hemanta Kumar Kar, Pankaj Sharma
Section 5: Systemic Involvement and Special Situations in Leprosy

23. Systemic Manifestations ..............................................................................................................................293
V Ramesh, Joginder Kumar
24. Leprosy and HIV Infection ............................................................................................................................305
Archana Singal
25. Leprosy and Pregnancy ................................................................................................................................313
Neena Khanna
26. Leprosy in Children .......................................................................................................................................325
Rajeshwar Dayal, Sunil Sanghi
Section 6: Therapeutics (Medical and Surgical),

Prophylaxis and Monitoring
27. Chemotherapy: Drugs Used in Leprosy Including Newer Drugs .....................................................................335
BK Girdhar
28. Development and Evolution of WHO MDT and Newer Treatment Regimens ..................................................353
VV Pai, R Ganapati, Raghuram Rao
29. Recording, Reporting and Monitoring of MDT and Post-treatment Follow-up .................................................368
PR Manglani
30. Management of Leprosy Reactions ..............................................................................................................386
Contributors
Contents xix
31. Management of Neuritis and Neuropathic Pain ..............................................................................................400
32. Leprosy Vaccines and Immunotherapy .........................................................................................................410
Kiran Katoch
33. Chemoprophylaxis ........................................................................................................................................418
BK Girdhar
34. Deformities of Face, Hands and Feet, and Their Management ......................................................................424
Atul Shah, Neela Shah
35. Deformity/Disability Prevention .....................................................................................................................447
GN Malaviya
36. Nursing Care for Leprosy Patients ................................................................................................................468
Vineet Kaur, Gurmohan Singh
Section 7: Miscellaneous Issues in Leprosy

37. Relapse in Leprosy .......................................................................................................................................483
Devinder Mohan Thappa, Sowmya Kaimal
38. Drug Resistance Studies, Viability and Bacterial Persisters and Animal Models in Leprosy ..........................492
Umesh D Gupta, Vanaja P Shetty
39. Ocular Leprosy .............................................................................................................................................503
Swapan K Samanta, Manav Deep Singh
Section 8: Rehabilitation and Social Issues

40. Rehabilitation ................................................................................................................................................525
D Kamaraj
41. Community-based Comprehensive Leprosy Work .........................................................................................538
R Ganapati, VV Pai
42. Health Education, Promotion and Counseling ...............................................................................................545
Manimozhi Natarajan
43. Psychosocial Aspects ..................................................................................................................................559
PK Gopal
44. Human Rights and Leprosy...........................................................................................................................565
VV Dongre
45. Role of NGOs in National Leprosy Eradication Program ...............................................................................572
Thomas Abraham, Pankaj Sharma, R Ganapati, Atul Shah
46. Case Studies ................................................................................................................................................585
Pankaj Sharma, Hemanta K Kar
Section 9: Future Prospects

47. Leprosy Scenario Beyond 2010 ....................................................................................................................605
PSS Sundar Rao
Index ............................................................................................................................................................613
Section
1 The Disease History

and Epidemiology
1
Historical Background
Shubhada S Pandya
INTRODUCTION
A complex disease such as leprosy has a correspondingly
multi-faceted history ranging from medical-scientific, to
social, legal and political. The present historical overview
of the above facets does not claim to be exhaustive, since
its focus is chiefly on the nineteenth and early twentieth
centuries (which happen to coincide with the British colonial
period in India). This is justified, since many of the ideas
and practices familiar to us today first saw the light of day Fig. 1.1: DC Danielssen (Left); CW Boeck (Right). From Atlas de la
during this period. Wherever possible, work conducted, lèpre ... Bergen en Norvège 1847. Edition commemmorative du
policies generated, and observations made in India are centenaire. Edited by HC de Souza-Araujo. With portraits
detailed and examined. Within the historical time frame
selected, it is not surprising that European observations basis of detailed clinical and postmortem observations
and researches were prominent in the scientific field, as made on leprosy asylum inmates in the city Bergen,
also the events associated with the British presence in proposed a dual classification system for the disease,
India. With regard to the latter, two initiatives launched in based on the dominant clinical features. They traced the
this country in the first decades of the twentieth century seat of pathology to the nervous system (central and
(ironically, both were failures) are particularly noteworthy. peripheral), and the pathogenesis to an excess of
These were: (1) large-scale "chaulmoogra" oil-based "albumen" circulating in the blood, which was deposited in
treatment and (2) the leprosy control strategy launched by the skin and nervous system. But it was Danielssen and
the Indian Council of the British Empire Leprosy Relief Boeck's pronouncement on the etiology of leprosy—that it
Association (ICBELRA). was hereditary—that was to arouse the greatest controversy
in nineteenth century Europe and also found an echo in
THE BEGINNINGS OF LEPROLOGY India. The contemporary evidence relied on by them, of
course, pre-dated the late nineteenth century advances in
To two researchers, Daniel Cornelius Danielssen and Carl- the knowledge of laws of heredity. Thus, they regarded the
Wilhelm Boeck (Fig. 1.1) in the small European country occurrence of two cases of leprosy in a family within
Norway, must go the credit for the first ever scientific study 4 generations as proof of hereditary origin, irrespective of
of leprosy published in the beautifully illustrated treatise whether the later case was in a direct or collateral line of
Om Spedalskhed (On Leprosy) in 1847, and published in descent; or was born before or after the disease was
French translation the next year.1 These pioneers, on the detected in the ancestor; or even if more cases were present
Note: The use of the term 'leper' in this chapter is in its historical context, and is not intended to denigrate a person with leprosy.
CHAPTER
1
4 The Disease History and Epidemiology
in collateral than direct lines of descent in a statistical theories as mutually incompatible, since it was conceivable
analysis. to them that sub-standard living conditions might weaken
a body constitution enough to unmask a hereditary pre-
ETIOLOGICAL DEBATES disposition; or that the optimum environmental and dietary
conditions might protect against the development of leprosy
In 1895, Armauer Hansen (1841-1912), the discoverer of
even in "pre-disposed" individuals; or that susceptibility to
the bacillus of leprosy, remarked wryly:
leprosy (rather than leprosy per se) was transmitted through
There is hardly anything on earth, or between it and
heredity, which in turn facilitated familial spread of the
heaven, which has not been regarded as the cause of
supposed leprous ‘contagion’.
leprosy; and this is but natural, since the less one knows,
Gerhard Armauer Hansen, another Norwegian, (Fig. 1.7)
the more actively does his imagination work.2
The disease exhibited apparently contradictory features entered leprosy work in 1869, and was deeply influenced
which lead the opinions in different directions, depending by a pamphlet which had been published in that year by a
on the biases of the observer. For example: (1) although Dutchman in Surinam, which drew attention to the disease
sporadic cases occurred, leprosy was seen in direct as developing in expatriates returning to Holland after sojourns
well as collateral descendants of lepers—hence it was in the colonies. Such cases could not have arisen from
due to hereditary transmission of an unspecified, structural heredity, pointed out the author. The pamphlet declared
defect; (2) although a rich man could get leprosy, it more that contagion was the "sole" etiology, and that Danielssen
often occurred in people living in unsanitary environments— and Boeck had been led to "absurd" conclusions by faulty
hence it was a non-specific disease of a poor environmental interpretation of family data, and too generous interpretation
and living conditions; (3) it was frequent in countries of "hereditary transmission".4 Hansen conducted field
subjugated by European colonialism—hence it was a surveys in leprosy-endemic hamlets in and around Bergen,
disease of their low level of 'civilization' and their state of and noted that sporadic cases had arisen in strangers
'demoralization'; and (4) although conjugal leprosy was originally from leprosy-free regions, now resident in Bergen.
uncommon, the disease appeared to be communicated He concluded that leprosy was not hereditary but
by contact, direct or mediate, with a leper—hence it was contagious. In 1875, in a critique of the hereditary theory,
'contagious', and like syphilis, conveyed by contact. he postulated that leprosy was a specific disease
As noted above, Danielssen and Boeck held strong connected with the bacillus discovered by him in 1873.5
hereditarian views. Rudolf Virchow, the father of cellular An important visitor to Hansen's laboratory in Bergen
pathology, was struck by the rarity of leprosy among in 1873-74 was Henry Vandyke Carter of the Mumbai
Norwegian immigrants to the United States, and inclined Medical Service. Carter is unjustly forgotten by leprologists,
towards 'locality' (climatic and soil conditions) as the but he must be acknowledged as the foremost authority
reason. He remained a firm anti-contagionist for most of on the disease in late nineteenth century India. Carter had
his life, eventually conceding the bacillary origin only the good fortune to be shown the putative bacillus of leprosy
reluctantly.3 Some observers did not regard the above by the discoverer himself. The visitor from India, who had
Fig. 1.2: The English-speaking world first learned of Hansen’s discovery of the leprosy bacillus in
1873, through HV Carter of the Mumbai Medical Service (Source: Reference 6)
CHAPTER
1
Historical Background 5
hitherto inclined towards the hereditary etiology, quickly
grasped the implications of Hansen's yet-unconfirmed
discovery.6 Carter's account and its effect on him are seen
in Figure 1.2.
On his return to India Carter, with the zeal of a new
convert to contagionism, bombarded the colonial
Government with memoranda on the infectiousness of
leprosy and the necessity for segregation of the affected,
as a control measure. It was Britain's imperial duty, he
said, to eradicate leprosy from India and to ameliorate the
sufferings of lepers. Carter cited "the enlightened Kingdom
of Norway". In that country, a sustained reduction in Fig. 1.3: Henry Vandyke Carter, portrait at Grant Medical College,
prevalence was taking place since the year 1856, a Mumbai (Left); Lepra leprosa (Right). From: HV Carter, On Leprosy
phenomenon which he (Carter), like Hansen, confidently and Elephantiasis, 1874, Plate I1.
attributed to the legislation compulsorily segregating in
asylums, those lepers who were unable or unwilling, to later proposed by the Norwegians). He also described
isolate themselves at home.7 the natural history of the latter variety, characterized by
Despite the plethora of causation theories, and the enlarging pale anesthetic macules, and spreading
efforts of die-hard anti-contagionists, and not withstanding anesthesia leading inexorably to deformity and disability.10
failed attempts to transmit the disease to experimental The "mixed" variety was described and referred to as
animals), it became increasingly untenable in late Lepra leprosa by Carter of Mumbai, in his beautifully self-
nineteenth century scientific circles to dismiss the bacterial illustrated tome On Leprosy and Elephantiasis which was
published in 1874.11 His illustration of this variety identifies
etiology of leprosy. A ringing endorsement of Hansen's
it as today's "borderline tuberculoid" (Fig.1.3).
discovery and his long-held opinions on the efficacy of
leper segregation came in 1897 at the First International
Leprosy Congress.8 REACTIONS
The so-called "acute manifestations" in the course of
CLINICAL leprosy were noted by the pioneer leprologists. For example
repeated crops of reddish nodules accompanied by fever
Danielssen and Boeck classified leprosy as two types, were described by Danielssen and Boeck as one of the
Elephantiasis Graecorum Tuberosa and Elephantiasis presenting signs in nodular ["tubercular"] leprosy, and were
Anesthetosa, the terms defining the chief clinical interpreted by them as evidence of dissemination of the
characteristics. Patients' portraits of each type were disease.
provided (Fig. 1.4). A "mixed" form displaying features of
both main types was also recognized.
However, it is not well known that such a classification
had been anticipated almost three decades earlier by British
colonial physicians in India. Francis Buchanan-Hamilton
(1762-1825) of the Bengal Medical Service, noted as follows
during a tour of Bihar (in the then Bengal Province):
There is … reason to think that there are two varieties
of the disease that differ much, both in symptoms and
virulence, the one attacking the small joints and the other
the skin, of which it renders large portions totally
insensible.9
James Robinson (1785-1819) also of the Bengal Service
actually named the two types as Elephantiasis tuberculata Fig. 1.4: Elephantiasis Anaesthetosa (Left); Elephantiasis Graecorum
and Elephantiasis anaisthetos, (terms identical to those Tuberosa (Right). From Atlas de la lèpre ... Bergen en Norvège 1847.
CHAPTER
1
A bacteriologic interpretation of the phenomenon was It was noticed that fever, softening of nodules and
attempted in 1883 by Vandyke Carter in Mumbai, a decade fragmentation of intralesional bacilli occurred
after Hansen's discovery. As recounted above, Carter spontaneously, but more particularly during reactions'
became an avid protagonist of the germ theory of disease, brought on by putative therapies such as vaccines; salts,
before the work of Koch and Pasteur, which was yet to be such as potassium iodide and the salts of chaulmoogra
universally accepted in scientific medicine. Carter was oil. Were spontaneous "reactionary episodes" evidence of
struck by the contrast between the often "scanty" [indolent] increased immunity to the bacillus? Were episodes
constitutional response of the human system to the leprosy occurring in the course of treatment, evidence of
bacillus interrupted by "occasional reproduction of the therapeutic efficacy? Should the severity of a "reaction"
nodules", with the "violent" symptoms attending acute be controlled? All these points were moot. Rogers, an ardent
infections with "pathogenetic" [pyogenic] bacteria. He
advocate of intravenous treatment with salts of hydnocarpus
concluded that the "interruptions" in the course of leprosy
oil (which he introduced into leprosy therapy in the 1920s;
were due to "infection" of the system from reabsorption
see below), declared that "the intravenous method … led
and "auto-inoculation" of leprous matter from softening
to a most important and encouraging advance, for in certain
nodules.12
cases, especially marked nodular ones, local inflammatory
A foretaste of the modern terminology for the episodic
skin eruptions is provided in an early twentieth century reactions, sometimes accompanied by fever, took place
German textbook of tropical medicine, in which "acute in the thickened cutaneous lesions, and were followed by
inflammatory skin nodules" having their seat in the cutis rapid absorption of the diseased tissues. Still more striking
and sub-cutis were labelled as a type of "erythema was the fact that microscopical examination proved that
nodosum" (rose rash) resulting from bacillary emboli,13 while these local reactions were accompanied by active
the specific term "erythema nodosum leprosum" (ENL) destruction of the innumerable bacilli in the lesions".15
was first employed by Murata of Japan in 1912. Sir Leonard
Rogers of the Indian Medical Service (see below), who NERVE INVOLVEMENT AND NEURO-
was a well-known tropical diseases expert, cited his PATHOGENESIS
collaborator Ernest Muir's description of the clinical picture
during acute "reactionary episodes" (the term "reaction" Danielsson and Boeck stated that the nervous system in
was probably employed in the belief that it represented an general was the seat of leprous pathology, evidenced by
'allergic reaction' to the bacterial toxin): "sudden swelling diffuse spinal and cranial meningitis as well as peripheral
and redness of existing lesions with appearance of new nerve enlargement. But it was Carter working in Mumbai
ones with toxemia and fever…. this is often followed by in the early 1860s who cast leprosy as a sensory peripheral
spontaneous subsidence".14 nerve disease par excellence.
Fig. 1.5: Skin lesions and neural involvement (Left); Peripheral neuroanatomy in leprosy (Right).
From HV Carter, On Leprosy and Elephantiasis, 1874, Plates I and IX
CHAPTER
1
The principles which he propounded on neuro- the "granulomatous diseases".19 Virchow was of the
pathogenesis were based on close clinical examination [probably mistaken] view that the neural pathology in
and postmortem dissections (Fig.1.5) carried out at the leprosy was "trophic" and secondary to the primary
Jamsetjee Jejeebhoy (JJ) Hospital at Mumbai, are valid pathology in the skin, but he was more percipient when he
even today. Carter stated that leprosy "is probably the stated that "compared to the sensory disturbances, the
only disease known which is confined to the [peripheral] motor changes lie in the background". By the first decade
nerves and the sentient [sentient: able to perceive of the 20th century, leprosy neuropathy was recognized
sensation] skin"; that neither nerve involvement nor its as a specific primary inflammatory and destructive process
enlargement were random, but followed a pattern, e.g. the in the nerve; with the bacillus providing the stimulus.
ulnar at the elbow, the median above the wrist, the Carter's observations on neurohistology were more
cutaneous nerves in their superficial course after they have creditable even though, unlike his contemporaries in
pierced the deep fascia; that "the nerve centers [the central Europe, he did not have access to the latest microscopes.
nervous system] are not necessarily affected".16 It is The names of Dehio and his pupil Gerlach are
remarkable that Carter postulated that progression of the associated with arguably the most important late nineteenth
disease within the peripheral nerves was facilitated by intra- century postulate relating to neuropathogenesis. On the
neural anastomoses, a feature illustrated together with a basis of a case observed clinically and minutely examined
dissection of the arm nerves.11,17 anatomically, these researchers proposed that in the
Symptoms in the extremities in the anesthetic variety anesthetic form, the disease commenced in the skin. The
of leprosy were in direct relation with the "neuritis" of the local circumscribed anesthesias were caused by the spread
nerves which supplied the benumbed part, said Carter. of leprous granuloma in the diseased skin, which invaded
The importance of the intraneural anastomosis in the the lymph spaces and lymphatics in the skin and penetrated
sequential appearance of sensory and motor signs and the tubular tissue spaces in which the most delicate terminal
symptoms in leprosy originally stated by Carter, were 're- branches of the dermal nerves are distributed. In
stated' and illustrated by modern neuroanatomists18 consequence, the skin nerves within the "maculae"
(Fig.1.6). disintegrated, and the maculae became anesthetic. In the
Carter also reported the presence of numerous dark further course of the disease the granuloma spread upwards
"nuclei" in histologic sections of peripheral nerves and by way of the nerve sheaths, creeping gradually to the
surmised that they were derived from the exudate within larger ramifications and finally to the nerve trunks, and the
the diseased tissue, a fact confirmed by the great muscular atrophy occurring as a consequence (Fig. 1.7).
pathologist Rudolf Virchow in his own investigations into The Dehio-Gerlach hypothesis retains its credibility even
Fig. 1.7: Schematic of Gerlach-Dehio of neuropathogenesis. Ascent

Fig. 1.6: Schematic of intraneural anastomoses by of neuritis from dermal nerve a, to the mixed nerves i and l, causing
Sunderland in 1975.18 paralysis in muscles b and d. 20
CHAPTER
1
today, because it is in harmony with current knowledge of "bacteria" within granular cells. (Unstained bacilli mounted
the internal anatomy of limb peripheral nerves.20 in distilled water showed vigorous movements, which he
mistook for true motility; he also described "spores".)
PATHOLOGY Despite numerous attempts by Hansen and his
contemporaries, no experimental animal proved susceptible
In his landmark book Pathology of Tumours (published to leprosy, and the putative "leprosy germ" faced
1864-65), Virchow described the microscopic picture in a
scepticism and even outright rejection for several decades.
group of nodule-forming ulcerous diseases—syphilis, lupus
Contrast this with the approbation which greeted Koch's
vulgaris, leprosy - which he labelled as the "granulomas",
discovery of the tubercle bacillus almost a decade later,
because they were marked by the growth of "granulation
fortified by ample experimental authentication and the
tissue". The leprosy granuloma was composed of sheets
statement of his "postulates". The pathogenicity of Bacillus
and masses of small and larger cells, some multi-nucleated,
leprae was finally acknowledged on empirical grounds by
infiltrating the dermis and extending into the sheath of
the international scientific community at the Berlin
peripheral nerves in the anesthetic variety. In nodular
Congress in 1897.
leprosy, thinning of the epidermis and flattening of the
A notable advance was Paul Ehrlich's introduction of
papillae were described, as also the presence of vacuolated
("physaliferous") cells. "Virchowian leprosy" became a aniline dyes as bacillary stains and acid decolorization,
synonym for nodular leprosy, characterized by the so-called Ziehl's substitution of carbolic solution for aniline oil became
"lepra cell".20 Elucidation of the contents of the cell had to a standard practice in the demonstration of the so-called
await Armauer Hansen's discovery of the bacillus in 1873, 'acid-fast bacilli'.21
almost a decade after Virchow's studies. All early investigators noticed that leprosy bacilli were
not evenly stained. Carter (of Mumbai) made the first
demonstration of Hansen's leprosy and Koch's tuberculosis
DISCOVERY AND PROPERTIES
bacilli in India in 1883, using the Ehrlich stain to bring out
OF THE BACILLUS
the morphological differences and similarities between the
GA Hansen's discovery (in 1873) of the causative organism two species of organism12 (Fig.1.9).
was a landmark event, but ahead of its time (Fig.1.8). The
bacillus was the first to be proposed as the cause of a
human disease, though the germ theory in general was
yet to be universally accepted. Using osmic acid to stain
cells teased out from a freshly excised leproma from a
man with nodular leprosy, Hansen described rod-shaped
Fig. 1.8: GA Hansen (Left); Hansen’s depictions of intracellular bacilli

(Right). From G.A. Hansen, “The Bacillus of Leprosy”, Quarterly Fig. 1.9: The first display of leprosy and tuberculosis bacilli in India
Journal of Microscopical Sciences, 20: (1880) Plate VIII was by Carter in Mumbai in 1883, using Ehrlich stain
CHAPTER
1
In 1897, Jeanselme of France reported lepra bacilli in cells and Langhans "giant cells" were demonstrated within
the nasal mucosa in several leprosy sufferers and "necrotic areas". The term "tuberculoid" was first employed
speculated that the nose was the site of entry of the in 1898 by Jadassohn, in acknowledgment of the numerous
infection. histologic similarities with tuberculosis. This scientist also
A detailed study conducted at the "Homeless Leper illustrated tuberculoid leprous neuropathy in the skin.24
Asylum" in Mumbai by a distinguished German bacterio- (Fig.1.12).
logist in the same year, amply confirmed the finding. Georg
Sticker, a member of the German Commission
investigating the plague epidemic then raging in Mumbai,
used the opportunity to visit the Asylum to investigate
leprosy and found large bacillary clusters and intracellular
globi in nasal smears in 128 of 153 inmates (Fig.1.10). He
reported these findings at the First International Leprosy
Congress held at Berlin in 1897.22 Incidentally, the German
Plague Commission was led by Robert Koch, who was a
sponsor of the Congress. Sticker and Koch raised the
possibility that the nose was the escape route of leprosy
bacilli.
Fig.1.11: Paul Unna (Left); Depiction of the “grenz”

zone in nodular leprosy (Right)26
Fig.1.10: Georg Sticker (Left) and his demonstration of bacilli in the

nasal mucosa in inmates of the Homeless Leper Asylum, Mumbai in
1897
In 1909, the German pathologist Paul Unna showed Fig.1.12: Characteristic histology of “tuberculoid” leprosy first
the "grenz" zone or cell-free sub-epidermal zone in described by Jadassohn24
histological sections in "tubercular" (i.e., nodular) leprosy.
(Fig. 1.11). He also postulated that the clustering of the
CLASSIFICATION
bacilli into "globi" was due to exudation of a glia in which
they lay embedded. Also insightful was his general An inkling into the evolving ideas on relationship between
observation that in "nerve leprosy", infiltrations similar to histological and clinical categories in leprosy can be
that in the skin occur in the nerves, leading to connective usefully followed up in successive editions of an important
tissue formation and induration.23 textbook of leprosy based on Indian experience, which
By the 1920s the characterization of specific cellular first appeared in 1925 (the second and third editions came
features of the two main types of leprosy was well out in 1940 and 1946). The authors were Sir Leonard Rogers
advanced, particularly on the Continent where epithelioid and Ernest Muir from Calcutta (see below).25 The first
CHAPTER
1
edition in 1925 contained no reference at all to the leprosy nosologists (nosology: systematic classification
characteristic histological features of the major varieties of disease) obviously dominated over the "lumpers", for
of leprosy, indicating that these were yet to enter the special sub-classifications were recommended according
general discourse. By 1940 however, epithelioid cells and to the nature of the lesions present—e.g., "anesthetic
Langhans giant cells; and the appellation "tuberculoid" neural", "macular neural". The macular variety was sub-
leprosy were incorporated. On pathogenesis, Rogers and divided into "simple" and "tuberculoid", and the latter further
Muir cited the nasal mucosa as a route of infection, but split into "tuberculoid macular minor" and "tuberculoid
stress was also laid on the skin. The majority of skin lesions macular major".27
in Indian patients being seen on the exposed areas, A significant contribution of the 5th International
bacillary entry was postulated to be facilitated by insect Congress at Havana in 1948 (the first to be held after World
bites and scratching. The earliest histopathology, the War II), was the inclusion of "indeterminate" leprosy and
authors said, was in relation to dermal papilli, from where dimorphous leprosy in the classification.28
bacillary dissemination was said to occur through dermal Robert Cochrane, the clinician and Vasant Khanolkar,
lymphatics and capillaries during periodical "exacerbations" the pathologist, both workers in India, were prominent in
(i.e. reactions), the nerves being implicated after the skin the Classification Sub-Committee at the next Congress
in the anesthetic variety. held at Madrid (Spain) in 1953. The proposal that the primary
While the multifarious manifestations of leprosy and classification should be based on clinical features was
their regional and geographical peculiarities had been noted unanimously accepted, as was the use of Lepromin test
by 19th century observers, the advent of influential multi- (introduced by Mitsuda of Japan in 1920), as an
national bodies such as the British Empire Leprosy Relief immunological indicator in the study of cases, with a
Association in 1924 (see below), the League of Nations secondary role for histological classification. The
Leprosy Commission in 1930, and the International Leprosy classification system proposed and adopted was as under:
Association in 1931, signalled a progressive "internationali- 1. Lepromatous Type (L): Comprising Macular, Diffuse,
sation" aimed at reconciling medical experience and Infiltrated, Nodular and? Pure neuritic varieties;
2. Tuberculoid Type (T): Comprising Macular, Minor
harmonizing theory and practice across the globe. The most
tuberculoid, Major tuberculoid, and Pure neuritic
important fora for deliberations on classification were the
varieties;
International Leprosy Congresses, starting with the Third
3. Indeterminate Group (I): Comprising Macular and? Pure
Congress held at Strasbourg (France) in 1923.
neuritic varieties;
A three-type classification was agreed, based on the
4. Borderline or Dimorphous Group (B): Comprising
consideration that while lepra bacilli were to be found in
Infiltrated and macular varieties.29
various other organs of the body, broadly speaking there
was (a) Skin leprosy; (b) nerve leprosy; (c) mixed leprosy.
The reciprocal relationship between the skin and the nerve NERVE ABSCESS
involvement in each type, was illustrated diagrammatically In 1924, Ernest Muir working in Calcutta documented nerve
by Rogers and Muir in their textbook. Starting with the abscesses in anesthetic leprosy in India and also surgically
International Congress at Cairo in 1938, the classification explored their relation to the funiculi. He pointed out the
systems showed progressive division of types into sub- poor correlation between the degree of nerve enlargement
types. The skin type being associated histologically with and the severity of fiber damage in such nerves.30
the 'leproma' populated by lepra cells, became
"lepromatous"—the first example of clinico-histological THE ERA OF CHAULMOOGRA/
correlation. The two main types, "lepromatous" and "neural"
HYDNOCARPUS OIL THERAPY IN INDIA
were sub-classified according to the degree of
advancement (e.g. L1 for slight lepromatous to L3 for With the passing away from Mumbai of Vandyke Carter in
advanced; N1 for slight neural to N3 for advanced neural 1888, there was a vacuum in scientific leprology in India
subtype). Combinations and permutations of the sub- for almost three decades. In 1915 a center of study arose
classes described the mixed forms, e.g. L2N2). The in Calcutta, with the work of Sir Leonard Rogers (1868-
Congress also suggested "+" and "-" as symbols to indicate 1962) of the Indian Medical Service and Ernest Muir (1880-
bacteriological status.26 The 'splitters' in the fraternity of 1974) a medical missionary (Fig.1.13). Both gentlemen
CHAPTER
1
attained worldwide reputation and influence through their Two related species of forest trees, namely Taraktogenos
prolific writings and the institutions and organizations which kurzii ("chaulmoogra") from the north-east, and Hydno-
they founded or nurtured. Rogers was the spirit behind the carpous wightiana, ("marotti", "kowti") from the coastal
establishment of the Calcutta School of Tropical Medicine south-west, were the best regarded. The latter, (marotti)
in 1920, just prior to his retirement from India. By that time was first reported to Western readers in 1687 in a beautifully
he had introduced sodium hydnocarpate (later marketed illustrated tome of the flora of Malabar (Kerala) brought out
as ALEPOL) as a new therapy (more accurately an old by the Dutch Governor31 (Fig. 1.14). The opinions of
therapy in a new avtar), and he with Muir had outlined a nineteenth century British colonial physicians employing
revolutionary approach to leprosy control. "Chaulmoogra" and "Marotti" oils were uneven,
improvement being variously found to be "decided",
"impermanent", or "none at all". Frequently patients refused
to persist with oral treatment because of nausea and gastric
irritation. Thus, while the oils continued to be employed, it
was primarily by default, rather than the proven merit or
the patient satisfaction. Rogers's contribution was to
substitute oral administration of the oil with parenteral
administration (injection) of an oil derivative.
Fig.1.13: Sir Leonard Rogers (Left); Ernest Muir (Right), the guiding
spirits in anti-leprosy work in India in the first half of the twentieth
century
Rogers was one of the most prominent tropical medicine

specialists in the Indian Medical Service around the turn
of the twentieth century, with a reputation second only to
that of Ronald Ross in malaria. Rogers's fame was
grounded in his contributions to tropical disease thera-
peutics, e.g. treatment of amoebic dysentery with emetine, Fig.1.14: Leaves, fruit and seeds of “Marotti” (Hydnocarpus
wightiana), a tree indigenous to Kerala. See reference 34
of cholera with hypertonic saline, of kala azar with
potassium antimony tartrate. It was his wishful ambition
to close his career in India in a blaze of glory with another After a series of laboratory experiments, Rogers, with
therapeutic triumph—“the successful treatment of leprosy”. technical assistance from Indian organic chemists, settled
Rogers's collaborator in India was Ernest Muir (1880-1974) on the water-soluble sodium salt of the fatty acids of
a medical missionary who came to India in the first decade chaulmoogra—sodium chaulmoograte. Therapeutic trials
of the twentieth century with a primary interest in kala were launched in late 1915, and results were published
azar. It was Rogers who inducted him into full-time leprosy frequently as more patients were added. In some patients
work. Unlike most missionaries at the time, Muir was very given the injection sub-cutaneously for "six months and
well qualified, with a postgraduate degree from his alma over"; Rogers claimed that lost sensation and muscle power
mater the Edinburgh Medical School; his association with had returned. His next 'advance' was intravenous 3%
Edinburgh was to prove crucial in his leprosy work. sodium chaulmoograte, which was declared to be not only
It was a hoary belief in Indian folk medicine and painless, but better than the subcutaneous route at initiating
ayurveda that seed oils from certain indigenous tree species softening of nodules, clearing bacilli, and overall clinical
were potent remedies for skin diseases, especially leprosy. improvement.32
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His first consolidated report was published in India in hydnocarpate injection in early leprosy. The most fulsome
1917, containing a tabulated summary of "two years' flattery (flattery: insincere praise) came from the authorities
experience" with the sodium chaulmoograte administered at the Mission Asylum and Hospital at Dichpalli,
subcutaneously and intravenously to 26 patients.33 Nizamabad, where 90% of early cases were discharged
Although claiming "two years' experience", his Table shows "symptom-free". Hydnocarpus acquired iconic status in
that actually just 2 patients of the 26 had been treated for the Hospital (Fig. 1.15). Unfortunately the early impressions
that length of time! By 1919 sodium chaulmoograte had were to be belied: By the early 1930s John Lowe originally
been replaced with sodium hydnocarpate (hydnocarpus of Dichpalli, who succeeded Muir at the Calcutta School
oil being more easily available), and by 1920, (Rogers's in 1935, turned from enthusiast to a strong critic of
last year in India), his final patient tally from 5½ years chaulmoogra-based treatments. Muir himself became a
work with the compounds was 51 cases, of whom 13 had sceptic, placing greater confidence in upkeep of general
been given the treatment (intravenously and/or sub- health and morale to ameliorate leprosy.
cutaneously) for "upwards of a year". He waxed eloquent
over the "unique" ability of this drug of plant origin to induce
local "reactions" and active destruction of leprosy bacilli,
but glossed over the serious side-effects of intravenous
administration-dizziness and fainting, and venous
thrombosis.
In England, Rogers talked and wrote repeatedly of the
series of 51 patients before august medical bodies and in
prestigious medical journals. In 1924, he used the study
cases to launch an ambitious campaign to "stamp out
leprosy in the British Empire ... probably within three
decades" (sic).34
At the end of over four years' patient work, 82% of 50
cases treated for from three to eighteen months were either
greatly improved with good prospects of completely
clearing up, or had already lost all symptoms and become Fig.1.15: Emblem (1934) of the Victoria Hospital, Dichpalli, Nizamabad,
free of the bacillus, a little over half falling into the apparently incorporating hydnocarpus tree and syringe. The 3-point Motto
translates as: “Faith Oil Work”
cured class.35
It was Britain's imperial duty, declared Rogers, to
provide "our lepers" with the benefits of the latest treatment. Rogers's therapeutic trials were flawed methodologically
The organization, which Rogers was largely responsible even by the standards of his day. Rigorous scientific trials,
for launching, was the British Empire Leprosy Relief as we know them today, were still a matter of future, but
Association (BELRA). A contemporary ironically observed Rogers made no attempt whatever at objectivity. The bluff
that BELRA (today known as LEPRA, one of the most of "chaulmoogra" enthusiasts such as Rogers, came to
successful non-sectarian international leprosy NGOs), was the fore in 1931, when the Leprosy Commission of the
in effect, founded on thirteen leprosy cases treated "for League of Nations pointed out that the so-called remedy
upwards of a year" with the sodium salts!.36 had never been subjected to double-blind controlled clinical
The sodium salt treatment had some enthusiastic trials, hence "no conclusive evidence exists of the efficacy
supporters in India. Muir himself was initially impressed of chaulmoogra as such".37
enough by the results he obtained with it in Mission asylum Ironically, the most influential critic of chaulmoogra oil
inmates in Bengal, to agree to Rogers's suggestion to take emerged from BELRA's own ranks. Robert Cochrane (1899-
up full-time leprosy work at School of Tropical Medicine at 1985), BELRA Medical Secretary, who was like others,
Calcutta in 1921, in order to exploit the potential of the initially well-disposed to the therapy, but became
therapy. disillusioned and expressed his opinion forthrightly. He
In England Rogers, as BELRA Medical Adviser, was wrote after an extensive tour of the Indian sub-continent in
particularly gratified by favorable reports on sodium 1934, that he discerned "an altogether more reasoned
CHAPTER
1
outlook" which emphasised leprosy prevention by selective which provided him an unparalleled opportunity to refine
segregation, rather than oil treatment of early cases.38 his ideas and make improvements in the treatment itself.
For some reason, the League of Nations recommended By 1925 he had demonstrated the feasibility of diagnosis
trials never got materialized: hydnocarpus and and treatment of early cases at the School's Out-patient
chaulmoogra oils retained their place in the British clinic, which suggested to a wider application of the clinic
Pharmacopoeia till the 1940s. Another irony was that in concept. The opportunity came with Rogers's establishment
India, the country where it was first introduced, Rogers's of BELRA in 1924 in England, which was followed the
sodium hydnocarpate never became the preferred next year by its Indian auxiliary, the Indian Council
treatment for leprosy. It was supplanted by intradermal (ICBELRA). Launched through an eloquent public appeal
injection of the purified, freshly expressed hydnocarpus by the Viceroy Lord Reading, ICBELRA was so generously
oil itself, which Muir declared to be more "effective", funded by Indian donations that it was able to function
cheaper and easier to purify. independently of the parent body in London. Muir, as its
Leprosy Expert and Research Worker, authored and
INDIAN COUNCIL OF THE BRITISH EMPIRE supervised a country-wide disease control strategy
LEPROSY RELIEF ASSOCIATION (ICBELRA) (launched in 1926), to optimize the benefits of "the
favorable results obtained from the new treatment".41 The
Very early in their collaboration Rogers and Muir foresaw a "Propaganda, Treatment, Survey" (PTS) scheme, as it
bright future for leprosy eradication through sodium came to be known, was a pattern-setting strategy emulated
chaulmoograte/ hydnocarpate treatment—a future which around the British Empire. It inspires the national control
they outlined at a Mission to Lepers ( today's The Leprosy schemes even today.42
Mission or simply TLM), Conference held at Calcutta in 1920. As suggested by its name, PTS was tri-linked, and
Their ideas inaugurated the chaulmoogra era in India and attention was directed as much on patient's family and
the British Empire. Rogers envisioned transformation of leper community as the patient himself. PTS's most tangible
asylums into leprosy hospitals for early leprosy detection manifestation was the leprosy clinic, inspired by the
when the disease was most amenable to the salt treatment: pioneering "tuberculosis dispensary" scheme fashioned
Recent improvements of methods of injection… have by Sir Robert Philip at Edinburgh in the first decade of the
now reached a stage … affording hope of more satisfactory twentieth century. It may be recalled that Muir himself was
results when our leper asylums can be converted more a product of the Edinburgh Medical School.43
into leper colonies and hospitals, to which earlier cases Propaganda was carried out in the clinic through health
will be attracted by the prospect of receiving beneficial posters directed at the patient, as to how and why he had
treatment with even some hope of ultimate cure.39 become a victim of leprosy, the measures he must adopt
Muir went a step further and outlined a strategy for to improve his condition and prevent the spread of the
leprosy control centerd on upgrading the scientific skills disease to his family. The serious consequences of
of leprosy physicians and through education of patients neglecting to segregate an infectious family member in
and the public: the home was emphasised. A glance at Figure 1.16 shows
[Medical] men should … be further trained and that greatest importance was attached to general health
encouraged to keep up to date in all improvements in measures, and less to "specific" treatment with the oil.
treatment. Wherever the treatment is carried out the doctor Muir, carrying the analogy of tuberculosis into leprosy,
should be trained in the use of the microscope if possible.... remained a great believer in the prophylactic and therapeutic
With a view to bringing early cases as soon as possible value of fresh air, high morale, nourishing food and cleanli-
under treatment every effort should be made through ness. The dominant message (perhaps inadvertently)
schools and the press to educate the public of the cause, conveyed by PTS propaganda was that a person got
early symptoms and the hopefulness of treatment in early leprosy because he was dirty, lazy, ate unwisely, and
cases, and inducements [to the patients] should be created careless in protecting himself. A poverty-stricken laborer,
to undertake treatment.40 attending the clinic on the promise of effective treatment,
Muir joined the newly opened Calcutta School of Tropical might well have been disappointed to learn that his disease
Medicine in 1921 as Head of the Leprosy Department, was due to his own fault.
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1
Fig.1.16: Some propaganda posters brought out in Kolkata by the Indian Council
of the British Empire Leprosy Relief Association, 1930s. Scans kindly supplied by Ms. Allen, LEPRA, UK
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1
Treatment was made available in leprosy clinics manned few weeks, travelling long distances. Conducting the
by medical personnel trained in the diagnosis of early community survey was facilitated by using clinic patients
leprosy. Patients were registered and administered as intermediaries. Santra always pointed out that leprosy
hydnocarpus oil injections to prevent them from slipping rates in India were far higher than those supposed from
into the infectious stage. Family contacts were called for the general decennial population censuses. Muir and Santra
examination, and the statistics were compiled. By all were greatly influenced by each other. For example, initially
accounts, twice-weekly intralesional injections of Muir supposed that he had the explanation for the high
hydnocarpus oil were painful. Muir estimated that eighty frequency of positive Wassermann tests among those
to one hundred needle punctures were required to deliver attending the leprosy out-patient clinic at Kolkata: "The
5 ml of the drug (Fig. 1.17), added to which was the fact conclusion is obvious, all these positive reactions in early
that the optimum duration of treatment had not been leprosy are due to syphilis".44 This implied that lepers were
standardized. As one American leprosy sufferer remarked: sexually promiscuous. Santra confidently declared: "We
"Chaulmoogra oil was to be taken internally, externally, do not generally ask our patients if they have suffered
and eternally". from Syphilis but we ask straight off as to when they
suffered from it".45
Both men conceptualized the spread of leprosy in India
as the penalty for the breaking of traditional social barriers
by urbanization and industrialization.
Santra—Leprosy-free adivasis stepped out of their
pristine forests into leprosy-ridden industrial ghettos in
search of employment and became infected by mixing
with low-caste lepers.
Muir—Leprous low-caste domestic servants infected
the children of "highly civilized" high-caste Brahmins in
the city.46
Almost every feature of the traditional Indian rural social
scene, such as the joint family, early marriage, the village
barber, wandering sadhus were blamed for the spread of
leprosy in a community47 (Fig. 1.19).
OTHER ICBELRA INITIATIVES

Two ICBELRA initiatives launched under Muir's guidance,
are still with us today. The first was the launch of the Journal
Leprosy in India in 1929 (now known as Indian Journal of
Fig.1.17: Multiple intralesional injections of Hydnocarpus
oil were required
Leprosy), the first such in the country, if not the English-
speaking world. Leprosy Review (published by BELRA in
England) was first published in 1930, while the International
The survey arm of PTS was conducted by Muir's Leprosy Association's International Journal of Leprosy first
disciple Isaac Santra (1892-1968) of Sambalpur (Orissa) came out in 1933.
who, as ICBELRA's Chief Propaganda Officer tirelessly The second important initiative was the convening in
toured all parts of the country, including adivasi regions, 1933, of the first conference of personnel working in various
conducting surveys, setting up clinics for the cases disciplines in the field of leprosy (including doctors,
detected, and training local health authority doctors in leprologists, rehabilitative persons, social workers, etc.)
diagnosis and treatment, before passing to the next station in the country, to discuss various problems and to suggest
(Fig. 1.18). His reports in Leprosy in India make interesting guidelines for improvement (Fig. 1.20). Some of the original
reading, revealing as much about contemporary social attendees (exclusively medical graduates) were
perceptions as Santra's own biases. Some clinics were instrumental in forming the Indian Association of
reported to have attracted hundreds of patients within a Leprologists (IAL) in the post-independence period, and
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1
Fig. 1.18: Isaac Santra (Left); ICBELRA Survey party setting up a Leprosy Clinic to be run by the Union Board of villages in rural Bengal,
1930s (Right). From Leprosy in India, July, 1934
Fig.1.19: ICBELRA publications faulted familiar rural customs as agents in the spread of leprosy47
thus, the first body of IAL was constituted in 1950 with to which was the discomfort and pain associated with intra-
Dr Dharmendra (the father figure of leprosy in India) as its dermal injection. Their dissatisfaction was expressed in
first President. absenteeism at leprosy clinics, including that at the
By the mid-1930s, however, portents of failure were Calcutta School. Patients were probably put off by Muir's
discernible on the treatment front—the crux of the entire philosophy of vigorous exercise, fresh air and nutritious
PTS edifice. Patients appeared unimpressed by the diet for remedying and preventing leprosy, where the blame
claimed results of chaulmoogra oil-based treatment, added and the onus of recovery was placed squarely on them.
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Fig. 1.20: The First “All India Leprosy Conference” held at Kolkata in 1933. The group comprised physicians
engaged in leprosy work in India. RG Cochrane attended as BELRA Secretary.
Seated on floor : BN Ghosh, DN Mukherjee
Seated (Left to Right) : I Sen, J Lowe, CR Avari, E Muir, SN Chatterjee, RG Cochrane, V Rambo.
Standing (Left to Right) : GR Rao, S Jaikaria, AD Miller, HN Gupta, CS Ryles, HH Gass, PC Verghese, DS Baxter, I Santra, AT Roy
From Leprosy in India, 1933
Lastly, the political scenario in India after 1920 Revision of Policy…. In other words, without effective
(Montagu-Chelmsford Reforms) was not conducive to the isolation of all -or at least the great majority—of dangerous
success of ICBELRA's initiative. Provincial governments lepers, there is little hope of controlling and curtailing the
to whom executive responsibilities were devolved in the disease…. [E]ven more prominence must be given to
Reforms, had meagre funds, and were not enthusiastic isolation.48
about taking on leprosy among their numerous other health
and medical responsibilities. ROBERT COCHRANE(1899-1985)
On the retirement of Muir from India in 1935, and the arrival
DEATH OF THE CLINIC: RESURGENCE
in the country of Robert Cochrane as a medical missionary,
OF SEGREGATION
the center of influence in leprosy shifted once again—this
When BELRA was founded in 1924 the chief emphasis time from Bengal to Madras Province. Cochrane, two
was laid upon treatment. As a result of ICBELRA's work decades younger than Muir, was like him, Scottish and
leprosy was found to be more frequent than was at first medically well-qualified, and moved seamlessly between
supposed, with the non-infectious variety predominating. the Mission to Lepers and secular BELRA (Fig. 1.21).
The majority of the affected thus did not spread the disease, Cochrane became the chief spokesman for leprosy in India
but a single infectious case had the potential to transmit in the immediate pre-independence period (1935-1947) and
the disease, especially to children. A change in emphasis left his imprint on official policy, besides training a dedicated
was required, which was eloquently articulated by BELRA band of pioneer Indian leprologists. In addition, he was the
(probably by Cochrane): "catalyst" instrumental in the entry of specialists from other
CHAPTER
1
graduate medical curriculum. He was thus a pioneer in

bringing leprosy into the mainstream of medicine. His pre-
occupation with isolation not withstanding, it should be
emphasized that this originated in his scepticism about
chaulmoogra oil treatment, not treatment per se. It is not
surprising that the two leprologists—John Lowe and Robert
Cochrane - who contributed significantly to inaugurate the
Dapsone tablet era in India and the British Empire, were
the products of the Indian experience and also the earliest
critics of chaulmoogra oil therapy.
THE BHORE COMMITTEE

The Montagu-Chelmsford Reforms passed on the health
Fig. 1.21: Robert G Cochrane care (including leprosy services on the PTS pattern) and
the other responsibilities, to Provincial and local health
medical disciplines, e.g. Vasant Khanolkar (pathologist), authorities who unfortunately, were cash-strapped. The
and Paul Brand (surgeon) into leprosy work. aloofness of the Central Government for the execution of
It was in Madras Presidency that leprosy "prevention" the ICBELRA Control Program was also a major reason
by isolation of the infectious in institutions was pursued for the failure of ICBELRA to achieve anything substantial.
most energetically. The leprosy clinic's prime purpose The issue was addressed to some extent in the Government
shifted from detection and treatment of the early case, to of India Act of 1935 with the appointment of a Central
netting persons with infectious leprosy for admission into Health Advisory Board to coordinate health services
leprosy settlements. The phrase "leprosy can be cured" throughout the country. Its Report on Leprosy has been
was studiously avoided in ICBELRA's Madras Provincial referred to above. The International Leprosy Congress at
Branch campaign, which for practical purposes became Cairo in 1938 also urged national Governments to involve
PSS (Propaganda, Survey, and Segregation). Most telling themselves actively in leprosy control.
of the change in emphasis was that Muir's landmark In all histories of public health in modern India the
"Propaganda, Treatment, Survey" scheme did not merit starting point is the "Health Survey and Development
even a mention in a report to the Government of India, Committee" (known as the Bhore Committee, after its
which had Cochrane and the like-minded John Lowe among Chairman Sir Joseph Bhore), which was constituted in
the authors. "Group isolation" of infectious patients in preparation for independence. The Committee's
villages, as carried out in Madras, in the endemic districts Recommendations on Leprosy which are summarized
was recommended for wider adoption.49 Cochrane declared below, show the long shadow cast by Robert Cochrane:
that "without adequate [voluntary] institutional acco- 1. Creation of provincial leprosy organizations.
mmodation a complete anti-leprosy system is impossible 2. Increase of the existing provision for institutional
to organize".50 He deprecated the view that leprosy could treatment of out-patients and in-patients.
be controlled by treatment alone, re-iterating that the most 3. Development of group isolation colonies.
effective methods were (1) the segregation and treatment 4. Substantial financial help to voluntary organizations
of infective cases; (2) the prevention of child leprosy. engaged in anti-leprosy work.
In addition to superintending the Lady Willingdon 5. Establishment of a Central Leprosy Institute for training
leprosy asylum at Chingleput, Cochrane successfully of doctors, promotion of research, and provision of
lobbied the Madras Provincial health authorities for opening information on best practices to governments and
leprosy out-patient departments in public hospitals, and voluntary organizations.51
for (non-infectious) leprosy patients suffering from other
diseases to be treated in general medical wards. At the INSTITUTIONS
Christian Medical College at Vellore, of which he later The medical texts of Susruta, Charaka and Vagbhata,
became the Principal, leprosy was taught in the under- compiled in the first to the sixth century CE, show that
CHAPTER
1
Indian physicians regarded leprosy as a disease to be infesting the streets of prosperous colonial cities such as
cured or alleviated. As for the Indian [Hindu] leper himself, Mumbai (see below) and Calcutta. Thirdly, leprosy
a moral taint as well as civil disabilities hung over him, institutions had medical justification. Hereditarians saw
which they had over and above his medieval European them as places to ensure sexual segregation of lepers
counterpart. According to Manusmriti, the leper was entitled and prevent the hereditary transmission; contagionists
to maintenance and care from his kin, but he could not regarded them as a measure to isolate dangerously
inherit property. Generous family spirit was not invariably contagious persons; sanitarians thought these were the
shown to him, since thousands of sufferers—men, women places to re-invigorate and rehabilitate demoralised
and children—were expelled from their homes to join other sufferers in a wholesome environment. To Christian
bands of vagrants, mendicants and destitutes. It was for missionaries, who soon dominated the field, leprosy
persons in such straits (who were not necessarily lepers), asylums provided scope and space for preaching the
that shelters called dharmashalas were established and gospel.54
maintained by communities, princely rulers and devout The large-scale involvement of Protestant missionaries
persons. Dharmashalas were generally situated near with leprosy asylums in India commenced with the founding
temples, holy places or in the larger towns and cities. Such of "The Mission to Lepers in India and the East" (today
institutions, therefore, traditionally accommodated all known as "The Leprosy Mission") by Wellesley Bailey in
varieties of needy and handicapped persons, there being 1874.55 The Mission established its own asylums and also
no facilities, or even intention, to regard lepers as a special aided other Protestant denominations involved in leprosy
class of indigent requiring isolation. Dharmashalas were work. The asylums at Purulia in Bengal, Faizabad and Naini
used as temporary night shelters for those who might in Uttar Pradesh, Vadathorasalur in Tamil Nadu are but a
spend their days begging for alms.52 Sometimes, the few of such notable institutions.
ravages of his disease drove the leper to suicide. At times The scale and modalities of leper segregation in Mission
he was assisted to end his life by well-meaning and pious institutions evolved over decades, largely as a result of
relatives. This shows that being helped to "die with dignity" the entry of medically and technically qualified missionaries
is not a modern concept. The favored modes of ending the into leprosy work. Pioneering agricultural experiments were
lives sanctioned by the scriptures were drowning, burial undertaken by Dr Isobel Kerr and her husband at the Victoria
alive and jumping off the sea-side cliffs.53 Hospital at Dichpalli; and by Sam Higginbottom at Naini.
The concept of an institution for a special category of The inmates were taught improved farming practices in
sick is a peculiarly European one, and leprosy (and lunatic) the expectation that they would disseminate the new ideas
asylums were and are some of the tangible symbols of when they returned to their villages. Robert Cochrane
India's colonial encounters. Some nineteenth century devoted much attention to making segregation and
leprosy historians attributed the disappearance of leprosy isolation acceptable, practicable and effective. He
from medieval Europe partly to such institutions. One of envisaged leprosy sanatoria, leprosy colonies, domestic
the first leper asylums in India was established by the isolation, night isolation of infectious lepers outside the
Dutch at Cochin in 1728. Probably the first institution village, and leprosy-affected children's sanatoria. The aim
established under British aegis was that at Almora (now in was to fashion all-round morally regenerated persons rather
Uttarakhand) in 1835, by Henry Ramsay, Chief than merely 'cured lepers'. Kakar has written an important
Commissioner of Kumaon. It is of interest to examine the account of the impact of policies and medical
purpose of establishing such institutions from medical, developments on leper inmates in Mission asylums in India
social and political angles. in the early twentieth century.56
While there is no doubt that genuine charitable feeling The "Homeless Leper Asylum" which was established
and pity inspired many such acts, associated intentions in Mumbai in 1890 (Fig. 1.22) was unique in many ways.
were equally important. Firstly, such acts bolstered British Housing over 300 pauper lepers, it was the largest non-
colonialism's anxiety to project itself as a caring system sectarian institution in the country. It was built by Harry
amidst "apathetic" and "unfeeling" Hindu society. Secondly, Acworth, the Municipal Commissioner of Mumbai, in order
by the end of the nineteenth century the leprosy asylum to purge the streets of leper beggars. The seed money
became the solution to the fear and loathing caused to was donated entirely by the shethias and ordinary citizens
well-to-do urban Indian society by crowds of begging lepers of Mumbai and the rulers of princely states subservient to
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1
Fig.1.22: Abandoned military barracks were converted into the “Homeless Leper Asylum” at Mumbai in 1890. (Left)., http://
www.skyscrapercity.com/showthread.php?p=18133253; The first group of women inmates at the Asylum in 1890 (Right). Photograph at
Acworth Leprosy Hospital archives
the Mumbai Government. Maintenance funds were provided Indian cities. However, in 1889, medical circles were not
equally by the Provincial Government and the Municipality. yet of one mind on the etiology of leprosy, and sceptics
As such it was completely non-sectarian, with Acworth labelled the mass hysteria in India as the motivated one,
declaring that he did not care about the criticism from and warned against police zoolum (atrocity) against the
missionaries that he was encouraging 'idol worship'. The hapless leper. In 1890, a four-member Leprosy Commission
inmates' religious and caste preferences were respected, was despatched from London to report on the disease in
and there was no rigid rule on segregation of the sexes. India and make policy recommendations. The
This asylum was a pioneer in other respects too—it was Commissioners concluded that though leprosy was an
here that biogas was first used for lighting and sewage infective disease, caused by a specific bacillus, and
farming, adding to the income of the institution. An moreover also a contagious disease, there was not
interesting account of the early years of the institution sufficient evidence that it was diffused by contagion
was authored by its first Superintendent, NH Choksy.57 (contact). The amount of contagion in the surroundings
Indian social workers such as Baba Amte and Manohar was so small that it could be disregarded, they said. "No
Diwan in Maharashtra (inspired by Gandhi Ji and Vinoba legislation is called for on the lines of either segregation or
Bhave), who entered leprosy work around the time of the interdiction of marriages with lepers".58 The Commission
independence were also agreed on the importance of therefore rejected compulsory segregation, but
isolation. Their institutions were situated in the rural areas, recommended asylums situated near cities to house pauper
non-sectarian and run in accordance with the Gandhian lepers.
ideals of simplicity and service. The recommendations formed the basis of "The Lepers
Act" of 1898, the only leprosy-specific legislation enacted
by the British (Fig.1.23).
LEGISLATION
The well-to-do leper was not compulsorily isolated; the
The time-line of leprosy history in colonial India shows a Act initially mandated institutionalization of ulcerous pauper
sharp politicization of the leprosy problem in the last two lepers only. Following representations from the Mission to
decades of the nineteenth century. The immediate trigger Lepers, its purview was extended to all pauper lepers. Such
was the death from leprosy in 1889, of Father Damien who persons were arrested and given a "Certificate" by a
had lived with the lepers at Molokai in Hawaii for fifteen competent medical officer before being despatched to the
years. The fact that a European had fallen victim to leprosy asylum. Lepers were also prohibited from plying trades/
was seized on by British imperialists, Indian alarmists and professions such as butcher, washer man, nurse, etc.
contagionists to agitate for segregation of lepers in major Existing institutions were slowly recognized as statutory
CHAPTER
1
Fig. 1.23: The Lepers Act of 1898. Gazette of India dated 5 February 1898
leper institutions under the Act. Governments gave grants- launched in 1955, and fashioned by Wardekar, broke fresh
in-aid to such asylums, most of which were Mission-run; it ground by adopting the SET (Survey, Education &
was a symbiotic relationship since it was economical for Treatment) Program (implicitly derived from Muir's PTS
the State, and benefited the missionary enterprise too. scheme), with Wardekar's crucial added innovations. The
However, on the whole, the Act was a dead letter. leprosy asylum and leper isolation were downgraded as
The civil disabilities (e.g. in marriage and inheritance) being detrimental to patient co-operation. The SET Program
suffered by lepers were not redressed by colonial courts utilized trained leprosy paramedical personnel for field and
who preferred to be guided by Hindu Law and medical clinic activities and house-to-house visiting, spreading
evidence. Unfortunately, some civil proscriptions against "Health Education" rather than "Propaganda". Wardekar
leprosy sufferers still remain on the statute books. could afford to be optimistic about SET. Not only did he
have the full support of the Government of independent
India, but equally importantly, by 1955 he (and also the
CODA
rest of the world) was armed with the first well-researched,
A notable exception to the emphasis on segregation was scientifically proven therapy—Dapsone.
the Gandhi Memorial Leprosy Foundation (GMLF) which The downfall of PTS following the failure of chaulmoogra
entered the leprosy field in 1950 under the dynamic oil had proved that without the backing of a credible
leadership of its Director, the noted pathologist Dr Ram treatment, there could be no successful SET Program
Chandra Wardekar. The National Leprosy Control Program either.
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1
REFERENCES 25. Rogers L, Muir E. Leprosy, Bristol, John Wright and Sons, 1925,
1940, 1946.
1. Danielssen DC and Boeck CW. Traite de la Lepre, Paris, Balliere, 26. Rogers L, Muir E. Leprosy. Bristol, John Wright and Sons, 1940,
1848. 172-74.
2. Hansen GA, Looft O. Leprosy in its Clinical and Pathological 27. Cochrane RG. A Practical Textbook of Leprosy, London, Oxford
Aspects, Transl. N. Walker, London, John Wright, 1895, 86. University Press 1947, 66-67.
3. Pandya SS. "Anti-Contagionism in Leprosy 1844-1897", Int J 28. Sehgal VN, Jain MK, Srivastava G. Evolution of the Classification
Lepr 1998; 66:374-84. of Leprosy. Int J Dermatol 1989; 28:161-67.
4. Drognat-Landré CL. De la Contagion Seule Cause de la 29. Memoria del VI Congreso Internacional de Leprologia, Madrid,
Propagation de la Lèpre, Paris, Germer Baillière, 1869, 19-25. Octobre de 1953; 75-80.
5. Hansen GA. "On the Aetiology of Leprosy", Brit Foreign Medico 30. Muir E. "Nerve Abscess in Leprosy". Ind Medical Gaz February
Chirurg Rev1875; 55: 459-89. 1924, 87-89.
6. Carter HV. Report on Leprosy and the Leper Asylums in Norway, 31. Rheede V. Hortus Malabaricus, Amsterdam, 1687, Vol. 1, Plate
London, Her Majesty's Stationery Office 1874, 27. 36.
7. Carter HV. "Memorandum on the Prevention of Leprosy by 32. Sir Leonard Rogers, "Preliminary Note on the Intravenous
Segregation of the Afflicted", Bomb Gov Gaz, dated 7/12/1882 Injection of Gynocardates of Soda in Leprosy". Brit Med J, 1916;
8. Pandya SS. "The First International Leprosy Conference, Berlin, 550-52.
1897: The Politics of Segregation". Indian J Lepr 2004;76:51-70. 33. Rogers L. "Two Years' Experience of Sodium gynocardate and
9. Sinha KK. "Francis Buchanan (Hamilton): Physician, Botanist Chaulmoograte Subcutaneously and Intravenously in the
and Surveyor", Proc Roy Coll Physicians Edin, 1993; 23:36-42. Treatment of Leprosy". Indian J Med Res 1917; 5: 277-300.
10. Robinson J. "On the Elephantiasis as it Appears in Hindoostan". 34. "British Empire Leprosy Relief Association", 1924. Wellcome
Medico-Chirurg Trans 1819; 10: 27-37. Institute of the History of Medicine, ROG/C.13/126-364/BOX8.
11. Carter HV. On Leprosy and Elephantiasis, Eyre and 35. Editorial. "The British Empire Leprosy Relief Association". Lancet,
Spottiswoode, 1874. 1924: 306.
12. Carter HV. "Note on the Pathology of Leprosy". Maharashtra 36. Tomb JW. "Chaulmoogra Oil and its Derivatives in the Treatment
State Archives General Department, 1883: Publication No: of Leprosy", Part III, J Trop Med and Hyg 1933; 36: 201-07.
14494, Appendix 7. 37. Report of the Study Tour of the Secretary of the Leprosy
13. Scheube B. The Diseases of Warm Countries, Transl. P. Falcke, Commission in Europe, South America and the Far East January
edited by James Cantlie, 2nd. Rev. Edition, London, John Bale, 1929-June 1930. Geneva, League of Nations No: C.H. 887,
Sons and Danielsson, Ltd., 1903, 231-89. 1930, 39-40.
14. Rogers L. "Leprosy" in Sir Leonard Rogers and John WD Megaw, 38. Cochrane RG. "Leprosy in India and Ceylon", Lepr Rev 1934; 5:
Tropical Medicine, London, J&A Churchill, 1930, 320-44. 28-32.
15. Rogers L. "The Treatment of Leprosy", Ind Medical Gaz, April 39. Report of a Conference of Leper Asylum Superintendents and
1920; 125-28. Others on the Leper Problem in India, under the Auspices of the
16. Carter HV. "Case of Anaesthetic Leprosy with Post-mortem Mission to Lepers, Cuttack. Orissa Mission Press 1920; 8-23.
Examination and Remarks", Trans. Medical and Physical Soc. 40. Muir E. "The Results of Trials of Sodium Hydnocarpate and
Mumbai, VII :(1862) xxviii-xxix. Sodium Morrhuate in Thirteen Leper Asylums in India", Report
17. Carter HV. "On the Symptoms and Morbid Anatomy of Leprosy: of a Conference of Leper Asylum Superintendents and Others
with Remarks", Trans. Medical and Physical Soc. Mumbai, VIII: on the Leper Problem in India, under the Auspices of the Mission
(1863) 1-104. to Lepers, Cuttack. Orissa Mission Press 1920; 32-33.
18. Sunderland S. "The Internal Anatomy of the Nerve Trunks in 41. "Annual Report of the British Empire Leprosy Relief Association,
Relation to Leprosy". Brain 1975; 96:865-88. Indian Council, 1926", 1.
19. Virchow R. "Virchow's Leprosy: From Die Krankhaften 42. Andy A Louhenapessy, Bos Zuiderhoek, "A Practical Method of
Geschwulste" (Berlin 1863), Part II; Transl. G. L. Fite, Int J Lepr Active Case Finding and Epidemiological Assessment: its Origin
1954; 22: 205-16. and Application in the Leprosy Control Project in Indonesia." Int
20. Dehio K. "On the Lepra Anaesthetica on the Pathogenetical J Lepr 1997; 65: 487-91.
Relation of the Disease Appearances", Transl. M.G. Biswas, 43. Muir E. "Past and Future of Anti-Leprosy Work in India", Lepr
Lepr India 1952; 24:78-83. India 1951; 23:8-13.
21. Mettler CC. History of Medicine, Philadelphia, The Blakiston 44. Lloyd RB, Muir E, Mitra GC. "The Influence of Syphilis on Leprosy
Company 1947, 471-72. as indicated by the Wassermann Reaction". Indian J Med Res
22. Sticker G. Mittheilungen und Verhandlungen derInternationalen 1926; 14:667-78.
Wissenschaftlichen Lepra-Conferenz zu Berlin 1897, Vol. 2, 55- 45. "Annual Report of BELRA", 1933, 73.
59. 46. Muir E. "The Infectiousness of Leprosy". Ind Medical Gaz,
23. Unna PG. Histologischer Atlas zur Pathologie de Haut,, Hamburg, November 1929, pp. 620-23.
Verlag von Leopold Voss, 1909, Figs. 255, 256. 47. Muir E. "How Leprosy is spread in the Indian Village". Lepr India
24. Jadassohn J. "Lepra" in W. Kolle und A.V. Wassermann, (eds.) 1932; 4: 63-66.
Handbuch der Pathogenen Mikroorganismen, Berlin, Gustav 48. "Leprosy: a Problem of Colonial Development", Report for 1936
Fischer und Urban & Schwarzenberg 1928; 1150. of the British Empire Leprosy Relief Association, 4.
CHAPTER
1
49. Report on Leprosy and its Control in India, Central Advisory 54. RS Kipp. "The Evangelical Uses of Leprosy", Social Science
Board of Health, Government of India, New Delhi 1942. and Medicine 1994; XXXIX: 165-78.
50. Cochrane RG, "Leprosy Control with Particular Reference to 55. Jackson J. Lepers: Thirty One Years' Work among Them, Being
the Madras Presidency", Lepr India 1945; 17: 47-57. the History of the Mission to Lepers in India (1874-1905). London,
51. Report of the Health Survey and Development Committee, Marshal Brothers, 1905.
Vol. IV: Summary. Government of India Press, New Delhi 56. Kakar S. "Medical Developments and Patient Unrest in the
1946,43-45. Leprosy Asylum 1860-1940". Social Scientist 1996; 24: 62-81.
52. Anonymous. "Notes on Early Leprosy Institutions in India". Lepr 57. NH Choksy. Report on Leprosy and the Homeless Leper Asylum
India 1940; 12:85-87. Matunga, Mumbai (1890-97). Mumbai, British India Printing Works
53. Pandya SS. "Very Savage Rites: Suicide and the Leprosy 1900.
Sufferer in Nineteenth Century India". Indian J Lepr 2001; 73: 58. Leprosy in India: Report of the Leprosy Commission in India
29-38. (1890-91), Calcutta. Government Printing Press 1892, 289-90.
CHAPTER
2
2
Epidemiology
Dhaval M Thorat, Pankaj Sharma
INTRODUCTION treatment the persons affected with leprosy can lead

productive life in the community.
Leprosy is a chronic infectious disease caused by
Mycobacterium leprae. It usually affects the skin and
peripheral nerves. It can also affect muscles, eyes, bones, LEPROSY AND INTERNATIONAL
testes, and other internal organs. Leprosy has a wide range DISEASE CLASSIFICATION
of clinical manifestations. Occurrence of the disease International classification of diseases ICD-10 was
depends upon the immunological status of the individual endorsed by the forty-third World Health Assembly in May
which in turn is influenced by genetic factors. Perhaps it is 1990 and came into use in WHO Member States as from
the only bacillus that can invade nerves causing nerve 1994. The classification is the latest in a series which has
damage leading to disability. The epidemiology of leprosy, its origin in the 1850s. The first edition, known as the
particularly its transmission is still not fully understood. International List of Causes of Death, was adopted by the
The disease is mainly classified as paucibacillary (PB) International Statistical Institute in 1893. WHO took over
and multibacillary (MB), leprosy depending on the number the responsibility for the ICD at its creation in 1948 when
of skin lesions and nerve involvement. Paucibacillary the Sixth Revision was published which included causes
leprosy is a milder disease characterized by few (up to of morbidity for the first time. The World Health Assembly
five) hypopigmented, pale/reddish colored, hypoesthetic adopted in 1967 the WHO Nomenclature Regulations that
or anesthetic skin lesions, which at many times are stipulate use of ICD in its most current revision for mortality
infiltrated. Multibacillary leprosy is associated with multiple and morbidity statistics by all Member States.
(more than five) skin lesions, which manifest as nodules, The ICD is the international standard diagnostic
plaquesor with diffuse skin infiltration. classification for all general, epidemiological, health
Among the communicable diseases, leprosy is a management purposes and clinical use. These include the
leading cause of permanent physical disability. Due to the analysis of the general health situation of population groups
involvement of peripheral nerves, there is weakness of and monitoring of the incidence and prevalence of diseases
muscles and loss of sensations in hands, feet and eyes and other health problems in relation to other variables
leading to ulceration and deformity. However, timely such as the characteristics and circumstances of the
detection and treatment of cases (including leprosy individuals affected, reimbursement, resource allocation,
reactions and neuritis) before nerve damage has occurred, quality and guidelines.
is the most effective way of preventing disability due to It is used to classify diseases and other health problems
leprosy and its complications. Social stigma and recorded on many types of health and vital records
discrimination associated with leprosy is mainly due to including death certificates and health records. In addition
disability and ulcers caused by the disease. Therefore, to enabling the storage and retrieval of diagnostic
early detection of the disease and prompt treatment information for clinical, epidemiological and quality
prevents stigma and discrimination. With appropriate purposes, these records also provide the basis for the
CHAPTER
2
Epidemiology 25
compilation of national mortality and morbidity statistics Prevalence is not a very reliable epidemiological indi-
by WHO Member States.1 cator of leprosy, as it is subject to a number of confounding
factors. It reflects only the leprosy cases registered for
Leprosy in ICD-10 (Version 2007)2 chemotherapy, and no account is given of the patients
who are undetected or those who abandoned their treatment
A30 Leprosy [Hansen’s disease] some time ago. Registered prevalence is also subject to
Includes: Infection due to Mycobacterium leprae change abruptly if the treatment duration is changed
Excludes: Sequelae of leprosy ( B92 ) suddenly, e.g. when the treatment duration of WHO
A30.0 Indeterminate leprosy (I leprosy) recommended MDT for MB leprosy was changed in 1997
A30.1 Tuberculoid leprosy (TT leprosy) from 2 years to 1 year. At best it serves as an indicator of
A30.2 Borderline tuberculoid leprosy (BT leprosy) treatment load of the health service at a given time.
A30.3 Borderline leprosy (BB leprosy)
A30.4 Borderline lepromatous leprosy (BL leprosy) Criteria of Leprosy Elimination
A30.5 Lepromatous leprosy (LL leprosy)
A30.8 Other forms of leprosy WHO defines the “elimination of leprosy” as the
A30.9 Leprosy, unspecified achievement of prevalence rate below 1 case per 10,000
population (Fig. 2.1). Although adopted in most of the
Leprosy Control Programs globally, this definition has some
EPIDEMIOLOGICAL INDICATORS FOR
problems:
MONITORING
1. The rate of 1 case per ten thousand is completely
Epidemiology describes the distribution of disease in arbitrary.
populations with respect to variables like age, sex; and 2. The rate intended (when the elimination strategy was
also the determinants like host, agent and environmental launched) was based on the actual prevalence and
factors. There are several indicators to assist in monitoring not the prevalence of registered cases.
of leprosy control activities, the most important and 3. The strategy of elimination was based on the
commonly used are described below. assumption that transmission would be reduced, once
the prevalence is below a certain threshold. There is
Prevalence no scientific basis for such a hypothesis when the
Prevalence is the total number of leprosy cases in a defined fall in prevalence is the result of shortening of the
population at a specified time. It gives the total quantum duration of treatment; rather than of a declining
of case load in an area and is a useful indicator in planning incidence of the disease. Hence, the prevalence rate
health care activities in the specified area. However, if is often irrelevant.3
one needs to make an idea about the comparative
account of leprosy prevalence in different areas, then
this indicator does not convey the clear picture. For that
purpose, another indicator (called as rate) is used which
expresses the number of leprosy cases in a unit population,
e.g. cases per one thousand, or ten thousand or one lakh
or one million population. When the leprosy prevalence
was very high in pre-MDT era, the rates used to be
expressed in terms of per 1000; e.g. in Kanpur Dehat
district, the prevalence of leprosy was 18 per one thousand Fig. 2.1: The criteria of leprosy elimination as a public health problem
defined by WHO, usually expressed as less than 1 case per 10,000
during 1980. Later on following reduction of number of cases
population
after MDT success, reference is made to leprosy
elimination criteria of less than 1 per ten thousand
population, which itself is derived from the non-status of Incidence
the disease as a public health problem of less than 100 This indicates the number of newly detected cases in a
cases per one million population. defined population over a defined period of time (usually
CHAPTER
2
one year). For comparison in different areas, like prevalence, detected cases is usually high at the beginning of the
incidence is expressed in terms of number of cases per Leprosy Control Program, due to the fact that MB cases
unit population in one year. Incidence is the most effective would have accumulated over the years, and the PB cases
indicator of the transmission of disease. It gives an account would have undergone self healing in many cases. The
of the population at risk of getting the disease. If any definition of MB case itself has undergone considerable
disease control programs aims at prevention, the goal must changes over the years. In 1981, the MB-MDT was
be to reduce the incidence. Thus, incidence is a far better recommended for any case that fell in LL, BL and BB type
indicator than prevalence to judge the success of a disease of Ridley Jopling classification; or any case that had
control program. bacteriological index of 2+ or more at any site. In 1988, all
In case of leprosy the true incidence is difficult to obtain cases with BI smear positivity were to be considered as
because it depends on the thoroughness of case finding/ MB. From 1995 onwards, the definition of MB is any case
reporting; and can also be confounded by over-diagnosis. with more than 5 patches with anesthesia or smear
Usually, the newly registered cases are considered as positivity (if facility is available) irrespective of the number
substitutes for incidence. Since the incidence is also of lesions. As a result of these changes in definition, the
influenced by age, reporting of case detection should be proportion of MB cases is increasing over the years.
expressed in two age groups above and below 15 years Moreover, MB leprosy is less frequent among females and
age. They can also be grouped separately as paucibacillary children; the MB proportion is likely to be influenced by
and multibacillary, by presence or absence of deformities. age and sex composition of the population under
consideration. MB proportion is also a good indicator for
Annual New Case Detection Rate estimation of drug requirements.
The annual new case detection rate (ANCDR) is the
indicator used in Leprosy Control Program and indicates
Lepromatous Rate
the new cases recorded in an area per one lakh population This is the proportion of cases with lepromatous leprosy,
over a period of one year. Since actual incidence is difficult among the total number of cases. This indicator was in
to estimate due to operational reasons, the case detection use in pre-MDT era when the definition of MB case was
is considered as a proxy indicator of incidence. Case different from that of today. Wide geographical differences
detection rate should also form the basis for evaluation of were seen in the proportion of MB cases across the world,
requirement for MDT supply. ranging from 5-70% (Table 2.1).4
Age and Sex Specific Prevalence Table 2.1: Variations in MB proportion in leprosy
cases across the world
and Incidence Rates
World region Prevalence (Low) Prevalence (High)
These indicators are used to remove the age and gender
related bias in reporting the data of leprosy cases. As is Africa Burkina Faso (4%) Tanzania (18%)
South America Honduras (17%) Cuba (63%)
well-known, that leprosy is comparatively less common in Oceania Solomon Island (19%) Tonga (45%)
children and women. The male predominance is observed Asia Myanmar (27%) Malaysia (63%)
in adults but in children the gender distribution is nearly
equal. Also leprosy is less common among children, more There did not seem to be any correlation between in
truely for lepromatous type. The most common type of the total prevalence in the population area and the proportion
disease among children is borderline tuberculoid. of lepromatous cases. Now since the redefinition of MB
case in last decade, the lepromatous rate of pre-MDT era
MB Proportion is no longer relevant.
The percentage of multibacillary cases among the total
number of new leprosy cases detected during the reporting Child Proportion
year. This is the percentage of children among all new cases
People with MB leprosy are considered to be more detected during the reporting year.
infectious, and thus more likely to be responsible for leprosy As in children very little time would have elapsed from
transmission. The proportion of MB cases among newly the time of getting infection, a high child proportion would
CHAPTER
2
Epidemiology 27
indicate an active and recent transmission of the disease. and divide into two every 12-14 days. The life span of
It is an important epidemiological indicator and is useful in M. leprae is about 6 months. They do not produce toxins
estimating the drug requirement for the program. Since and occur both extracellularly as well intracellularly with
most of the child leprosy cases fall in paucibacillary type, affinity for Schwann cells and cells of reticuloendothelial
the case detection through self reporting is bound to be system. They can remain dormant in various body sites
low, as the patches are hardly noticeable in majority of the and tissues causing relapse. The organism is killed by
cases. If active case finding is pursued, this proportion boiling and autoclaving. Its susceptibility to air, cold, water,
would be higher. drying and disinfectants is uncertain. The bacillary load is
highest in lepromatous cases.5
Deformity Rate Mycobacterium leprae grows best in cooler tissues like
the skin, peripheral nerves, upper respiratory tract and
This is expressed in terms of percentage of patients with
testes, sparing warmer areas. They are found in large
deformities among newly detected cases in a period of
quantity in the nasal mucosa and skin of earlobes, face
one year. This is expressed separately for grade 1 and
and buttocks.6 Number of antigens have been detected in
grade 2 deformities, as per the WHO grading (0, 1, 2). This
M. leprae, the most significant of which is the phenolic
indicates the delay in time between a case getting infection
glycolipid -1(PGL-1) detected on serological test. M. leprae
and getting diagnosed and treated. Decreasing this rate is
can survive outside the human body for 2 to 9 days
one of the major objectives of the control program. This
depending upon the environmental conditions. Successful
rate is usually high at the beginning of the leprosy control
transmission of M. leprae has been observed in
activities due to accumulation of backlog cases, and experimental animals like 9-banded armadillo and nude
stabilizes subsequently. mouse. M. leprae can be grown experimentally by injecting
them into the foot pad of mice. However, it has not yet
Basic Reproduction Rate (BRR) been shown to grow in artificial media. The natural life
This is an indicator of disease transmission, though not span of the bacillus in human body is not known, but
used very often. It is a measure of new cases arising from persisters have been isolated from patients even after 10
the index cases. For a disease to be considered as an years.7
epidemic the BRR must be more than one. It may be used
to monitor disease control. HOST FACTORS
Treatment Completion Rate Age
This is the proportion of cases who complete the treatment Leprosy can occur at any age but is more commonly seen
in the stipulated time, i.e. 6 pulses of PB-MDT in 9 months; in the age group between 20 to 30 years. In endemic areas,
and 12 pulses of MB-MDT in 18 months period. This is a the infection generally takes place during childhood. In
very sensitive indicator since the effectiveness of MDT low endemic areas, the infection may occur in adult or
totally depends on the single factor that it is taken in time. later part of life. Increased proportion of child leprosy cases
Irregular treatments and defaults make the person prone in the population has epidemiological significance as it
to getting the complications of the disease. For a Leprosy indicates presence of active transmission of the disease
Control Program. It is highly desirable to keep this rate as in the community. As transmission of the disease declines,
high as possible. If this rate is below 85% in any control it occurs more in older age group. Age distribution of
program, the strategy calls for a review. lepromatous cases generally shows that the disease has
a later onset as compared with non-lepromatous cases.8
AGENT FACTORS
Gender
Agent Leprosy affects both the sexes, however, males are
Leprosy is caused by Mycobacterium leprae. These are affected more often as compared to females, generally in
acid-fast, straight / slightly curves rod shaped gram-positive the proportion of 2:1.8 Sex difference is least among
bacilli which can be seen as clumps or bundles on children below 15 years and more marked among adults.
microscopic examination. They are slow growing bacilli More number of male cases could be attributed to their
CHAPTER
2
greater mobility and increased opportunity for contact. BCG vaccine can provide some protection against leprosy.
Males are also more active in reporting to health facility Trials have shown that BCG offers significant but varying
for seeking treatment. levels of protection.
Migration Genetic Factors

Due to migration of population from rural to urban areas, The role of genetic factors in leprosy has been under
leprosy cases have increased in urban areas in recent consideration for a long time and investigated thoroughly.
years. The urban slums have a distinct geographic and Studies suggest that, among monozygotic (identical) twins
population characteristic, common to all urban areas. The if one had leprosy, the other almost always had leprosy,
population density is very high (10,000 to 15,000 per while this was not the case with dizygotic twins.
sq. km), most of the inhabitants are migrants from distant Monozygous (MZ) twins share all the genes while dizygous
villages, the hygienic and living conditions are poor, (DZ) twins share half the genes. The oft-quoted study of
breathing space is greatly compromised (8-10 or even more leprosy occurrence among twins, from Chakravarty and
Vogel in 1973, was conducted in endemic areas of Andhra
people sharing the same room and other utilities). The
Pradesh and West Bengal.11 The study included a total of
conditions are nearly the same both, at home and place of
102 twins affected by leprosy. As shown in Table 2.2, in
work, in many situations both premises are the same.
59.7% of monozygotic twins, both the twin children
Two types of leprosy carriage can be noted: (a) the two
developed leprosy, and among dizygotic twins, in only 20%
way traffic, to and from the villages and slums, and (b) one
cases both the twins developed leprosy. The concordance
way from slums to middle class localities where the
was not limited to the disease per se; it was reflected in
population density and living conditions are different from
the type of the disease developed too. Table 2.2 further
those in slums. The most of the household helps and maids
shows that among the twins concordant for leprosy, 86.5%
working in middle class urban localities are originating from twins were concordant for leprosy type also. These studies
slums inhabited by the village population.9 suggest genetic susceptibility to the disease.8
Immunity Familial Clustering

Occurrence of the disease depends on susceptibility/ The occurrence of leprosy has been found more in certain
immunological status of an individual. Large proportion of clusters of communities and especially in family clusters.
early lesions in leprosy heals spontaneously. Such self The community clusters can be explained in terms of
healing lesions suggest innate or acquired immunity. Cell environmental factors of exposures, e.g. local myco-
mediated immunity is responsible for resistance to infection bacterial flora; and other environmental conditions to which
to M. leprae. Only a few persons (about 1%) exposed to all community people are exposed. But for the family
infection develop disease. Subclinical infections also clusters it becomes difficult to explain whether it is due to
contribute to development of immunity. A certain degree similar environmental conditions or due to the close familial
of immunity also appears likely through infections with (genetic) relatedness. Also it has been shown that the
other related mycobacteria.10 There is good evidence that probability of finding familial occurrence of leprosy is higher
Table 2.2: Study of concordance in 102 twin pairs for leprosy concordance, and for leprosy type
Concordance for leprosy Concordance for leprosy type
Gender MZ (62) DZ (40) (Only the twins concordant for leprosy)
Male 24 (60.0%) 5 (22.7%) Zygosity Concordant Discordant Total
for type for type
Female 13 (59.1%) 1 (16.7%) MZ 32 (86.5%) 5 37
M+F —- 2 (16.7%) DZ 6 (75%) 2 8
Total 37 (59.7%) 8 (20.0%) Total 38 7 45
CHAPTER
2
Epidemiology 29
in families that include a lepromatous patient; than in those that leprosy in wild animals could be a threat to human
where it does not.12 beings.
ENVIRONMENTAL FACTORS Portal of Exit
Humidity favors survival of the bacterium in the Respiratory tract especially the nose is the major portal of
environment. The bacilli remain viable for about 9 days in exit of M. leprae from the body of an infected person.
dried nasal secretions and for almost 46 days in moist Millions of bacilli are discharged from the nasal mucosa of
soil at room temperature.13 Thus, risk of transmission a bacteriologically positive case during sneezing. Patients
increases with humid conditions. In leprosy endemic areas, with leprosy harbor most bacilli in their skin, but they are
the risk of developing the disease is more among household shed from intact skin in only small numbers.14 However,
contacts of cases. The risk is increased by closeness and bacilli can be shed from broken skin and ulcers of
duration of contact. But all these factors would be operative lepromatous cases. Only a small percentage (less than
only, if the exposed person is genetically susceptible. This 3%) of these escaping bacilli are viable even in untreated
is supported by the observation that the rate of conjugal patients.
leprosy is generally low.
Portal of Entry
SOCIAL FACTORS Respiratory route is the major portal of entry for the bacilli.
The possibility of infection by entry through skin, particularly
Leprosy is a social disease and is generally associated broken skin cannot be ruled out.
with poverty related factors such as overcrowding, lack of
education, lack of personal hygiene, lack of ventilation, Mode of Transmission
etc. which favors transmission of the disease. However, it
may affect persons from any socioeconomic group. Fear Various modes of transmission of the leprosy are described
of leprosy, guilt, stigma and discrimination associated with but it is still not established with certainty that only one is
the disease in the community and unfounded prejudices the major mode or all of them play a contributory role . The
regarding leprosy forces a person to hide the disease and main likely modes of transmission are:
contribute to delay in seeking treatment and thus promote Inhalation (Droplet infection)
transmission of the disease.14 Even today, in spite of
availability of enormous scientific information about The mode of transmission of the leprosy bacilli from person
leprosy, the legend is deeply rooted in minds of people at to person is mainly due to nasal droplet infection. This
all level of society that it is highly contagious and incurable. may occur during sneezing and blowing of nose.
People still associate leprosy with gross deformities Contact
affecting hands and feet which could have been otherwise
To a smaller extent, the disease may also be transmitted
prevented by early diagnosis and treatment with MDT or
from person to person by skin to skin contact. As leprosy
could have been corrected with reconstructive surgery and
bacilli can survive in favorable environmental conditions
regular physiotherapy.
for quite a long duration, the hypothesis that it can be
TRANSMISSION transmitted by indirect contact cannot be ruled out.16
Source of Infection In utero Transmission

Man is the only natural reservoir of M. leprae and the only There have been reports of detection of leprosy in infants
source of infection is an untreated case of leprosy. of very young age. Brubaker et al reported a series of
Multibacillary cases are the more important source of about 100 patients with leprosy below 1 year age, most of
infection compared to paucibacillary cases. However, all them indeterminate and BT.17 The youngest reported age
active leprosy cases should be considered as a potential of leprosy case was 3 weeks from Martinique.18 Another
source of infection.15 It is now evident that, wild animals patient with histopathologically proven tuberculoid leprosy
like armadillos, mangabey monkeys and chimpanzees at 2.5 months age was reported by Noordeen.19 In the
show infections with M. leprae. However, it is least likely series of Brubaker only 50% cases had their mother with
CHAPTER
2
clinical leprosy or history of leprosy, suggesting that about disease is considered to be 5-7 years. Persons with
half the mothers had subclinical infection. In all such cases paucibacillary leprosy may have shorter incubation period.
the possibility could be that the disease presented after a
very short incubation period if the infection occurred after SUMMARY
birth; or the infection occurred in utero. High levels of IgG
and IgM antibodies to M. leprae have been demonstrated Leprosy is eliminated from India in terms of statistical
in infants 3-24 months of age born to lepromatous prevalence but from disease problem point of view it still
mothers.20 Occasional M. leprae have been demonstrated poses many challenges, especially in view of integration
in the placenta and cord blood in humans21 and armadillo.22 approach. In absence of vertical program active case
Despite all this body of evidence supporting uterine transfer finding is not there, which now depends upon either self-
of infection, one normally does not come across infection reporting or case detection at the common health facility.
of babies in untreated mothers infected with lepromatous Both the situations subject to certain serious limitations;
leprosy. the self reporting may be delayed due to acts of omission
or commission on the part of patient, i.e. ignorance of the
Transmission through Ingestion (Breast Milk) disease or hiding the disease. The case detection at
The possibility has always been expressed in the past general health facility may fail sometimes, if the staff
that leprosy could be transmitted through ingestion of bacilli. particularly at peripheral level is not sufficiently trained to
The presence of M. leprae in the breast milk of mothers spot leprosy, especially at the earlier stage which is
with lepromatous leprosy also raised this possibility. The important from point of arrest of transmission and disability
impressive investigative work by Pedley showed leprosy prevention.
bacilli in the epithelial linings of lactating mammary glands A big chunk of backlog cases with grade 2 and grade 3
which are excreted in milk. They also estimated that deformities exists in need of surgical rehabilitation. Efforts
through a feed of 4 oz; the baby would ingest about 2 million are required to bring those people within reach of
leprosy bacilli.23 Despite all the evidence, the fact remains appropriate health interventions. One can hope that once
as of date, that there is no convincing evidence that: the incidence rate drops down considerably, the
(i) breast milk with viable leprosy bacilli acts as a source transmission of disease would be arrested. But the answer
of infection and also (ii) that M. leprae containing breast lies in future, when will it happen!
milk induces any protective immune response in the child.
REFERENCES
Inoculation Following Trauma
1. WHO. International classification of diseases (ICD). Available at
A number of cases have been reported where development http://www.who.int/classifications/icd/en/
of leprosy was linked to the trauma of various kinds. It 2. WHO. International classification of diseases (ICD) Version 2007.
has been observed after thorn prick, tattooing, 24,25 Available at http://apps.who.int/classifications/apps/icd/
icd10online/
vaccination,26,2 roadside injury,28 after dressing of a wound
3. ILEP. The interpretation of epidemiological indicators in leprosy.
in a leprosy hospital,28 dog bite,29 and following injury Technical Bulletin 2001; ILEP, London, 3.
sustained by a surgeon during operating a lepromatous 4. Bechelli LM, Martinez DV. Further information on the leprosy
leprosy patient. 30 Although it may be difficult to problem in the world. Bull W H O 1972; 46:523-36.
demonstrate the presence of M. leprae over the objects or 5. Van Brakel WH, de Soldenhoff, Mc Dougall AC. The allocation of
leprosy patients into paucibacillary and multibacillary groups for
instrument involved in producing trauma but the fact that multidrug therapy, taking into account the number of body areas
development of leprosy lesions was related to the site of affected by skin, or skin and nerve lesions. Lepr Rev 1992; 63:
the trauma, is a sufficient evidence that the sites served 231-45.
as entry points for leprosy bacilli. 6. Gelber RH. Leprosy (Hansen’s disease). In: Harrison’s Principles
of Internal Medicine, 15th edn, Volume 1. Braunwald E, Hauser
SL, Fauci AS et al (Eds). McGraw Hill (Pub), New Delhi, 2003;
Incubation Period 1035-40.
7. Waters MFR, Rees RJ, Mc Dougall AC et al. Ten years of
Incubation period or latent period for leprosy is variable
dapsone in lepromatous leprosy: Clinical, bacteriological and
and unusually long. It may vary from few weeks to even histological assessment and the finding of viable leprosy bacilli.
20 years. However, average incubation period for the Lepr Rev 1974; 45: 288-98.
CHAPTER
2
Epidemiology 31
8. Thangaraj RH. A Manual of Leprosy, 3rd edn. South Asia, The 19. Noordeen SK. The epidemiology of leprosy. In: Leprosy 2nd edn,
leprosy Mission (Pub.), New Delhi 1983; 3-9. Hastings RC (Ed). Churchill Livingstone (Pub), London. 1994;
9. Chatterjee BR. The importance of urban slums in leprosy. In: 31.
Leprosy, etiobiology of manifestations, treatment and control. 20. Melson R, Harboe M, Duncan ME. IgA, IgG and IgM anti M. leprae
Chatterjee BR (Ed). Leprosy Field research unit, Jhalda, W antibodies in babies of leprosy mothers during first 2 years of
Bengal (Pub.) 1994; 5. life. Clin Exp Immunol 1982; 49: 532-42.
21. Valla MC. Lepre et grossesse. Thesis, University of Lyon, France
10. Noordeen SK. In: A Manual of Leprosy, 2nd edn. Thangaraj RH
1976.
(Ed), The Leprosy Mission, New Delhi,1980.
22. Job CK, Sanchez RÌ, Hastings RC. Lepromatous placentitis
11. Chakravarti MR, Vogel FA. Twin study on leprosy. In: Becker
and intrauterine fetal infection in lepromatous 9-banded armadillo.
PE (Ed), Topics in Human Genetics Vol.1, Publisher: Georg Lab Invest 1986; 56: 44-48.
Thieme Verlag, Stuttgrat, 1973;1-123. 23. Pedley JC. Presence of M. leprae in the nipple secretion and
12. Kapoor P. Epidemiologic survey of leprosy in Maharashtra State lumina of hypertrophied mammary glands. Lepr Rev 1968; 39:
(India). Lepr India 1963; 35:83-89. 67-73.
13. WHO. Natural history of leprosy. In: Technical Report Series 24. Ghorpade A . Inoculation indeterminate leprosy localized to a
No.716, WHO, Geneva, 1985, 21. smallpox vaccination scar. Lepr Rev 2007;78:398-400.
14. Park JE. Leprosy. In: Textbook of Preventive and Social Medicine, 25. Sehgal VN, Rege VL, Vediraj SN . Inoculation leprosy subsequent
16th edn. Park K (Ed), Banarsidas Bhanot (Pub.), Jabalpur to smallpox vaccination. Dermatologica 1970;141:393-96.
(India), 2000; 242. 26. Mittal RR, Handa F, Sharma SC. Inoculation leprosy subsequent
15. Job CK, Selvapandian AJ, Rao CK. In: Leprosy: Diagnosis and to roadside injury. Indian J Dermatol Venereol Leprol 1976;
Management, 4th edn. Hind Kusht Nivaran Sangh (Pub), New 42:175-77.
27. Brandsma JW, Yoder L, Macdonald M. Leprosy acquired by
Delhi, 1991.
inoculation from a knee injury. Lepr Rev 2005; 76:175-79.
16. Job CK. Transmission of leprosy. Indian J Lepr 1987;59:1-8.
28. Gupta CM, Tutakne MA, Tiwari VD. Inoculation leprosy
17. Brubaker ML, Meyers WM and Bourland J. Leprosy in children
subsequent to dog bite. Indian J Lepr 1984; 56: 919-21.
under one year of age. Int J Lepr Other Mycobact Dis 1985; 53:
29. Girdhar BK. Skin to skin transmission of leprosy. Indian J
516-23. Dermatol Venereol Leprol 2005; 71: 223-25.
18. Montestruc E, Berdonneau R. Two new cases of leprosy in 30. Achilles EK, Hagel M, Dietrich M. Leprosy accidentally transmitted
infants in Martinique” (in French). Bull Soc Pathol Exot Filiales from a patient to a surgeon in a non-endemic area. Ann Int Med
1954; 47: 781-83. 2004; 141:51.
CHAPTER
3
3
Global Scenario
Vijay K Pannikar
World Health Organization has been regularly collecting detection of new cases showed a decline of more than
data on a number of indicators from the various WHO 9,126 cases (3.54%) during 2008 compared to 2007.
regions and member States. These include: registered Table 3.2 shows the region wise new case detection
prevalence, new cases detected, new Grade-2 disabled, trends from 2001 to 2008. Globally, the annual new case
new multibacillary, new child cases, new cases among detection continues to decline from a peak of over 763,000
female, number of relapses reported and cure/treatment cases in 2001 to 249,007 in 2008.
completion rates for paucibacillary and multibacillary cases. One of the key features of the information available on
Even though the data are known to be affected by several the trend of new case detection is the wide variations across
operational factors including changes in the methodology space and time, across the countries (and within the
for case detection, treatment and registration procedures, countries) over the years. This is obvious especially in
they constitute an important source of information for global major endemic countries like India and Brazil. The
action. information on 18 countries (Angola, Bangladesh, Brazil,
China, DR Congo, Cote d’Ivoire, Ethiopia, India, Indonesia,
PROGRESS WITH LEPROSY SITUATION Madagascar, Mozambique, Myanmar, Nepal, Nigeria,
At the beginning of 2009, the registered prevalence of Philippines, Sri Lanka, Sudan and Tanzania) reporting 1000
leprosy globally was 213,036; the number of new cases and more new cases shows that these countries contribute
detected during 2008 was 249,007 (Table 3.1). The global 94% of the global new cases detected in 2008 (Table 3.3).
It also highlighted the fact that not all countries are showing
Table 3.1: Leprosy situation by WHO Regions
at the beginning of 2009 (excluding European Region) a declining trend. In fact, between 2007 and 2008 in 6
countries (China, Madagascar, Nepal, Nigeria, Sudan and
WHO Region a Registered Prevalence b New cases detected c
at beginning of 2009 during the year 2008
Tanzania) the detection has increased. The dramatic
increase observed in Sudan in the last years is due to the
African 30,557 (0.45) 29,814 (4.37)
American 47,069 (0.54) 41,891 (4.85)
combination data from Southern Sudan. The rate of decline
South-East Asia 120,689 (0.69) 167,505 (9.60) in some countries such as India, Myanmar and Philippines
East 4,967 (0.10) 3,938 (0.80) is slowing or stabilizing. India, which reports the highest
Mediterranean
number of new cases annually, showed a decline of 2.54%
Western Pacific 9,754 (0.05) 5,859 (0.33)
Total 213,036 249,007
between 2007 and 2008, as compared to 1.2% decline
a
between 2006 and 2007. It is likely that a stabilizing trend
Population data from the United Nations Population Division
(Reference: World Population Prospects, 2004 Revision, Volume 1: may be predicted in the following years.
Comprehensive Table A20) The profile of newly detected cases observed in the
b Prevalence rate is shown in parenthesis as the number of cases per
various countries in each of the WHO Regions is shown in
10,000 population.
c Case-detection rate is shown in parenthesis as the number of cases Table 3.4. Wide variations exist among countries in all
per 100,000 population. regions in terms of the proportion of newly detected cases
CHAPTER
3
Global Scenario 33
Table 3.2: New case detection trend during the years 2001-2008 by WHO Region (excluding European Region)
WHO Region Number of new cases detected during the year
2001 2002 2003 2004 2005 2006 2007 2008
African 39,612 48,248 47,006 46,918 45,179 34,480 34,468 29,814
American 42,830 39,939 52,435 52,662 41,952 47,612 42,135 41,891
South-East Asia 668,658 520,632 405,147 298,603 201,635 174,118 171,576 167,505
Eastern Mediterranean 4,758 4,665 3,940 3,392 3,133 3,261 4,091 3,938
Western Pacific 7,404 7,154 6,190 6,216 7,137 6,190 5,863 5,859
Total 763,262 620,638 514,718 407,791 299,036 265,661 258,133 249,007
Table 3.3: New case detection in top endemic countries reporting 1000 and more new cases: 1993 and from 2003 to 2008
No. Country Number of new cases detected
1993 2003 2004 2005 2006 2007 2008
1. Angola 339 2,933 2,109 1,877 1,078 1,269 1,184
2. Bangladesh 6,943 8,712 8,242 7,882 6,280 5,357 5,249
3. Brazil 34,235 49,206 49,384 38,410 44,436 39,125 38,914
4. China 3,755 1,404 1,499 1,658 1,506 1,526 1,614
5. DR Congo 3,927 7,165 11,781 10,369 8,257 8,820 6,114
6. Cote d’Ivoire 2,186 1,205 1,066 NA 976 1,204 NA
7. India 456,000 367,143 260,063 169,709 139,252 137,685 134,184
8. Ethiopia 4,090 5,193 4,787 4,698 4,092 4,187 4,170
9. Indonesia 12,638 14,641 16,549 19,695 17,682 17,723 17,441
10. Madagascar 740 5,104 3,710 2,709 1,536 1,644 1,763
11. Mozambique 1,930 5,907 4,266 5,371 3,637 2,510 1,313
12. Myanmar 12,018 3,808 3,748 3,571 3,721 3,637 3,365
13. Nepal 6,152 8,046 6,958 6,150 4,235 4,436 4,708
14. Nigeria 4,381 4,799 5,276 5,024 3,544 4,665 4,899
15. Philippines 3,442 2,397 2,254 3,130 2,517 2,514 2,373
16. Sri Lanka 944 1,925 1,995 1,924 1,993 2,024 1,979
17. Sudan 1,489 906 722 720 884 1,706* 1,901*
18. Tanzania 2,731 5,279 5,190 4,237 3,450 3,105 3,276
Total (%) 557,940 495,773 389,599 287,134 249,076 243,137 234,447
(94%) (96%) (96%) (96%) (96%) (94%) (94%)
Total Global 590,933 514,718 407,791 299,036 259,017 258,133 249,007
* includes data from Southern Sudan
NA=not available
Table 3.4: Profile of newly detected cases reported by countries (reporting 100 or more new cases), by WHO Region, 2008
WHO Regions MB Proportion Female Proportion Child Proportion Grade 2 Disabilities
range (%) range (%) range (%) Proportion range (%)
African Comoros: 19.7 Madagascar: 22.75 Niger: 0.82 Comoros: 3.57
Kenya: 91.62 Congo:64.52 Comoros: 30.95 Benin: 25.17
American Bolivia: 538.76 Argentina: 22.16 Argentina: 0.52 Argentina: 3.09
Mexico: 78.32 Cuba: 46.35 Brazil: 7.46 Columbia: 10.33
South-East Asia Bangladesh 44.77 India: 35.17 Thailand: 2.99 India: 2.80
Indonesia: 82.15 Thailand: 41.65 Indonesia: 11.40 Myanmar: 13.10
Eastern Mediterranean Somalia: 30.40 Yemen: 32.27 Somalia: 4.0 Egypt: 7.28
Egypt:89.46 Somalia: 52.0 Yemen: 15.5 Sudan: 23.25
Western Pacific FSM: 58.06 Philippines: 12.01 China: 2.48 FSM: 0
Philippines: 90.27 FSM: 43.55 FSM: 39.5 China: 22.1
Dom. Rep= Dominican Republic; FSM= Federated States of Micronesia
CHAPTER
3
with multibacillary (MB) disease, of children, of females Similarly, the grade 2 disabilities among the newly
and of those with Grade 2 disabilities. Countries in all detected cases show a wide variation in all the Regions.
regions are reporting a wide range of MB proportion among In the African Region, it ranges from 3.57% in Comoros to
the newly detected cases. In the African Region, it ranges 25.17% in Benin and in the American Region from 3.09%
from 19.70% in Comoros to 91.62 in Kenya and in the in Argentina to 10.33% in Columbia. In the South-East
American Region from 38.76% in Bolivia to 78.32% in Asia Region, it varies from 2.80% in India to 13.10% in
Mexico. The Eastern Mediterranean Region has a range of Myanmar. In the Western Pacific Region, Federated States
30.40% in Somalia to 89.46% in Egypt. The South-East of Micronesia is reporting 0% grade 2 disabilities among
Asia Region is reporting 44.77% in Bangladesh to 82.15% new cases and China 22.10%.
in Indonesia and the Western Pacific Region is reporting India, Brazil and Indonesia are the main contributors
58.06% in the Federated States of Micronesia (FSM) to to the total new case load. As far as the percentage of
90.27% in Philippines. new cases detected with grade-2 disabilities, China stands
The female proportion among the newly detected cases out as having more than 20% while most others are between
in the African Region ranges from 22.75% in Madagascar 5-10%. Sudan, Nigeria, Myanmar, Columbia, Benin, are
to 64.52% in the Republic of Congo. In the American Region all above 10% while India, Comoros and Argentina are
it ranges from 22.16% in Argentina to 46.35% in Cuba; in below 5%. Countries with the highest rates of grade-2
the South-East Asia Region, from 35.17% in India to disabilities per 100,000 population are Benin, Sudan and
41.65% in Thailand. In the Eastern Mediterranean Region, China.
the female proportion ranges from 32.27% in Yemen to The global data shows much variation in new case
52.00% in Somalia and in the Western Pacific Region, detection, making it difficult to make reasonable projections
from 12.01% in the Philippines to 43.55% Federal States regarding trends, especially at the country level. National
of Micronesia. The extent to which this reflects differences programmes should review their data regularly to ensure
in case ascertainment is unclear. that the reported data are complete, reliable and valid. It is
A wide variation is seen regarding the child proportion useful to analyze and present data on new case detection
among newly detected cases especially in the African, between areas, using absolute numbers and rates per
American and Western Pacific Regions. The child proportion 100,000 population. Similarly, in comparing trends in profile
in the African Region, ranges from 0.82% in Niger to of new cases in terms of female, child or those presenting
30.95% in Comoros and in the American Region, from with grade-2 disabilities etc., absolute numbers and rates
0.52% in Argentina to 46.35% in Cuba. In the Western per 100,000 population be considered rather than their
Pacific Region, it ranges from 2.48% in China to 39.5% in proportions among all new cases detected during the year.
the Federated States of Micronesia; in the South-East Asia
region it ranged from 2.99% in Thailand to 11.40% in Source
Indonesia. In Eastern Mediterranean Region, it ranges from World Health Organization. Global leprosy situation, 2009.
4.0% in Somalia to 15.5% in Yemen. Weekly Epidemiological Record, No. 33, 2009; 84:333-40.
4 National Scenario, National Leprosy
Eradication Program (NLEP) and
New Paradigms
PL Joshi
HISTORICAL ASPECTS OF LEPROSY from 1982 following the recommendations of WHO. Since
then the services for leprosy patients have gradually
changed from institutional to outpatients care through
Mycobacterium leprae. It mainly affects the skin and
health centres and field clinics. Gradually the infected and
peripheral nerves, but has a wide range of clinical
cured leprosy patients began to be accepted by the
manifestations. The disease is characterized by long
community as a result of intensive health education and
incubation period (generally 5-7 years) and is classified as
visibly successful results of MDT.
paucibacillary (PB) & multibacillary (MB) types, depending
Government of India started National Leprosy Control
on the bacillary load. Leprosy is a leading cause of
Program (NLCP) in 1955, based on dapsone domiciliary
permanent physical disability. Timely diagnosis and treatment through vertical units, by implementation of
treatment of cases, before nerve damage, is the most survey education and treatment (SET) activities. The whole
effective way of preventing disability due to leprosy. concept of NLCP was based on design of leprosy treatment
The earliest records of a ‘leprosy like’ disease come and care devised by Dr RV Wardekar (the renowned
from Egypt dating as far back as 1400 BC and the word Leprologist), and practised at Gandhi Memorial Leprosy
leper comes from a Greek word meaning scaly. In India, Foundation at Wardha (Maharashtra) since 1951.
leprosy was first described in the Sushruta Samhita and The MDT came into wide use from 1982, following the
treatment with ‘chaulmoogra’ oil was known at that time. It recommendations by the WHO Study Group. Govt. of India
is said that leprosy was referred to as “Kushth” in the Vedic established a high power committee under chairmanship
writing, which is how the disease is known as even to this of Dr MS Swaminathan in 1981 and based on its
day in India. recommendations the NLEP was launched in 1983 in India
Initially, leprosy patients were strictly isolated and with support from WHO, International Federation of Anti-
segregated. Communities were hostile to them and the Leprosy Association (ILEP), Sasakawa Memorial Health
patients were also self conscious and afraid to mix with Foundation & the Nippon Foundation, Novartis, DANLEP
the community. Leprosaria were built to segregate the and the World Bank. However, coverage remained limited
patients from the community in various countries. Several due to organizational issues and fear of the disease
statutory acts and laws were also enacted during that time becoming disclosed and the associated stigma. In view of
against them. substantial progress achieved with MDT, in 1991, the World
In 1873, GA Hansen of Norway discovered M. leprae Health Assembly resolved to eliminate leprosy at a global
however, there was no effective treatment for the disease. level by the year 2000. In order to strengthen the process
Chaulmoogra oil was used for leprosy treatment until of elimination in the country, the 1st phase of the World
“Dapsone” was discovered with antileprosy effects during Bank supported Project was started from 1993-94 and was
1940s. It was in 1970s when multi drug therapy (MDT) completed in March 2000. During this phase, 3.8 million
consisting of rifampicin, clofazimine and dapsone were leprosy cases were new detected and 4.4 million leprosy
identified as cure for leprosy; which came into wide use cases were declared cured with MDT.
CHAPTER
4
To further consolidate the gains the 2nd Phase of World 2002-2004 A system of monitoring of the programme
Bank Project on NLEP was started in 2001 which ended in was started in the form of Leprosy Elimination
December 2004. Decentralization of NLEP to States/UTs Monitoring (LEM) exercise jointly by Govt. of
and integration of leprosy with General Health Care System India with WHO, ILEP in collaboration with
(GHS) was carried out during this phase. the National Institute of Health and Family
The NLEP is being continued with Govt. of India funds Welfare (NIHFW). These studies were carried
since January 2005 onwards. Additional support for the out during the year 2002, 2003 and 2004.
programme continues to be received from the WHO and During the last two years a component of
ILEP organizations. MDT is being supplied free of cost by validation of case diagnosis was introduced.
Novartis through WHO. 2005 A survey to monitor performance at close of
the 2nd National Leprosy Elimination Project
MILESTONES UNDER NLEP (December 2004) was carried out during
April-May 2005 through an independent
1955 Govt. of India launched NLCP based on agency, the Indian Institute of Health
dapsone domiciliary treatment through Management and Research, Jaipur.
vertical units implementing survey education 2005 Leprosy was declared eliminated as a public
and treatment (SET) activities. health problem in India at National level in
1981 Govt. of India established a high power the month of December 2005.
committee under chairmanship of Dr MS 2005 onwards Program continues with Government of India
Swaminathan for dealing with the problem support since January 2005.
of leprosy.
1982 The MDT came into use from 1982, following NATIONAL LEPROSY ERADICATION
the recommendation by the WHO Study PROGRAM (NLEP)
Group, Geneva in October 1981.
1983 NLEP was launched, districts were covered Epidemiological Situation
in a phased manner and all the districts in After introduction of MDT in 1982, spectacular success
the country were covered by the year 1996. has been achieved in reducing the disease burden. A goal
1991 World Health Assembly resolved to eliminate was set by National health policy in 2002 to achieve the
leprosy at a global level by the year 2000. level of leprosy elimination (i.e. Prevalence rate of less
1993-2000 The 1st Phase of the World Bank supported than one case per 10,000 population, where leprosy is
National Leprosy Elimination Project, considered to cease as a public health problem) at the
launched in 1993 and completed in March National level by December 2005. This came to be realised
2000. on December 31, 2005 when the prevalence in the country
1998-2004 NLEP introduced the Modified Leprosy was recorded as 0.95 per 10,000 population. The National
Elimination Campaign (MLEC) activities in prevalence rate which stood at estimated 57.6 per 10,000
the year 1997-98. Five such campaigns were in 1981; has come down to 0.72 per 10,000 by March
conducted up to year 2004. 2009. The same has been shown in the country map of
2001-2004 The 2nd phase of the World Bank supported leprosy depicted in Figure 4.1.
National Leprosy Elimination Project was The current leprosy situation in all the states and UTs
launched in 2001 and completed in December for the year of 2008-09 ending on 31st March 2009, can be
2004. During this phase the NLEP summarized as follows:
responsibilities were decentralized from the 1. A total of 1.34 lakh new cases were detected during
centre to the states/UTs through State/ the year 2008-09, which gives Annual New Case
District Leprosy Societies. Leprosy Services Detection Rate (ANCDR) of 11.19 per 100,000
were also integrated with the General Health population, a reduction of 4.36% from the figure of 11.70
Care System from the erstwhile vertical during 2007-08. The break up of total new cases
system. detected in various states in the year 2008-09 is given
in a pie diagram depicted in Figure 4.2.
CHAPTER
4
National Scenario, National Leprosy Eradication Program (NLEP) and New Paradigms 37
Fig. 4.1: The leprosy scenario in the country witnessed a sea change in the period of nearly three decades after introduction MDT in 1982
Fig. 4.2: A total number of 134184 new leprosy cases (48% MB) were recorded in India in the year 2008-09. The figure shows the
contribution of cases from various states.
CHAPTER
4
2. A total of 0.86 lakh cases are on record as on 1st April 7. The trends in PR and ANCDR, as observed in a period
2009 giving a prevalence Rate (PR) of 0.72 leprosy of about last two decades are shown in Figure 4.3.
cases per 10,000 population. 8. Out of 630 districts, 301 (47.8%) had > 2% patients
3. Detailed information on 1.34 lakh new leprosy cases with Grade2 disability, amongst the new cases
detected during 2008-09 indicates the proportion of MB detected.
cases (48.4%), Females (35.2%), Children (10.1%), 9. Out of the total 1.30 lakh new cases deleted from
patients with visible deformity (2.8%). records, a total of 1.21 lakh (92.7%) completed their
4. 32 States/UTs have achieved the status of leprosy treatment within the specified period and were released
elimination. Only 3 states/UTs viz. Bihar, Chhattisgarh from treatment (RFT) as cured during 2008-09
and Dadra & Nagar Haveli are yet to achieve the
10. Out of the total 12,182 “others cases” recorded for
elimination level (PR between 1 and 2.5 per 10,000
treatment during 2008-09, a total of 8,771 (72%)
population). These 3 States/UTs with 10.4% of
completed their treatment in time and were released
country’s population; contributed to 18.9% of the
from treatment (RFT) as cured during 2008-09.
country’s recorded caseload and 21% of new cases
detected during 2008-09. 11. Total number of cases released as cured during 2008-
5. District wise situation on the basis of ANCDR as on 09, thus comes to 129,798 (90.9%) as against total
31st March 2009 shows that out of 630 districts in the deletion of 142,772. This brings the total number of
country, 394(62.54%) have ANCDR < 10 per 100,000 leprosy affected persons cured of the disease in the
population. Only 4 districts have ANCDR > 50/100,000 country with MDT, since the launch of MDT in 1982, to
population and these are located in Chhattisgarh (3), 12.27 million.
Gujarat (1), shown in Table 4.1.
6. District wise situation on year wise endemic status NEW PARADIGMS IN NLEP
during last 9 years is shown in Table 4.2. As on March
31, 2009, only 26 districts in 9 states have PR >2/ In view of the need to sustain leprosy services for many
10,000 population. These districts are located in Bihar years to come, there has to be a shift from a campaign
(2), Chhattisgarh (8), Jharkhand (1), Gujarat (5), Orissa like elimination approach towards the long term process
(3), Maharashtra (3), West Bengal (2), Dadra & Nagar of sustaining integrated high quality leprosy services. This
Haveli (1) and Delhi (1). Overall, 81% of districts in the in addition to case detection and treatment with MDT; also
country now have recorded PR < 1/10,000 population. includes prevention of disability and program for
There is no district with PR>10/10,000. rehabilitation. There is an opportunity for this process to
Table 4.1: Annual new case detection rate (ANCDR) in India at district level
ANDCR/100,000 Number of districts
population 2004-05 2005-06 2006-07 2007-08 2008-09
< 10 253 317 376 377 394
10-20 110 141 132 141 159
> 20-50 163 124 97 90 73
> 50-100 59 13 5 6 4
> 100 10 1 1 0 0
Total 595 596 611 614 630
Table 4.2: Prevalence rates of leprosy in the country at district level in last 9 years
Prevalence Number of districts
(PR/10,000) 2001 2002 2003 2004 2005 2006 2007 2008 2009
<1 171 181 212 250 337 439 487 482 510
1-2 82 80 88 105 131 128 105 111 94
2-5 179 156 172 163 118 28 18 20 25
5-10 91 108 90 68 8 0 0 1 1
> 10 40 51 28 4 1 1 1 0 0
Total 563 576 590 590 595 596 611 614 630
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4
Fig. 4.3: Trends of leprosy Prevalence (PR) and Annual New Case Detection (ANCDR) in India in last two decades.
build on the gains made by the elimination campaigns, system under NLEP in the country. By reducing the
such as increased awareness about leprosy, political duration of treatment to just one year or less, MDT has
commitment and involvement of general health services. greatly reduced the numbers on treatment at any point
of time and hence the “burden” on health services.
Burden of Leprosy Although registered prevalence was a useful indicator
The burden of leprosy can be looked at in three ways: to achieve the leprosy elimination milestone, it is not
1. Firstly, the most relevant epidemiological measure of adequate indicator to reflect changes in the
the burden of leprosy is the incidence of disease, which epidemiological trend of leprosy.
is the number of people developing leprosy during a 3. Thirdly, the burden of leprosy can be viewed through
set period of time, usually one year. Because incidence the eyes of affected people themselves. Leprosy
is difficult to measure directly, the ‘Case Detection Rate’ complications can lead to disability of hands and feet
should be used as a proxy for incidence rate. The and sometimes also to blindness. These physical
number of cases detected is generally lower than the problems are often overshadowed by the social rejection
actual number of incident cases, as some new cases and mental suffering caused by the stigma that persists
never come for diagnosis and treatment. Changes in around this treatable disease in many communities.
incidence take places slowly, over decades and are Much of this disability can be prevented and the new
related to factors such as immunization with BCG and Global strategy calls for increased efforts to reduce
economic development, as well good leprosy control this “burden by preventing disability in new cases, by
services. For monitoring of the programme, emphasis helping to rehabilitate those with disability and by
would be given to track the incidence of the disease at fighting stigma.
every level.
2. Secondly, the burden may be related to the registered
Improving the Quality of Services
prevalence of disease, which is the number of people The quality of care can only be as good as the quality of
on treatment at a certain point of time. The prevalence technical supervision provided by the program. In addition,
of the disease has declined throughout the country over the availability of strong back up from an effective referral
the past 15 years because of Multi Drug Therapy (MDT), system will improve the quality of care provided by the
now being provided through the primary health care integrated leprosy services. The pursuit of quality assumes
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4
the willingness of staff to make changes aimed at improving identified. In practice this does not happen in many
their skills and the functioning of the health services. situations. For too long the responsibility of identifying a
Quality leprosy services should have universal coverage, case of leprosy was held solely by health services,
i.e. MDT treatment should be provided at all health units, particularly, specialized (vertical) leprosy services. While
without any geographical, economic or gender barriers, this approach had certain advantages in certain situations;
should be patient-centred and recognising the patient’s the major disadvantage was relatively poor coverage of
rights, including the rights to timely and appropriate population resulting in large number of patients remaining
treatment; and to privacy and confidentiality. The quality undetected. The role of the individual, the family and the
leprosy services should address each aspect of case community in suspecting leprosy and reporting was not
management, based on firm scientific evidence, like, given due importance. This neglect towards creating
diagnosis is carried out timely and accurately; coupled community awareness was based on the assumption that
with supportive counselling, and timely free treatment with the health provider knew everything that needs to be done
MDT in a user friendly environment. It should also for leprosy and the community was a mere recipient of
incorporate appropriate disability prevention interventions; services. This has not worked in improving case detection
referral services for complications, appropriate beyond a point. Thus, the major focus should now shift to
rehabilitation, maintaining simple records and encourage creating community awareness about the disease, its
periodical review and evaluation. The services should be curability and the availability of MDT services.
based on principles of equity and social justice. Equity Over the years, the diagnosis of leprosy and its
means that leprosy patients should have the same treatment, have been simplified to a great extent. Today it
opportunity to attend health services that are of satisfactory is possible to provide the necessary minimum skills and
quality to deal with their problems. Social justice means competence to deal with leprosy to practically any health
an absence of discrimination for any reason, including type worker. This means that leprosy work including diagnosis
of disease, level of disability, race, gender, social class or and treatment can be handled by general health care
religion. services and there is no need to build or perpetuate
The main principle of leprosy control is “morbidity specialized services for leprosy except for some very
control”, i.e. timely detection of new cases, their treatment restricted activities. It may be true that the quality of
with effective chemotherapy in the form of multi drug services provided by the general health services may be
therapy, prevention of disability and rehabilitation. less than perfect, but no other services can match their
outreach, familiarity with the community and acceptability.
Integration of Leprosy Services with Primary Leprosy mostly is not a complicated, difficult to manage
Health Care System for Sustainability or expensive to treat disease. Most, if not all, patients can
Integration means active involvement of general health be diagnosed by classical clinical signs and managed by
services in leprosy control activities. The general health trained health workers in a primary health care system.
care services should take full responsibility for leprosy
Referral Services and Long-term Care
control in their areas, as part of their routine day to day
activities. The rationale behind this approach is that the Effective leprosy control requires an integrated approach,
general health services are widely distributed; have close which provides wider equity and accessibility, improved
and frequent contact with local community, and involving cost-effectiveness and long-term sustainability. This
them in leprosy control will improve case finding, case implies that leprosy control activities should be
holding and awareness of the local community about the implemented by the general health services, including
disease. Integration will improve efficiency and effective- integrated referral facilities. The referral network must be
ness, optimize the use of resources, provide greater equity, part of the integrated system, providing referral services
reduce stigma and discrimination and ensure long term even for other diseases and conditions in the area, e.g.
sustainability. district hospitals or medical colleges. Community health
When we refer to case detection, it is important to centres with adequate infrastructure including trained
recognize that in order to achieve leprosy eradication, manpower and equipment may serve as the first referral
nearly every case of leprosy in the community should be unit in the referral network.
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4
An adequate referral system means that specialist detection and effective management of leprosy-related
services should be accessible and available to any patient, reactions and nerve damage, proper counselling on self
who needs them. The main obstacle to referral services in care, participation of household members in home based
many places is the difficulty for the patient to reach the care development and use of locally produced and culturally
referral unit at the right time. and esthetically acceptable footwear and other appliances.
One important (and frequently neglected) aspect in care
of leprosy affected persons (LAP) is the long-term care of Improving Community Awareness
patients suffering the sequelae of nerve damage, e.g.
and Involvement
chronic foot ulcers or chronic leprosy reactions. These will
need, besides medical and surgical interventions, support The major theme of community awareness will be to provide
from the counselling services. accurate information about the disease, its curability and
Staff at the peripheral level should develop good links availability of services at the nearest health facility. The
with the referral units they are most likely to use regularly. objective of such information, education, communication
Staff at peripheral centres should know the specialist clinics (IEC) efforts should be to encourage self-reporting of new
and other professionals to whom they may refer patients. cases and to reduce stigma and discrimination.
The different indications for referring the patients are: There are four key messages for the general public
1. Ophthalmology clinic: For significant eye pathology, which can be expressed in many different ways:
as a result of the disease or reactional involvement.
1. Curable: Leprosy is an infectious disease but the risk
2. Dermatology clinic:
of developing the disease is low. It can be cured with
a. For confirming the diagnosis in difficult cases.
drugs that are widely available and free of charge.
b. Medical management of reactions.
c. For the diagnosis of other skin conditions which 2. Early signs of leprosy: Pale or reddish, skin patch or
may mimic leprosy. patches with loss or impairment of sensation. Early
3. Laboratory: For skin smears and histopathology. detection with appropriate treatment helps to prevent
4. Physiotherapy: For assessment and management of disabilities from the disease.
disability. 3. No need to fear: The disease can be managed just like
5. Podiatrist/ Chiropodist: For the feet and footwear. any of the other diseases, affected people should not
6. Occupational therapy: For rehabilitation and adaptations suffer any discrimination; treated patients are no longer
etc. infectious.
7. Plastic and reconstructive surgery: For various recons- 4. Support: Affected people need support and encourage-
tructive procedures, skin grafting for non-healing ulcers, ment of their family and community, firstly to take MDT
8. Orthopedic surgeon: For reconstructive surgery, wound and any other treatment as prescribed, and secondly,
debridement, arthritis, etc.
to be able to live as normal a life as possible.
9. Social workers: For assessment and further referral,
Activities in this area particularly awareness have been
communicating with family members, relatives about
part of the National Leprosy Programme for many years.
disease and stigma, for Community Based Rehabilitation
(CBR) programme. These activities were also widely promoted during the
modified leprosy elimination campaigns or MLECs. A
Prevention and Management of Impairments considerable part of the investment in MLECs had gone
and Disabilities to putting out messages through media including electronic
media. Other local approaches have also been tried.
The current situation with regard to the number of persons
living with leprosy-related disabilities and impairments may Fortunately, the inter MLECs period did not show any
need reassessment, particularly at the national level. In marked depletion in case detection. However, we continue
addition, programme should ensure that persons affected to receive new cases with long standing disease and often
by leprosy have access to services by other programmes in relatively advanced stage. The indicator that we often
dealing with other disabling diseases or conditions. use to measure delayed detection, i.e. “proportion of patient
Interventions aimed at preventing disabilities/ with visible deformity” is too crude to measure all delayed
impairments from occurring and/or worsening, include early diagnosis. The important thing is to recognize that leprosy
CHAPTER
4
is a disease which is visible on the skin as insensitive during the treatment or post treatment period or at any
patches, and people in leprosy endemic areas often know other time, requires immediate treatment with a complete
that these patches could be due to leprosy. Still, a course of prednisolone as well as other supportive drugs.
proportion of them do not report to health services in time. Any delay in treatment of reaction may lead to further
1. Is it because some of them do not know that they damage to affected nerves resulting in disability / deformity.
have the disease? Similarly, medical rehabilitation of persons affected with
2. Or is it because that they do not know leprosy is leprosy may be supported by the Rogi Kalayan Samities.
curable? District Health Mission which is chaired by the president
3. Or further still, is it because that the patients fear that of Zila Parishad may be helpful for advocacy of the
they won’t get sufficient attention when they report to program.
health facility?
4. What happens to all messages which we display? Rehabilitation
5. Why their penetration is not adequate?
Leprosy is feared because of the occurrence of disabilities
The answer is that the communities are often dealt
it causes. The problem in social, economic and human
with as passive recipients, and not involved in the process;
terms is enormous and will need many partners to solve
and not encouraged to accept ownership of their problem.
it, including the affected communities. However, early
A totally health oriented approach can only provide limited
detection and treatment with MDT will remain the best
success. We have to encourage the grass route institutions
strategy for preventing the occurrence of disabilities.
such as “Panchayati Raj” or village health and sanitation
Leprosy may lead to physical, functional, social
committees to discuss leprosy as their own problem and
and/or economical problems. Physical rehabilitation
seek help and collaboration from the health services.
includes physiotherapy and occupational therapy, orthotics
Support of National Rural Health Mission and prosthetics services, assistive and protective devices
and sometimes corrective surgery. Social and economic
Under the National Rural Health Mission (NRHM), rehabilitation aims at social integration, equal opportunities
institutional mechanisms have been created at each level and economic advancement.
to support National Health programmes and improve A comprehensive approach to rehabilitation is needed
delivery of health care services. to maximize the benefit for the individual, family and society
At village level there are multi stakeholders: at large. Community Based Rehabilitation (CBR) approach
Village Health and Sanitation Committee emphasizes community participation and empowerment
of the individual involved. Poverty has been identified as
To decide the health priorities in the village and taking
a root problem causing and aggravating disability.
appropriate action.
Addressing poverty is therefore an essential part of
Accredited Social Health Activist (ASHA) rehabilitation. Govt. of India/State Governments have
For every village there is a female volunteer belonging to schemes for providing financial support to disabled
the same village, selected by the community. ASHA could persons. We have to ensure that persons affected with
be utilized for early detection of suspected cases of leprosy are also included in these schemes.
leprosy, referral of such cases to nearest health centre for The Ministry of Health and Family Welfare and Ministry
confirmation and completion of treatment. of Social Justice and Empowerment, Govt. of India, are
expanding rehabilitation services to persons with disabilities.
Rogi Kalyan Samities For example, Ministry of Health and Family Welfare, Govt.
At PHC, CHC and district hospitals these are autonomous of India, is under the process of establishing Physical
registered bodies constituted at each level to facilitate in Medicine and Rehabilitation Department in Medical
management of hospitals and delivery of quality care to Colleges and Regional Hospitals. Additional support is
patients. Rogi Kalyan Samiti is authorized to procure drugs being provided to institutions carrying polio disability related
at local level in emergency, out of the funds available with corrective surgeries. In addition, there are several NGOs /
the Samiti. Leprosy reaction occurring in persons affected Institutions supported by the Leprosy Mission of India and
with leprosy is an emergency condition which can occur other ILEP partners for carrying out rehabilitation services.
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4
Persons affected by leprosy, who are in need of 1. Effectiveness of IEC activities in promoting awareness
rehabilitation, should have access to any existing (general) and self-reporting.
rehabilitation services. Similarly the other way, where 2. Health workers competence to make an accurate and
leprosy specific rehabilitation services are available, people timely diagnosis.
with other disabilities should be given access. This would 3. Quality of supervision by programme managers.
facilitate integration, help to break stigma and promote 4. Completeness of program coverage, ensuring that all
sustainability of rehabilitation services. Harmonization of inhabitants are reached.
rehabilitation services provided by public and private
sectors would be crucial in making such services a realty. Treatment Completion/Cure Rate
The most important components of the leprosy control
Indicators for Monitoring and Evaluation programme are: timely detection of new cases and ensuring
that all new patients who start multidrug therapy complete
Indicators are tools for measuring the magnitude of the the full course of treatment within a reasonable period of
leprosy problem and progress made towards achieving the time.
objective of the program. They can be used to set targets The proportion of new patients who complete their
for the quality of the program, e.g. the proportion of patients treatment on time is an indication of how well the leprosy
with grade II disabilities among new cases as an indicator patients are being served by the health services. A
for the quality of case detection and treatment completion satisfactory completion rate is indicative of efficient case
rate as an indicator for quality of patient management. holding, counselling and patient satisfaction. All states
The following are the main indicators used for should undertake a cohort analysis for treatment completion
monitoring the epidemiological trends of leprosy: rates for both paucibacillary and multibacillary leprosy.
The Number of New Case Detected in Registered Prevalence

a Given Area Each Year Prevalence of registered cases will continue temporarily
to be an indicator till the target of elimination has been
The number of new cases indicates how much leprosy reached by all states.
there is in an area. This helps to estimate how much MDT
should be supplied to that area during the following years. Additional Indicators for Case Detection
Given consistent procedures for case detection, figures The following indicators will be collected as a part of
for a period of several years will show there is an increase simplified information system:
or decrease in numbers, which may indicate whether the 1. Proportion of new cases presenting with grade 2
activities aimed at controlling the disease are effective. In disabilities / impairments at the time of diagnosis.
order to ensure quality of new case detection, the 2. Proportion of child cases (under 15 years of age) among
programme should ensure that: new cases.
1. Case finding is mainly focused on promoting self- 3. Proportion of multibacillary cases among new cases.
reporting, with appropriate clinical examination and 4. Proportion of female cases among new cases.
history taking so as to avoid wrong diagnosis and
re-registration. Indicators for Patient Management
2. Case definitions are adhered to as per the national The state and district programme managers and
guidelines. coordinators / consultants should periodically collect the
3. Previously fully or partly treated cases are not registered following indicators on a sample basis.
as new case. However, partly treated cases should be 1. Proportion of new cases verified as correctly diagnosed.
given a full course of treatment again. 2. Proportion of treatment defaulters.
The nature and number of new cases detected in a 3. Number of relapses.
given area are mainly influenced by the following four 4. Proportion of patients who develop new / additional
factors: disability during multi drug therapy.
Section
2 Basic Scientific
Considerations and Pathology
5 Genetic Susceptibility and
Immunogenetics
Rajni Rani
INTRODUCTION 3. Low molecular weight proteases 2 and 7 (LMP2 and

LMP7)
Leprosy, caused by Mycobacterium leprae (M. leprae),
4. Transporters associated with peptide loading 1 and 2
presents in the form of a spectrum of different mani-
(TAP1 and TAP2)
festations. On one pole of the spectrum are patients with
5. Protein tyrosine phosphatase nonreceptor type 22
paucibacillary tuberculoid leprosy (TT) and on the other
(PTPN22)
pole, we see multibacillary lepromatous leprosy (LL)
When an infection takes place, the infectious agent is
patients. In between the two polar forms there are cases
endocytosed by the macrophages/dendritic cells or
showing variable features of tuberculoid and lepromatous
B lymphocytes (antigen presenting cells or APCs) and its
lesions which could clinically be classified into borderline
proteins are processed and presented on the surface of
tuberculoid (BT), mid-borderline (BB) and borderline
the APCs in the context of MHC molecules. The peptides
lepromatous (BL) forms of the disease. While clinically
of the antigen (which has been processed after
they can be easily differentiated, there is a difference in
endocytosis) are presented by the MHC molecules in their
the immune responses too in the patients against M. leprae
peptide binding groves to the T cell receptor on T helper
antigens. Most healthy people exposed to M. leprae are
cells, which in turn secrete cytokines and activate B
resistant to the infection and with an effective immune
lymphocytes to become plasma cells; or the precursor
response, do not develop the clinical disease.1 On the
cytotoxic T cells to become effector cytotoxic T cells.
other hand, while all leprosy patients show humoral
immunity, cell mediated immunity (CMI) is observed
towards tuberculoid end, i.e. TT and BT.2 GENES AND PROTEINS OF THE MAJOR
Nerve damage is seen throughout the spectrum. One HISTOCOMPATIBILITY COMPLEX (MHC)
wonders, when the infectious agent is the same, why The human MHC, human leukocyte antigen (HLA) system
different people get different forms of the disease. is the most polymorphic system of the human genome. It
Obviously, there are host factors which are involved in codes for glycoprotein molecules which are expressed on
differential immune responses to the infectious agent giving all nucleated cells and are responsible for the recognition
rise to differential manifestations of leprosy. Several recent of nonself from self. The function of MHC molecules is to
reviews discuss the host genetic factors in leprosy.3-5 There present exogenous and endogenous antigens in the form
are several proteins/molecules which are involved in the of peptides to the T cells for subsequent immune response
immune responses; these proteins are coded for by to take place. There are several genes for the HLA which
different genes which are polymorphic in nature. are tightly linked to each other in such a way that they are
The most common genes involved in immune responses inherited en-bloc most of the time. A set of genes on a
which have been shown to be polymorphic are: chromosome that are inherited together en-bloc is termed
1. Major histocompatibility complex (MHC) genes as a haplotype. HLA genes are located on chromosome
2. Cytokine genes 6p21.3 (Fig. 5.1). The gene map of the MHC region of man
CHAPTER
5
48 Basic Scientific Considerations and Pathology
The MHC class-I molecule is a heterodimer of a heavy

alpha chain (about 40-45 kDa) and the light chain beta 2
microglobulin (β2m) of 12 kDa.8 While the genes for the
heavy chains of the MHC class-I molecules are encoded
on chromosome 6, the gene for β2m is encoded on human
chromosome 15. The MHC class-I molecule can be divided
into (i) membrane-distal domains, (ii) membrane proximal
domains, (iii) transmembrane domain and (iv) the
cytoplasmic tail which are encoded by different exons of
the gene (Fig. 5.3). The membrane distal domains are two
polymorphic domains alpha 1 (α1) and alpha 2 (α2)
domains which are encoded by second and the third exons
of the alpha chain gene, α3 domain, on the other hand, is
Fig. 5.1: Chromosomal localization of human leukocyte antigens membrane proximal domain and is encoded by exon 4 of
(HLA) Class I and II the alpha chain gene. Exon 5 codes for the transmembrane
domain, exon 6 for cytoplasmic tail and exons 7 and 8 for
was published recently.6 This is the most gene-dense the 3’ un-translated region (UTR). The α1 and the α2
region of the human genome and spans about 4 megabases domains form the peptide binding grove of the molecule.
The peptides that are presented by the MHC molecules
(3,838,986 bp to be precise). At least 224 known genes
have allele specific motifs, which means that certain
are identified in this region with 128 known to be expressed.
peptides can be presented by certain MHC molecules.
Nearly 40% of these expressed genes have immune related
This is determined by anchors present on the peptide
functions.6
binding groves where the peptides go and bind through
There are two types of MHC molecules: MHC Class-I
hydrogen bonds. Specific motifs on the peptides determine
and Class-II which differ from each other in their
which peptides would bind to which MHC molecule.9,10
constituents as well as their functions. In MHC (the most
For the antigen to be presented on the MHC molecule,
polymorphic region of the human genome) this poly-
it needs to be processed and loaded on to the MHC
morphism is required for the survival of the species since
molecule’s peptide binding grove. Cytosolic or viral proteins
MHC has a significant role in adaptive immune responses
are degraded in the cytoplasm by a complex of
against infectious agents.
proteosomes called low molecular weight proteases or
polypeptide complex 2 and 7 (LMP2 and LMP7). These
MHC Class-I Genes and Proteins
proteosomes LMP2 and LMP7 are involved in proteolytic
MHC class-I genes are expressed on all nucleated cells in degradation of the antigen into small peptides. 11-13
the form of cell surface glycoproteins. The classical class- Simultaneously, the MHC class-I molecules are being
I genes in humans are HLA-A, HLA-B and HLA-C. Besides, synthesized in the endoplasmic reticulum (ER). The short
there are non-classical class-I genes HLA-E, HLA-F and peptides are loaded on to the newly formed MHC class-I
HLA-G. Classical and non-classical class-I genes are molecules in the ER with the help of transporters associated
organized in the telomeric region of the chromosomal with peptide loading 1 and 2 (TAP1 and TAP2).14 Now, the
segment 6p21.3 (telomere → centromere HLA-F, -G, -A, fully loaded MHC molecule is transported to the cell surface
-E, -C and -B) (Fig. 5.2A). The alleles of HLA loci are co- through Golgi apparatus. An MHC class-I molecule without
dominant. The classical class-I genes are very polymorphic a peptide is unstable and degrades.12,13 The fully loaded
with 853 alleles for HLA-A locus, 1249 alleles for B-locus MHC class-I molecule presents antigen to the cytotoxic
and 463 alleles for C-locus and these numbers are T cells (CD8+ T cells). As stated earlier, the peptides bound
increasing with the discovery of new alleles everyday to different MHC molecules have allele specific motifs,
(Fig.5.2B). On the other hand, nonclassical class-I genes this suggests that an immune response to a particular
are less polymorphic with only 9, 21 and 44 alleles for antigen depends on the types of MHC molecules which
HLA-E, -F and -G respectively.7 are involved in antigen presentation. Hence, some people
CHAPTER
5
Genetic Susceptibility and Immunogenetics 49
B
Figs 5.2A and B: (A) Organization of HLA class I and II loci. (B) Number of alleles, for Class I and II loci
Fig. 5.3: Structural arrangement of MHC class-I and II molecules: showing the alpha chain of class-I molecule with three domains α1, α2 and
α3 which are non-covalently associated with β2m. MHC class II structure has an alpha chain and a beta chain with two domains each: α1, α2
and β1, β2. α1 and α2 domains of the MHC class-I molecule make the peptide binding grove which is the most polymorphic region of the whole
molecule. For class II, α1 and β1 domains form the peptide binding grove and α1 domain of alpha chain and β1 domain of beta chain are the most
polymorphic regions of the class II molecule.
CHAPTER
5
mount a good immune response to the infectious agent, so that no other peptide from the ER binds to the peptide
clear the infection and become immune to further infection binding grove of the MHC class-II molecule.18 The alpha1
while others may develop the disease or develop chronic and beta1 domains of the alpha and beta chain constitute
infection depending on the peptides of the infectious agent the peptide binding cleft of the MHC class-II molecule
being presented by MHC molecules. (Fig. 5.3). An antigen/ infectious agent is phagocytosed
and a phagosomal-lysosomal fusion takes place where
MHC Class-II Genes and Proteins lysosomal cysteine proteases cathepsin S and L play
MHC class-II genes in humans are HLA-DR, -DP and -DQ important role in degradation of the antigen in to small
which code for the HLA class-II glycoproteins. The MHC peptides and result in epitope generation. The MHC class-
class-II molecule is a heterodimer of two polypeptide II molecule gets synthesized in the ER and is transported
chains: an alpha (25-33 KDa) and a beta chain through the Golgi apparatus to the endosomal-lysosomal
(24-29 KDa).15,16 Unlike MHC class-I, both alpha and beta compartment where the Ii is degraded by cathepsin S and
chains of the class-II molecule are encoded on a small peptide of the invariant chain18,19 called CLIP
chromosome 6 (Fig.5.2a). DRB1 gene encodes DR beta (class-II associated invariant chain peptide) is still bound
chain while DRA1 encodes DR alpha chain with 748 DRB1 to the peptide binding grove of the MHC class-II molecule.
alleles and 3 DRA1 alleles. Similarly, DQB1 and DPB1 The CLIP is replaced by the antigenic peptide with the
encode beta chains of DQ and DP molecules with 99 and help of another MHC molecule called HLA-DM.20 HLA-DM
135 alleles respectively and DPA and DQA encode the is also encoded on the MHC class-II region on
alpha chains of DP and DQ molecules with 27 and 34 chromosome 6 and has a very specialized function of
alleles respectively7 (Fig.5.2b). Interestingly, the MHC editing the peptide repertoire to be presented by MHC class-
class-II region has several pseudogenes for HLA-DP, DQ II molecules. Finally, the fully-loaded MHC class-II
and DR beta and alpha chains. The HLA DR region on the molecule goes and expresses on the cells surface.
chromosome is more complicated with 9 DRB genes There are about 50,000-100,000 MHC molecules on
starting from functional DRB1 to DRB9, some of which each cell. Most MHC molecules are occupied by self
are functional and others pseudogenes. peptides and the T cells are tolerized against them during
While HLA class-I molecules are expressed on all thymic education. However, during infection a number of
nucleated cells, HLA class-II molecules are expressed on foreign peptides are presented by the MHC molecules and
antigen presenting cells like macrophages, dendritic cells, immune response takes place against them. Sometimes,
B cells, thymic epithelium and activated T cells.17 The the infectious agent may mimic the self antigens and in
function of MHC class-II molecules is to present antigen such cases, the infection is able to survive without any
to the T helper cells (Th cells). This is the initiation of an antagonistic immune response against them, resulting in
adaptive immune response. When a non-self antigen is the establishment of the infection. Sometimes, even with
presented to CD4+ T helper cells, they get activated and an immune response against the infectious agent, the
secrete certain cytokines like Interferon gamma and TNF- infectious agent may thrive as the infection becomes more
alpha in case of Th1 cells and IL-4, IL-5 and/or IL-6 in dominant as compared to the immune response and that
case of Th2 cells. While the cytokines secreted by Th1 depends on a lot of factors other than the MHC, like the
cells in turn activate the cytotoxic T cells which have already cytokine genes and other genes involved in the immune
seen the antigen in the context of HLA class-I, Th2 cytokine responses.
activate the B cells to become plasma cells which make
the antibodies against antigen they have seen. Thus an
Nomenclature of the HLA
immune response takes place which varies in strength There are more than 3300 alleles for different MHC loci.
depending on the host factors and the peptides being So a system has been developed to identify the MHC
presented. alleles. Initially, the HLA antigens were typed using
The DR molecule is also synthesized in the endoplasmic serological assays when antibodies were derived from
reticulum (ER). The alpha chain and the beta chains are multiparous women who developed anti-HLA antibodies
synthesized and invariant chain (Ii) is attached to the against the HLA antigens of the spouse (since the fetus is
peptide binding grove of the newly synthesized molecule haploidentical to the mother). At that time the HLA antigens
CHAPTER
5
were given numbers like HLA-A1, -A2, -A3, A9, A10, A11, Table 5.1: Nomenclature for the HLA system:
A19, and so on for A locus and HLA-B4, B5, B6, B7, B8, How the alleles are named?
B12, B13, B14, B15, B16, B17, B18, B21, B22, etc. for B Nomenclature Indicates
locus. It may be noted that the numbers after the A locus HLA The HLA region and prefix for an
and B locus are not in continuation. This is because initially HLA gene
when HLA was discovered the numbers were given to the HLA-DRB1 A particular HLA locus, i.e. DRB1
antigens which were discovered in continuation. However, HLA-DRB1*13 A group of alleles which encode the
DR13 antigen
later it was discovered that these antigens belonged to HLA-DRB1*1301 A specific HLA allele for DR13
two different loci, which were called HLA-A and B loci. The antigen
numbers remained the same but their locus was added HLA-DRB1*1301N A DRB1*1301 null allele
before the numbers to clarify the locus. HLA-DRB1*130102 An allele which differs by a
synonymous mutation
Now with the advent of molecular techniques we know
HLA-DRB1*13010102 An allele which contains a mutation
the sequences of these antigens and it was realized that outside the coding region
each of these serologically defined antigens are actually a HLA-DRB1*13010102N A null allele which contains a
cluster of several alleles which differ from each other in mutation outside the coding region
certain nucleotide sequences. Most of the variability is
seen in the second exons of the MHC class-II genes and
HLA AND LEPROSY
exons 3 and 4 for the class-I genes since these exons
code for the peptide binding grove of the MHC molecules. With the above introduction, it will become easy to
So, based on the nucleotide sequences, the alleles are understand the association of HLA alleles present in leprosy
named after their serological counterparts. For example, if patients. Several studies have been done on leprosy
there are 10 alleles for HLA-A1, based on their nucleotide patients; either on families with index cases of leprosy or
sequences the alleles would be called HLA-A*0101, case control studies. The initial studies on association of
A*0102, A*0103, A*0104 … and so on. However, the HLA with leprosy were done on class-I antigens. Most
nomenclature is slightly different for MHC class-II alleles. studies done earlier used conventional serological
Both the alpha chain and the beta chain of the class-II techniques and the results have been inconsistent.21-27
alleles are polymorphic so the nomenclature shows whether However, HLA A11 and B40 seem to be significantly
increased consistently in a few of these studies in Indians.
one is referring to the alpha chain or beta chain allele. For
Association of MHC class-II alleles has been shown
instance, alleles of antigen DR1 can be written as
to be consistent in almost all the studies. HLA-DR3 has
DRB1*0101, DRB1*0102, DRB1*0103 and so on. Here DR
been shown to be associated with tuberculoid leprosy in
is the locus, B1 stands for the beta chain gene 1 (since
Surinam, Venezuela and Mexico patients.28-30 Most of the
there are nine DRB loci, one needs to clarify the locus)
studies show an association of HLA-DR2 with leprosy per
and the number is separated by a star (*), the first two
se. However, earlier studies showed association of HLA-
numerals show the serological specificity and the next
DR2 with tuberculoid leprosy 31-33 while later studies showed
two numerals show the allele which is defined by the
an association of DR2 with lepromatous leprosy as
nucleotide sequences. If there is an N after the four digits,
well.21,27,34-41 Most of these studies were done using
it shows a null allele. If there are fifth and sixth numerals serological techniques. With the advent of molecular typing
after the four numerals, it show a silent mutation which of HLA, one can study different alleles of DR2. HLA-DR2
does not change the amino acid residue. If there are has several alleles which are subdivided into two broad
seventh and eighth numerals after the star it shows that categories DRB1*15 and DRB1*16 which could be further
the mutation is out of the coding region and if there is an N subdivided into DRB1*1501, DRB1*1502, DRB1*1503, etc.
after the eighths digit, it shows that it is a null allele which and DRB1*1601, DRB1*1602, etc. We have studied the
carries the mutation outside the coding region. Table 5.1 multibacillary leprosy patients consisting of lepromatous,
shows how to decipher the HLA alleles. However, for all borderline lepromatous and paucibacillary tuberculoid
practical purposes we will be discussing about the allele leprosy patients. The results show that while one of the
up to four digits only in this chapter. alleles of DR2, DRB1*1501 is significantly increased in
CHAPTER
5
lepromatous leprosy patients, 39,41 DRB1*1502 was to MHC class-I molecules, with three extracellular domains
significantly increased in tuberculoid patients39,42 as α1, α2 and α3, one transmembrane and cytoplasmic
compared to healthy controls. However, DRB1*0701 is domain. However, unlike MHC class-I molecules they do
significantly reduced in multibacillary patients as compared not need beta2 microglobulin to stabilize the molecule. γδ
to controls and the tuberculoid patients who have similar T cells and NK cells and CD8+ αβ T cells which express
frequency of DRB1*0701 as in healthy controls.39 NKG2D receptor respond to MICA and MICB, these may
HLA-DRB1 genes are in linkage disequilibrium with or also contribute to innate immune response against
in simpler terms closely linked to HLA-DQA1 and DQB1 mycobacteria. MICA and MICB are highly polymorphic with
genes which code for DQ alpha and beta chains 67 and 30 alleles respectively. A small study done in South
respectively. DRB1*1501 and DRB1*1502 are in linkage Chinese patients suggested that an HLA-linked disease-
disequilibrium with HLA-DQB1*0601 and DQA1*0102 and resistant gene to lepromatous leprosy is in strong linkage
DQA*0103. The product of DQB1*0601 gene forms the disequilibrium with the HLA-B46/MICA-A5 haplotype.44
heterodimer with the products of DQA*0102 or DQA*0103. Recently, Tosh et al have shown that MICA*5A5.1 allele is
We observed DQA1*0103 to be significantly increased in associated with leprosy susceptibility in South Indians.45
LL patients while DQA1*0102 was significantly increased This allele encodes a protein that lacks the cytoplasmic
in BL patients, suggesting that the products of alleles tail providing a possible mechanism for defective immune
DQB1*0601-DQA1*0103 and DQB1*0601-DQA1*0102 surveillance against mycobacteria.45
present different peptides of M. leprae leading to differential
immune responses and thus resulting in differential Transporters Associated with
manifestations of the disease, i.e. LL and BL respectively. Peptide Loading (TAP)
As previously mentioned tuberculoid patients have The genes for the TAP are localized in the HLA class-II
milder form of the disease as they resemble the healthy region. TAP1 and TAP2 have a very important function of
control MHC profile at some places whereas they also translocating the peptide from the cytosol onto the newly
resemble the MHC profile of the leprosy patients. synthesized MHC class-I molecule in the endoplasmic
Interestingly DQB1*0503 is significantly reduced in TT reticulum. TAP2 has been shown to have three polymorphic
patients as compared to controls. This suggests that while sites at codons 379, 565 and 665 which result in eight
the TT patients have predisposing MHC alleles, there are TAP2 alleles which are called A, B, C, D, E, F, G and H.
differences as well as similarities in their HLA profiles with TAP-2B has been reported to be associated with TT form
that of healthy controls which renders them to have good of leprosy in North India.46
immune response against the infectious agent resulting in
milder form of the disease. These data suggest certain TNF-alpha Gene
fine differences involving DQA1 and DQB1 alleles which TNF-α is proinflammatory, pleiotropic cytokine produced
seem to separate the three subtypes of LL, BL and TT by macrophages with its gene being localized on the MHC
types of leprosy.39 A recent study in leprosy patients from chromosome in between the Class-I and Class-II region,
Argentina however, showed DRB1*1401 and DRB1*1406 the class-III region. Certain single nucleotide polymor-
to be significantly increased in leprosy patients.43 phisms (SNPs) in the promoter of the TNF-α gene have
been shown to be associated with the amount of cytokine
OTHER GENES INVOLVED IN that would be produced for example at position -308, there
SUSCEPTIBILITY TO LEPROSY could be either a G nucleotide or an A nucleotide. -308A
allele has been associated with higher production of TNF-
MICA
alpha while -308G allele has been associated with lower
MHC class-I region has another set of genes which are production of TNF-α.47-50 However, several other studies
involved in innate immunity. These are MHC class-I chain did not find this SNP to have functional implications.51-54
related genes A and B (MICA and MICB) which are Kroeger et al47 showed that the elevated levels of TNF-
encoded 46.4 and 110 kb centromeric to HLA-B locus alpha were produced by the -308A allele when certain types
respectively. They are conserved in many mammals but of cells were stimulated with certain stimuli and that was
are not found in rodents. MIC molecules are highly probably the reason for controversial results obtained by
glycosylated, stress induced proteins with structure similar different investigators.
CHAPTER
5
In terms of association of the -308 SNPs with leprosy SNP 73 detected with TaqI, located in Exon 9. The alleles
too, there are controversial results. While in Indians from of the SNPs are named based on the presence or absence
Bengal -308A has been reported to be predisposing55 for of the restriction site. For example, presence of restriction
lepromatous leprosy, in Brazil the same allele has been site for Fok1 is denoted by ‘f’ while absence of restriction
associated with protection from lepromatous leprosy, is denoted by ‘F’, similarly presence of the restriction site
tuberculoid leprosy and leprosy per se.56,57 However, these for Taq1 is denoted by ‘t’ while its absence is denoted as
associations could not be reproduced in Karonga district ‘T’. Roy et al have reported an association of genotype ‘tt’
of Malawi.5,58 TNF-alpha is an important cytokine involved with tuberculoid and ‘TT’ with lepromatous leprosy.74
in activation of macrophages which in turn are involved in Fitness et al reported that in Karonga the ‘tt’ genotype was
killing of the mycobacteria and also in granuloma formation, associated with susceptibility to leprosy per se.58 In Mali,
which helps in containment of the mycobacteria. However, no association was found for the VDR genotype with either
these different results from different populations could be lepromatous or tuberculoid leprosy or leprosy per se. FokI
a result of difference in the genetic background of the and TaqI genotypes have been reported to be independent
patients and also different strains of mycobacteria infecting determinants of VDR mRNA and protein levels.75 More
the patients. However, more studies need to be done to studies are required to be done to establish the role of
unequivocally show the role of this SNP in manifestation VDR in manifestations of leprosy.
of leprosy.
Toll-like Receptor 2 (TLR2)
Vitamin D Receptor
Toll-like receptors are important cell surface molecules
Vitamin D Receptor (VDR) is a ligand dependent trans- that are involved in innate immune response and recognize
cription factor that belongs to the superfamily of the nuclear the pathogens through specific patterns which result in
hormone receptors.59 The ligand for VDR is vitamin D3, i.e. facilitating transcription of certain genes that regulate
1,25-(OH)2D3 which mediates its biological actions through adaptive immune responses. Since they provide the first
VDR. Binding of 1,25-(OH)2D3 induces conformational line of defence against microbes, they have been studied
changes in VDR which promotes its hetero-dimerization in leprosy. Of the ten TLRs, TLR2 has been shown to control
with Retinoid X Receptor (RXR), followed by translocation the production of cytokines, cell signaling and resistance
of this complex into the nucleus. The RXR-VDR to M. leprae. Kang et al have reported the detection of a C
heterodimer binds to the vitamin D3 responsive elements to T mutation in TLR2 resulting in Arg to Trp at highly
(VDRE) in promoter regions of 1,25-(OH)2D3 responsive conserved amino acid 677 in lepromatous leprosy.76
genes,60 which in turn results in the regulatory function of Further, Kang et al reported that the innate immune
1,25-(OH)2D3. In the absence of classical responsive response of monocytes against M. leprae is mediated by
elements, 1,25-(OH)2D3 may controls the expression of TLR2, and suggested that the mutation in the intracellular
some genes like cytokine genes by targeting inducible domain of TLR2 gene is associated with IL-12 production
transcription factors like NFAT in IL-2 in a sequence specific in lepromatous leprosy.77 Bochud et al subsequently
manner.61 1,25-(OH)2D3 has been shown to have an investigated the role of TLRs in recognition of M. leprae
important immunomodulatory role since it represses and they studied the significance of TLR2Arg(677)Trp
transcription of IL-262,63, IFN-γ64, GM-CSF65 and IL-1266 SNP.78 They reported an impaired function of the variant
and upregulates the production of Th2 cytokines IL-4 and TLR2Arg(677) Trp which provides a molecular mechanism
TGF-β1,67 thereby inhibiting the overall Th1 responses. It for the poor cellular immune response associated with
has been shown to enhance the development of Th2 cells lepromatous leprosy and may have important implications
via a direct effect on naive CD-4 cells.60 Besides 1,25- for understanding the pathogenesis of other mycobacterial
(OH)2D3 has also been shown to modulate the expression infections. Kang et al further studied the cytokine
of HLA class-II alleles on monocytes and human bone responses against M. leprae in peripheral blood
cells.68,69 VDR gene is localized on chromosome 12q 13- mononuclear cells (PBMCs) with the TLR2 mutation
14 with several SNPs which include the T>C SNP in exon2 Arg677Trp.79 In leprosy patients with the TLR2 mutation,
initiation codon detected with FokI restriction enzyme,70 production of IL-2, IL-12, IFN-gamma, and TNF-alpha by
the A>G SNP detected with BsmI 71 and G>T SNP M. leprae-stimulated PBMC were significantly decreased
detected with ApaI 72 located in Intron 8, and a silent C>T and IL-10 was significantly increased compared with that
CHAPTER
5
in groups with wild-type TLR2, suggesting that the TLR2 Genome wide association studies provide a high throughput
signal pathway plays a critical role in the alteration of genotyping technology that can screen thousands of
cytokine profiles in PBMC from leprosy patients and the polymorphic SNPs and microsatellites throughout the
TLR2 mutation Arg677Trp provides a mechanism for the genome. The advantage of using this technology is that
poor cellular immune response associated with lepromatous one does not need a prior knowledge of the genes to be
leprosy. associated with the disease. Strong associations with the
Interestingly, a follow-up study was done by Malhotra chromosomal regions may be used to determine the
et al to study the role of Arg677Trp polymorphism in Indian probable genes localized in the region of interest (i.e. the
leprosy patients.80 Genotyping results after direct PCR regions showing strong associations) using the draft
sequencing showed that the TLR2 Arg677Trp polymorphism human genome sequence. Very few studies on genome
associated with lepromatous leprosy in the Korean population wide associations have been done on different diseases,
was not a true polymorphism of the TLR2 gene. They primarily due to the costs involved in such studies. Genome
concluded that the so-called functional mutation has resulted wide association study on 86 multiplex leprosy families
from the duplication of TLR2 exon 3 present approximately from South Vietnam with multibacillary and paucibacillary
23 kb upstream of TLR2 and shares 93% homology with patients showed strong evidence for linkage in
exon 3 of TLR2. These results suggest that TLR2 chromosomal region 6q25-27. This was confirmed by
polymorphism needs to be studied with caution in future, family-based association analysis in an independent panel
because of the presence of variations in the duplicated of 208 Vietnamese leprosy simplex families. Of seven
(pseudogene) region representing exon 3 of the TLR2 gene. microsatellite markers underlying the linkage peak, alleles
The absence of any variant in the conserved promoter of two markers (D6S1035 and D6S305) showed strong
and intracellular signaling regions of the TLR2 gene in their evidence for association with leprosy (P = 6.7 x 10-4 and
study indicates a need to investigate other regulatory P = 5.9 × 10-5, respectively).83
mechanisms which could control TLR2 function.80 In a follow-up study, Mira et al investigated this region
further by using a systematic association scan of the
NRAMP 1 or Solute Carrier Family 11 chromosomal interval most likely to harbor this leprosy
Member 1 (SLC11A1) susceptibility locus.84 In 197 Vietnamese families, they
Natural resistance associates macrophage protein 1 found a significant association between leprosy and 17
(NRAMP1) maps to chromosome 2q35 and influences the markers located in a block of approx. 80 kilobases
antimicrobial activity of macrophages. Abel et al reported overlapping the 5′ regulatory region shared by the
segregation of NRAMP1 haplotypes into affected siblings Parkinson's disease gene PARK2 (also known as parkin)
was significantly nonrandom in 16 Vietnamese families, and the co-regulated gene PACRG. Presence of two SNPs
however, not so in 4 Chinese families.81 Similarly, no (rs1040079) and PARK2-e1 (-2599), of the 17 risk alleles
association of NRAMP1 was observed in Indians74 and in was highly predictive of leprosy. This was confirmed in a
Mali82 leprosy patients in case-control studies. However, study in Brazilian leprosy patients in whom the same alleles
in Mali study a deletion of 4 bp in the 3’UTR was associated were strongly associated with leprosy. Variants in the
with leprosy type.82 Heterozygotes were more frequent regulatory region shared by PARK2 and PACRG, therefore
among multibacillary than paucibacillary leprosy cases. act as common risk factors for leprosy.84 This was followed
Thus, variation in or near the NRAMP1 gene may exert an by an Indian study, where Malhotra et al showed that T
influence on the clinical presentation of leprosy, possibly allele of SNPs PARK2_e01 (-2599) and 28 kb target_2_1
by influencing cellular immune response type. were significantly associated with susceptibility to leprosy
per se (P=0.03 and 0.03, respectively).85 The haplotype
analysis for the two alleles studied by previous investigators
PARK2/PACRG Genes
showed a lack of significant association of any haplotype
Numerous studies have been done on candidate genes with cases or controls. The non-involvement of major risk
based on their functions however; many genes which may SNPs in the regulatory region of PARK2 and PACRG locus
have a role to play in manifestations of different diseases with leprosy susceptibility in Indian population highlights
may have been ignored due to either unknown functions the differential effect of these SNPs in regulating genetic
or not suspected to be associated with the disease. susceptibility to leprosy in different populations.85
CHAPTER
5
Chromosomal Regions 10p13 and 20p12 involvement in downregulation of T cell functions and in
invasive bacterial diseases, one could hypothesize that
Siddiqui et al reported a genetic linkage scan of the
LYP-Trp620 may have a role in manifestation of
genomes of 224 families from South India, containing 245
mycobacterial diseases as well.
independent affected sib pairs with paucibacillary leprosy.86
Hence, to study the role of PTPN22 C1858T SNP, 153
Using 396 microsatellite markers, they found significant
leprosy patients consisting of 103 lepromatous patients
linkage (maximum lod score (MLS) = 4.09, P<2 × 10-5) on
(including borderline lepromatous) and 50 tuberculoid
chromosome 10p13 for a series of neighboring
patients (including borderline tuberculoid) from North India
microsatellite markers, providing evidence for a major locus
were compared with 365 ethnically matched healthy
for this prevalent infectious disease. Mira et al confirmed
controls.98 The frequency of 1858T allele was significantly
these results in paucibacillary patients from Vietnam.83
increased in both lepromatous (p<0.00006) and tuberculoid
Eichbaum et al showed that human macrophage mannose
(p<0.001) leprosy patients as compared to normal healthy
receptor gene (MRC1) is localized on this chromosome
controls. We also studied the role of predisposing HLA
10p13 region by in situ hybridization and PCR based
alleles in combination with the PTPN22 alleles. DRB1*1501
somatic cell hybrid mapping.87 The macrophage mannose
along with both PTPN22 1858CC and CT was significantly
receptor is a transmembrane protein that is expressed on
increased in lepromatous patients. There was no significant
the surface of mature macrophages88 that mediates
difference between tuberculoid patients and controls with
endocytosis of glycoproteins from pathogens with terminal
respect to simultaneous presence of DRB1*1501 and
mannose and fucose structures present on their cell
PTPN22 1858 genotypes. However, a significantly higher
surface.89 MRC has been shown to be responsible for
number of the tuberculoid patients had predisposing
uptake of mycobacterial lipoglycan lipoarabinomannan
DRB1*1501 (p<0.04) and PTPN22 1858CT (p<0.001)
(LAM) for the presentation by CD1b molecules to LAM-
independent of each other. Interestingly, the protective
reactive T cells. This pathway links recognition of microbial
DRB1*0701 along with PTPN22 1858CC was significantly
antigens by a receptor of the innate immune system to
reduced in lepromatous patients as compared to controls
the induction of adaptive T cell responses.90 This suggests
(p<1x10-6) and tuberculoid patients (p<0.0001). In spite of
that MRC1 may have a role in immune response to
a significant increase of PTPN22 1858CT in tuberculoid
M. leprae.
patients as compared to controls, a significant increase of
Tosh et al subsequently reported a second region of
HLA DRB1*0701 along with PTPN22 1858CC (both
linkage on chromosome 20p12 at marker D20S115 with a
protective) as compared to lepromatous patients who have
significant maximum logarithm of Odds Score of 3.48
increased frequencies of both PTPN22 1858CC and
(p = 0.00003). The transmission linkage disequilibrium test
PTPN22 1858CT along with DRB1*1501, suggests that
(TDT) showed that another marker D20S835 was
these genes play an integrated role in manifestation of
associated with protection from leprosy.91
different forms of leprosy through their functional roles in
antigen presentation and inhibition of T cell responses.98
PTPN22
Thus, while predisposing MHC alleles may be involved
PTPN22 encodes for an 807 amino acid residue protein in inefficient antigen presentation, LYP-Trp620 allele may
called lymphoid tyrosine phosphatase (LYP) which has have a pathogenic role in hyporesponsiveness of T cells
been shown to negatively regulate T cell signalling.92 A due to anomalies in early T cell signaling resulting in clinical
single nucleotide polymorphism in the PTPN22 gene at manifestations of leprosy per se. Contrary to our
nucleotide position 1858 C>T (codon 620) resulting in an expectations, significantly higher number of the tuberculoid
arginine to tryptophan (CGG to TGG) transition has been patients had PTPN22 1858CT suggesting that there may
shown to be a gain-of-function mutant with more potent be early T cell defects in these patients resulting in a
negative regulation of T cell signaling through reduced Lck- compromised immune response to the infectious agent
mediated phosphorylation of the TCRξ chain, reduced which manifests in the milder form of the disease since
tyrosine phosphorylation of LAT and reduced activation of most healthy people exposed to M. leprae are resistant to
Erk2.93 The mutant, LYP-Trp620 has been associated with the infection and with an effective immune response, do
several autoimmune diseases.94-96 Recently, Chapman not develop the disease.1 An account of different genetic
et al have shown its involvement in invasive pneumococcal markers found to be associated with various leprosy forms
disease and gram-positive bacterial disease.97 Due to its is given in Table 5.2.
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5
Table 5.2: Different genetic markers found associated with different types of leprosy
SN Gene- allele, Chromosomal localization Type of leprosy Function of the gene Reference
1. HLA-DR2, Ch. 6p21 Tuberculoid To present peptides for immune response 31-33
2. HLA-DR2, Ch. 6p21 Lepromatous Same as above 21,27,34-41
3. HLA-DR3, Ch. 6p21 Tuberculoid Same as above 28-30
4. HLA-DRB1*1501 (allele of DR2), Ch. 6p21Multibacillary Same as above 39,41
5. HLA-DRB1*1502 (allele of DR2), Ch. 6p21Tuberculoid Same as above 39,42
6. HLA-DQB1*0601, Ch. 6p21 LL, BL, TT Same as above 39
7. HLA-DQA1*0103 , Ch. 6p21 LL Same as above 39
8. HLA-DQA1*0102, Ch. 6p21 BL Same as above 39
9. HLA-DRB1*0701, Ch. 6p21 Reduced in Same as above 39
Lepromatous
10. HLA-DRB1*1401, HLA-DRB1*1406, Ch. 6p21 Leprosy per se Same as above 43
11. MICA-A5, Ch. 6p21 Resistant to LL Role in innate immunity 44
12. MICA-5A5.1, Ch. 6p21 Tuberculoid Role in innate immunity 45
13. TNF-α -308A, Ch. 6p21 LL Associated with high secretion of the 55
cytokine
14. TNF-α -308A, Ch. 6p21 Protective from LL, Associated with high secretion of the 56,57
TT and leprosy per se cytokine
15. TNF-α -308A, Ch. 6p21 No association Same as above 5,58
16. Vitamin D Receptor (VDR) Taq 1 site, tt in Tuberculoid Binds to1,25-(OH)2D3 to induce its 74
Ch. 12q 13-14 TT in lepromatous regulatory functions
17. Vitamin D Receptor (VDR) Taq 1 site, tt in leprosy per se Binds to1,25-(OH)2D3 to induce its 58
Ch. 12q 13-14 regulatory functions
18. TLR2 Arg677Trp, Ch 4q32 Lepromatous Innate immune response 76-78
19. NRAMP1(SLC11A1), Ch 2q35 Heterozygous more influences the anti-microbial activity of 82
4bp deletion in 3’UTR frequent in MB macrophages
than PB
20. PARK2/PACRG Leprosy per se Ubiquitin E3 ligase involved in delivery of 84,85
SNPs (rs1040079) and PARK2-e1 (-2599), ubiquitinated proteins to the proteosomal
Ch. 6q25-27 complex.
21. MRC1, microsatellite markers, Paucibacillary Mediates endocytosis of glycoproteins from 86,87
Ch. 10p13 pathogens with terminal mannose and fucose
structures present on their cell surface
22. Chromosomal region 20p12, D20S835 Protection from Function not known 91
leprosy
23. Chromosomal region 20p12, D20115 Leprosy per se Function not known 91
24. PTPN22 C1858T SNP, Ch. 1p13 MB and PB A gain-of-function mutant with more potent 98
negative regulation of T cell signaling
Ch = Chromosome
CONCLUSION the alleles of different genes (See Table 5.2) that an

It is clear from the above discussion that several genes individual possesses, one may get a milder or severe form
are involved in host’s response to the mycobacterial of the disease or may be able to resist the infection totally.
antigens. While some may have a role in adaptive immune However, some of the studies listed above have been done
responses (like HLA, TAP2, VDR, PTPN22), others may on either a few populations or on a few number of subjects
have a role in innate immunity (NRAMP1, TLR2, MICA, in some populations, hence, large scale studies are
TNF-alpha, MRC1). Since several molecules are involved, required to confirm the associations before the actual
they probably play an integrated role in determining the pathways could be formulated as to how these genes
immune response to the infectious agent. Depending on interact in integrated networks to fight against the infection.
CHAPTER
5
REFERENCES 23. Chiewsilp P, Athkambhira S, Chirachariyavej T, Bhamarapravati
N & Entwistle C. The HLA antigens and leprosy in Thailand.
1. Bongiorno MR, Pistone G, Noto S, Arico M. Tuberculoid leprosy Tissue Antigens 1979;13:186-88.
and Type 1 lepra reaction. Travel Med Infect Dis 2008;6:311-14. 24. Fine PE, Wolf E, Pritchard J et al. HLA-linked genes and leprosy:
2. Ridley DS, Jopling WH. Classification of leprosy according to a family study in Karigiri, South India. J Infect Dis 1979;140:152-
immunity: A five-group system. Int J Lepr Other Mycobact Dis 61.
1966;34:255-73. 25. Wolf E, Fine PE, Pritchard J et al. HLA-A, B and C antigens in
3. Schurr E, Alcais A, de Leseleuc L, Abel L. Genetic predisposi- South Indian families with leprosy. Tissue Antigens 1980;15:436-
tion to leprosy: A major gene reveals novel pathways of immunity 46.
to Mycobacterium leprae. Semin Immunol 2006;18:404-10. 26. Agrewala JN, Ghei SK, Sudhakar KS et al. HLA antigens and
4. Mira MT. Genetic host resistance and susceptibility to leprosy. erythema nodosum leprosum (ENL). Tissue Antigens
Microbes Infect 2006;8:1124-31. 1989;33:486-87.
5. Fitness J, Tosh K, Hill AV. Genetics of susceptibility to leprosy. 27. Rani R, Zaheer SA, Mukherjee R. Do human leukocyte antigens
Genes Immun 2002;3:441-53. have a role to play in differential manifestation of multibacillary
6. Horton R, Wilming L, Rand V et al. Gene map of the extended leprosy: a study on multibacillary leprosy patients from north
human MHC. Nat Rev Genet 2004;5:889-99. India. Tissue Antigens 1992;40:124-27.
7. Robinson J, Waller MJ, Fail SC et al. The IMGT/HLA database. 28. van Eden W, de Vries RR, D'Amaro J et al. HLA-DR-associated
Nucleic Acids Res 2009;37:D1013-07. genetic control of the type of leprosy in a population from surinam.
8. Bjorkman PJ, Saper MA, Samraoui B et al. Structure of the Hum Immunol 1982;4:343-50.
human class I histocompatibility antigen, HLA-A2. Nature 29. van Eden W, Gonzalez NM, de Vries RR et al. HLA-linked control
1987;329:506-12. of predisposition to lepromatous leprosy. J Infect Dis 1985;151:9-
9. Falk K, Rotzschke O, Stevanovic S, Jung G, Rammensee HG. 14.
Allele-specific motifs revealed by sequencing of self-peptides 30. Gorodezky C, Flores J, Arevalo N et al. Tuberculoid leprosy in
eluted from MHC molecules. Nature 1991;351:290-96. Mexicans is associated with HLA-DR3. Lepr Rev 1987;58:
10. Garrett TP, Saper MA, Bjorkman PJ, Strominger JL, Wiley DC. 401-06.
Specificity pockets for the side chains of peptide antigens in 31. van Eden W, de Vries RR, Mehra NK et al. HLA segregation of
HLA-Aw68. Nature 1989;342:692-96. tuberculoid leprosy: confirmation of the DR2 marker. J Infect Dis
11. Spies T, Bresnahan M, Bahram S et al. A gene in the human 1980;141:693-701.
major histocompatibility complex class II region controlling the 32. de Vries RR, Mehra NK, Vaidya MC et al. HLA-linked control of
class I antigen presentation pathway. Nature 1990;348:744-47. susceptibility to tuberculoid leprosy and association with HLA-
12. Van Kaer L. Pillars article:antigen presentation:discovery of the DR types. Tissue Antigens 1980;16:294-304.
peptide TAP. J Immunol 2008;180:2723-24. 33. Miyanaga K, Juji T, Maeda H et al. Tuberculoid leprosy and HLA
13. Cresswell P, Ackerman AL, Giodini A, Peaper DR, Wearsch PA. in Japanese. Tissue Antigens 1981;18:331-34.
Mechanisms of MHC class I-restricted antigen processing and 34. Visentainer JE, Tsuneto LT, Serra MF et al. Association of leprosy
cross-presentation. Immunol Rev 2005;207:145-57. with HLA-DR2 in a Southern Brazilian population. Braz J Med
14. Groothuis TA, Griekspoor AC, Neijssen JJ, Herberts CA, Neefjes Biol Res 1997;30:51-59.
JJ. MHC class I alleles and their exploration of the antigen- 35. Schauf V, Ryan S, Scollard D et al. Leprosy associated with
processing machinery. Immunol Rev 2005;207:60-76. HLA-DR2 and DQW1 in the population of northern Thailand.
15. de Vries RR, van Rood JJ. Immunobiology of HLA class-I and Tissue Antigens 1985;26:243-47.
class-II molecules. Introduction. Prog Allergy 1985;36:1-9. 36. Serjeantson SW. HLA and susceptibility to leprosy. Immunol Rev
16. Brown JH, Jardetzky TS, Gorga JC et al. Three-dimensional 1983;70:89-112.
structure of the human class II histocompatibility antigen HLA- 37. Cem Mat M, Yazici H, Ozbakir F, Tuzun Y. The HLA association of
DR1. Nature 1993;364:33-39. lepromatous leprosy and borderline lepromatous leprosy in
17. Holling TM, Schooten E, van Den Elsen PJ. Function and Turkey. A preliminary study. Int J Dermatol 1988;27:246-47.
regulation of MHC class II molecules in T-lymphocytes:of mice 38. Todd JR, West BC, McDonald JC. Human leukocyte antigen
and men. Hum Immunol 2004;65:282-90. and leprosy:study in northern Louisiana and review. Rev Infect
18. Cresswell P. Antigen processing and presentation. Immunol Rev Dis 1990;12:63-74.
2005;207:5-7. 39. Rani R, Fernandez-Vina MA, Zaheer SA et al. Study of HLA
19. Costantino CM, Ploegh HL, Hafler DA. Cathepsin S regulates class II alleles by PCR oligotyping in leprosy patients from north
class II MHC processing in human CD4+ HLA-DR+ T cells. India. Tissue Antigens 1993;42:133-37.
J Immunol 2009;183:945-52. 40. Izumi S, Sugiyama K, Matsumoto Y et al. Analysis of the
20. Denzin LK, Cresswell P. HLA-DM induces CLIP dissociation immunogenetic background of Japanese leprosy patients by
from MHC class II alpha beta dimers and facilitates peptide the HLA system. Vox Sang 1982;42:243-47.
loading. Cell 1995;82:155-65. 41. Joko S, Numaga J, Kawashima H et al. Human leukocyte
21. Kim SJ, Choi IH, Dahlberg S et al. HLA and leprosy in Koreans. antigens in forms of leprosy among Japanese patients. Int J
Tissue Antigens 1987;29:146-53. Lepr Other Mycobact Dis 2000;68:49-56.
22. Mohagheghpour N, Tabatabai H, Mohammad K, Ramanujam K, 42. Mehra NK, Rajalingam R, Mitra DK et al. Variants of HLA-DR2/
Modabber FZ. Histocompatibility antigens in patients with leprosy DR51 group haplotypes and susceptibility to tuberculoid leprosy
from Azarbaijan, Iran. Int J Lepr Other Mycobact Dis 1979;47: and pulmonary tuberculosis in Asian Indians. Int J Lepr Other
597-600 . Mycobact Dis 1995;63:241-48.
CHAPTER
5
43. Borras SG, Cotorruelo C, Racca L et al. Association of leprosy 60. Boonstra A, Barrat FJ, Crain C et al. 1alpha,25-Dihydroxyvitamin
with HLA-DRB1 in an Argentinean population. Ann Clin Biochem d3 has a direct effect on naive CD4(+) T cells to enhance the
2008;45:96-98. development of Th2 cells. J Immunol 2001;167:4974-80.
44. Wang LM, Kimura A, Satoh M et al. HLA linked with leprosy in 61. Takeuchi A, Reddy GS, Kobayashi T et al. Nuclear factor of
southern China:HLA-linked resistance alleles to leprosy. Int J activated T cells (NFAT) as a molecular target for 1alpha,
Lepr Other Mycobact Dis 1999;67:403-08. 25-dihydroxyvitamin D3-mediated effects. J Immunol
45. Tosh K, Ravikumar M, Bell JT et al. Variation in MICA and MICB 1998;160:209-18.
genes and enhanced susceptibility to paucibacillary leprosy in 62. Bhalla AK, Amento EP, Serog B, Glimcher LH. 1,25-
South India. Hum Mol Genet 2006;15:2880-87. Dihydroxyvitamin D3 inhibits antigen-induced. T cell activation.
46. Rajalingam R, Singal DP, Mehra NK. Transporter associated J Immunol 1984;133:1748-54.
with antigen-processing (TAP) genes and susceptibility to 63. Alroy I, Towers TL, Freedman LP. Transcriptional repression of
tuberculoid leprosy and pulmonary tuberculosis. Tissue Antigens the interleukin-2 gene by vitamin D3:direct inhibition of NFATp/
1997;49:168-72. AP-1 complex formation by a nuclear hormone receptor. Mol
47. Kroeger KM, Carville KS, Abraham LJ. The -308 tumour necrosis Cell Biol 1995;15:5789-99.
factor-alpha promoter polymorphism effects transcription. Mol 64. Cippitelli M, Santoni A. Vitamin D3:a transcriptional modulator of
Immunol 1997;34:391-99. the interferon-gamma gene. Eur J Immunol 1998;28:3017-30.
48. Wilson AG, Symons JA, McDowell TL et al. Effects of a polymor- 65. Lemire JM. Immunomodulatory role of 1,25-dihydroxyvitamin
phism in the human tumour necrosis factor alpha promoter on D3. J Cell Biochem 1992;49:26-31.
transcriptional activation. Proc Natl Acad Sci USA 1997;94:3195- 66. D’Ambrosio D, Cippitelli M, Cocciolo MG et al. Inhibition of IL-12
99.
production by 1,25-dihydroxyvitamin D3. Involvement of NF-
49. Knight JC, Udalova I, Hill AV et al. A polymorphism that affects
kappaB downregulation in transcriptional repression of the p40
OCT-1 binding to the TNF promoter region is associated with
gene. J Clin Invest 1998;101:252-62.
severe malaria. Nat Genet 1999;22:145-50.
67. Cantorna MT, Woodward WD, Hayes CE, DeLuca HF. 1,25-
50. Louis E, Franchimont D, Piron A et al. Tumour necrosis factor
dihydroxyvitamin D3 is a positive regulator for the two anti-
(TNF) gene polymorphism influences TNF-alpha production in
encephalitogenic cytokines TGF-beta 1 and IL-4. J Immunol
lipopolysaccharide (LPS)-stimulated whole blood cell culture in
1998;160:5314-19.
healthy humans. Clin Exp Immunol 1998;113:401-06.
68. Rigby WF, Waugh M, Graziano RF. Regulation of human
51. Stuber F, Udalova IA, Book M et al. -308 tumour necrosis factor
monocyte HLA-DR and CD4 antigen expression, and antigen
(TNF) polymorphism is not associated with survival in severe
presentation by 1,25-dihydroxyvitamin D3. Blood 1990;76:
sepsis and is unrelated to lipopolysaccharide inducibility of the
189-97.
human TNF promoter. J Inflamm 1995;46:42-50.
69. Skjodt H, Hughes DE, Dobson PR, Russell RG. Constitutive
52. Brinkman BM, Zuijdeest D, Kaijzel EL et al. Relevance of the
and inducible expression of HLA class II determinants by human
tumor necrosis factor alpha (TNF alpha)-308 promoter poly-
osteoblast-like cells in vitro. J Clin Invest 1990;85:1421-26.
morphism in TNF alpha gene regulation. J Inflamm 1995;46:32-
41. 70. Gross C, Eccleshall TR, Malloy PJ et al. The presence of a
53. Somoskovi A, Zissel G, Seitzer U et al. Polymorphisms at position polymorphism at the translation initiation site of the vitamin D
-308 in the promoter region of the TNF-alpha and in the first receptor gene is associated with low bone mineral density in
intron of the TNF-beta genes and spontaneous and lipopoly- postmenopausal Mexican-American women. J Bone Miner Res
saccharide-induced TNF-alpha release in sarcoidosis. Cytokine 1996;11:1850-55.
1999;11:882-87. 71. Morrison NA, Yeoman R, Kelly PJ, Eisman JA. Contribution of
54. Kaijzel EL, Bayley JP, van Krugten MV et al. Allele-specific trans-acting factor alleles to normal physiological variability:
quantification of tumor necrosis factor alpha (TNF) transcription vitamin D receptor gene polymorphism and circulating
and the role of promoter polymorphisms in rheumatoid arthritis osteocalcin. Proc Natl Acad Sci USA 1992;89:6665-69.
patients and healthy individuals. Genes Immun 2001;2:135-44. 72. Faraco JH, Morrison NA, Baker A et al. ApaI dimorphism at the
55. Roy S, McGuire W, Mascie-Taylor CG et al. Tumor necrosis human vitamin D receptor gene locus. Nucleic Acids Res
factor promoter polymorphism and susceptibility to lepromatous 1989;17:2150.
leprosy. J Infect Dis 1997;176:530-32. 73. Durrin LK, Haile RW, Ingles SA, Coetzee GA. Vitamin D receptor
56. Santos AR, Almeida AS, Suffys PN et al. Tumor necrosis factor 3'-untranslated region polymorphisms:lack of effect on mRNA
promoter polymorphism (TNF2) seems to protect against stability. Biochem Biophys Acta 1999;1453:311-20.
development of severe forms of leprosy in a pilot study in Brazilian 74. Roy S, Frodsham A, Saha B et al. Association of vitamin D
patients. Int J Lepr Other Mycobact Dis 2000;68:325-27. receptor genotype with leprosy type. J Infect Dis 1999;179:
57. Santos AR, Suffys PN, Vanderborght PR et al. Role of tumor 187-91.
necrosis factor-alpha and interleukin-10 promoter gene poly- 75. Ogunkolade BW, Boucher BJ, Prahl JM et al. Vitamin D receptor
morphisms in leprosy. J Infect Dis 2002;186:1687-91. (VDR) mRNA and VDR protein levels in relation to vitamin D
58. Fitness J, Floyd S, Warndorff DK et al. Large-scale candidate status, insulin secretory capacity, and VDR genotype in
gene study of leprosy susceptibility in the Karonga district of Bangladeshi Asians. Diabetes 2002;51:2294-2300.
northern Malawi. Am J Trop Med Hyg 2004;71:330-40. 76. Kang TJ, Chae GT. Detection of Toll-like receptor 2 (TLR2)
59. Evans RM. The steroid and thyroid hormone receptor superfamily. mutation in the lepromatous leprosy patients. FEMS Immunol
Science 1988;240:889-95. Med Microbiol 2001;31:53-58.
CHAPTER
5
77. Kang TJ, Lee SB, Chae GT. A polymorphism in the toll-like 88. Harris N, Peters LL, Eicher EM et al. The exon-intron structure
receptor 2 is associated with IL-12 production from monocyte in and chromosomal localization of the mouse macrophage
lepromatous leprosy. Cytokine 2002;20:56-62. mannose receptor gene Mrc1: identification of a Ricin-like domain
78. Bochud PY, Hawn TR, Aderem A. Cutting edge:a toll-like receptor at the N-terminus of the receptor. Biochem Biophys Res Commun
2 polymorphism that is associated with lepromatous leprosy is 1994;198:682-92.
unable to mediate mycobacterial signaling. J Immunol 2003; 89. Taylor ME, Drickamer K. Structural requirements for high affinity
170:3451-54. binding of complex ligands by the macrophage mannose receptor.
79. Kang TJ, Yeum CE, Kim BC et al. Differential production of J Biol Chem 1993;268:399-404.
interleukin-10 and interleukin-12 in mononuclear cells from 90. Prigozy TI, Sieling PA, Clemens D et al. The mannose receptor
leprosy patients with a Toll-like receptor 2 mutation. Immunology delivers lipoglycan antigens to endosomes for presentation to
2004;112:674-80. T cells by CD1b molecules. Immunity 1997;6:187-97.
80. Malhotra D, Relhan V, Reddy BS & Bamezai R. TLR2 Arg677Trp 91. Tosh K, Meisner S, Siddiqui MR et al. A region of chromosome
polymorphism in leprosy:revisited. Hum Genet 2005;116: 20 is linked to leprosy susceptibility in a South Indian population.
J Infect Dis 2002;186:1190-93.
413-15.
92. Hasegawa K, Martin F, Huang G et al. PEST domain-enriched
81. Abel L, Sanchez FO, Oberti J et al. Susceptibility to leprosy is
tyrosine phosphatase (PEP) regulation of effector/memory
linked to the human NRAMP1 gene. J Infect Dis 1998;177:133-45.
T cells. Science 2004;303:685-89.
82. Meisner SJ, Mucklow S, Warner G et al. Association of NRAMP1
93. Vang T, Congia M, Macis MD et al. Autoimmune-associated
polymorphism with leprosy type but not susceptibility to leprosy
lymphoid tyrosine phosphatase is a gain-of-function variant. Nat
per se in west Africans. Am J Trop Med Hyg 2001;65:733-35.
Genet 2005;37:1317-19.
83. Mira MT, Alcais A, Van Thuc N et al. Chromosome 6q25 is linked
94. Bottini N, Musumeci L, Alonso A et al. A functional variant of
to susceptibility to leprosy in a Vietnamese population. Nat Genet
lymphoid tyrosine phosphatase is associated with type I diabetes.
2003;33:412-15. Nat Genet 2004;36:337-38.
84. Mira MT, Alcais A, Nguyen VT et al. Susceptibility to leprosy is 95. Begovich AB, Carlton VE, Honigberg LA et al. A missense single-
associated with PARK2 and PACRG. Nature 2004;427:636-40. nucleotide polymorphism in a gene encoding a protein tyrosine
85. Malhotra D, Darvishi K, Lohra M et al. Association study of major phosphatase (PTPN22) is associated with rheumatoid arthritis.
risk single nucleotide polymorphisms in the common regulatory Am J Hum Genet 2004;75:330-37.
region of PARK2 and PACRG genes with leprosy in an Indian 96. Kyogoku C, Langefeld CD, Ortmann WA et al. Genetic associa-
population. Eur J Hum Genet 2006;14:438-42. tion of the R620W polymorphism of protein tyrosine phosphatase
86. Siddiqui MR, Meisner S, Tosh K et al. A major susceptibility locus PTPN22 with human SLE. Am J Hum Genet 2004;75:504-07.
for leprosy in India maps to chromosome 10p13. Nat Genet 97. Chapman SJ, Khor CC, Vannberg FO et al. PTPN22 and invasive
2001;27:439-41. bacterial disease. Nat Genet 2006;38:499-500.
87. Eichbaum Q, Clerc P, Bruns G et al. Assignment of the human 98. Rani R, Singh A, Israni N, Sharma P, Kar HK. The Role of
macrophage mannose receptor gene (MRC1) to 10p13 by in situ Polymorphic Protein Tyrosine Phosphatase Non-Receptor
hybridization and PCR-based somatic cell hybrid mapping. Type 22 in Leprosy. J Invest Dermatol 2009;doi:10.1038/
Genomics 1994;22:656-58. jid.2009.140.
CHAPTER
6
6
Immunological Aspects
Indira Nath, Mehervani Chaduvula
INTRODUCTION from leprosy patients was described in great detail by Indian

and Latin American pathologists, Ridley and Jopling drew
Leprosy is an infectious disease whose clinical
attention to the finer details reflecting immunological
manifestations are highly influenced by the immune
features based on lymphocyte and macrophage populations
response of the subject and is a model disease in clinical
in the skin lesions. 1 Since these cells were being
medicine for understanding the human host defences
discovered to be the major players in an immune response
against intracellular pathogens. The leprosy spectrum is
at that time, the Ridley-Jopling classification which divided
one of the clearest examples of the same pathogen leading
the leprosy spectrum into 5 groups, became popular
to varied clinicopathological presentations in man. That
amongst immunologists and laboratory based researchers.
the host response to the leprosy bacillus determines the
However, it may be pointed out that subsequent studies in
subsequent clinical features was pointed out in 1954 when
immune responses do not uphold the immunologists’
Mitsuda first showed that intradermal injection of killed
enthusiasm of the Ridley-Jopling classification, as the clear
M. leprae led to a skin reaction 3-4 weeks later with
cut differences are not observed in many of the in vitro
erythema and swelling at the site. Such reaction was
investigations between borderline and polar counterparts.
observed only in the patients with tuberculoid and not those
It is also considered too complicated to be used in the
with lepromatous leprosy, indicating that the inflammatory
field conditions. Nevertheless, this classification continues
response of the subject to the bacillus was dependant on
to be used in laboratory based research. As the chapters
the host immune response. Later, Dharmendra showed that
on clinical features of leprosy and classification would point
a lipid-free soluble factor from the leprosy bacilli also
out; the most significant feature of the classification is the
produced such a reaction in the shorter time period of 48-
stability of polar forms of TT and LL; whereas the borderline
72 hours. Whereas the Mitsuda test measures the ability
forms of their counterparts (BT and BL) are unstable and
of the host to mount a granulomatous response, the time
show a greater propensity to develop leprosy reactions.
kinetics of the Dharmendra test matches the delayed type
hypersensitivity reaction and explains the time difference
between the two tests. Neither of the tests are strictly GENERAL IMMUNE RESPONSES
leprosy specific, as individuals who have not been exposed The defence against pathogens/external agents is first
to leprosy may also show positive skin reaction. initiated by the innate immune response and subsequently
Nevertheless these tests may have been the earliest after a lag period, by the acquired immune response. Both
markers for the leprosy spectrum since PPD used for the responses function through cells as well as soluble factors.
Mantoux test. The innate response requires macrophages and their lineage
Further evidence for the varied immune response as well as natural killer cells. Though the cells recognize
emerged through the histopathological examination of many pathogens via general molecular pattern recognition;
dermal lesions. Though the histopathology of the skin patch the complement receptors and the Toll-like receptors (TLR)
CHAPTER
6
Immunological Aspects 61
are of considerable relevance in leprosy. The innate system leprosy on the other hand show bacilli filled macrophages
also includes complement and some cytokines as the which lack the ability to kill bacilli efficiently.
soluble factors. The acquired immune response in contrast, Taken together with skin tests; the implications for
involves highly specific mechanism through ligand receptor leprosy are, that the tuberculoid leprosy patients have T
interaction. The major players are lymphocytes, dendritic cell immunity/ DTH to the pathogen whereas lepromatous
cells, macrophages and their lineage cells. The soluble subjects have antibodies but little or no T cell functions.
factors released subsequently can be exquisitely specific Thus began the saga of immunology of leprosy.
as in antibodies; or may lead to a generalized nonspecific This chapter would focus mainly on human T cell
functions, as with cytokines. Though the cell recognition mediated immune responses as they are more important
is specific, the cytokine released may affect the other from immunopathological viewpoint. The antibody (humoral)
pathogens and also cause immunopathological responses are discussed in the Chapter 15 (Serological
derangements in the tissues through bystander effects. and Molecular Diagnosis). For experimental murine models
Moreover, the acquired immune system retains a memory of leprosy please see the review by Scollard et al.2
of its first encounter with the pathogen through memory
cells, and subsequent encounter with the same pathogen IMMUNOLOGICAL FEATURES
produces a more rapid and enhanced response. It is being OF LEPROSY
increasingly recognized that these two systems are not Innate Immunity
totally compartmentalized and that there is overlap in some
Diseases are rarely caused by the direct attack of a
critical areas.
pathogen; they result usually by complex interaction of
Lymphocytes are known to be of two major types on
the pathogen and the host. Innate immune responses have
the basis of their cell surface markers and functions. The
been difficult to study in man as leprosy has a long
B cells bearing immunoglobulin (Ig) surface marker, produce
incubation period. However some clues have emerged both
antibodies and lead to humoral immunity that can capture
from experimental models and from the associations
the circulating free microbes. Antibodies cannot crossliving
observed with genetic studies. The entry of pathogens into
cell membrane and thus, are unable to attack microbes
macrophages or their lineage is not necessarily antigen
that live within cells (intracellular pathogens). T cells have
specific and is mediated by the common phagocytosis.
the surface CD3 marker and are responsible for cellular
Attachment of the pathogen to the cell membrane and the
immunity (CMI)/delayed type hypersensitivity (DTH) type of phagocytosis may vary for different pathogens.3
required for limiting and killing the intracellular pathogens Entry is the first step for intracellular lifestyle of
such as those causing leprosy, tuberculosis, typhoid and pathogens such as M. leprae. In leprosy, receptors to
leishmaniasis. The T cells achieve this mainly by complement fragments of CR1, CR3, and CR4 help in
differentiating to effector cells that function directly in killing phagocytosis. Phenolic glycolipid 1 (PGL-1) an M. leprae
(CD8, cytotoxic T cells) through granules present in them specific cell wall lipid is recognized by complement 3.4 It
or through production of cytokines or biological modulators would appear that susceptibility to leprosy may be linked
which are varied and have multiple functions. They (CD4, to genes that are involved in macrophage function in the
T helper cell) also help B cells to produce antibodies against mouse such as NRAMP-1 (Iron transporter natural
protein antigens and have an immunoregulatory role. resistance associated macrophage protein-1) which assists
Macrophages, the very cells that carry pathogens within in viability/multiplication of pathogen within the macrophage
them, are required to present antigens to T cells which are and in iron transport into the phagosome. The human
unable to recognize and respond to pathogens/pathogen homologue of the gene encoding the protein has been
products unless they were presented by macrophages along identified to chromosome 2q35 (Table 6.1).5 The gene
with self antigens such as histocompatiabilty antigens associated with early onset Parkinson’s disease PARKI2/
(HLA). Thus, it is evident that lesions of tuberculoid leprosy PACRG responsible for the synthesis of a ligase in the
that had more lymphocytes and macrophages which had proteosome pathway has been recently identified as
been transformed into epithelioid cells manifest cellular susceptibility gene in the Vietnamese and Brazilian
immunity and explain why they do not show leprosy bacilli population, suggesting its role in innate immune based
in the lesions. The lymphopenic lesions of lepromatous defect.6
CHAPTER
6
Table 6.1: Gene polymorphisms involved in innate and acquired immune responses in
leprosy patients from various populations
S. No Gene/Function of product Position/ Country Reference Conclusion

1. TNF-α/ inflammatory – 308 (G →A) & Santos AR TNF2 allele frequencies significantly
cytokine – 238 promoter et al27 lower in leprosy than control subjects.
region/Brazil
2. IL-10/ anti-inflammatory – 819 (C→ T) prompter Santos AR Homozygous genotype significantly
cytokine region/Brazil et al27 higher among patients. Associated
with tuberculoid leprosy
3. IL-10/ anti-inflammatory – 3575T/–2849G/–2763C/ Malhotra D et al65 Resistance to leprosy
cytokine – 1082A/–592 (C → A) &
– 819 (C →T)/India
Minor haplotype in promoter Santos AR et al27 Resistance to leprosy
region–3575A/–
2849G/–2763C/–/Brazil
4. NRAMP1(iron transporter polymorphism (GT)(n) Ferriera FR et al59 The NRAMP1 promoter genotypes 22
natural resistance in the promoter region of and 23 combined with negative
associated macrophage the NRAMP1 gene / Brazil Mitsuda test showed greater chance
protein 1) of developing leprosy.
5. TLR1/Toll receptors N248 S SNP, S248 and Schuring RP et al60 N248 SNP variant diminished the
involved in innate immunity I620S/Bangladesh response of TLR1. Homozygous S248
increases and SN decreased
susceptibility to leprosy. S 248 allele
and I620 S association more frequent
with reversal reactions.
TLR1/ Toll receptors Isoleucine –serine mutation, Misch EA et al66 1805G allele was associated with
involved in innate immunity. TLR1→T1805G/ Nepal protection from RR. 1805 genotypes
GG or TG had a reduced risk of RR in
comparison to genotype TT.
6. TLR2 / a. TLR2 597C→T, 597C→T susceptibility to reversal
(Toll receptors involved b. 1350T→C, reaction. -597T alleleprotective
in innate immunity) c. 280 bp microsatellite Bochud PY et al31 effect. Homozygosity for the 280-bp
marker/ Ethiopia homozygous—risk of reversal
reaction.
TLR2 Arg 677 Trp mutation Kang TJ et al8 IL-12 decreases in lepromatous
in TLR 2 gene/ leprosy.
TLR2 Arg 677 Trp mutation in Kang TJ et al61 Cytokines- decrease in IL-2, IL-12,
TLR 2 gene/Korea IFN-γ, and TNF-α by M. leprae—
stimulated PBMC: increase in IL-10.
7. TLR4 TLR4 896G>A [D299G] and Bochud PY et al62 TLR4 SNPs – protection against
1196C>T [T399I])/ Ethiopia leprosy.
8. IFN-γ CA repeat microsatellite/ Reynard MP et al67 The alleles contribute a role in leprosy
Brazil postinfection
9. IL-12 R (IL-12p40) 3’UTR 1188 A/C / Mexico Alvarado-Navarro Susceptibility to lepromatous leprosy
A et al63 independent of IL-12
10. IL-12 Rβ2 Multiple SNPs detected within Ohyama H et al64 Implicated in leprosy spectrum
the 5' flanking region of
IL12RB2/ Japan
Toll receptors are a highly conserved family of proteins the activation of the TLRs (Table 6.2).7,8 Activation of
present on macrophages and dendritic cells which seem monocytes and dendritic cells by TLR1, TLR2 heterodimers
to play a role both in innate and acquired immune has been observed with 19 and 33 KDa lipopeptides of
responses. They are crucial for recognition of microbial M. leprae.9
pathogens. TLR 2 and 4 recognize the leprosy bacillus. C-type lectin receptors present on mature macrophages
Since they are transmembrane molecules, the cytoplasmic (such as the mannose receptor), bind carbohydrate
tail signals through transcription factor, NF κB leading to moieties, mannose-capped lipoarabinomannan on
induction and release of IL-12, a cytokine that induces M.tuberculosis and M. leprae and influence macrophage
pro-inflammatory cytokines; Th2 cytokines seem to inhibit functions (such as phagocytosis and production of
CHAPTER
6
Table 6.2: Immunological features of leprosy and leprosy reactions in circulation and after
antigen induced peripheral blood mononuclear cells
Features Tuberculoid leprosy Lepromatous leprosy RR ENL
Total T cells number → ↓ → →
B cells number → →↑ → →
Lymphoproliferation ↑ ↓ ↑ ↑
Mitogen ↑ ↓ ↑ ↑
M. leprae specific ↑ ↓ ↑ ↑
PPD ↑ → ↑ →
Cytokines
IL-1 ↑ ↓ ↑ ↑
IL-2 ↑ ↓ ↑ ↑
IL-12 ↑ ↓ ↑ ↑
IFN-10 ↓ ↑ ↓ ↓
INF ↑ ↓ ↑ ↑
IL-2 receptor ND ND ↑ ↑
IP-10 → → ↑ →
Th phenotype Th 1+Th 0 Th 2+Th0 Th 1 Th 1
→ Normal, ↑ Increase, ↓ Decrease, ND= Not done, RR = Reversal/Type1 reaction, ENL = Erythema nodosum leprosum/Type2 reaction
prostaglandin-2 (PGE2), nitric oxide (NO) and tumor to be a source of intense research. In contrast to T cell
necrosis factor alpha (TNF-α) production.10 DC-SIGN11 and functions, it would appear that antibody responses of both
langerin granules of Langerhans cells have also been general and antigen specific type are enhanced in
implicated in the uptake of nonpeptide mycobacterial lepromatous and unimpaired in tuberculoid leprosy patients.
antigens.12 In the former, there is a polyclonal B cell response as
Schwann cells (SC) are another group of cells of the even autoantibodies are observed in circulation. However,
macrophage lineage which reside in peripheral nerves. it must be pointed that the latter are not associated with
M. leprae is the only bacterium that infects them. SC manifestations of autoimmune disease in leprosy. Thus it
dystroglycans interact with PGL-1 of the bacillus for is evident that leprosy shows an inverted relationship
interiorization. between humoral and T cell mediated immunity. Moreover,
the presence of antibodies is associated with presence of
Acquired Immunity bacilli in lepromatous leprosy indicating thereby that
In addition to the in vivo studies as indicated by the skin protection to this disease is not mediated by antibodies.
tests described above, it has been shown (Table 6.2) that This is in conformity with the finding that antibodies do not
T cell numbers were reduced in lepromatous leprosy and penetrate living cell membrane and thus have no effect on
failed to respond to M. leprae antigens. Indian subjects intracellular pathogens such as M. leprae. However, they
also showed a general depression of T cell functions in may play a role in capturing bacilli or their products when
addition to the antigen specific one as reflected by low they are released into tissues or circulation. They may
lymphocyte transformation to T cell mitogens; such as also lead to immune complexes as observed in
concanavalin A (ConA) and phytohemagglutinin (PHA). lepromatous patients when the abundant bacillary antigens
Whereas the specific unresponsiveness was longlasting associate with the circulating antibodies under appropriate
and persisted for many years after bacillary clearance by conditions. Antibodies being biological markers of infection
drugs, the general unresponsiveness and T cell numbers can be exploited for diagnosis of the disease or clinical
returned to normal.13 The lepromatous patients had unique complications (See Chapter on Serological and Molecular
and exquisitely antigen specific unresponsiveness, as Diagnosis).
indicated by the fact that the T cell response to other Cell surface CD3 molecule distinguishes all T cells. In
antigens and related antigens of the tuberculosis pathogen addition, the presence of CD4 and CD8 respectively
is unimpaired. The mechanisms underlying this continue indicates subsets of helper and cytotoxic/suppressor T
CHAPTER
6
cells. Such cells have been shown to be in normal numbers different methodologies by various workers. Groups in India
in tuberculoid leprosy. Both conventional  and non showed that in lepromatous patient’s macrophages21,22 or
conventional  T cell receptor (TCR) may be present in macrophage factors23 suppressed T cell lymphoproliferation
these cells. Whereas CD4 cells recognize antigen in and IL-2 production. Such factors were non-specific and
conjunction with MHC Class II, CD8 cells use MHC consisted of prostaglandins E2, leukotrienes and IL 10.
Class I. All nucleated cells have MHC Class I; whereas This evidence was further supported by the in vitro reversal
MHC Class II is restricted to antigen presenting cells such of suppression in lepromatous lymphocytes with the use
as macrophages, dendritic cells and Langerhans cells in of HLA matched tuberculoid macrophages and antagonists
the skin. Functional subpopulations also exist based on to the soluble factors. Phenolic glycolipid (PGL) the specific
the type of cytokines that the T cells produced. Cytokines antigen of the leprosy bacillus was also thought to be
are glycoproteins which are defined after international responsible for T cell suppression.20 However, Indian
consensus as interleukins (IL) followed by a number i.e. IL studies showed PGL-1 to be generally suppressive in
1, 2, etc. Some may have the name defined by their major lymphoproliferative assays, but could not explain the
function e.g. interferons. Cytokines IL-2 and IFN-γ are unique antigen specificity noted in lepromatous leprosy.24
produced by peripheral blood mononuclear cells (PBMC) The concept of suppressor T cells lost credibility in basic
on stimulation with leprae specific antigens in tuberculoid immunology in the 90s as no phenotype or gene could be
but not in lepromatous patients.14,15 In contrast, the latter associated with this function. Currently, the concept of
showed release of IL-10 by both CD8 T cells16 and negative regulation is making a reappearance in the form
macrophages.15 Cytokine release was influenced by of Foxp3 regulatory T cells which would be discussed later.
dendritic cells as compared to monocytes from the same The peripheral unresponsiveness in leprosy can be
patients.17 That cytokines played an important role in overcome both in vitro and in vivo as shown above with
protection against leprosy was indicated by rapid bacillary HLA matched cell cultures wherein tuberculoid monocytes
clearance by IFN-γ and IL-2 injections in dermal and were able to reconstitute lymphoproliferation of lepromatous
subcutaneous sites of lesions in lepromatous patients as subjects. Moreover, during leprosy reactions, lepromatous
well as by mounting a delayed type reaction with PPD subjects develop T cell activation and entry of T cells into
injections.18,19 lesions as described below.
The discovery of Th phenotypes by the cloning of murine
Immunological Unresponsiveness
T cell subsets which showed mutually exclusive cytokine
The basis for immunological unresponsiveness in patterns responsible for cellular or humoral immunity was
lepromatous leprosy continues to evade consensus even an attractive concept in diseases such as leprosy which
though it has been intensely studied using the state of art has an inverted relationship between the two types of
concepts and methodologies of the given time. immune responses. Th1 and Th2 subsets of CD4 cells
Nevertheless it is generally accepted that this produce mutually exclusive, interferon gamma (IFN-γ), a
unresponsiveness is not due to central tolerance or deletion marker of DTH and IL-4 which promotes antibodies
of M. leprae specific T cells. In certain situation such as respectively; and are thus considered responsible for
ENL, T cells can be shown to emerge in the periphery both delayed type hypersensitivity or humoral immunity
in peripheral blood and in dermal lesions in the unresponsive respectively (Fig. 6.1). Such clear polarization of subsets
lepromatous leprosy. It is thought that the lack of is seen mainly in the mouse and under only special
responsiveness is due to peripheral factors. It was initially situations in man, e.g. helminthic infestations and allergies.
suspected that antibody mediated suppression may be a When both cytokines are produced the phenotype is
feature. But that theory lost ground subsequently. In the considered to be Th0. In initial studies, tuberculoid leprosy
eighties, the concept of suppressor T cells gained popularity patients were shown to have Th1 subset, whereas Th2
as evidence of their role in experimental tolerance was seemed to be the predominant subset in lepromatous
shown. leprosy.25 However, ours (Misra et al 1995) as well some
The presence of CD8 T cells was thought to indicate other studies from Latin America and Mexico using both
suppressor T cells by some groups both in circulation and ELISA and RT-PCR for expression of cytokine genes
in lesions.20 Immune suppression was detected in vitro by showed that there was a mixture of Th phenotypes in
CHAPTER
6
Fig. 6.1: Immunological features of the leprosy spectrum (Ridley-Jopling classification), leprosy reactions and their relationship to bacillary
load. TT=polar tuberculoid, BT= borderline tuberculoid, BB= borderline borderline, BL=Borderline lepromatous, LL=polar lepromatous leprosy,
RR=Type 1/Reversal ENL= Type 2/erythema nodosum leprosum reactions. TH1=T helper 1, TH 2= T helper 2, TH0= T helper 0
leprosy patients. Though 50% of tuberculoid patients had the antigen specific unresponsiveness may be many and
Th1 others had Th0. Similarly Th0 was again noted in 40% differ in various populations studied in the various
of lepromatous leprosy patients with the remainder having laboratories. Consensus is lacking as to, which is the
Th2 phenotype.15 There were no clinically detectable principle mechanism underlying the unresponsiveness.
differences between patients having polarized Th Recently, other phenotypes such Th17 or Th9 are being
phenotypes from those having the mixed Th0 functional described which produce respectively IL-17 that promotes
phenotype. Our group also showed that monocyte derived inflammation; and IL-9 which is involved in autoimmunity.
IL-10 and PGE2 played a role in Th2 phenotype in Another CD4 cell having the Foxp3 (forkhead box protein
lepromatous leprosy.26 Thus it would appear that there is a 3) transcription factor in the nucleus has been shown to
trend towards Th1 and Th2 respectively in tuberculoid and have a regulatory role and is involved in the downregulation
lepromatous leprosy, however, this may not be absolute of the immune response (Fig. 6.2). Their roles in leprosy
or a paradigm. have not been reported. In summary, it is evident that
The roles of co-stimulatory molecules such as B7, T cell biology involves a complex interaction between
CD40/CD40L and CD28 have also been investigated as effector and regulatory cells and is a double-edged sword
an explanation for the Th phenotype paradigm but definitive which may lead to protection through elimination of the
evidence for their direct effect is still awaited.27 In pathogen and/or immunopathology as a result of tissue
conclusion, it is evident that the mechanisms underlying damage caused by DTH.
CHAPTER
6
Fig. 6.2: The development of Th phenotypes from a CD4 precursor cell, with
the help of cytokines released by accessory cells
LEPROSY REACTIONS increased cellular immune responses may be beneficial,

because they promote bacterial killing mechanisms.
Leprosy reactions are acute inflammatory episodes which
However, the accompanying inflammation in and around
occur in 10-20% of Indian patients and are seen more
the infected nerve tissue can result in severe and
frequently (40-50%) in Latin America and Mexico where
irreversible damage within a matter of days. It is not clear
the severity of tissue injury is also greater. Since severe
what initiates this spontaneous and natural T cell activation.
inflammation is a hall mark of reactions, injury to the
During reactions, the PBMC of patients show increased
neighboring nerves may also occur which requires lymphoproliferation to the M. leprae antigens28 as well as
immediate medical attention to prevent nerve damage and increased expression and release of proinflammatory
deformity. Leprosy reactions can occur spontaneously but cytokines such as IL-1, IL-2, IL-12, IFN-γ and TNF-α.29
are mainly observed during or after institution of multi- These features are also noticed in the dermal lesions and
drug therapy (MDT). They are of two major clinical types: nerves where increased infiltration by CD4 cells has also
(i) Type1 or reversal reactions (RR) which are localized to been observed. Recent evidence has indicated that IP-10
the dermal patch and neighboring nerve and occur mostly a chemokine induced by IFN-γ seems to be a biomarker
in patients with borderline leprosy, i.e. BT, BB, and BL. for Type1 reactions as it is consistently observed to increase
(ii) Type 2 or erythema nodosum leprosum (ENL) occurring in the serum during or just prior to reversal reactions.30
predominantly in patients on the lepromatous end of the Some cytokines such as TNF-α, IL-6, IL-10, IL-12 and
spectrum, i.e. BL and LL. Patients develop crops of tender soluble receptors of IL-2 have been demonstrable in
erythematous nodules over the body and have circulation. A TLR-2 mutation has been implicated in
accompanying systemic symptoms of fever, joint pain and reversal reactions.31
neuropathy. In some patients ENL episodes occur multiple ENL or Type 2 reactions were initially thought to be due
times in spite of anti reaction treatment with steroids or to immune complex deposition in the vessels and it was
thalidomide. suggested that ENL was due to Arthus reaction.32 Such
In Type1 reactions, T cell mediated responses towards deposition is not consistently demonstrable and
M. leprae are activated resulting in an inflammatory conventional immune complex disease is not a clinical
response in the areas of the skin and nerves affected by feature in ENL. Vasculitis is observed in ENL with
the disease. From the point of clearing bacteria, such immunoglobulin and complement in the vessel walls in
CHAPTER
6
the skin and nerves. Ours and other studies have drawn cytokine mediated killing of bacilli may release pathogen
attention to antigen specific T cell activation, and release related antigens, which then bind with existing antibodies
and expression of IFN-γ and IL-12.25,28,29 As mentioned to create immune complexes.
above the lesions also show entry of T cells.33 Moreover,
lymphocytes in circulation show lympho-proliferation and IMMUNOPATHOLOGY OF
cytokine release after stimulation in vitro with M. leprae
DERMAL LESIONS
antigens. In addition, some studies have shown increase
in IL-4, IL-6 and IL-8 which are chemotactic for neutrophils Leprosy lesions in the skin have also been studied for
and consistent with histological evidence of neutrophil understanding immunopathology.38,39 As mentioned above,
infiltration in ENL lesions. However, such emergence of T the descriptions of earlier pathologists had given clues
cells / functions in circulation or lesions does not reverse that the granuloma seen in tuberculoid leprosy has an
the negative skin test seen in LL patients and points to immunological basis. In tuberculoid leprosy the granuloma
the gap between cellular immunity and the ability to develop shows the presence of lymphocytic cuff around the
delayed hypersensitivity in the skin. The latter involves epithelioid cell center and lacks leprosy bacilli. The converse
other factors also that lead to inflammation, and the infected features are observed in the multibacillary lepromatous
skin may lack such factors which would otherwise result leprosy where lymphopenia is a hall mark and the
in clinical hallmarks of DTH, viz. erythema and induration. macrophages lacking evidence of activation are filled with
The trigger for the spontaneous development of antigen bacilli. Using cell surface markers defining the cell types,
specific immune responses in leprosy reactions has been it was established that the lymphocytes were mainly of
a puzzle. Molecular recognition may vary during the natural the CD4+ T cells commonly known as helper T cells as
course of diseases. With a view to investigate whether they are required to provide help to B cells to produce
there were cryptic/hidden sites in the bacillus in the natural
antibodies against protein antigens. Such cells were both
state which become exposed at such times, synthetic
in the periphery of the tuberculoid granuloma as well as
peptides covering the entire region of an immunologically
scattered amongst the epithelioid cells. CD8+ T cells were
active recombinant protein designated LSR 234 and A1535
fewer but formed a distinct ring around the epithelioid cells.
were designed. Screening with leprosy sera in ELISA
CD8+ cells were known to be cytotoxic particularly in the
demonstrated that two amino acid sequences were
transplant graft site and in malignancies and also
specifically recognized during and prior to ENL,36 whereas
considered by some to have suppressive functions in
antibodies to NAA motif were seen only in active ENL
leprosy. In recent times (in the animal model particularly)
patients, antibodies to RGD was recognized before and
CD8+ cells were thought to have a containing role in
during the reaction. Motif GVTY was also recognized in
mycobacterial infections such as tuberculosis. Surprisingly
ENL but its recognition was masked by flanking glutamic
B cells are in low numbers even in LL.
acid.37 Another model for the understanding of reactions
About 90% of peripheral lymphocytes are
may be via the therapeutic approach. As indicated above,
T lymphocytes which exist as different subpopulations and
mounting delayed type response with PPD or intra-lesional
injection of IFN-γ reduces bacillary load in the skin within have the αβ receptor (TCR) which recognizes protein
3-6 weeks and also precipitates ENL in Brazilian patients. antigens in association with major histocompatibilty (MHC/
Thalidomide, another effective drug for steroid resistant HLA) Class II molecules. A small subset (<1%) have an
ENL patients has been shown to inhibit TNF-α, IgM unconventional γδ T cell receptor which has antigen
response, but increased IL-2 and apoptosis of neutrophils. specificity and plays an additional role. It detects bacterial
Cyclosporine seems to also clinically improve ENL by lipid antigens in association with non classical MHC Class
inhibition of IL-2 and other cytokines. Ib and CD1 molecules. The γδ T cells have been reported
In summary, it would appear that there is emergence to be concentrated in leprosy granulomas40 and are
of T cell responses in reactional states. Antibodies which increased in mucosal epithelia which may be the entry
recognize molecular motifs in the pathogen are also seen point for most pathogens. They appear to recognize
concurrently. Taken together with earlier data of increased mycobacterial glycolipids in particular and have been
levels of polyclonal antibodies at the LL end of the identified in leprosy lesions during reactions. They seem
spectrum, it is possible that T cell activation leading to to have a regulatory role and appear before the conventional
CHAPTER
6
T cells suggestive of their role in innate immunity. injected sites showed a faster clearance of bacilli and the
Conventional α/β TCR bearing T cells are commonly seen entry of CD4 T cells.45 These changes were observed as
in lesions and PBMC. CD1 molecules bind hydrocarbon early as three weeks after IFN-γ injections indicating the
chain of lipids and present them to CD1 restricted T cells. effectiveness of cytokines as compared to combination
Such T cells have been shown to be increased in TT and of multiple anti-leprosy drugs which produce one log
Type1 reaction skin lesions.41 reduction of bacilli in the skin, only after one year of therapy.
In addition, Langerhans cells, another class of antigen
presenting cells present in the epidermis appear to migrate NERVE DAMAGE IN LEPROSY:
into the tuberculoid leprosy granulomas as CD6+ cells and THE IMMUNE MECHANISMS
are seen to be scattered amongst the lymphocytes.33 Such
Involvement of peripheral nerves is a hall mark of leprosy.
migration may reflect a mode for transport of antigens
M. leprae is the only bacterium that infects the nerves.
from the skin to the lymph nodes for presentation to the
Though occasional reports of bacilli in the mouse brain
appropriate T cells to initiate cell mediated immunity. The
have been reported, it is the peripheral nervous system
lymphocytes in the skin reaction to lepromin also show
that is the target of immunologically mediated tissue
the predominance of CD4 T cells. This is not surprising as
destruction. Though the clinical and pathological features
soluble antigens do not use the MHC Class I pathway and
of leprosy neuropathy were well known; the mechanism of
therefore would not engage CD8 T cells. In reactional states
interaction between M. leprae and peripheral nerves, in
the dermal lesions show an increase in CD4 T cells and
particular the Schwann cells (SC), were described only in
enhanced MHC Class II on Langerhans cells. It is of interest
the last decade.
that the earlier lymphopenic lepromatous leprosy lesions
Entry of leprosy bacillus into SC is through multiple
also showed entry of CD4 T cells.33 Local antibody release
mechanisms. Mannose capped lipoarabinomannan has
of IgG and IgM has also been demonstrated in leprosy
been shown to bind to a dystroglycans of SC. MLpLBP21
lesions and from lesional cell cultures.42 TLR1 and TLR2
a cell wall fraction of M. leprae binds to α laminin on the
are expressed more in macrophages and dendritic cells in surface of SC. PGL-1 has also been shown to bind in a
tuberculoid lesions.9 laminin-2 dependant manner to the SC of a schwannoma
Cytokine expression as evidenced by mRNA detection cell line as do many other mycobacterial species without
has also been observed in dermal lesions. The tuberculoid causing infection in human nerves. Following adhesion,
leprosy granulomas show expression of IFN-γ suggestive interiorization occurs which prevents the bacilli from being
of a Th1 bias, whereas lepromatous lesions had evidence killed by antibodies. In patients, the infected nerves may
of Th2 cytokines. Interestingly, during both reversal (Type1) be damaged by concurrent immunological and inflammatory
and erythema nodosum (ENL, Type2) reactions, there is a events. Intraneural macrophages are capable of secreting
distinct polarization to Th1, type both in our as well as a wide array of cytokines and chemokines, some of which
other studies. The lesions in both type 1 and 2 leprosy may be deleterious to the nerve. TNF-γ and TNF-γ mRNA
reactions showed not only an increase in CD4 T cells (as have been observed in leprosy nerve lesions, both in stable
mentioned above) but also the expression of Th1 cytokine and reactional states. In some cases they may act
IFN-γ and IL-12 p40, indicating a shift in Th type in ENL, synergistically with other cytokines to initiate demyelination
from Th2 to Th1. That cytokines such as IFN-γ are relevant and apoptosis of SC. Oliveira et al demonstrated the
for killing/clearance of leprosy bacilli is further endorsed presence of Toll receptor 2 (TLR2) on the human Schwann
by studies where genetically engineered IFN-γ injected cell line ST88-14 and on SC in the leprosy skin.46
into dermal lesions showed a faster clearance of bacilli as Activation of SC in vitro with a synthetic lipo-peptide of
compared to a control group that received only MDT. The the putative M. leprae 19 kDa lipoprotein lpqH, ML1966,
lesional cells were shown to have enhanced arginine triggered apoptosis which is in conformity with SC
dependant nitric oxide (NO) synthetase in the injected sites apoptosis seen in leprosy lesions. These observations
which is a well recognized radical responsible for killing indicate that activation of TLR 2 on SC may contribute to
the organisms and damaging tissues. 43 Immuno- nerve damage in leprosy and draw attention to the overlap
cytochemical demonstration of iNOS has also been shown of innate and adaptive immunity during the development
independently in leprosy lesions.44 More importantly, such of nerve damage.
CHAPTER
6
In Type1 reactions, DTH response was induced against a component of the dystroglycan complex (DG) in the SC
M. leprae antigenic determinants released from SC, leading plasma membrane.50 Other receptors may also be involved
subsequently to damage of the nerve. Chronic ENL often in the M. leprae—Schwann cell interaction, since blocking
leads to nerve damage, probably induced by local immune of the DG complex with purified α DG in competition assays
complex deposition with granulocyte attraction leading to did not completely inhibit adhesion of M. leprae. The
tissue damage, and complement activation. In long-term bacterial ligand that binds to the laminin-dystroglycan
cultures, human SC were shown to express MHC ClassI complex is thought to be PGL-1 glycolipid found only in
and Class II, ICAM-1, and CD80 surface molecules which M. leprae. Thus PGL-1 is important for the bacillary invasion
are known to be involved in antigen presentation. Sperings of SC via the basal lamina in a laminin-2-dependent
et al showed that human SC processed and presented pathway. It is thought to act as a second receptor on
native M. leprae bacilli as well as recombinant M. leprae M. leprae in which the combined action of LBP21 and
proteins and peptides to MHC Class II-restricted CD4+ T PGL-1 appears to provide sufficient energy of binding and
cells. Such activated T cells subsequently lysed the thereby ensure safe entry of M. leprae into the SC.
infected SC. M leprae infected SC predominantly produced DG complexes link the basal lamina to the actin
IL-4 and IL-10 (Th2 type) and failed to produce the pro- cytoskeleton of SC through membrane-associated linker
inflammatory cytokines (Th1).47 proteins called dystrophins. They are believed to lend
That inflammation is the main component for nerve mechanical stability to SC and the nerve axons and may
damage in reactional states particularly in Type 1 reactions also transduce signals from the exterior to the interior of
has also been shown elegantly in patients using imaging the cell.51
techniques such as high resolution ultrasonography Contact-dependent demyelination induced by
(Fig. 6.3). Intraneural blood flow signals indicative of M. leprae in nerve tissue culture in the absence of immune
increased blood flow as well as intraneural edema caused cells has been described by Rambukkana suggesting a
during inflammation has been observed in peripheral nerves role for non immune mechanisms during the initial stage
during reactions.48,49 of nerve infection.52 Using a rat SC/axon co-culture system,
they reported rapid demyelination following adherence of
M. leprae to SCs in the absence of immune cells,
interpreted to be a contact-dependent mechanism
dependent on PGL-1, a component of the M. leprae cell
wall.53 It has been suggested in cultures that myelin-
associated SC seem to be relatively free from M. leprae
infection, whereas non-myelinating SC were heavily
colonized. Whether, only non-myelinated SC permit
infection by M. leprae, is currently controversial, though
other studies have shown no such distinction.54 Moreover,
earlier ultrastructure studies on nerves from leprosy
Fig. 6.3: High resolution ultrasonography and color Doppler image of
patients had demonstrated clearly the presence of the bacilli
right popliteal nerve showing intraneural blood flow signals inside the SC of myelinated axons.55
(arrow and circle) indicative of inflammation in a patient with The major toxic effector molecule known to kill M. leprae
Type1 (reversal) reaction (Photo courtesy: Dr Suman Jain, Dr LN
Abhishek, Blue Peter Research Center (LEPRA), Hyderabad, India)
is nitric oxide (NO), and NO has been demonstrated in the
inflammatory infiltrates of nerves in leprosy lesions.56
Nitrotyrosine, an end product of the metabolism of NO,
Nonimmune Mechanism of Nerve Damage
has also been observed in nerves in BL lesions, and this
M. leprae colonizes SC by attaching to the G domain of molecule has been associated with lipid peroxidation of
laminin-α2–chain (LN-α2), a protein constituent of the myelin leading to demyelination of nerves in other
extracellular basal lamina, and its receptor a-dystroglycan, diseases.57
CHAPTER
6
IMMUNOGENETICS OF LEPROSY agonists whereas, S 248 variant enables normal functioning.

The homozygous S 248 genotype increases the
That genetic predisposition rather than environmental
susceptibility to leprosy whereas, the heterozygous SN
factors may predispose to leprosy has been considered
genotype decreases and NN genotype shows no
for decades, but consensus for the type of genetic
association. S 248 allele and I620 S are also more frequent
susceptibility was not available. It is well-known that
in patients with reversal reactions. In humans, the 1805 G
household contacts are at a higher risk for developing
variant does not mediate an inflammatory response to the
leprosy. Moreover, only 0.1 to 1% of the exposed population
leprosy bacillus in vitro and is associated with protection
gets the disease and patients with a particular leprosy
from reversal reaction. These data suggest that a common
type not commonly change to another indicating that the
variant of TLR1 is associated with altered adaptive immune
immune response to the disease is set early in the host.
responses to M. leprae as well as to the clinical outcome.60
Moreover BCG vaccination provides protection at different
That innate and adaptive responses can overlap is
levels in diverse populations. One of the first evidence for
indicated by the mutation in TLR 2. A mutation substituting
the role of genetics was provided by Chakravarthy and
arginine with tryptophan at residue 677 in one of the
Vogel who showed that monozygotic as compared to
conserved regions of TLR 2 was shown to have a role in
dizygotic twins had a greater propensity to develop the
susceptibility to lepromatous, but not tuberculoid leprosy.
same leprosy type.58
Later, this mutation was shown to abolish intracellular
Modern genetic methods have established that there
signalling and activation of NF-κB after exposure of different
is little diversity in the leprosy bacillus and made possible
cell types to M. leprae and M. tuberculosis leading to
human genome studies to identify susceptibility regions.
decreased production of IL-2, IL-12, IFN γ, and TNF α by
No single genetic factor has been shown to be common
M. leprae stimulated PBMC as compared with groups with
and universal to different population groups. This may point
wild-type TLR2. Moreover, the cells from patients with the
towards a multifactorial genetic control affecting multiple
TLR 2 mutation showed increased production of IL-10,
pathways of the defense mechanisms against infections.
which is known to suppress inflammation and Th1 type
It is clear that polymorphism in genes affecting both innate
response. There was no significant difference in IL-4
and acquired immunity is identifiable in various populations
production between the mutant and wild-type during
indicating that leprosy may be a polygenic disease. But
stimulation. Thus, these results suggest that the TLR2
consensus is lacking on the details of how the immune
signal pathway plays a critical role in the alteration of
system initiates, maintains and regulates the antigen
cytokine profiles in leprosy patients and that the TLR2
specificity which is unique to leprosy and the leprosy
mutation Arg677Trp provides a mechanism for the poor
spectrum.
cellular immune response associated with lepromatous
Innate Immunity leprosy.61 In contrast, TLR 4 SNPs are associated with
protection against leprosy.62
With the deciphering of the human genome, whole gene
scans and single nucleotide polymorphisms (SNP) have
ACQUIRED IMMUNITY
been used to test high-risk or susceptibility to diseases.
NRAMP1 which is present on macrophages is important IL-12 polymorphism is associated with greater
for antigen presentation. The promoter genotypes susceptibility to lepromatous leprosy in patients from
22 and 23 were found to be unfavorable when combined western Mexico, independently of IL-12 p40 and p70
with a negative Mitsuda test in leprosy patients.59 expression levels.63 SNPs within the 5' flanking region of
TLRs are transmembrane molecules which engage the IL-12 Rβ2 affect the degree of expression of this gene and
lipid antigens, of mycobacteria/pathogens and signal may be implicated in individual differences in CMI
cytokine induction via NF- κB. TLR 1, 2 and 4 have been responsiveness to mycobacterial antigens, leading to
studied in leprosy.9 N 248 SNP variant of TLR1 diminishes lepromatous or tuberculoid leprosy.64 TNF-α2 allele
but does not totally abolish the response to bacterial frequency was significantly higher among control subjects
CHAPTER
6
than among all patients with leprosy or in the LL group. 10. Chatterjee D, Roberts AD, Lowell K et al. Structural basis for the
capacity of lipoarabinomannan to induce secretion of tumour
IFN-γ mutated alleles contribute a role in leprosy post-
necrosis factor. Infect Immun 1992; 60:1249-53.
infection and polymorphism of its receptor has been 11. Maeda YM, Gidoh N. Ishii MC et al. Assessment of cell mediated
reported. immunogenicity of Mycobacterium leprae-derived antigens. Cell.
Immunol 2003; 222:69-77.
12. Hunger RE, Sieling PA, Ochoa MT et al. Langerhans cells utilize
CONCLUSION
CD1a and langerin to efficiently present nonpeptide antigens to
The continuing challenges that face leprosy research has T cells. J Clin Investig 2004; 113:701-08.
13. Nath I, Curtis J, Sharma AK, Talwar GP. Circulating T-cell numbers
been elegantly reviewed by Scollard et al.2 In conclusion,
and their mitogenic potential in leprosy-Correlation with
it is possible that many of the differences reported in the mycobacterial load. Clin Exp Immunol 1977; 29: 393-400.
leprosy patients from different laboratories may be due to 14. Haregewoin A, Godal T, Mustafa AS et al. T-cell conditioned
genetic differences in populations studied and the media reverse T-cell unresponsiveness in lepromatous leprosy.
Nature 1983; 303 (5915): 342-46.
environmental stimuli that determine the innate immune
15. Misra N, Murtaza A, Walker B et al. Cytokine profile of circulating
response which may reflect on the subsequent acquired T cells of leprosy patients reflect both indiscriminate and polarised
immunity to the leprosy bacillus. Such findings draw Th subsets: Th phenotype is stable and uninfluenced by related
attention to the need for local research to define the antigens of Mycobacterium leprae. Immunol 1995; 86: 97-103.
16. Salgame PR, Mahadevan PR, Antia NH. Mechanism of
immunological profile of patients and modes of transmission
immunosuppression in leprosy: presence of suppressor factor(s)
which would help to design control measures, from macrophages of lepromatous patients. Infect Immun 1983;
immunodiagnostics, vaccines and appropriate therapy for 40(3):1119-26.
a given population. 17. Nath I, Vemuri N, Reddi AL et al. The effect of antigen presenting
cells on the cytokine profiles of stable and reactional lepromatous
leprosy patients. Immunol Lett 2000; 75(1): 69-76.
REFERENCES 18. Kaplan G, Laal S, Sheftel G et al. The nature and kinetics of a
delayed immune response to PPD in the skin of lepromatous
1. Ridley DS, Jopling WH. Classification of leprosy according to
leprosy patients. J Exp Med 1988; 168: 1811-24.
immunity—a five-group system. Int J Lepr Other Mycobact Dis
19. Sampaio EP, Moreira AL, Sarno EN at al. Prolonged treatment
1966; 34:255–73.
with recombinant interferon gamma induces erythema nodosum
2. Scollard DM, Adams LB, Gillis TP et al. The Continuing Challenges
leprosum in lepromatous leprosy patients. J Exp Med 1992;
of Leprosy. Clin Microbiol Rev 2006; 19: 338-81.
175 (6):1729-37.
3. Nath I. Immune mechanisms of intracellular pathogens.
20. Mehra V, Brennan PJ, Rada E et al. Lymphocyte suppression in
Encyclopaedia of Life sciences, John Wiley & Sons Ltd. Published
leprosy induced by unique M. leprae glycolipid. Nature1984; 308
online 15th December 2008. doi: 10.1002/9780470015902.
(5955):194-96.
a0000480.pub2
21. Nath I, Van Rood JJ, Mehra NK et al. Natural suppressor cells in
4. Schlesinger LS, Horwitz MA. Phenolic glycolipid-1 of
Mycobacterium leprae binds complement component C3 in serum human leprosy: The role of HLA-D identical peripheral
and mediates phagocytosis by human monocytes. J Exp Med lymphocytes and macrophages in the in vitro modulation of
1991; 174:1031-38. lymphoproliferative responses. Clin Exp lmmunol 1980; 42:
5. Skamene E, Gros P, Forget A, et al. Genetic regulation of 203-10.
resistance to intracellular pathogens. Nature 1982; 297: 22. Salgame PR, Birdi TJ, Mahadevan PR, Antia NH, 1980. Role of
506-09. macrophages in defective cell mediated immunity in lepromatous
6. Mira MT, Alcaïs A, Van Thuc N, et al. Chromosome 6q25 is leprosy. I. Factor(s) from macrophages affecting protein
linked to susceptibility to leprosy in a Vietnamese population. synthesis and lymphocyte transformation. Int J Lepr Other
Nat Genet 2003; 33 (3):412-15. Epub 2003 Feb 10. Mycobact Dis 1980; 48 (2):172-77.
7. Bochud PY, Hawn TR, Aderem A. Cutting edge: a Toll-like 23. Sathish M, Bhutani LK, Sharma AK, Nath I, Monocyte derived
receptor 2 polymorphism that is associated with lepromatous soluble suppressor factor(s) in patients with lepromatous leprosy.
leprosy is unable to mediate mycobacterial signalling. J Immunol Infect Immun 1983;42: 890-99.
2003; 170:3451–54. 24. Prasad HK, Misra RS, Nath I. Phenolic glycolipid-1 of
8. Kang TJ, Lee SB, Chae GT. A polymorphism in the toll-like Mycobacterium leprae induces general suppression of Con-A
receptor 2 is associated with IL-12 production from monocyte in responses unrelated to leprosy type. J Exp Med 1987; 165:
lepromatous leprosy. Cytokine 2002; 20(2):56-62. 239-44.
9. Krutzik SR, Ochoa MT, Sieling PA et al. Activation and regulation 25. Yamamura M, Wang XH, Ohmen JD, et al. Cytokine patterns of
of Toll-like receptors 2 and 1 in human leprosy. Nature Med immunologically mediated tissue damage. J Immunol 1992;
2003; 9: 525-32. 149:1470-75.
CHAPTER
6
26. Misra N, Selvakumar M, Singh S et al. Monocyte derived IL-10 spectrum and reactions. Int J Lepr Other Mycobact Dis 1999;
and PGE2 are associated with Th2 cells and in vitro T cell 67(4): 422-28.
suppression in lepromatous leprosy. Imm Letters 1995; 48: 43. Sivasai KSR, Prasad HK, Misra RS et al. Effect of Interferon
123-28. gamma administration on lesional monocytes/macrophages in
27. Santos AR, Suffys PN, Vanderborght PR et al. Role of tumour lepromatous leprosy patients. Int J Lepr Other Mycobact Dis
necrosis factor-alpha and interleukin-10 promoter gene 1993; 61: 259-69.
polymorphisms in leprosy. J Infect Dis 2002; 186 (11): 1687-91. 44. Khanolkar YS, Snowdon D, Lockwood DN. Immunocytochemical
Epub 2002 Nov 11. localization of inducible nitric oxide synthase and transforming
28. Laal S, Bhutani LK, Nath I. Natural emergence of antigen reactive growth factor-beta (TGF-beta) in leprosy lesions. Clin Exp
T-cells in lepromatous leprosy patients during erythema nodosum Immunol 1998; 113(3):438-42.
leprosum. Inf Immunity 1985; 50(3):887-92. 45. Kaplan G, Mathur NK, Job CK. Effects of multiple interferon
29. Sreenivasan P, Misra RS, Wilfred D, Nath I. Lepromatous leprosy γ injections on the disposal of Mycobacterium leprae. Proc Natl
patients show Th1 like cytokine profile with differential expression Acad Sci USA 1989; 86: 8073-77.
of interleukin-10 during type1 and type2 reactions. Immunology 46. Oliveira RB, Ochoa MT, Sieling PA. Expression of Toll-like receptor
1998; 95:529-36. 2 on human Schwann cells: a mechanism of nerve damage in
30. Stefani MM, Guerra GK, Sousa ALM et al. Potential plasma leprosy. Infect Immun 2003; 71: 1427-33.
markers type1 & type2 leprosy reactions: a preliminary report. 47. Spierings E, De Boer TT, Zulianello L et al. Novel mechanisms in
BMC Infectious Diseases 2009; 9:75. the immuno-pathogenesis of leprosy nerve damage: the role of
31. Bochud PY, Hawn TR, Siddiqui MR et al. Toll-like receptor 2 Schwann cells, T cells and Mycobacterium leprae. Immunol Cell
Biol 2000; 78: 349-55.
(TLR2) polymorphisms are associated with reversal reaction in
48. Martinoli C, Derchi LE, Bertolotto M et al. US and MR imaging of
leprosy. J Infect Dis 2008; 197 (2): 253-61.
peripheral nerves in leprosy. Skeletol Radiol 2000; 29:142-50.
32. Wemambu SN, Turk JL, Waters MF et al. Erythema nodosum
49. Jain S, Leo HV, Praveen TLN, Narasimha Rao P et al. High
leprosum: a clinical manifestation of the arthus phenomenon.
resolution ultrasonography: a new technique to detect nerve
Lancet 1969; ii: 933-35.
damage in leprosy. 2009 PLOS Negl Trop Dis (In Press)
33. Narayanan RS, Bhutani LK, Sharma AK, Nath I. Normal numbers
50. Rambukkana A, Salzer JL, Yurchenco PD et al. Neural targeting
of T6 positive epidermal Langerhans cells across the leprosy
of Mycobacterium leprae mediated by the G domain of the laminin
spectrum. Lepr Rev 1984; 55: 301-08.
alpha-2 chain. Cell 1997; 88: 811-21.
34. Laal S, Sharma YD, Prasad HK et al. Recombinant protein
51. Rambukkana A, Zanazzi G, Tapinos N et al. Contact-dependent
identified by lepromatous sera mimics native M. leprae in T cell
demyelination by Mycobacterium leprae in the absence of
responses across the leprosy spectrum. Proc Natl Acad Sci
immune cells. Science 2002; 296: 927-31.
USA 1991; 88:1054-58.
52. Rambukkana A. Mycobacterium leprae-induced demyelination:
35. Sela S, Thole JER, Clark-Curtiss JE et al. Identification of
a model for early nerve degeneration. Curr Opin Immunol 2004;
Mycobaterium leprae antigens from a cosmid library:
16: 511-18.
characterization of a 15-kilodalton antigen that is recognized by 53. Ng V, Zanazzi G, Timpl R, et al. Role of the cell wall phenolic
the humoral and cellular immune system in leprosy patients. glycolipid-1 in the peripheral nerve predilection of Mycobacterium
Infect Immun 1991; 59: 4117-24. leprae. Cell 2000; 103: 511-29.
36. Singh S, Jenner PJ, Shanker Narayanan NP et al. Critical 54. Hagge D, Robinson SO, Scollard D et al. A new model for studying
residues of Mycobacterium leprae LSR recombinant protein the effects of Mycobacterium leprae on Schwann cell and neuron
discriminate clinical activity in Erythema Nodosum Leprosum interactions. J Infect Dis 2002; 186: 1283-96.
Reactions. Inf Immun 1994; 62(12): 5702-05. 55. Job CK, 1971. Pathology of peripheral nerve lesions in
37. Singh S, Shankar Naryanan NP, Jenner PJ et al. Sera of Leprosy lepromatous leprosy—A light and electron microscopic study.
Patients with type2 Reactions Recognize Selective Sequences Int J Lepr Other Mycobact Dis 1971; 39: 251-68.
in Mycobacterium leprae Recombinant LSR Protein. Infect 56. Khanolkar-Young S, Rayment N, Brickell PM et al. Tumour
Immun 1994; 62(l): 86-90. necrosis factor-alpha (TNF-alpha) synthesis is associated with
38. Modlin RL, Hofman FM, Taylor CR et al. T lymphocyte subsets in the skin and peripheral nerve pathology of leprosy reversal
the skin lesions of patients with leprosy. J Am Acad Dermatol reactions. Clin Exp Immunol 1995; 99: 196-202.
1983; 8:182-89. 57. Schon T, Herna´ndez-Pando R, Negesse Y et al. Expression of
39. Narayanan RB, Bhutani LK, Sharma AK, Nath I. T-cell subsets in inducible nitric oxide synthase and nitrotyrosine in borderline
leprosy lesions: in situ characterisation using monoclonal leprosy lesions. Br J Dermatol 2001; 145: 809-15.
antibodies. Clin Exp Immunol 1983; 51: 421-29. 58. Chakravarthy MR, Vogel F. A twin study on leprosy. Top Hum
40. Uyemura K, Ho CT, Ohmen JD, et al. Selective expansion of Genet 1973; 1: 1-123.
gamma delta1+ T cells from leprosy skin lesions. J Invest 59. Ferreira FR, Goulart LZ, Silva HD et al. Susceptibility to leprosy
Dermatol 1992; 99(6): 848-52. may be conditioned by an interaction between NRAMP1 promoter
41. Rosat JP, Grant EP, Beckman EM, et al. CD1-restricted microbial poly-morphisms and the lepromin response. Int J Lepr Other
lipid antigen-specific recognition found in the CD8+ alpha beta T Mycobact Dis 2004; 72:457-67.
cell pool. J Immunol 1999; 162 (1):366-71. 60. Schuring RP, Hamann L, Faber WR, et al. Polymorphism N248S
42. Beuria MK, Mohanty KK, Katoch K. Determination of circulating in the human Toll-like receptor 1 gene is related to leprosy and
IgG subclasses against lipoarabinomannan in the leprosy leprosy reactions. J Infect Dis 2009; 199(12): 1816-19.
CHAPTER
6
61. Kang TJ, Yeum CE, Kim BC, et al. Differential production of determines the clinical types of leprosy through impaired
interleukin-10 and interleukin-12 in mononuclear cells from transcriptional activity. J Clin Pathol 2005;58 (7): 740-43.
leprosy patients with a Toll-like receptor 2 mutation. Immunology 65. Malhotra D, Darvishi K, Sood S et al. IL-10 promoter single
2004; 112 (4):674-80. nucleotide polymorphisms are significantly associated with
62. Bochud PY, Sinsimer D, Aderem A et al. Polymorphisms in Toll- resistance to leprosy. Hum Genet 2005;118 (2): 295-300.
like receptor 4 (TLR4) are associated with protection against 66. Misch EA, Macdonald M, Ranjit C et al. Human TLR1 Deficiency
leprosy. Eur J Clin Microbiol Infect Dis 2009 May 9. [Epub ahead
Is Associated with Impaired Mycobacterial Signalling and
of print]. DOI 10.1007/S10096-009-0746-0.
Protection from Leprosy Reversal Reaction. PLoS Negl Trop
63. Alvarado-NA, Montoya-BM, Muñoz-Valle JF et al. The 3’UTR
Dis 2008; 2 (5): e231.
1188 A/C polymorphism in the interleukin-12p40 gene (IL-12B)
is associated with lepromatous leprosy in the west of Mexico. 67. Reynard MP, Turner D, Junqueira-Kipnis AP et al. Allele
Immunol Lett 2008; 118 (2):148-51. frequencies for an interferon-gamma microsatellite in a population
64. Ohyama H, Ogata K, Takeuchi K et al. Polymorphism of the of Brazilian leprosy patients. Eur J Immunogenet 2003; 30 (2):
5' flanking region of the IL-12 receptor beta2 gene partially 149-51.
CHAPTER
7
7
Bacteriological Aspects
Balaraman Sekar
INTRODUCTION molecular biological studies, carried out in the present era.

Many attempts have been made to cultivate M. leprae
Leprosy is an ancient, clinically well-recognized disease.
in vitro but all of them turned futile and as such, no artificial
Though leprosy was known to the mankind as a contagious
medium is available as yet for the in vitro cultivation of
disease since olden times, nothing was known about its
M. leprae.
causative agent till mid-nineteenth century. The
Following the genome sequencing of Mycobacterium
coincidental development of microscopy and the
tuberculosis, the genome sequencing of M. leprae was
emergence of ‘germ theory’ favored the young Norwegian
completed in 2000 by Cole, which enabled us to understand
physician GHA Hansen, to demonstrate by microscopy
its biology in more detail. M. leprae has undergone a
the presence of rod-shaped bodies in unstained preparation
reductive evolutionary process through adaptation to its
of nodular lesions from leprosy patients in 1873.1 Though
intracellular parasitic lifestyle. Comparative analysis of the
Danielssen in 1847 came across globi, solid and beaded
genome sequences with M. tuberculosis established that
rods, coccoid forms, etc. both within and out of the cells
gene deletion and decay in M. leprae have resulted in the
in leprosy lesions, but because of his strong faith in the
formation of 1,116 non-functional pseudogenes, resulting
hereditary nature of the disease, he failed to associate his
in an elimination of many key metabolic activities of
findings with cause of the disease.2 Although it was one
M. leprae.7 Thus, M. leprae barely maintains its existence
of the first organisms demonstrated by microscopy, it has
with a minimal gene set.8
not yet been possible to cultivate it in vitro, in an artificial
media, till today.
In 1960, Charles C Shepard, demonstrated a limited MYCOBACTERIA
growth of M. leprae in the footpad of mouse.3 This landmark These are a group of bacteria, initially thought to be a
discovery proved to be a major contribution, as it made fungus (myco=fungus), well known for their unique
possible the screening of drugs, assessment of their character of acid-fastness. These bacteria do not stain
efficacy and detection of drug-resistant strains. Mouse readily; but once stained, resist the decolorization with
foot-pad experiments paved a way for understanding many acid/alcohol. Hence, they are called as acid-fast bacteria
biological properties of M. leprae. Further, RJW Rees (AFB). The acid-fastness is due to the presence of a
showed enhanced growth of M. leprae in the footpad of chemical in the cell wall, called “mycolic acid”. Amongst
thymectomized-irradiated (nude) mice in the year 1966.4 different species of mycobacteria, some are patho-
In 1971, Kirchheimer and Storrs, demonstrated genic, e.g. M. tuberculosis, M. leprae, M. marinum,
unlimited multiplication of M. leprae in nine banded armadillo M. scrofulaceum etc; and some are saprophytic (non-
(a Southern American rodent).5 Subsequently in 1976, pathogens), e.g. M. fortuitum, Mycobacterium w (now
Draper developed a procedure for the purification of finally renamed after complete genomic sequencing as
M. leprae from armadillo tissues.6 This made available a Mycobacterium indicum pranii), etc. Some of the
large number of M. leprae for the immunological and mycobacteria are fast growers in vitro and some are slow
CHAPTER
7
Bacteriological Aspects 75
growers. M. leprae is physiogenetically placed somewhere T-cell activation. The accumulation of an increased number
in between M. tuberculosis and M. avium-intracellulare- of T-lymphocytes and simultaneous release of interleukins
scrofulaceum (MAIS) complex. from activated T-cells results in macrophage activation.
Thus, the macrophages limit the further multiplication or
Clinical Spectrum of Leprosy kill the intracellular M. leprae.
Leprosy exhibits diverse manifestations from a highly In immunosuppressed individuals, M. leprae infection
resistant tuberculoid type to poorly resistant lepromatous leads to lepromatous leprosy due to inefficient CMI
type. Ridley and Jopling in 1962 described five overlapping response. This immunodeficiency is due to predisposing
groups of leprosy based on the immunological status of genetic factors and extent of exposure to M. leprae; and
the patients. It extends from tuberculoid type (TT) through, is highly specific. This immunodeficiency persists even
borderline tuberculoid (BT), mid-borderline (BB), borderline after prolonged chemotherapy and it is therefore considered
lepromatous (BL), to the lepromatous type (LL). to be responsible for the increased risk of relapse or
The LL and TT are relatively stable and the BL, BB reinfection in these patients.
and BT types are unstable. Of these, the BB type is more Mycobacterium leprae
inconsistent form and rarely encountered.9,10
It is a rod-shaped bacterium, measuring 1-8 microns in
The indeterminate leprosy patients do not fall in the
Ridley-Jopling spectrum because of the unpredictable length and 0.3 micron in diameter, with parallel sides and
behavior and lack of specific clinicohistological features rounded ends. It is strongly acid fast when stained by
necessary for inclusion in the spectrum. Ziehl-Neelsen method. In skin smears towards the
lepromatous end of the disease spectrum M. leprae are
Immunological Properties of M. leprae predominantly found in clumps or globi within the
macrophages (lepra cells). Inside these cells M. leprae
M. leprae induces both humoral and cell-mediated immune
multiply unrestricted, which may contain hundreds of bacilli
responses. The immunogenic components of M. leprae
arranged in parallel arrays, placed side by side by the
include polysaccharides and proteins. Polysaccharide
presence of surface lipids (glial substances) suggesting
components induce mainly humoral immune response.
“bundle of cigars”. Globi are characteristically seen in the
Proteins induce both humoral and cell-mediated immune
smears of BL and LL patients. These are spherical
response. The immunogens in M. leprae form two distinct
conglomeration of rods, presenting in unusually
groups: cytoplasmic antigens and antigens actively
symmetrical circumference, the wet mount reveals a
secreted from the mycobacterial cell. A species specific
membrane confining the rods, giving a spherical shape to
phenolic glycolipid PGL-1 has been identified in M. leprae
which has immunogenic properties. the cluster. Though it is thought to be the characteristic of
The variety of M. leprae antigens identified using leprosy, such phenomenon is reported to be occurring in
monoclonal antibodies include 18 KDa, 28 KDa, 7 KDa, M. avium infected specimens from severely immune
14 κDa, 36 KDa, 65 KDa and 70 KDa antigens which could compromised AIDS patients. This would imply that the
possibly express immune response. The 65 KDa antigen globus phenomenon manifests in situations where the
was the first M. leprae antigen to be cloned and environment is favorable for a rapid multiplication, free of
characterized.11 immunobactericidal/ bacteriostatic mechanisms –such an
environment with deficient or immune compromised
Pathogenesis of M. leprae cellular immunity, exists in lepromatous leprosy and AIDS
patients.2
M. leprae is an obligate intracellular parasite. It grows very
slowly in vivo and in vitro in macrophage cultures.
CELLULAR MORPHOLOGY
In immunocompetent individuals, the growth of
M. leprae is arrested due to effective cellular immunity. M. leprae is a non-motile, non-spore forming,
After uptake of M. leprae in the macrophages follows the microaerophilic, acid-fast staining bacterium that usually
intracellular multiplication, some antigens of M. leprae are forms slightly curved or straight rods. Electron microscopy
processed and presented as peptides in the groove of HLA (EM) revealed the details of the ultra structure of M. leprae
Class-II molecules on the macrophage surface to induce which is found to have the following structures:
CHAPTER
7
Cell Wall phthiocerol dimycocerosates as well as phenolic glycolipids

This outer coat protects bacteria from environment and (PGLs), forming the electron-transparent zone.
gives definite shape to the bacterial cell. It has an inner Phosphatidylinsitol mannosides and phospholipids are
electron-dense and an outer electron transparent layer. The released from the cell wall after synthesis, forming a
cell wall is a covalently linked peptidoglycan- capsule-like region. The dominant lipid in the cell wall,
arabinogalacton-mycolic acid complex; similar in which gives M. leprae immunological specificity, is
composition to all mycobacterial cell walls.12,13, 8 PGL-1.14 Recent studies suggest that PGL-1 is involved
The cell wall in the core contains peptidoglycan, in the interaction of M. leprae with laminin of Schwann
composed of chains of alternating N-acetylglucosamine cells, suggesting a role for PGL-1 in peripheral nerve-
and N-glycolylmuramate linked by peptide cross-bridges, bacillus interactions.15
which are linked to the galactan layer by arabinogalactan. Annotations of M. leprae genome and comparative
Three branched chains of arabinan are in-turn linked to the genomic studies with other mycobacterial genomes have
galactan, forming along with the peptidoglycan layer, an produced insight into the putative genes needed to direct
electron-dense zone around M. leprae. Mycolic acids are the synthesis of this complex cell wall biopolymer. Most
linked to the terminals of arabinan chains to form the inner of the genes necessary to build the peptidoglycan-
leaflet of a pseudolipid bilayer. The outer leaflet is arabinogalactan-mycolate polymer appear to be present
composed of an array of intercalating mycolic acids of in the M. leprae genome and fit a reasonable strategy for
trehalose monomycolates and mycoserosoic acids of its construction (Fig. 7.1).16
Fig. 7.1: Schematic model of the cell envelope of M. leprae (Reproduced from: The Continuing Challenges of Leprosy.
Scollard DM et al. Clin Microbiol Rev 2006;19:338-81)
CHAPTER
7
Cell Membrane identified with monoclonal antibodies. An analysis of their
This structure seems to contain proteins which controls sequence showed 90% identity between M. leprae and
the active and passive transport of substances across, M. tuberculosis; and 44% homology with the GroES heat
between inside and outside of the cell. Enzymes shock protein of Escherichia coli.25 The protein induced a
synthesizing the cell wall and capsular lipids are also strong delayed-type hypersensitivity and Th1 cytokine
present. There is evidence for the presence of phos- production. Monoclonal antibody studies have also
pholipids, characteristic of membrane of cultivable identified a 18 kD protein which is structurally related to a
mycobacteria including members of phosphatidylinosiyol loosely conserved family of low molecular weight heat
mannosides (PIM).17,18 Biochemical fractionation studies shock proteins.26
identified two major polypeptides—major membrane
protein–I (MMP-I) and major membrane protein–II Capsule
(MMP-II)- associated with the cell membrane of M. leprae.19 EM confirmed the observation of capsule around M. leprae
MMP-I is a 35 kD protein independently identified as a in tissues by light microscopy. It contains bacterial lipid
serologically active component recognized by murine found to be in large amounts in infected tissues. The two
monoclonal antibodies specific to M. leprae.20 A study by main bacterial lipids present are (1) Pthiocerol
Triccas et al with r35kDa antigen indicated proliferative dimycocerosate, a highly apolar substance, which seems
response predominantly from PB leprosy patients and to have a purely passive protective function, (2) Phenolic
healthy contacts of leprosy.21 The gene encoding for glycolipid 1, a specific glycolipid for M. leprae found to be
M. leprae 35 kDa has been identified, isolated and active serologically.27 The PGL-1 is found in abundance in
characterized.22 It was further shown that 35 kDa protein infected tissue (armadillo liver and skin of lepromatous
has no homologue within the Mycobacterium tuberculosis patient). M. leprae secretes this glycolipid locally, and may
complex, but it has a homologue in Mycobacterium avium. constitute the characteristic foamy appearance seen within
MMP-II was originally identified from M. leprae as a major
the macrophages of lepromatous leprosy patients. PGL-1
native protein, and was recognized to be identical to
is highly immunogenic, generating IgM class of
mycobacterial bacterioferritin. MMP-II protein has a large
immunoglobulin, demonstrable in 60% of TT and 90% of
molecular mass of 380 kDa, which has a feroxidase-center
LL patients. ELISA test to detect the specific antibody
residue and was conserved among M. leprae,
(anti-PGL) has been used as a serological test for leprosy.
M. tuberculosis and M. avium. The homology at the amino
acid level is about 86% among them.
Solid Bacteria
Cytoplasm M. leprae is a strongly acid fast bacterium which appears
bright pink on Ziehl-Neelsen staining. In practice, in a
Earlier studies of fractionation by SDS-polyacrylamide gel
stained smear M. leprae shows highly polymorphic
electrophoresis revealed the presence of three major
morphology. Few are brightly and uniformly stained with
proteins in cytoplasmic extracts of M. leprae.19 They were
parallel sides, rounded ends, length being 5 times the
found to be a doublet at 28 kDa, a second one with a
breadth—such bacteria are called “solid bacteria”. Mostly
molecular weight of 17 kDa and the third corresponded to
M. leprae in smear appear irregularly stained and
GroES heat shock protein found also in cell wall fractions. fragmented or granular. Mouse foot-pad experiments have
Studies on the protein composition of M. leprae based on shown that the solid bacteria are viable bacteria whereas
serological techniques resulted in identification of another the morphologically imperfect (fragmented and granular)
component; with 65 kD antigen appearing particularly forms are usually considered to be dead. This was even
prominent.23 A 65 kD protein (identified as the M. leprae cited by Hansen—As the bacilli at first multiply in the cells,
homologue of the GroEL heat shock protein)24 is generally and the breaking down appears most definitely and freely
found in an extensively degraded form in M. leprae when the cells are crammed full of bacilli. It is equally
preparation. Proteins with a molecular mass of 10 to 12 possible that it is the result of diminished nutrition, and as
kDa from M. leprae and M. tuberculosis were originally they break down more rapidly in the internal organs, it is
found to carry separate species—specific epitopes also possible, indeed probable, that the higher temperature
CHAPTER
7
in these organs favors disintegration. The transformation

into granules is considered as degeneration, and that the
bacilli are altered dead.28 In case of irregularly stained
bacteria EM further confirmed that contents of the
cytoplasm disappeared and severely distorted; and the
plasma membrane is incomplete.
These findings are the basis for the morphological index
(MI), which gives an idea of solid, fragmented and granular
forms in a smear (Figs 7.2A to C).
Pyridine Extraction
Mycobacterium leprae smears on treating with pyridine,
lose the ability to stain subsequently with carbol fuchsin
and thereby appear nonacid-fast. This property of pyridine
extraction is considered unique for M. leprae.29 A
ZN staining
M. leprae Acid-fast
+
ZN staining
Pyridine Non-acid-fast
However, some nonleprosy mycobacteria have been

reported to lose their acid fastness after pyridine treatment
and also, not all the bacilli of leprosy smears may lose the
red stain.30 Nocardia recovered from LL showed such
characteristics. So this test may be regarded as an optional
confirmatory test, provided the culture growth is “pure”;
without any co-existing cultivable mycobacteria.
Metabolism of M. leprae B
The microbiological interest of understanding the
metabolism of M. leprae has been to formulate a special
medium that could support in vitro growth of the bacilli;
to learn more about the intrinsic metabolic pathways and
to utilize them for developing newer antileprosy drugs.
Earlier works of Rees and Young have portrayed some
information on the anabolic and catabolic pathways needed
for the survival of the bacterium.31 However, with the
complete sequencing and annotation of M. leprae genome,
an improved understanding of metabolic capabilities of
M. leprae now exists.32-34
Inspection of the 3.27 MB genome sequence of
M. leprae (of an armadillo-derived Indian isolate of the
leprosy bacillus) identified 1,605 genes encoding for C
proteins and 50 genes for stable RNA species. Comparison Figs 7.2A to C: M leprae in skin smear demonstrated by Ziehl-
with the genome sequence of Mycobacterium tuberculosis Neelsen staining; Solid bacilli (A); non-solid bacilli (B); Schematic model
revealed an extreme case of reductive evolution, since of Solid and non-solid lepra bacilli (C)
CHAPTER
7
less than half of the M. leprae genome contains functional 2. Biosynthetic pathways for lipids and amino acids are
genes while inactivated or pseudogenes are highly also complete with the exception that M. leprae is a
abundant. The level of gene duplication was approximately methionine auxotroph.
34% and on classification of the proteins into families, the 3. Only central pathways of carbon and energy
largest functional groups were found to be involved in the metabolism are complete but alternative pathways are
metabolism and modification of fatty acids and polyketides, degenerate.
transport of metabolites, cell envelope synthesis and gene 4. The co-enzymes central to the most universal metabolic
regulation.33 pathways-NADH cannot be recycled to NAD by the
Annotation of the genome identified genes showed that usual oxidative respiratory route.
M. leprae has the capacity to generate energy by oxidizing 5. Redundancy seen in M. tuberculosis is often lost in
glucose to pyruvate through the Embden-Meyerhof-Parnas M. leprae, as most paralogues seen in M. tuberculosis
(EMP) pathway. Acetyl-coenzyme A from glycolysis enters are pseudogenes (non-functional) in M. leprae.
the Krebs cycle, producing energy in the form of ATP. In 6. Defence against toxic radicals is severely degenerate,
addition to using glycolysis for energy production, these as neither katG nor the narGHJI cluster is functional.
organisms rely heavily upon lipid degradation and the 7. None of the few (142) additional genes found only in
glyoxylate shunt for energy production. In this regard, M. leprae, appears to conquer additional metabolic
M. leprae contains a full complement of genes for B pathways.
oxidation but compared to M. tuberculosis, very few genes
capable of lipolysis. Acetate has been lost to M. leprae as BIOLOGICAL PROPERTIES
a carbon source since only pseudogenes are present for OF M. LEPRAE
acetate kinase, phosphate acetyltransferase, and acetyl-
coenzymeA synthase.34 The understandings about the biological properties of
Overall, M. leprae has much fewer enzymes involved M. leprae have come from the mouse foot-pad experiments.
in degradative pathways for carbon and nitrogenous
compounds than M. tuberculosis. This is reflected in the
Bacterial Growth and Cell Division
paucity of oxidoreductases, oxygenases, and short-chain
Growth
alcohol dehydrogenases and their probable regulatory
genes. In addition, other major problems associated with Despite repeated failures in achieving in vitro cultivation
metabolism of M. leprae are that the bacilli have lost of M. leprae by various scientists over the last 125 years35
anaerobic and microaerophilic electron transfer systems; many investigators have continued their attempts in growing
and that the aerobic respiratory chain is severely curtailed, M. leprae in vitro.36 Many of such attempts have been
making it impossible for M. leprae to generate ATP from reported from India. Some of them have reported the
the oxidation of NADH. In contrast to the reduction in isolation of coccoids and L-phase like forms36 and repeated
catabolic pathways, the anabolic capabilities of M. leprae isolation of Nocardia like organisms from leprosy lesions.37
appear relatively unharmed. For example, complete Interestingly in many of these in vitro attempts, organisms
pathways are predicted for synthesis of purines, belonging to Mycobacterium avium-intraceullare-
pyrimidines, most amino acids, nucleosides, nucleotides, scrofulaceum (MAIS) complex have also been isolated.
and most vitamins and cofactors. The maintenance of It was suggested that it could be due to the fact that skin
these anabolic systems suggests that the intracellular of leprosy patients is colonized by the members of this
niche that M. leprae has found for itself may not contain complex.38 However, M. leprae has never been grown on
these compounds or transport systems.14 artificial media but maintained in axenic cultures in what
appears to be a stable metabolic state for a few weeks.39
Salient Features of Metabolism of Mycobacterium As a result, propagation of M. leprae has been restricted
leprae as Deduced from its Genome34 to animal models, including the armadillo40 and normal,
1. Uniquely for a host-dependent pathogen the biosyn- athymic, and gene knockout mice.41 These systems have
thetic pathways for purine and pyrimidine nucleotide provided the basic resources for genetic, metabolic, and
are complete. antigenic studies of the bacillus. Growth of M. leprae in
CHAPTER
7
mouse footpads also provides a tool for assessing the They can remain dormant in the host tissues. M. leprae
viability of a preparation of bacteria and testing the drug in skin of dead armadillo was observed to live up to 3 weeks
susceptibility of clinical isolates.39,42 and in soils of their dwellings up to 5 weeks.47 M. leprae
remains viable for up to 5 months, particularly under humid
Generation Time atmospheric conditions; even 3 hours a day exposure to
It is the time taken by a bacterium to divide into two cells. sunlight for 7 days could not kill the bacteria and at 26.7oC
In case of M. leprae the generation time during the and 77.6% humidity, they could survive for 14 days.48 So,
logarithmic multiplication is calculated to be 11 to 13 days. it is clear that large numbers of viable bacteria are being
Thus, M. leprae has a slow rate of multiplication, in contrast continuously discharged from active LL patients and with
to M. tuberculosis, and other slow growing cultivable the stability in the outside environment, act as a potential
mycobacteria which have a generation time of 20 hours. source of infection. M. leprae can be preserved in
This may be the reason for the long incubation period of laboratories by cryo-preservation in liquid nitrogen (at
leprosy. Reductive evolution, gene decay and genome –190oC) for indefinite period of time.
downsizing all may explain the unusually long generation Even on passage from one mouse foot-pad to another
time and account for our inability to culture the leprosy over a period of many years, the pathogenicity of M. leprae
bacillus.33 is unaltered. Also M. leprae, isolated from disseminated
infection of armadillo or immuno-deficient mice and
Temperature for Optimum Growth inoculated into the immuno-competent adult mouse, have
shown the usual characteristics of limited growth in foot-
M. leprae has a preference for temperature less than 37oC
pad.
for its optimal growth. Many studies showed the optimum
growth of M. leprae in footpad at 27 to 30oC.43 Clinical
Strain Differences
evidence also shows that leprosy predominantly involves
skin, nasal mucosa, peripheral nerves, where the 1. In drug resistance, strain differences in the resistance
temperature is lesser than core body temperature. to different anti-leprosy drugs (Dapsone, Rifampicin,
M. leprae causes a natural, systemic infection in nine and Clofazimine) have been shown.
banded armadillos (Dasypus novemcinctus), whose core 2. In growth pattern, mouse foot-pad experiments have
body temperature is 33-34°C. This obligate pathogen has shown differences in the growth of isolates. These
been shown to maintain its metabolic activity in axenic differences are: (i) high plateau strain which grows
medium cultured murine and human macrophages and faster, with high yield in mouse foot-pad and (ii) low
primary rat Schwann cells for several weeks at 33°C but plateau strain which grows slower with low yield.31
rapidly loses this activity at 37°C. A possible explanation Recently, M. leprae genome sequencing and
for the inability of M. leprae to survive at elevated identification of some tandem repeat loci have paved the
temperatures is that it is unable to mount a protective way for studying strain variation among M. leprae isolates.
heat stress response.44 Strain typing of M. leprae is currently achieved by mapping
alleles at a minimum of 15 short tandem repeats (STR)
Minimum Infective Dose loci and three known single nucleotide polymorphisms
Mouse footpad experiments show that the minimum (SNPs) using DNA extracts from clinical specimens such
infective dose ranges from 1-10 solidly staining (viable) as slit skin scrapings and biopsies. Throughput is being
bacteria.45 enhanced by multiplex PCRs, automated fragment length
analyzes and other DNA sequencing independent
Viability and Stability techniques. Variations in the patterns of alleles and their
M. leprae retains its viability at 4oC in biopsies or tissue frequencies in M. leprae strains (within and between
suspensions for 7 to 10 days. In dried nasal discharges geographically separated populations) indicate that STR
viability is maintained for 7 days at 20.6oC and 43.7% loci can be suitable for short range transmission, and also
humidity.46 for separating the long range dispersing events.49
CHAPTER
7
EXPERIMENTAL ANIMAL MODELS FOR OTHER EXPERIMENTAL ANIMALS
M. LEPRAE
Armadillo
With the non-availability of an artificial media for in vitro Nine-banded armadillo (Dasypus novemcinctus Linn.)
growth of M .leprae, cultivation of M. leprae in mouse foot- available in Southern United States was shown to develop
pad and the inoculation of armadillos with M. leprae still lepromatous like leprosy when experimentally infected by
plays an important role in understanding of the biological Kirchheimer and Storrs in 1971.5 On inoculation of 108
properties of M. leprae.5,50 Extensive utilization of these M. leprae intravenously into armadillo, it develops
two animal models has made possible many of the generalized progressive disease with up to 1010 lepra bacilli
remarkable advances in recent years in leprosy research. per gram of tissue in liver, spleen and lymph nodes.
Mouse Nonhuman Primates

Immunocompetent rodents: In 1960, Shepard Experimental inoculation was shown to develop
demonstrated that M. leprae multiply to a limited extent in disseminated leprosy in chimpanzees52, white handed
the hind foot-pad of immunologically intact mice. The gibbons53, and rhesus monkeys.54 Sooty Mangabey
observation on the manner of multiplication of M. leprae in monkeys developed extensive infiltration with clawing of
mouse foot-pad shows a characteristic pattern, as toes during the course of disease55; and African Green
elaborated below: monkeys developed lesions of MB leprosy and polyneuritic
1. Lag phase—lasting for 3 to 6 months after inoculation, leprosy within 4 to 6 months.54,56
showing no multiplication of M. leprae in the mouse
foot-pad. DRUG RESISTANCE
2. Logarithmic phase—usually starts 6 months after Bacteriological proof of the emergence of drug resistant
inoculation showing active multiplication of M. leprae strain of M. leprae as a cause of relapse in treated patients,
up to 105 per foot-pad. was dependent on the application of mouse footpad
3. Stationary phase—usually after 12 months, showing techniques. This involves identifying multiplication of
no further multiplication. bacteria in treated mice receiving diets containing doses
Experiments conclude that in an adult immuno- of the drug in excess of the minimum effective dose (MED)
competent mouse, an inoculum size of less than 104 can for the respective drug. The first bacteriological proof of
be inoculated and once the multiplication reaches more drug resistance to DDS was demonstrated when M. leprae
than 106, it starts acting as an immunogen in the mouse, from three relapsed lepromatous patients receiving DDS
preventing further multiplication of lepra bacilli. were not inhibited from multiplying in DDS treated mice at
a dose 1000-fold above the MED for DDS. 57 The
Immunodeficient mouse: Inoculation of M. leprae in
emergence of drug resistance per se during treatment
artificially immuno-suppressed or naturally immuno-
(referred to as secondary drug resistance) is confined to
deficient mice showed greater multiplication even after the
multibacillary leprosy. This is due to the fact that the
inoculation of a large number of M. leprae (105), prolonged frequency of drug-resistant mutants in a bacterial
survival of organisms and grossly evident clinical lesions population is never greater than one per million bacteria;
at the site of inoculation.51 and the bacterial population of this size is only present in
Many immunosuppressed/immunodeficient animal patients with multibacillary leprosy. Primary DDS resistance
models have been studied. They are: refers to the patients who have never received DDS but
1. Adult thymectomized-irradiated mice present with a DDS-resistant strain of M. leprae. The first
2. Nude mice case of primary DDS resistance was reported from
3. Other rodents studied Ethiopia58 and has since been reported from many countries
a. Neonatally thymectomized rat around the world, where secondary DDS resistance is
b. Congenitally athymic rat common.
CHAPTER
7
Rifampicin, although a highly bactericidal drug and proteins from several mycobacteria to that of M. leprae
being used in leprosy since 1970, two rifampicin-resistant demonstrated that M. leprae shares six highly conserved
mutants had been reported by 1976.59 Later, rifampicin functional regions common to this enzyme in mycobacteria.
resistance was reported among 39 cases of relapse by Mycobacterial resistance to rifampicin correlates with
Grosset et al in 1989.60 Rifampicin-resistant M. leprae the changes in the structure of the β-subunit of the DNA-
appear to be single-step mutants. All these earlier patients dependent RNA polymerase, primarily due to mis-sense
had received monotherapy with rifampicin. Although DDS mutations within codons of a highly conserved region of
resistance along with rifampicin resistance; has been the rpoB gene, referred to as the rifampicin resistance-
reported elsewhere, rifampicin resistance among patients determining region.75-77 Rifampicin resistance in M. leprae
receiving multi-drug therapy has not been reported so far also correlates with mis-sense mutations within this region
from India.61 However, a report from southern India of rpoB.74,78 Substitutions within codon Ser425 have been
shown to be the most frequent mutations associated with
demonstrated 19% of 265 M. leprae isolates from biopsied
the development of the rifampicin-resistant phenotype in
samples of leprosy patients resistant to dapsone,
M. leprae.
rifampicin, or clofazimine. All the resistant strains reported
Clofazimine is a substituted iminophenazine with
in this study had low rifampicin resistance (against 0.003%
antimycobacterial activity for which the mechanism has
of rifampicin in diet).62 Resistance against clofazimine has
not been fully elucidated.67 Clofazimine attains high
been reported in few studies.63-66 Resistance against intracellular levels in mononuclear phagocytic cells, its
Ofloxacin has also been reported in 1996.67 metabolic elimination is slow, it has an anti-inflammatory
effect and the incidence of resistance to it in M. leprae is
Molecular Mechanism of Drug Resistance low. It is highly lipophilic and appears to bind preferentially
Dapsone is a synthetic sulfone, structurally and to mycobacterial DNA. Binding of the drug to DNA appears
functionally related to sulphonamide drugs and targets to occur principally at the base sequences containing
dihydropteroate synthase, a key enzyme in the folate guanine, thus explaining clofazimine’s preference for the
biosynthesis pathway in bacteria, by acting as a competitive G+C-rich genomes of mycobacteria over human DNA.
inhibitor of p-aminobenzoic acid.68,69 Dapsone has also Lysophospholipids appear to mediate the activity of
been shown to target the folate biosynthetic pathway of clofazimine in some gram-positive bacteria.79 However; it
M. leprae.70 is unclear whether this mechanism of action is operational
in M. leprae. Since clofazimine may act through several
Specific mutations within the highly conserved
different mechanisms, it is not difficult to understand why
p-aminobenzoic acid binding sites of E.coli dihydropteroate
only a few cases of clofazimine-resistant leprosy have
synthase, encoded by folP gene, result in the development
been reported over the years.64-66
of dapsone resistance.71 The new evidence from the
M. leprae genome sequencing project has indicated that
LABORATORY DIAGNOSIS OF LEPROSY
M. leprae possesses two folP homologues (folP1 and
folP2). Through surrogate genetic studies with Since majority of the cases of leprosy are paucibacillary
M. smegmatis, the relationship between dapsone in nature and also M. leprae is not cultivable, the laboratory
resistance and the dihydropteroate synthase of M. leprae diagnosis of leprosy and determination of the viability of
has been established.72 Mis-sense mutations within codons M. leprae have always been challenging. Over the years
53 and 55 of the sulfone resistance-determining region of with the developments in technology, many attempts have
folP1, result in the development of high-level dapsone been made to improvize one laboratory technique over the
resistance in M. leprae. Similar observation was also other. These include microscopic staining methods,
reported from India.73 metabolic assays, radiolabelled techniques, molecular
Rifampicin is the key bactericidal component of all methods, etc.
recommended antileprosy chemotherapeutic regimens.
The target for rifampicin in mycobacteria and E.coli is the
Slit- Skin Smear
β-subunit of the RNA polymerase, encoded by rpoB.74-76 Lab investigations of leprosy patients for diagnosis,
Comparison of the deduced primary structure of β-subunit classification and monitoring of chemotherapy, have
CHAPTER
7
traditionally been depending on slit-skin smear of applicability to patients with paucibacillary leprosy are
examinations. the main limitations of this method.81
Skin smear examinations is carried out by slit-scrape
technique. The chosen skin site is cleaned with cotton Determination of Bacillary ATP Biomass
soaked in spirit and allowed to dry. Next, the skin is pinched Estimation of adenosine triphosphate (ATP) content has
up into a fold between the index finger and thumb, exerting been established as an important parameter for
enough pressure to stop or minimize bleeding. A clean- determination of viable biomass of different mammalian,
cut about 5 mm long and deep enough (3 mm) to get into other eukaryotic and bacterial species. Techniques for ATP
the infiltrated layer of the dermis, is made with a sterile assays for mycobacteria including M. leprae have been
scalpel. Then the blade of the scalpel is turned through 90 developed. By optimizing the techniques for extraction and
degrees and using the blunt edge of the blade the side of assay conditions, ATP assay has been observed to detect
the cut is scraped two or three times, sufficiently to obtain even as low as 100 viable mycobacterial cells. This
tissue pulp from below the epidermis. This material is then technique has been successfully applied to monitor the
transferred from the tip of the scalpel blade to a glass trends of responses to chemotherapy as well as to
microscopic slide, where it is spread in a circular motion demonstrate persisters.81
by the flat of the blade to produce a uniform and moderately
a thick smear over an area of 5-7 mm in diameter. Two to Assays Using Radiolabeled Substrate
four smears may be placed on a single slide and carefully Several in vitro methods based on incorporation/ utilization
labeled. Then the smear is stained by acid-fast staining, of various substrates in cell free media conditions have
preferably undertaken by staining at room temperature. been published. These assays are based on uptake of
The smears are microscopically examined to measure the labeled DOPA, thymidine (or) incorporation of 14C palmitic
bacterial load in the form of bacteriological index (BI). This acid into phenolic glycolipid of M. leprae. The measurement
method helps in the estimation of total number of M. leprae of oxidation of 14C-palmitic acid to 14 CO2 by M. leprae is
both viable and dead present in the tissue. Alternatively, done using Buddemeyer type counting system or BACTEC
morphological index (MI) is a method done for the 400 system. These assays have been reported to be useful
estimation of the proportion of viable M. leprae amongst for drug sensitivity screening using bacilli harvested from
the bacterial population in a patient.80 patients and experimental animals.81
This investigation is less sensitive as it requires a
Molecular Identification by Polymerase Chain
minimum 1-3 X104 AFB/ml.
Reaction (PCR)
Fluorescein Diacetate-ethidium Rapid molecular assays for detection of M. leprae directly
Bromide Staining from patient specimen using available M. leprae genetic
data have been developed. These assays have been based
Live cells can split fluorescein diacetate (FDA) to fluoresce
on the amplification of M. leprae specific DNA fragment.
green, while dead cells takes the red ethidium bromide
Many M. leprae genes and sequences like hsp18, ag36,
(EB) stain. The proportion of stained green cells by this
groEL, 16S rRNA, RLEP, etc. have been targeted in the
staining method has been observed to correlate with viable
development of PCR. These techniques have been applied
populations in several eukaryotic and prokaryotic cells.
not only in skin biopsy samples but also to several different
These techniques have been standardized for mycobacteria specimen like skin-smear, nasal-smear, Paraffin-embedded
including M. leprae for use in direct clinical specimens as skin biopsy samples, blood, nerve lesions, Ocular lesions,
well as for assessing the growth/viability in macrophages. etc. RNA analysis using 16S rRNA and reverse
Their application to lepromatous leprosy patients shows transcription- PCR has the added benefit of measuring
that this parameter is good for monitoring the trends of viability of M. leprae also. These PCR- based and reverse
chemotherapy responses. This technique can therefore transcription-PCR- based techniques have shown a
be used to confirm relapse provided sequential samples specificity of 100% and a sensitivity ranging from 34 to
are studied and statistical limits defined. The persistence 80% in PB form of leprosy and greater than 90% in MB
of green-staining signals for sometime after death and lack form of leprosy.14
CHAPTER
7
CONCLUSION AND FUTURE PROSPECTS 10. Ridley DS. The pathogenesis and classification of polar
tuberculoid leprosy. Lepr Rev 1982; 53: 19-26.
M. leprae, even though being one of the oldest micro- 11. Young RA, Mehra V, Sweetser D etal. Genes for the major protein
organisms identified, has been bundled with many un- antigens of leprosy parasite M. leprae. Nature 1985; 316: 450-52.
answered puzzles. Now the bacteriology of leprosy is 12. Daffe M, McNeil M and Brennan PJ. Major structural features of
the cell wall arabinogalactans of Mycobacterium, Rhodococcus,
becoming clearer after the sequencing of the genome of
and Nocardia spp. Carbohydr Res 1993; 249: 383-98.
M. leprae was completed. Molecular microbiology has 13. Draper P, Kandler O, Darbre A. Peptidoglycan and
begun to explain some intrinsic factors like the fastidious arabinogalactan of Mycobacterium leprae. J Gen Microbiol 1987;
nature of M. leprae and its predilection for an intracellular 133:1187-94.
life. Still there are many grey areas in the comprehension 14. Scollard DM, Adams LB, Gillis TP et al. The continuing challenges
of leprosy. Clin Microbiol Rev 2006; 19(2): 338-81.
of biology of M. leprae to be unravelled—The challenges
15. Ng V, Zanazzi G, Timpl RJ. et al. Role of the cell wall phenolic
in the laboratory diagnosis can be addressed with the glycolipid-1 in the peripheral nerve predilection of Mycobacterium
development of high sensitive and specific molecular tools. leprae. Cell 2000; 103:511-29.
The inherent problems of time-consuming and laborious 16. Brennan PJ and Vissa V. Genomic evidences for the retention of
nature of the conventional mouse footpad technique in the essential mycobacterial cell wall in the otherwise defective
Mycobacterium leprae. Lepr Rev 2001; 72: 415-28.
determining the viability and screening of the drug
17. Young DB. Detection of mycobacterial lipids in skin biopsies
susceptibility may be overcome by further refinement of from leprosy patients. Int J Lepr Other Mycobact Dis 1981; 49:
the PCR based molecular assays in near future. However, 198-204.
the inability to grow M. leprae in vitro would still continued 18. Minnikin DE, Dobson G, Draper P. The free lipids of
to be an enigma for the bacteriologists. It is hoped that Mycobacterium leprae harvested from experimentally infected
after the successful genome mapping of M. leprae, the nine-banded armadillos. J Gen Microbiol 1985; 131: 2007-11
19. Hunter SW, Rivoire B, Mehra V et al. The major native proteins of
knowledge gained in M. leprae genomics, proteomics and
the leprosy bacillus. J Biol Chem 1990; 265: 14065-68.
bioinformatics may be integrated for better understanding 20. Ivanyi J, Sinha S, Aston R et al. Definition of species-specific
of the further puzzles around M. leprae. and crossreactive antigenic determinants of Mycobacterium
leprae using monoclonal antibodies. Clin Exp Immunol 1983, 52:
528-36.
REFERENCES 21. Triccas JA, Roche PA, Winter N et al. A 35 kDa protein is a major
1. Pallamary P. Translation of ‘Spedalskhedens Arsager’ (cause of target of the human immune response to Mycobacterium leprae.
leprosy) by G Armauer Hansen, from Norsk magazine for Infect Immun 1996; 64: 5171-77.
Laegervidenskaben 1874 4: 76-79. Int J Lepr Other Mycobact 22. Winter N, Triccas JA, Rivoire B et al. Characterization of the
Dis 1955; 23: 307-09. gene encoding the immunodominant 35 kDa protein of
2. Chatterjee BR. Mycobacterium leprae and the bacteriology of Mycobacterium leprae. Mol Microbiol 1995; 16: 865-76.
Leprosy. In: Leprosy- Etiobiology of Manifestations, Treatment 23. Engers HD, Abe M, Bloom BR et al. Results of a World Health
and Control. 1993; ed BR Chatterjee, Calcutta, Statesman Organization sponsored workshop on monoclonal antibodies to
Commercial Press, pp 42-80. Mycobacterium leprae. Infect Immun 1985; 48: 603-05.
3. Shepard CC. The experimental disease that follows the injection 24. Young DB, Lathigra R, Hendrix et al. Stress Proteins are immune
of human leprosy bacillus into foot pads of mice. J Exp Med targets in leprosy and tuberculosis. Proc Natl Acad Sci USA
1960; 112: 445-54. 1988; 85: 4265-70.
4. Rees RJW. Enhanced susceptibility of thymectomized and 25. Rivoire B, Pessolani MCV, Bozie CM et al. Chemical definition,
irradiated mice to infection with M. leprae. Nature (London) 1966; cloning and expression of the major protein of the leprosy bacillus.
211: 657-58. Infect Immun 1994; 62: 2417-25.
5. Kirchheimer WF, Storrs EE. Attempts to establish the armadillo 26. Nerland AH, Mustafa AS, Sweetser D et al. A protein antigen of
(Dasypus novemcintus Linn.) as a model for the study of leprosy. Mycobacterium leprae is related to a family of small heat shock
Report of lepromatoid leprosy in an experimentally infected
proteins. J Bacteriol 1988; 170: 5919-21.
armadillo. Int J Lepr Other Mycobact Dis 1971; 39: 693-702.
27. Hunter SW. Fujiwara T, Brennan PJ. Structure and antigenicity
6. Draper P. Cell walls of M. leprae. Int J Lepr Other Mycobact Dis
of the major specific glycolipid antigen of M. leprae. J Biol Chem
1976; 44:95-98.
1982; 257: 15072-78.
7. Cole ST, Eiglmeier K, Parkhill J et al. Massive gene decay in the
28. Hansen GHA and Looft C . Leprosy: in its clinical and pathological
leprosy bacillus. Nature 2001; 409: 1007-11
aspects (translated by Norman Walker). Wright. Bristol 1895,
8. Vissa V, Brennan PJ. The genome of Mycobacterium leprae: a
42-43.
minimal mycobacterial gene set. Genome Biology 2001; 2: 1-7
29. Fisher CA and Barksdale L. Elimination of acid fastness but not
9. Ridley DS, Waters MFR. Significance of variations within
the gram-positive of leprosy bacilli after extraction with pyridine.
lepromatous leprosy group. Lepr Rev 1969; 40: 77-81.
J Bacteriol 1971; 106: 707- 08.
CHAPTER
7
30. Slosarek M, Sula L, Theophilus S et al. Use of pyridine for 51. Prabakaran K, Harris EB, Kirchheimer WF. Hair less mice, human
differentiating Mycobacterium leprae from other mycobacterium leprosy and thymus-derived lymphocytes. Experientia 1975;
in direct microscopy. Int J Lepr Other Mycobact Dis 1978; 46: 31(7): 784-85.
154-59. 52. Gunders AE. Progressive experimental infection with
31. Rees RJW and Young DB. The Microbiology of Leprosy. In: Mycobacterium leprae in chimpanzee: a preliminary report.
Leprosy. Hastings RC (Ed). Churchill Livingstone Publication J Trop Med Hyg 1958; 61(9): 228-30.
2nd edn. 1994; 49-83. 53. Waters MF, Bakri IB, Isa HJ et al. Experimental leprosy in a
32. Brosch R, Gordon SV, Eiglmeier K et al. Comparative genomics white handed gibbon (Hylobates lar): successful inoculation with
of the leprosy and tubercle bacilli. Res Microbiol 2000; 151:135- leprosy bacilli of human origin. Br J Exp Pathol 1978; 59(6):
42. 551-57.
33. Eiglmeier K, Simon S, Garnier T et al. The integrated genome 54. Wolf RH, Gormus BJ, Martin LN et al. Experimental leprosy in
map of Mycobacterium leprae. Lepr Rev 2001; 72:462-69. three species of monkeys, Science 1985; 227 (4686):
34. Wheeler PR. The microbial physiologist’s guide to the leprosy 529-31.
genome. Lepr Rev 2001; 72: 399-407. 55. Meyers WM, Binford CH, Brown HL. Leprosy in wild armadillos.
35. Yoshie Y. Advances in the microbiology of M. leprae in the past In: comparative pathology of zoo animals (proceedings of a
century. Int J Lepr Other Mycobact Dis 1973; 51: 361-67. symposium on comparative pathology of zoo animals, National
36. Chatterjee BR. Mycobacterium leprae and the bacteriology of zoological park, Washington DC Oct 1978) Smithsonian
Leprosy. In: Leprosy- Etiobiology of Manifestations, Treatment insituation, Washington, 1980 pp 247-51.
and Control. 1993; ed BR Chatterjee. Calcutta, Statesman
56. Baskin GB, Gormus BJ, Martin LN et al. Experimental leprosy in
Commercial Press, 42-80
a rhesus monkey: necropsy findings. Int J Lepr Other Mycobact
37. Chakraborty AN, Dastidar SG. Leprosy-derived chemo-
Dis 1987; 55(1): 109-15.
autotrophic nocardioform (CAN) bacteria closely resemble or
57. Pettit JHS, Rees RJW, Sulphone resistance in leprosy. An
are identical with Mycobacterium leprae on mycolate and other
experimental and clinical study. Lancet 1964; 2: 673-74.
lipid profile. Indian J Lepr 1992; 64: 529-36.
58. Pearson JMH, Haile GS, Rees RJW. Primary dapsone-resistant
38. Sharma RK, Katoch K, Sharma VD et al. Isolation and
leprosy, Lepr Rev 1977; 48: 129-32.
Characterization of cultivable mycobacteria from leprosy skin.
59. Jacobson RR, Hastings RC. Rifampicin- resistant leprosy. Lancet
Indian J Lepr 1995; 67: 321-25.
39. Truman RW, Krahenbuhl JL. Viable M. leprae as a research 1976; 2: 1304-05.
reagent. Int J Lepr Other Mycobact Dis 2001; 69: 1-12. 60. Grosset JH, Guelpa-Lauras CC, Bobin P et al. Study of 39
40. Truman R. Leprosy in wild armadillos. Lepr Rev 2005; 76: documented relapses of multibacillary leprosy after treatment
198-208. with rifampin. Int J Lepr Other Mycobact Dis 1989; 57: 607-14.
41. Krahenbuhl JL, Adams LB. Exploitation of gene knockout mice 61. Sekar B, Elangeswaran N, Jayarama E et al. Drug susceptibility
models to study the pathogenesis of leprosy. Lepr Rev 2000; of Mycobacterium leprae: a retrospective analysis of mouse
71: S170-75. footpad inoculation results from 1983 to 1997. Lepr Rev 2002;
42. Shepard CC, Chang YT. Effect of several anti-leprosy drugs on 73: 239-44.
multiplication of human leprosy bacilli in footpads of mice. Proc 62. Ebenezer GJ, Norman G, Joseph GA et al. Drug resistant
Soc Exp Biol Med 1962; 109: 636-38. Mycobacterium leprae-results of mouse footpad studies from a
43. Shepard CC. Temperature optimum of M. leprae in mice. laboratory in South India. Indian J Lepr 2002; 74:301-12.
J Bacteriol 1965; 90: 1271-75. 63. Kar HK, Bhatia VN, Harikrishnan S. Combined clofazimine and
44. Williams DL, Pittman TL, Deshotel M et al. Molecular basis of the dapsone-resistant leprosy: a case report. Int J Lepr Other
defective heat stress response in Mycobacterium leprae. Mycobact Dis 1986; 54: 389-91.
J Bacteriol 2007; 189(24):8818-27. 64. Shetty VP, Uplekar MW and Antia NH. Primary resistance to
45. McRae DH and Shepard CC. Relationship between the staining single and multiple drugs in leprosy: a mouse footpad study.
quality of M. leprae and infectivity for mice. Infect Immun 1971; Lepr Rev 1996; 67:280-86.
3: 116-20. 65. Mehta VR. Leprosy resistant to multidrug-therapy (MDT)
46. Davey RF, Rees RJW. The nasal discharges in leprosy, clinical successfully treated with ampicillin-sulbactam combination—
and bacteriological aspect, Lepr Rev 1974; 45: 121-34. a case report. Indian J Med Sci 1996; 50:305-07.
47. Harris EB, Landry M et al. Viability of M. leprae in soil and dead 66. de Carsalade GYD, Wallach E, Spindler J et al. Daily multidrug
armadillo tissue and it’s significance. Abst. 13th International therapy for leprosy: results of a fourteen year experience.
Leprosy Congress. The Hague, 1988 FP 100. Int J Lepr Other Mycobact Dis 1997; 65:37-44.
48. Desikan KV, Sreevatsa S. Effect of adverse environmental 67. Ji B, Perani EG, Petinom C et al. Clinical trial of ofloxacin alone
conditions of Mycobacterium leprae. Indian J Clin Biochem 1997; and in combination with dapsone plus clofazimine, for treatment
12(Suppl): 89-92. of lepromatous leprosy. Antimicrob Agents Chemother 1994;
49. Vissa V. Molecular epidemiology of leprosy and applications in 38: 662-67.
endemic situations, in Split plenary – 17th International Leprosy 68. Richey DP and Brown GM. The biosynthesis of folic acid. IX.
Congress, 30 th January to 4th February 2008, Hyderabad India Purification and properties of the enzymes required for the
50. Storrs EE, Walsh GP, Burchfield HP. Development of leprosy in formation of dihydropteroic acid. J Biol Chem 1969; 244:
the armadillo: new model for bio medical research. Science 1974;
1582-92.
183: 851-52.
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69. Seydel JK, Richter M and Wempe E. Mechanism of action of the 75. Telenti A, Imboden P, Marchesi F et al. Detection of rifampicin-
folate blocker diamino-diphenyl-sulfone (dapsone, DDS) studied resistance mutations in Mycobacterium tuberculosis. Lancet
in E. coli cell-free enzyme extracts in comparison to sulfona- 1993; 341: 647-50.
mides (SA). Int J Lepr Other Mycobact Dis 1980; 48:18-29. 76. Williams DL, Waguespack C, Eisenach K et al. Characterization
70. Kulkarni VM and Seydel JK. Inhibitory activity and mode of action of rifampin resistance in pathogenic mycobacteria. Antimicrob
of diamino-diphenyl-sulfone in cell-free folate-synthesizing Agents Chemother 1994; 38: 2380-86.
systems prepared from Mycobacterium lufu and Mycobacterium 77. Musser JM. Antimicrobial agent resistance in mycobacteria:
leprae: A comparison. Chemotherapy 1983, 29:58-67. molecular genetic insights. Clin Microbiol Rev 1995; 8: 496-514.
71. Dallas WS, Gowen JE, Ray PH et al. Cloning, sequencing, and 78. Cambau E, Bonnafous P, Perani E et al. Molecular Detection of
enhanced expression of the dihydropteroate synthase gene of Rifampin and Ofloxacin Resistance for Patients WHO Experience
Escherichia coli MC4100. J Bacteriol 1992; 174: 5961-70. Relapse of Multibacillary Leprosy. Clin Infect Dis 2002; 34:
72. Williams DL, Spring L, Harris EB et al. Dihydropteroate synthase 39-45.
of Mycobacterium leprae and dapsone resistance. Antimicrob 79. De Bruyn EE, Steel HC, Van Rensburg EJ et al. The
Agents Chemother 2000; 44:1530-37. riminophenazines, clofazimine and B669, inhibit potassium
73. Sekar B, Arunagiri K, Nirmal Kumar B et al. Detection of mutations transport in gram-positive bacteria by a lysophospholipid-
in the rpoB and folp 1 gene of M. leprae using molecular methods. dependent mechanism. J Antimicrob Chemother 1996. 38:
In: The proceedings of 17th International Leprosy Congress 30th 349-62.
January to 4th February 2008, Hyderabad, India 100 (0–99). 80. WHO. The Smear. In: Laboratory Techniques for leprosy, WHO/
74. Honore N and Cole ST. Molecular basis of rifampin resistance in CDS/LEP/ 86.4. 1987; 21-25.
Mycobacterium leprae. Antimicrob Agents Chemother 1993; 37: 81. ICMR Bull. In vitro methods for rapid monitoring of drug therapy
414-18. and drug resistance in leprosy 2001;31:73-84.
CHAPTER
8
Biochemical Aspects 87
8
Biochemical Aspects
Krishnamurthy Venkatesan, Nirmala Deo
INTRODUCTION MYCOBACTERIUM LEPRAE, THE

ETIOLOGIC AGENT OF LEPROSY
Leprosy, also called Hansen’s disease, is a chronic
granulomatous infection principally affecting the skin and Cellular Morphology
peripheral nerves caused by the obligate intracellular
Mycobacterium leprae, the etiological agent of leprosy, is
organism Mycobacterium leprae. The clinical manifestations
a nonmotile, nonspore-forming, microerophilic, acid-fast
of the disease are primarily due to: (i) bacterial progression
staining bacterium that usually appears as slightly curved
in the host and (ii) immunologic responses of the host. It
or straight rod. In size and shape it closely resembles the
is primarily an infection of the peripheral nerves with
tubercle bacillus. It occurs in large numbers in the lesions
secondary skin manifestations. One may therefore, wonder
of lepromatous leprosy, chiefly in masses within the lepra
how biochemical studies can be relevant in leprosy.
cells, often grouped together like “bundles of cigars” or
However, biochemical investigations show that the situation
arranged in a palisade. Chains are never seen. Most striking
is not so simple, but far more complex. Changes noted in
are the intracellular and extracellular masses, known as
biochemical, hematological and serological profiles,
consequent to either the leprosy infection including globi, which consist of clumps of bacilli in capsular material.
reactions; as well as following treatment, are important in Under the electron microscope the bacillus appears to have
understanding the consequences of the disease conditions. a great variety of forms. The commonest is a slightly curved
It is interesting to note that biochemical studies in filament 3-10 microns in length containing irregular
leprosy were initiated over 60 years ago, two decades arrangements of dense material; sometimes, in the shape
before the effective treatment with dapsone was introduced of rods. Short rod-shaped structures can also be seen
in leprosy. The limitation in leprosy research due to inability (identical with the rod-shaped inclusions within the
to grow M. leprae in vitro was overcome by the availability filaments) along with dense spherical forms. Some of the
of armadillo derived M. leprae in the pregenomics era. groups of bacilli can be seen to have a limiting membrane.1
However, the scenario of understanding biochemistry of It is believed that only leprosy bacilli which stain
the leprosy bacillus and hence the disease, has become uniformly with carbol-fuchsin as solid acid-fast rods are
much better after the annotation of the genome of the viable, and the bacilli which stain irregularly are probably
causative organism M. leprae. The global leprosy scenario dead and degenerating. These differences are valuable
has witnessed significant change towards optimism with pointers in biopsy specimens to observe the effects of
the advocating of WHO recommended multidrug therapy treatment. In patients receiving standard multidrug therapy
in 1982. This chapter therefore, gives a bird’s eye view of (MDT), a very high proportion of bacilli are killed within
the morphology, cell wall chemistry, genomics, etc. of the days, which suggests that many of the manifestations of
causative organism, Mycobacterium leprae, host-parasite leprosy, including reactions which follow the initial treatment,
interactions, and changes in the hematological, serological must be due in part to antigens released from the dead
and biochemical profiles as a result of this infection. organisms rather than from the living ones. Therefore, there
CHAPTER
8
is a need for drugs which will help the body to dispose of in the plasma membrane, are also found in the capsular
dead leprosy bacilli. Two indices which depend on layer.7
observation of M. leprae in skin or nasal smears are useful
in assessing the quantum of infection, the viability of the Growth and Metabolism
organisms and the progress of the patient under treatment. As of date, it has not been possible to grow M. leprae on
They are the bacteriological index (BI) and the artificial media. However, they can be maintained in axenic
morphological index (MI).1 cultures perhaps in a stable metabolic state for a few
weeks.8 Consequently, propagation of M. leprae has been
Chemical Composition of Cell Wall of M. leprae restricted to only animal models, including the armadillo
The cell wall of the organism is a covalently linked and normal, athymic, and gene knockout mice.9.10 Genetic,
peptidoglycan-arabinogalactan-mycolic acid complex metabolic and antigenic studies of the bacillus have all
similar in composition to all mycobacterial cell walls.2,3 been conducted using the organisms provided by these
Draper analysed the chemical composition of cell walls of systems. Growth of M. leprae in mouse footpads has also
M. leprae and found a rare combination of glycine and been providing a tool for assessing the viability of a bacterial
diaminopimelic acid (DAP) which has not so far been shown preparation and testing the drug susceptibility of clinical
to occur in other mycobacteria.4 It is considered to be an isolates. 11 Metabolic studies have been/are being
important characteristic of the organism. M. leprae cell conducted on M. leprae to explore the possibility of
wall core contains peptidoglycan, composed of chains of formulating a special media that could support in vitro
alternating N-acetylglucosamine and N-glycolylmuramate growth of the bacilli and the knowledge on its metabolic
linked by peptide cross-bridges, which is then linked to pathways could help in developing new antileprosy drugs.
the galactan layer by arabinogalactan. Three branched Consequent to completed sequencing and annotation of
chains of arabinan are in turn linked to the galactan, forming M. leprae genome, a better knowledege of the metabolic
along with the peptidoglycan layer, an electron-dense zone capabilities of M. leprae is now available.12-14
around M. leprae. Mycolic acids are linked to the termini of Mycobacterium leprae has the capacity to generate
arabinan chains to form the inner leaflet of a pseudolipid energy by oxidizing glucose to pyruvate through the
bilayer. The outer leaflet is composed of a rich array of Embden-Meyerhof-Paras (EMP) pathway. Acetyl-
intercalating mycolic acids of trehalose monomycolates coenzyme A from glycolysis enters the Krebs cycle,
and mycoserosoic acids of phthiocerol dimycocerosates producing energy in the form of adenosine triphosphate
as well as phenolic glycolipids (PGLs), forming the electron- (ATP). The genome analysis as well as biochemical studies
transparent zone.5,6 in M. leprae and M.tuberculosis suggest that these
The chemical composition of this immunologically organisms, in addition to glycolysis, rely heavily upon lipid
active phenolic glycolipid resembles mycoside-A produced degradation and the glyoxylate shunt for energy production.
by M.kansasii. However, the terminal trisaccharides in the Mycobacterium leprae contains a full complement of genes
phenolic glycolipids (PGLs) of M. leprae are different. They for beta oxidation but, compared to M. tuberculosis, has
are 3,6-di-O-methyl-β-D-glucopyranosyl- (1→4)-2,3-di-O- very few genes capable of lipolysis. Since only
methyl-α-L-rhamnopyranosyl- (1→2)-3-O-methyl-α-L- pseudogenes are present for acetate kinase, phosphate
rhamnopyranose in phenolic glycolipidI-1, and 3,6-di-O- acetyltransferase, and acetyl-coenzyme A synthase,
methyl-β-D-glucopyranosyl-(1→4)-3-O-methyl-α-L- M. leprae fails to use acetate as a carbon source. M. leprae
rhamnopyranosyl-(1→2)-3-O-methyl-α-Lrhamnopyranosyl overall has fewer enzymes involved in degradative
in phenolic glycolipid III. Since these are highly specific pathways for carbon and nitrogenous compounds than
for M. leprae, these are found useful in the serodiagnosis M. tuberculosis. The paucity of oxidoreductases,
of leprosy. A capsule presumably composed of largely oxygenases, and short-chain alcohol dehydrogenases and
PGLs and other molecules such as pthioceroldimy- their probable regulatory genes in M. leprae reflects this
cocerosates (PDIMs), phosphatidylinositol mannosides, fact. In addition, other major problems associated with the
and phospholipids surrounds the bacterium. Lipoglycans metabolism of M. leprae are loss of anaerobic and
such as phosphatidylinositol mannosides, lipomannan microaerophilic electron transfer systems and severe
(LM), and lipoarabinomannan (LAM), known to be anchored limiting of the aerobic respiratory chain in M. leprae.
CHAPTER
8
Consequently, it is impossible for M. leprae to generate mycobactin/exochelin.15 Although genes known to be
ATP from the oxidation of NADH. In contrast to the reduction involved in iron acquisition are not obvious in its genome,
in catabolic pathways, the anabolic capabilities of M. leprae M. leprae utilizes iron as shown by the presence of genes
appear relatively unharmed. To cite few examples, complete for cytochrome c (ccsAB), a ferredoxin (fdxCD),
pathways are predicted for synthesis of purines, biosynthesis of the heme group (hem genes), a hemogloblin-
pyrimidines, most amino acids, nucleosides, nucleotides, like oxygen carrier (glbO), the iron storage bacterioferritin
and most vitamins and cofactors.15,16 bfrA, and ideR, the iron regulation protein dependent on
intracellular iron.14 Intact polymorphic G+C-rich sequence
Genome of M. leprae vis-à-vis that of or major polymorphic tandem repeat-related repetitive
M. tuberculosis sequences are not found in the genome of M. leprae and
The source of DNA for sequencing M. leprae genome was only a limited number of proline-proline-glutamic acid and
the M. leprae originally purified from the skin lesions of a proline-glutamic acid proteins are present.18
multibacillary leprosy patient from Tamil Nadu, India (TN
strain), and subsequently expanded in and purified from
Molecular Identification of M. leprae
the liver of a nine-banded armadillo. Comparison of the Rapid molecular-type assays have been developed for
genome of M. leprae with that of its close relative detection of M. leprae directly from patient specimens
M.tuberculosis suggests that M. leprae has undergone an using available genetic data.19-21 These assays have been
extreme degree of reductive evolution.15,17 This is firmly based primarily on the amplification of M. leprae-specific
reflected by its smaller genome (3.3 Mb for M. leprae vs sequences using PCR and identification of the M. leprae
4.4 Mb for M.tuberculosis) and a major reduction in G+C DNA fragment. Many different M. leprae genes have been
content (58% for M. leprae vs 66% for M.tuberculosis). utilized in the development of PCR assays for detection of
The annotated genome of M. leprae contains only 1,614 M. leprae in clinical specimens. RNA analysis using 16S
open reading frames potentially encoding functional rRNA and reverse transcription-PCR has the added benefit
proteins, compared to 3,993 open reading frames predicted of measuring post-treatment viability.22.23 PCR has been
in M. tuberculosis. M. leprae genome possesses 1,133 found very useful in the detection and identification of M.
leprae and when coupled with mutation detection analyses,
inactivated genes (genes lost through mutation, or
it has the ability to provide rapid drug susceptibility results
pseudogenes), compared to six pseudogenes in
from clinical specimens. The readers may find more details
M. tuberculosis18 and a large number of genes apparently
in Chapter 15 (Serological and Molecular Diagnosis).
have been entirely deleted from the genome of M. leprae.
The result of massive gene loss has left M. leprae with
Genotypic Variations in M. leprae
less than 50% of its genome encoding functional genes
whereas in M.tuberculosis 90% of the genome encodes Genetic markers are increasingly found useful in
functional genes. Also 34% of M. leprae proteins identified establishing species and strain-specific markers for
in silico appear to be the products of gene duplication assessing exposure to M. leprae and tracing transmission
events or share common domains.19 Downsizing of the patterns. These genetic tools can also help in improving
genome has its own consequence of the elimination of our understanding of the epidemiology of leprosy. A wide
several metabolic pathways, making the pathogen need range of molecular markers have been applied to
very specific growth requirements. The largest functional understand genotypic variations in M. leprae. Restricted
groups of genes in M. leprae are those involved in gene Fragment Length Polymorphism (RFLP) analysis of M.
regulation, metabolism and modification of fatty acids and leprae isolates using different combinations of restriction
polyketides, cell envelope synthesis, and transport of enzymes and probes as well as sequencing of the internal
metabolites.13,15,17 transcribed spacer region of the 16S-23S rRNA operon
The ability of any microorganism to acquire iron from yielded no polymorphic DNA sequences.24,25 Based on
environment is essential for its pathogenic lifestyle. But it the analysis of chromosomal DNAs encoding all or part of
appears that M. leprae has a major deficiency in this aspect the 12kDa, 18kDa, 28kDa, 65kDa and 70 kDa proteins of
as entire mbt operon appears to have been deleted. So M. leprae as well as M. leprae specific sequence using
M. leprae is unable to make iron-scavenging siderophores DNA probes, Williams et al concluded that their isolates
CHAPTER
8
contained no polymorphism.26 Polymorphism in another room temperature and at 68°C and pH 7.0, arylsuphatase
locus polA and variation in the number of TTC repeats (3 and 14 days) and urease. Catalase was found to be
have been described.27,28 Variation in the number of copies present in M. leprae, arylsuphatase could be demonstrated
of the 6 bp tandem repeat in the rpoT gene have been on the 14th day and urease was found absent.36
reported in 100 strains from Northern Indian patients. The
variation in a GACATC repeat in the rpoT gene have also HOST—M. LEPRAE INTERACTIONS
been described, but the value of these elements for
differentiating possible M. leprae strains appears to be The clinical and immunological manifestations and the
limited at present.29,30 Based on the frequency of TTC associated hematological, serological and biochemical
repeats located downstream of a putative sugar transporter changes in leprosy patients can be well understood only
pseudogene. Shin et al reported evidence for diversity with an insight into the finer aspects of the interactions of
among M. leprae isolates obtained from several patient the causative organism, M. leprae with the host. In the
biopsy samples from patients in the Philippines.31 past 10-15 years, lot of studies have been conducted on
the interactions of M. lepare with the Schwann cells,
Pregenomic Study of a Few Enzymes of macrophages, dendritic cells and endothelial cells which
M. leprae could explain the pathogenesis and spread of the M. leprae
infection.
Consequent to the continued failure in attempts to culture
M. leprae, the complete understanding of this fascinating Interactions with the Schwann Cells and
mycobacterium has been eluding the scientists till Mechanisms of Nerve Injury
annotation of M. leprae genome was completed in 2000.
Today, however, some very useful basic information has Mycobacterium leprae has a unique host cell tropism in
been made available by their persistent efforts. While that, it preferentially infects and grows within Schwann
carrying out certain investigations on the metabolic cells (SC) surrounding the axons of the nerve cells. It is
properties of the leprosy bacilli isolated from leprous therefore, postulated that nerve damage in leprosy; and
nodules and examining the activities of oxidative enzymes the resultant deformities and disabilities related to the
and enzyme related to amino acid metabolism in M. leprae disease, result from M. leprae invasion of human SC.37-39
suspension, Prabhakran and Braganca were able to show In patients with advanced leprosy, both myelinated and
for the first time, the presence of oxidative enzymes such nonmyelinated Schwann cells are infected by M. leprae
as succinic oxidase, lactic dehydrogenase, peroxidase, although some reports have suggested some preference
etc. in M. leprae and that the bacillus is capable of getting for nonmyelinated SC. Several potential mechanisms of
its energy requirement with their help.32,33 Prabhakaran binding of M. leprae to the SC have been elucidated.
made a very important finding that M. leprae possesses Antibodies directed against the polysaccharide and lipid
DOPA oxidase, an enzyme, which oxidises DOPA and components of M. leprae inhibited adhesion to SCs, while
this enzyme is highly specific to M. leprae, as he could those directed against both surface and cytoplasmic protein
not detect this enzyme activity in eight other mycobacteria epitopes did not show any such effect, indicating that the
studied.34 However, there is still a debate over the validity association of M. leprae with SCs may be mediated by
of Prabhakaran’s claim of the presence of DOPA oxidase more than one of its cell surface molecules.40
in M. leprae. A host molecule laminin-2 is the initial target for
Apart from DOPA oxidase activity attempts to identify M. leprae seeking the Schwann cell niche. Laminin
other enzymes have also been made. Shetty et al reported molecule comprises of α2, β1 and γ1 chains and is
the presence of gamma glutamyl transpeptidase (enzyme anchored to SC via the laminin receptor, alpha Dystroglycan
catalyzing the transfer of glutamyl groups) in suspensions (α -DG). The globular(G) domain of the laminin α2 chain is
prepared from biopsy materials obtained from leprosy the specific subunit with which M. leprae interact.41 It is
patients.35 Dhople carried out some taxonomic studies with relevant that the natural sites of M. leprae infection in the
a view to comparing the biochemical properties of M. leprae human is the Schwann cells, striated muscle and the
with those of certain slow as well as rapid growing placenta where laminin α2 is distributed.42 The specific
mycobacteria. The enzymes assayed were catalase at receptor for M. leprae on Schwann cells is α DG receptor.43
CHAPTER
8
Phenolic glycolipid (PGl-1), a molecule unique to M. leprae an inability to stimulate the production of reactive oxygen
cell wall, has been shown to specifically bind to the lamnin metabolism; (c) prevention of the interaction of the oxygen
via its terminal trisaccharide in vitro.15,44 Another specific metabolites with the bacillus following phagocytosis; or
putative bacterial adhesion, H1p/LBP21, potentiates (d) resistance to the oxygen metabolites. A disarrangement
interaction of M. leprae with the Schwann cells.42 of nonoxidative antimicrobial systems cannot be ruled out.7
After M. leprae adhere to the Schwann cells surface, The basic biology of macrophage interactions with M.
they are slowly ingested as evidenced by the studies using leprae has been reviewed excellently by Krahenbuhl and
denervated rat SC cultures and SC-neuron co-cultures45 Adams.50 The macrophage is a primitive cell type being
and several protein kinases (except cAMP-dependent found in both early and advanced life forms, and possesses
kinases) have been demonstrated to be essential for the a variety of functions, such as phagocytosis of invaded
ingestion.46 The findings of these studies that acidification bacteria, production of cytokines, antigen presentation and
of vesicles containing lethally irradiated (killed) M. leprae tumor killing. Macrophages in specific tissue and infection
proceeded normally, while acidication was minimal when sites can play an important role in pathogenesis of leprosy
live M. leprae were used, suggest that viable M. leprae by releasing cytokines, including TNF-α consequent to their
can interfere with normal endocytic maturation of the stimulation by whole M. leprae and/or its cell wall
Schwann cells. Infection of SC with whole viable M. leprae components51 and by bridging, as antigen-presenting cells,
appears to favor survival of SC rather than apoptosis.47 the innate and acquired immunity of the host by evoking T-
But binding of an M. leprae-derived lipoprotein to Toll-like cell and B-cell responses.42 It has also been shown that
receptor 2 (TLR2) expressed by human SC is set to result PGL-1 addition to human mononuclear cells exposed to
in apoptosis.48 M. leprae stimulates them to produce TNF-α.52
It has been reported that following adherence/binding Macrophages from lepromatous leprosy patients
of M. leprae to SCs in the absence of immune cells, a exposed to M. leprae, showed reduced protein synthesis,
rapid demyelination occurs perhaps through a contact- unlike those from tuberculoid leprosy patients or normal
dependent mechanism dependent on cell wall PGL-1.47,49 individuals.53 Both cured and active lepromatous leprosy
The immune responses on M. leprae infected SCs have patients have defective macrophages, unable to respond
been described in detail by Scollard.40 Based on the studies to live M. leprae to produce superoxide anion, in contrast
reported in this review, it appears that human Schwann to the situation with the cells from normal healthy
cells express MHC class II molecules after infection with individuals.54 Macrophages cultured from the peripheral
M. leprae and the infected SCs appear to be able to process blood of normal individuals, tuberculoid leprosy patients
and present M. leprae antigens to CD4+ T cells. In addition and long-term-treated, bacteriologically negative
to MHC class II molecules, human SCs can also express lepromatous leprosy patients are able to release hydrogen
MHC class I, ICAM-I, and CD80 surface molecules involved peroxide on stimulation with M. leprae. But macrophages
in antigen presentation.The nerve infected with M. leprae from bacteriologically positive lepromatous leprosy patients
can also be affected by concurrent immunological/ produce considerably lower levels of hydrogen peroxide
inflammatory events, through cytokines and chemokines. even with demonstrable stimulation of these cells with
Molecules like TNF-α, other pro-inflammatory cytokines M. leprae. This differential stimulation of macrophages
and nitric oxide have also been reported to be involved in appears to be largely specific to M. leprae. It is possible
apoptosis and demyelination of SCs.40 that while other factors aid survival of M. leprae in the
macrophages, hydrogen peroxide may not be highly
Interactions of Macrophages with M. leprae effective in the killing of the bacteria in infected patients.55
As an obligate intracellular pathogen, the principal host
cells for M. leprae are the mononuclear phagocytes or
Interaction with Dendritic Cells
macrophages where they can survive and replicate. The Though M. leprae is known to reside in Schwann cells and
mechanism by which it resists destruction by phagocytes macrophages, many other cell types such as dendritic
is not fully understood. The possibilities in the context of cells and endothelial cells also appear to harbor the
oxidative killing are: (a) an ability to combat phagocytic organism. Infection of the monocyte-derived dendritic cells
microbicidal activity by inhibiting the respiratory burst; (b) (DCs) in vitro with foot-pad derived M. leprae are able to
CHAPTER
8
effectively phagocytose M. leprae and the DCs are able to Hematological Profile in Leprosy
present M. leprae specific antigens, including PGL-1.56
Hematological profile has been studied in adult leprosy
Langerhans cells, a subset of DCs that initiate the immune
patients with different types of leprosy, in various stages
responses in the skin, are more efficient at M. leprae
of the disease and treatment. Hemoglobin, packed cell
antigen presentation than monocyte-derived DCs.57 MMP-
II (Major membrane protein II), an isolated and purified M. volume, and serum iron are significantly lower among
leprae protein, has been found to be highly immunogenic.58 lepromatous leprosy patients as compared with non-
This protein stimulated the DCs directly and is suggested lepromatous patients. The serum B 12 levels were
to result in high levels of T-cell activation when used to significantly higher among the lepromatous group. With
pulse the monocyte-derived DCs.58,59 rising bacterial load, there was a trend towards lower
hemoglobin concentration, higher vitamin B12 level and
Mycobacterium leprae and Endothelial Cells lowered serum folate levels.63,64
M. leprae has been reported to be present in the endothelial Methemoglobinemia and hemolytic anemia were the
of the skin, nervous tissue and nasal mucosa, indicating principal side effects observed with dapsone long-term
that endothelial cell may be a site for M. leprae persistence treatment. The hematological alterations occur in leprosy
and replication.60,61 Based on a seminal study using patients taking dapsone both as a single drug (DDS group)
armadillo model of M. leprae to determine the extent to or as part of a multidrug therapy in combination with
which the bacilli could be found in endothelial cells, Scollard rifampicin and clofazimine (MDT group). Reticulocytes were
et al (1999) have suggested that the endothelial cells in found to be elevated in 90% of the patients. Heinz bodies
the epineurial and perineurial blood vessels could be a have also been detected in 6.6% of the patients. The
reservoir for actively replicating M. leprae that would osmotic fragility test showed a reduction in cell resistance
subsequently infect the Schwann cells in adjacent tissue. and a severe eosinophilia was found. The hematological
Their findings implicate that some mechanism of M. leprae side effects of dapsone are significant even at doses
attachment to the endothelial cells could be required for currently used to treat leprosy (100 mg/day). Rifampicin
the establishment of infection and that M. leprae can reach and clofazimine however, do not increase the incidence of
the peripheral nerve tissue through the bloodstream.62
these effects during long-term treatment.65
HEMATOLOGICAL, SEROLOGICAL AND Serological Profile in Leprosy

BIOCHEMICAL CHANGES IN PATIENTS
Sera of patients with lepromatous leprosy have been
WITH LEPROSY
studied for the presence of a variety of antibodies and
The clinical manifestations of leprosy disease are primarily immune complexes (IC).66 Significantly higher frequencies
due to: (i) bacterial progression in the host, (ii) immunologic of heterophile, Hanganutziu-Deicher and Forssman
responses of the host, and (iii) the peripheral nerve damage antibodies were found in the sera of LL patients. The
due to either or both bacterial progression and immunologic frequency of antibodies to cardiolipin was the highest and
responses of the host. Although typically, leprosy causes
the frequency of rheumatoid factor was marginally high.
manifestations in the skin and peripheral nerves; leading
Circulating ICs were demonstrated in 54% and 43% of the
to disability and deformity, it also affects multiple organs,
patients’ sera by Raji-cell test and anti-antibody inhibition
making its recognition highly challenging. Extensive work
test, respectively. Analysis of immunoglobulin classes of
has been done on the evaluation of changes in hematolgical,
IC showed that that IgG was predominant in IC of patients
serological and blood biochemical profile. Many of such
reported studies are of sequential nature. The studies have with leprosy reaction (LR) and IgM in patients without LR.
been conducted across the leprosy clinical spectrum In a study on leprosy patients from Papua New Guinea,
highlighting the profound changes in lepromatous leprosy antibodies to human collagen (ACA) were detected by
and reactional episodes, particularly erythema nodosum hemagglutination assay in the serum, with variation in the
leprosum (ENL). prevalence of elevated titres of 1:4 or more, according to
clinical spectrum of leprosy in the highland patients.67 The
CHAPTER
8
gradient was significant from high prevalence in the serum proteins are significantly raised in lepromatous group
immunodeficient polar lepromatous patients (53%); to a and in reactional forms of leprosy. This hyperproteinemia
low prevalence at the tuberculoid end of the clinical is mainly due to hyperglobulinemia which is present in all
spectrum (9%). It is not clear whether these antibodies forms of leprosy with progressive rise from TT to LL and
are implicated either in the pathogenesis of the the highest values are noted in ENL. Highest values for
complications of leprosy, or in the prolongation and plasma fibrinogen are observed in ENL patients while rest
intensification of inflammatory reactions involving collagen of the groups of leprosy patients showed progressive rise
at sites such as the skin, nerves, and glomerular basement in the parameter from TT to LL.73-76
membrane, and if so; to what extent. Gupta et al have studied serum proteome of leprosy
A study on the assessment of the prevalence of patients undergoing ENL reactions and compared it with
autoantibodies in lepromatous leprosy patients by ELISA that of healthy noncontact controls. Differentially expressed
has shown SS-B (anti-La) antibodies, antibodies to proteins were identified by MALDI-TOF and MALDI-TOF
mitochondria, and cardiolipin were most prevalent in the MS/MS mass spectrometry. Significant increase in one of
sera.68 The study further observed that antimitochondrial the isoforms of α2 chain of heptoglobin was observed in
antibodies, distinct from those seen in biliary cirrhosis, ENL. Hp 0-0 phenotype was detected in 21.4% of the ENL
and antiphospholipid antibodies with variable ligand activity patients undergoing treatment.77
to B2GIP were frequent in the sera of leprosy patients.
Lipid Profile
Biochemical Changes in the Host The ability to synthesize different lipid moieties and their
Hepatic Involvement distribution through plasma to all the body tissues seems
Of the various organs studied in leprosy, liver happens to to be altered in leprosy.78 Misra et al found a general
be the most intensively investigated. The involvement of lowering in total serum lipids, cholesterol and phospholi-
liver by way of formation of granuloma is a well-known pids in LL and increase in serum triglyceride in LL.79 On
feature in lepromatous leprosy and liver involvement has the contrary, a lowering in the levels of serum triglyceride
even been reported in cases of tuberculoid leprosy (TT). in multibacillary patients was observed by Bansal et al.80
Several attempts have since been made to investigate Sritharan et al opined that the decrease could be explained
the liver patholgy in leprosy. The earlier studies were based by the decreased adrenocortical functions in LL patients
on single parameters for liver function.69-71 Increase in which may result in decreased activity of lipogenic and
thymol turbidity and cephalin-cholesterol flocculation and glycolytic enzymes.81 Low incidence of atherosclerosis
reversal of albumin:globulin (A:G) ratio have been reported and coronary heart disease in patients of leprosy has been
in the sera of lepromatous leprosy (LL) patients, with related to elevation of HDL cholesterol and reduction of
minimal changes in the TT spectrum. Serum transaminase total cholesterol in patients with high bacterial indices.
levels in LL have been found to be elevated. In a study of Ahaley et al documented lowered serum cholesterol levels
hepatic involvement and hepatitis B surface antigenemia in patients of leprosy.78 On the other hand, Gokhale and
in leprosy, HbsAg was detected in 7.54% of lepromatous Godbole observed higher levels in their study.82 Bansal
leprosy patients.72 There was also a decrease in albumin et al found significant increase in the values of HDL
and increase in globulin levels with significant decrease in cholesterol in multibacillary patients in their series.80
A:G ratio. SGPT levels were significantly raised in Sritharan et al also observed an increase in HDL-
lepromatous leprosy patients. Histopathological changes cholesterol and a decrease in the level of LDL cholesterol
were present in 57.1 % of lepromatous leprosy and 23.8% in active LL patients.83 Gupta et al have documented
of tuberculoid leprosy patients.72 decreased values of LDL cholesterol in leprosy, more so
in LL groups.84 Mycobacterium leprae, is thought to be the
Serum Protein Profile mycobacterium most dependent on host metabolic
A variety of methods including electrophoresis have been pathways, including host-derived lipids. In lepromatous
employed to study the serum protein profile. It is difficult leprosy lesions, there was preferential expression of host
to list the battery of published reports. Precisely, total lipid metabolism genes, including a group of
CHAPTER
8
phospholipases, and that these genes were virtually absent The endocrine dysfunction in leprosy has been extensively
from the mycobacterial genome. Host-derived oxidized reviwed recently.92 The testes are the most commonly
phospholipids were detected in macrophages within affected endocrine organs. Leprosy may lead to azospermia,
lepromatous lesions and these oxidized phospholipids and sterility and gynecomastia. A significant increase in
HDL regulate innate immunity in leprosy.85 gonadotrophins has been reported with significantly low
level of testosterone in leprosy patients.93 Increase in
Renal Involvement and Kidney Function levels of luteinizing hormone (LH), follicle stimulating
Leprosy is well-known for its multivisceral involvement hormone (FSH) and testosterone has been reported by
though Mycobacterium leprae ordinarily does not invade Rea.94 A study on the ovarian function in female patients
the renal parenchyma, yet considerable functional with multibacillary leprosy has reported increased mean
impairment in leprosy has been reported. Presence of levels of LH and FSH vis-a-vis controls.95 Koshy and Karat
edema, proteinuria, and biochemical abnormalities – more reported normal basal pituitary-adrenal functions in LL
so in the reactional phase – have been reported.86 Renal patients.96 However, response to the administration of
involvement in leprosy was first described by Mitsuda and Metapyrone and Synacten indicated a poor adrenal reserve
Ogawa in 1937.87 They described nephritis of all kinds in in patients with chronic leprosy reactions. Balakrishnan et
leprosy and also observed that renal failure was a frequent al observed a significant lowering in 17-ketosteroids as
cause of death in their patients. Though renal involvement well as 17-hydroxycorticosteroids in LL patients during
occurs throughout the spectrum of leprosy, it is more often reactive phase and a subnormal response to ACTH
administration, suggestive of a certain degree of
seen in patients with lepromatous leprosy, especially those
adrenocortical insufficiency in leprosy reaction.97 Thus,
with history of frequent attacks of type 2 reactions, in which
most of the investigators who have studied hormone
deposition of immune complexes occurs in kidneys. In a
function in patients with gynecomastia, have got evidence
study of renal profile of leprosy patients, proteinuria was
for adrenocortical dysfunction. However, mention should
seen in 20% of patients while GFR was low in 27%
be made of a report by Dass et al who investigated the
patients.88 Renal biopsy specimens showed various types
androgenic status of leprosy patients with gynecomastia.
of nephritis—mesangioproliferative glomerulonephritis, They noticed that plasma testosterone levels were
membranoproliferative, and chronic interstitial nephritis. significantly diminished along with inflammatory
Mesangioproliferative glomerulonephritis was the degenerative fibrotic changes in testes.98
predominant lesion, no acid-fast bacilli, amyloid deposit, Structural abnormalities of the thyroid, amyloid
or granulomas were seen. deposits, have been reported in leprosy, but the data on
functional abnormalities of thyroid gland are controversial.
Connective Tissue Catabolism
Rolston et al99 and Yumnam et al100 reported normal serum
Estimation of hydroxyproline and hexosamine levels of levels of tri-iodothyronine (T3) and thyroxine (T4), and
skin tissue from patients with different types of leprosy thyroid-stimulating hormone (TSH) in leprosy, while Garg
and in different phases revealed a significant increase in et al101 and Kheir et al102 observed lower mean T3 and T4
the two constituents in LL during reactive phase.89 Urinary levels and higher mean TSH levels in leprosy patients
levels of hydroxyproline were also found to be significantly compared to the controls. Sehgal noticed a normal uptake
elevated. Cherian et al carried out longitudinal study of of radioactive iodine by thyroid tissues from leprosy
hydroxyproline excretion by leprosy patients and made patients.103
similar observations. These findings are suggestive of a A study on the functional status of pituitary-gonadal
possible breakdown of connective tissues during reactive hormones and their relationship to the pattern of
phases of LL.90 Naik et al have confirmed the increased inflammatory cytokines in the lepromatous (LL/BL) and
urinary excretion of hydroxyproline levels in leprosy tuberculoid (TT/BT) poles of leprosy reported significantly
reaction.91 higher levels of gonadotropins [luteinizing hormone (LH)
and follicle-stimulating hormone (FSH)], interleukin (IL)-
Endocrine Function 1β, IL-6, tumor necrosis factor (TNF)-α and C-reactive
The endocrine manifestations caused by leprosy have been protein (CRP) concentrations and erythrocyte
long recognized but underestimated, even by specialists. sedimentation rate (ESR) in LL/BL leprosy patients than
CHAPTER
8
in controls.104 LH and FSH were positively correlated with Glucose Tolerance
IL-1β, IL-6 and TNF-α, and CRP concentrations and ESR. Glucose tolerance test has been carried out in patients
Plasma testosterone levels were significantly decreased with tuberculoid, borderline, lepromatous leprosy and those
in LL/BL patients. The significant correlations between with leprosy reaction. A normal curve was common in
gonadotropins and testosterone and cytokines in leprosy tuberculoid leprosy while a flat glucose tolerance curve
patients suggest that cytokines may have a direct influence was observed in borderline and lepromatous leprosy.
at testicular level and may be of pathogenetic significance However, the diabetic curve was common in leprosy
in leprosy and in other inflammatory states involving reactions. Fasting blood sugar was low in lepromatous
reproductive dysfunction. Hypercalcemia and abnormal leprosy and it tended to be marginally high in leprosy
1,25(OH) dihydroxy vitamin D, parathyroid hormone (PTH), reaction. Also flat GTT curves are observed in those with
and parathyroid hormone-related protein (PTHrP) duration of disease between 7-12 months while diabetic
concentrations have been reported in only a few patients curve was more common in those with disease duration of
with borderline and lepromatous leprosy.105-107 more than 2 years.121,122
The most common metabolic bone disease,
Serum Enzymes
osteoporosis, is of special importance in leprosy because
of the risk of bone fracture in patients who already have Apart from transaminases, which have been referred to
neural lesions and both specific and nonspecific bone under liver function tests, a number of other enzymes in
changes that result in deformities and disabilities.108 serum have also been investigated in leprosy patients.
Radiological osteoporosis changes have been detected in Normal to decreased levels of serum alkaline phosphatase,
almost 40% of leprosy patients and with the measurement lipase and amylase have been reported in leprosy to be
of bone mineral density (BMD), the incidence of generally in the normal range.123 Saito noticed an elevation
osteoporosis might be higher.109 Bone mass loss has of LDH4-LDH5 isozyme fractions in serum in patients with
recently been reported to be an early event in leprosy progressive LL, probably as a result of injury to tissues
like liver, skeletal muscle and skin which are rich in these
patients.110
enzymes.124
Minerals and Trace Elements A significant lowering in serum cholinesterase activity
has also been noticed in leprosy patients.125 The mean
Apart from the study on functional aspects of the different
values of butyryl cholinesterase (BuChE) in sera. of all
organs, isolated observations on certain blood constituents
forms of leprosy are lower than in normal sera, when each
like minerals in leprosy patients have also been made.
group was compared with the normal mean, the value was
Some of them do have clinical implications.
not significantly different for any group except pure neuritic
Significant decrease of serum calcium in lepromatous leprosy, thus the specific relationship of BuChE to nerve
leprosy seems to be related with the extent of leprosy damage needs further investigation.126 Balakrishnan in a
lesions and duration. Serum calcium and magnesium were study of serum enzymes in the reactive phase of LL noticed
significantly decreased in all types of leprosy cases and a consistent increase in aldolase, creatine phosphokinase,
lepromatous leprosy patients showed highly significant LDH and GOT.127 All these observations are suggestive of
decrease in serum magnesium level.111-114 In chronic a generalised breakdown of tissue constituents in active
infections as well as conditions associated with an excess LL and in particular, the reactive phase of LL.
circulating estrogens, increase in serum copper and There are reports on the blood and tissue levels of
decrease in serum zinc are generally observed . Similar lysosomal enzymes, viz. lysozyme, beta-glucuronidase
observations on serum copper and zinc have been made and N-acetyl beta-glucosaminidase in adult and pediatric
by other investigators.115-118 Foster et al have reported leprosy correlating the levels with activity of the disease.
significantly higher serum levels of titanium, silicon, Increase in the level of circulatory hydrolytic enzymes could
potassium and platinum, lower levels of phosphorus in red be a tissue damaging factor and may be responsible for
blood cells and decreased whole blood levels of many of the lesions seen in leprosy.128-132
phosphorus, selenium, antimony and silver in leprosy
Oxidative Stress and Antioxidant Status
patients.114 Significantly low serum iron and total iron
binding capacity have been reported in lepromatous leprosy A constellation of reactive oxygen species (ROS) capable
patients.119,120 of damaging cellular constituents is generated in excess
CHAPTER
8
during the chronic, inflammatory, neurodegenerative 11. Shepard CC, Chang YT. Effect of several anti-leprosy drugs on
disease process of leprosy. The consequences of this lead multiplication of human leprosy bacilli in footpads of mice. Proc
Soc Exp Biol Med 1962; 109:636-38.
to enhanced oxidative stress and lower antioxidant status.
12. Brosch R, Gordon SV, Eiglmeier K et al. Comparative genomics
The serum lipid peroxidation products, serum LDH and of the leprosy and tubercle bacilli. Res Microbiol 2000; 151:135-
important free radical scavenging enzymes, i.e. superoxide 42.
dismutase (SOD), catalase and antioxidant glutathione 13. Eiglmeier K, Simon ST, Garnier T et al. The integrated genome
levels; and total antioxidant status have been studied in map of Mycobacterium leprae. Lepr Rev 2001; 72:462-69.
14. Wheeler PR. The microbial physiologist’s guide to the leprosy
different types of leprosy patients. The levels of lipid
genome. Lepr Rev 2001; 72: 399-407.
peroxidation product, malondialdehyde (MDA), and LDH 15. Cole ST, Eiglmeier K, Parkhill J et al. Massive gene decay in the
increased significantly in MB patients, and both gradually leprosy bacillus. Nature 2001; 409:1007-11.
decreased with clinical improvement following MDT. The 16. Scollard DM, Adfams LB, Gillis TP et al. The continuing challenges
serum levels of SOD, catalase and glutathione, and the of leprosy. Clin Microbiol Rev 2006; 19: 338-81.
17. Eiglmeier K, Parkhill J, Honore N et al.The decaying genome of
total antioxidant status decreased significantly in MB
Mycobacterium leprae. Lepr Rev 2001; 72 :387-98.
patients, in comparison with normal human volunteers 18. Cole ST. Comparative Mycobacterial genomics. Curr Opin
(NHVs). High free radical activity and low antioxidant levels Microbiol 1998; 1: 567-71.
observed in MB leprosy patients indicate that there is an 19. Gillis TP, Williams DL. Polymerase chain reaction and leprosy.
oxidative stress in MB cases, irrespective of the treatment Int J Lepr 1991; 59: 311-16.
20. Katoch VM. Molecular techniques for leprosy: Present
status and suggest a suitable antioxidant therapy to the
applications and future perspectives. Indian J Lepr 1999; 71:45-
MB leprosy patients to prevent possible tissue injury.133,134 59.
Coadministration of vitamin E along with MDT decreases 21. Scollard DM, Gillis TP, Williams DL. Polymerase chain reaction
oxidative stress and activate the antioxidant status in assay for the detection and identification of Mycobacterium
leprosy patients.135 leprae in patients in the United States. Am J Clin Pathol 1998;
109:642-46.
The changes in biochemical profile including
22. Haile Y, Ryon JJ. Colorimetric microtitre plate hybridization assay
hematological and serological alterations in leprosy for the detection of Mycobacterium leprae 16S rRNA in clinical
affected persons have been studied extensively during specimens. Lepr Rev 2004; 75:40-49.
the last seven decades and these have been presented 23. Kurabachew M, Wondimu A, Ryon JJ. Reverse transcription-
precisely in the chapter. PCR detection of Mycobacterium leprae in clinical specimens.
J Clin Microbiol 1998; 36:1352-56.
24. Clark-Curtiss JE, Walsh GP. Conservation of genomic
REFERENCES sequences among isolates of Mycobacterium leprae. J Bacteriol
1989; 171: 4844-51.
1. World Health Organization. Microbiology of M. leprae. 2009;
25. de Wit MY, Klatser PR. Mycobacterium leprae isolates from
www.who.int/lep/microbiology/en/index.html.
different sources have identical sequences of the spacer region
2. Draper P, Kandler O, Darbre A. Peptidoglycan and arabino-
between the 16S and 23S ribosomal RNA genes. Microbiol 1994;
galactan of Mycobacterium leprae. J Gen Microbiol 1987;
140:1983-87.
133:1187-94.
26. Williams DL, Gillis TP, Portaels F. Geographically distinct isolates
3. Vissa VD, Brennan PJ. The genome of Mycobacterium leprae: a
of Mycobacterium leprae exhibit no genotypic diversity by
minimal mycobacterial gene set.Genome Biol 2001; 2:1023-30.
restriction fragment-length polymorphism analysis. Mol Microbiol
4. Draper P. Cell walls of M. leprae. Int J Lepr 1976; 14:95-97.
5. Hunter SW, Brennan PJ. A novel phenolic glycolipid from M. 1990; 4:1653-59.
leprae possibly involved in immunogenicity and pathogenicity. J 27. Fishi H, Cole ST. The Mycobacterium leprae genome: Systematic
Bacteriol. 1981; 147:728-35. sequence analysis identifies key metabolic enzymes, ATP
6. Draper P, Payne SNL, Rees RJW. Isolation of a characteristic dependent transporter system and a novel pol(A) locus
phthioceroldimycocerosate from M. leprae. J Gen Microbiol 1983; associated with genomic variability. Mol Microbiol 1995; 16: 909-
129: 859-63. 19.
7. Brennan PJ. Mycobacterium leprae- The outer lipoidal surface. 28. Lavania M, Katoch VM, Singh HB, et al. Genetic polymorphism
J Biosci 1984; 6: 685-89. among Mycobacterium leprae strains from Northern India using
8. Truman RW, Krahenbuhl JL. Viable M. leprae as a research TTC repeats. Indian J Lepr 2005; 77: 60-65.
reagent. Int J Lepr 2001; 69: 1-12. 29. Lavania M, Katoch K, Singh HB et al. Predominance of three
9. Truman R. Leprosy in wild armadillos. Lepr Rev 2005; 76:198- copies of random repeats in rpoT gene of Mycobacterium leprae
208. from Northern India. Infect Genet Evol 2007; 7: 627-31
10. Krahenbuhl JL, Adams LB. Exploitation of gene knockout mice 30. Matsuoka M, Maeda S, Kai M et al. Mycobacterium leprae typing
models to study the pathogenesis of leprosy. Lepr Rev 2000; 71: by genomic diversity and global distribution of genotypes. Int J
S170-75. Lepr 2000; 68:121-28.
CHAPTER
8
31. Shin YC, Lee H, Walsh GP et al. Variable numbers of TTC 52. Charlab R, Sarno EN, Chatterjee D et al. Effect of unique
repeats in Mycobacterium leprae DNA from leprosy patients Mycobacterium leprae phenolic glycolipid (PGL-1) on tumor
and use in strain differentiation. J Clin Microbiol 2000; 38:4535- necrosis factor production by human mononuclear cells. Lepr
38. Rev 2001; 72:63-69.
32. Prabhakaran K. Metabolism of M. leprae separated from human 53. Mahadevan PR, Antia NH. Biochemical alteration in cells following
nodules. Int J Lepr 1967; 35: 34-41. phagocytosis of M. leprae—the consequence-a basic concept.
33. Prabhakaran K, Braganca MB. Glutamic acid decarboxylase Int J Lepr 1980; 48:167-71.
activity of M. leprae and occurrence of gamma-aminobutyric 54. Marolia J, Mahadevan PR. Superoxide production from
acid in skin lesions of leprosy. Nature 1962; 196: 589-90. macrophages of leprosy patients after stimulation with
34. Prabhakaran K. Specificity of O-Diphenol oxidase in M. leprae. Mycobacterium leprae. J Biosci 1987; 12:273-79.
An identification test. Lepr India 1976; 48:19-23. 55. Marolia J, Mahadevan PR. Mycobacterium leprae mediated
35. Shetty KT, Antia NH, Krishnaswamy PJR. Occurrence of stimulation of macrophages from leprosy patients and hydrogen
glutamyl transpeptidase activity in several mycobateria including peroxide production. J Biosci 1988; 13: 295-303.
Mycobacterium leprae. Int J Lep 1981; 49: 49-56. 56. Hasimoto K, Maeda Y, Kimura H et al. Mycobacterium leprae
36. Dhople AM. Taxonomic studies on M. leprae. Lepr India 1983; infection in monocyte-derived dendritic cells and its influence on
55:39-44. antigen-presenting function. Infect Immun 2002; 70: 5167-76.
37. Skinsnes OK. Mycobacterium leprae and its affinity for nerves. 57. Hunger RE, Sieling POA, Ocoa MT et al. Langerhans cells utilize
Int J Lepr 1971; 39:762-65. CD1a and langerin to efficiently present nonpeptide antigens to
38. Stoner GL. Importance of the neural predilection of T-cells. J Clin Invest 2004; 113:701-08.
Mycobacterium leprae in leprosy. Lancet 1979; 10: 994-96. 58. Makino M, Maeda Y, Ishii N. Immunostimulatory activity of major
39. Job CK. Nerve damage in leprosy. Int J Lepr 1989; 57: 532-39. membrane protein–II from Mycobacterium leprae. Cell Immunol
40. Scollard D. The biology of nerve injury in leprosy (Review). Lepr 2005; 233: 53-60.
Rev 2008; 79:242-53. 59. Maeda Y, Mukai T, Spencer J et al. Identification of
41. Rambukkana A, Salzer JL, Yurchenco PD et al. Neural targeting immunomodulating agent from Mycobacteium leprae. Infect
of Mycobacterium leprae mediated by the G domain of the laminin Immun 2005; 73:2744-50.
α2 chain. Cell 1977; 88: 811-21. 60. Mcdougall AC, Rees RJW, Weddell AG et al. The histopathology
42. Barker LP. Mycobacterium leprae interactions with the host cell: of lepromatous leprosy in the nose. J Pathol 1975; 115:215-26.
Recent advances (Review). Indian J Med Res 2006; 123: 748- 61. Coruh G, McDougall AC. Untreated lepromatous leprosy:
59. Histopathological findings in cutaneous blood vessels. Int J Lepr
43. Rambukkana A, Yamada H, Zanassi G et al. Role of α- 1979; 47: 500-11.
dystroglycan as a Schwann cells receptor for Mycobacterium 62. Scollard DM, McCormick G, Allen JL. Localization of
leprae. Science 1998; 282: 2076-79. Mycobacterium leprae to endothelial cells of epineurial and
44. Ng V, Zanazzi G, Timpl R et al. Role of the cell wall phenolic perineurial blood vessels and lymphatics. Am J Pathol 1999;
glycolipid-1 in the peripheral nerve predilection of Mycobacterium 154:1611-20.
leprae. Cell 2000; 103:511-29. 63. Karat AB, Rao PS. Haematological profile in leprosy. Part I-
45. Hagge D, Robinson SO, Scollard D et al. A new model for studying General findings. Lepr India 1977; 49:187-96.
the effects of Mycobacterium leprae on Schwann cells and 64. Karat AB, Rao PS. Haematological profile in leprosy. Part II-
Relationship to severity of disease and treatment status. Lepr
neuron interactions. J Infect Dis 2002; 186: 1283-96.
India 1978; 50:18-25.
46. Alves L, de Mendonca Lima L, da Silva Maeda E et al.
65. Queiroz RHC, Melchior Jr E, De Souza AM et al. Haematological
Mycobacterium leprae infection of human Schwann cells
and biochemical alterations in leprosy patients already treated
depends on selective host kinases and pathogen-modulated
with dapsone and MDT. Pharmaceutica Acta Helvetiae 1997;
endocytic pathways. FEMS Microbiol Lett 2004; 238: 429-37.
72:209-13.
47. Rambukkana A, Zanassi G, Tapinos M et al. Contact-dependent
66. Kano K, Aranzazu A, Nishimaki T et al. Serological and
demyelination by Mycobacterium leprae in the absence of
immunohistological studies on lepromatous leprosy. Int Archs
immune cells. Science 2002; 296: 927-31.
Allergy Appl Immun 1981; 64:19-24.
48. Oliviera RB, Ochoa MT, Sieling PA et al. Expression of Toll-like
67. McAdam KPWJ, Fudenberg HH, Michaeli D. Antibodies to
receptor 2 on human Schwann cells: A mechanism of nerve
collagen in patients with leprosy. Clin Immunol Immunopathol
damage in leprosy. Infect Immun 2003; 71: 1427-33
1978; 9:16-21.
49. Rambukkana A. Mycobacterium leprae induced demyelination:
68. Guedes-Barbosa LS, Gilbrut B, Shoenfeld Y et al. Autoantibodies
A model for early nerve degeneration. Curr Opin Immunol 2004;
in leprosy sera. Clin Rheumatol 1996; 15:26-28.
16: 511-18. 69. Kaur S, Chakravarti RN, Wahi PL. Liver pathology in leprosy.
50. Krahenbuhl JL, Adfams LB. The role of the macrophage in Lepr India 1974; 46:222-25.
rsistance to the leprosy bacillus. Immunol Ser 1994; 60: 70. Verghese A, Job CK. Correlation of liver function with pathology
281-302. of liver in leprosy. Int J Lep 1965; 33:342-48.
51. Susuki K, Fukutomi Y, Matsuoka M et al. Differential production 71. Dhople AM, Balakrishnan S. Liver function tests in leprosy. Indian
of interleukin 1 (IL-1), IL-6, tumor necrosis factor, and IL-1 J Med Res 1968; 36: 1552-58.
receptor antagonist by human monocytes stimulated with 72. Nigam PK, Gupta GB, Khare A. Hepatic involvement and hepatitis
Mycobacterium leprae and M. bovis BCG. Int J Lepr 1993; 61: B surface antigen (HbsAg) in leprosy. Indian J Dermatol Venereol
609-18. Leprol 2003; 69:32-34.
CHAPTER
8
73. Parvez M, Sharda DP, Jain AK et al. A study of serum proteins in 96. Koshy TS, Karat ABA. Assessment of pituitary- -adrenal functions
leprosy. Lepr India 1980; 52:374-82. in lepromatous leprosy. Lepr India 1973; 45:12-17.
74. Kurade N, Dhamanaskar PK, Jadhav VH et al. Protein profile in 97. Balakrishnan S, Ramanujam K, Ramu G. Adrenocortical function
leprosy. Indian J Med Sci 2001; 55:319-25. tests in lepra reaction. Indian J Med Res 1974; 62: 1166-70.
75. Baji PS, Kher JR, Ganeriwal SK et al. Electrophoretic patterns of 98. Dass J, Murugesan K, Laumas KR et al. Androgenic status of
proteins in lepromatous leprosy. Lepr India 1982; 54:82-94. lepromatous patients with gynaecomastia. Int J Lepr 1976; 44:
76. Ramu G, Balakrishnan S. Plasma fibrinogen and fibrinolytic 469-74.
activity in lepromatous leprosy. J Assn Physcn India 1977; 99. Rolston R, Mathews M, Taylor PM et al. Hormone profile in
25:133-38. lepromatous leprosy. A preliminary study. Int J Lepr 1981; 49:31-
77. Gupta N, Shankernarayan NP, Dharmalingam K. Serum 36.
proteome of leprosy patients undergoing erythema nodosum 100. Yumnam IS, Kaur S, Kumar B. Evaluation of thyroid functions in
leprosum reaction: Regulation of expression of the isoforms of leprosy. I. Thyroid function tests. Lepr India 1977; 49:485-91.
haptoglobin. J Proteome Res 2007; 6:3669-79. 101. Garg R, Agarwal JK, Singh G et al. Thyroid function in leprosy.
78. Ahaley SK, Sardeshmukh AS, Suryakar AN et al. Correlation of Indian J Lepr 1990; 62: 215-18.
serum lipids and lipoproteins in leprosy. Int J Lepr 1992; 64:91- 102. Kheir MM, Ahmed AM, Elsarrag AA. Thyroid fiunctional status in
97. leprosy patients in Sudan. East Mediterr Health J 2001; 7:79-83.
79. Misra UK, Venkitsubramanian TA. Serum lipids in leprosy by 103. Sehgal VN, Basu AK. Thyroid function in leprosy as determined
silicic acid column choromatography. Int. J Lepr 1964; 32:248- by uptake of radioactive iodine. Int J Lepr 1967; 35: 58-64.
59. 104. Leal AMO, Magalhães PKR, Souza CS et al. Pituitary-gonadal
80. Bansal SN, Jain VK, Dayal S et al. Serum lipid profile in leprosy.
hormones and interleukin patterns in leprosy. Trop Med Int Health.
Indian J Dermatol Venereol Leprol 1997; 63:78-81.
2006; 11: 1416-21.
81. Sritharan V, Venkatesan K, Bharadwaj VP et al. Serum lipid
105. Couri CEB, Foss NT, Dos Santos CS et al. Hypercalcemia
profile in leprosy. Lepr India 1979; 51:515-20
secondary to leprosy. Am J Med Sci 2004; 328:357-59.
82. Gokhale SK, Godbole SH. Serum lipolytic enzyme activity and
106. Hoffman VN, Korzeniowski OM. Leprosy, hypercalcemia, and
serum lipid partition in leprosy and tuberculosis. Indian J Med
elevated serum calcitriol levels. Ann Intern Med 1986; 105: 890-
Res 1975; 45:327-36.
91.
83. Sritharan V, BharadwajVP, Venkatesan K et al. High density
107. Vidal MC, Botasso OA, Lehrer A et al. Altered calcium-binding
lipoprotein cholesterol (HDL-C) analysis in leprosy patients. Lepr
ability of plasma proteins as the cause of hypocalcemia in
Rev 1984; 55:167-71.
lepromatous leprosy. Int J lepr 1993; 61: 586-89.
84. Gupta A, Koranne RV, Kaul N. Study of serum lipids in leprosy.
108. Thappa DM, Sharma VK, Kaur S et al. Radiological changes in
Indian J Dermatol Venereol Leprol 2002; 68: 262-66.
hands and feet in disabled leprosy patients: A clinico-radiological
85. Cruz D, Watson AD, Christopher S et al. Host-derived oxidized
correlation. Indian J Lepr 1992; 62:58-66.
phospholipids and HDL regulate innate immunity in human leprosy.
109. Chouduri H, Thappa DM, Kumar RH et al. Bone changes in
J Clin Invest 2008; 118: 2917-28.
86. Thomas G, Karat ABA, Rao PSS et al .Changes in renal functions leprosy patients with disabilities/deformities (a clinico-radiological
during reactive phase of lepromatous leprosy. Int J lepr 1970; correlation). Indian J Lepr 1999; 71: 203-15.
38: 45-46. 110. Ribiero FB, Pereira F de A, Muller E et al. Evaluation of bone and
87. Mitsuda K, Ogawa M. A study of one hundred and fifty autopsies mineral metabolism in patients recently diagnosed with leprosy.
on cases of leprosy. Int J Lepr 1937; 5: 53-60. Am J Med Sci 2007; 334:322-26.
88. Aggarwal HK, Sharma P, Jaswal TS et al. Evaluation of renal 111. Nigam P , Mukhija R D , Agrawal AK et al. Serum cations (calcium
profile in patients of leprosy. J Indian Acad Clin Med 2004; 5: 316- and magnesium) in leprosy. Indian J Lepr 1985; 57:529-33.
21. 112. Rao KN, Gupta JD, Sehgal VN et al. Trace elements in the sera
89. Balakrishnan S. Some aspects of collagen metabolism in leprosy. of leprosy patients. Indian J Lepr 1985; 57: 556-61.
Indian J Med Res 1970; 58:1044-49. 113. Saxena N, Sharma RP, Singh VP. Study of serum calcium and
90. Cherian MG, Karat ABA, Radhakrishnan AN. Urinary excretion magnesium in leprosy. Indian J Dermatol 1989; 34: 48-51.
of hydroxyproline in leprosy. Clin Chem Acta 1969; 25:395-401. 114. Foster R, Sanchez A, Foulkes J et al. Profile of blood elements
91. Naik SS, Tanksiile KG, Ganapati R. Study of urinary nitrogenous in leprosy patients. Indian J Lepr 1991; 63:12-33.
constituents in reactions in leprosy. Indian J Med Res 1971; 115. Venkatesan K, Kannan KB, Bharadwaj VP et al. Serum copper
65:193-200. and zinc in leprosy and effect of oral zinc therapy. Indian J Med
92. Leal AMO, Foss NT. Endocrine dysfunction in leprosy (Review). Res 1983; 78:37-41.
Eur J Clin Microbiol Infect Dis 2009; 28:1-7. 116. Mathur NK, Sharma M, Mangal HN et al. Serum zinc levels in
93. Kannan V, Vijaya G. Endocrine testicular functions in leprosy. subtypes of leprosy. Int J Lepr 1984; 52: 327-30.
Horm Metab Res 1984; 16: 146-50. 117. George J, Bhatia VN, Balakrishnan S et al. Serum zinc/copper
94. Rea TH. A comparative study of testicular involvememnt in ratio in subtypes of leprosy and effect of oral zinc therapy on
lepromatous and borderline lepromatous leprosy. Int J Lepr 1988; reactional states. Int J Lepr 1991; 59:20-24.
56:383-88. 118. Mennen U, Howells C, Wiese AJ. Serum zinc, sodium, calcium,
95. Khanna N, Ammini AC, Singh M et al. Ovarian Function in Female magnesium and potassium levels and standard diet in leprosy
Patients with Multibacillary Leprosy. Int J Lepr 2003; 71:101-05. poatients. Indian J Lepr 1993; 65: 415-21.
CHAPTER
8
119. Bharadwaj VP, Venkatesan K, Ramu G et al. Serum iron and total 127. Balakrishnan S. Biochemical aspects of reactional states in
iron binding capacity in leprosy patients. Lepr India 1978; 50:11- leprosy. Lepr India 1976; 48: 406-12.
17. 128. Venkatesan K, Bharadwaj VP, Ramu G et al. Serum beta-
120. Saxena N, Sharma RP, Singh VS. Serum iron and total iron glucuronidase in leprosy—a preliminary report. Indian J Med
Res 1979; 69: 553–56.
binding capacity in leprosy patients. Indian J Lepr 1990; 62:
129. Naik SS, Gurnani S. Serum lysozyme in leprosy. Indian J Lepr
219-22.
1980; 52: 501-07.
121. Garg R, Agrawal JK, Bajpai HS et al. Glucose tolerance test in
130. George J, Rajendran M, Bhatia VN. Serum beta-glucuronidase
leprosy. Indian J Lepr 1990; 62: 50-54. in subtypes of leprosy. Indian J Med Res 1990;91:106-10.
122. Bharadwaj VP, Venkatesan K, Ramu G et al. Glucose tolerance 131. Vaishnavi C, Dhawan V, Ganguly NK et al. Hydrolytic enzymes
and serum free fatty acid levels in leprosy. Indian J Med Res in leprosy sera. J Hyg Epidemiol Microbiol Immunol 1992; 36:
1979; 69: 567-70. 401-04.
123. Balakrishnan S. Biochemical aspects of leprosy. Erwin Stindl 132. Nandan D, Venkatesan K, Katoch K et al. Serum beta-
Memorial Oration-organised by Greater Calcutta Leprosy glucuronidase levels in children with leprosy. Lepr Rev 2007; 78:
Treatment and Health Educaion Scheme (GRECALTES) in 243-47.
collaboration with OXFAM (India) Trust. Printed and Published: 133. Reddy YN, Murthy SV, Krishna DR et al. Oxidative stress and
GRECALTES: Kolkata 1986; 6-40. antioxidant status in leprosy patients. Indian J Lepr 2003; 75:
307-16.
124. Saito N. Lactic dehydrogenase isozymes in leprosy patients.
134. Jyothi P, Riyaz N, Nandakumar G et al. A study of oxidative
(1) Serum lactic dehydrogenase. Lepr India 1972; 44: 82-89.
stress in paucibacillary and multibacillary leposy. Indian J
125. Gokhale BB, Desai BL. Cholinesterase activity in leprosy. Lepr
Dermatol Venereol Leprol 2008; 74:80 (E-IJDVL).
India 1960; 32:22-24. 135. Vijayaraghavan R, Suribabu CS, Sekar B et al. Protective role of
126. Suneetha LM, Karunakar V, Karuna M et al. Serum butyrylcholine vitamin E on the oxidative stress in Hansen’s disease (Leprosy)
esterase activity in leprosy. Int J Lepr 2004: 72: 324-26. patients. Eur J Clin Nutr 2005; 59:1121-28.
CHAPTER
9
9
Pathological Aspects
Dullobho Porichha, Mohan Natrajan
INTRODUCTION patients. These are subsequently stained with simple dyes

such as hematoxylin and eosin. Additional special stains,
immunohistochemistry and immune electron microscopy
Mycobacterium leprae, an acid-fast bacillus (AFB). The
techniques are now available making the histological
organism is not known to possess any toxin and the
evaluation more informative.
histopathological changes are mostly due to the host tissue
response to the bacillus or its antigens. In the fully evolved
Need for Biopsy/Histopathology
stage, the main manifestation of the disease is formation
of distinct granulomas, which lead to host tissue damage The applications of histopathology are manifold. It provides
resulting in the clinical features of skin and nerve lesions. diagnosis in a clinically difficult situation; it also provides
Hence, it is also known as a granulomatous disease. information on the nature of the host response by which
M.leprae is minimally infectious and less pathogenic. It one can predict the likely course of the disease and the
has a unique affinity for the peripheral nerves, in which it likely response to therapy. An exaggerated/atypical
initially colonizes.1,2,3 The pathogenic process mostly starts histological response would also indicate the need for
in the peripheral nerves and many workers view leprosy, additional therapy or modification of standard therapy. The
primarily as a neural disease, with Schwann cells as the contribution of histopathology towards the understanding
main target.4,5 In the words of Fite; there is no non-neural of the disease has been immense. Histopathology
leprosy.6 Though this chapter primarily deals with continues to be regarded as the ‘gold standard’ for the
histopathology, for better understanding, it is felt diagnosis, particularly in the early stages. Histopathology
appropriate to describe in brief the immunopathogenesis is also thought central to the understanding of the spectral
along with a brief note on the participating cells which concept of leprosy.
form the granulomas. Though leprosy is a chronic disease, The present day applications of histopathology are
it is unique to have periodic acute episodes known as several and include:
reactions, resulting in rapid tissue damage. During these 1. Confirmation of diagnosis in a clinically ambiguous
episodes, the granulomas are acutely inflamed and produce situation as ‘suspect leprosy,’ this aspect is elaborated
enhanced tissue damage. later.
2. Diagnosis of reaction states and differentiation of
HISTOPATHOLOGY type 1 from type 2 reaction as well as from relapse.
3. Identification of relapse.
Histopathology essentially captures the disease in question 4. Accurate classification by defining the spectral position
at the time of biopsy and provides insights into the disease of a given case in research-based studies as well as
process within. Conventional histopathology usually therapy.
involves the examination of formalin fixed paraffin 5. Assessment of response to chemotherapy and/or
embedded sections obtained from biopsy tissue of the immunotherapy.
CHAPTER
9
Pathological Aspects 101
Role of Immunohistochemistry
In most of its applications conventional histopathology
fulfils its role adequately. However, there are limitations in
the early stages of the disease where confirmation of the
diagnosis is required. It may be recalled that there are two
distinct aspects of the histological diagnosis of leprosy-
one, morphological and the other - detection of pathogen.
When the disease has evolved histologically into a
granuloma, confirmation of diagnosis is seldom difficult.
In the pre and post-granulomatous stages cardinal signs
are ambiguous and negative for AFB; in such a scenario
diagnosis becomes difficult. Literature reveals the
histopathological confirmation rates in several studies to
be 29-58% in early leprosy and clinically suspect leprosy7;
while if the sections are of good size and cover adequate Fig. 9.1: Mycobacterial antigens in dermal nerves-histochemical
depth, the ambiguity of diagnosis could be narrowed down stain -1 × 1000
to around 15%.8 A note of caution is that ‘histopathological’
diagnosis should not be offered if the skin sections are
not good and the facility for good Fite-Faraco stain is not
available.
Methods enhancing sensitivity for both the morphology
and pathogen detection through histopathology are now
available. Techniques targeting the morphological aspects
include the usage of additional stains (e.g. nerve stains),
quantitative morphometric methods and the use of semi-
thin sections. Also available now are more sensitive and
specific methods of detecting pathogens or their
components on routinely processed tissue specimens. The
technique of immunohistochemistry can be applied to
detect different antigens, applying either monoclonal or
polyclonal antibodies (Fig. 9.1). For these studies multiple-
step procedures are available, which make them highly
sensitive. Several studies using immunohistochemical Fig. 9.2: Positive signals indicating M. leprae specific antigens
(hybridization)-1 × 1000
methods have demonstrated mycobacterial antigens in
AFB negative tissue sections from leprosy lesions.9-12
Technological advances have made it possible to use The polymerase chain reaction (PCR) has been used
the techniques of molecular biology on routinely processed in conjunction with hybridization, to detect M.leprae specific
tissue specimens.13 The in situ hybridization procedure nucleic acid sequences with good results.13,15,16 This also
can be used to detect pathogen specific nucleic acid achieves amplification within tissue specimens and is even
sequences within tissue sections. Several studies have more sensitive than the in situ hybridization procedure.17
employed the procedure to detect the presence of viral as However, technical constraints need to be overcome to
well as bacterial pathogens and many have used non- enable its wider use.
radioactive systems on paraffin sections. Some of these
procedures have been employed in the diagnosis of early
ATTRIBUTES INFLUENCING THE
and clinically suspected leprosy (Fig. 9.2) with satisfactory
PATHOGENESIS
results.14 The procedures of immunohistochemistry and
in situ hybridization can be performed in any histopathology M. leprae is an obligatory intracellular parasite. Entry into
set up, if the reagent costs are taken care of. Schwann cells favors its long generation time (11-13 days),
CHAPTER
9
a state of dormancy and enhances protection.18 This also add uncharacteristic/ indeterminate in between;28 if five,
defies elimination from the body by humoral antibody and keep indeterminate out of the spectrum and slice BT and
as with M. tuberculosis, it requires adequate CMI for their BL from either side of borderline24 and so on. Spectral
containment and clearance. To this may be added two more concept is also sometimes referred to in diseases like
attributes: tropism of M. leprae for Schwann cells and tuberculosis (TB), dermal leishmaniasis and in some
macrophages around which the entire pathogenic events systemic mycosis such as South American blastomycosis
revolve; and the tendency of lepra bacilli to multiply in the and rarely in onchocerciasis,29 though there is no evidence
tissues with a lower temperature. of their wider use as compared to that in leprosy.
The tropism for Schwann cells is probably determined
by the mycobacteria binding to the G domain of the α2 THE NATURE OF GRANULOMA
chain of laminin-2,19 a component of the basal lamina of
Schwann cells. This type of laminin is confined to only A granuloma is a tumor like compact collection of
peripheral nerves. These cells can express HLA class II macrophages or any other cells derived from them.3 Other
molecules and play an important role in immune reaction blood cells, particularly lymphocytes, always accompany
by presenting mycobacterial peptide to HLA class II them in varying number. Macrophages belong to an
restricted CD4+ Th1 cells.20 The subsequent uptake of extensive system of cells and tissues called the reticulo-
M.leprae depends on alpha dystroglycan which in turn is endothelial system, presently renamed as mononuclear
the receptor for laminin, within the cell membrane and other phagocytic system.30 Depending on the predominance of
intracellular components. macrophages or epithelioid cells (to be described latter)
the granuloma is called macrophage or epithelioid cell type.
THE CONCEPT OF SPECTRUM Though some authors restrict the word granuloma to an
aggregation of only epithelioid cells, in leprosy the word
The cellular differentiation as reflected in the histopathology, encompasses both macrophages and epithelioid cells3,
is due to the influence of host immune response to M.leprae the former being a feature of lepromatous and the latter
and its antigens, since the organism is not known to indicating tuberculoid leprosy. There are also stages of
possess any toxin to directly damage the host tissue.21 leprosy devoid of any classical granuloma but only
The disease exhibits a spectrum with largely varied clinical, aggregation of inflammatory cells.
histological and immunological features at extreme poles.
Cochrane as early as 1961, correlated the histological and
AGRANULOMATOUS STAGE
clinical features at arbitrary points on the spectrum.22 Later
the features were further standardized through Ridley On the basis of histology, leprosy lesions can be captured
Jopling classification (1962), for research purposes23 and in one of the two evolutionary states and one of them is
the same was finally upgraded in 1966 by addition of pregranulomatous.31 This is an early lesion not in term of
immunologic correlates (lepromin response) as a reflection the disease duration but in term of the disease evolution.
of cell mediated immune reaction.24 The low mortality and From this stage the disease completely disappears or
longer span of the disease make leprosy a suitable model slides into the granulomatous stage, depending on the
for studying a chronic infectious disease. Its manifestations immunity status of the infected person. Such early stage
including the often debated classification25 depend more clinically presents as indeterminate leprosy.
on the host resistance rather than the virulence or species
specificity of the organism. Indeterminate Leprosy
In indeterminate leprosy the granuloma has not yet fully
Classification or Splitting of the Spectrum developed. From the days of Havana Congress (1947) this
The spectrum of leprosy has been metaphorically type of leprosy remained a much discussed subject so far
compared to salami26 (salami: a spicy meat dish served as the nomenclature, evolution and clinicopathological
as slices). It can be sliced into any numbers. If two thick disparity were concerned and these aspects were referred
slices, the result is tubercular (nodular) and maculo- in an elaborate review.32 Histological examination is of
anesthetic leprosy27 which in course of time came to be considerable help in ascertaining the diagnosis. Ridley
known as lepromatous and tuberculoid respectively; if three, suggested early and late stages of indeterminate leprosy.33
CHAPTER
9
The former shows occasional acid-fast bacillus either in nerves these cells show baton shaped nuclei oriented
non-inflamed nerve, erector pylorum muscle or the sub- longitudinally. Once there is presence of bacilli or
epidermal zone. lymphocyte infiltration, the nuclear orientation is
The features of second stage indeterminate leprosy disorganized and the nerve looses the wavy pattern.
are neural inflammation evidenced by lymphocyte infiltration Occasionally, a few epithelioid cells, too less to be
(Fig. 9.3) or Schwann cell proliferation. In the former stage, called a granuloma, may also be seen within the nerve
varying numbers of lymphocytes are seen in the perineural parenchyma along with the lymphocytes. Examination of
sheath but the nerve parenchyma is well appreciated in some more sections may reveal a definite granuloma.
the longitudinal section. Sometimes the nerve fiber in a Since, M.leprae is the only bacterium to parasitize a
neurovascular bundle is hardly detectable as it is almost peripheral nerve, the above neural changes are diagnostic
replaced by the lymphocytes (Fig. 9.4). The entire nerve of indeterminate leprosy.18 Lymphocyte infiltration of other
may at times appear as a band of lymphocytes. appendages such as hair follicles, sweat and sebaceous
Schwann cells have the tendency to proliferate if they glands and erector pylorum muscles are features for
react to any injury or to the presence of bacilli. In normal suspicion. These are not diagnostic and warrant
examination of more sections.
Histological change is known to precede the clinical
manifestations by 3-6 months.34 There can be as high as
30% damage in nerve fibers without any clinical
manifestations35 and this can be viewed as an advantage
of histology over clinical sign. Sometimes the nerve
element in a neurovascular bundle may be completely
replaced by a very small granuloma with reaction (micro-
reaction) in the presence of an effective CMI; and by a
clump of macrophages if the CMI is weak. There can also
be clinicopathological disparity with histology indicating
an early BT.
Being outside the spectrum, status of indeterminate
leprosy was questioned from time to time. Skinsnes36
Fig. 9.3: Indeterminate leprosy. Perineural infiltration of lymphocytes,
believed that leprosy also presents as ‘first infection’ and
around a dermal nerve (the area encircled by arrows). (H & E × 400)
‘second infection’ like tuberculosis. According to this
analogy first type of responses are expected prior to
development of cellular immunity or hypersensitivity or in
a pre-sensitized state. In tuberculosis, the primary lesion,
the Ghon’s focus shows an epithelioid cell granuloma and
hence sensitized state. If at all there is an equivalent to
primary TB in leprosy, the self-healing TT seems to be
nearest one.
Though about 70% of the cases are known to heal
spontaneously,37 it is not known which indeterminate cases
evolve into a granulomatous state and hence all cases if
unequivocally diagnosed need to be treated.
Healed Lesions
Non-granulomatous stages are also seen in post-
Fig. 9.4: Indeterminate leprosy. Neurovascular bundle where nerve is granulomatous healed macular skin lesions. This will be
replaced by lymphocytes. (H & E × 400) dealt with later.
CHAPTER
9
GRANULOMATOUS STAGE are round cells appearing non-aggressive, as if peace time

travelers in the blood. When they migrate to the tissue to
Granuloma is Often Nonspecific
deal with organisms or any unwanted element, they are
Granuloma formation is mostly non-specific and its exact like fighters on the front. They increase in size, develop
pathogenesis is not understood. In conditions such as pseudopodia and start phagocytosing anything that comes
sarcoidosis and Crohn’s disease of the ileum, the etiology in the way. M.leprae after reaching the tissues also fall
is unknown. In infectious diseases as leprosy and TB, the victim to these cells. The subsequent fate of the bacilli
granuloma formation is in response to specific pathogens, depends on the immune status of the infected person. If
but the role those bacilli play, is not adequately known. the CMI is ineffective, macrophages phagocytose the bacilli
Foreign body as a cause of such response is a frequent but can not destroy them. Being protected and nurtured
observation. Of relevance to leprosy is the experimental by these cells, the bacilli multiply unchecked. With increase
evidence of producing epithelioid cell granuloma by in the number of organisms the macrophages ultimately
inoculating antigens from sensory nerve fibers. This die, releasing hundreds of M.leprae to be phagocytosed
indicates an autoimmune response.38 The granuloma of by fresh macrophages. So long there is multiplication of
late lepromin reaction is also a response indicative of the organisms, the influx of the cells continues. In an
sensitized state, manifesting as delayed type advanced case the entire dermis may contain a layer of
hypersensitivity (DTH).29,39 macrophages loaded with bacilli. The piling of macrophages
and other inflammatory cells even lifts up the overlying
Fully Developed Granulomas in Leprosy skin producing plaques and nodules. Such accumulation
Fully evolved leprosy is manifested by epithelioid cell of macrophages; is a granuloma by definition.3 The
granuloma, macrophage granuloma or one with varying organisms also multiply in phagocytes, such as Kupffer
proportions of both the cell types. The manifestation is not cells, obligatory phagocytes, as the endothelial cells and
an all-or-none phenomenon and a large number of Schwann cells.
borderline cases in between the two, show varying Granuloma in LL is always large and expansile. Due to
proportions of both the cell types. Though the disease is the pressure from within, the epidermis often becomes
caused by a single organism, the differences in the flattened in the entire stretch of the granuloma (Figs 9.5
manifestations are varied. Hence, the classification and 9.6). A compressed strip of clear subepidermal zone
remained a subject of discussion almost in all fora. Silence (SEZ) also known as Grenz zone, always demarcates the
could prevail only with the introduction of MDT40 and MB, granuloma from the epidermis. Lymphocytes are very few
PB grouping proposed for field operations. This is a and are seen scattered in the sea of macrophages. Nerves
rediscovery of the simplicity of the grouping that prevailed are not infiltrated by either lymphocytes or macrophages
at the time of Hansen.27 The other classification in leprosy, up to a late stage and the constituent Schwann cells are
discussed mostly in the institutional level is Ridley-Jopling fairly intact. Bacilli are innumerable with considerable
classification which includes 5 types- TT, BT, BB, BL and number of globi with logarithm index of the granuloma (LIG)
LL whose clinical, histological, immunological and bacterial of 5+ to 6+ (Figs 9.7A and B). Macrophage granuloma is
features are well described.24 Though subsequently easy to diagnose if a good AFB stain is available.
spectrum has another split, with subpolar forms of TT and
LL,41 the seven group system is not widely used and hence, Histoid Leprosy
discussion in this chapter will be confined to only five types Histoid leprosy is considered as a variant of lepromatous
of lesions. leprosy. Described in 1963 by Wade,43 it presents as
localized crops of shiny nodules of different sizes. The
Lepromatous Leprosy nodules are sometime large and pedunculated. In sections
Macrophage granuloma is the hallmark of lepromatous they show hypercellular granuloma, composed
leprosy (LL). Macrophages are derived from monocytes of predominantly of spindle shaped cells. These cells give
the blood and are vividly phagocytic. Macrophage (literally an impression of expanding centrifugal growth compressing
meaning a ‘big eater’) contributes to both the natural and the fibrous tissue into a clear ‘pseudocapsule’. The young
adaptive immunity.42 So long in the bloodstream, monocytes cells are so uniform in appearance that they give the
CHAPTER
9
impression of a tumor. The cells are arranged in compact
bundles and whorls mimicking the morphology of a
histiocytoma (Fig. 9.8), from which the name histoid is
derived.43 The cells are highly bacillated with predominantly
solid organisms, arranged in parallel stacks- familiarly
known as ‘histoid habitus’.
Fig. 9.5: LL leprosy. Lepromatous granuloma with bacilli (pink color)

laden macrophages (MF), flattened epidermis (Epi.) and clear sub-
epidermal zone (SEZ). (Fite-Faraco Stain × 400)
Fig. 9.8: Histoid leprosy. Spindle shaped cells arranged in bundles

and whorls. (H & E × 400)
Some of the cases show areas with predominately

polygonal cells which resemble conventional macrophages.
Surprisingly some lesions show nests of epithelioid cells
with almost no organism in them.43,44 Some call such island
A B of cells as ‘epithelioid contaminants’ or “tuberculoid
Figs 9.6A and B: LL leprosy. (A) shows the typical LL granuloma contaminants”. These features initially described by Wade
composed of foamy macrophages (H & E × 40). (B) in higher were described later by other workers.44-47 There are
magnification (× 100), showing the foamy histiocytes. The subepidermal speculations about the presence of epithelioid cells. The
zone remains intact (arrow marked)
histoid lesions might have evolved in the course of
downgrading, from a tuberculoid stage or due to the
influence of immunity, operating locally. The spindle shaped
cells also lack convincing explanation. Though origin of
these cells from fibroblasts and perithelial cells is
suggested,48 the electron microscopic studies have
confirmed their origin from macrophages.49 During the days
of dapsone monotherapy with emerging resistance, many
cases presented nodular type of lepromatous leprosy with
cellular features, suggestive of histoid lesions.50
Tuberculoid Leprosy
A B Histology of tuberculoid leprosy (TT) is characterized by
Figs 9.7A and B: LL leprosy. (A) low power (Fite Faraco Staining × epithelioid cell granuloma. The events after entry of
1000) and (B) high power showing numerous M.leprae, some of them
solid staining, lying scattered or in clumps, few globi are also visible.
M. leprae in the macrophages are likely to be different in
(Fite Faraco Staining × 1000) face of a strong immunity in the affected person.
CHAPTER
9
Macrophages kill the bacilli, process the antigens and

present with a molecule of MHC II complex to a T-helper
lymphocyte.42 The latter can amplify their number through
interleukins. A set of lymphocytes can produce different
lymphokines which in turn recruit new macrophages and
activate them. These activated macrophages can easily
kill the bacilli and the disease process gets arrested.
Their job completed and nothing left to phagocytose,
the victorious macrophages convert into cells, modified in
their morphology and function. These cells are elongated
like epithelial cells, have bean shaped pale staining nucleus
and marginalization of chromatin. Their borders inter-digitate
with neighboring cells and hence, they are ill-defined. These
cells are less phagocytic but are rich in hydrolytic enzymes Fig. 9.9: TT leprosy. Typical epithelioid cell granuloma-1 × 100. GC
leading to autolysis.51 The epithelioid cells have great (Giant cells, in yellow arrows), Lym. (Lymphocytic infiltrate, in red
tendency to fuse to produce giant cells. A nest of epithelioid arrows), Epi. (obliteration of SEZ and epidermis by the granuloma, in
black arrows). (H & E × 400)
cells is often surrounded by a dense mantle of lymphocytes.
It is rare to find M.leprae in such a granuloma, presumably
due to their efficient killing and subsequent elimination. In
an elaborate article Wiersema and Binford have delineated
various points which identify leprosy amongst epithelioid
cell granulomas.52
Jadassohn seems to be the first to have described
the tissue changes with tubercle formation and used the
term ‘tuberculoid’ for such lesions.53 Wade later delineated
the tubercular pole in the spectrum on the basis of
histopathology.54 Epithelioid cell granuloma of TT always
erodes a chunk of epidermis by obliterating the sub-
epidermal clear zone. Lymphocyte density is high and often
these cells make a dense collar around a nest of epithelioid
cells resulting in a compact, focalized granuloma. Giant
cells are scanty and predominantly of Langhan’s type
(Fig. 9.9). Granuloma is often extensive occupying the
Fig. 9.10: TT leprosy. A dermal nerve completely replaced by epithelioid
entire width of the dermis with more or less round margin cell granuloma and showing central caseation (arrow marked zone)-
indicating arrest of the spread. (H & E × 100)
Conspicuous absence of the nerve in the granuloma
due to its complete effacement is the usual finding; though two cell types are cuffed by a dense mantle of lymphocytes.
occasionally remnants of neural elements may be seen. If The central ones are identified as the CD4+ cells secreting
a nerve is clearly identifiable, it is generally a large one gamma interferon (IFN-α), while the outer ones are CD8+
situated in the deeper dermis. Its parenchyma is completely cells. Strong cellular hypersensitivity (rather cellular
replaced by the epithelioid cells often with central caseation immunity) is confirmed by a positive lymphocyte
(Fig. 9.10). It is interesting to find that caseation necrosis transformation test (LTT) and strong Mitsuda reaction.29,55
is mostly associated with nerve lesions.52 The regressing epithelioid cell granuloma in leprosy
Often the granuloma can be the tomb of the bacilli or more or less seems to be a colony of old inactive cells.56
nerves or both. The lymphocytes in the granuloma exhibit The fact that these cells are less phagocytic, poor in
two types of distribution. In the central part they are bacterial destruction, but rich in autolytic enzymes further
scattered uniformly amongst the epithelioid cells and these supports this contention.51
CHAPTER
9
Borderline Tuberculoid especially if the lesion is near to mid-borderline (BB)
spectrum (Fig. 9.13). Clear subepidermal zone is a rule
Borderline tuberculoid (BT) leprosy shows an epithelioid
though a spur of granuloma may abut the epidermis at
cell granuloma with mild admixture of macrophages, but a
predominant feature (seen in TT), a distinct collar of some points. There is no evidence of intense DTH. AFB
stain sometimes shows few fragmented bacilli with LIG of
lymphocytes around a compact group of epithelioid cells,
around 1+ to 2+.
is lacking. The epithelioid cells are also loosely distributed.
In early cases the granuloma is often branching and
Mid Borderline (BB)
projecting as spurs along the neurovascular bundles
(Fig. 9.11), indicating a tendency to spread. Lymphocyte Midborderline (BB) granuloma shows the admixture of
number is moderate with fairly good number of giant cells almost equal number of macrophages and epithelioid cells
scattered amongst them (Fig. 9.12), which are often of (Fig. 9.14). Lymphocytes are scattered and lesser in
foreign body type. Nerves are replaced by granuloma but number as compared to the other two cell populations.
stretched out or fragmented perineurium is often present. SEZ is always clear. Nerves are not completely destroyed
Occasional nerve shows lamination of the perineurium, with surviving Schwann cells visible within the granuloma.
Transverse section of few nerves may present a cut-onion
appearance (Fig. 9.15). This is thought to be due to
proliferation of perineural cells in an attempt to repair, which
results in a multilayered laminated structure detailed in an
illustrative article.57 Giant cells are absent and this finding
often helps in differentiating it from BT. Tissue changes in
this type are highly unstable and transient. There is always
some amount of intercellular edema as the BB cases are
often seen with some degree of type1 reaction. AFBs are
always present with higher density in nerves with a LIG of
about 3+.
Borderline Lepromatous
Fig. 9.11: BT leprosy. A band of lymphocytes along the course of the The granuloma in borderline lepromatous (BL) consists
nerve (Red arrow) and foci of epithelioid cell differentiation. Also note predominantly of macrophages with isolated clump of
a capillary (Yellow arrow). (H & E × 100) epithelioid cells. The macrophages are generally young
Fig. 9.12: BT leprosy. Typical BT with early giant cell (GC) formation,
Epithelioid cells (red arrows), lymphocytes (yellow arrows). Note the
multiple nuclei (coenocytic) of the giant cells arranged at the periphery, Fig. 9.13: BB leprosy. Nerve involvement showing lamination of the
forming a horse-shoe pattern. (H & E × 400) perineurium (H & E × 100)
CHAPTER
9
Fig. 9.14: BB leprosy. The granuloma is semi-compact and semi-loose, with in between histopathological features of TT and LL leprosy. The
infiltrate comprises lymphocytes (blue arrows) and few foamy histiocytes (red arrows) and sparse epithelioid cells (green arrow). Giant cells
are absent (H & E × 400)
by concentric perineural cell proliferation presenting a cut-

onion appearance. Occasional segment of nerve
may be intact even though surrounded by the granuloma.
There is a clear SEZ. Bacilli are always in plenty with
small globi and the LIG is about 4+. Early foamy change
may be a conspicuous feature in some regressing
lesions.
REGRESSING LESIONS
The process of regression is well appreciated in macrophage

granuloma. Regression process starts with aging of the
cells. Death of bacilli results in decrease of macrophages
Fig. 9.15: BB leprosy. Multilayering of perineurium (cut onion due to the arrest of both, multiplication and influx. The
appearance) in a BB case. The whole round structure (nerve bundle)
infiltrated by lymphocytes (red arrows) and epithelioid cells (black cytoplasm of the cells becomes foamy, giving a “soap
arrow) (H & E × 400) bubble” appearance (Fig. 9.17). It is due to accumulation
of fat, thought to be released from the disintegrated bacilli
with uniformly stained bright eosinophilic cytoplasm. as well as host cells.58 These cells mostly contain the
Granuloma is mostly branching type. It is sometimes granular bacilli. On further aging, with the death of
difficult to differentiate between nascent macrophages macrophages a large amount of fragmented bacilli together
and epithelioid cells; though the latter are in compact act as foreign body and provoke formation of vacuolated
clumps and devoid of bacilli in sections stained for giant cells. Such phenomenon is like disposables moving
AFB. Lymphocytes are sparse and scattered over most from smaller bins to larger ones for final disposal.59 Once
part of the granuloma (Fig. 9.16). Occasionally, few the cells constituting the granuloma disappear; the space
aggregates of lymphocytes are seen at some foci as if a is filled by adipose tissue with small aggregates of
group surviving ravages of war. Nerves are conspicuous lymphocytes. Few bundles of nerves showing fibrosis, hair
CHAPTER
9
Fig. 9.16: BL leprosy. The granuloma is diffuse and branching (in the area encircled in arrows (left picture, × 40), the sub-epidermal zone is
intact. The details of granuloma are shown in picture on right, sparse lymphocytes (in red arrows) and foamy histiocytes (black arrows)
( H&E ×100)
Fig. 9.18: Regressing epithelioid cell granuloma (H&E x 100)

Fig. 9.17: Regressing macrophage granuloma with foamy change,
the “soap bubble” appearance. (H&E x 400) giant cells are the first to disappear followed by the
epithelioid cells. Aggregates of lymphocytes continue to
follicle(s) and glandular structures are seen embedded in
survive for quite sometime. Finally their disposition reverts
the adipose tissue. Some nerves show hyaline change
to what prevailed prior to infection. A clump of epithelioid
depending on the age of the granuloma. The epidermis
cells with one or two giant cells and mild edema (Fig. 9.19)
continues to remain flat and thinned out.
indicates an early granuloma; while the compact epithelioid
Morphology of the epithelioid cells does not change
cells without edema, typical Langhans’ giant cells, within
with their age. Their number gradually decreases as they
dense lymphocytes are the features of regressing lesion.
die and so does the size of the cell aggregates (Fig. 9.18).
The lifespan of granuloma cells, in order from shortest to
LEPROSY REACTIONS
the longest, is that of: (i) giant cell, (ii) epithelioid cell,
(iii) macrophage in active lesion and (iv) the macrophage Reactions are periodic episodes of acute inflammation
in regressing lesions.3 Thus in an inactive granuloma, the caused by immune responses to M.leprae or its antigens
CHAPTER
9
Fig. 9.19: Microreaction showing an early epithelioid cell differen-

tiation. E: Epithelioid cells, L: lymphocytic cells (H&E x1000)
superimposed on the chronic course of leprosy. Depending

on the immunological mechanism these episodes have
Fig. 9.20: The borderline tuberculoid granuloma comprising giants
been classified into two types: reversal reaction (RR) and cells (GC) with nuclei arranged in a ring form, lymphocytes (Lymphos.)
erythema nodosum leprosum (ENL). These are also known and epithelioid cells (Epith.) are shown with arrows. (H&E × 400)
as type1 and type 2 reactions respectively.60
mostly starting in the dermal nerves.62 In severe cases
Reversal Reaction (RR)
there is focal erosion of the epidermis and focal fibrinoid
RR occurs in the borderline cases and is a reflection of necrosis in the dermis (Fig. 9.20). Sometimes the necrosis
immunological instability. It is due to increase in the delayed is so extensive that a part or whole of the skin lesion
cellular hypersensitivity (DTH) which is reflected by sloughs out. Some workers phrase the phenomenon as
increase in lymphocyte transformation response.55 As per ‘immunological excision’.63 This process also occurs in
the classic immunological classification proposed by the nerve trunks giving rise to caseation and nerve abscess.
Coombs’ and Gell, it is type IV hypersensitivity or DTH.61 The reaction in the nerves is more severe, and is thought
Being acute in nature the lesions show all the cardinal to be due to high lipid content in the neural tissue.64 The
signs of acute inflammation such as redness, swelling, non-yielding perineurium increases the pressure of the
local warmth and tenderness over the skin lesions. Pain inflammatory exudates and hastens the process of nerve
is more intense in the nerves due to acute neuritis, destruction. The leprosy bacilli in reversal reactions are
commonly associated with inflammatory skin lesions. mostly in fragmented and granule forms (Fig. 9.21).
Often new skin lesions also crop up with many of these An increase of antigen due to multiplication of bacilli;
acute features. uncovering of hidden antigen and improvement of patients
In histology, the prominent signs are infiltration of the immunological performance due to therapy or recovery from
granuloma with neutrophils, dilatation of lymphatics in an immune depressed state (e.g. postpartum); are some
upper dermis and varying degree of intra and extracellular of the predisposing factors implicated in etiopathogenesis
edema. Intense edema leads to separation of collagen of type1 reaction.
and pale appearance of the granuloma. There is also influx Ridley and Radia in a study on the course of reaction
of additional lymphocytes. Macrophages differentiate into in borderline leprosy have described four stages viz. early,
epithelioid cells, increasing the proportion of the latter. Often acute, late and resolving.65 These stages when considered
there is increase of giant cells which are generally of foreign with the description of reactional states in the article
body type with bizarre shapes and sizes. “Leprosy as a model of subacute and chronic immunologic
The cellular component of the granuloma becomes so diseases” by Turk,29 the tuberculoid segment of leprosy
disorganized that the overall impression is described as a makes a spectrum of inflammation acute to chronic; with
‘tissue panic’. There may be areas of caseation necrosis, an intervening subacute stage. In other words tissue
CHAPTER
9
demonstrated that the dense pattern of staining was
identified with antilipoarabinomannan (LAM) antibodies.
LAM is a cell wall associated glycolipid secreted by
mycobacteria. It persists in the lesions even in the treated
cases and explains the late reactions occurring years after
completion of treatment.70
The questions, whether the granulomatous
hypersensitivity is a separate entity; and the way it differs
from type-IV hypersensitivity of Coombs’ and Gell type,
have not yet been fully understood.
Erythema Nodosum Leprosum (ENL)

ENL is also commonly known as type 2 reaction. It occurs
in LL and BL types of leprosy, because in these forms the
Fig. 9.21: BT leprosy with type1 reaction. Shows M.leprae in
bacillary load tends to be high. It is an immune complex
morphological compositions of non-solid (fragmented and granular). mediated disease, similar to Arthus phenomenon but there
(Fite Faraco stain × 1000) is evidence that imbalanced activity in the T lymphocyte
subpopulation might initiate the immune complex
formation.71 These episodes are accompanied by high
morphology of DTH constitutes a spectrum of inflammation
levels of circulating TNF-α as well as systemic toxicity.72
within a larger spectrum of leprosy. It is almost similar to
It is a generalized condition often associated with
the sequential tissue response seen in lepromin test.66
constitutional symptoms. Several organs and tissues with
Delineating the stage of inflammation seems to have a
rich blood supply are targets in ENL. Organs commonly
prognostic implication. The cellular presentation of the
affected are nerves, testes, joints, eyes, kidneys and lymph
whole process due to DTH seems to be the epithelioid cell
nodes and all the organs more or less share similar
differentiation.67,68 The presence of epithelioid cells is a
histology.
measure of the activation of macrophages and is
associated with increased capacity of eliminating The histology in ENL is that of lepromatous granuloma
intracellular organisms.29 superimposed by the features of acute inflammation. There
At the molecular level, the events in type1 reaction are is varying degree of neutrophil influx accompanied by
responses to an array of cytokines, secreted by edema. Infiltration of additional lymphocytes is also a
lymphocytes and macrophages. Both, the skin and nerves common feature, more prominent if ENL is of long standing.
in such reaction; are infiltrated by both; IFN-γ and tumor Deposition of immune complexes in the arterioles and
necrosis factor alpha (TNF-α) secreting CD4+ lymphocytes. venules and the resulting vasculitis (Figs 9.22 and 9.23)
These cytokines are responsible for edema, painful is a constant finding.73 In severe cases, the vessels are
inflammation and rapid host tissue damage. There is obliterated by thrombosis, resulting in local ischemia and
increase in cytokine production by peripheral-blood necrosis.
lymphocytes leading to rise of cytokine levels in the blood. Though not part of the granuloma, plasma cells are
The details of cellular and cytokine dynamics have been found in considerable number in the lepromatous segment
described by Britton and Lockwood in a seminar paper.69 of the spectrum. These cells produce large amount of
The antigens involved in type1 reaction are also described antibodies, which are less protective but highly tissue
in some detail. The antigen staining pattern in the lesions, damaging. Tissue injury is due to formation of the immune
both skin and nerve, are diffuse as well as intracellular. complexes, both in the extravascular spaces and in the
The latter is confined mostly to macrophages, as identified wall of the blood vessels. There follows series of events
by CD68+ staining.70 The 28 Kd protein, a superoxide as complement activation; chemotaxis driven accumulation
dismutase, is strongly associated with reactional states. of inflammatory cells and release of cytokines;
In addition, strong association of 68 kd antigen, a highly compounding the host tissue damage.
conserved heat shock protein; has also been shown to The episodes are more common after initiation of
play an important role in type1 reaction. They have also treatment; some cases report for the first time with
CHAPTER
9
colleagues in Mexico in 1948; almost a century later.75

This condition is manifested by ulcerative type of skin
lesions occurring in diffusely infiltrative type of lepromatous
leprosy. The features are similar to those of ENL with
histology of vasculitis, thrombosis and other features of
acute inflammation. There is thrombosis of vessels leading
to local ischemia and the ulceration- commonly known as
Lucio phenomenon. This type of reaction is more common
in Mexico compared to other parts of the world. This
reaction can be considered as a special variety of ENL,
thought to be a result of endothelial cell damage caused
by M. leprae within;76 and the release of antigens from the
endothelial cells.21
Fig. 9.22: BL Leprosy with ENL reaction. (H&E × 400). The structure
RELAPSE
encircled by blue arrows is a capillary lumen, with lymphocytic infiltrate
Relapse is the recurrence of the disease after cure. Cure
and neutrophils (marked in pink arrows), the histological feature
suggestive of vasculitis. from a disease as per the general perception of the patients
and treating physician, is a state of relief from symptoms
and disappearance of the signs.77 But it is difficult to apply
these criteria in leprosy, especially when treated for fixed
duration, due to delayed resolution of lesions in several
cases.78 Appearance of solid bacilli in a background of
granular bacilli or foamy macrophages; presence of young
and uniformly stained macrophages on a similar back drop;
change in the disease classification are some of the
indications of relapse.79 To this may be added the foci of
epithelioid and giant cell differentiation, sometimes with
type1 reaction, on a regressing epithelioid cell granuloma.
Reinfection, to which the response is similar, frequently
produces a more rapid and effective immune response
especially in tuberculoid cases. Since, lepromatous case
lacks immunity, it is likely to relapse as a hyperactive
macrophage granuloma, though occasional cases relapse
Fig. 9.23: Vasculitis with plenty of neutrophils in a macrophage as BT. Tendency of the granuloma to branch is also an
granuloma. (H & E × 1000)
indication of activity. It is preceded by bacterial multiplication
as evidenced by a negative case becoming positive or an
symptoms of ENL while in others, the episodes continue
increase of BI by log 2. Increase in the proportion of solid
long after completion of treatment. The disintegration of
staining bacilli (Morphological Index or MI) is also a
bacilli, host macrophages and neutrophils also constitutes
dependable sign, though its practice lacks standardization.
part of the histology. By immunohistochemistry antigens
Increase in MI is mostly associated with hypercellular
have been demonstrated in the extravascular
macrophage granuloma.80 In a disease like leprosy; in which
compartment.74 Such finding in sections, negative for AFB,
residual signs last long, regression (inactive disease) of
indicates the role of residual antigens.
the granuloma can be taken as cure. With this logic,
reappearance of cellular and/or bacterial activity as
Lucio Leprosy
described above, on the backdrop of regression constitutes
Lucio leprosy was first described by Rafael Lucio in 1851. relapse. The terms reactivation, reaction and relapse; all
It was rediscovered and extensively studied by Latapi and mean the return of disease activity. In the histology, the
CHAPTER
9
interplay of component cells (also the shade of nodules extending up to vocal cords. The histology of
inflammation) does not differ much between active disease lepromatous granuloma is similar to that of skin.86
and relapse and there lies the challenge.81 Superimposed ENL in such cases can sometimes be life-
threatening if there is a delay in performing the emergency
INVOLVEMENT OF OTHER ORGANS procedure of tracheostomy.
Leprosy especially at the lepromatous segment of the
Lymph Nodes
spectrum manifests as a generalized disease. This is more
obvious during type 2 and sometimes type1 reaction. Dissemination of M. leprae generally occurs through the
Organs of the mononuclear phagocytic system mostly bloodstream and like any other organism, M. leprae are
placed superficially as lymph nodes, testes and peripheral also caught in the organs which function as filters in the
nerves are commonly affected. The morphology of the path of blood and lymph circulation. It is natural therefore,
granuloma is similar to that seen in the skin except that that such organisms entangled in the meshwork of reticulo-
the background of the tissue is that of the organ affected. endothelial tissues, multiply in the lymph nodes, spleen,
Pathological features in some important organs are briefly liver and bone marrow. Cells of monocyte-macrophage
described below: lineage namely Kupffer cells in liver, littoral cells in spleen
and reticulum cells in bone marrow are the main target
Nose cells. All these cells act as footholds for miliary lepromas
and in advanced cases these organs get studded with
Nasal mucosa is an important receptive as well as
disseminative site for M.leprae. The interior of the nose is multiple lesions of differing sizes. The architecture of some
commonly affected in the lepromatous type of leprosy. of the lymph nodes is found completely replaced by either
The entire subepithelial tissue gets replaced by a layer of the macrophage or epithelioid cell granuloma. While lymph
bacilli laden macrophages accompanied by scattered node affection in multiple sites is a common feature of
lymphocytes and plasma cells. Initially there is copious lepromatous leprosy; in tuberculoid cases only the nodes
nasal discharge which forms crusts on drying and bleeds draining leprosy lesions are commonly affected. Autopsy
on peeling.82 Nasal mucosa is affected in all types of study has showed that while there is frequent involvement
leprosy with varying frequency and the detailed morphology of the hepatic, para-aortic and iliac lymph nodes, the
of granuloma and the BI are similar to that found in the bronchial and mesenteric groups are free.86
skin.83 The thickened mucosa is akin to the diffusely Lymph nodes draining the skin lesions of particular
infiltrated skin and if more advanced, there is formation of type leprosy are infiltrated by the corresponding types of
plaques and nodules. The site also often shows secondary granuloma cells. Caseation in epithelioid cell granulomas
infection by pyogenic bacteria, ulceration with frequent is less common as compared to that seen in the nerves
epistaxis. In course of time lepromatous granuloma is seen and hence, epithelioid cell granuloma of tuberculoid
in the nasal bones and cartilages and finally these leprosy is not easy to differentiate from granuloma of
structures are destroyed and replaced by fibrosis. This sarcoidosis. Though epitrochlear lymph nodes are
results in the typical depression (collapse) of the bridge of frequently affected in leprosy, any group of superficially
nose, a deformity typical of lepromatous leprosy. Two case situated nodes can be affected; especially in lepromatous
reports with epithelioid cell granuloma of tuberculoid leprosy. Regarding histology, normal structure can either
leprosy negative for leprosy bacillus have been described. be replaced by the granuloma partially or completely,
Nasal secretion is known to discharge an enormous amount though initial infiltration is seen in the paracortical areas
of bacilli84 and nasal mucus has been shown to be an and marginal medullary sinuses. Thickening of the lymph
important medium to disseminate M. leprae.85 node capsule is a constant feature in any type of leprosy.
Macrophages are laden with bacilli in lepromatous cases
Larynx but rarely seen in the tuberculoid leprosy.87 During ENL
Hoarseness of voice, a typical clinical feature of advanced the lymph glands swell up with acute inflammatory
lepromatous leprosy, is a rare occurrence now due to exudates and neutrophils. The latter some time form micro-
effective chemotherapy. This was due to the submucosal abscess and rarely, a large one draining outside through a
granuloma manifesting as diffuse infiltration, plaques and skin sinus.
CHAPTER
9
Liver hyperplasia. In the tissue sections of testis any stage of

the granuloma and surviving normal tissue can be
Involvement of liver is next only to lymph nodes; with similar
appreciated depending upon the extent of pathology. The
histology of the granuloma. The discrete initial infiltrates
macrophages would be laden with M. leprae in Fite-Faraco
are predominantly seen around the portal triads and central
stain. The cause of damage is pressure of the granuloma
veins. The Kupffer cell hyperplasia is generally a prominent
with episodes of immune mediated acute inflammatory
feature.
response.92
Cirrhotic changes have been reported in a couple of
early studies.6,88 There are reports that liver function tests
Eyes
become abnormal, though the test results do not correlate
with the BI of the patient.89,90 Case reported with tuberculoid Eyes are damaged in leprosy both, due to primary and
hepatitis show conventional epithelioid cell granuloma secondary lesions. The primary lesions are miliary lepromas
without any caseation.91 which are aggregates of macrophages containing M. leprae.
These microgranulomas can be found in every tissue of
Spleen anterior segment, namely cornea, conjunctiva, iris and
ciliary body.92 After reaching through the blood-stream,
As an organ of the reticuloendothelial system (RES),
the entry of the bacilli is probably through the ciliary body.
spleen is often involved in the lepromatous segment of
The outcome of this seeding mostly depends on the
leprosy. Though both; the red and white pulp; of the organ
immunity of the person and the type of leprosy he suffers
are replaced by miniature macrophage granulomas, the
from. Beading of the corneal nerves is considered as one
latter are more prominent in the periarteriolar region. The
of the earlier lesions of leprosy. These beads in tissue
replacement of lymphocytes of the thymus dependant
section show clump of macrophages containing bacilli,
areas by macrophages explains the role of spleen in
lymphocytes and plasma cells. M.leprae seem to have
generalized suppression of CMI in lepromatous leprosy.
high affinity for the iris. Iris is rich in small muscle and
Testes unmyelinated nerve fibers, rich in DOPA- a preferred
substrate for the organism’s enzyme diphenyl oxidase and
Testis is the only organ situated out side the body cavity a cooler temperature, all providing a site of warm hospitality
and maintains comparatively a lower temperature (about for multiplication.93 Miliary lepromas in the iris, known as
2°C less than the core body temperature). This is favorable iris ‘pearls’, so named due to their appearance in the slit
for the multiplication of M.leprae and subsequent lamp examination, are well appreciated along the rim of
inflammatory response leading to the damage of tissue. the pupil. These pearls could grow into miniature nodules
The organisms gain entry to the organ from the lesions of and distort the shape of iris leading to eccentricity of the
the scrotal skin and also through the blood circulation. The pupil; or dislodge and form floating aggregates in the
early response is perivascular accumulation of anterior chamber. In the course of time, microlepromas
lymphocytes and macrophages. The latter cells help in spread to ciliary body, sclera, episclera and even to the
multiplication of M. leprae. In response to the bacilli there retina through the vitreous which rarely shows discrete
is further accumulation of macrophages by local granuloma. All pearls irrespective of the site, including that
multiplication and migration leading to formation of of pannus, exhibit scattered lymphocytes, plasma cells
granulomas. The inflammation leads to thickening of and macrophages with M.leprae, if stained for AFB. In
basement membrane of the seminiferous tubules. The advanced stage, the smooth muscle fibers and endothelial
result is the focal destruction of germinal layer and cessation cells, show bacilli in addition to the macrophages which
of spermatogenesis, with survival of only the supporting mostly form perivascular micronodules. The components
Sertoli cells. Sometimes the entire tubule is atrophied, of uveal tract are rich in capillaries and are severely affected
destroyed and replaced by fibrosis and hyalinization.92 The during ENL.
inflammatory process gradually spreads to the interstitial During reactions the miniature granulomas will show
tissue, leading to edema and accumulation of acute edema and infiltration of neutrophils. Repeated
inflammatory cells. The damage of tissue is hastened during inflammation leads to vascularization and finally to
ENL reaction. For reasons not fully understood, the epithelialization of the cornea and its resultant opacity. All
interstitial Leydig cell survive longer with some degree of structures of the anterior segment are affected during ENL.
CHAPTER
9
There is acute inflammation with inflammatory exudates 6. Fite GL. Leprosy from the histopathologic point of view. Arch
Pathol Lab Med 1943;35:611-44.
which end up in the formation of anterior and posterior 7. Fine PEM, Job CK, Lucas SB, et al. Extent, origin and implications
synechiae. The iris is irreversibly constricted and when of observer variation in the histopathological diagnosis of
such narrowed pupil is plugged by fibrin, blindness ensues. suspected leprosy. Int J Lepr 1993; 61:270-82.
8. Porichha D, Mishra AK, Reddy BN. Ambiguities in histopathology
The uveal tract peculiarly continues to harbour M. leprae
of leprosy. Int J Lepr 1993;61:428-33.
and its antigens after skin smear becomes negative. A 9. Ramu G, Karthikeyan S, Balkrishnan S, et al. Histological and
state of chronic iridocyclitis lasts longer than the skin smear immunological correlates of suspected leprosy patients. Indian
negativity. Destruction of the ophthalmic branch of trigeminal J Lepr 1996; 68:155-59.
10. Barbosa AD, Silva TC, Patel, BN, et al. Demonstration of
nerve results in anesthesia of cornea and exposure mycobacterial antigens in skin biopsies from suspected leprosy
keratitis. Similarly affection of the zygomatic branch of cases in the absence of bacilli. Path Res Prac 1994; 190: 782-
facial nerve results in lagophthalmos. Together, both act 85.
11. Huerre M, Desforges S, Bobin P, et al. Demonstration of PGL-1
as double disadvantage subjecting the cornea to dryness antigens in skin biopsies in indeterminate leprosy patients,
and repeated injuries. There follows cornel ulceration, comparison with serological anti- PGL-1 levels. Acta Leprol
perforation, panophthalmitis and eventually blindness. 1989;7(suppl.):125-27.
12. Natrajan M, Katoch K, Katoch VM. Enhancement in the histological
diagnosis of indeterminate leprosy by the demonstration of
Kidneys mycobacterial antigens. Acta Leprol 1995; 9:201-07.
13. Katoch VM. Molecular techniques for leprosy: present application
Mesangial cells of kidney are of monocyte macrophage and future perspectives. Indian J Lepr 1999;71:45-49.
lineage and these cells are phagocytic. Glomeruli act as 14. Natrajan M, Katoch K, Katoch VM, et al. In situ hybridization in
fine filters. These two factors lead to glomerulonephritis the histological diagnosis of early and clinically suspicious
leprosy. Int J Lepr 2005; 72: 296-305.
involving all combinations of mesangial cell and membrane 15. De Wit NYL, Faber WR, Krieg SR, et al. Application of polymerase
proliferation in borderline and lepromatous leprosy.94 These chain reaction for the detection of Mycobacterium leprae in skin
lesions are due to the deposition of immune complexes, tissues. J Clin Microbiol 1991; 29: 906-10.
16. Arnold IJ, Scindler C, Duchow M, et al. Species specific
complements and immunoglobulins, mostly during ENL. assessment of Mycobacterium leprae in skin biopsies by in situ
hybridization and polymerase chain reaction. Lab Invest 1992;
66: 618-23.
ACKNOWLEDGMENTS
17. Komminoth P, Long AA. In situ polymerase chain reaction. An
We express our hearty thanks to Dr Ranganadha Rao, overview of methods, applications and limitations of a new
molecular technique. Virchows Arch B Cell Pathol Incl Mol Pathol
Chief Executive, LEPRA Society, for his constant 1993; 64:67-73.
encouragement and to Dr CK Job for his critical review 18. Shetty VP, Mistry NF, Antia NH. Current understanding of leprosy
with suggestions in enriching the text. We also feel greatly as a peripheral nerve disorder: significance of involvement of
peripheral nerve in leprosy. Indian J Lepr 2000; 72:339-50.
indebted to Dr Vanaja P Shetty, Director, The Foundation
19. Rambukkana A, Salzer JL, Yurchenco PD et al. Neural targeting
for Medical Research, Mumbai, Dr KV Desikan, Wardha of Mycobacterium leprae mediated by the G domain of the
MGIMS, Sewagram Wardha and Dr Minakshi Bhardwaj, laminin-alpha 2 chain. Cell 1997; 88:811-21.
20. Spierings E, de Boer T, Wieles B et al. M.leprae specific, HLA
Senior Pathologist, Dr Ram Manohar Lohia Hospital, New
class II-restricted killing of Schwann cells by CD4+ Th1 cells: A
Delhi, for sharing many of the microphotographs: (Authors). novel mechanism of nerve damage. J Immunol 2001;166:5883-
88.
REFERENCES 21. Harboe Mortem. The Immunology of leprosy. Hastings Robert C;
editor. Leprosy, 1st Edn (London): Churchill Livingstone. 1985:53.
1. Nayar S, Narayanan JS, Job CK. Histopathological study of 22. Cochrane RG. The correlation of the histologic picture with the
early skin lesions in leprosy. Arch Path 1972; 94: 199-204. clinical signs. Ciba Symposium 1961; 9:238-47.
2. Binford CH. The histologic recognition of early lesions in leprosy. 23. Ridley DS, Jopling WH. A classification of leprosy for research
Int J lepr 1971; 39: 225-30. purposes. Lepr Rev; 1962; 33:119-28.
3. Ridley DS. The pathogenesis of skin lesions. Skin biopsy in 24. Ridley DS, Jopling WH. Classification of leprosy according to
Leprosy. 1st Edn. (Basle): Documenta Geigy, Ciba Geigy Limited; immunity - a five group system. Int J Lepr 1966; 34: 255-73.
1977:18. 25. Dharmendra. Classification of leprosy. Hastings Robert C, editor.
4. Khanolkar VR. Studies in the histology of early lesions in leprosy. Leprosy, 1st Edn (London): Churchill Livingstone: 1985:88.
Indian Council of Medical Research, Special Series 1951;19:1- 26. Rea TH, Levan NE. Current concept in the immunology of leprosy.
18. Arch Dermatol 1977; 113:345-52.
5. Antia NH. Leprosy—a disease of Schwann cells. Lepr India 27. Hansen GA, Looft G. Leprosy: In its clinical and pathological
1982;54:599. aspects. Bristol. John Wright and Sons: 1895:67.
CHAPTER
9
28. International Congress of Leprosy, Havana. Report of the 54. Wade HW. Tuberculoid changes in leprosy. Int J Lepr 1934; 2: 7-
Committee on classification and nomenclature. Int J Lepr 1948; 38.
201-08. 55. Bjune G, Barnetson RS, Ridley DS et al. Lymphocyte
29. Turk JL. Leprosy as a model of subacute and chronic transformation test in leprosy; correlation of the response with
granulomatous disease. J Invest Dermatol 1976; 67:457-63 inflammation of lesions. Clin Exp Immunol 1976; 25:85-94.
30. Inflammation and repair. Robbin’s Pathologic Basis of Disease, 56. Porichha D. Tuberculoid leprosy- one phenomenon with many
5th Edn (Bangalore): B Saundersons Company, Prism Books perceptions. A point of view. Indian J Lepr 1997; 69:183-88
Pvt Ltd; 1994:76. 57. Pearsom JMH, Weddel AGM. Perineural changes in untreated
31. Azulay RD. Histopathology of skin lesions in leprosy. Int J Lepr leprosy. Lepr Rev 1975; 46:51-67.
1971; 39:244-50. 58. Sakurai I, Skinsnes OK. Histochemistry of lipids in human leprosy.
32. Sehgal VN, Srivastava G. Indeterminate leprosy. A passing phase Int J Lepr 1970; 38:389-403.
in the evolution of leprosy. Lepr Rev 1987; 58:291-99 59. Porichha D, Mukherjee A, Ramu G. Neural pathology in leprosy
33. Ridley DS. Classification and the spectrum. Skin Biopsy in during treatment and surveillance. Lepr Rev 2004; 75:233-41
Leprosy. (Basle): Documenta Geigy, Ciba Geigy Limited; 1977:37.
60. Jopling WH. Leprosy reactions (reactional states). Hand book
34. Ridley DS. Classification of leprosy. In: Window in Leprosy. BR
of leprosy. London: William Heinemann Medical Books; 1971:42
Chatterjee, editor. 1st Edn (Wardha): Gandhi Memorial Leprosy
61. Roit IM. Hypersensitivity. Essential Immunology, 2nd Edn Oxford:
Foundation; 1978:105-19.
Blackwell: 1974:129.
35. Pearson JMH, Ross WF. Nerve involvement in leprosy- pathology,
62. Ridley DS, Job CK. The pathology of leprosy. Hastings Robert
differential diagnosis and principles of management. Lepr Rev
C, editor. Leprosy. London: Churchill Livingstone; 1985:117.
1975; 46:199-212.
63. Rook GAW. The immunology of leprosy. In: Leprosy. Chatterjee
36. Skinsnes OK. ‘First infection’ type leprosy. Int J lepr 1969; 37:310-
13. BR, editor. Jhalda, West Bengal: Leprosy Field Research Unit;
37. Lara CB, Nolasco JO. Self-healing or abortive and residual forms 1993:128-51.
of childhood leprosy and their probable significance. Int J Lepr 64. Fantone P, Ward J. The role of oxidized free radicals in leukocyte
1956; 24:246-63. dependant inflammatory reaction. Am J Pathol 1982; 107: 397-
38. Crawford CL, Hardwicke PMD, Evans DHL et al. Granulomatous 401.
hypersensitivity induced by sensory peripheral nerve. Nature 65. Ridley DS, Radia KB. The histological course of borderline leprosy.
1977; 265: 457-59. Int J Lepr 1981; 49: 383-92
39. Thomas J, Joseph M, Ramanujam K et al. The histology of 66. Desikan KV, Mukherjee A, Ramu G, et al. Sequential histological
Mitsuda reaction and its significance. Lepr Rev1980; 51:329-39 study of lepromin reaction. Int J Lepr.1983; 51:473-80
40. WHO study Group for Chemotherapy of leprosy for control 67. Epstein WL. Granulomatous hypersensitivity. Prog. Allergy 1967;
program. Technical Report Series No 675. WHO Geneva 1982. 11:36-88.
41. Ridley DS, Waters MFR. Significance of variation within the 68. Maier M. The relation between allergy and immunity in leprosy.
lepromatous group. Lepr Rev 1969;40:143-52 Editorial, Int J Lepr1987; 55:116-39.
42. Abbas AK, Andrew LH. Innate Immunity. Basic Immunology, 2nd 69. Britton WJ, Lockwood DNJ. Leprosy (Seminar paper) The Lancet
Edn. (New Delhi): Saunders- Elsevier, Rajkamal Press, 2005:30 2004; 363: 1209-19.
43. Wade HW. The histoid variety of lepromtous leprosy. Int J Lepr 70. Lockwood DNJ, Colston MJ, Khanolkar Young SR. The detection
1963; 31:129-42. of Mycobacterium leprae protein and carbohydrate antigens in
44. Bhutani LK, Bedi TR, Malhotra YK et al. Histoid leprosy in North skin and nerves from leprosy patients with Type1 (reversal)
India. Int J Lepr 1974; 42:174-81 reaction. Am J Trop Med Hyg 2002; 66: 409-15.
45. Desikan KV, Iyer CGS. Histoid variety of lepromatous leprosy. A 71. Wemambu SNC, Turk JL, Waters MFR. Erythema nodosum
histopathologic study. Int J Lepr 1972; 40:149-56 leprosum: A clinical manifestation of Arthus phenomenon. The
46. Job CK, Dharmendra. Histopathology of skin lesions in leprosy. Lancet 1969; 2:1933-35.
Leprosy Dharmendra, Ed Vol. 2. (Bombay): Samant and Company; 72. Sarno EN, Grau GE, Vieira LMM et al. Serum levels of tumor
1985:820. necrosis factor-alpha and interleukin-1 beta during leprosy
47. Porichha D, Bhatia VN. Epithelioid and polygonal cells in histoid reactional state. Clin Exp Immunol 1991; 84:103-08.
leprosy. Indian J Lepr 1987;59:191-93. 73. Job CK, Gude S, Macaden VP. Erythema Nodosum Leprosum.
48. Ridley MJ, Ridley DS. Histoid leprosy: An ultrastructural
Int J Lepr 1964; 32: 177-84.
observation. Int J Lepr 1980; 48:135-39.
74. Ridley MJ, Ridley DS. The immunopathology of erythema
49. Job CK, Chacko CJG, Taylor PM. Electron microscopic study of
nodosum leprosum: the role of extravascular complexes. Lepr
histoid leprosy with special reference to its histogenesis. Lepr
Rev 1983; 54: 95-107.
India 1977; 49:467-71.
75. Latapi C, Chevez Zamora. The spotted leprosy of Lucio. An
50. Pettit JHS, Rees RJW, Ridley DS. Studies on sulphone resistance
introduction to the clinical and histological study Int J Lepr 1948;
in leprosy. I: Detection of cases. Int J Lepr1966; 34: 375-90.
16: 421-29.
51. Pappadimetriu JM, Spector WG. The origin, properties and fate
of epithelioid cells. J Pathol 1971; 105:187-203. 76. Vargas-Ocampo F. Diffuse leprosy of Lucio and Latapi: a histologic
52. Wiersema JP, Binford CH. The identification of leprosy among study. Lepr Rev 2007; 78: 248-60.
epithelioid cell granulomas of skin. Int J Lepr 1972; 41:10-31. 77. Desikan KV. The risk of relapse after multi drug therapy in leprosy.
53. Jadassohn J. Ueber Tuberculoid Verranderrungen in der Haut Lepr Rev 1997; 68:114-16.
bei nicht tuberoser Lepra. Proc. VI German Congress of 78. Job CK, Jayakumar J, Asccoff M. Delayed resolution versus
Dermatology, 1898. Reprinted in English translation by R L Meyer, treatment failure in paucibacillary leprosy patients. Indian J Lepr
Int J Lepr 1960; 28: 444-52. 1997; 69: 131-42.
CHAPTER
9
79. Ridley DS, Job CK. The Pathology of Leprosy. Robert C Hastings, 86. Desikan KV, Job CK. A review of postmortem findings in 37
Editor. Leprosy. Churchill Livingstone, London 1985:104 cases of leprosy. Int J Lepr 1968; 36: 32-44.
80. Porichha D, Mahapatra DC. Cellularity of macrophage 87. Turk JL, Waters MFR. Immunological significance of changes in
granuloma and Morphological Index. Indian J Lepr 1996; 67: lymph nodes across the leprosy spectrum. Clin Exp Immunol
217-23. 1971;8:363-76.
81. Porichha D. Histopathology and its relevance in leprosy. Sood 88. Kean BE, Childress ME. Summary of 103 autopsies of leprosy
OP, Ashok Ratan, (Eds). Proceedings of Round Table patients on the Isthmus of Panama. Int J Lepr 1942; 10:51-58.
Conference of leprosy- Series 10. (New Delhi): Ranbaxy 89. Verghese A, Job CK. Correlation of liver function tests
Scientific Foundation: 2002:41. with pathology of the liver in leprosy. Int J Lepr 1943; 33: 342-48.
82. Job CK, Karat ABA, Karat S. The histopathological appearance 90. Gharpuray SM, Gharpuray MB, Kelkar SS. Liver function in
of leprous rhinitis and pathogenesis of septal perforation in leprosy. Lepr India 1977; 49: 216-20.
leprosy. J Laryngol Otol 1966; 80: 718-32. 91. Singh P, Koranne RV. Systemic involvement in tuberculoid
83. Chacko CJG, Bhanu T, Victor V. et al. The significance in changes leprosy: Pathogenesis of leprosy. Lepr India 1979; 51:451-58
in nasal mucosa in indeterminate, tuberculoid and borderline 92. Ridley DS, Job CK. The pathology of leprosy. Hastings RC,
leprosy. Lepr India 1979; 51: 8-22. editor. Leprosy. London: Churchill Livingstone; 1985:128.
84. Davey TF, Rees RJW. The nasal discharge in leprosy. Clinical 93. Brand EM, Ffytche TF. Eye complications of leprosy. Hastings
and bacteriological aspects. Lepr Rev 1974; 45:121-35. RC, (Ed) Leprosy. London: Churchill Livingstone; 1984:228.
85. Pedley JC. The nasal mucus in leprosy. Lepr Rev 1973; 44: 33- 94. Date A. The immunologic basis of glomerular disease in leprosy:
35. a brief review. Int J Lepr 1982; 50: 351-54.
Section
3 Clinical and Laboratory

Diagnosis
10 History Taking and Clinical
Examination
Aparna Palit, S Ragunatha, Arun C Inamadar
INTRODUCTION 4. Past history.

5. Family history.
Leprosy is a chronic inflammatory disease caused by
6. Personal history.
M.leprae, primarily affecting the peripheral nerves and skin.
In the following section, the importance and relevance
The clinical presentation of leprosy mainly depends on
of eliciting specific history from the patients suffering from
the ability of the host to induce cell mediated immunity
leprosy will be discussed.
(CMI) against the lepra bacilli. The type of immune
response, which varies from person to person, determines
Identification and Demographic Data
the manifestations of the disease in various clinico-
pathological patterns. In the spectrum of leprosy, the patient In any leprosy control program the main focus is on early
presents with a combination of different types of skin diagnosis and treatment. The demographic factors
lesions and nerve function impairments, simulating a wide determine the attitude of the patient towards the disease,
variety of dermatological and neurological diseases. Early compliance to treatment, risk of deformities and
and accurate diagnosis of leprosy is crucial because late rehabilitation. Apart from medical management, the
recognition may leave the patient with some permanent knowledge of demographic factors helps in formulating
deformity and sequelae of the disease. policies and logistics for the proper control of leprosy as a
Apart from the host and agent factors, geographic, major public health problem.
sociocultural and economic factors also play a role in the Name
outcome of the disease and its complications. Hence,
Addressing the patients by name helps in gaining their
history taking and clinical examination in leprosy should
confidence and building good rapport with them. It is also
address all these aspects, which ultimately help in
important for identification/recording of the patient.
decision-making regarding chemotherapy, prevention of
disability, health planning and community-based Age
rehabilitation (CBR). Though children are more susceptible, the clinical leprosy
is now more commonly observed in adults. Paucibacillary
HISTORY TAKING disease is commoner in children and the incidence of
reactions is lower in this age group. Epidemiologically,
Primary goal of history taking is to establish the diagnosis
childhood leprosy is an index of transmission of the disease
by excluding other conditions simulating leprosy. History
in a population and helps in detection of the source of
should be taken according to the following steps, mostly
infection.1
like any other medical history:
1. Personal identification and demographic data. Sex
2. Presenting complaints. There exists a gender inequality in leprosy. Though it
3. History of present illness. affects both sexes, the disease is more severe in males
CHAPTER
10
122 Clinical and Laboratory Diagnosis
but the sociocultural impact of the disease is more in Marital Status

females.2 Women are at higher risk of development of The diagnosis of leprosy has a profound effect on marriage.
reactions. However, the deformities are less common in Leprosy has been a reason for rejection of bride/bridegroom
females.3 and divorce in many communities.3 Unfortunately leprosy
During pregnancy, the patient may be at increased risk is still a ground for divorce in the Indian law, as of date.
of development of the disease, relapse and reactions. Post-
partum period is temporally associated with occurrence of Presenting Complaints
reversal reaction due to recovery of cell mediated immunity. Patients with leprosy may present with varied clinical
While treating a woman of child-bearing age with manifestations (Table 10.1). The symptoms suggestive of
thalidomide, due precaution must be taken to avoid peripheral nerve involvement with or without skin lesions,
teratogenicity.3 should direct the history taking and clinical examination
towards diagnosis, differential diagnoses and
Address complications, which the individual patients might have.
Residential address is necessary for tracing and Table 10.1: Various presenting features of leprosy
surveillance. Distance between home and the health center
1. Skin lesions; hypopigmented patches, skin-colored/
is one of the factors for delay in coming for follow-up, erythematous papules, nodules, which may be waxy ±
increased incidence of deformities and default of umbilication (non reactional leprosy)
treatment.4 In non-endemic states/countries, specific 2. Tingling and numbness of hands and/or feet
3. Weakness of hands and/or feet
enquiry should be made to know whether the patient 4. Ulcers on the hands and/or feet
originally belongs to that region or had migrated/travelled 5. Spontaneous blisters on the hands and/or feet
from a state/country endemic for leprosy, for occupational 6. Sudden redness, swelling and pain of existing lesions with or
without constitutional symptoms (Type1 reaction)
or some other reasons. The important differential diagnoses 7. Sudden appearance of painful nodules with or without
of leprosy like leishmaniasis (cutaneous, muco-cutaneous constitutional symptoms (erythema nodosum leprosum)
and visceral), onchocerciasis, etc. are to be considered in 8. Painful swelling on the back of wrists (tenosynovitis)
9. Diffuse swelling of hands and feet (early sign of lepromatous
certain geographical regions, where these diseases are leprosy/ reaction)
prevalent.5 10. Inability to close eye lids
11. Pain in and around eyes, redness, photophobia or diminished
Occupation vision (iridocyclitis)
12. Nasal stuffiness, epistaxis (early sign of lepromatous leprosy)
Occupation is one of the factors determining susceptibility 13. Irregular thickening of ear and on face (lepromatous leprosy)
of the already diagnosed leprosy patients to develop 14. Inability to use hands for precision works; e.g., button a shirt,
deformities. Such patients should be identified for advice eating rice with hands, typing, etc; inability to make a power-grip;
e.g., holding a rod, carrying utensils. Inability to wear slipper. (All
either to use protective measures or change of occupation. these are indicative of peripheral anesthesia and poor functioning
In manual labourers, the peripheral nerves are usually of small muscles of hands and feet).
prominent and due care should be undertaken while
interpreting nerve enlargement in the absence of nerve History of Present Illness
function impairment (NFI).6
Any question asked to the patient or information collected
Socioeconomic Status should be interpreted in relation to the diagnosis, differential
diagnosis, management, prevention of disability and
Low socioeconomic status, poor housing, over crowding
rehabilitation. In addition, these observations should also
and rural inhabitation are associated with increased
guide the examiner regarding further questioning. The
incidence of leprosy. Alternatively, the diagnosis of leprosy
following points should be asked to get clues about the
carries a stigma and can worsen the socioeconomic status disease.
of a patient. Type of occupation, housing status and number
of dependants are the key socioeconomic indices. Duration
Identification of these factors and early socioeconomic The duration of the presenting complaints has both
rehabilitation decreases the risk of disability.6 diagnostic and prognostic importance. Hypopigmented
CHAPTER
10
History Taking and Clinical Examination 123
patches present since birth or of few days duration are Patients may complain of spontaneous blistering after
unlikely to be due to leprosy. The former is suggestive of a long walk. Painful trophic ulcer indicates presence of
nevus anaemicus or nevus depigmentosus.7 NFI of less secondary infection or involvement of underlying structures
than 6 months duration responds better to systemic like bone.10 The presence of pain along with paresthesia
corticosteroid therapy than that of more than 6 months. and impaired sensation, differentiates diabetic and alcoholic
The delay in presentation (>6 months) is one of the risk neuropathy from leprosy.5 Constitutional symptoms like
factors for development of deformities.8 Multibacillary fever, malaise, joint pain, etc. usually accompany reactions
disease of duration more than 10 years, is a risk factor for
and infected trophic ulcer.7,10
ocular complications.9
Distribution of Lesions
Mode of Onset
Skin lesions and NFIs in leprosy usually have insidious The hypopigmented patches in tuberculoid spectrum are
onset. Sudden appearance of skin lesions and NFIs is usually localized and few in number; whereas they are
indicative of leprosy reactions. Eruption of new lesions generalized and wide spread in the lepromatous spectrum.7
may suggest ENL or reversal reaction. However, the ENL Involvement of three or more body areas is one of the risk
lesions are evanescent, appear in crops and last for few factors for NFI and reversal reaction.12 Patches over major
days; whereas the lesions are persistent in reversal nerve trunks and face are associated with increased risk
reactions.7 of underlying nerve damage.13 The sensory impairment is
difficult to elicit if the patches are present over the face
Progression and Evolution
because of its overlapping nerve supply. The ENL lesions
The hypopigmented patches and NFIs in non-reactional commonly occur on face and extensors of extremities.7
leprosy undergo a gradual, continuous course. Increase in Lesions of erythema nodosum are usually localized to legs.
the size of lesion and/or appearance of new lesions in a
The interpretation of the presenting complaints leads
patient with apparently stable disease, indicates persistent
to further enquiry into the disease depending upon the
activity, downward progression of disease or relapse. History
spectrum of leprosy and reactional state. For example, if
of rapid nerve function deterioration resulting in paralysis
indicates lepra reactions or neuritis. Rarely, the ENL lesions the history is suggestive of lepromatous spectrum, the
may develop bullae and undergo ulceration, which is seldom symptoms related to visceral involvement should be asked
seen in erythema nodosum.7 for. If the history is suggestive of ENL reaction, apart from
The trophic ulcer evolves initially from a trauma/deep symptoms of systemic involvement, precipitating factors,
fissure/ callosity/ tenderness over pressure-bearing areas if any should also be enquired.
of soles and palms; due to a deep abscess breaking down
Visceral Involvement and Complications
into a frank painless ulcer discharging sero-sanguineous
fluid.10 Usually clinical manifestations of leprosy are limited to
The hypopigmented lesions of nevus anemicus increase the skin and peripheral nervous system. However, other
in size proportional to the body growth. Postinflammatory organs can also be affected mainly in patients with
hypopigmentation remains stationary and regresses in few lepromatous leprosy and ENL reactions. Only few organs
weeks. The lesions of pityriasis alba may be persistent, present with symptoms suggestive of their involvement
recurrent and respond to topical therapy.7 and specific questions can be asked to detect such
NFIs in leprosy are mostly localized, asymmetrical and involvement (Table 10.2).9,14
distal unlike, the NFIs secondary to toxic, nutritional,
metabolic, or hereditary causes which are more diffuse, Precipitating Factors
symmetrical and involve both proximal and distal areas of
If history is suggestive of reaction; precipitating factors
limbs.11
should be searched for:7
Symptoms 1. Any recent infection? (sore throat / frequency of
As such, skin lesions in leprosy are asymptomatic. The urination/ loose motions).
presence of itching may help in differentiating urticaria from 2. Physical and mental stress? (over-work, familial
red papules and nodules of lepromatous leprosy or ENL. dispute/marital disharmony/ employment status
Pain is a common feature of both type1 reaction and ENL.7 (whether recent loss of job), etc.
CHAPTER
10
Table 10.2: Looking for visceral involvement in leprosy 9, 14

Organ Specific questions to be asked:
Eye • Difficulty in eye closure? (Lagophthalmos)
• Itchy sensation in the eye? (Corneal anesthesia)
• Red eye with pain, watering and sticky discharge? (Corneal ulceration)
• Red eye with pain, photophobia and diminished vision? (Iridocyclitis)
• Localized redness, severe radiating pain to temporal region, normal/ slightly reduced vision?
(Scleritis)
• Localized redness, mild pain, normal vision? (Episcleritis)
Upper respiratory tract • Able to perceive smell of food and scented materials? (Anosmia)
• Nose is blocked with occasional bleeding?
• Change of voice, chronic cough, and occasional breathlessness? (Laryngeal involvement)
• Any episode of acute respiratory distress? (Laryngeal edema)
Cardiovascular system * • Palpitation?
• Dyspnea on exertion?
• Swelling of feet?
Adrenal glands** • Features of adrenal insufficiency? e.g., hypotension, asthenia, prostration
Male reproductive system • Normal / diminished libido? (Testicular atrophy)
• Enlarging breasts? ( Testicular atrophy)
• If married, whether having children? (Sterility)
*Cardiovascular involvement in leprosy is very rare and rarely gives rise to symptoms. Involvement of peripheral blood vessels, though
frequent, is rarely symptomatic.
** Adrenal suppression is very rare in leprosy. However, it may occur rarely during an episode of type 2 lepra reaction.
3. Recent vaccination? Past History

4. Recent surgical procedures?
The factors that influence the course, classification,
5. Pregnancy / recent child birth?
prognosis and management of leprosy are recorded in the
In case of trophic ulcers, history of trauma, penetrating
past history. If the patient had been diagnosed as having
injury, barefoot walking or ill fitting footwear should be
leprosy before, following details should be elicited:
noted.10
1. Predominant clinical features; skin lesions and/or area
Associated Diseases of loss of sensation, diagnosis made in the past (type
of the disease).
Certain diseases are commonly associated with leprosy
2. History of spontaneous disappearance of a skin patch,
and influence the course of the disease. Tuberculosis is
with persistence of nerve thickening and area of sensory
common in leprosy patients; moreover different therapeutic
loss, poses a difficulty in diagnosing a primary neuritic
regimen has to be used to treat this co-infection in order to
leprosy.
prevent rifampicin resistant tuberculosis.14 Concomitant
3. Any deformities developed?
HIV infection is associated with increased risk of recurrent
4. If treatment taken, the treatment schedule, its duration
reversal reactions, ENL and immune reconstitution
and side effects? (Multibacillary leprosy with high BI is
inflammatory syndrome (IRIS), especially after the
associated with increased chances of relapse).
institution of anti-retroviral therapy (ART).15
5. If the patient is a defaulter, reason for default?
Treatment Taken for Presenting Complaints 6. In case of history suggestive of reaction,
a. Its duration?
Leprosy patients may have tried many topical and
b. Number of episodes?
systemic medications before consulting / referred to the
c. Any precipitating factor(s)?
specialists, mistaking hypopigmented patches for
d. How the reaction was managed earlier? (If the
pityriasis versicolor, dry eczema or dermatophytic
patient is educated, try to elicit the history of
infection. A persistent, asymptomatic, hypopigmented
treatment taken with duration, doses of steroid
patch not responding to topical therapy should arouse the
required, and any side effects thereof)
suspicion of leprosy.
CHAPTER
10
e. Relationship of reaction with starting of multidrug 2. Appetite; poor appetite should lead the clinician to
therapy (MDT); search for a cause beyond anaemia and malnutrition.
Reversal reaction usually occurs after initiation of MDT. 3. Sleep (adequate sleep is necessary in patients with
The interval between initiation of therapy and onset of reaction).
reaction will be shorter at tuberculoid pole and longer at 4. Bowel and bladder function,
the lepromatous pole. The reversal reaction may occur 5. Hobbies and habits; alcoholic neuropathy is one of the
without therapy in BT leprosy or may also occur after differential diagnoses and may occur together with
completion of MDT, especially in BL and subpolar LL. In leprosy.5 Chronic alcoholism and liver damage are
associated with increased incidence of severe
the absence of therapy, the course of the disease or type1
hepatotoxicity; when rifampicin is given alone or
reaction is more likely to be downgrading. Downgrading
concurrently with other hepatotoxic drugs.16 Chronic
phase of the disease /Type1 reaction in a patient on MDT
smokers may have pre-existing vascular compromise
may suggest delayed initiation of therapy; inadequate
and may be more susceptible to develop blistering and
therapy, treatment default, resistance or immunological
ulceration.
deterioration. ENL may occur before or after initiation of History gives clues only to the spectrum of leprosy,
MDT. However, it is more common after initiation of therapy complications and associated risk factors. Based on these
because of increased antigenic load following the killing of historical findings the clinical examination should be
bacilli.7 conducted. For example, if the patient is in lepromatous
• History of any chronic illness like diabetes mellitus, spectrum or type 2 reaction, apart from cutaneous and
jaundice, HIV infection, etc.? peripheral nerve examination, thorough systemic
Diabetes mellitus also causes peripheral neuropathy examination should de done to detect the underlying organs
and it is one of the differential diagnoses.5 Rifampicin, a involved, if any.
microsomal enzyme inducer, is known to decrease the
plasma levels of oral hypoglycemic agents.16 Leprosy CLINICAL EXAMINATION
reactions do not seem to be a primary cause of hepatitis,
but may worsen underlying liver disease.14 Treatment with An adequate history taking is followed by thorough clinical
examination of the patient. This is imperative in all cases
anti-retrovirals in presence of co-infection with HIV, can
of leprosy, as it is a disease with wide variations in the
result in IRIS and in untreated patients reactions may be
clinical features. Moreover, morphological details of the
more frequent.
skin lesions, extent of peripheral nerve involvement, areas
Any history of drug hypersensitivity syndrome induced
of sensory loss and systemic involvement allow the
by sulfonamides should be asked for, as cross reactivity
clinician to assess the disease spectrum the patient
may occur with dapsone.17
belongs to. This in turn helps in individualizing the
therapeutic schedules for patients and assessing the
Family History chances of complications the patient may face during the
Household contacts are at an increased risk of contracting course of illness and/or treatment.
leprosy. History of leprosy in the family and examination Clinical examination involves the following steps:
of other family members is vital, especially if the patient 1. General physical examination
is a child.18 Number of dependants in a family is one of 2. Cutaneous and mucosal examination
the indices of socioeconomic factors. History of any drug 3. Ocular examination
reaction (especially with sulfonamides) in a family member 4. Palpation of peripheral nerves and testing for sensory
or any close relative should be specifically asked for as it impairment.
may be predictive of an increased risk of the same in the 5. Examination of musculoskeletal system
patient.17 6. Examination of external genitalia
7. Other systemic examination
Personal History
General Physical Examination
Daily routine of the patient is asked with regards to:
1. Diet (though not specifically associated, concomitant Overall nutritional status of the patient should be assessed,
malnutrition may slow the recovery)19 as patients with long-standing lepromatous disease may
CHAPTER
10
develop malnutrition. Thorough general physical gynecomastia in males suggests impairment of testicular
examination should be performed with special search for function in lepromatous disease.
pallor, edema and lymphadenopathy. These may be a part An overall brownish pigmentation involving skin,
of lepromatous disease or may be associated with leprosy conjunctiva and oral mucosa indicates treatment with
reactions. If a patient on dapsone therapy shows profound clofazimine currently, or in the recent past.
pallor of sudden onset, evidence of hemolysis and jaundice In an institutional set-up, individual skin lesions should
should be looked for. preferably be documented on a printed proforma with
Pulse and blood pressure of all patients should be diagrammatic representation (Fig. 10.1).20 This allows a
recorded at presentation and followed up thereafter during proper follow-up of the patients in respect of course of
every visit. Tachycardia may be noted in patients with existing skin or nerve lesions, appearance of new lesions
leprosy reactions. Hypertension in patients with leprosy or fresh peripheral nerve involvement during the course of
may result from chronic renal impairment due to repeated the disease.
type 2 leprosy reactions or amyloidosis.
Bilateral pedal edema, often also involving the dorsa Examination of Individual Skin Lesion
of hands, is seen in lepromatous patients. Generalized While examining individual skin lesions, the following points
edema may be reactive, resulting from autonomic should be noted:
neuropathy affecting the small blood vessels; or it may be 1. Total number:
indicative of acute glomerulonephritis associated with type Single, 1-5, >5 (multiple) or innumerable. Fewer the
2 lepra reactions or severe hypoproteinemia, common number of the lesions, lower the bacillary load; the
among the leprosy patients. Widespread tender higher is the level of resistance of the patient to disease
lymphadenopathy is suggestive of type 2 reaction.7 and vice versa.
If the patient is acutely ill with fever, arthralgia and 2. Distribution:
prostration, possibility of type 2 reaction or severe type1 Trunk, extremities, face; protected sites like, scalp,21
reaction should be considered and cutaneous examination axillae, groin, perineum, genitalia,22 palms and soles23
should be directed to confirm it. may also be involved and should be searched for
lesions. Covered body sites like genitalia24 or buttocks
Cutaneous Examination may be the only site of initial skin lesions and should
A quick general cutaneous survey should be done followed never be overlooked.
by examination of individual skin lesions. Prior explanation Bilateral symmetric or asymmetric distribution;
to the patient along with gaining his/her confidence is of symmetry indicates lowest spectrum (LL) and
immense importance in achieving patient cooperation. asymmetry indicates borderline spectrum of the
Cutaneous examination should be done in adequate day- disease.
light, following proper exposure and ensuring privacy. The 3. Shape:
patient should face the source of light (e.g. window) with Regular (round / oval), irregular / bizarre, annular.
the examiner sitting against it.19 The skin lesions are better 4. Size:
appreciated in an oblique light (especially the ill-defined A lesion may occupy an entire limb or a quadrant of
macules of LL disease), initially from a distance, thereafter trunk (TT, BT) or may be small and multiple (BL, LL).
close examination is done.19 Widespread, monomorphic, coalescent macules are
Widespread infiltration, evident by shiny skin, sparse suggestive of LL disease.
body hair, prominent follicular openings and mild thickening 5. Morphology:
appreciable by gentle pinching of the skin, is suggestive Patch / plaque, papule /nodule / vesicle / bulla. Lesions
of lepromatous disease. Infiltrated face with thick skin folds should be examined for;
and nodularity (leonine facies), depressed nose, enlarged, a. Color (hypo/hyperpigmented, skin-colored,
pendular ear lobules (Buddha ears), sparse beard and erythematous, coppery).
moustache, are all indicative of advanced lepromatous b. Surface (no change, dry / scaly / smooth and
leprosy. Sagging / loose facial skin (rather than infiltration) shiny / edematous / ulcerated).
is seen in treated lepromatous cases; as well as in patients c. Border [well / ill-defined, raised / flat, sloping (in or
with long-standing or burnt-out disease. Unilateral / bilateral outward), punched-out]. Well-defined border of a
CHAPTER
10
Fig. 10.1: Diagrammatic charting of skin lesions, nerves and areas of sensory changes in patients with leprosy to be used for keeping
records, (Modified from Thangaraj RH, Reference no.20)
CHAPTER
10
lesion is indicative of tuberculoid pole of the

disease.
d. Presence / absence / sparseness of hair.
e. Lesional tenderness.
An ill-defined, hypopigmented, flat, imperceptible lesion
without surface changes (preserved skin markings) may
be an indeterminate leprosy patch (Figs 10.2 and 10.3).
Thick, elevated margin of a lesion with or without
granularity is suggestive of TT/BT lesion (Fig.10.4). In
annular lesions, both inner and outer margins are to be
palpated. A better-defined inner border with outer border
sloping (into the surrounding skin) giving a “punched-out”
appearance (inverted saucer-shaped) is suggestive of a
BB lesion (Fig. 10.5).25 The type with inner sloping border
and well defined outer border indicates a TT lesion.
Presence of pseudopodia and satellite lesions along
the margins of large lesions are suggestive of a BT lesion.25
New satellite lesions may also appear, when such a patient
is in reaction or the disease is downgrading (Fig.10.6). A
‘feeding nerve to the lesion’ can be detected by gentle Fig. 10.3: A patch around knee, with similar features as that of lesion
in Fig. 10.2, a case of Indeterminate leprosy (Photo courtesy:
rolling of a finger along the borders mostly in TT or BT Dr Pankaj Sharma, PGIMER, Dr RML Hospital, New Delhi)
spectrum. In case of single or few large BT lesions, the
entire border should be inspected thoroughly to see whether
it is well-defined all around or ill-defined and vague at places
(partially defined), indicative of downgrading of a particular
lesion.
Morphology of nodules should be studied carefully:
1. Persistent, asymptomatic erythematous/ coppery/
normal skin colored nodules, firm on palpation, of
variable sizes, with sloping edges on to the surrounding
Fig. 10.4: The typical patch of TT leprosy over cheek, the outer
border is well defined, raised, ending abruptly; while the inner margin is
ill-defined, sloping, waning towards the centre of the lesion. Also note
the enlarged great auricular nerve, this nerve is often appreciable
better by inspection than on palpation. (Photo courtesy: Dr HK Kar,
PGIMER, Dr RML Hospital, New Delhi)
infiltrated skin are seen in lepromatous spectrum of

the disease (BL / LL).
Fig. 10.2: An ill-defined patch over face with sensory impairment, 2. Well-defined, succulent, hemispherical glistening
close to the patch a small nerve twig (marginal mandibular) was palpably nodules, with or without umbilication, present on normal-
enlarged. Diagnosis of Indeterminate leprosy was made on clinical appearing skin may suggest histoid leprosy (Fig.10.7).
grounds. Histopathology is frequently inconclusive in such situations
3. Recurrent, erythematous, evanescent, tender, nodules
(Photo courtesy: Dr Pankaj Sharma, PGIMER, Dr RML Hospital,
New Delhi) on the skin, commonly distributed over face, arms and
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Fig. 10.7: Histoid leprosy. The glistening shiny hemispherical nodular

lesions over earlobe and pinna. Similar nodules were present it over
trunk also. (Photo courtesy: Dr HK Kar, PGIMER, Dr RML Hospital,
New Delhi)
Fig. 10.5: A case of BB leprosy with reversal reaction, the typical Rarely, few ulcerated lesions may be present in patients
lesions of this type are shown with arrows. The inner border is raised, with untreated LL leprosy, histoid leprosy, ENL lesions or
well defined, ending abruptly; while the outer margin is ill-defined, sloping over the lesions of type1 reaction. Such ulcers are usually
and wanes imperceptibly into surrounding skin, giving to lesion the
present on the dorsa of the fingers and toes, instep of the
“punched out” appearance. (Photo courtesy: Dr HK Kar, PGIMER, Dr
RML Hospital, New Delhi) soles or other non-weight bearing areas,26 unlike trophic
ulcers (which may co-exist), present over the pressure
points. Sometimes in severe type 2 reactions, ENL lesions
may become vesicular and bullous and break down
(erythema necroticans) to produce ulcers.
Sudden onset of lesional erythema, edema (lesions
may stand out clearly from the surrounding skin) and
tenderness are suggestive of type1 reaction (Fig. 10.8).
Ulceration of such a lesion indicates increased severity of
the reaction. Presence of scaling / wrinkling in a patch or
plaque suggests subsiding type1 reaction. Showers of
small, new lesions while the patient is in reaction; may
indicate downgrading.
Patients may have a combination of lesions
characteristic of different spectra of the disease, e.g. large,
Fig. 10.6: A case of BT leprosy. The patch is well defined, hypoesthetic, dry patch of BT, annular plaque of BB and
hypopigmented, with definite sensory loss. A satellite lesion is visible numerous macular/papular lesions of BL, indicative of a
at the periphery (shown with arrow), is separated from the main lesion downgrading course.
by a small area of normal skin, and is usually indicative of unstable
disease. (Photo courtesy: Dr Pankaj Sharma, PGIMER, Dr RML
Testing Sensations
Hospital, New Delhi)
Lesional sensation should be tested for
thighs, unrelated to pre-existing skin lesions and healing 1. Temperature (hot /cold water in test-tubes),
with postinflammatory hyperpigmentation are 2. Touch (wisp of cotton-wool)
suggestive of erythema nodosum leprosum (ENL), a 3. Pain (pin-prick; the pin should be discarded after use
feature of type 2 leprosy reaction. on each patient).
CHAPTER
10
normal) and different parts of a large lesion (center/

periphery).
2. Lesions on face may not show expected degree of
hypoesthesia.
3. A patient in reaction may not be able to appreciate
lesional sensory loss and such lesions may show
hyperalgesia.7
4. Testing sensations in a child could be difficult at times.
Distal extremities should be examined for ‘gloves and
stockings’ hypoesthesia, demonstrable in lepromatous pole
of the disease. Though named so, it may be patchy and
asymmetrical; in contrast to other causes of predominantly
sensory peripheral neuropathy.11
Fig. 10.8: A patch of TT leprosy in reversal reaction. Note the prominent Some sites should specifically be tested even when
erythema and scaling. (Photo courtesy: Dr HK Kar, PGIMER, Dr RML definite hypoesthesia is not demonstrable in skin lesions;
Hospital, New Delhi)
or along the distribution of a peripheral nerve.
These sites of early cutaneous sensory loss in
Before starting the sensory testing, the patient should diseases of lower spectrum are as follows:11
be explained the procedure in colloquial language and a 1. Dorsa of the hands and feet
trial of the method is conducted with eyes of the patient 2. Dorsomedial aspect of forearm
open. He/she is asked to count loudly each time the 3. Anterolateral aspect of legs.
stimulus is felt or to locate the area tested, with finger. The recommended sensory testing sites (WHO) on
Once followed it correctly, the patient is instructed to close palms and soles (10 sites on each side) for disability grading
the eyes, and the test is repeated to interpret. have been presented in Figure 10.9.28 Brandsma et al have
While testing sensation, the examiner should proceed suggested lesser number of testing sites for this purpose,
from uninvolved to the involved skin. All the sensations as follows28:
should be tested gently, only once at one site, for a short 1. Hands: Ulnar nerve: distal pulp and proximal phalanx
while, not pressing the test object too hard or brushing it of little finger and hypothenar eminence.
on patient’s skin. 7,19 The clinician may obtain an Median nerve: distal pulp of thumb and index fingers
approximate idea by prior application of the test object on and thenar eminence.
his / her skin to assess the pressure and duration of contact 2. Feet: Big toe, metatarsal heads (1st, 5th), mid-lateral
required to elicit a normal sensory response. Even with border of foot.
adequate explanation and prior demonstration, the patient
may not be able to point the exact location of the application Trophic Changes
of stimulus (mis-reference), which may be an early sign of Asymptomatic, deep, non-healing fissures on heels and
hypoesthesia.7 The permissible limits of mis-reference on toes may be observed in people who walk bare foot and
hands are 1 cm, on face, 2 cm and on back it is up agricultural/manual workers suffering from leprosy.
to 7 cm.7 Callosities may be present on both palms and soles.
In regions with thicker skin (palms and soles) touch Multiple, spontaneous and asymptomatic blisters on hands
sensation can be tested with the tip of a ball-point pen and feet (which might have gone unrecognized by the
gently, so as not to produce an indentation deeper than 2 patient), are indicative of anesthetic hands and feet.
mm.27 Testing with Semmes-Weinstein monofilaments Vulnerable pressure points on palms, soles and bony
helps in detecting early hypoesthesia. pressure points like lateral malleoli, heel of the hand
The examiner should keep in mind the following facts (pisiform bone) and point of the elbow should be inspected
while interpreting sensory impairment in a patient with for trophic ulcers.26 Some sites of predilection for plantar
leprosy: ulcers are as follows26:
1. The degree of sensory loss may be variable in different 1. Head of first metatarsal
lesions (indeterminate +/–, TT and BT ++, LL +/–, or 2. Mid-portion of plantar surface of big toe
CHAPTER
10
3. Mid-lateral border of the foot at the base of b. Nodular infiltration (reddish / reddish-yellow, sessile/
5th metatarsal pedunculated lesions) of lip, tongue, palate (may
4. Heel be ulcerated / perforated) and uvula may be seen
5. Tips of the clawed toes in presence of claw feet in patients with lepromatous disease. Fissuring of
The clinician should aim at identifying a trophic ulcer tongue may be present in florid LL disease.7,34
at an early stage. Some subtle clinical clues to a ‘threatened c. Uvula; intact or partial / complete destruction. Uvular
ulcer’ on feet are as follows:26 movement normal / restricted (fibrosis).
1. Mild edema and warmth on the dorsum of fore-foot. 2. Nasal mucosa
Nasal mucosal examination should be performed in
2. Slight splaying of the adjacent toes.
suspected lepromatous disease with an artificial light
3. Deep tenderness over plantar surface of metatarsal
source and nasal speculum. Mouth-breathing and foul-
head / base of proximal phalanx.
smell may indicate presence of nasal crusts. Removal
Presence of a blister at pressure points may represent
of crusts facilitates better visualization of the mucosa,
a ‘concealed ulcer’ which, when ruptures, forms the which is insensitive, pale, thickened and irregular with
‘manifest ulcer,’ with a hyperkeratotic rim around it.26 destruction of inferior turbinates. Presence of bleeding
Each trophic ulcer should be examined carefully for and septal perforation should be looked for. Neglected
evidence of secondary bacterial infections (foul smell, dirty patients may harbour maggots in the nasal cavity.7
slough, discharge). Constant discharge of pus, in spite of
adequate wound care, suggests involvement of deeper Ocular Examination
structures like pulp space, synovial sheath, tendon,
Patient’s face should be inspected closely for:
capsule or bone.29 Absence of discharge, sloping edge of
1. Any skin lesion involving the peri-ocular area.
the ulcer and bluish epithelium covering the granulation
2. Frequency of blinking, blink-interval and blink-
tissue at the floor, are the signs of healing.26
completeness should be observed. A regular blinking
Ichthyosis (normally 6/ minute) is indicative of preserved protective
corneal sensation.35
Widespread dryness indicates lack of sweat and sebum
3. Width of palpebral fissure, while the patient gazes
secretion (autonomic neuropathy). 7 Large areas of
straight at a distant object.
ichthyosis may be present over extremities. Brownish
4. Photophobia, redness of eyes, watering and any other
discoloration of the ichthyotic scales indicates that
obvious ocular deformities.
the patient is receiving/has received treatment with
Ocular examination is done with a well-focused torch
clofazimine.
and preferably with a corneal loupe.25 Opinion of the
Sweating ophthalmologist should be sought for in situations difficult
to reach a conclusion.
A dry lesion (TT / BT) indicates focal loss of sweating. In Intraocular pressure is assessed by gentle palpation
case of doubtful lesions, anhidrosis can be detected by of the closed eyes with both index fingers; and ocular
pilocarpine test25 or the non-invasive ninhydrin test.30
Compensatory hyperhidrosis, especially involving face,
trunk and axillae is present in some patients.
Mucosal Examination
Mucosal involvement is indicative of an untreated disease
of long duration and should be examined with equal care
as skin. Following findings should be looked for31,32:
1. Lips and oral mucosa
a. Diffuse enlargement of lips / macrocheilia, may be
part of infiltration in lepromatous disease or type1
reaction involving a BT lesion overlying lips and Fig. 10.9: Recommended sensory testing sites (WHO) on palms
surrounding areas.33 and soles
CHAPTER
10
tenderness should be noted at the same time by looking

at patient’s face. Raised intraocular tension may be
indicative of glaucoma.
Presence or absence of following features should also
be noted;
1. Eyebrows and eyelashes: Superciliary (loss of / sparse
eyebrow) and ciliary (loss of eyelashes) madarosis are
features of advanced lepromatous leprosy (Fig. 10.10).
Look for inwardly directed eyelashes (trichiasis).
2. Eyelids: In all cases of facial BT lesion, patient should
be examined for lagophthalmos at an early stage.
Normally, while the gaze is fixed straight at a distant
object, the upper lid covers the upper 2 mm of the
cornea and the lower lid is at the level of lower border Fig. 10.10: LL leprosy. Note the loss of eyebrows and eyelashes,
of limbus, so that sclera is not visible above or below diffuse infiltration of face, earlobes and lips. The Bacteriological Index
cornea.35 Visible thin strip of white sclera above or (BI) was 6+ in this case (Photo courtesy: Dr HK Kar, PGIMER,
Dr RML Hospital, New Delhi)
below cornea, in this position, is suggestive of lid
retraction/lago-phthalmos.35
If lagophthalmos is not obvious, patient is asked to
close the eyes gently. Faulty eye-closure with visible Bell’s
phenomenon is due to improper approximation of the
eyelids. Mild lag / ectropion of only lower eyelid with pooled
tear-film suggests selective involvement of the zygomatic
branch of the facial nerve, which may result from an
overlying BT lesion, with or without type1 reaction.25 It
may rarely be bilateral due to large BT lesion involving
eyelids on both sides.36 Bilateral lagophthalmos may be a
feature of widespread pure neuritic disease37 or untreated,
advanced LL disease. Lagophthalmos is of sudden-onset
and severe in borderline disease (mostly related to type1
reaction), whereas, more gradual in onset and milder in LL
disease.35 Fig. 10.11: Redness of eye in a treated case of LL Hansen’s disease
3. Pterygium: If pterygium is present, it usually harbours (Photo courtesy: Dr Pankaj Sharma, PGIMER, Dr RML Hospital,
bacilli, and indicates high ocular bacillary load.9 New Delhi)
4. Redness of eyes: A peri-limbal redness is indicative of
iridocyclitis, which may be a part of LL disease or looks straight (Fig. 10.12).35 Normally there should be a
associated with type 2 lepra reaction. Redness of the brisk blink response.
entire conjunctiva is suggestive of conjunctivitis or Unilateral loss of corneal reflex may result from the
scleritis (Fig. 10.11).25 involvement of ophthalmic nerve (trigeminal) due to a same-
5. Cornea: Corneal surface is looked for xerosis and / or sided peri-ocular BT lesion. Bilateral absence of corneal
abrasions or obvious corneal ulcer. Xerosis of eye can reflex indicates damage of corneal nerves due to advanced
be detected by Schirmer test38 and staining the tear- LL disease. 7 Testing for corneal sensation is not
film with 1% fluorescein dye (with the help of a glass- recommended during field survey for safety reasons.28
rod), helps in detecting corneal abrasions.35 6. Pupil: Small, irregular pupil, non-reactive to light is
Corneal sensation is tested (following proper cleaning indicative of iridocyclitis, or adhesions of iris.
of hand) with a clean wisp of cotton-wool, rolled in to a 7. Visual acuity: Visual acuity of the patient should be
point on one end. The examiner approaches the patient assessed by finger-count test and thereafter using
from one side and the cornea is touched gently, 2 mm Snellen’s chart; it may be impaired due to large corneal
inside the limbus at the 6 O’clock position while the patient opacity, cataract or glaucoma.
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10
Palpation of Peripheral Nerves
Clinician should be well aware of the specific sites / bony
land-marks along which the peripheral nerves commonly
involved in leprosy are to be palpated, as well as the area
of distribution of sensory nerves. Method of palpation of
some peripheral nerves has been presented in Tables 10.3A
and B (Figures 10.13 to 10.18).39,40
Nerve palpation should be gentle (using pulps of fingers
rather than tips) to avoid causing pain to an inflamed nerve
(neuritis).19,20 Each nerve should be palpated on both sides
for comparison, even if the involvement is felt to be
asymmetric.
It is prudent to remember that interpretation of palpation
Fig. 10.12: Testing of corneal sensation of peripheral nerves is subjective in nature (may vary from
Table 10.3A: Methods of palpating different peripheral nerves (Head and neck; and upper extremity)39,40
Nerve Site / bony landmark Patient position Method
Head and neck

Supraorbital Supraorbital notch at the junction of Sitting / standing with head kept Palpate with both thumbs on
medial 1/3rd and lateral 2/3rd of straight both sides (Fig. 10.13)
supraorbital ridge
Supratrochlear Medial to the supraorbital nerve Same as above Same as above
Infraorbital Infraorbital foramen, just below the Same as above Same as above
medial part of inferior orbital margin
Branches of facial Zygomatic arch Same as above Same as above
nerve: Zygomatic
and temporal
Great auricular Lateral side of neck, crosses Sitting / standing with head turned Easily visible, crossing
sternomastoid muscle, from lateral completely to opposite side sternomastoid obliquely.
side to infra-auricular area. May be palpated with 2 fingers
Clavicular (3 sets) Shaft of clavicle Sitting / standing straight Fingers rolled on the shafts of
both clavicles
Upper Limb
Radial Spiral groove on humerus, posterior Sitting / standing with elbow flexed at Examiner’s left fingers roll the
to the deltoid insertion. 90°. Examiner’s right hand holds nerve in the radial groove
patient’s right hand in shaking-hand
manner (and vice versa).
Ulnar Ulnar groove on medial epicondyle Same as above.(Both the nerves Examiner’s left little finger locate
of humerus, medial to the point of may be palpated simultaneously the nerve in the groove; other
elbow. for better comparison) fingers palpate the nerve
upwards along medial aspect of
arm (Fig. 10.14).
Radial cutaneous Lateral border of radius, just proximal Same as above. Examiner’s left fingers roll the
to the wrist; thereafter along the Patient is asked to extend the thumb nerve against radius (Fig. 10.15).
proximal part of extensor pollicis to visualize the anatomical snuff box. It can be further traced and
longus tendon, which stands out rolled from side to side on
prominently on ulnar side of the extensor pollicis longus tendon
anatomical snuff box and dorsum of hand
Median Proximal to the flexor aspect of wrist Sitting / standing with elbow flexed at Examiner’s right fingers palpate
joint (proximal to flexor retinaculum), 90°, and wrist in supination. the nerve deep between the
between the tendons of palmaris Examiner’s left hand stabilizes tendons
longus and flexor carpi radialis patient’s left hand and vice versa
CHAPTER
10
Fig. 10.13: Palpation of supraorbital nerve with the thumbs; fingers Fig. 10.16: Palpation of lateral popliteal nerve
are used to stabilize the head
Fig. 10.14: Palpation of ulnar nerve Fig. 10.17: Palpation of sural nerve
Fig. 10.15: Palpation of radial cutaneous nerve Fig. 10.18: Palpation of posterior tibial nerve
CHAPTER
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Table 10.3B: Methods of palpating different peripheral nerves (Lower extremity)39,40
Nerve Site / bony landmark Patient position Method
Lower extremity
Anterior cutaneous Anterior aspect of thighs Sitting; Fingers rolled on the anterior
nerves of thigh Standing upright may help to aspect of both thighs
(3 sets) visualize the nerves better.
Lateral popliteal Just below the lateral aspect of knee, Sitting with legs dangling freely. Knee stabilized by placing the
along neck of fibula thumbs on upper border of
patella on both sides and the
nerve rolled with fingers, against
neck of fibula (Fig. 10.16).
Sural Posterior aspect of leg, between the Standing / lying prone Palpated on both sides with
two bellies of gastrocnemius above fingers (Fig. 10.17).
and tendo Achilles below.
Anterior tibial On the dorsum of foot, lateral to the Patient sitting on bed with legs Palpated by rolling of fingers
tendon of extensor hallucis longus straight and is asked to extend the
and dorsalis pedis artery great toe to make the extensor
hallucis longus tendon stand out.
Posterior tibial Medial aspect of ankle (deep to flexor Sitting on bed with knee flexed / Palpated by rolling of fingers
retinaculum), between medial standing (Fig. 10.18).
malleolus and tendo Achilles.
examiner to examiner).41,42 Moreover, peripheral nerve The aim is to detect early neuritis. Sometimes, there
trunks may be palpable normally, especially in thin-built may be very little or no demonstrable nerve tenderness.
individuals and manual workers. Hence while interpreting Such cases should be examined with due care, as
nerve thickening in doubtful cases, associated loss of demonstration of an increase in the ‘area of anesthesia’
sensation in its distribution (one of the cardinal features of or in ‘weakness of the muscles supplied by the nerve
leprosy) and /or weakness of the muscles supplied by the trunk’ may suggest silent neuritis.7 Neuritis is much more
affected nerve should be looked for.42 Comparison of nerves severe in type1 reaction; as compared to that in type 2
on both sides helps in appreciating unilateral nerve reaction.
enlargement. It should also to be remembered that the Hypoesthesia/anesthesia along the course of a
ulnar nerve on the dominant (working) side is usually peripheral nerve may be the chief complaint in pure neuritic
comparatively slightly thicker than on the opposite side. disease. However, unlike other causes of peripheral
Following features should be assessed while palpating neuropathy, sensory impairment in leprosy may not follow
a peripheral nerve: the distribution of a peripheral nerve / nerve root strictly.11
1. Enlarged or not? Large peripheral nerve trunks are The areas of sensory distribution by cutaneous branches
usually not palpable in indeterminate and TT disease. of major nerve trunks on hands and feet are given in
2. Is the nerve compressible? (Lack of compressibility Figures 10.19A and B.
indicates a fibrosed nerve, which may appear even Among cranial nerves, peripheral branches of trigeminal
thinner and cord-like). (supratrochlear, supraorbital) and facial nerves (zygomatico-
3. Unilateral / bilateral? If enlarged bilaterally, assess the temporal, buccal, marginal mandibular, cervical) may be
difference between two sides, if any. Asymmetric nerve palpable in presence of facial lesions or as part of pure
enlargement is a feature of borderline disease. neuritic leprosy.37,43 These nerves should be looked for
4. Extent of the nerve palpable in its course (ulnar, lateral in presence of facial lesions. The anatomical location of
popliteal, etc.) the terminal branches of facial nerve has been shown in
5. Presence of nodularity (single/multiple)/abscess Figure 10.20. Involvement of other cranial nerves
(diffuse, fusiform swelling). (glossopharyngeal, vagus, hypoglossal) in leprosy has
6. Nerve tenderness (indicative of neuritis); look at been reported rarely,44 and this may be the cause of nasal
patient’s face for a wince. regurgitation, complained by some patients. However,
CHAPTER
10
A B
Figs 10.19A and B: Sensory coverage of hands (A) and feet (B) by various nerves
routine examination of these nerves is not done, unless Examination of Musculoskeletal System
specific clinical features, not attributable to other causes,
Inspection of the patient as a whole, provides clues to the
are present.
involvement of musculoskeletal system. Detailed
Features like postural hypotension and asymmetric
examination can be done thereafter.
pupil may indicate presence of advanced autonomic
1. Face: Look for the contour of the nose:
neuropathy.7
a. Collapse of the bridge (destruction of anterior nasal
spine).
CHAPTER
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Fig. 10.21: A case of Bell’s palsy (right side). The facial paralysis in
leprosy usually involves upper part of face (due to involvement of
Fig. 10.20: Terminal branches of facial nerve upper branches of facial nerve by a leprosy patch in the vicinity. In
Bell’s palsy the involvement of facial nerve is higher up, due to
edematous compression in Facial canal; that affects all branches,
leading to paralysis of both upper and lower parts of face
b. Destruction of alae nasi.
c. Columella, rarely may be destroyed.45
Teeth should be inspected for the loosening / loss of b. Compare thenar and hypothenar eminences of
upper incisors. Nasal and dental changes, in association patient’s palm with opposite normal side or with
with flat cheeks and thin upper lip constitute the ‘facies examiner’s hand to detect wasting.
leprosa, as seen in patients with advanced lepromatous c. Guttering of the interosseus spaces, suggestive of
disease.7,25 wasting of the interossei and lumbricals.
Facial muscle paralysis in tuberculoid leprosy mostly d. Normal bulging contour of medial aspect of forearm;
involves the upper face (orbicularis oculi), in contrast to flattened due to wasting of flexor carpi ulnaris (high
other common causes of lower motor neuron facial palsy ulnar paralysis).
(e.g. Bell’s palsy), where both upper and lower parts of the e. Swelling (fusiform / sausage-shaped) of fingers with/
face are involved (Fig. 10.21). Mask-like facies may be a without tenderness, suggestive of dactylitis.
feature of advanced LL disease and indicates paralysis of f. Test patient’s grip; whether pinch grip (holding small
muscles of facial expression (involvement of terminal objects with tips of fingers) and power grip (holding
branches of facial nerve in their superficial course).11 a rod firmly) are possible; or only hook grip (holding
Usually such paralysis is asymmetric and patchy. Careful a bucket by handle) is retained, suggestive of both
examination may reveal following unusual deformities at ulnar and median nerve palsy.46
the initial stages: g. Secondary deformities due to nerve palsy;47
a. Out-pouching of the lips at the angle of the mouth Hooding, contracture of the fingers due to
(weakness / paralysis of orbicularis oris muscle). attenuation of central extensor tendons of
b. ‘V’-like configuration of lateral part of forehead fingers in long-standing claw hand.
wrinkles, on attempt to raise eyebrows (medial part Z-thumb, hyperextension of metacarpo-
of frontalis muscle, which is paralyzed earlier than phalangeal (MCP) joint and hyperflexion of
the lateral part). interphalangeal (IP) joints of thumb; loss of
c. Concentric creases extending from corners of mouth primary flexion of MCP joint due to ulnar nerve
(buccinator smile; superficial facial muscles forming palsy.
the nasolabial fold are paralyzed, but action of h. Shortening of fingers indicative of resorption of
buccinator is retained). terminal phalanges e.g. paddle hand, mitten hand
2. Upper extremity: Look for: (severe shortening of digits).47
a. Obvious deformities like wrist drop / claw hand i. Frozen hand (non-functional hand, flexed at wrist
(partial / complete). with stiff, twisted fingers at odd directions, dorsal
CHAPTER
10
skin is hyperpigmented, leathery and tethered to Functions of the muscles of the forearm, hand, leg
deeper tissue) indicates repeated lepra reactions and feet are assessed by certain tests like voluntary muscle
in the past.46 testing (VMT), which have been presented in Tables
j. Soft silky hand (loss of normal resilient feel of palms 4A to C (Figs 10.22 to 10.25).7,19,20,25,39,40,48 The six grades
due to lepromatous infiltration and destruction of for voluntary muscle testing (Medical Research Council –
the fibrous septa attaching palmar skin to the palmar MRC Scale) are as follows49:
fascia).23 Grade 5 : Normal power (with full resistance).
3. Lower extremity: Look for: Grade 4 : Muscle contraction against slight
a. Gait abnormality (high-stepping gait) and obvious resistance but power subnormal.
deformities like foot drop / claw toes. Grade 3 : Movement possible without resistance.
b. Collapsed arch(es) of the foot / feet. Grade 2 : Active movement when gravity is
c. Guttering of the interosseus spaces, wasting of eliminated.
interossei and lumbricals. Grade 1 : Flicker of movement
d. Shortening of toes indicative of resorption of terminal Grade 0 : No movement.
phalanges. Before starting VMT, the power of the muscle is
e. Wasting of peronei muscles in lateral compartment assessed approximately by noting the range of movement
of leg (supplied by superficial peroneal branch of the patient can perform with the affected limb / digit. If it is
lateral popliteal nerve). apparently normal, muscle power testing can be started
Deep tendon reflexes are usually preserved in patients directly against resistance. For testing small muscles of
with leprosy, or there may even be hyperreflexia. hands and feet, effect of gravity is negligible.50
Table 10.4A: Examination of muscles of face, upper extremities7, 19, 20, 25, 39, 40, 48
Muscle to be tested Nerve supply Test Interpretation Deformity/ disability
Face
Orbicularis oculi Zygomatic and temporal Patient asked to close the In normal eye, separation Lagophthalmos
branches of facial eyes forcefully and examiner of the eyelids is quite (vide text for details)
tries to separate the eyelids. difficult. Ability to open the
eyelids indicates weak-
ness of the muscle.
Upper extremity
Extensors of Posterior interosseous Close fist and dorsiflex the Weakness: radial nerve Inability to extend wrist and
wrist joint branch of radial wrist against resistance involvement fingers, wrist drop
Flexor digitorum Median nerve at or Patient asked to clasp both Index finger of affected Pointing index /
superficialis and above elbow hands (Ochsner’s clasping side does not flex and Benediction sign.48
profundus (lateral test) (Fig. 10.22). remains straight Outstretched index finger with
part) flexion of other fingers.
Abductor pollicis Median nerve Patient’s hand is laid flat Inability to touch the pen, Thumb lies flat in the same
brevis (palmar surface up) on a loss of abduction move- plane of hand (adducted,
table and asked to touch a ment of thumb. hyperextended and rotated at
pen held slightly higher, by carpometacarpal joint and
moving the thumb vertically flexed at MCP and IP
up (abduction) (Pen Test) joints) Ape-thumb deformity
(Fig. 10.23).
Opponens pollicis Median nerve Examiner stabilizes patient’s Inability to perform the
hand with own and patient is action against resistance
asked to swing the thumb indicates weakness of
across the palm (the thumb- opponens pollicis
nail lying parallel to palm) to
touch the tips of other fingers,
while examiner resisting this
action with his index finger
IP – Interphalangeal
MCP-Metacarpophalangeal
CHAPTER
10
Table 10.4B: Examination of muscles of upper extremities (contd.) 7,19,20,25,39,40,48
Upper extremity
1st palmar Deep branch of ulnar Patient asked to hold a book Flexion of the distal IP Guttering of 1st interosseous
interossei and nerve between two hands by joint of thumb (Froment’s space.
adductor pollicis keeping the adducted sign) with hyperextension
thumbs straight on its upper of MCP joint on affected
surface. Examiner tries to side indicates weakness
pull the book in opposite of these two muscles and
direction. (Book Test) action of flexor pollicis
(Fig. 10.24) longus (median nerve)
Lumbricals + Lumbricals:1st and Patient asked to flex the Inability indicates Claw hand;
interossei 2nd : Median nerve; fingers at MCP joints against weakness of these two (hyperextension at MCP and
3rd and 4th: deep resistance groups of muscles flexion at IP joints).
branch of Ulnar Partial (1st, 2nd, 3rd or 4th
nerve Interossei: deep and 5th fingers): only median
branch of ulnar nerve nerve OR only ulnar nerve
involvement; Complete (all
fingers): both median and ulnar
nerve involvement.
Difficulty in grasping.
Palmar interossei Deep branch of ulnar Patient asked to keep fingers Inability to hold the card Subtle abducted position of
nerve extended as well as adducted. tightly indicates weakness little finger (Wartberg’s
A firm paper-card is inserted of palmar interossei sign)29 earliest sign of ulnar
in each web-space serially nerve involvement.
and patient is instructed to Mild guttering of interosseous
grasp it tightly while the spaces.
examiner tries to pull it out. Inability to bring fingers together.
(Card Test) (Fig. 10.25). Difficulty in eating rice with
hands and holding small
objects like coin46
Dorsal interossei Deep branch of ulnar Patient asked to spread out Inability indicates Guttering of interosseous
nerve fingers against resistance by weakness of dorsal spaces.
examiner’s hand. interossei Reduced finger span.
Function like typing is
difficult46
Table 10.4C: Examination of muscles of lower extremities7, 19, 20, 25, 39, 40, 48
Lower extremity
Dorsiflexors of Common peroneal Patient asked to perform Inability indicates Foot drop
ankle nerve following movements against weakness of these In long-standing
Extensor hallucis resistance by examiner’s muscles cases, foot is fixed at
longus hand plantar-flexed and inverted
Peronei longus • Dorsiflexion at ankle position (late stage, rigid
and brevis • Extension of great toe equino-varus deformity)
• Eversion of foot
Intrinsic muscles Medial and lateral Patient asked to adduct/ Inability indicates Collapse of arch of foot.
of feet plantar branches of abduct toes against weakness of these Guttering of inter-tarsal spaces.
tibial nerve resistance muscles Clawing of toes (ground is
touched by the tip of toes
rather than the pad).
Inability to squeeze the toes
together or spread them.
Inability to use regular foot
wears and requires special
one.
CHAPTER
10
Fig. 10.22: Ochsner’s clasping test with pointing index Fig. 10.25: Card test
Some simple, quick and easy methods of muscle

testing, appropriate for field workers, suggested by different
authors have been presented in Table 10.5.51, 52, 53
Claw hands should be tested for mobility. Passive
flexion (by examiner) of the hyperextended MCP joint
enables the patient to extend the flexed proximal IP joints
(mobile claw hands / toes), indicating early stage of
deformity which may be amenable to physiotherapy or
corrective surgery.39 Fixed flexion along middle finger
creases suggests long-term, neglected claw hand.39
Acute-onset, symmetric, peripheral, polyarthralgia may
be an accompaniment of both type 1 and type 2 reactions34
and has to be differentiated from rheumatoid arthritis by
ancillary clinical findings.
Fig. 10.23: Pen test
Presence of globular, cystic, tender swelling, usually
on the dorsal surface of wrist joint, following an episode of
type1 reaction in borderline disease is indicative of teno-
synovitis. Individual joint effusion or bursitis may be
present.34
Examination of External Genitalia

Though a protected site, lesions of the external genitalia
are not uncommon in leprosy. Hence genitalia of both male
and female patients should be inspected for presence of
skin lesions. In addition, in male patients, testicles should
be palpated gently to see for34:
1. Size and consistency: Whether the testicles are firm,
resilient and of appropriate size or small and soft
(advanced disease and / or sequel of repeated type 2
Fig. 10.24: Book test with positive Fromment’s sign reaction).
CHAPTER
10
Table 10.5: Some tests for quick examination of muscle power / nerve paralysis in the field51, 52, 53
Nerve supply Test Interpretation
Upper extremity
Median nerve Affected palm facing up or both palms facing each other the If tip of the thumb points to the roof at the end of 30
patient is asked to abduct the thumb / thumbs and maintain it seconds, it is normal. If points anteriorly, it indicates
in that position for 30 seconds. 51 weakness of median nerve.
Tip-to tip thumb opposition to the 4th finger: 52 The angle between long axis of both the nails
Patient asked to oppose the thumb to touch tip of 4th finger, measured approximately;
with slight flexion of thumb IP joint and nails of both thumb and <100°: evident median nerve function loss.
4th finger lying in the same plane, so as to form an ‘O’ and <150° but >120°: minimal median nerve function loss
maintain this position. >150°: Normal nerve function
Detection of hidden / latent clawing of index and middle finger Digging of examiner’s forearm by the tips of index
(performed when clawing is not evident): and middle fingers of patient due to hyper flexion of
Patient asked to grasp and squeeze examiner’s forearm.53 IP joints and limited flexion of MCP joint.
Ulnar nerve Flap-flexion of fingers: wrist of the patient kept in neutral Normal person is able to keep the fingers straight.
position, and asked to perform flexion and extension of MCP Flexion of the fingers at IP joints indicates clawing.
joints few times keeping the fingers straight (like a flap).
Thereafter the hand is held in this position (MCP joints flexed
and IP joints extended, fingers straight) for few seconds. 52
Lower extremity
Common Patient is asked to stand on both heels and keep all the toes Normal persons are able to maintain this position for
peroneal lifted. 51 few seconds. Inability indicates weakness of
dorsiflexors.
Tibial nerve Patient is asked to retract / pull back the toes by keeping the Curling of the toes, rather than retraction indicates
feet firmly on ground. 51 weakness of intrinsic muscles of feet
IP – Interphalangeal
MCP—Metacarpophalangeal
2. Testicular sensation: If absent, indicates fibrosis Lower respiratory tract should be examined for evidence
resulting from repeated episodes of epididymo-orchitis of bronchopneumonia which is a common sequel of
(type 2 reaction). laryngeal dysfunction. Pulmonary tuberculosis may be an
3. Tenderness: Acute testicular pain indicates epididymo- accompaniment in leprosy patients (2.4- 13.3%, Indian
orchitis, a part of type 2 reaction and this may be the study 7.7%);54 hence clinical evidence of pulmonary
presenting feature of type 2 reaction. tuberculosis has to be ruled out in each patient as such
While examining for testicular sensation and cases need alteration in the treatment schedule for leprosy,
tenderness, the examiner should observe the patient’s to avoid rifampicin resistance.
face. Clinical features of renal dysfunction may be evident
in patients with long-standing disease (renal amyloidosis),
Other Systemic Examination or patients suffering from recurrent episodes of ENL which
Upper respiratory tract is the most common site of may lead to glomerulonephritis.
involvement. Though several other organs are involved in In patients with repeated episodes of lepra reactions,
lepromatous leprosy and also during type 2 reaction, clinical any focus of infection should be sought for (caries teeth,
manifestations of such involvement are unusual and are pharyngitis, tonsillitis, urinary tract infection, chronic
recognized only during histopathological examination or amoebiasis etc.), which might precipitate the recurrence.
autopsy.14 Patient’s mental status should also be assessed as
A hoarse voice, dry, hacking cough and occasional depression is commonly associated, especially in patients
breathlessness are indicative of laryngeal involvement and/ with recurrent reactions.55
or uvular dysfunction, features of LL leprosy. Acute Examination of a patient suffering from leprosy is an
respiratory distress during an episode of type 2 reaction art indeed. It requires immense patience and empathy for
may be a pointer to the rapidly developing laryngeal edema. the patient. A searching eye and an eager mind is
CHAPTER
10
imperative to scan the patient as a whole, in a brief span 18. Krishnamoorthy KV, Desikan KV. Indeterminate leprosy in an
of time to detect as many clinical findings as possible. infant. Lepr Rev 2006; 77: 377-80.
19. Bryceson ADM, Pfaltzgraff RE. Symptoms and signs. In:
Bryceson ADM, Pfaltzgraff RE, editors. Leprosy, 3rd edn.
REFERENCES Edinburgh: Churchill Livingstone;1990. 25-54.
20. Thangaraj RH. Clinical examination. In: Thangaraj RH, (Ed).
1. Sardana K. A study of leprosy in children from a tertiary pediatric
A manual of leprosy, 4th edn. New Delhi: The Leprosy Mission,
hospital in India. Lepr Rev 2006; 77: 100-02.
Southern Asia; 1985. 78-87.
2. Pfaltzgraff RE. What is the actual male/ female ratio in leprosy
21. Shaw IN, Ebenezer G, Babu B, et al. Borderline tuberculoid
patients. Lepr Rev 2003; 73: 180-81.
leprosy of the scalp. Lepr Rev 2001; 72:357-61.
3. Shale MJH. Women with leprosy. A woman with leprosy is in
22. Kumar B, Kaur I, Rai R, et al. Involvement of male genitalia in
jeopardy. Lepr Rev 2000; 71: 5-17.
leprosy. Lepr Rev 2001; 72:70-77.
4. Heynders ML, Meijs JJ, Anderson AM. Towards an
understanding of non compliance. An assessment of risk factors 23. Indira D, Kaur I, Sharma VK, et al. Palmoplantar lesions in leprosy.
for defaulting from leprosy treatment. Lepr Rev 2000; 71: Indian J Lepr 1999; 71:167-72.
369-76. 24. Ghorpade A, Ramanan C. Primary penile tuberculoid leprosy.
5. Nunzi E, Fiallo P. Differential diagnosis. In: Hastings RC, Diltor Indian J Lepr 2000; 72:499-500.
VAO (Eds). Leprosy. 2nd edn. Edinburgh: Chuchill Livingstone; 25. Jopling WH, McDougall AC. The disease. In: Jopling WH,
1994.pp 291-315. McDougall AC, (Eds). Handbook of leprosy. 5th edn. Delhi: CBS
6. Withington SG, Joha S, Baird D, et al. Assessing socioeconomic Publishers and Distributors;1996. 10-53.
factors in relation to stigmatization, impairment status and 26. Srinivasan H, Dharmendra. Treatment of ulcers in leprosy
selection of socio-economic rehabilitation: a 1 year cohort of patients. In: Dharmendra (Ed). Leprosy. Bombay: Kothari Medical
new leprosy cases in north Bangladesh. Lepr Rev 2000; 71: Publishing House;1978. 599-616.
120-32. 27. Owen BM, Stratford CJ. Assessment of the methods available
7. Pfaltzgraff RE, Ramu G. Clinical leprosy. In: Hastings RC, Diltor for testing sensations in leprosy patients in a rural setting. Lepr
VAO, editors. Leprosy. 2nd edn. Edinburgh: Churchill Rev 1995; 66:55-62.
Livingstone;1994;237-86. 28. Brandsma JW, Van Brakel WH. WHO disability grading:
8. WHO Expert Committee on leprosy, 7th report. WHO Technical operational definitions. Lepr Rev 2003; 74:366-73.
Report Series No 874.Geneva: World Health Organization;1998; 29. Virmond M. Indications for surgery in leprosy. Lepr Rev 1998;
1-43. 69: 297-304.
9. Thompson K, Daniel E. Management of ocular problems in 30. Markendeya N, Srinivas CR. Ninhydrin sweat test in leprosy.
leprosy. Indian J Lepr 1998;70:295-315. Indian J Lepr 2004; 76:299-304.
10. Bryceson ADM, Pfaltzgraff RE. Complications due to nerve
31. Girdhar BK, Desikan KV. A clinical study of the mouth in untreated
damage. In: Bryceson ADM, Pfaltzgraff RE, editors.Leprosy, 3rd
lepromatous patients. Lepr Rev 1979; 50:25-35.
edn. Edinburgh: Churchill Livingstone; 1990;133-52.
32. da Costa APF, da Costa Nery JA, de Oliveira MLW, et al. Oral
11. Sabin TD, Swift TR, Jacobson RR. Leprosy. In: Dyck PJ, Thomas
lesions in leprosy. Indian J Dermatol Venereol Leprol 2003; 69:
P, editors. Peripheral neuropathy, 4th edn. Philadelphia: Saunders;
381-85.
2005. 1354-80.
33. Singh G, Nagaraja, Prabhu S. Leprosy presenting as
12. Van Brakel WH, Khawas IB. Nerve damage in leprosy: an
macrocheilia. Indian J Lepr 1999; 71:341.
epidemiological and clinical study of 396 patients in west Nepal.
34. Kumar B, Rai R, Kaur I. Systemic involvement in leprosy and its
Part 1. Definition, methods and frequencies. Lepr Rev 1994; 65:
204-21. significance. Indian J Lepr 2000; 72: 123-42.
13. Van Brakel WH, Nicholls PG, Das L et al. The INFIR cohort 35. Daniel E. Lagophthalmos in leprosy. Indian J Lepr 1998; 70:
study: investigating prediction, detection and pathogenesis of 39-47.
neuropathy and reaction in leprosy. Methods and baseline results 36. Inamadar AC, Palit A. Bilateral facial palsy in Hansen’s disease.
of a cohort of multibacillary leprosy patients in north India. Lepr Lepr Rev 2003; 74:383-85.
Rev 2005; 76:14-34. 37. Khan A, Sardana K, Koranne RV, et al. Bilateral seventh nerve
14. Klioze AM, Ramos-Caro FA. Visceral leprosy. Int J Dermatol palsy – a manifestation of polyneuritic leprosy. Indian J Lepr
2000; 39: 641-58. 2005; 77:140-46.
15. Trindade MAB, Manini MIP, Masetti JH, et al. Leprosy and HIV 38. Passerotti S, Salotti RA, Vieth H. Assessment and treatment of
co-infection in five patients. Lepr Rev 2005; 76: 162-66. the dry eye in leprosy. Indian J Lepr 1998; 70:103-08.
16. Petri WA, Jr. Chemotherapy of Tuberculosis, Mycobacterium 39. Yawalkar SJ. Deformities and their management. In: Yawalkar
avium complex disease and leprosy. In: Brunton LL, Lazo JS, SJ, editor. Leprosy for medical practitioners and paramedical
Parker KL, (Eds). Goodman and Gillman’s The Pharmacological workers, 6th edn. Basle: Ciba Geigy Ltd; 1994. 92-133.
Basis of Therapeutics. 11th edn. New York: McGraw Hill; 2006. 40. Das S. Examination of peripheral nerve lesions. In: Das S, editor.A
1203-41. manual on clinical surgery, 6th edn. Calcutta: Dr. S.Das; 2007.
17. Knowels SR, Shear NH. Cutaneous drug reactions with 90-105.
systemic features. In: Wolverton SE, (Ed). Comprehensive 41. Brown TR, Kovindha A, Wathanadilokkol U, et al. Leprosy
dermatologic drug therapy, 2nd edn. Philadelphia: Saunders; neuropathy: correlation of clinical and electrophysiological tests.
2007. 977- 90. Indian J Lepr 1996; 68:1-14.
CHAPTER
10
42. McDougall AC. The clinical examination of peripheral nerves in 49. Pearson JMH, The evaluation of nerve damage in leprosy. Lepr
leprosy. Indian J Lepr 1996; 68:378-79. Rev 1982; 53:119-30.
43. Desikan KV, Anbalagan J, Maheshwari PK. Pure neuritic leprosy 50. Brandsma JW. Monitoring motor nerve function in leprosy
of supraorbital nerve as unusual presentation. Indian J Lepr patients. Lepr Rev 2000;71:258-67.
2001; 73:47-50. 51. Srinivasan H. Guidelines for implementing disability prevention
44. Dhar S, Sharma VK, Kaur S. Facial, glossopharyngeal, vagus programme in the field. Indian J Lepr 1999; 71(S):541-612.
and hypoglossal nerve palsy in a case of lepromatous leprosy. 52. Bourrel P. Two objective ‘Archivable” tests for voluntary muscle
Indian J Lepr 1993;65:333-36. testing in ulnar and median nerve paralysis. Indian J Lepr 1997;
45. Siddappa K, Inamadar AC, Reddy LS. Destruction of ala nasi
69:13-23.
and loss of columella in borderline tuberculoid leprosy—a case
53. Brandsma JW, Schwarz RJ. Re-enablement of the neurologically
report. Indian J Lepr 1989; 61:113-14.
impaired hand – 1: terminology, applied anatomy and assessment.
46. Srinivasan H, Dharmendra. Deformities of hands. In:
Report of a Surgical Workshop held at Green Pastures Hospital
Dharmendra, (Ed). Leprosy. Bombay: Kothari Medical Publishing
and Rehabilitation Centre, November 2004, Pokhara, Nepal. Lepr
House;1978. 205-17.
47. Schwarz RJ, Brandsma JW. Re-enablement of the neurologically Rev 2006; 77:317-25.
impaired hand – 2: Surgical correction. Report of a Surgical 54. Kumar B, Kaur S, Kaur I, et al. Concomitant occurrence of leprosy
Workshop held at Green Pastures Hospital and Rehabilitation and tuberculosis. A clinical, bacteriological and radiological
Centre, November 2004, Pokhara, Nepal. Lepr Rev 2006; evaluation. Lepr India 1982; 54:671-76.
77:326-42. 55. Nishida M, Nakamura Y, Aosaki N. Prevalence and
48. Lumley JSP. Peripheral nerve injuries. In: Hamilton Bailey’s characteristics of depression in a Japanese leprosarium from
physical signs. Demonstration of physical signs in clinical the view points of social stigma and ageing. A preliminary report.
surgery. 18 th edn. Oxford: Butterworth-Heinemann;2000. 411- Lepr Rev 2006;77:203-09.
18.
CHAPTER
11
11
Classification
Radhe Shyam Mishra, Joginder Kumar
INTRODUCTION the tuberculoid and lepromatous which came to be regarded

as polar types; a widespread discontentment among the
Leprosy is a chronic disease with the manifestations as
leprologists had been simmering over maculoanesthetic
varied as the single cutaneous/nerve lesion to the
lesions and pure neuritic cases. The confusion over
involvement of whole of the integument and systemic
placement of the maculoanesthetic lesions and pure
organs. The disease can present with predominantly neural
neuritic types became so obvious at the Tokyo International
symptoms or mainly with the cutaneous involvement. In
Leprosy Conference in 1958 that the decision to categorize
ancient India the disease had been called ‘vat rakta’
these cases was left to the individual leprologist.5
denoting the cases with neural component while ‘arun
Since long the Indian leprologists regarded the
kushta’ represented the cutaneous form of leprosy.1 This
maculoanesthetic and pure neuritic forms as distinct
categorization was almost similar to the classification entities and to remove the confusion surrounding these
prevalent elsewhere dividing the leprosy into the nodular categories the Indian classification was drafted in 1953,
and anesthetic groups.2 This simplicity of classification just a little before the Madrid classification came into
was also seen even in 20th century when the Leonard existence. The Indian classification had been proposed
Wood Memorial in Manila in 1931 evolved an international by Dharmendra and Chatterjee on behalf of Indian
system of classification for the first time. 3 In this Association of Leprologists (IAL). It was almost similar to
classification the disease had been categorized into the Madrid classification and was officially accepted and
cutaneous, neural and mixed types. This Manila adopted by the Indian Association of Leprologists in 1955.6
classification formed the basis of future classifications In 1962, the spectral classification was advanced by
and underwent several transformations that finally Ridley and Jopling calling it a classification for research
culminated in the so called International or Madrid purposes.7 This five group classification was detailed
classification in 1953 which became the official further in 1966.8 and later on called Ridley and Jopling
classification of international bodies.4 In the following classification. It failed to excite leprologists initially but
period, the terminology changed with various modifications. slowly gained global acceptance. The high point of this
The term cutaneous was replaced by lepromatous that classification was its precision and stress upon the disease
represented a widespread involvement of the skin and the as a spectrum, dictated by the immunological response of
term neural got replaced by tuberculoid that represented the patients.
raised lesions with neural deficit. These terms – tuberculoid In the year 1982, to give a momentum to the leprosy
(tuberculosis like histopathology) and lepromatous (foam control, the WHO gave definitiveness to the treatment of
cell histopathology) had initially depicted the pathological leprosy by introducing the concept of fixed duration
changes but later acquired the clinical dimensions multidrug therapy (FD-MDT). For FD-MDT the disease was
representing specific clinical and morphological lesions. categorized into paucibacillary (PB) and multibacillary (MB)
Throughout the evolution of classification while there was on the basis of lesional bacterial density as estimated by
no conflict over the specific and definite entities namely bacterial index in slit skin smears.9 To overcome the
CHAPTER
11
Classification 145
operational difficulties, especially at the field worker level, meet everyone’s expectation though desirable may be very
the necessity of slit skin smear was done away in 1998 difficult to arrive at. Defining the criteria for any type of
and a clinical criterion in the form of number of skin lesions categorization is crucial, for the specific groups of workers
was added to this categorization.10 Henceforth, all the may lay more stress upon certain specific parameters
patients with six or more skin lesions were also to be more useful to them. Leprosy may be classified based
classified as MB without any reference to the slit skin upon bacteriological, immunological, clinical or
smears. This newer classification as such or with some histopathological parameters individually or by using a
minor modification is now being followed in the Leprosy correlated combination of these.
Eradication Program in India as well as all over the world.
At present the most common classifications in use Bacteriological Criteria
the world over, are the WHO classification for treatment The Bacterial Index (BI) is a measure of the density of the
purposes; and Ridley-Jopling classification for academic organisms in the lesional tissue and is estimated by slit-
and research purposes. skin smear technique or in a biopsy specimen. The latter
is more sensitive 11 but technically is not feasible
NEED FOR CLASSIFICATION universally. The skin smears are easier to perform and
The wide variation in the disease presentation, its course, their specifications and grading criteria have been
prognosis and complications forces one to consider these standardized. They are regarded as the gold standard for
variants as distinct entities making the classification a the bacteriology based WHO classification for treatment
purposes.
contentious issue. The classification becomes important
to thread these entities as a single disease yet maintaining Infective (open) and Non-infective Categorization
the distinctiveness of each one of these.
In this epidemiologically valuable classification, the patient
With the WHO guidelines for leprosy control programs,
is classified as an open and infective case if his routine
the classification assumes utmost importance to decide
slit skin smears or nasal scrapings demonstrate bacilli.12
upon the line of treatment. The correct classification not
only helps to decide upon the treatment options but the Immunological Factors
clinician can visualize beyond the present stage of the
disease also. He can envisage the nature, progression The basic immunological aberration in leprosy, the specific
and prognosis of the patient’s disease with the relative deficiency of cell mediated immunity against M.leprae, is
risk to development of deformities and his response to the measured indirectly by lepromin testing and the patients
classified as lepromin positive (good immunity) to lepromin
therapy. The frequency and the type of lepra reaction that
negative (poor immunity) on a standard scale. The
the patient is likely to undergo also becomes clear. The
categorization into immune and non-immune status may
clinician can educate the patient and plan for the future to
be perceived as a better predictor of the course of the
prevent the deformities. The infectivity of a case and its
disease than any other criterion. The test is also very useful
epidemiological importance can also be determined.
in classifying the ‘difficult to classify cases’ (i.e. the
The comparison of clinical, histopathological,
indeterminate and pure neuritic leprosy) into lepromatous
bacteriological and immunological parameters among the
or non lepromatous categories.
classified groups helps to understand the finer nuances of
the disease. A uniform classification helps in Histopathological Features
communication with the other workers, sharing the ideas
on a common platform and the comparison of data The histopathological observations reflect the actual
becomes more clear and realistic. processes going on inside the body in the form of tissue
reactions to the injury or insult. The varied lesions of leprosy
have distinct histopathological pictures which form a good
CLASSIFICATION CRITERIA
ground for the classification. The histopathological features
For a clinician the issues pertaining to the treatment are have been precisely defined and can be described as the
vital while an epidemiologist or a research worker has most definitive criteria for defining the different entities.
different perceptions altogether. A single classification to The interpretations are not influenced by external factors,
CHAPTER
11
are less prone to the subjective errors and are not erratic Lepromatous Type (L)
as the clinical judgment at times tends to be. However, Macular
histological studies are tedious to perform and it is not Diffuse
Infiltrated
practicable to apply them universally over a large leprosy
Nodular
population. Neuritic, pure (?)
Tuberculoid Type (T)
Clinical Features Macular (Tm)
Minor tuberculoid (micropapuloid) (Tt)
A classification based on the clinical features is the easiest Major tuberculoid (plaques, annular lesion etc.) (TT)
to apply and the most desirable because the clinician has Neuritic, Pure (Tn)
the advantage of examining the patient in entirety rather Indeterminate Group (I)
Macular (Im)
than looking at selected presented material. It can be used Neuritic type (In)
even at the distant peripheral level by a health worker. Borderline (Dimorphous) Group (B)
The typical morphological descriptions may be used Infiltrated
(Others ?)
(macular, nodular, etc.) or classification can have a well
defined terminology denoting clinical picture (tuberculoid, Fig. 11.1: The Madrid classification (1953)
lepromatous, etc.). The presently used WHO classification
for leprosy control is entirely based on clinical features.
All other classifications in practice have used a THE INDIAN CLASSIFICATION6 (FIG. 11.2)
combination of these parameters.
The well accepted classifications include Madrid, Indian, The Indian classification was drafted on behalf of the Indian
new IAL, Ridley- Jopling, and WHO classification for leprosy Association of Leprologists (IAL) at almost the same time
control. as the Madrid classification (1953) but was accepted and
adopted in 1955. The Indian leprologists were not satisfied
THE MADRID CLASSIFICATION4 (FIG. 11.1) with the earlier international classifications (prior to Madrid
classification). The main objection was that the
Conceived and adopted at the International Leprosy
classification criteria were not entirely clinical and their
Congress held at Madrid in 1953, this classification was
applicability and usefulness at all levels of leprosy workers
regarded as a major improvement over the preceding ones.4
was doubtful. There was much confusion regarding the
Often referred to as The International Classification, it
categorization of maculoanesthetic and pure neuritic
included two types and two groups. The term ‘Type’ denoted
leprosy which were thought to be separate entities. The
definite and typical clinical entities while the ‘Groups’ were
maculoanesthetic was said to be a separate category
less distinct non typical entities. The two types were
Lepromatous (L) and Tuberculoid (T); while the two groups because of the flat lesions in contrast to the raised lesions
were Indeterminate (I) and Borderline or Dimorphous (B). of tuberculoid.13
The morphological subtypes had been added up under each The Indian classification recognized six groups that
of these entities and were called the varieties. Though the included maculoanesthetic and pure neuritic as separate
classification was exhaustive, yet the pre-existing categories (Fig. 11.2). The classification was kept flexible
objections could not be done away with entirely. Many a for workability at various levels i.e. for field workers it was
leprologist earlier tended to regard pure neuritic leprosy as made to be a three group classification comprising (1) Non-
a homogenous clinical entity and its placement under lepromatous (N) that collectively included tuberculoid,
different categories was not considered to be justified. maculoanesthetic and polyneuritic, (2) Lepromatous (L)
However, in the present perspective of better understanding, and (3) Intermediate (N?L) group. The latter entity (N?L)
the so called splitting of pure neuritic cases under different was applicable to doubtful classification cases. On the
types appears to be more appropriate. The pure neuritic other hand the research workers could go further than the
type under lepromatous group and that under tuberculoid simple six groups mentioned and could classify even up
group are likely to differ in their course and prognosis and to varieties or subtypes (i.e. nodular, macular etc). The
would also be treated on different lines. It is a different slit-skin smear studies, if possible, could be used as an
matter altogether that the existence of pure neuritic variety additional criteria and the positivity denoted by putting a
under lepromatous group is still doubtful. sign of + after the disease entity i.e. T+ or I+.
CHAPTER
11
Classification 147
1. Lepromatous (L) extremes which are more or less immunologically stable.

2. Tuberculoid (T) Between these two polar forms lies a big immunologically
3. Maculoanesthetic (MA) unstable borderline group which has been subdivided into
4. Polyneuritic (P)
5. Borderline (B)
three categories- borderline tuberculoid (BT), mid borderline
6. Indeterminate (I) or borderline borderline (BB) and borderline lepromatous
(BL). BB is the most unstable form of the leprosy. All
Fig. 11.2: The Indian classification (1955) these entities form a continuous spectrum with frequent
transformation of one form into another especially among
NEW IAL CLASSIFICATION14 (FIG. 11.3) the borderline group by the process of the so called
upgrading or downgrading. The clinical, histopathological,
A modification in the Indian Classification had been adopted bacteriological and immunological features show slow but
in 1981 by the Indian Association of Leprologists (IAL) continuous changes from one pole to the other pole. For
wherein the maculoanesthetic leprosy (MA) was merged example the immunity decreases while the lesional
with tuberculoid leprosy (T). The resultant five group bacterial density increases from TT to LL pole. The
classification was called the New IAL Classification of immunological variation also manifests as lepromin
Leprosy. positivity in tuberculoid and negativity in the lepromatous
type. The spectral concept helps to understand all these
1. Lepromatous (L) entities as denominations of a single disease in spite of
2. Tuberculoid (T)
3. Polyneuritic (P)
their diverse course and prognosis. One can predict the
4. Borderline (B) course, outcome and complications of a patient’s disease
5. Indeterminate (I) depending upon its place in the spectrum. It also helps us
to understand leprosy reactions in their true perspective.
Fig. 11.3: The New IAL classification (1981)
The advantages of Ridley-Jopling classification are that
not only it is easier to comprehend but it also helps to
RIDLEY-JOPLING CLASSIFICATION 7,8 understand the disease and its nuances in a better way. It
(FIG. 11.4) also strengthens the polar and spectral concept. It is based
on the foundation of correlationship among the various
Also referred to as the immunological classification, the
parameters that describe the entities more precisely. For
Ridley-Jopling classification (R-J classification) is based
these reasons, this classification has now been widely
upon the fact that bacteriological, immunological,
accepted. Initially suggested as classification for research
histopathological and clinical features of leprosy are purposes, this classification has almost replaced the other
intrinsically interwoven. After bacteriological invasion the classifications even for the clinical purposes (with inclusion
immunological factors come to play in the form of cell of indeterminate as a separate entity by some workers).
mediated immunity (CMI) and delayed type of
The main drawback of Ridley-Jopling classification is
hypersensitivity (DTH) determining the tissue reactions
that there is no specific place for the indeterminate and
and the resultant clinical picture. In effect this is the
pure neuritic leprosy in the spectrum. The indeterminate
classification based upon the correlation of all these leprosy had been regarded as the incipient stage of leprosy
parameters. Most important aspect is the emphasis on that has not yet fully evolved to be classifiable in the
the spectral concept of leprosy. spectrum as the features are rather vague.15 Though it is
It is essentially a five group classification with two polar
not part of the spectrum yet it can be placed near tuberculoid
forms – tuberculoid (TT) and lepromatous (LL) at the two
or near lepromatous end of the spectrum depending upon
the lepromin testing and slit-skin smear results. The pure
1. Tuberculoid leprosy (TT) neuritic leprosy was said to have evolved by a similar
2. Borderline tuberculoid leprosy (BT) pathogenetic mechanism, through the same immunologic
3. Mid-borderline leprosy (BB) interactions as that of the skin lesions and hence needed
4. Borderline lepromatous leprosy (BL)
5. Lepromatous leprosy (LL) to be classified with in the TT-LL spectrum in the similar
manner, on the same criteria.16 The pure neuritic cases
Fig. 11.4: Ridley-Jopling classification (1966) can be classified into any of five types on the basis of
CHAPTER
11
number of nerves involved, lepromin testing and through a borderline phase while TTs is said to arise by
histopathology. upgrading from borderline leprosy. However, the
In general, the bacteriological and immunological immunological behavior of TTp and TTs does not equate
parameters do not present any problem in correlating them to that of LLp and LLs.
with the various subtypes; rather it is the clinico-
histopathological discordance that may cause confusion. THE WHO CLASSIFICATION (1988) FOR
The histopathological concordance with the clinical features LEPROSY CONTROL PROGRAMS9,10,26
has been reported to be about 70-98%.17-21 In a large series (FIG. 11.5)
of 2696 leprosy biopsies, the histopathological picture
This happens to be the most important categorization of
coincided with the clinical diagnosis in 98%, 97%, 95%,
the disease for any treating leprologist. The patients are
89%and 87% in LL, TT, BT, BB and BL disease respectively,
categorized into paucibacillary (PB) or multibacillary (MB)
which appears to be quite satisfactory.21 However, it must
leprosy depending upon whether the slit skin smears
be remembered that any change in pathological picture
demonstrate any bacilli or not. The concept was conceived
may be reflected clinically only after 2-3 months and some and implemented in 1982.9 Earlier the cases with a bacterial
degree of discordance may be observed which can be index of 2 or less had been categorized as paucibacillary9
explained on this basis, especially discordance of one step but later on, for feasibility and operational difficulties, all
higher or lower.15 Moreover, the clinical diagnosis is more the patients with demonstrable bacilli in slit skin smear
prone to the error depending upon the clinician’s alertness without any reference to bacterial index were to be
and his/her expertise while histopathological interpretations categorised as multibacillary.26
do not show much subjective variations. Here again, it
should be remembered that the biopsy sample sent for 1. Paucibacillary leprosy
the histopathological evaluation, may also have missed It included only smear negative cases belonging to
the granuloma, which may reflect in discordant clinical a. Indeterminate (I), tuberculoid (TT), and borderline
tuberculoid (BT) cases as classified under Ridley-Jopling
and histopathological observations.
classification and
The suitability of this classification for the field level b. indeterminate (I), and tuberculoid (T) cases under Madrid
worker is open to discussion. classification
2. Multibacillary leprosy
included all
CONCEPT OF POLAR AND a. mid-borderline(BB), borderline lepromatous (BL), and
SUBPOLAR FORMS lepromatous (LL) under Ridley-Jopling classification and
b. borderline (B) and lepromatous (L) cases under the Madrid
The LL group at the pole appears to be heterogeneous and classification
includes two subgroups named polar LL (LLp) and subpolar c. any other smear positive case
LL (LLs). The LLp is immunologically stable and starts as

Fig. 11.5: WHO classification (1988)
lepromatous and remains lepromatous throughout without
any downgrading while LLs, (earlier called LI or leproma The pure neuritic leprosy deserved special comments.
indefinite),22 is immunologically unstable and originates While most of these cases were said to belong to the
from downgrading of borderline group. It may even upgrade paucibacillary group, the correct classification was
afterwards. The LLs may still have some lesions of its considered difficult. Lepromin testing, number of nerves
predecessor borderline leprosy as the evidence of having involved and nerve biopsy were thought to be some useful
downgraded from it and also has lesser foamy changes parameters towards classification of these pure neuritic
histologically.23 It has somewhat higher immunity and cases.
occupies the place between LLp and BL in the spectrum. This strategic WHO classification for control programs
During an upgrading reaction LLs may regain its lost cell was necessitated to streamline and optimize the limited
mediated immunity.24 On the tuberculoid end of the resources to overcome the financial constraint. The large
spectrum a similar sub-classification has been predicted number of patients and operational difficulties had to be
in the form of primary (TTp) and secondary (TTs) types.25 kept in mind. The basis of this categorization had been
The TTp originates as polar tuberculoid never having gone the observation that paucibacillary patients have the
CHAPTER
11
Classification 149
bacillary count of less than 106 log and hence the drug The main objection to this solely operational
resistant mutants are unlikely to originate.9 In multibacillary classification is the wrong categorization of some MB
forms the number is likely to exceed 106 log and the cases into PB that may result in under treatment, hence
chances of at least one mutation leading to drug resistant the increased possibility of relapse and emergence of drug
organisms is strong. The classification was established resistance. The apprehension may not be totally
once the field trials and studies justified segregation of these unfounded.29-32 However, on operational side, since 1985
two groups for treatment purposes as the less bacillated more than 14 million leprosy cases have been treated using
patients could be treated with lesser number of drugs for MDT with only very few relapses and hence its performance
shorter period; while to control the heavily bacillated cases appears to be satisfactory.33 It is the success of MDT
one needed additional drugs for longer periods. based control programs that gave an impetus to the
activities making the target of leprosy eradication
THE WHO CLASSIFICATION (1998) achievable. The sensitivity and specificity of this
FOR LEPROSY CONTROL PROGRAMS classification has been reported to be about 90%.34,35
(FIG.11.6) Moreover, a good clinical examination by an experienced
clinician may further increase its sensitivity.34 Inclusion
Application of slit skin smears universally and to maintain of the number of involved nerves (not included in the WHO
their quality control emerged as the biggest hurdle in the 1998 classification) as an additional criterion, may add up
implementation of control programs.27, 28 The operational on the sensitivity of this classification. 32,35 Later on, NLEP
problems led to the suggestion of doing away with the in collaboration with Global Alliance for leprosy elimination
skin smear if it is not practicable and the new criterion of and WHO; prepared a document on classification of leprosy
paucibacillary and multibacillary categorization, proposed wherein, the nerve involvement was kept as a factor to
in 1998 by WHO was based upon the total number of classifying leprosy into paucibacillary & multibacillary
leprosy lesions in the patient.10 This is a corollary to the forms.36
fact that paucibacillary patients have good immunity and Presently in India the number of nerves involved is
present with only a limited number of lesions. Furthermore also taken into consideration while categorizing the patients
the single lesion leprosy was also segregated on the ground into paucibacillary and multibacillary types as per criteria
that this can be treated with the limited amount of laid down under the National Leprosy Eradication
chemotherapy. On the practical side the WHO expert Programme (NLEP) of Government of India37 (Fig. 11.7)
committee’s conclusions about new classification based which are similar to those of the International Federation
on the number of lesions translated as shown in of Anti-leprosy associations (ILEP).38 Inclusion of the factor
Figure 11.6. of nerve involvement becomes important especially in pure
neuritic leprosy which constitutes about 4-5% of all leprosy
1. Paucibacillary single lesion leprosy (SLPB); cases in our country39-41 with more than one nerve
2. Paucibacillary leprosy (2-5 skin lesions); involvement in over 60% of these.40 Henceforth an MB
3. Multibacillary leprosy- six or more skin lesions and also, all
smear positive cases. case has been defined as the one having six or more lesions
and/or more than one nerve involvement and/or a positive
Fig. 11.6: WHO classification based on the number skin smear from any site.
of lesions (1998) Presently all over the world the treatment guidelines
as proposed by WHO (with or without some modifications)
It should be emphasized that the classification based are being used. A plan for uniform MDT (U-MDT) is already
on the number of lesions is not intended to replace the under trial by WHO42 and if it succeeds, soon the present
previously defined paucibacillary and multibacillary WHO classification will loose its relevance.
definitions. Wherever skin smears are practiced any patient
with positive smear should be placed in multibacillary type
CORRELATION AMONG VARIOUS
irrespective of the number of lesions. Skin smears (if
CLASSIFICATIONS
performed) remain the gold standard for the classification.
Presently the single lesion leprosy has been merged with There is not much difference in the Madrid and Indian
the paucibacillary type for treatment purposes. classifications. Tuberculoid, lepromatous, borderline and
CHAPTER
11
Sr. No. Characteristics PB MB

1. Skin lesions 1-5 lesions 6 and above
2. Peripheral nerve involvement No nerve/ only one nerve with or More than one nerve irrespective of the
without 1-5 lesions number of skin lesions
3. Skin smears Negative at all sites Positive at any site
Note: if skin smear is positive, irrespective of number of skin and nerve lesions, the disease is classified as MB leprosy but if skin smear
is negative it is classified on the basis of the number of skin and nerve lesions.
Fig. 11.7: Classification under NLEP, India (2009)
indeterminate remain the same entities in both these 2. Danielssen DC; Boeck CW. Traite de la Specalsked ou
elephantiasis de grecs. Bailliere. Paris. 1848.
classifications. The maculoanesthetic of Indian
3. Leonard Wood Memorial Conference on Leprosy. Round Table
classification corresponds to the macular variety of Conference in Manila. Philippine Journal of Science.1931; 44:449.
tuberculoid under Madrid classification while the neuritic 4. International Congress of Leprosy, Madrid. Report of the
leprosy of Indian classification represents a heterogenous committee on classification. Int J Lepr 1953; 21:504-16.
5. International Congress of Leprosy, Tokyo: Report of the
group that has been split and placed separately as varieties
Committee on Classification. Int J Lepr 1958; 26:379-84.
under tuberculoid, lepromatous and indeterminate in the 6. All India Leprosy Workers Conference 1955. Classification of
Madrid classification. The borderline group is very broad leprosy adopted by the Indian Association of Leprologists. Lepr
in both these classifications and includes all three subtypes India 1955; 27: 93-95.
7. Ridley DS, Jopling WH. A classification of leprosy for research
of borderline in Ridley-Jopling classification. Under Ridley- purposes. Lepr Rev 1962; 33:119-128.
Jopling classification the maculoanesthetic type of Indian 8. Ridley DS, Jopling WH. A classification of leprosy according to
classification has been included in the tuberculoid while immunity- a five- group system. Int J Lepr 1966; 34:255-273
the indeterminate has been left unclassified. Similarly the 9. WHO Study Group. Chemotherapy of leprosy for control
programmes. Geneva: World Health Organization. 1982. Tech
pure neuritic of Madrid and Indian classifications has not Rep Ser 675.
been separated as distinct entity in Ridley-Jopling system 10. WHO Expert Committee on Leprosy. Seventh report. Geneva:
but is to be classified under the TT-LL groups on the basis World Health Organization. 1998. Tech Rep Ser 874.
of lepromin and histopathology. In WHO classification also, 11. Bhushan P, Sardana K, Koranne RV, Choudhary M, Manjul P.
Diagnosing multibacillary leprosy: A comparative evaluation of
the pure neuritic leprosy does not find any place as such diagnostic accuracy of slit-akin smear, bacterial index of
but can be classified as MB or PB on the basis of number granuloma and WHO operational classification. Indian J Dermatol
of nerve involvement, lepromin testing and nerve biopsy. Venereol Leprol 2008; 74:322-26.
12. Dharmendra, Chatterjee SN. Examination for Mycobacterium
Relationship of Ridley-Jopling classification and Madrid
leprae. In: Dharmendra (edit). Leprosy. Vol-1. Bombay: Kothari
classification with WHO classification has already been Medical Publishing House 1978; 258-62.
mentioned under definitions of paucibacillary and 13. Dharmendra. The International Classification. In: Dharmendra
multibacillary leprosy. The corresponding categories under (edit). Leprosy. Vol-1. Bombay: Kothari Medical Publishing
House. 1978;326-29.
Indian classification for paucibacillary include tuberculoid,
14. Clinical, Histopathological, and immunological features of the
maculoanesthetic and indeterminate while borderline and five type classification approved by the Indian Association of
lepromatous belong to multibacillary. Leprologists. Lepr India 1982; 54: 22-32.
A consensus classification that can be applied at all 15. Ridley DS. Classification. In: Chatterjee BR (Ed), Leprosy-
Aetiobiology of manifestations, treatment and control. Published
levels of leprosy work has not yet been worked out. for Leprosy Field Research Unit, Jhalda, West Bengal. Printed
Presently, the WHO classification for treatment purposes at Calcutta. Pp 280-93. (Reprinted from ‘A Window On Leprosy’
and Ridley-Jopling classification for academic and research January 1978).
work is being followed satisfactorily. 16. Ridley DS. The R-J classification re-viewed: Classification of
Leprosy- Origin and Outcome. In: Chatterjee BR (Ed), Leprosy-
Etiobiology of manifestations, treatment and control. Published
REFERENCES for Leprosy Field Research Unit, Jhalda, West Bengal. Printed
at Calcutta. 295-97.
1. Kaviraj Kunjlal English translation of Sushrat Samhita in 3 volumes. 17. Bhatia AS, Katoch K, Narayanan RB, Ramu G, Mukharjee A,
Calcutta. 1907, 1911 and 1916. Quoted by Dharmendra. In: Lavania RK. Clinical and histopathological correlation in the
classification of leprosy. classification of leprosy. Int J Lepr 1993; 61: 433-38.
CHAPTER
11
Classification 151
18. Sehgal VN, Rege VL, Reys M. Correlation between clinical and 32. Chandna R, Patnaik A, John O, Rao PSS. Does nerve examination
histopathological classification in leprosy. Int J Lepr 1977; 45: improve diagnostic efficacy of the WHO classification of leprosy?
278-80. Indian J Dermatol Venereol Leprol 2008; 74: 327-30.
19. Narayan NP, Ramu G, Desikan KV, Vallishayee RS. Correlation 33. Global strategy for further reducing the leprosy burden and
of clinical, histological and immunological features across the sustaining leprosy control activities. (Plan period 2006-2010).
leprosy spectrum. Indian J Lepr 2001; 73: 329-42. World health Organization, 2005.
20. McDougall AC, Ponnighaus JM, Fine PE. Histopathological 34. Croft RP, Smith WC, Nicholls P, Richardus JH. Sensitivity and
examination of skin biopsies from an epidemiological study of specificity of methods of classification of leprosy without use of
leprosy in northern Malawi. Int J Lepr 1987; 55: 88-98. skin-smear examination. Int J Lepr other Mycobact Dis 1998;
21. Nadkarni NS, Rege VL. Significance of histopathological 66: 445-50.
classification in leprosy. Indian J Lepr 1999; 71: 325-32. 35. Norman G, Joseph G, Richard J. Validity of the WHO operational
22. Ridley DS, Waters MFR. Significance of variations within the classification and value of other clinical signs in the classification
lepromatous group. Lepr Rev 1969; 40:143-52. of leprosy. Int J Lepr Other Mycobact Dis 2004; 72: 278-83.
23. Ridley DS. Histological classification and the immunological 36. Guide to eliminate leprosy as a public health problem. NLEP,
spectrum of leprosy. Bulletin World Health Organization 1974; India. WHO/CDS/CPE/CEE/2000.14.
51:451-65. 37. Training manual for medical officers: NLEP. Chapter 7.
24. Jopling WH, McDougall AC. The Disease: Handbook of leprosy, Classification and management of leprosy. Directorate of Health
5th edn (International). New Delhi, India. CBS Publishers and Services, Ministry of Health and Family Welfare, Nirman Bhavan,
distributors; 2005 (reprinted). pp10-53. New Delhi. Available on internet: http://nlep.nic.in/training.html
25. Ridley DS. The pathogenesis and classification of polar
(last accessed on 18-02-2009) 54-65.
tuberculoid leprosy. Lepr Rev 1982; 53: 19-26.
38. Learning material on leprosy for capacity building of District
26. WHO Expert Committee on Leprosy. Sixth report. Geneva: World
Nucleus Staff and Medical officers working in Hospital/PHC/
Health Organization. 1988. Tech Rep Ser 768.
CHC and dispensaries. Govt. of India and International
27. Georgiev GD, McDougall AC. Skin smears and Bacteriological
Federation of Anti-leprosy Associations (ILEP). Directorate
Index (BI) in multiple drug therapy control program: an
General of Health Services. Min of Health and Family Welfare
unsatisfactory and potential hazardous state of affairs. Int J Lepr
(leprosy division) 2005. (also available at http://ilepindia.org/).
1988; 56:101-04.
39. Mahajan PM, Jogaikar DG, Mehta JM. A study of pure neuritic
28. Vetton L, Pritze S. Reliability of skin smear results: experience
leprosy: clinical experience. Indian J Lepr 1996; 68:137-41.
with quality control of skin smears in different routine services in
40. Kumar B, Kaur I, Dogra S, Kumaran MS. Pure neuritic leprosy in
leprosy control programs. Lepr Rev 1989; 60: 187-97.
India: an appraisal. Int J Lepr Other Mycobact Dis 2004; 72:
29. Dasananjali K, Schreuder PA, Pirayavaraporn C. A study on the
284-90.
effectiveness and the safety of the WHO/MDT regimen in the
41. Arora M, Katoch K, Natrajan M, Kamal R, Yadav VS. Changing
Northeast of Thailand. A prospective study. 1984-1996. Int J
profile of disease in leprosy patients diagnosed in a tertiary
Lepr Other Mycobact Dis 1997; 65:28-36.
30. Fleury RN, Aranda CM. Detection of AFB in tuberculoid biopsies. care centre during years 1995-2000. Indian J Lepr 2008; 80:
Int J Lepr 1995; 63:103. 257-65.
31. Pardillo FE, Fajardo TT, Abalos RM, Scollard D, Gelber RH. 42. Report of the eighth meeting of WHO Technical advisory group
Methods for the classification of leprosy for treatment purposes. on leprosy control held at Aberdeen, Scotland, April 2006.
Clin Infect Dis 2007; 44:1096-99. Published by WHO regional office, New Delhi, Sept 2006.
CHAPTER
12
12
Case Definition and Clinical Types
Leprosy is a slowly progressive; mildly infectious disease whereas using the "AND" connector, i.e. a combination of
caused by Mycobacterium leprae (M. leprae) complicated two or more signs must be present for the diagnosis,
by potential intermittent hypersensitivity reactions (leprosy increases specificity at the expense of sensitivity). Each
reactions) in its rather placid course. It is a disease which sign is also quite specific in itself so that specificity is
primarily affects the skin and nerves and in highly bacillated high. The most important potential source of error is the
state; the internal organs also. The damage to peripheral reliability of the examination of an individual patient and
nerves results in sensory and motor impairment with reading of the slit skin smear slides, referred to as inter-
characteristic hideous deformities and disabilities so deeply observer variation.2
associated with the stigmatization of the disease. Stigma
remains a major obstacle to the social management of CLINICAL PROBLEMS WITH CARDINAL
leprosy despite good leprosy control as a result of advances SIGNS
in bacteriology, chemotherapy and epidemiology. Early
diagnosis and therapy are most important for the control It is very pertinent to highlight that the diagnosis of leprosy
of disease and prevention of disabilities. Diagnosis and should be made after very careful and detailed clinical
classification of leprosy have been based on the clinical consideration. A useful maxim which should not be
features and skin smears, and histopathology is also forgotten, especially when dealing with children, is: 'when
considered contributory when facilities are available. in doubt, never diagnose leprosy'. The statement like 'you
have suspicious signs of leprosy', should be avoided as
the outlook of society toward leprosy has not changed
CASE DEFINITION
radically even in the 21st century. The psychological and
At the Seventh Meeting of the WHO Expert Committee on emotional distress caused to patients and relatives, by
Leprosy in 19971, a case of leprosy was defined as an diagnosis of leprosy should be kept in mind. When a
individual who has not completed the course of treatment diagnosis is certain, encourage the patient to adopt a
and has one or more of the three cardinal signs responsible attitude towards the disease and its
• Hypopigmented or erythematous skin lesion(s) with management by taking treatment regularly. Even the
definite loss/impairment of sensations; cardinal signs (vide supra) are quite sensitive and specific
• Involvement of the peripheral nerves, as demonstrated but are not infallible in certain situations when the signs
by definite thickening with sensory impairment; are borderline, the intra-observer variation is wide and in
• Skin smear positive for acid-fast bacilli situations where leprosy is very rare and likely to be a
Any one of these signs has been regarded as sufficient diagnosis at the bottom of the list.3 Details are provided
for the diagnosis of leprosy using the "OR" connector so about the occurrence of lesions which may closely mimic
that the sensitivity is high. (The use of OR connector means the situation in leprosy due to nerve involvement or
that only one sign of the several is required for the diagnosis, presence of similar looking skin lesions (see the chapter
sensitivity is increased at the expense of specificity, on differential diagnosis).
CHAPTER
12
Case Definition and Clinical Types 153
Given below are the details of the sensitivity and lesions of leprosy may be labeled as tinea, psoriasis, lupus
specificity of the cardinal signs in the different conditions- vulgaris, etc. and the hypopigmented patches are often
dermatological and non-dermatological. confused with post-inflammatory hypopigmentation,
pityriasis alba, pityriasis versicolor and vitiligo, etc.
Skin Lesions with Sensory Impairment The specificity of the diagnosis based on the presence
Hypopigmented or erythematous patches/plaques are often of anesthetic and hypopigmented or erythematous
the first clinical sign of the disease in many newly diagnosed macular/papular lesions is still more reduced in multi-
leprosy patients. Since many other conditions produce bacillary cases because the lesions can be less distinct
similar lesions, accompaniment of definite sensory loss and less anesthetic. Consequently presence of macular
is a must to be specific for leprosy. Requirement of anesthetic lesions as a single diagnostic criterion for
presence of both the signs together greatly reduces the multibacillary (MB) disease has resulted in up to 30% of
sensitivity of this feature, especially in MB cases where patients being missed; this contrasts with the distinct
lesions are less distinct and less likely to be anesthetic. maculoanesthetic lesions of paucibacillary (PB) disease,
In a most rigorous study carried out in Malawi, sensory which are reportedly diagnostic in 90% of cases. In Ethiopia
examination was done in histopathologically proven where all 3 cardinal signs were used, the diagnostic
paucibacillary (PB) lesions.4 The sensitivity of the loss of sensitivity was 97%.7
touch sensation in a lesion as a diagnostic test was 48.5%
and the specificity 72%. Other published studies gave Peripheral Nerve Trunk Enlargement
higher figures for the sensitivity of this test among PB Peripheral nerve enlargement usually appears later than
patients, 93% from India5, 92% from Bangladesh6 and 86% the skin lesions. The most commonly involved nerves are
from Ethiopia7. It is likely that the mixture of cases in the ulnar and common peroneal. The presence of one or
different stages of evolution and stage of the disease at more enlarged nerves is seen more commonly in
which they were examined, account for some of these multibacillary disease.
differences. However, specificity was not calculated in Thickened nerves are more common in MB than among
these studies. Hypoesthesia in some of the lesions is PB patients in late stages of the disease. Nerve
occasionally seen in conditions other than leprosy such enlargement was found in a greater proportion of new cases
as chronic dermatitis producing thick lichenified skin, which in Ethiopia (ulnar nerve in 68%)7 where the patients typically
may lead to over diagnosis in some situations. present late, than in India (ulnar nerve in 23%)8, where
Very few studies have examined anesthesia as a detection is generally much earlier. Reported figures for
marker in lesions of MB cases, because there is less nerve enlargement in MB and PB patients from Bangladesh
perceived difficulty in the diagnosis, using the traditional are 96% and 86% respectively6, whereas in Ethiopia the
cardinal signs, including skin smears. Published figures corresponding figures were 91% and 76%.7 In a study of
for the sensitivity of anesthesia in skin lesions in MB early PB patients from India, only 20% patients had
patients are almost similar to the figures for PB disease, enlarged nerves.5
i.e. 49% from Bangladesh6 and 54% from Ethiopia.7 The reproducibility and specificity of the examination
In Ethiopia, the sensitivity of this single criterion was for nerve enlargement has been questioned.9 A study from
70% for all patients. A large proportion (74%) of those India found only moderate reproducibility among eight
whose lesions were not anesthetic were smear-positive, experienced paramedical workers.8 False positive findings
and therefore, represented potential source of M. leprae in may occur because of poor examination technique or
the community.7 In other words, employing anesthesia over because of non-specific enlargement of a nerve seen in
the skin patches as the single criterion, almost 30% of some heavy manual workers. On the other hand, some
leprosy patients may be missed and most of them would diseases and conditions with nerve thickening (hereditary
be smear positive. sensory motor neuropathy, Dejerine-Sotta syndrome,
Skin lesions of without sensory loss can also be amyloidosis, and neurofibromatosis) or without nerve
confused with some common dermatoses resulting in thickening (diabetic, alcoholic neuropathy, lead/arsenic
misdiagnosis. In the field conditions, erythematous plaque toxicity, and vitamin B deficiency) may simulate leprosy
CHAPTER
12
like sensory loss; with or without deformities, paralysis, patients as reported in various studies. The inherent
trophic ulcers, etc. problems of skin smears are the logistics and the reliability
To improve certainty of the diagnosis of leprosy, a of the technique of taking, staining, and interpreting the
balanced approach is strongly recommended and it would slides. Skin smears identify those with multibacillary
be the presence of a thickened nerve and one other disease who are the most infectious and also those patients
diagnostic sign such as typical hypopigmented or who are experiencing clinical/bacteriological relapse.14
erythematous skin lesions with or without sensory loss or
typical nerve-function impairment such as loss of sensation CLASSIFICATION OF DISEASE
in the area supplied by the involved nerve.
Neuritic leprosy presents as peripheral neuropathy in Ridely & Jopling (1966) defined 5 groups on the basis of
which there are no skin lesions suggesting leprosy. The clinical, bacteriological, histological and immunological
diagnosis depends on finding definite nerve enlargement features (Table 12.1); tuberculoid leprosy (TT), borderline
with nerve function impairment.10 In Ethiopia, this diagnosis tuberculoid (BT), mid-borderline (BB), borderline
was made in 0.5% of newly detected cases;11 whereas in lepromatous (BL) and lepromatous leprosy (LL).15 This is
India 4.6% of newly detected cases exhibit this form of a very useful classification for research purposes but often
disease.12 In Nepal, 8.7% of new patients in the field were not feasible in field conditions and primary health centers.
found to have neuritic leprosy.13 These patients would be This classification does not include indeterminate and pure
diagnosed by the classical cardinal sign of peripheral nerve neuritic types of leprosy. In general, PB disease is
enlargement but not by the single criterion of an anesthetic equivalent to indeterminate (I), TT and BT, and MB is
skin patch. equated with BB, BL and LL disease. In 1998, the WHO
Expert Committee on Leprosy declared skinslit smears
Slitskin Smears as not essential for institution of MDT. 1 This was
Skin smears have traditionally represented one of the necessitated by the unavailability or unreliability of
cardinal signs of leprosy with the specificity of 100%. technical expertise for the skin smear in many leprosy
However, the sensitivity of this examination alone is low, control programs and the potential for transmitting HIV
because smear positive patients represent 10-50% of all and hepatitis by unsterile techniques.
Table 12.1: Characteristics of Ridley- Jopling classification *

Observations in the TT BT BB BL LL
lesions
Number Usually single Few Several Many, asymmetrical Innumerable,
(up to 3) (up to 10) (10-30) (>30) symmetrical
Size Variable, Variable, Variable Small, some can Small
usually large some are large be large#
Surface Very dry, scaly, Dry, scaly, look bright Dull/ slightly shiny Shiny Shiny
look turgid & infiltrated
Sensations Absent Markedly diminished Moderately Slightly diminished Minimally
diminished diminished,
not affected
Hair growth Absent Markedly diminished Moderately Slightly diminished Not affected
diminished initially@
AFB Nil Nil or scanty Moderate in Many Plenty, including
number globi
Lepromin reactivity Strongly positive Weakly positive Negative/ weakly Negative Negative
(+++) (+ or ++) positive
* Compartmentalization of the features is not very stringent. All these features occur in various combinations as the disease progresses
(AFB) acid fast bacilli, (TT) tuberculoid,
(BT) borderline tuberculoid, (BB) borderline borderline,
(BL) borderline lepromatous, (LL) lepromatous lepromatous.
# Presence of large lesions indicates downgrading of the disease from higher spectrum
@ In disease of long standing - almost all body hair are lost.
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12
For field workers, WHO has classified leprosy based erythematous, anesthetic/ hypoesthetic skin lesion. These
on number of skin lesions for treatment purpose.1 lesions have no distinctive diagnostic features and are
often not reported to the physician. Early tuberculoid lesions
Current WHO Classification are more or less well defined hypopigmented and often
Based on number of skin lesions (for treatment purposes erythematous anesthetic plaques. Early lepromatous
in the field) lesions are vague, ill defined coppery or hypopigmented;
minimally infiltrated macules which are often missed, and
1. Paucibacillary leprosy the disease remains unnoticed until the skin becomes
i. Single skin lesion leprosy (SLPB) infiltrated or gross neurological deficit sets in. Rarely nasal
ii. 2-5 skin lesions stuffiness and epistaxis may be the initial symptoms in
2. Multibacillary leprosy: 6 or more skin lesions lepromatous patients. In some patients the presenting
If facility is available, any patient with positive slitskin complaint is anesthesia with or without muscular weakness
smear should be considered as multibacillary leprosy of the hand or foot; without any apparent skin lesions
noticed by the patient. This could be due to early nerve
CLINICAL FEATURES function impairment when neurological symptoms draw
The clinical features of leprosy reflect the pathology, which attention of the patient towards the disease. A small
in turn is dependent upon the balance between bacillary proportion of such cases may have pure neuritic leprosy.
multiplication and the host cell mediated immune response. Rare presenting complaints may be a result of reactions
Leprosy affects skin, nerves and produces systemic like fever, joint pains, painful erythematous tender
involvement in lepromatous disease. Patients commonly skin lesions, edema of hands and feet and neuropathic
present with skin lesions, weakness of hands or feet or pains.3,17
numbness caused by a peripheral nerve trunk involvement,
deformities, resorption of fingers and toes or a burn or Indeterminate Leprosy
ulcer in an anesthetic hand or foot. Sometime patients It is contended that though most workers consider these
may present in reaction with nerve pain, sudden palsy, lesions under the title 'indeterminate', this is not an
new skin lesions, painful red eye, or a systemic febrile appropriate designation because they have definite clinical
illness. The severity of disease in a given patient may and certain histopathological features and are in the process
vary from the presence of an insignificant hypopigmented of evolution. The first lesion to appear is not infrequently a
anesthetic skin patch; to widespread damage to peripheral medium sized to large hypopigmented patch, often situated
nerves and signs and symptoms suggestive of systemic on the external aspect of the thigh, face, extensor aspects
involvement. of limbs with rather vague edges and some loss of tactile
Leprosy is unique as an infectious disease for the width and thermal sensations (Figs 12.1A to C). With the
of the spectrum of signs and symptoms that it exhibits. progression of disease, similar patches may appear over
Clinical features of the disease are more often the result
other parts of body. The edges of the larger macules are
of the host response to the bacilli rather than of damage
usually fairly definite, whereas the periphery of the smaller
directly due to bacillary invasion.16
macules is indefinite and fades imperceptibly into the
Inspection of the whole body in good light is important,
surrounding skin. Great majority of these lesions are small
because lesions with faint erythema or slight
with somewhat hazy edges. Hair growth and nerve
hypopigmentation, more often on covered areas in
functions are usually not affected. These lesions may be
borderline disease, might be missed. Skin lesions should
slightly dry than the normal adjacent skin and occasionally
be examined for hypoesthesia to light touch, temperature
present with a creased or wrinkled appearance. There may
and for loss of sweating (anhidrosis).
be a suggestion of hypoesthesia; however, usually there
is no morphological change except for a slight change in
EARLY LESIONS AND PRESENTING skin color.18, 19
SYMPTOMS The diagnosis of indeterminate leprosy can only be
The common presenting symptom is an area of variable confirmed when a biopsy has shown the presence of bacilli
sensory loss in the skin or a visible hypopigmented/ or typical perineural infiltration; or when there is definite
CHAPTER
12
A B C
Figs 12.1A to C: Examples of indeterminate leprosy; the patches are faintly visible, with not very clear sensory impairment. The diagnosis
usually requires histopathological evaluation, besides clinical criteria (Photo courtesy: Dr Pankaj Sharma, PGIMER, Dr RML Hospital,
New Delhi)
impairment of sensations. Biopsy may show peri- Tuberculoid Leprosy (TT)

neurovascular infiltrate, however AFBs are mostly not
A benign and relatively stable disease form; infrequently
demonstrable, even by newer molecular diagnostic
positive on bacteriological examination and presents
methods. A striking feature of all these cases is the
clinically as erythematous elevated well defined lesion(s).
variability of the lepromin reaction. It is seldom strongly Sequelae of peripheral nerve involvement appear only in a
positive, may be weakly positive or negative and in some limited proportion of cases. The nerve involvement occurs
instances a negative reaction has been reported to as a result of extension from or through cutaneous nerve
transform to a positive one. Indeterminate leprosy is the branches rather than through systemic dissemination of
first sign of the disease in 20 to 80% of patients.18 When lepra bacilli and hence the nerve damage is patchy,
populations are regularly examined, or patients come asymmetrical and often unilateral.
forward early, it is by far the most common presentation. The skin lesions are single or up to three in number
Many patients, however, do not notice such lesions and and seldom measure more than 10 cm in diameter. The
present only with characteristic determinate lesions at typical lesion is a well-defined erythematous plaque with
some point. raised and clear-cut edges sloping inwards. Many times
Many minor childhood skin ailments like pityriasis alba the center of the lesion is rather flattened and even
may be mistaken for indeterminate leprosy.20 Movement hypopigmented acquiring an annular configuration. Dark
into the tuberculoid pole of the spectrum is indicated by skins may not show the erythema clearly. The surface is
lesions exhibiting increasingly defined margins, dry, hairless, anesthetic and usually scaly. Sensory
hypopigmentation and anesthesia. Perhaps three out of impairment may be difficult to demonstrate on the face
four indeterminate lesions undergo self healing and the because of the generous supply of sensory nerve endings
rest become determinate and enter the clinical spectrum.21 (Fig. 12.2).
The prognosis with treatment is excellent; lesions clear Autonomic nerve damage within the lesions is often
without any reactional or neurological sequelae. When the severe, the surface is dry and sweating is lost. Skin texture
clinical diagnosis of indeterminate leprosy is doubtful and is rough, creases are exaggerated and the lesion has
histology is not available or inconclusive, it is appropriate scanty hair which may be completely lost. Tuberculoid
to keep the said patient in close supervision for few months skin lesions may appear at any site on the skin, though
to observe its course rather than to label a patient having there may be a predilection for body parts not covered by
leprosy and make him/her suffer with the stigma. clothing.22 Usually a solitary peripheral nerve trunk may
CHAPTER
12
to the patch). Thickened nerve may persist for long
after the patch has regressed.
True tuberculoid leprosy is expected to heal itself in
majority of patients even without treatment.25 Since skin
lesions of tuberculoid leprosy seldom lead to significant
peripheral nerve damage or related disability; the prognosis
can be stated to be good. Only if a large nerve trunk is
involved it may lead to gross deformity. When the lesions
are located on the face or on the fingers, some damage
can occur indirectly due to anesthesia.
BORDERLINE LEPROSY
Fig. 12.2: A single patch of TT leprosy with reversal reaction. Note Borderline leprosy spans the spectrum between the
the erythema and scaling in the patch which had sensory impairment tuberculoid and lepromatous poles. It is the most important
(Photo courtesy: Dr HK Kar, PGIMER, Dr RML Hospital, New Delhi)
part of the spectrum in terms of number of patients,
frequency and severity of reactions and nerve damage.
be thickened in the vicinity of a TT lesion, for example, a Patients with borderline disease suffer most of the
thickened ulnar nerve if the lesion is on the fore-arm. On disabilities and deformities seen in leprosy.
slit skin smear examination often no AFBs are found. In this spectrum (also known as dimorphous leprosy),
Lepromin test is strongly positive. Tuberculoid disease it is often possible to find features suggestive of two forms
has also been subdivided into minor and major tuberculoid of leprosy in a single patient. These dimorphous
forms.23,24 appearances reflect the instability of borderline disease.
1. Minor tuberculoid—Skin lesions are usually hypo- Often histology is necessary to appreciate how far the
pigmented, only slightly to moderately elevated, often patient's disease may have shifted from its starting point
only at the margin or even in a part of the margin and on the spectrum. If histology is unavailable, the bacterial
mostly have a irregular surface. The loss of sensation index obtained from a SSS is useful. For accurate
to touch and temperature is common, but presence of classification within the borderline part of the spectrum,
AFB on slit-skin smear (SSS) is very rare. Enlarged careful consideration should be given to various
cutaneous nerve in vicinity of the lesion is infrequently characteristics like the distribution and symmetry of the
found. skin lesions, clarity and type of borders, sensory
2. Major tuberculoid—In general characteristics there is impairment, sweating and hair growth; distribution, extent
little difference between major and minor lesions. This and nature of peripheral nerve damage; mucosal and
division is arbitrarily for convenience; the difference is systemic involvement and presence of slitskin smear
seen in the degree and not the nature of changes. Major positivity.26
tuberculoid lesions manifest in individuals in whom there Patients who are untreated, or inadequately treated or
is an active, severe immune response in skin and who have relapsed, may downgrade towards the
nerves to the presence of M. leprae. Lesions are well lepromatous pole and may finally lose all CMI responses
defined, erythematous, grossly infiltrated plaques which to M. leprae, and become sub-polar lepromatous. Some
are very large with loss of touch, pain and temperature clinical features such as skin lesions of different
sensations. The lesions are frequently seen on the face. morphologies, thickened, asymmetrical nerves give a clue
Interestingly, major tuberculoid lesions tend to invade to their former state at higher placement in the spectrum.
certain 'immune zones' like axilla, lumbosacral area, In most of the patients the spectrum does not shift
palms, etc. In lesions with marked erythema, AFBs considerably and the clinical features retain the
may be seen on routine methods of examination. characteristic of BT or BL form. In BT the cell-mediated
Frequently the small cutaneous nerves may become hypersensitivity underlies most of the clinical features
enlarged and the thickened nerve can usually be traced whereas in BL the bacillary growth and its sequelae are
to an erythematous infiltrated lesion (the feeding nerve more important for the clinical manifestations.
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12
While mid-borderline (BB) disease is rare, the ratio of Several of the peripheral nerves are likely to be enlarged
BT to BL patients shows an interesting geographical irregularly and in an asymmetrical pattern. Nerve damage
pattern. BT predominates in Africans while BL disease is is an important characteristic of BT leprosy and anesthesia
mostly seen in Asians. This difference presumably reflects or motor deficit is often found at the time of presentation.
a genetic difference in the ability to express cell-mediated Even when treated with antileprosy drugs, nerve damage
immunity to M. leprae. Some patients (not necessarily as may progress to produce extensive anesthesia with
a result of treatment) may revert or upgrade, their disease destruction and deformities, unless the patient is closely
becoming more towards tuberculoid in nature but supervised and appropriate preventive measures taken.
downgrading occurs more often. Downgrading and BT leprosy with large pale macules and nerve
upgrading may occur silently but is often associated with involvement is often called maculoanesthetic or low-
type1 reactions. resistant tuberculoid leprosy (macular tuberculoid). These
may present as single or a few lesions. Lesions tend to be
Borderline Tuberculoid (BT) large and asymmetrical in their distribution, and are more
The skin lesions resemble those of tuberculoid leprosy, commonly found on the face, lateral aspects of the
but there is evidence of the disease not being contained.
Individual lesions do not show the well-defined margins
and the border in part may start sloping outwards and even
fade imperceptibly into normal skin (Figs 12.3 and 12.4).
There may be small extension of the lesion at one edge
(pseudopodium) or there may even be satellite lesions.
The number of lesions may vary from 3 to 10 and they
show variation in size and contour. The size of lesions
tends to be larger and at times it may cover the whole
limb. Loss of sensations is less intense than in the lesions
of TT. Dryness, scaling and erythema or hypopigmentation
of the lesions are also less conspicuous than in TT.
B
Figs 12.4A and B: BT leprosy in two patients, the lesions are
Fig. 12.3: BT leprosy in a child. The patch is hypopigmented, dry, hypopigmented, dry, with definite sensory loss. The lesions are not
scaly, with erythema and well defined margin raised (maculo-anesthetic type)
CHAPTER
12
extremities, buttocks and scapulae. The lesions are Borderline Borderline (BB)
hypopigmented but not depigmented, with well defined
Mid-borderline disease is unstable and mostly 'down-grades'
edges which show a clear demarcation between affected
towards the lepromatous pole especially if untreated.
and healthy skin, but are not raised (Fig. 12.3 and 12.4).
Presence of dimorphous type of lesions is the rule. There
The macules especially over the extremities usually feel
are multiple skin lesions with a tendency to symmetry.
dry to touch and show some degree of loss of sweating.
The lesions are of all shapes and sizes including papules,
The main differentiating features from other types of macular
plaques, circinate lesions and rarely even nodules.
lesions in leprosy are: a clear definition of the edge of the
Characteristic skin lesions are the annular lesions where
lesion, limited number of macules, asymmetry of their
the inner edge is well demarcated 'punched out' and the
distribution; and finally, they show a dry and somewhat
outer edge is ill defined and slopes towards normal skin.
rough surface, and the loss of sensation to light touch or
Clinically, normal looking skin; within such plaques gives
temperature is clearly demonstrable. In addition, there may
a "Swiss cheese" appearance (Figs 12.6 and 12.7).
also be areas of sensory loss on the extremities which
Face may show infiltration with occasional nodules over
follow the course of large cutaneous nerves.27
ears and chin. Because of immunological instability, the
One of the most striking features of BT leprosy is the
BB state is short-lived and such patients are evidently
susceptibility to type1 reactions in either skin lesions or
rarely seen and the disease rapidly changes, rarely to BT
nerves or both. Often it is the onset of type1 reaction that
but more often to BL. Many nerves are involved, though
causes a patient with longstanding BT leprosy to seek
not symmetrically as in LL.
medical help. Such a patient should be carefully examined
Nerve damage is variable in mid-borderline disease. If
for nerve tenderness and early evidence of weakness or
the patient is downgrading from BT many nerves may be
anesthesia of hands or feet requiring immediate
enlarged but asymmetrically. In a patient upgrading from
intervention. If left untreated, BT leprosy may continue
BL, often as a result of treatment, the peripheral nerves
even for many years with recurrent bouts of reactions;
will be affected but there may not be much neurological
leading to progressive nerve damage, paralysis and
deficit until a type1 reaction precipitates the loss. Peripheral
deformity. Few patients with repeated reactions tend to
sensory loss in a symmetrical fashion in BB is unusual.
deteriorate and the disease downgrades across the
Skin smears show moderate number of AFBs in majority
spectrum becoming BL or LLs with an increasing bacterial
of the lesions.
load in a person already suffering extensive nerve damage
(Fig. 12.5). Borderline Lepromatous (BL)
There are numerous skin lesions classically distinct but
not so well defined. There occur slightly infiltrated macules
with copper hue, round or oval about 2-3 cm in diameter,
in not so symmetrical distribution with areas of apparently
normal skin in between. With disease progression, papules,
nodules and plaques may develop, with slopping margins
which merge imperceptibly into normal skin (Fig. 12.8).
Infiltration takes place within the initial macules, creating
a plaque like appearance, especially on the face and ears.
Signs of nerve damage within the lesion such as loss
of sensation, decreased sweating and hair growth start
sooner in BL than in LL. Associated large lesions (and of
variable morphology) indicate downgrading of disease from
a higher spectrum. However, the real place of the disease
on the spectrum may be suspected from the extent,
number and small size of majority of the skin lesions and
Fig. 12.5: Downgrading of unstable disease to BL leprosy. The lesions
are small numerous papules and plaques with erythema and in bilateral the fact that the infiltration is central rather than peripheral,
symmetrical distribution. There was no history of anti-leprosy treatment especially in the newer lesions.
CHAPTER
12
Fig. 12.7: Annular (punched out) lesion, the hallmark of borderline

leprosy. It has sharp abrupt ending inner margin while the outer margin
is slopping outwards into the surrounding skin. Also note the other
types of lesions i.e. papules, plaques over the trunk (Photo courtesy:
Dr HK Kar, PGIMER, Dr RML Hospital, New Delhi)
B
Figs 12.6A and B: A case of midborderline leprosy. Note the presence
of all types of lesions representing those from tuberculoid (plaques) Fig. 12.8: BL leprosy, the lesions are ill-defined, showing tendency to
and lepromatous (papules and nodules), and the annular lesions bilateral symmetry, some of them with coppery hue. In between the
(characteristic of borderline leprosy) (Photo courtesy: Dr HK Kar, diffuse infiltration; some ichthyosis can be observed which can occur
PGIMER, Dr RML Hospital, New Delhi) as a result of disease itself (due to dryness of skin as a result of
autonomic neuropathy) or due to treatment with clofazimine component
of MDT
Peripheral nerve trunks become thickened at the sites

of predilection but lack symmetry with corresponding pertaining to oral cavity or eyes. The testes are normal in
anesthesia and paresis. Nerves get damaged not as quickly size and texture on palpation. BL patients are more prone
as in BB and BT leprosy; but sooner than in LL. Eyebrows to develop type 2 reactions (erythema nodosum leprosum)
are either not involved or are lost partially. Symmetrical than those in BB spectrum. Type 1 reactions in skin lesions
anesthesia involving hands and feet does not develop till and nerves, though uncommon, also add to the morbidity
late in the disease and usually there are no symptoms of disease.
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The prognosis in BL is very variable. If the disease better appreciated by touch rather than sight. This infiltration
began as BL and it is diagnosed and treated before further is more easily appreciated by pinching the skin of the
downgrading, the prognosis should be good. With careful patient between the fingers. Thickness of skin is most
supervision and management for type1 reactions, which marked over the face especially the forehead, earlobes,
are likely to occur during the chemotherapy, there should eyebrows, nose and malar surfaces (Figs 12.9A and B).
be little disability. Patients downgrading from BT to BL The ear-lobes are usually thickened and shiny. Thickening
may already have significant nerve damage and leprosy and nodulation of the ear lobes is best appreciated by
reactions (as may be expected during chemotherapy) which standing behind the patient.
further complicate neuritis and disabilities. Patients who
downgrade to subpolar LL, face the additional complications
of further extension of cutaneous and nerve involvement
and type 2 reactions during or after chemotherapy.26,27
Lepromatous Leprosy (LL)

Multiplication and universal spread of M. leprae; accounts
for many of the features of the disease at the lepromatous
pole. The early lesions of lepromatous leprosy are small
macules, innumerable in number, widely disseminated and
distributed symmetrically. Although the infiltration is
clinically not very obvious, on careful examination, these
macules are found to be slightly infiltrated. The edges are
indistinct, their surface shiny and erythematous, rather
than hypopigmented. The early macules of LL are not
anesthetic. Unlike macules of BT, the edges are not well
demarcated, show little difference in texture than normal A
skin, exhibit lack of sweating, and have in addition, a slightly
shiny appearance. The inconspicuous edge and lack of
significant tissue reaction result in minimal color contrast
between affected and the normal skin. Owing to erythema,
these lesions are better seen in an oblique light as shiny
waxy macules. Insidious onset and steady progression
may allow the disease to advance for years before the
patient or his associates recognize a shiny, waxy
appearance. Although all the lepromatous macules are
infiltrated; it is not of a sufficient degree to alter the grossly
macular nature of the lesions.
Lepromatous leprosy with infiltrated lesions presents
as three distinct forms; diffuse, infiltrated and nodular
forms.
(a) Diffuse Lepromatous Leprosy

It is believed that this is a true subtype of LL, but many
workers are of the opinion that diffuse LL is usually the
result of the gradual coalescing of the numerous vague
macules of macular LL. These cases in the initial stages B
are often missed since no actual lesions are discernible. Figs 12.9A and B: Diffuse LL (A) and infiltrated LL (B). In both the
The skin has a shiny look with slight infiltration which is cases the slit-skin smears were highly positive (6+ with globi)
CHAPTER
12
Eyebrows may show some thinning or loss of hair, but

it must be remembered that loss of eyebrows is often a
late sign of LL.
(b) Infiltrated Lepromatous Leprosy

Lepromatous leprosy may be detected clinically at the stage
of macules, diffuse infiltration or as areas of marked
infiltration or nodules. Infiltrated leprosy is merely a more
advanced stage of macular LL with easily visible infiltration
which may be a sign of advancement of diffuse LL disease.
It must be emphasized, that when gross infiltration
appears, characteristics of the lepromatous lesion remain
the same. Thus edges, while raised, do not stand out as
in tuberculoid leprosy. Lesions are often shiny and
succulent in consistency but color may vary in different
ethnic populations. A
(c) Nodular Lepromatous Leprosy

Nodular leprosy is the result of progressive deterioration
of the macular, diffuse or infiltrated forms of LL. In the
early stage, nodules appear first on the ears, and as the
disease advances they may appear any where on the body
and are commonly seen over the buttocks and extremities
especially the elbows, fingers, over the joints and
sometimes on the genitals. Diagnosis is never in doubt
when disease has reached to such a nodular stage. The
infiltrated plaques accentuate the skin folds producing the
classical leonine facies (Figs 12.10 and 12.11). Nodules,
even plaques on the face and other areas of body may
follow. At first many of such nodules tend to be adherent
to the skin and are movable in the subcutaneous tissues,
but later they become fixed and are liable to ulcerate.
By this time the peripheral anesthesia is extensive and B
is accompanied by anhidrosis with compensatory Figs 12.10A and B: LL, the typical “leoline facies” in an elderly female
hyperhidrosis of the face, trunk and axillae. The sensory (A). An advanced LL case with diffuse infiltration, “saddle nose” and
eye involvement (B). Skin smear were 6 + in both cases
loss is symmetrical and is first detected over the extensors
of forearms, legs, hands and feet, which gradually results
in the typical glove and stocking anesthesia. The nail downgraded from borderline spectrum, in that the disease
growth may be disturbed late in the course of the disease may not be so symmetrical and other evidence of variable
and nail plates become lustreless, ridged and curved. sized lesions, asymmetrical nerve thickening may be
Weakness usually starts in the intrinsic muscles of hands present indicating downgrading (sub-polar LL).
and feet. Despite the gradual appearance of sensory and
This perfectly symmetrical, diffuse infiltrative type of autonomic nerve damage, it may be difficult to find a clinical
leprosy typifies the relatively uncommon patient whose sign of damage to the large peripheral nerves until the
disease has been pure lepromatous (polar LL) from the disease is well advanced especially in polar LL. Sensory
start of the illness. In patients, in whom the disease has fibers are usually damaged first. The nerves are often not
CHAPTER
12
been no ulceration and secondary infection. When
significant anesthesia has developed, the hands and feet
are liable to trauma and pressure necrosis of soft tissue,
which leads to ulceration and secondary infection with
clinical signs of cellulitis and osteomyelitis. Deformity from
bony destruction may then proceed rapidly.
Involvement of the upper respiratory tract mucosa is
found in about 80% of new LL cases. It may be noted that
involvement of lower respiratory tract below the level of
larynx, have never been seen in leprosy. It causes (not
invariably the first symptom) a stuffy or blocked nose like
that in coryza often followed by epistaxis. There may be
anosmia, crusting or bleeding and nasal septal perforation
A in up to 40% of LL patients. The septal perforation in leprosy
is due to destruction of bony portion (anterior nasal spine)
of the nasal bridge leading to the typical saddle nose
deformity, commonly seen in advanced lepromatous
cases. Just to recall for academic interest, in syphilis, the
destruction of nasal septum involves only cartilaginous
portion (chondritis) wherein the shape of the nose is
preserved. Oral mucosa may be involved in the form of
nodules and plaques involving tongue and palate. In severe
cases, involvement of larynx can cause hoarseness of
voice and stridor. Early eye involvement includes corneal
anesthesia due to bacillary infiltration of corneal nerves
and later from damage to the ophthalmic division of the
trigeminal nerve. Other ocular manifestations include
B
lagophthalmos, uveitis, corneal opacity, perforation and
Figs 12.11A and B: Nodular LL. The nodular lesions over ears are
blindness.
prominent in both cases shown. The BI smears are highly positive
Lepromatous leprosy does not remit naturally, though
in few patients it does burn itself out. Before the days of
palpably enlarged and nerve conduction studies may be effective treatment, the disease used to continue its
normal early in the disease. As the disease progresses relentless course. The patient's downhill course was
the peripheral nerves first become firm, hard and then accelerated by bouts of acute inflammation in nerves and
fibrosed at the sites of predilection where nerve trunks are systemic illness (type 2 reactions). Death supervenes due
close to cooler skin surface (like radial grove, behind medial
to secondary infection, (particularly pneumonia and
epicondyle of ulna, neck of fibula). Muscular weakness of
tuberculosis), amyloidosis and renal failure. If patients are
the hands sometimes appears early in disease, possibly
treated properly with effective antileprosy drugs (multidrug
because the muscles of hand and feet are affected directly
therapy), anti-inflammatory drugs when indicated and with
as well as through the peripheral nerves.
sustained efforts for prevention of disabilities - LL disease
In lepromatous disease, the hands and feet take on a
does have a much better prognosis and better quality of
characteristic appearance with swollen digits tending to
life.26,27
taper toward the tips (fusiform swelling). Before the stage
of anesthesia, hands and feet may be hypersensitive, so
that small knocks or even walking cause feelings like RARE VARIANTS OF LEPROSY
electric shocks or (neuralgic) pain. Frequently the joints Few unusual forms or expressions of leprosy do not fit
become swollen and later angulated. Digits may shorten into the standard classification of disease. Rarely these
due to resorption of phalanges, even though there have presentations may pose a difficulty in diagnosis.
CHAPTER
12
LUCIO LEPROSY only a small number of cases have been reported in the
Lucio leprosy (LuLp) is a pure, primitive and diffuse form literature. Necrotizing ENL has a similar clinical picture
of lepromatous leprosy, common in Mexico (23%) and but the presence of large areas of ulceration and of AFB in
Costa Rica; not infrequent in the Gulf coast; but quite rare the vascular endothelium favors the diagnosis of LP.32
in the rest of the world. There is not yet an appropriate The LP and its management has been described in detail
definition and its nosological status, underlying patho- elsewhere in the textbook (see the chapter on management
mechanisms; and reasons for its restricted global of leprosy reactions).
distribution are far from clear.
PURE NEURITIC LEPROSY
It presents as slowly progressive diffuse infiltration of
It is characterized by an area of sensory loss in the absence
skin of face and most of the body without any previous
of any skin patch along the distribution of an involved nerve
evidence of discrete lesions. The skin looks waxy and
trunk with or without motor deficit. This form is seen most
has shiny appearance (Lepra bonita: beautiful leprosy) with
frequently, but not exclusively, in India and Nepal, where
obvious diffuse infiltration of the ear lobes and forehead,
it accounts for 5-10% of all patients with leprosy. Histology
loss of eyebrows and sometimes eyelashes, and not
of a cutaneous nerve usually reveals an infiltrate,
infrequently all body hair. There may be hoarseness of
characteristic of leprosy.10
voice, numbness and edema of hands and feet mimicking
myxedema.28 The disease is often unmasked by a specific
severe reactional state, Lucio phenomenon (LP), akin to
HISTOID LEPROSY
(see Chapter on Histoid Leprosy)
type 2 lepra reaction. Lucio phenomenon or "lepra
Histoid leprosy first described in 1960; is now a well-
manchada" was first described by Lucio and Alvarado in
recognized but rarely reported entity.33 Controversy still
Mexico in 1852, and further elaborated on by Latapi and
remains whether to consider histoid leprosy as a separate
Zamora in 1948. Although LP peculiarly develops in the
entity or as part of the general spectrum of leprosy. It was
untreated diffuse form of leprosy in the Mexican region, it
thought that this type of disease occurs as a consequence
is clinically indistinguishable when seen in other parts of
of dapsone monotherapy or inadequate therapy but now it
world or when it develops in the classic nodular form of
is recognized that it does occur de novo more often.34
lepromatous leprosy.29-31
Clinically, the histoid lesions commonly appear as smooth,
Clinically, LP presents as multiple, well-defined, angular,
shiny, hemispherical, dome-shaped, non-tender soft to firm
jagged purpuric lesions evolving into massive ulcerations,
nodules which may be superficial, subcutaneous or fixed
spreading in a characteristic ascending fashion over the
deeply under the skin and plaques or pads appearing on
extremities and healing with atrophic scarring.
otherwise normal-looking skin (Figs 12.12A and B). In a
Bacteriological and morphological indices show high
given patient the number of lesions may vary from a few
positivity. Histologically, there is necrosis of the epidermis
to a hundred. The lesions are usually located on the face,
and dermis, a histiocytic and neutrophilic infiltrate in and back, buttocks and extremities and over bony prominences,
around nerve fibers, blood vessels and adnexae, and
especially around the elbows and knees. Histopatholgically,
fibrinoid vasculitis. Although it is not entirely clear, it seems the striking feature is predominance of spindle shaped cells
that pathogenesis of LP involves uninhibited multiplication and unusually large numbers of acid-fast bacilli.35, 36
of bacilli leading to diffuse infiltration of the integument in
an anergic background.
LAZARINE LEPROSY
LP usually begins in untreated leprosy and treatment
with antileprosy regimens containing rifampicin is quite An unusual expression of BT leprosy is spontaneous
effective. High-dose corticosteroids help in controlling the ulceration of skin lesions. This is presumably the result of
immune reaction to M. leprae antigens. Thalidomide and exaggerated hypersensitivity in type1 reactions. Rarely
clofazimine are less effective as compared to their efficacy this occurs without any history or evidence of pre-existing
in ENL. Whether LP is restricted to LuLp or it is a reactional skin lesions or coexistent nerve pathology. Histopathology
manifestation of nodular forms of leprosy with a similar shows necrosis due to extreme cellular hypersensitivity.
background, e.g. a high bacterial load, anergy or an Systemic corticosteroids are necessary for the treatment;
exaggerated humoral response, is not understood because in addition to antileprosy drugs. If the disease remains
CHAPTER
12
A Fig. 12.13: Enlargement of Great auricular nerve (between the arrows

over neck). Also note the tuberculoid patch over left side of cheek
(arrows at the lesion margin). This nerve is usually better appreciated
by inspection, than palpation (Photo courtesy: Dr Pankaj Sharma,
auricular nerve is better seen than felt (Fig. 12.13). Rarely

nerve abscess is encountered in the thickened peripheral
nerve trunks primarily in the TT and BT spectrum, mostly
in the ulnar and lateral popliteal nerves. The mutilations,
morbidity and disability associated with leprosy are
secondary to nerve damage which is hastened by reactions.
About 25% of leprosy patients have some degree of
disability, which is greatest in patients with BL and LL
disease. Early recognition and treatment is crucial to the
B prevention of deformities.40-42
Figs 12.12A and B: Histoid leprosy. The lesions over face present
as dome-shaped thick, nontender, hemispherical shiny papules and
nodules. Slitskin smear show innumerable M. leprae with globi
SYSTEMIC INVOLVEMENT
(see section on Systemic Involvement and Special
Situations in Leprosy)
undiagnosed and untreated, patients subsequently manifest Features of systemic involvement occur usually in a long
with typical skin lesions and nerve involvement.37-39 standing disease and are mainly seen in patients near the
lepromatous pole due to bacillary deposits and associated
NERVE INVOLVEMENT granulomatous infiltration affecting various organs
(see chapter on Management of Neuritis and Neuropathic especially nasal mucosa, larynx, eyes, bones, testes,
Pain) kidneys, lymph nodes, liver and spleen. Besides the
Nerve damage occurs in two anatomical settings-peripheral disease, systemic manifestations in the form of consti-
nerve trunks and small dermal nerves. Small dermal tutional symptoms like fever, malaise, joint pains and acute
sensory and autonomic nerves are affected in the early inflammation of eyes, joints, reticuloendothelial system,
part of disease producing hypoesthesia and anhidrosis etc. can occur as a part of type 2 lepra reaction.43
within skin lesions. Of the nerve trunks, ulnar nerve is the
most commonly affected followed by the median, lateral REFERENCES
popliteal and facial nerves. Involvement of these nerves
1. WHO Expert Committee on Leprosy. Seventh Report. Technical
produces enlargement with or without tenderness, and Report Series No.874. World Health Organization, Geneva.
regional sensory and also motor loss. Thickening of greater 1998.
CHAPTER
12
2. Georgiev GD, McDougall AC. Skin smears and the bacterial 22. Imbiriba EB, Hurtado-Guerrero JC, Garnelo L. Epidemiological
index (BI) in multiple drug therapy leprosy control programs: An profile of leprosy in children under 15 in Manaus (Northern Brazil),
unsatisfactory and potentially hazardous state of affairs. Int J 1998-2005. Rev Saude Publica 2008; 42: 1021-26.
Lepr Other Mycobact Dis 1988; 56: 101-4. 23. Ramanujam K. Findings of a nineteen-year follow-up of children
3. Kumar B, Dogra S. Leprosy: A disease with diagnostic and with untreated leprosy. In: Latapi F, Saul A, Rodriguez 0,
management challenges! Indian J Dermatol Venereol Leprol Ma'lacara M, Browne SG (eds) Leprosy. Proceedings of the XI
2009; 75: 111-15. International Leprosy Congress, Mexico City November 13~18,
4. Ponnighaus JM, Fine PE. A comparison of sensory loss tests 1978, Excerpta Medica, Amsterdam, 1980;75-79.
and histopathology in the diagnosis of leprosy. Lepr Rev 1989; 24. Ekambaram V, Sithambaram M. Self-healing in non- lepromatous
60: 20-27. leprosy in the area of ELEP leprosy control project Dharmapuri
5. Sirumban P, Kumar A, Durai V, et al. Diagnostic value of cardinal (Tamil Nadu). Lepr India 1977; 49: 387-92.
signs/symptoms in paucibacillary leprosy. Indian J Lepr 1988; 25. Noordecn S K. Evolution of tuberculoid leprosy in a community.
60: 207-14. Lepr India 1975; 47: 85-93.
6. Groenen G, Saha NG, Rashid MA, et al. Classification of leprosy 26. Moschella SL. An update on the diagnosis and treatment of
cases under field conditions in Bangladesh. II. Reliability of clinical leprosy. J Am Acad Dermatol 2004; 51: 417-26
criteria. Lepr Rev 1995; 66: 134-43. 27. Pfaltzgraff RE, Bryceson A. Clinical leprosy. In: R.C. Hastings, Editor,
7. Saunderson P, Groenen G. Which physical signs help most in Leprosy, Churchill Livingstone, New York,1989;134-76.
the diagnosis of leprosy? A proposal based on experience in the 28. Latapi F, Zamora AC. The spotted leprosy of Lucio: An
AMFES project, ALERT, Ethiopia. Lepr Rev 2000; 71: 34-42. introduction to its clinical and histopathological study. Int J Lepr
8. Kolappan C, Selvaraj R, Khudoos A et al. Repeatability of nerve Other Mycobact Dis 1948; 16: 421-29.
29. Quismorio FP Jr, Rea TH, Chandor S, et al. Lucio's phenomenon:
thickness assessment in the clinical examination for leprosy.
An immune complex deposition syndrome in lepromatous
Lepr Rev 1995; 66: 224-28.
leprosy. Clin Immunol Immunopathol 1978; 9: 184-93.
9. McDougall AC. The clinical examination of peripheral nerves in
30. Saoji V, Salodkar A. Lucio leprosy with Lucio phenomenon. Indian
leprosy. Indian J Lepr 1996; 68: 378-80.
J Lepr 2001; 73: 267-72.
10. Kumar B, Kaur I, Dogra S et al. Pure neuritic leprosy in India: an
31. Kumari R, Thappa DM, Basu D. A fatal case of Lucio phenomenon
appraisal. Int J Lepr Other Mycobact Dis. 2004; 72:284-90.
from India. Dermatol Online J 2008; 14: 10-18.
11. Saunderson PR, Gebre S, Desta K, et al. The ALERT MDT Field
32. Sehgal VN. Lucio's phenomenon/erythema necroticans. Int J
Evaluation Study (AMFES): A descriptive study of leprosy in
Dermatol 2005; 44: 602-5.
Ethiopia. Patients, methods and baseline characteristics. Lepr
33. Wade HW. The histoid variety of lepromatous leprosy. Int J Lepr
Rev 2000; 71: 273-84.
Other Mycobact Dis 1963; 31: 129-42.
12. Mahajan PM, Jogaikar DG, Mehta JM. A study of pure neuritic
34. Sehgal VN. Spontaneous appearances of papules, nodules,
leprosy: clinical experience. Indian J Lepr 1996; 68: 137-41. and/or plaques: A prelude to abacillary, paucibacillary, or
13. van Brakel WH, de Soldenhoff R, McDougall AC. The allocation multibacillary histoid leprosy. Skinmed 2006; 5:139-41.
of leprosy patients into paucibacillary and multibacillary groups 35. Sehgal VN, Srivastava G. Histoid leprosy: A prospective
for multidrug therapy, taking into account the number of body diagnostic study in 38 patients. Dermatologica 1988;177:
areas affected by skin, or skin and nerve lesions. Lepr Rev 212-17.
1992; 63: 231-46. 36. Kaur I, Dogra S, De D, et al. Histoid leprosy: A retrospective
14. Porichha D. A plea to revive skin smear examination. Int J Lepr study of 40 cases from India. Br J Dermatol 2009; 160: 305-10.
Other Mycobact Dis 2001; 69: 116-69. 37. Nanda S, Bansal S, Grover C, et al. Lazarine leprosy—revisited?
15. Kundu SK. Features of Ridley-Jopling classification and its Indian J Lepr 2004; 76: 351-54.
application in the clinical field. Int J Lepr Other Mycobact Dis 38. Thappa DM. What is lazarine leprosy? Is it a separate entity?
1979; 47: 64-65. Indian J Lepr 2005; 77: 179-81.
16. Abulafia J, Vignale RIA. Leprosy: pathogenesis updated. Int J 39. Skinsnes LK, Higa LH. The role of protein malnutrition in the
Dermatol 1999; 38: 321-34. pathogenesis of ulcerative "Lazarine" leprosy. Int J Lepr Other
17. Britton WJ, Lockwood DN. Leprosy. Lancet 2004; 363: 1209- Mycobact Dis 1976; 44: 346-58.
19. 40. Spierings E, De Boer T, Zulianello L, et al. The role of Schwann
18. Cardama J E . Early lesions (indeterminate forms). In: Latapi F, cells, T cells and Mycobacterium leprae in the immunopatho-
Saul A, Rodriguez O, Malacara M, Browne SG (Eds) Leprosy. genesis of nerve damage in leprosy. Lepr Rev 2000; 71(Suppl):
Proceedings of the XI International Leprosy Congress, Mexico S121-29.
City November 13-18, 1978, Excerpta Medica, Amsterdam, 1980 41. Shetty VP, Mistry NF, Antia NH. Current understanding of leprosy
i 68-74. as a peripheral nerve disorder: significance of involvement of
19. Gomez L. The question of the initial lesion of leprosy. Journal of peripheral nerve in leprosy. Indian J Lepr 2000; 72: 339-50.
the Philippine Islands Medical Association 1923; 3: 227-29. 42. Ooi WW, Srinivasan J. Leprosy and the peripheral nervous
20. Pettit J H. Should indeterminate leprosy ever be diagnosed? Int system: basic and clinical aspects. Muscle Nerve 2004; 30:
J Lepr Other Mycobact Dis 1981; 49: 95-96. 393-409.
21. Lara CB. Leprosy in children. General considerations: Initial and 43. Kumar B, Rai R, Kaur I. Systemic involvement in leprosy and its
early stages. WPRfLEPI24, 23 November 1961, World Health significance. Lepr Rev 2000; 72: 123-42.
Organization, Geneva.
13
Histoid Leprosy
Virendra Nath Sehgal, Govind Srivastava
INTRODUCTION inadequate dapsone monotherapy, but later de novo cases

were also encountered.1,13
Histoid leprosy is a well-recognized clinical entity, an
Despite sporadic reporting, histoid leprosy was not
expression of multibacillary leprosy, characterized by
given a thought, until Sehgal et al documented for the first
typical cutaneous and/or sub-cutaneous nodules and
time the immunological profile of this unique expression
plaques present over an apparently normal skin with unique
of multibacillary leprosy.16
histopathology and characteristic bacterial morphology.1-3
It usually manifests itself in patients on diamino-diphenyl-
sulphone (DDS) for a long time, reflecting initial DEFINITION
improvement followed by a relapse. Irregular and inadequate Histoid leprosy is an expression of multibacillary leprosy,
therapy may further compound its occurrence. Some characterized by the occurrence of nodules and/or plaques
workers4,5 believe that it is due to the development of drug in the skin or the subcutaneous tissues. Well-demarcated,
resistance to DDS, while others postulate that mutant cutaneous nodule is its cardinal feature. They are present
organisms, that emerge from a predominantly sulphone over an apparently normal skin.8 Reactional episodes are
susceptible bacterial population, may be responsible.6,7 seldom recorded in this entity.1,3
Apart from its occurrence in lepromatous leprosy,
histoid lesions may occasionally be seen in borderline8,9 EPIDEMIOLOGY
and indeterminate leprosy.10
Ever since the description of histoid leprosy by Wade, Sehgal and Srivastava diagnosed 50 patients of histoid
an emphasis was laid on its retrospective histological leprosy amongst a total of 1551 fresh leprosy patients,
diagnosis.3,11,12 However, in the experience of some thus giving its incidence as 3.2 percent.1,13 Rodriquez found
authors1,13 it can be diagnosed with certainty, relying only that of the 72 relapsed lepromatous leprosy patients, 28
on its clinical features, a fact reiterated by Professor (39%) ultimately developed histoid lesions.6 The data thus
Moschella, while reviewing a report on this entity in the far available therefore, indicates that its incidence is
Year Book of Dermatology 1988.14 significant in multibacillary leprosy per se or in relapsed
patients taking irregular anti-leprosy drugs.1,13 Kalla et al
HISTORICAL from northwest Rajasthan, recorded 25 biopsy proven
histoid leprosy patients amongst a total of 893 new leprosy
The term histoid was originally coined in the year 1960 by patients, thus giving an incidence of 2.8 percent.17
Wade.11 Since then many reports have documented this Histoid leprosy has rarely been reported in children.
entity.1-13 Although some authors,1,14,15 regard it as a However, histoid lesions have been recorded to occur at
distinct clinicopathological entity; yet others consider it an age as early as 10 years4 and as late as 84 years.9
as a variant of lepromatous leprosy.3-6,9 The entity initially Sehgal and Srivastava reported that 58 percent of their
was recorded in multibacillary patients, on irregular, and patients were between the age of 20 and 39 years.13
CHAPTER
13
A B C
D E
Figs 13.1A to E: Histoid leprosy. The characteristic lesions are papulonodular, firm, erythematous or copper-colored, hemispherical, dome
shaped, glistening shiny, present over apparently normal looking skin. The common sites are face, ears, limbs and trunk. Note the development
of new lesions as a result of scratching (Koebner’s phenomenon) in picture marked 3 (Photo courtesy: Dr Inderjeet Kaur and Dr Sunil Dogra,
PGIMER, Chandigarh, India)
CLINICAL FEATURES and even pedunculated. Typical young lesions are firm,
reddish, or skin colored, dome shaped or oval papules,
Histoid lesions have been variously classified as
regular in contour with shiny and stretched overlying skin
subcutaneous nodules, deeply fixed cutaneous nodules,
and, at times, constriction around their bases. The skin
superficially placed cutaneous nodules, soft nodules, and
surrounding the lesion is apparently normal.
plaques or pads1-3,11-13 (Figs 13.1A to E).
In a single patient, 3 to more than 50 such lesions may Subcutaneous Nodules
be seen.1,3,9 The lesions are usually located on the back, These may vary in size but usually are not larger than
buttocks, face, extremities 1,9,13,18 and over bony 5 cm in diameter. The smaller nodules are soft and on
prominences, especially, around the elbows, and the scraping the cut surface is abundantly pulpy (Figs 13.2 to
knees. 13.4). The older larger nodules are relatively, but
The cutaneous histoid lepromas, which arise directly secondarily fibrotic, and so the cut surface is likely to be
in the dermis, promptly become elevated and protuberant, pale and tough.1,3,11,12
CHAPTER
13
Histoid Leprosy 169
A B
Figs 13.2A and B: Histoid leprosy. Papules and nodules over thighs and gluteal regions. The lesions are usually present over normal looking
skin (Photo courtesy: Dr Inderjeet Kaur and Dr Sunil Dogra, PGIMER, Chandigarh, India)
C D
Figs 13.3A to D: Histoid leprosy, shiny hemispherical nodules over ear, nape of the neck, trunk regions, histoid nodules on the prepuce (Photo
courtesy: Dr Aparna Palit and Dr A C Inamadar, BLDEA’S SBMP Medical College Hospital and Research Centre, Bijapur, Karnataka, India)
CHAPTER
13
C D
Figs 13.4A to D: Generalized innumerable histoid lesions (papules, nodules and plaques) present over limbs and trunk areas (Photo
courtesy: Dr Aparna Palit and Dr A C Inamadar, BLDEA’S SBMP Medical College Hospital and Research Centre, Bijapur, Karnataka, India)
Cutaneous Plaques Two types of histoid facies can be seen in these

Another form of histoid lesions is the cutaneous patients. The first type of facies is seen as the old,
plaque.1,11,12 They are non-nodular and of a different growth wrinkled, atrophic facial skin, relics of a burnt out
pattern from the nodules but of a similar nature cytologically lepromatous leprosy, with scanty/absent eyebrows, and
as well as bacteriologically. 3,6 These are sharply sometimes with depressed nasal bridge and eye changes.
delineated, thick scaly pads, which in some cases develop These patients had scanty histoid lesions on their face.
on pressure points, especially on the elbows.1,3,19 It is The second type of facies is essentially the apparently
generally believed that histoid leprosy patients do not normal face without any apparent manifestation of leprosy.
undergo ENL type of reaction.11,19 Some patients do Histoid lesions, however, were regularly present over the
develop ENL only after the institution of therapy.4,6,8,20,21 face (Fig. 13.5).13
CHAPTER
13
Histoid Leprosy 171
A B
Figs 13.5A and B: Hemispherical nodules in a case of histoid leprosy on right. The patient on left has grossly enlarged nodules and
plaques over face, ears (Photo courtesy: Dr Inderjeet Kaur and Dr Sunil Dogra, PGIMER, Chandigarh, India)
A noticeable feature in majority of histoid patients is however, reported mild acanthosis and flattening of rete
the persistence of eyebrows.4 Nasal mucosa is usually ridges in the epidermis in some of his patients.24 In most
spared. Even after years of uncontrolled disease, the nasal cases, a free subepidermal zone is present.2,3,7,11,13
cartilage remains unaffected.4,6 Histoid patients usually The lesion is usually located in the dermis, subcutis
are in good general health and they tend to remain so.4 or both. A pseudocapsule is often seen surrounding the
lesion, formed by the compression of the adjacent tissue
BACTERIOLOGY due to the expanding nature of the lesion, but, it may not
be well appreciated in specimens from plaques. The
Skin-slit smears, taken by standard methods from these
circumscribed nature of lesion is one of the most cardinal
lesions, always reveal an abundance of organisms occurring
features of the histoid lepromas2,11,12,22 by virtue of which,
singly, in clusters or as globi. 1,2,11-13 Majority of the
it resembles a tissue forming process rather than a
organisms are solid staining bacilli. They are well preserved
granuloma.3,11
and appear as uniformly stained, long rods with tapering
The most striking and classical feature is the
ends, distinctly longer than the (ordinary) lepra bacilli.1,11,13
presence of numerous, thin, spindle-shaped histiocytes
forming interlacing bands, whorls and at times tight
HISTOPATHOLOGY curlicules.1-3,11-13 The constituent spindle-shaped cells
Several striking features are usually seen in histoid have a moderate amount of cytoplasm, with oval and lightly
histopathology, the most prominent being the circumscribed stained nuclei.2,7 A higher magnification of the cells may
nature of the lesion, the predominance of spindle-shaped reveal slight vacuolation of their cytoplasm, but this never
cells and/or polygonal cells, and unusually large number assumes marked cytoplasmic vacuolation of typical lepra
of acid-fast bacilli1,2,12 better seen in young active lesions, cells in their full stage of development.5 An admixture of
and found in both subcutaneous and cutaneous nodules. spindle-shaped histiocytes and polygonal cells in various
Histoid lepromas, unlike ordinary lepromatous lesions, grow proportions may be found within the histoid lepromas. Their
in an expansible rather than an infiltrative fashion.1-3,11 presence signifies the ageing of the lesions.5,6,11
The epidermis overlying the lesion is usually stretched Histoid lesions can also have lymphocytes and
and atrophic due to expanding lesion in the dermis. Sanchez occasionally, polymorphonuclear leucocytes, especially
CHAPTER
13
at the periphery of the nodule.7 Plasma cells can also be lepromatous lesions, the cross sections of most of the
observed in some sections.4 Deposition of collagen is not organisms show uniformly electron-dense cytoplasm.30
present in early stages, but as the lesion grows older, the Usually, the bacilli are scattered singly, but globi can also
amount of collagen increases, and the lesion may even be seen. Sometimes, several cross-divisions of bacilli can
turn fibrotic.11 be noted.15 An electron-transparent zone (ETZ) is always
The bacilli in the histoid lesions constitute one of the seen around single bacillus or globi.15,29,30
most distinctive and interesting features. The acid-fast One of the most significant differences of histoid lesions
bacilli in these cases are described as measurably longer from lepromatous lesions, is the absence of large amount
than the ordinary lepra bacilli.1,3,11,13 In the spindle-shaped of electron-transparent substance (ETS) or foam in the
histiocytes, they are arranged in groups or parallel bundles former, which could be due to the rapidity of the formation
aligned along the long axis of the cell, described as ‘histoid of the lesion. It is believed that ETS interferes with bacterial
habitus’ by Wade.11 The isolated bacilli are scattered metabolism, and causes their death. Its absence might
throughout the lesion.26 Often a relatively large number of help preserve the bacilli within cells.30
bacilli within the histoid lesions are solid-staining.1,3,11,13
Wade found the characteristic absence of globus formation IMMUNOPROFILE
in histoid lesions, which he attributed to the lack of
production of gloea, the essential matrix substance Sehgal et al were the first to study the immunological profile
secreted by metabolism of such bacilli.12 However, of histoid leprosy patients, and comparison thereof with
presence of few globi is not unusual on slit-skin smear as the non-histoid active lepromatous as well as healthy
well as histopathological examination. controls.16 The observations could be summarised as
follows:
Tuberculoid Contamination
Lowered Cell-mediated Immunity
A peculiar phenomenon – the tuberculoid contamination
may be seen in cases of subcutaneous histoid lepromas. A diminished CMI response was observed in histoid leprosy
This is the occurrence of definite foci of epithelioid cells, patients when compared with healthy controls. This was
located within the lesion substance or in the encircling evident by the lowered percentage of early as well as total
fibrous tissue encapsulation.2,11,13,27,28 No satisfactory T-lymphocytes, and negative early (Fernandez) and late
explanation of this occurrence is postulated, but it is likely (Mitsuda) lepromin test. The cell-mediated immunity,
that the epithelioid cells represent the tuberculoid however, was found to be relatively better, when compared
component of the earlier borderline phase of the disease.27 with active lepromatous patients. This may well explain
the attempted localization of the lesions, to limited regions
ULTRASTRUCTURE of the body in histoid leprosy.1,16
The appearance of cells of histoid lesions varies widely Enhanced Humoral Immune Response
within the granuloma. In the center of the lesions, the cells
are either polygonal or of classical type. At the periphery, The humoral immunity was found to be considerably
on the other hand, they are elongated or spindle-shaped, augmented, as revealed through the increased percentage,
especially in the area adjoining the capsule.15 The main as well as absolute count of B-lymphocytes and the raised
cell type in the lesion is a macrophage of which 3 variants levels of immunoglobulins IgG, IgA, IgM.
are seen.15,29 The first variant is a rounded cell with a very
large, oval nucleus and sparse cytoplasm, containing a
Diminished Complement
few mitochondria and a little rough endoplasmic reticulum The levels of the complement C3 were significantly lowered
(RER). It thus resembles a monocyte. A few cells of this in the patients while the total protein concentration of
type, which usually contain bacilli as single, solid circulating immune complexes (CIC) was grossly raised.
organisms form the second category. The third variant is Cryoglobulins were also detected in majority of patients.
a more mature cell of the same size with uniformly granular The pathogenesis of this rare and unusual variant of
nucleus, and cytoplasm containing bacilli, which are solid.29 leprosy still remains unresolved. The interplay of genetic
An abundance of bacilli is seen in histoid lesions.15,29-31 factors, immune response, and treatment received in a
Most of them are solid in appearance. Unlike the usual given patient seems to influence the manifestations of
CHAPTER
13
Histoid Leprosy 173
histoid leprosy. Though histoid leprosy is considered to be DIFFERENTIAL DIAGNOSIS
a variant of LL, there exists an enhanced immune response
Clinically, cutaneous histoid lesions may simulate either
against M. leprae in these patients compared to LL with
conventional lepromatous nodules, erythema nodosum
respect to both cell- mediated (CMI) and humoral
leprosum, von Recklinghausen’s disease,8,9 or molluscum
immunity.20 An indication in favor of an augmented local
contagiosum.6,8 However, there are certain distinguishing
CMI is the presence of necrosis and ulceration as observed features with regard to cutaneous histoids. Unlike the
in some histoid lesions that might be considered as a resilient von Recklinghausen nodules, they are firm on
localized effort to combat M. leprae. 21 Immunohisto- palpation, and also histoid lesions lack umbilication so
chemical correlations of increased CMI include increased typical of molluscum contagiosum.
CD36 expression by the keratinocytes, predominance of Cutaneous plaques can sometimes be confused with
CD4 lymphocyte over CD8 lymphocytes, and high numbers keloids. However, they are less firm, skin-slit smears show
of activated lymphocytes and macrophages in the lesions.20 the presence of numerous acid-fast bacilli. Other disorders
Despite the presence of adequate numbers of macrophages, that can mimic histoid leprosy include multiple
it has been claimed that they lack the functional property to subcutaneous lipomatosus,32 post-kala-azar dermal
kill bacilli that exist in high numbers in histoid lesions.20 It leishmaniasis33 and cutaneous sarcoidosis.34
is possible that under the influence of M. leprae antigens,
Histologically, histoid lesions may mimic nodular
they lose their bacteriolytic property or produce ‘suppressor’
subepidermal fibrosis,34 dermatofibroma and similar skin
cytokines, such as IL-10, that adversely inhibit T- cell
tumors, on routine hematoxylin-eosin stains. Staining for
mediated responses to M. leprae.21,22
acid-fast bacilli may however, easily differentiate histoid
from such tumors.
DIAGNOSIS
The diagnosis of this entity is fairly easy if the classical TREATMENT
clinical features are carefully looked for.
It is imperative to ‘suspect’ this entity in multibacillary The effect of drug therapy is variable in histoid leprosy
leprosy, per se or on treatment. patients. Wade remarked on the resistance of these
patients to treatment.31 Price and Fitzherbert observed an
History adequate response to treatment in some of their patients
The natural history should include the details of treatment, by using sulforthomidine after they had unsuccessfully
namely; the nature of drug(s), the duration of treatment, tried sulphone, thiambutosine, sulfamethoxypyridazine and
the regularity, the dose and its frequency. ditophal, singly or in combination, for one to 5 years.4 A
few investigators report the occurrence of erythema
Characteristic Clinical Features nodosum leprosum (ENL), during treatment, but this
The clinical peculiarities of histoid lepromas are resolves without the need to stop the treatment.4,20,21
characteristic enough to delineate this entity with certainty The recommended schedule of treatment of histoid
in most patients. The facial appearance often gives a clue leprosy as practiced is outlined in Table 13.1. It is very
towards the development of histoid lesions, and thus may
similar to the earlier recommendations of WHO for the
aptly be designated as ‘histoid facies’.
treatment of multibacillary leprosy for two years, preferably
Microscopic Examination till skin smear negativity.
With the advent of more rapid treatment modalities for
Skin-slit smears reveal an abundance of uniformly stained
acid-fast bacilli. In contrast, there is relative paucity of the treatment of multibacillary leprosy, the same regimens
them in the surrounding normal-looking skin, a feature can be applied to histoid leprosy. Various workers have
helpful in distinguishing histoid from lepromatous nodules. tried pefloxacin and ofloxacin36,37 in the treatment of histoid
Moreover, the morphology of ‘histoid’ bacilli is striking, for leprosy.
they are long, strongly and uniformly stained throughout The role of immunotherapy in histoid leprosy has not
their length, and invariably fail to form globi.13 been evaluated.
CHAPTER
13
Table 13.1: The recommended dosage schedule for histoid leprosy (Advet patients)
Drug Dose Duration
}
1. Rifampicin 600 mg once a month, supervised All the three drugs for at least two years; and
preferably till smear negativity.
2. Clofazimine 300 mg, once a month, supervised and 50 mg
daily, self-administered
3. Diamino-diphenyl sulfone
(Dapsone, DDS) 100 mg daily, self-administered
SIGNIFICANCE OF HISTOID LEPROMAS This review of histoid leprosy brings out the salient
features of this entity namely:
Only a few studies have so far been done to elucidate the 1. The lesions are cutaneous and/or subcutaneous
significance of histoid leprosy.1,3,11,13,38 The presence of nodules and less frequently plaques.
elongated, well-preserved, peculiarly arranged acid-fast 2. They most frequently occur on the lower back and
bacilli, invariable absence of globi formation and sometimes buttocks. They also involve the hands and the face.
the resistance of these patients to sulfone treatment, 3. There are usually 6 to 50 lesions. Majority of patients
suggest that one is probably dealing with sulfone-resistant have fewer than 30.
mutant organisms. Mouse footpad sensitivity tests have 4. The patients seldom develop erythema nodosum
shown that the bacilli present in histoid lesions are often leprosum (ENL).
resistant to diamino-diphenyl sulfone. Many workers do 5. On histopathologic examination, one sees large number
not believe dapsone resistance to be the principle cause of spindle-shaped cells with enormous number of bacilli,
for the development of histoid nodules or even an important especially in the spindle cells. Few globi are present.
factor in the epidemiology of this variant of leprosy. 6. There is augmented cell-mediated immunity in histoid
The immunohistochemical expression of these lesions leprosy compared to that in active lepromatous leprosy.
indicates an augmented cell-mediated immunity. These The humoral immunity is also considerably enhanced.
lesions remain well-circumscribed tumorous collections of Its importance in National Leprosy Eradication Program
spindle-shaped histiocytes trapping the ‘mutant’ histoid cannot be overemphasized. Hence, the details about the
entity should be well known to all those working in
bacilli.1,11,13 The appearance of histoid lesions certainly
institutions and the field.40-42
indicates a highly active lepromatous process. The striking
histologic features, morphology of the lesion, which mimics CHANGING SCENARIO
a neoplasm, would suggest a possible cellular alteration.
Presence of enormous number of bacilli in the lesion and It is worthwhile to recall 5 group classification of Ridley
and Jopling43 – Tuberculoid (TT), Borderline Tuberculoid
a paucity in its neighbouring areas would indicate the failure
(BT), Borderline Borderline (BB), Borderline Lepromatous
or alteration of an immunologic mechanism or the presence
(BL), and Lepromatous Lepromatous (LL) – which
of other factors resulting in uninhibited multiplication of
subsequently was expanded to a 7 group classification38
bacilli in limited areas.1,7,11,39
by the inclusion of indeterminate(I) and primary neuritic
Although structurally resembling a neoplasm, they are
leprosy (PNL).40 The indeterminate leprosy has been
essentially an inflammatory condition. This could be borne termed as a pivot from where the other well established
out by the fact that many such cases respond adequately clinical groups of leprosy (other than the polar forms at the
to standard anti-leprosy multidrug treatment of leprosy.4,8,9 two extremes of the disease spectrum i.e. TT(p) and LL(p),
In a recent appraisal of clinical, bacteriological, which are believed to arise de novo, and not as a result of
histopathological and immunological features, it was upgrading or downgrading of disease) emanate. The
postulated by Sehgal and Srivastava that histoid leprosy conversion of indeterminate leprosy into histoid form per
is a relatively stable component of multibacillary se has recently been demonstrated, thus establishing
leprosy.1,13 It has its unique status in the leprosy spectrum histoid leprosy as one of the groups (8th) on a continuous
with its fairly delineated characteristics – both clinical and leprosy spectrum. It is, therefore, envisaged that histoid
investigational –a postulate commented upon by Professor leprosy (HL) may have multi-bacillary or pauci-bacillary
Moschella.14 variants.42,44,45
CHAPTER
13
Histoid Leprosy 175
REFERENCES 24. Sanchez J. Lepromatous leprosy with lesions resembling nodular
subepidermal fibrosis. Int J Lepr 1965; 33: 179-85.
1. Sehgal VN, Srivastava G. Status of histoid leprosy–a clinical, 25. Bopp C, Bakos L. The histoid variety of lepromatous leprosy.
bacteriological, histopathological, and immunological appraisal. Arch Dermatol Forsch 1975; 252: 1-10.
J Dermatol (Tokyo) 1987; 14: 38-42.
26. Misra RC. Leprous histiocytoma. Lepr India 1980; 52: 582-85.
2. Sehgal VN, Srivastava G, Beohar PC. Histoid leprosy—a
27. Srivastava G. Epithelioid cells in histoid histology. Indian J Lepr
histopathological reappraisal. Acta Leprologica 1987; 5: 125-
1988; 60:136.
31.
3. Wade HW, Tolentino JG. Histoid (high-resistance) lepromatous 28. Porricha D, Bhatia VN. Epithelioid and Polygonal cells in histoid
leprosy. Abstracts of congress papers 191. Int J Lepr 1963; leprosy. Indian J Lepr 1987; 59: 191-93.
31:608-09. 29. Ridley MJ, Ridley DS. Histoid leprosy. An ultrastructural
4. Price EW, Fitzhebert H. Histoid variety of lepromatous leprosy. observation. Int J Lepr other Mycobact Dis 1980;48:135-39.
Int J Lepr 1966; 34:367-74. 30. Job CK, Chacko CJ, Taylor PM. Electron microscopic study of
5. Mansfield R. Histoid leprosy. Arch Pathol 1969; 87:580-85. histoid leprosy with special reference to its histogenesis. Lepr
6. Rodriguez JN. The histoid leproma, its characteristics and India 1977; 49: 467-71.
significance. Int J Lepr 1969; 37:1-21. 31. Liu JH, Liw Z, Yang LH, et al. Further observations on ultra-
7. Desikan KV, Iyer CG. Histoid variety of lepromatous leprosy. A structure of histoid leprosy. Abstract of XII International Leprosy
histopathologic study. Int J Lepr 1972; 40:149-56. Congress Papers. Int J Lepr 1984; 52: 755-56.
8. Ramanujam K, Ramu G. Wade’s histoid lepromatous leprosy. 32. Kumaravel S. Multiple subcutaneous lipomatosis in a case of
Report of a clinical study. Lepr India 1969; 41:293-97.
relapsed lepromatous leprosy masquerading as histoid leprosy.
9. Bhutani LK, Bedi TR, Malhotra YK et al. Histoid leprosy in north
Indian J Lepr 1995; 67: 187-90.
India. Int J Lepr other Mycobact Dis 1974; 42:174-81.
33. Chakrabarti A, Kumar B, Das A et al. Atypical postkala-azar
10. Ramanujam K, Ramu G. Histoid transformation from unstable
dermal leishmaniasis resembling histoid leprosy. Lepr Rev 1997;
forms of leprosy. Abstract of Congress Papers 17/335. Int J
Lepr 1973; 41:685. 68: 247-51.
11. Wade HW. The histoid leproma. Abstract. Int J Lepr 1960; 28: 34. Sehgal VN, Bhattacharya SN, Sardana K et al. Cutaneous
469. (papulonodular) sarcoidosis following hilar lymphadenopathy:
12. Wade HW. The histoid variety of lepromatous leprosy. Int J Lepr an intriguing manifestation. SKIN med 2002; 2: 131-33.
1963; 31:129-42. 35. Anonymous. WHO Expert Committee on Leprosy. 6th Report,
13. Sehgal VN, Srivastava G. Histoid leprosy – a prospective Technical Report Series 761. Geneva. World Health
diagnostic study in 38 patients. Dermatologica 1988; 177: Organization, 1988.
212-17. 36. Vora NS, Vora VN, Mukhopadhyay AK et al. A case of histoid
14. Sehgal VN, Srivastava G. Status of histoid leprosy – a clinical, leprosy responding to ofloxacin along with standard MDT. Indian
bacteriological, histopathological, and immunological appraisal. J Lepr 1995; 67: 183-86.
In the year Book of Dermatology. Year Book Medical Publishers, 37. Mahajan PM, Jadhav VH, Mehta JM. Pefloxacin in histoid leprosy.
1988.
Int J Lepr Other Mycobact Dis 1994; 62: 297-98.
15. Liu J, Kong QY, Ye GY et al. Observations on ultra-structure
38. Sehgal VN. A seven group classification for institutional and field
of histoid leproma. Int J Lepr other Mycobact Dis 1982; 50:471-
work. Lepr Rev 1989; 60:75
76.
16. Sehgal VN, Srivastava G, Saha K. Immunological status of histoid 39. Sehgal VN, Srivastava G, Gautam RK et al. ENL in histoid leprosy.
leprosy. Lepr Rev 1985; 56: 27-33. Int J Lepr Other Mycobact Dis 1984; 52: 543-44.
17. Kalla G, Purohit S, Vyas MC. Histoid, a clinical variant of 40. Sehgal VN, Sardana K. ‘Intriguing’ repercussions of primary
multibacillary leprosy: report from so-called non-endemic areas. neuritic leprosy in evolution of leprosy across the leprosy
Int J Lepr Other Mycobact Dis 2000; 68: 267-71. spectrum. Int J Dermatol 2006; 45:1121-23.
18. Sehgal VN. Clinical Leprosy. 4th edn. Jaypee Brothers Medical 41. Sehgal VN, Aggarwal A, Srivastava G et al. Evolution of histoid
Publishers, New Delhi, 2004; 187. leprosy (de novo) in lepromatous (multibacillary) leprosy. Int J
19. Chaudhary DS, Chaudhary M, Armah K. Histoid variety of Dermatol 2005; 44: 576-78.
lepromatous leprosy. Lepr Rev 1971; 42: 203-07. 42. Sehgal VN. Spontaneous appearances of papules, nodules,
20. Sehgal VN, Srivastava G, Gautam RK et al. Erythema and/or plaques: A prelude to abacillary, paucibacillary, or multi-
nodosum leprosum (ENL) in histoid leprosy. Indian J Lepr 1985; bacillary histoid leprosy. SKINmed 2006; 5:139-41.
57:346-49.
43. Ridley DS, Jopling WH. Classification of leprosy according to
21. Sehgal VN, Chaudhary A, Mahajan DM, et al. Type2 (ENL)
immunity. Int J Lepr 1966; 34: 255-73.
reaction in histoid leprosy in a child. Lepr Rev 1991; 62: 431-37.
44. Sehgal VN, Srivastava G, Singh N. Histoid leprosy:
22. Sehgal VN, Srivastava G, Sharma VK. Simultaneous occurrence
histopathological connotations’ relevance in contemporary
of upgrading and downgrading type 1 (lepra) reaction. Int J
Dermatol 1990; 29:356-57. context. Am J Dermotopathol 2009; 31: 268-71.
23. Sehgal VN, Srivastava G, Sharma VK. Immune responses in 45. Sehgal VN, Srivastava G, Singh N et al. Histoid leprosy: the
disseminated necrotizing histoid leprosy. Int J Dermatol 1988; impact of the entity on post-global leprosy elimination era. Int J
27: 413-14. Dermatol 2009; 48:603-10.
CHAPTER
14
14
Laboratory Diagnosis
Charles K Job, Joyce Ponnaiya
Early diagnosis of leprosy is very important, and can not 4. To assess the progress of the disease,
be over emphasized. Institution of early treatment will 5. To follow up the patients on treatment.
prevent further progression of the disease especially,
damage to the peripheral nerves causing paralytic Indications for Slit-Skin Smear Examination
deformities and destructive lesions in hands, feet and eyes 1. Diffuse skin infiltration without any sensory impairment
due to sensory loss. Although the clinical picture of leprosy or with vague sensory impairment
varies widely from a small area of hypopigmented skin, to 2. Innumerable, bilaterally symmetrical, ill defined macular
extensive damage to peripheral nerves and its lesions without any (or vague) sensory impairment.
consequences; it is generally accepted that an expert 3. Papules, plaques and nodules on the earlobes, face,
leprologist can identify most patients by clinical trunk back and extensor aspects of limbs, without any
examination alone. Therefore in the recent past, the value (or vague) sensory impairment.
of laboratory tests in the early diagnosis has been 4. A clinical situation where it is unclear whether the
underestimated and hence underutilized. It is heartening patient is suffering from paucibacillary (PB) or
to see that there is now an attempt to recognize the value multibacillary (MB) leprosy.
and importance of laboratory tests in the diagnosis and 5. Leprosy patient presenting with fresh lesions after
classification of leprosy, if they are carried out meticulously release from therapy (RFT).
by well trained technicians in adequately equipped 6. At the time of RFT of all MB patients, for reference
laboratories and supervised by experts. baseline data for the diagnosis of relapse, if at all, it
occurs late.
SLIT-SKIN SMEAR EXAMINATION
Slit-skin smear technique was first developed by Wade
Sites for Slit-Skin Smear
and Rodriguez in 1927, described by Wade in 1935 and When the technique was introduced, smears were obtained
standardised by Cochrane in 1947.1 Of all the laboratory from multiple sites which included both ear lobes, both
tests in leprosy service, the slit-skin smear examination cheeks, forehead, chin, both buttocks and additional 6
is the most simple and valuable one. suspicious sites. The number of sites is now brought down
to 4 without compromising the value of the test, now the
Role of Slit-Skin Smear Examination routine sites are: (i) right ear, (ii) right forehead, (iii) chin,
Demonstration of acid-fast bacilli (AFB) in skin smear (iv) left buttock in men and left upper thigh in women.2
examination serves several purposes:- However, the active or suspicious lesion must be included,
1. To confirm the diagnosis of leprosy, if the disease spectrum is closer to the paucibacillary side.
2. To classify the disease, In borderline leprosy, the bacterial load in different sites
3. To determine the infectivity of a patient, may vary considerably and it is recommended that in such
CHAPTER
14
Laboratory Diagnosis 177
cases smears may be obtained from 8 sites to include 4 • Allow smears to dry at room temperature.
active lesions in addition to the 4 routine sites. • Fix the smear by moving the slide briefly over a flame;
from a methylated alcohol lamp or a gas burner
Technique of Slit-Skin Smear (Alternatively the smears can be fixed by keeping in
Equipment Used formalin fumes for 10 minutes). They are now ready for
staining. Remember, the heating of slides should be
• Microscopic glass slides
gentle, excess heat is going to destroy the smear
• Disposable surgical gloves
tissue.
• Surgical scalpel with detachable sterile blades
• Slides used once should never be used again.
• Cotton swabs soaked in methylated alcohol
• Tincture benzoin Preparation of Dichromate Solution
• Methylated alcohol
• Dichromate solution is prepared by dissolving 25 g of
• Spirit lamp or a gas burner.
potassium dichromate in 25 ml of distilled water and
Method of Taking Slit-Skin Smears then adding 50 ml concentrated sulfuric acid slowly
Clean glass slides free of grease, are prepared as follows: with stirring (always add acid to water). Cool the solution
The slides are boiled in water with a detergent or soap for and store it in a glass bottle. Discard when it turns green.
30 minutes and washed in running water. They are then
Staining of Slides: Ziehl-Neelsen Method
kept in dichromate solution overnight, washed again in
running water, rinsed in distilled water and stored in Chemicals required
methylated alcohol. Just before use, the slides are taken a. Basic fuchsin
out using forceps and cleaned with a soft cloth. b. Decolorizing agent
• Using a diamond glass marker pencil write the patient’s c. Methylene blue (counter stain).
identification number on the extreme left side of the
glass slide. Preparation of Reagents
• Just before taking the smear, clean the skin site using Carbol fuchsin (to make 200 ml)
sterile cotton wool soaked in methylated alcohol. Let
the area become dry. Basic fuchsin … 2g
• Pinch the fold of skin tightly using the thumb and index Phenol-melted … 10 ml
finger till it blanches. Absolute alcohol (95%) … 20 ml
• Using a surgical scalpel with a detachable sterile blade Distilled water … 170 ml
(Bard Parker No.15), make a cut on the skin fold 5 mm In a large conical flask take 2 g of basic fuchsin and
long and 2 mm deep just to expose the subepithelial then add 10 ml of melted phenol. Mix well. Then add 20 ml
tissue. Ordinarily there should be no bleeding, if there of 95% of absolute alcohol and mix well. Finally add
is, wipe off the blood with a sterile swab. 170 ml of distilled water and shake until the dye is dissolved.
• Turn the blade at 90o and scrape out fragments of tissue Filter the solution (using Whatman filter paper No.40) every
and fluid from the bottom and side of the cut. time before use.
• Place the material thus obtained on the clean slide
Decolorizing agent
and spread evenly to make a smear about
8 to 10 mm in diameter. a. Sulfuric acid (5%) (to make 200 ml)
• Flame the blade and place it on its stand. 1-N Concentrated sulfuric acid … 10 ml
• The skin cut may be sealed with a small piece of cotton Distilled water … 190 ml
wool dipped in Tincture benzoin. Take 190 ml of distilled water in a large conical flask
• Using a second blade make the smear from the next and add to it (slowly down the side of the flask) 10 ml
site. The cooled first blade is used again to make the of concentrated sulfuric acid. Rotate the flask and
smear from the third site. Repeat the procedure until shake as you pour the acid.
all the smears are taken. About 4-5 smears can well Caution: Never pour water into the acid, always acid
be made on a single slide. into the water.
CHAPTER
14
b. Hydrochloric acid (1%) in 70% absolute alcohol BACTERIAL INDEX (BI)

(to make 100 ml)
The universally accepted standard method for assessment
Concentrated hydrochloric acid … 1 ml
of the mycobacterial load in a leprosy patient is the
Absolute alcohol (70%) … 99 ml
assessment of bacterial Index (BI) as defined by Ridley
Methylene blue (0.2%) (counter stain) (1958), based on a logarithmic scale and is a modification
(to make 200 ml) of Cochrane’s index. The bacterial load is graded as
Methylene blue powder … 0.4 g detailed below (Fig. 14.1).
Distilled water … 200 ml 6+ … Over 1000 bacilli and globi in an average
microscopic field
Method of Staining 5+ … Over 100 bacilli but less than 1000 in an average
microscopic field
• The slides with the fixed smears are stained individually. 4+ … Over 10 bacilli but less than 100 in an average
• They are placed separately on staining rods over a microscopic field
sink. 3+ … Over 1 bacillus but less than 10 in an average
• Flood the slides with freshly prepared and filtered carbol microscopic field
fuchsin (or filtered if made previously) and keep the 2+ … 1 to 10 bacilli in 10 microscopic fields
stain for 20 minutes. Alternatively, the slides may be
1+ … 1 to 10 bacilli in 100 microscopic fields
gently heated using a gas flame or a methylated alcohol
Zero … No bacilli observed after searching at least 100
lamp, under the slide, just to produce steam to rise from
microscopic fields.
all parts of the slide, but boiling must be avoided. The
The BI is arrived at by adding the values from all the
lamp should not be kept static at any area under the
skin sites examined (usually 4) and by dividing the total
slide; it should be kept moving side to side. Keep the
by the number of sites.
stain for 10 to 15 minutes without any further heating.
Example:
• Wash the slides gently in running water.
Right ear 5+
• De-stain the slide by using either 5% sulfuric acid for
Forehead 4+
10 minutes, or by using 1% hydrochloric acid in 70%
Chin 3+
absolute alcohol for 3-5 seconds.
Buttock 3+
• Wash the slides gently in running water.
——————
• Flood the slides with counter stain 0.2% methylene
Bacterial index (BI) is 15 ÷ 4 = 3.75
blue and keep it for 1 minute.
——————
• Wash the slides gently with running water.
• Stand the slide inclined on its narrow side on a blotting
MORPHOLOGICAL INDEX
paper until it is dry.
Morphological index (MI) is the percentage of solid stained
Examination of the Smear bacilli, calculated after examining 100 bacilli lying singly
Skin smears are examined using a light microscope under under the microscope.4 If the number of organisms present
an oil immersion objective. To make the examination easier are less than 100, the percentage is calculated according
a binocular microscope is preferred. Binocular microscopes to the number of bacilli available for examination. AFBs
should have clean lenses and uniformly lighted objectives, are considered solid staining if the organisms satisfy the
preferably with an artificial lamp for proper study of the following criteria:
slide. The number of AFB in each field is counted and • The entire organism must be uniformly stained,
graded as detailed below.3 In addition, the morphology of • The longitudinal sides are parallel,
the bacilli is carefully examined to find out whether the • Both ends are rounded,
AFB present are live or killed; if they are undergoing • The length is 5 times its width.
granularity and fragmentation. It is believed that the solid Slit-skin smear technique and the assessment of BI
staining organisms are probably live and viable; whereas and MI should be carried out by well trained technicians
the granular, broken and fragmented ones are dead and with meticulous care. Any compromise or shortcut in any
non-viable.4 of the steps namely taking of smears, numbering of the
CHAPTER
14
A B
C D
Figs 14.1A to D: Lepra bacilli in slit-skin smears after Ziehl-Neelsen staining, as seen in oil immersion objective. A to C are 4+ (100-1000 bacilli
in an average field. D is 6+ (with over 1000 bacilli and many globi in an average field) (Photo courtesy: Dr D Porichha, Lepra Healthinaction,
Bhubaneshwar)
slides, staining and examining the slides to measure the • If the specimen obtained is not immediately fixed the
bacteriological indices, will result in disastrous bacilli will degenerate and are lost in the count.
consequences in the diagnosis and management of • If the light source of the microscope is inadequate and
leprosy. Some of the possible (and common) errors, which not with uniform illumination, the identification of solid
must be avoided, include: staining bacilli will be erroneous.
• If the skin-cut is not deep enough to reach the The poor quality work in the slit-skin smear studies
granuloma and scraping of the cut surface is not done reported from laboratories attached to the Leprosy Control
properly, an adequate sample of the bacilli contained Programs had resulted in the abandonment of skin smear
in the tissue may not be obtained in the smear. studies altogether. Instead, steps should have been taken
• If the material obtained is not spread properly and to improve the work by offering periodic refresher courses
evenly in the slide, the count of the bacilli may be to technicians, strict supervision of laboratories, and
erroneous. introducing quality control measures. With the widespread
CHAPTER
14
implementation of multidrug therapy (MDT) during the past illumination. A nasal speculum may be used for adequately
2 decades the disease load has been brought down viewing the nasal mucosa. The smears are obtained either
considerably and the disease declared eliminated. In the from the anterior end of inferior turbinate or from the septum.
foreseeable future, the hope of eradicating the disease is The mucosa is not cut but scraped with the blade. Bleeding
bright. It is during this critical period, that there should be is avoided as far as possible. The material thus obtained
increased efficiency in our efforts to diagnose, assess, including the tissue fragments, is smeared on to a glass
and manage the disease in its early stages, when the slide and processed in a similar manner as for skin smears.
diagnosis offers many hurdles. Establishment of referral If crusts are present in the nasal mucosa, they are softened
centers with experts to offer supervision and quality control with irrigation using normal saline. Only after removing the
to peripheral laboratories, and reintroduction of the slit crusts the smears are taken. After taking the smear a
smear test as a routine procedure, is imperative to help in small ball of cotton is pressed into the nostril to stop the
hastening the eradication of the disease. bleeding, if there is any.
NASAL MUCOSAL SMEARS Method of Collecting Nasal Blows
In lepromatous leprosy the involvement of the nasal The patient is given a small thin cellophane bag with a
mucosa is almost 100%.5 Nasal mucosal epithelial lining 6 inches wide opening on one side and is asked to blow
is thin and is easily ulcerated and therefore, is the most his nose into it. It is preferable to obtain the specimen
common site from where M. leprae are disseminated into early in the morning soon after he gets up from the bed,
the environment. It has been reported that in a lepromatous even before he washes his face, mouth and nose.6 A smear
patient about 10 million bacilli per day can be collected is made on a slide from the specimen in the cellophane
from the nasal secretions.6 Following anti leprosy therapy, bag using a cotton swab mounted on a stick, then processed
the nasal ulcers heal fast and therefore examination of just as skin smears.
smears obtained from the nasal mucosa and its secretion In evaluating the specimens obtained from nasal smear
is very helpful in assessing the response of a patient to or nasal blow, it is important to remember that nose may
treatment and his infectivity. For a period nasal smears harbour acid fast saprophytes. Therefore the decolorisation
were discontinued because of the belief that the presence of the smears from the nose should always be done with
of acid fast saprophytes present in the nose may vitiate an acid-alcohol decolorising solution. Finding of a rare and
the findings. Now with careful staining these artefacts can a single organism in a nasal smear should be interpreted
be avoided. carefully, with much scrutiny and meticulous study of the
It has been found that material collected from nasal clinical picture and other relevant factors.
blows first in the morning, especially before the patient
has cleared his nose, contains enough AFB shed from the SKIN BIOPSY
ulcerated mucosa to evaluate the bacterial load in a Under ideal circumstances every patient of leprosy should
lepromatous patient. undergo skin biopsy examination to confirm the diagnosis
and type of leprosy, to identify the complications like
Method of Taking Nasal Mucosal Smears reactions, and to help in the management of the disease.
To obtain nasal smears, a nasal mucosal scraper specially In some countries where medical facilities are adequate
prepared for the purpose is used. A bicycle spoke 2 mm and leprosy patients are few, this is strictly followed. In
thick and 15 cm long is obtained; one end of it is beaten to countries where there are a large number of patients, and
a width of 4 mm to make a blade 1 cm long and 4 mm adequate funds and trained medical personnel are not
broad. One side of this blade is filed to make it blunt and readily available, a thorough and detailed clinical
the other side is sharpened. However, this simple examination and all required laboratory tests are not done
manufactured surgical instrument should always be as a routine. Now when there is worldwide reduction of
sterilized (either in the autoclave or in boiling water) before number of patients, and more and more, early and difficult-
use. to-diagnose patients are seen, it is essential that the
The collection of specimen is done very gently and patients are given the benefit of these laboratory studies.
only under direct vision of the nasal cavity with good Further following the integration of leprosy with general
CHAPTER
14
medical services, more patients will be cared for by primary local anesthetic intradermally, the needle is inserted into
care physicians, than by paramedical workers and the skin downwards in stages, injecting lignocaine. Then
hopefully, the efficiency in the care of leprosy patients will the skin piece should be excised with a cold knife or a
improve. 5 mm punch. While taking out the skin piece great care
should be exercised so that the tissue is not crushed with
Site of Skin Biopsy the forceps. If the biopsy specimen has to be held, while
If the presenting sign is a small hypopigmented patch removing it, only the edge of biopsy should be held by
suspected to be indeterminate leprosy, the biopsy should forceps. Once the biopsy specimen is crushed the cells
be taken from the middle of the lesion where the disease that form the tissue are also destroyed beyond recognition.
is active.7 Where there are multiple lesions, the most active Soon after removal, the skin biopsy is spread on a small
lesion should be chosen. In such patients the active piece of blotting paper (or filter paper) so that it will not curl
spreading edge should be chosen for the biopsy and no upon itself. Immediately the biopsy piece sticking to the
normal skin need be included. If there are numerous skin blotting paper is immersed into the fixative. Any delay in
lesions with different morphology, more than one biopsy transferring the tissue into the fixative will cause autolysis
is required for proper evaluation. In many patients reporting of cells and make it unsuitable for histopathologic study.
at early stage, the lesions are usually vague. When the A busy clinician taking time to do the biopsy should
skin is infiltrated with local anesthetic for the biopsy also spend a little more time to check and see that the
procedure, the vague skin lesion may become obscure biopsied skin piece is transferred into the fixative
and not be easily identifiable. Therefore it is better to mark immediately after removal and the bottle with the fixative
the biopsy site with a skin-marking-pencil before local and specimen is properly labeled.
anesthetic is administered.
FIXATIVES
Size of the Biopsy
Neutral Formalin (Universal fixative) (To make 1 liter)
The biopsy size may vary, depending on the clinical picture
Formaldehyde solution (40%) … 100 ml
and the purpose for which the biopsy is done. In early
lesions where diagnosis of the disease is in question, and NaH2 PO4.2 H2O … 3.5 g
the histopathologic changes present in the skin are Na2 HPO4.2 H2O … 6.5 g
minimal, (as in indeterminate leprosy), a fairly large sample Distilled water … 900 ml
of the skin lesion should be obtained to allow proper Neutral formalin 10% is a universal fixative and can be
evaluation. The biopsy should be an elliptical piece of skin easily and routinely used in a busy out-patient clinic. AFB
1.5 cm long, 0.6 cm wide and deep enough to include the stain also works well in tissues fixed in formalin. However,
full depth of the dermis and subcutaneous tissue, so that it has certain drawbacks, there is some shrinkage of
the nerves in the deep dermis and possibly in the collagen which pulls apart the tissue and the granuloma
subcutaneous region are available for study. For and blurs the cytological details. The use of pure 40%
assessment of clinically well established lesions, for repeat formalin as fixative is best avoided, as it causes distortion
biopsies for follow up studies and management of the of granuloma.
disease, a 5 mm punch biopsy sample is adequate. When
the lesion is on the face (especially in a child or a female Lowy’s Fixative (FMA- Formaldehyde, Mercuric
patient) care should be taken to reduce the size to the Chloride, Acetic Acid):
minimum necessary (3 mm punch) so that only a very Formaldehyde solution (40%) … 100 ml
small scar is left behind. Mercuric chloride … 20 g
Glacial acetic acid … 30 ml
Biopsy Procedure Distilled water … 1000 ml
The lesion and the surrounding areas are cleaned with First dissolve the mercuric chloride in water with gentle
spirit and covered with a sterile towel which has a small heat and then add the other reagents.
square cut-out at the center. One ml of 2% lignocaine is FMA fixative should be freshly prepared every
drawn into a syringe. After injecting a small quantity of 3 months. After 2 hours of fixation in this solution the tissue
CHAPTER
14
must be transferred to 70% ethyl alcohol in which it can 5 minutes. Wash well with water, before staining with
be stored for any length of time. If the tissue is kept in hematoxylin.
FMA fixative longer than 2 hours it gets hardened and • Stain with Harris hematoxylin for 10 minutes.
further processing of the tissue is hampered. If properly • Rinse in tap water to remove excess stain.
used, this fixative offers very good preservation of cellular • Decolorise by quickly dipping the stained slides into
details without any shrinkage of collagen. After the biopsies 1% Hydrochloric acid 2 or 3 times.
have undergone fixation they may be transferred to 70% • Wash in running water for 10 minutes.
alcohol and transported to properly equipped histopathology • Dip in lithium carbonate solution to stain the section
laboratory. It is advisable to use this fixative for research blue.
studies but only, if properly trained technical personnel • Wash in running water for 10 minutes.
are available. • Counter-stain with 1% eosin solution for 15 seconds.
The skin biopsies are processed for paraffin sectioning • Wash in running water.
and the sections are made of 4 to 5 micron thickness. • Dehydrate in graded alcohol.
Several staining procedures are now available to allow • Clear using 2 changes of xylene for 1 to 2 minutes.
detailed study of the biopsies, especially for early lesions; • Mount the section in DPX medium.
and to differentiate a leprosy lesion from that of other
granulomatous conditions. Preparation of Solutions
The following stains may be done depending on the
Harris Hematoxylin
nature of the study:
1. Hematoxylin-eosin stain (H & E) for routine histopatho- Hematoxylin … 5g
logic examination. Absolute alcohol … 50 ml
2. Job-Chacko modification of Fite-Faraco stain for Potassium alum … 100 g
M. leprae.8 Mercuric oxide … 2.5 g
3. Gomori-Grocott methenamine silver stain to demons- Glacial acetic acid … 25 ml
trate remnants of degenerating M. leprae.9 Distilled water … 1000 ml
4. Fluorescent microscopy to detect M. leprae.10 Dissolve hematoxylin powder in absolute alcohol.
5. Immunochemical staining using mycobacterial Separately dissolve potassium alum in warm distilled
antibodies to detect products of M. leprae in water. Mix the two solutions and heat to boiling point. Then
tissues.11-14 slowly add mercuric oxide. Cool the stain rapidly in ice or
6. S-100 stain, to selectively bring out neural fragments cold water. When it is cool, add glacial acetic acid.
from a destroyed nerve.15-17
Eosin Stain
Of all these above listed staining procedures, the
H & E stain and the Fite-Faraco stain for M. leprae are Eosin … 1g
done as a routine on all biopsies, which will be described Phloxin B (aqueous) … 100 mg
in detail. The other four staining procedures mentioned Glacial acetic acid … 4 ml
require well equipped laboratories and specially trained Distilled water … 100 ml
technicians, and are done only when a specific problem Absolute alcohol … 890 ml
arises or for research studies. Dissolve 1 gram of eosin in 100 ml of distilled water.
Add to it, 10 ml of an aqueous solution of 100 mg phloxin
HEMATOXYLIN-EOSIN (H&E) STAIN B. Add absolute alcohol to make up to 1000 ml. Finally
add 4 ml of glacial acetic acid.
• Paraffin sections 5 micron in thickness, are mounted
on clean glass slides. Alcohol Iodine Solution
• Deparaffinize using 2 changes of xylene for 5 minutes Iodine crystals … 1g
each. Alcohol 95% … 100 ml
• Bring to water using graded alcohol.
If the sections are from FMA fixative, treat them Sodium Thiosulfate Solution
with 1% alcohol-iodine solution for 10-15 minutes. Wash Sodium thiosulfate … 5g
with tap water. Treat with sodium thiosulfate for Distilled water … 100 ml
CHAPTER
14
Lithium Carbonate the microscope. The acid-fast stain fades in course of time
Lithium carbonate … 5g and it is difficult to preserve AFB stained slides for any
Distilled water … 500 ml length of time. The Gomori-Grocott method retains the stain
for many years.
Job-Chacko Modification of Fite-Faraco Stain Silver stains the fibrous connective tissue and elastic
for M. leprae tissue therefore, selective staining of M. leprae especially
in a tissue like skin, with abundant fibrous connective
Staining Procedure: Each slide is stained separately
tissue and elastic fiber, is not possible and therefore the
• Deparaffinize sections in a mixture of xylene and peanut specificity is poor, although the sensitivity is high. So it is
oil (2 parts of xylene, 1 part peanut oil), two changes of not ordinarily used in routine skin biopsy studies. In the
6 minutes each. internal organs such as lymph nodes, liver, spleen, bone-
• Drain, wipe off excess oil and blot with filter paper. marrow, and adrenals, where fragmented M. leprae may
• Wash in running tap water for 4 minutes. persist for many years inside small clumps of foamy
• Stain in Ziehl-Neelsen carbol fuchsin solution for 30 macrophages, this stain is very useful to identify the
minutes at room temperature. presence of remnants of M. leprae. Also in healed skin
• Wash in tap water for 2 minutes. lesions of patients in the lepromatous spectrum, where
• Differentiate slides in 5% sulfuric acid in 25% alcohol remnants of M. leprae may not be demonstrable using
for two changes of 1.5 minutes each. routine stains for AFB, Gomori’s stain will help to identify
• Wash in running tap water for 5 minutes. them.
• Counter stain with Harris hematoxylin for 5 seconds.
• Wash in running tap water for 5 minutes. FLUORESCENT MICROSCOPY TO
• Drain the excess water, blot with filter paper and air
DETECT M. LEPRAE
dry the section at room temperature. Do not use alcohol
to dehydrate. Finding of M. leprae during histopathologic examinations
• Clear in 2 changes of xylene and mount. of early lesions is an important criterion in the diagnosis of
This staining procedure has 2 modifications from the leprosy. Routine acid fast stains are not so sensitive
routine Fite-Faraco stain for M. leprae. Use of alcohol is because of the variability in the destaining procedures using
minimized to prevent over decolorization of already stained acid alcohol. In the search for more sensitive staining
M. leprae especially in biopsies from indeterminate procedures, fluorescent method of staining M. leprae has
patients. The other change is in the use of counter stain. been found to be useful.
Instead of methylene blue, hematoxylin is used. The nuclei In a study of 56 skin biopsies from early leprosy lesions,
are well stained and therefore the cells and the tissue using a slight modification of Kuper and May’s method to
structures are clearly identified in relation to the presence obtain optimum fluorescence, 39 showed M. leprae as
of AFB. Finding of AFB in any one of the following sites compared to only 25 in section stained by the Fite-Faraco
such as, the subepidermal region of the skin, inside stain for M. leprae.10 Although fluorescent staining has
Schwann cells, endothelial cells and arrectoris pilorum found a place in detection of M.tuberculosis, it has not
muscle cells, will confirm the diagnosis of leprosy. been widely used to detect M. leprae.
GOMORI-GROCOTT METHENAMINE IMMUNOCHEMICAL STAINING TO

SILVER STAIN DEMONSTRATE MYCOBACTERIAL
ANTIGENS
This staining procedure is ordinarily used for staining fungi
in tissue sections. It has been found that Mycobacteria It has been reported that the identification of early lesions
also take up the silver stain and appear black. Since the of leprosy using histopathologic techniques is very much
lipid coat of AFB is stained, even dead, fragmented and enhanced by using immunochemical staining procedures
granular M. leprae (which usually do not take up the Fite’s to demonstrate the presence of antigens of M. leprae.11-13
stain) can be visualized by using this method. Since the In a study of 51 skin biopsies from patients suspected of
organisms appear black, they are easily identified under early leprosy, only in 9 patients (17.6%) AFBs were found
CHAPTER
14
using routine AFB staining technique, whereas in 24 experts are not readily available, a physician, or a surgeon
patients (47.1%) the diagnosis of leprosy was confirmed well trained to do nerve biopsies, may perform the nerve
by finding mycobacterial antigens by immunostaining using biopsies. A thickened sensory nerve is selected for biopsy.
polyclonal BCG antibodies.11 If in a skin biopsy there are The suitable nerves include supraorbital branch of the Vth
histopathologic changes of early leprosy, such as cranial nerve, a supraclavicular nerve, the great auricular
perivascular, peri and intraneural inflammation; and if the nerve in the neck, the radial cutaneous nerve at the wrist,
antigenic components of M. leprae are demonstrated inside a cutaneous nerve of the forearm or thigh, the sural nerve
nerves and macrophages using immunohistochemical at the back of the leg or superficial peroneal nerve on the
techniques, it is reasonable to make a diagnosis of leprosy. dorsum of the foot.
In a recent study using in situ hybridization procedure The nerves usually chosen for biopsy are a branch of
for M. leprae, 25 patients each from early leprosy and sural nerve at the level of the above ankle, or a branch of
suspected leprosy were studied. The positivity rates for radial cutaneous nerve at the wrist region. In the tuberculoid
spectrum, cutaneous nerves adjacent to a skin lesion,
demonstrating the presence of M. leprae using in situ
may be enlarged and in such cases that nerve may be
hybridization procedures were considerably higher than
chosen for biopsy. The nerve deficit resulting from these
those with routine Fite-Faraco stain.14
procedures is usually minimal. 18
After proper sterilization of the area, small amount of
S-100 STAIN FOR SCHWANN CELL 2% lignocaine is injected around the nerve and after waiting
In skin biopsies from tuberculoid (polar & subpolar) and for 5 minutes, a transverse skin incision is made. The
borderline tuberculoid leprosy patients, AFBs are not nerve is separated by blunt dissection. A small nick is
ordinarily demonstrable. Therefore, a firm diagnosis made in the nerve, to divide one or two fasciculi, which
depends on demonstration of active invasion and are then picked up and stripped from the nerve bundle.
destruction of dermal and cutaneous nerves by the Since in tuberculoid and borderline leprosy the involvement
granulomas. In several patients these nerves are destroyed of nerve is longitudinal, a 2 cm long nerve twig may be
beyond recognition on routine histopathology. Only dissected out using fine iris forceps and scissors. The
remnants of these nerves (composed of Schwann cell- nerve tissue is then laid on a blotting paper or a filter paper
clumps) are left behind in the granulomas. In such to keep its longitudinal orientation preserved and
immediately transferred to fixative. The common fixative
instances, the spindle shaped Schwann-cell-clumps may
that is used for nerve biopsies is 10% neutral formalin.
not be easily distinguished from the collections of epithelioid
Nerve biopsies are done usually to confirm the diagnosis
cells. S-100 stain which selectively stains Schwann cells,
of leprosy, especially in patients who present with pure
may be used to bring out the remnants of the destroyed
neural leprosy where there are no skin lesions. The biopsies
nerves lying in tuberculoid granulomas. Several
are processed for paraffin sections and 5 micron thick
publications15-17 have clearly brought out the usefulness
sections are cut. The following staining procedures are
of this stain in the diagnosis of tuberculoid leprosy and
available for study.
differentiating it from other tuberculoid granulomas of the
1. Hematoxylin-eosin stain
skin such as tuberculosis, deep fungal infections and
2. Job-Chacko modification of Fite-Faraco stain for AFB.8
sarcoidosis.
3. Luxol fast blue stain for myelin19
It should be noted that S-100 stain also stains
4. Bodian stain for axons20
melanocytes, dendritic cells and the cells lining the sweat
During histopathological examination when acid fast
ducts. But they can be easily identified and differentiated
organisms are demonstrated inside nerves; or when
from Schwann cells by the morphological appearances.
granulomatous inflammation destroying the nerve
parenchyma is seen, the diagnosis of leprosy is easily
NERVE BIOPSY made. There is also patchy demyelination seen in luxol
Nerve biopsy is a procedure which should not be fast blue stain and fragmentation of axons in the Bodian
undertaken lightly and should ideally be done by either a stain. When these diagnostic evidences are absent, other
neurologist or a neurosurgeon. Since such highly qualified neurological diseases should be considered and further
CHAPTER
14
detailed studies may be done to identify specific changes Method of Doing the Test
due to the other neuropathies listed below: Two drops histamine hydrochloride solution 0.1% (1 mg in
Neuropathies are broadly classified into 4 groups: 1 ml) is placed, one on normal skin and the other on the
1. Disorders with thickened nerves suspected patch. With a sharp sterile needle a prick is
2. Disorders with patchy areas of cutaneous hypoesthesia made through the drops on both sites deep enough to
3. Polyneuropathy penetrate the epidermis. The histamine solution is wiped
4. Spinal cord disease off and the area is watched for 5 minutes. In the normal
A detailed description of these diseases is beyond the skin, a weal at the site of prick and a flare of 2 cm diameter
purview of this chapter. The reader is referred to the chapter surrounding the weal would be seen (test labeled as
in this textbook, on differential diagnosis of neurological positive). The flare disappears in 10 minutes. In the skin
conditions. patch of leprosy the flare is impaired or absent and only a
In a rare patient, there is total fibrous replacement of weal is seen (test negative). The flare is feeble and delayed
the nerve parenchyma and fibrosis of the perineurium. The in indeterminate and borderline leprosy; and absent in a
intraneural fibrous tissue may show extensive hyalinization. tuberculoid lesion.
No acid fast organisms or inflammatory granuloma or This test is useful only to differentiate hypopigmented
caseous necrosis is observed. The end stage of leprous macules of leprosy from those of other skin diseases.
neuritis may only show a totally hyalinized nerve and There will be a normal flare (positive test) in other
cannot be differentiated from the end stage of some of the hypopigmented macules due to non-leprosy conditions like
other neuropathies. Fortunately, this appearance is almost vitiligo, pityriasis alba, fungal infections, etc. Further, the
always present in healed leprosy lesions only. histamine test will also be negative in patients without any
skin changes but only with areas of nerve deficit due to
HISTAMINE TEST other peripheral neuropathies. Also, in patients with dark
There are few other diagnostic tests which should be skin this test may not be useful because the flare is not
easily visible.
mentioned although they are not ordinarily done in routine
practice.
THE SWEAT TEST
The Principle of Histamine Test21,22 The Principle of Sweat Test23, 24
The response in the skin to histamine depends on the Similar to histamine test, sweat test also evaluates the
integrity of nerves of the autonomic nervous system. The function of autonomic nerves which appear to be impaired
autonomic nerves are non-myelinated nerve fibers sheathed much earlier than the sensory nerves. The sweat glands
only by Schwann cells and are distributed along with the are activated by parasympathetic nerves and substances
small dermal blood vessels. In early leprosy, which that act upon these nerves will increase sweating.
manifests as localized skin patches, the Schwann cells Pilocarpine nitrate, methacholine chloride, acetyl choline,
are parasitized by M. leprae. There is perivascular and and carbaminoyal choline are some of the chemicals
perineurial inflammation and the functions of sympathetic injected into the skin to demonstrate increase of sweating.
nerves of the skin supplying the blood vessels are impaired, In tropical countries, the use of drugs may be avoided and
even before the sensory nerves are affected. the part of skin to be tested may be exposed to the sun for
Histamine elicits two reactions in normal skin in which a short period. The common drugs used are pilocarpine
the sympathetic nervous system is intact: a flare, caused nitrate and acetyl choline. Acetyl choline acts faster and
by dilatation of small blood vessels of the skin and a weal, its effects do not cause long lasting discomfort.
due to local injury to the skin. In the skin affected by
leprosy, flare may be impaired or absent, due to
Method of Performing the Test
malfunctioning of the sympathetic nervous system and The hypopigmented patch in the skin to be tested and the
only a weal is seen. adjoining area of normal skin are thoroughly cleaned with
CHAPTER
14
methylated alcohol, and painted with tincture iodine. Wait role of FNAC in the diagnosis and follow-up of leprosy. The
till the area dries and then dust the painted areas with technique of obtaining aspirates is simple and can be
starch. A watery solution of 0.05 ml of 0.1% of acetyl applied in the field.
choline is injected intradermally into the hypopigmented
lesion and also into the adjoining normal skin which acts FNAC FOR CUTANEOUS LESIONS OF
as control. Examine the areas 5 to 10 minutes later. The LEPROSY
area turns blue if there is sweating. Instead of acetyl
choline, 0.2 ml of 0.1% solution (1 in 1000) of pilocarpine Singh et al found FNAC of skin lesions to be of value in
nitrate or 0.1 ml of 1% solution of methacholine chloride the diagnosis of lepromatous leprosy.25 Aspirates from
may be also used. nodules and plaques yielded cellular material with an
Instead of Tincture iodine and starch powder to detect abundance of foamy macrophages and a few lymphocytes.
sweating, bromophenol paper may also be used. When a Acid fast bacilli were seen as negative images. The
strip of bromophenol paper is applied over the sites of aspirates from macular lesions were less cellular and the
injection, 2 to 5 minutes later, blue dots will be seen on numbers of macrophages and negative images were also
the paper if there is sweating. Bromophehol paper is less. In 15 of 22 patients studied, the cytomorphology and
prepared by soaking a Whatman filter paper with 1% the histological classification were concordant. In the
solution of bromophenol blue powder in absolute alcohol remaining seven patients, the diagnosis of leprosy could
or acetone. be made on FNAC, but classification on the Ridley Jopling
This test can also be used in dark skinned persons, scale was discordant by two positions – BB – BL.
unlike histamine test. It is of use only to differentiate Another larger series of 94 newly diagnosed cases of
hypopigmented macules of leprosy from macules of other leprosy was studied, comparing the FNAC and skin biopsy
diseases. The sweat function may also be lost in areas of from the same site. Satisfactory aspirates were obtained
skin with nerve impairment due to other neuropathies. in 61 cases and there was a good correlation of 90%
between FNAC and biopsy in tuberculoid (TT & BT) and
CYTOLOGICAL DIAGNOSIS OF LEPROSY 93.7 % in lepromatous (BL & LL) cases. Cases in the mid
borderline (BB) category showed correlation in only 30%
Histopathological examination of skin and nerve biopsies; of cases.26
and slit-skin smears examination to assess bacillary load, In another study, the same group27 studied FNAC in
have been the major tools used in the laboratory diagnosis, reactions in leprosy. They found that Type 1 reactions
classification and follow up of patients with leprosy.
showed collagen, elastin, loose epithelioid cell granulomas,
Obtaining and processing of skin biopsies requires
giant cells and giant cells with elastin phagocytosis and
technical expertise and the necessary laboratory
fibroblasts. Type 2 reactions showed a pattern of
infrastructure, and a pathologist experienced in interpreting
lepromatous leprosy with an abundance of neutrophils.
skin pathology. Reading of slit-skin smears requires trained
Similar findings have also been reported by others.19
personnel. As the disease burden is greatest in
Studies have also showed that FNAC is of value in the
communities and countries with limited resources, attempts
diagnosis of neuritic leprosy. In a study by Vijayakumar
have been made to find diagnostic tests that are cheaper
et al,19 the nerve aspirates in 23 of 25 cases could be
and less demanding in terms of technology, so that they
classified by the Ridley-Jopling method. They listed the
can be applied in the field.
following criteria for diagnosis and classification.
The technique of fine needle aspiration cytology (FNAC)
was first introduced in the late 1920s as an alternative to
Paucibacillary (Indeterminate, TT and BT)
incision and excision biopsies for the diagnosis of solid
tumors. It has proved to be a simple and effective • Good number of inflammatory cells in the aspirate
diagnostic tool, which can be performed in an office setting. • Predominantly epithelioid cell granulomas and moderate
It is widely used today both for palpable tumors; and with numbers of lymphocytes
radiological guidance, for more deep seated lesions. • Occasional giant cells and neutrophils
A limited number of studies have been done to assess the • BI zero to 1+
CHAPTER
14
Borderline Borderline (BB) Procedure
• Fair number of inflammatory cells in the aspirate For superficial lesions such as skin patches or palpable
• Predominantly lymphocytes and moderate numbers of cutaneous nerves, routine cleaning and sterilization as for
foamy macrophages percutaneous injection is adequate. Anesthesia is not
• BI 2+ to 3+ required except in children or very anxious patients. The
procedure should be explained to the patient who should
Borderline Lepromatous (BL) be instructed not to move during the aspiration.
The site to be aspirated is immobilized with one hand;
• Fair number of inflammatory cells in the aspirate
the needle is inserted in a near vertical direction and to the
• Predominantly lymphocytes and moderate numbers of
required depth. The plunger is withdrawn to create negative
foamy macrophages
pressure and the needle moved back and forth within the
• BI 4+ to 5+
tissue. The negative pressure is released while the needle
is still in the lesion. The needle is withdrawn and detached
Lepromatous Leprosy (LL)
from the syringe; air is drawn into the syringe and the
• Fair to poor inflammatory cells in aspirate aspirate blown out onto the slide.
• Predominantly foamy macrophages and few
lymphocytes Preparing the Aspirate
• BI 6+ The aspirated material is smeared onto the slide using
A similar study by Jayaseelan et al30 on 27 cases of another clean slide or a cover slip, exerting a light pressure.
pure neuritic leprosy found FNAC a good alternative to The smears are air dried and stained with H & E stain or
biopsy in neuritic leprosy, as the risk of motor deficit after May Grunwald Giemsa stain or modified Fite Faraco stain.8
this procedure is less than with that in nerve biopsy.
CONCLUSION
TECHNIQUE OF FNAC
In this chapter we have attempted to describe almost all
Equipment the available laboratory tests to diagnose and classify
1. Needles: Standard disposable needles are used. Gauge leprosy. We would like to again emphasize that skin smear
25 needles are recommended in children and in sites examination, perhaps the most important test in leprosy
like the eyelid; and gauge 22 or 23 in adults and for should be done in every patient. Although there are several
other sites. Local anesthesia is generally not required well equipped laboratories in India with well qualified
in these cases. experts, some of them offering their services free, biopsy
examination of skin and nerves of leprosy patients is
2. Syringes: Standard disposable plastic syringes of 10
woefully inadequate.
to 20 ml capacity are used.
We would like to point out that to diagnose indeterminate
3. Syringe holder: The syringe holder leaves one hand
leprosy with no detectable sensory impairment and purely
free to immobilize the tissue, but some authors have
neural leprosy, skin biopsy in the former and nerve biopsy
dispensed with the use of the syringe holder for
in the latter is mandatory.
superficial lesions.
Finally it should be mentioned that in a rare patient,
4. Slides: Clean glass slides, dry and free of grease, are
especially in children having facial lesions, even after a
used to prepare the smears. The aspirated material thorough clinical examination and after performing all the
can either be smeared between two glass slides or by necessary laboratory tests, diagnosis of leprosy may still
using a 0.4 mm cover slip. The smears are air dried be in doubt. The implications of over diagnosis of leprosy
before transporting. without proper evidence, is a serious matter, and it is
5. Fixation: Air dried smears are recommended. unethical and wrong. Ignoring such patients also may lead
6. Other: Skin disinfectant, sterile dressings, scalpel to serious consequences like in a 6-year-old boy reported
blades should be available. to have non-specific chronic dermatitis, who came back
CHAPTER
14
8 years later with lepromatous leprosy.31 If in doubt, the 13. Natrajan M, Katoch K, Katoch VM. Enhancement in the
patient must be followed up for one or two years and if the histological diagnosis of indeterminate leprosy by demonstration
of Mycobacterial antigens. Acta Leprol 1995; 9:201-07.
lesions persist, the biopsy must be repeated to rule out 14. Natrajan M, Katoch K, Katoch VM et al. In situ hybridization in the
leprosy. histological diagnosis of early and clinically suspect leprosy. Int
J Lepr 2004; 72: 296-305.
15. Fleury RN, Bachi CE. S-100 protein and immunoperoxide
ACKNOWLEDGMENTS
technique as an aid in the histopathological diagnosis of leprosy.
We wish to express our gratitude to The American Leprosy Int J Lepr 1987; 55:338-44.
16. Job CK, Drain V, Deming AT et al. Role of S-100 protein as a
Mission International, South Carolina, USA. and to The
marker for Schwann cells in the diagnosis of Tuberculoid type of
Leprosy Mission International, Brentford, London, for their leprosy (Letter). Int J Lepr 1990; 58:392-93.
generous financial support. 17. Thomas MM, Jacob M, Chandi SM et al. Role of S-100 staining
in differentiating leprosy from other granulomatous diseases of
the skin. Int J Lepr 1999; 67:1-5.
REFERENCES 18. Antia NH. Nerve biopsy. In: Antia NH. and Shetty VP. (eds). The
1. Trautman JR. History of Leprosy in Hastings RC. (Ed). Leprosy. peripheral nerve in leprosy and other neuropathies. Oxford
2nd edn. Churchill Livingstone N.Y. 1994;11-25. University Press, Delhi 1999;251-52.
19. Cook HC. Manual of histological demonstration techniques.
2. Chacko CJG. Microbiology in Thangaraj RH. A manual
Butterworth & Co. (Publishers) Ltd, London. 1974; 162-3.
of Leprosy, 4th edn. The Leprosy Mission, New Delhi, 1985;
20. Preece A. Manual for Histologic Technicians. 2nd edn. Little Brown
43-60.
& Co. Boston 1965; 224-25.
3. Ridley DS. Therapeutic trials in leprosy using serial biopsies.
21. Dharmendra, Chatterjee SN. The importance of early diagnosis–
Lepr Rev 1958; 29: 45-82.
some helpful procedures, In: Leprosy, Vol. I. Dharmendra, Ed.
4. Waters MFR, Rees RJW. Changes in the morphology of Kothari publishing house, Mumbai 1978; 263-72.
Mycobacterium leprae in patients under treatment. Int J Lepr 22. Rodrigues J, Plantilla FC. The histamine test as an aid in the
1962; 30: 266-77. diagnosis of early leprosy, In: Leprosy, Vol. I. Dharmendra, Ed.
5. Barton RPE. A clinical study of the nose in lepromatous leprosy. Kothari publishing house, Bombay 1978; 263-72.
Lepr Rev 1974; 45:135-44. 23. Parikh AC. Ganapati R, Kapadia BI et al. Acetylcholine test for
6. Davey TF, Rees RJW. The nasal discharge in leprosy, clinical anhydrosis in leprosy. Lepr Rev 1966; 37: 231-37.
and bacteriological aspects. Lepr Rev 1974; 45:121-34. 24. Sehgal VN. Significance of local sweat response in the diagnosis
7. Ridley DS. Skin biopsy in leprosy. 2nd edn. Documenta Giegy, of leprosy. Dermatological 1974; 148(4):217-23.
Basle 1985. 25. Singh N, Bhatia A, Arora VK, Bhattacharya SN. Fine needle
8. Job CK, Chacko CJG. A modification of Fite’s stain for aspiration cytology of lepromatous leprosy. Lepr Rev 1998;
demonstration of M. leprae in tissue sections. Indian J Lepr 69:145-50.
1986; 58:17-18. 26. Rao S, Singh MK, Datta Gula S et al. Utility of fine needle aspiration
9. Ambrogi LG. Manual of histologic and special staining technique. cytology in the classification of leprosy. Diagn Cytopathol 2001;
2nd edn. Blackiston Division, Mcgrath book company inc. New 24:317-21.
York 1960. 27. Malik A, Bhatia A, Singh N. Fine needle aspiration cytology of
10. Nayak SV, Sivarudrappa AS, Mukkamil AS. Role of Fluorescent reactions in leprosy. Acta Cytol 1999; 43(5):771-76.
28. Nigam TK, Kumar Prasanth, Pathak N, Mithal S. Fine needle
microscopy in detecting M. leprae in tissue sections. Ann Diag
aspiration cytology in reactional and non reactional leprosy.
Pathol 2003; 7(2):78-81.
Indian J Dermatol Venereol Leprol 2007; 73:247-49.
11. Schettini APM, Ferreira LE, Malagros R et al. Enhancement of
29. Vijayakumar M, D’Souza M, Kumar S, Badhe B. Fine needle
histological diagnosis of leprosy in patients with only sensory
aspiration of nerves in leprosy. Lepr Rev 2001; 72:171-78.
loss by demonstration of mycobacterial antigens using anti BCG
30. Jayaseelan E, Shariff S, Rout P. Cytodiagnosis of primary neuritic
antibodies. Int J Lepr 2001; 69:335-40. leprosy. Int J Lepr 1999; 67:429-34.
12. Weng XM, Chen SY, Ran SF, et al. Immunohistopathology in the 31. Binford CH. The histologic recognition of early lesions of leprosy.
diagnosis of early leprosy. Int J Lepr 2000; 68:426-33. Int J Lepr 1971; 39:225-30.
15
Serological and Molecular Diagnosis
Utpal Sengupta, Vishwa Mohan Katoch
INTRODUCTION confirmation by any laboratory test will be desirable in such

settings.
Diagnosis of leprosy has been based on classical cardinal
The standard method for the diagnosis of leprosy is by
signs, characteristic histology and/or demonstration of acid-
histopathological examination of tissue sections from the
fast bacilli in skin smears from the lesions. Using these
advancing margin of an active lesion. Standard histological
criteria for diagnosis along with the application of multi-
and immunological approaches for assessing leprosy have
drug treatment, the disease has been contained and
limited value for diagnosing new cases at the ‘suspicious’
controlled as a public health problem. India achieved the
and ‘indeterminate’ stages and for monitoring treatment.
target of elimination (prevalence below 1/10,000) in
Immunological technique for eliciting delayed type
December 2005, and currently has a prevalence of 0.74/
hypersensitivity (DTH) with lepromin is mainly useful in
10, 000. 1 While the number of leprosy cases has
the classification of disease. Further, serological responses
significantly decreased, the profile of disease has also
in leprosy have been reported to be useful mainly for
changed to some extent with atypical lesions and single
determining exposure, as the antigens and resultant
lesions showing uncharacteristic histology. Clinicians in
response persist for a long time after subsidence of clinical
the field and reference institutions need objective tests to
or subclinical disease. Demonstration of acid-fast bacteria
help in reaching a diagnosis in such cases. At least two of
in skin smears is also often not sufficiently sensitive more
the following findings have to be present for a clinical
so in the paucibacillary (PB) form, and in histological
diagnosis of leprosy: (a) a characteristic patch or skin lesion
assessments of atypical granuloma, the characteristics
with impaired sensations; (b) a thickened and/or tender
of inflammatory response are difficult to differentiate from
cutaneous or peripheral nerve with impairment of sensations
nonspecific dermatitis.
in the area supplied by it; and (c) acid-fast bacteria in the
In the diagnosis of any infectious disease serology
skin smear. The disease is formally classified into a range
and molecular biology are two complementary strategies.
of subtypes that include, in approximate order of extent of
While serodiagnosis represents a time tested, easy to apply
disease, indeterminate (I), tuberculoid (TT), borderline
approach, molecular methods provide unparalleled
tuberculoid (BT), mid borderline (BB), borderline
sensitivity and specificity to detect a pathogen, its
lepromatous (BL) and lepromatous leprosy (LL) types.
subtypes, determine its viability and also the drug
Other forms, such as pure neuritic leprosy (without skin
resistance genotype.
lesions), are also recognized.2 Diagnosis of leprosy can
be based on clinical examination only, but it may be difficult
to differentiate from diseases that cause similar symptoms SERODIAGNOSIS
or signs, especially in areas where its incidence is low. In Over the last three decades several workers have attempted
such a situation workers experienced in the examination the development of a specific serodiagnostic test(s) using
of skin along with nerve deficit will be best equipped to M. leprae specific antigens and their epitope specific
detect early cases, relapses and reactions.3 In addition, antibodies. The important methods are:
CHAPTER
15
Mycobacterium leprae Specific Lipid Antigen Recombinant Antigens of M. leprae

Phenolic glycolipid 1(PGL-1) or its terminal sugars have Developments in molecular biology have provided new
been used extensively for developing various types of information about the gene sequences of M. leprae, ability
serological tests. Finding of a specific lipid, PGL-1 on to recombine genes with appropriate vectors and clone
M. leprae cell wall by Brennan and Barrow4 led to the them in suitable hosts for production of their gene products.
development of an enzyme linked immunosorbent assay Construction of lambda gt11; 24 cosmid libraries of
(ELISA).5-7 Nearly, 90 to 95 percent of BL/LL and 25 to 60 M. leprae 25 and plasmid libraries 26 were important
percent of TT / BT patients were found to be positive for landmarks. Other libraries have since been constructed
PGL-1, whereas healthy endemic controls were mostly using different vector-host systems and many
found to be negative. Later, identification of specific B cell immunologically/biologically relevant genes have been
epitopes of PGL-1, 8 the sugar molecules, natural expressed in these systems. Many M. leprae protein
disaccharide (ND)/natural trisaccharide (NT) led to antigens produced by recombinant DNA technology have
synthesis of these sugars which were used conjugated been immunologically characterized.27 Their relevant
with bovine serum albumin (BSA) as ND-O-BSA/NT-O- original publications have been reviewed and cited
BSA in ELISA for diagnosis of leprosy. 9 These earlier.28,29 Several of them are highly immunodominant
glycoconjugates were found to have higher specificity than for both T and B cell responses and some have species
the copolymers of PGL-1.9 It has been noted that the and genus specific epitopes.
antibody response to the lipid is primarily of IgM type10 18 kDa antigen: Among these recombinant proteins, the
and its level gradually rises from TT through LL indicating 18kD antigen has been well characterized and has been
its direct correlation with bacterial load/bacterial index found to bear T-cell reactive epitopes.30 However, its
(BI).11-14 However, sometimes such a correlation was not serological reactivity has not been worked out adequately.
evident.15 Most of these studies have observed that for
LSR antigen: This antigen identified from recombinant
any specific value of BI there was a tremendous variation
clones has epitopes that are preferentially recognized in
in antibody levels and the reasons for this have been
ENL cases.31
discussed elsewhere. Using PGL-1 antigen and adopting
an immunochromatographic technique, a rapid lateral flow Recombinant 35 kDa protein: Triccas et al purified 35 kDa
assay, ML Flow Test, has been developed for detection of protein from the sonicate of recombinant M.smegmatis
antibody against PGL-1. This quick assay showed 91 transformed with pW19.32 This purified protein was used
percent agreement with that of ND-O-BSA based ELISA.16 in a direct ELISA and was compared with PGL-1 based
Using this assay 92 percent and 32 percent of patients ELISA. This assay was found to be highly specific (97.5%)
were proposed to be classified as multibacillary (MB) and and sensitive (90%) and was comparable to PGL-1 and
paucibacillary (PB) cases respectively.17 35 kDa Mab based serology.
M. leprae recombinant culture filtrate protein-10 (rCFP-10):
35 kD Antigen Serology A homologue 10 kDa protein, CFP-10 culture filtrate of
Monoclonal antibody (Mab), MLO4 which specifically M. tuberculosis having 36% identity has been found in
reacts with 35 kDa epitope of M. leprae, was used by M. leprae.33 This protein has been noted to be an inducer
Sinha et al for detection of antibodies in leprosy patients.18 of T-cell proliferation with γ-interferon release in a large
The assay which was developed as a radioimmunoassay number of M. leprae sensitized individuals. Recently, using
was later standardized as competition ELISA.19,20 Using direct ELISA, antibody levels against this protein were
this assay almost 100 percent of active BL / LL and more also evaluated in a group of leprosy patients and the test
than 40 percent of TT /BT patients were found to be was found to be highly specific and comparable to PGL-1
positive.21 Further, the antibody levels were noted to antibody assay.34
correlate with number of patches22 or number of nerves Other cloned proteins of M. leprae: Several other cloned
involved.23 The antibody levels also showed a gradual fall proteins of M. leprae have been tested for their antibody
with treatment.20 reactivity with sera obtained from leprosy patients in
CHAPTER
15
Serological and Molecular Diagnosis 191
Philippines, Brazil and Japan. Two proteins ML0405 and Genome of M. leprae
ML2331 which reacted with sera from all these regions
Extensive information about the molecular structure and
were further tested for their use in serodiagnosis of leprosy.
function of leprosy bacillus is now available and this has
It was noted that both of these proteins were recognized
helped in developing molecular techniques for early
by sera from MB patients.35 Recently, after screening a
diagnosis, monitoring of treatment and detection of drug
large number of serum samples it was noted that the fusion
resistance.29 Even before the publication of genome
construct of these two proteins [designated leprosy IDRI
sequence using conventional molecular tools, several
diagnostic 1 (LID-1)] retained the diagnostic potential.
genes related to the physiology of M. leprae were identified.
Further follow up study of household contacts showed rise
However, completion of sequencing of genome of M. leprae
in antibody levels against both LID-1 and ND-O-BSA before
has been an important landmark and it has provided a
clinical manifestation of leprosy.35
wealth of information, which was earlier impossible to
Immunohistochemistry-based Approaches obtain.40 Annotation of this genome sequence has shown
In histological diagnosis of leprosy, specimens showing that genome of M. leprae encodes for 1605 genes as
atypical features pose a challenge to histopathologists. compared to 3959 in M. tuberculosis.40 It has also been
Such cases are increasing proportionately, more so in the observed that this genome shows massive downsizing
changing scenario. Staining of these sections with and decay with 1116 pseudogenes. Based on genome
mycobacterial/ M. leprae specific antibodies can be a sequence information, DNA chips have been designed.
useful approach to improve the histological diagnosis of These have been utilized to identify genes of M. leprae that
leprosy.36, 37 are transcribed in animals.41 By using a DNA chip developed
at JALMA, genes of M. leprae expressed in human cases
Future Scope for Immunoassays have been identified and these could well be the future
therapeutic targets (patents filed, Nos. 2012/DEL/2006 and
Current diagnosis of leprosy is based on the presence of
884/DEL/2007). The chip designed at JALMA was
cardinal signs and is well accepted in the field for early
hybridized with the labeled cDNAs from the leprosy
diagnosis and for treatment and control of the disease.
patients (MB cases). In these experiments, several genes
None of the laboratory tests which have been described
which are differentially expressed and which could be
above are able to diagnose 100 percent clinical cases of
related to virulence and metabolic pathways have been
leprosy especially the early PB forms of leprosy which
can be easily diagnosed by the clinician even in the field. identified.29
The claim made in the recent multicentric study carried
Genomic Probes and Gene Amplification
out in Philippines, Brazil and Japan for predicting future
Assays for M. leprae
cases of leprosy in contacts using antibody assay against
LID-1 should be considered with care.35 Establishment of The information about molecular structure and functions
such a predictive assay especially for a long incubating has been used to develop molecular probes and assays
disease like leprosy, requires a survey of a large contact for diagnosis and/or to assess disease activity in leprosy.
population in a double blind manner. Earlier, such an attempt Several gene probes and gene amplification methods for
was made in a South Indian contact population which identification and detection of M. leprae specific sequences
showed that majority of leprosy cases appear from have been developed:
seronegative group compared to that from the seropositive
Probes Targeting DNA
group.38,39 Therefore, considering the chronicity of the
disease and the dynamism of immune system of the host, Several probes for detection of specific sequences of
hope for development of a predictive assay may be a M. leprae, including repetitive sequences42 and encoding
remote possibility. However, it is possible that in a doubtful protein antigens such as 18 kD antigen have been
case when the clinician is hesitant to make a definite developed.43 Because of the requirement of at least 104
diagnosis, these immunological tests specially targeting copies for a positive result, these probes have little clinical
specific antigens may help to confirm the case as of applicability and are better suited as laboratory tools for
leprosy. the identification of M. leprae.
CHAPTER
15
Ribosomal RNA and rRNA Genes based Probes In situ hybridization and in situ PCR: False positivity
It has been established that probes directed towards due to contamination in the clinic or laboratory is a major
ribosomal RNA (rRNA) are comparatively more sensitive drawback of PCR technology, but can be overcome by
than those which target DNA, since they need only 2000- developing suitable in situ protocols for PCR assays.50
5000 copies of rRNA per mycobacterium to be present.44 Buffered formalin fixed specimen are usually considered
Detection of rRNA correlates better with the presence of suitable both for histology as well as for PCR, as other
live M. leprae as ribosomes degenerate quicker than fixatives inhibit the reaction.67
genomic DNA. The existence of non-conserved (species
and possibly strain specific) variable sequences within Real Time PCR
rRNAs makes them attractive for the development of Real time PCR technology has improved molecular
probes.45-47 These RNA targeting probes are 10-100 fold diagnostics of many pathogens. One of the advantages of
more sensitive than DNA targeting probes48 and can be this method is the quantification of bacterial DNA content
used to monitor responses to therapy in MB and many PB in clinical specimens. Applications of PCR may be
leprosy cases.49 They may also help in identifying true improved or enhanced by the use of novel real time
relapses and differentiating them from reactions.28,44 These detection techniques. Kramme et al used real time PCR
probes used as in situ strategy can help in improving the for the detection and quantification for M. leprae in clinical
histological diagnosis of leprosy.50 specimens.68 In another study by Martinez et al TaqMan
Gene Amplification (PCR) Techniques real-time PCR was used for rapidly detecting and
quantifying M. leprae DNA in clinical specimens in which
There are several PCR methods to amplify different
bacilli were undetectable by conventional histological
gene stretches of M. leprae and include conventional
staining.69 It would be preferable to focus on rRNA or mRNA
DNA based PCR, reverse-transcription PCR and nested
based systems as these would correlate better with the
PCR.28, 29,44,52-60 These assays have been reported to be
presence of live M. leprae. Such assays have been recently
very sensitive (1 to 10 organisms) and exhibit a positivity
described for M. leprae and shown to be promising.70
of 60-75% in smear negative cases. Combined ethidium
Depending upon the availability of infrastructure and
bromide staining of gels and hybridization can improve
resources, real time PCR can be used for various aspects
the diagnosis by another 15% in smear negative PB
specimens.61 The availability of several nonisotopic of leprosy research.
detection methods has made the gene amplification and
gene probes practicable even in small laboratory settings. DETECTION OF DRUG RESISTANCE
Targeting M. leprae repetitive elements (RLEP) can improve Finding of multiplication of M. leprae in foot pads of mouse
the sensitivity.58 was a landmark which made drug susceptibility studies
Decrease in PCR signals has been observed to against M. leprae possible.71 As a result several antileprosy
correlate with the effect of therapy.52, 62, 63 Cases showing
drugs were identified and used as a component of multi-
persistence of signals for a longer period have been shown
drug treatment (MDT). With the widespread application of
to correlate with higher number of relapses.64 However,
MDT, the problem of drug resistance in leprosy appears to
because of the persistence of weak signals for a long-
be under control. With proper use of MDT, drug resistant
time even after effective treatment in general, DNA based
mutants are almost completely eliminated. Molecular
assays have sometimes been considered less useful in
methods can help in rapid direct detection of drug
differentiating late reactions from relapses.62 In such cases,
resistance without the need for growing the organisms.
RNA based reverse-transcription PCR (RT-PCR), which
Mutations in target genes can be identified by simple
involves the initial reverse transcription of target RNA to
DNA followed by amplification, is more appropriate.59,60 molecular approaches such as line probe assays and
Such assays are important because the change in sequencing which is the gold standard.72 Using these
molecular signals is much faster than the change in molecular assays surveillance programs can be planned
bacteriological indices which have been shown to change to determine the magnitude of drug resistant mutants from
after a long-time.65,66 biopsies.73
CHAPTER
15
Detection of Dapsone Resistance multiplicity of mechanisms of quinolone resistance,
Through surrogate genetic studies with M. smegmatis, the molecular detection of the same will not be that easy.
relationship between dapsone resistance and the
dihydropteroate synthase of M. leprae has been FUTURE PERSPECTIVE
established.74 Missense mutations within codons 53 and While the scope of molecular tools in diagnosis will be
55 of the sulfone resistance-determining region of folP1 mainly at reference level, knowledge gained on various
result in the development of high-level dapsone resistance aspects will help in unravelling the mysteries surrounding
in M. leprae.75 While the information is important, it is not the pathogenesis of this disease. As leprosy is at the stage
certain whether all dapsone resistant cases can be of elimination the present research approach should attempt
diagnosed by sequencing of this gene. in diagnosing the infection earlier than the appearance of
clinical manifestations. This could only be possible by a
Detection of Rifampicin Resistance laboratory test which would be able to discriminate between
an infected and healthy individual in the community.
Rifampicin (3-{[(4-methyl-1-piperazinyl)-imino]-methyl}
Therefore, search for new and novel antigen/s would be
rifamycin) is the key bactericidal drug of all recommended
required. In addition, search for new antigens specific for
antileprosy chemotherapeutic regimens. Mycobacterial
induction of M. leprae specific cell mediated immunity
resistance to rifampicin correlates with changes in the should be also encouraged.82,83
structure of the subunit of the DNA-dependent RNA
polymerase, primarily due to missense mutations within
ACKNOWLEDGMENTS
codons of a highly conserved region of the rpoB gene
referred to as the rifampicin resistance-determining The authors are thankful to various scientific and technical
region.72,76 Rifampicin resistance in M. leprae also colleagues for participation in different studies cited in this
correlates with missense mutations within this region of chapter. Financial support by ICMR, DST, DBT, WHO and
rpoB.73,77 Substitutions within codon Ser425 have been LEPRA for various studies cited from the institute is
shown to be the most frequent mutations associated with thankfully acknowledged.
the development of the rifampicin-resistant phenotype in
M. leprae. Like in tuberculosis, molecular detection of REFERENCES
rifampicin resistance in leprosy is possible by application 1. National Leprosy Elimination Programme (NLEP). http://
of easy approaches like line probe assay which appears nlep.nic.in/data.html, accessed on 6th June, 2009.
2. Dharmendra. Classifications of leprosy. In: Leprosy (Hastings,
to be quite reliable.78 RC, Ed.), Churchill Livingstone, London 1994;179-90.
3. Naafs B. Viewpoint: leprosy after the year 2000. Trop Med Int
Detection of Quinolones Resistance Health 2000; 5: 400-03.
4. Brennan PJ, Barrow WW. Evidence for species-specific lipid
Ofloxacin (4-fluoroquinolone) is a fluorinated carboxy- antigens in Mycobacterium leprae. Int J Lepr 1981; 48: 382-87.
quinolone and has moderate anti-M. leprae activity. The 5. Cho SN, Yanagihara DL, Hunter SW, et al. Serological specificity
of phenolic glycolipid I from Mycobacterium leprae and use in
mechanism of action of ofloxacin on M. leprae is unknown,
serodiagnosis of leprosy. Infect Immun 1983; 41: 1077-83.
but in the other bacteria it appears to inhibit DNA replication 6. Young DB, Buchanan TM. A serological test for leprosy with a
by inhibiting the DNA gyrase, a tetramer containing two A- glycolipid specific for Mycobacterium leprae. Science 1983;
221:1057-59.
subunits (GyrA) and two B-subunits (GyrB). Mutations
7. Brett SJ, Payne SN, Draper P et al. Serological activity of a
within a highly conserved region of gyrA, the quinolone characteristic phenolic glycolipid from Mycobacterium leprae in
resistance-determining region, are associated with the sera from patients with leprosy and tuberculosis. Clin Exp
development of ofloxacin resistance in most of the resistant Immunol 1983; 52: 271-79.
8. Fujiwara T, Hunter SW, Cho SN et al. Chemical synthesis and
strains of mycobacteria.79,80 The quinolone resistance serology of disaccharides and trisaccharides of phenolic
determining region of M. leprae gyrA is highly homologous glycolipid antigens from the leprosy bacillus and preparation of a
to that of M. tuberculosis, and missense mutations within disaccharide protein conjugate for serodiagnosis of leprosy.
Infect Immun 1984; 43: 245-52.
this region have been found in ofloxacin-resistant strains 9. Gigg J, Gigg R, Payne S et al. The allyl group for protection in
of M. leprae.81 However, in all mycobacteria because of carbohydrate chemistry. Synthesis of propyl O-(3, 6-di-O-
CHAPTER
15
methyl-B-D-glucopyranosyl)-(1-4)-O-(2,3-di-O-methyl-L- 25. Clark-Curtiss JE, Jacobs WR, Docherty MA et al. Molecular

rhamnopyranosyl)-(1-2)-3-O-methyl-L- rhamnopyranoside: The analysis of DNA and construction of genomic libraries of
oligosaccharide portion of the major serologically active glycolipid Mycobacterium leprae. J Bacteriol 1985; 161:1093-1102.
from Mycobacterium leprae. Chem Phys Lipids 1985; 38: 299- 26. Khandekar PS, Munshi A, Sinha S et al. Construction of genomic
307. libraries of mycobacterial origin; Identification of recombinants
10. Young DB, Dissanayake S, Miller RA et al. Humans respond encoding mycobacterial specific protein. Int J Lepr 1986; 54:
predominantly with IgM immunoglobulin to the species-specific 416-21.
glycolipid of Mycobacterium leprae. J Infect Dis 1984; 149: 870- 27. Young DB, Gaebe T, Lathigra R et al. Protein antigens: Structure,
73. function and regulation. In: McFadden JJ (Ed). Molecular biology
11. Schwerer B, Meeker HC, Sersen G et al. IgM antibodies against of mycobacteria. Surrey University Press: Surrey: 1990; 1-35.
phenolic glycolipid I from Mycobacterium leprae in leprosy sera: 28. Katoch VM. Advances in the diagnosis and treatment of leprosy.
Relationship to bacterial index and erythema nodosum leprosum. Expert Rev Mol Med 2002; 22:1-14.
Acta Leprol 1984; 2: 395-402. 29. Katoch VM, Lavania M, Chauhan DS et al. Recent advances in
12. Bach MA, Wallach D, Flageul B et al. Antibodies to phenolic molecular biology of leprosy. Indian J Lepr 2007; 79: 151-66.
glycolipid I and to whole M. leprae in leprosy patients: Evolution 30. Dockrell HM, Stocker NG, Lee SP, et al. T-cell recognition of the
during therapy. Int J Lepr 1986; 54: 256-67. 18 kilodalton mycobacterial antigen. Infect Immun 1979; 57:1979-
13. Sinha S, McEntegart A, Girdhar BK et al. Appraisal of two 83.
Mycobacterium leprae specific serological assays for monitoring 31. Singh S, Shankaranarayan NP, Jenner PJ et al. Sera of leprosy
chemotherapy in lepromatous (BL/LL) patients. Int J Lepr 1989; patients with type 2 reactions recognize sequences in
57: 24-32. Mycobacterium leprae recombinant LSR protein. Infect Immun
14. Roche PW, Britton WJ, Failbus SS et al. Operational value of 1994; 62:86-90.
serological measurements in multibacillary leprosy patients: 32. Triccas JA, Roche PW, Britton WJ. Specific serological diagnosis
Clinical and bacteriological correlates of antibody responses. of leprosy with a recombinant Mycobacterium leprae protein
Int J Lepr 1990; 58: 480-90. purified from a rapidly growing mycobacterial host. J Clin
15. Lyons NF, Shannon EJ, Eillis BPB et al. Association of IgG and Microbiol 1998; 36: 2363-65.
IgM antibodies to phenolic glycolipid-I antigen of Mycobacterium 33. Geluk A, van Meijgaarden KE, Franken KLMC et al. Immunological
leprae with disease parameters in multibacillary leprosy patients. cross-reactivity of the Mycobacterium leprae CFP-10 with its
Lepr Rev 1988; 59: 45-52. homologue in Mycobacterium tuberculosis. Scand J Immunol
16. Buhrer-Sekula S, Smits, HL, Gussenhoven GC et al. Simple and 2004; 59: 66-70.
fast lateral flow test for classification of leprosy patients and 34. Parkash O, Kumar A, Nigam A et al. Detection of antibodies
identification of contacts with high-risk of developing leprosy. against Mycobacterium leprae culture filtrate protein-10 in leprosy
J Clin Microbiol 2003; 41: 1991-95. patients. J Med Microbiol 2006; 55:1337-41.
17. Parkash O, Kumar A, Pandey R et al. Performance of a lateral 35. Duthie MS, Goto W, Ireton GC et al. Use of protein antigens for
flow test for the detection of leprosy patients in India. J Med early serological diagnosis of leprosy. Clin Vaccine Immunol
Microbiol 2008; 57:130-32. 2007; 14: 1400-08.
18. Sinha S, Sengupta U, Ramu G et al. A serological test for leprosy 36. Khanolkar SR, Mackanzie CD, Lucas SB et al. Identification of
based on competitive inhibition of monoclonal antibody binding Mycobacterium leprae antigens in tissues of leprosy patients.
to the My2a determinant of Mycobacterium leprae. Trans Roy Int J Lepr Other Mycobact Dis 1989; 57: 652-58.
Soc Trop Med Hyg 1983; 77: 869-71. 37. Natrajan M, Katoch K, Katoch VM et al. Improvement in the
19. Mwatha J, Moreno C, Sengupta U et al. A comparative evaluation histological diagnosis of indeterminate leprosy by demonstration
of serological assays for lepromatous leprosy. Int J Lepr 1989; of mycobacterial antigens. Acta Leprol 1995; 9: 201-07.
57: 744-51. 38. Sinha S, Kannan SA, Nagaraju B et al. Utility of serodiagnostic
20. Chaturvedi V, Sinha S, Girdhar BK et al. On the value of sequential tests for leprosy: A study in an endemic population in South
serology with Mycobacterium leprae specific antibody India. Lepr Rev 2004; 75: 266-73.
competition ELISA in monitoring leprosy chemotherapy. Int J 39. Sengupta U. Experience and lessons from the use of lepromin
Lepr 1991; 59: 32-40. and Mycobacterium leprae – specific serology. Lepr Rev 2000;
21. Sinha S, Sengupta U, Ramu G et al. Serological survey of leprosy 71 (suppl): S63-66.
and control subjects by monoclonal antibody based 40. Cole ST, Eiglmeier K, Parkhill J et al. Massive gene decay in the
immunoassay. Int J Lepr 1985; 55: 33-38. . leprosy bacillus. Nature 2001; 409: 1007-11.
22. Chaturvedi V, Sinha S, Girdhar BK et al. Association of 41. Williams DL, Torrero M, Wheeler PR et al. Biological implications
mycobacterial specific and Mycobacterium leprae specific of Mycobacterium leprae gene expression during infection. J Mol
antibody levels with clinical activity in tuberculoid leprosy: A Microbiol Biotechnol 2004; 8: 58-72.
comparative study of three serological enzyme immunoassays. 42. Clark-Curtiss JE, Docherty MA. A species specific sequence in
Lepr Rev 1991; 62: 122-33. Mycobacterium leprae DNA. J Infect Dis 1989; 159:7-15.
23. Roche PW, Britton WJ, Failbus SS et al. Serological responses 43. Williams DL, Gillis TP, Booth RJ et al. The use of specific DNA
in primary neuritic leprosy. Trans Roy Soc Trop Med Hyg 1991; probes and polymerase chain reaction for detection of
85: 299-302. Mycobacterium leprae. J Infect Dis 1990; 162:193-200.
24. Young RA, Mehra V, Sweetser O et al. Genes for major protein 44. Katoch VM. New investigative techniques in leprosy. In:
antigens of leprosy parasite Mycobacterium leprae. Nature 1985; Dermatology Update (Valia, RG, Valia AR, (Eds). Bhalani
316:450-52. Publishing House, Mumbai, 1998; 165-74.
CHAPTER
15
45. Pitulle D, Witt D, Stackebrandt E et al. Further evidence for the 62. Gupta UD, Katoch K, Sharma RK et al. Analysis of quantitative
exclusiveness of the Mycobacterium leprae specific probe. Int relationship between viability determination in leprosy by MFP,
J Lepr 1990; 58:130-33. ATP bioluminescence and gene amplification assays. Int J Lepr
46. Teske A, Walters J, Botter EC. The 16S rRNA nucleotide Other Mycobact Dis 2001; 69:328-34.
sequence of Mycobacterium leprae: Phylogenetic position and 63. Singh HB, Katoch K, Gupta UD et al. Effect of PCR positivity in
development of DNA probes. FEMS Microbiol Lett 1991; 64: MB patients treated with conventional and newer drugs ofloxacin
231-33. and minocycline. Acta Leprol 1999; 11: 179-82.
47. Katoch VM, Kanaujia GV, Shivannavar CT. Progress in 64. Katoch K, Katoch VM, Natarajan M et al. Long-term Follow-up
developing ribosomal RNAs and rRNA gene(s) based probes Results of 1 Year MDT in MB Leprosy Patients Treated with
for the diagnosis and epidemiology of infectious diseases including Standard MDT + once a Month Minocycline and Ofloxacin. Indian
leprosy. In: Kumar S, Sen AK, Dutta GP, Sharma RN (Eds). J Lepr 2008; 80: 331-44.
Trop Dis Mol Biol Control Start, New Delhi: CSIR; 1994; 581-87. 65. Dharmendra, Chaterjee SN. Examination for Mycobacterium
48. Sharma RK, Katoch VM, Katoch K et al. Comparison of probes leprae. In:Leprosy. Dharmendra, (Ed) Vol. I.: Kothari Medical
targeting ribosomal RNA vs DNA in leprosy cases. Indian J Med
Publishing House, Mumbai; 1978; 258-62.
Microbiol 1996; 14:99-104.
66. Ridley DS. Bacterial indices. In: Leprosy in theory and practice.
49. Sharma RK, Shivannavar CT, Katoch K et al. Microdensitometric
Cochrane RG, Davey TF, (Eds). Bristol: John Wright and Sons;
scanning procedure for quantitative assessment of hybridization
1964; 620-22.
of rRNA targeting probes in leprosy. Acta Leprol 1997; 10:213-
67. Singh HB, Katoch VM, Natrajan M et al. Improved protocols for
17.
PCR detection of Mycobacterium leprae in buffered formalin
50. Natrajan M, Katoch K, Katoch VM et al. In situ hybridization in the
fixed skin biopsies Int J Lepr and Other Mycobact. Dis 2004; 72:
histodiagnosis of early and clinically suspicious leprosy. Int J
175-78.
Lepr Other Mycobact Dis 2004; 72:296-305.
68. Kramme S, Bretzel G, Panning M et al. Detection and quantification
51. Hartskeerl RA, de Wit MYL, Klatser PR. Polymerase chain
reaction for the detection of Mycobacterium leprae. J Gen of Mycobacterium leprae in tissue samples by real time PCR.
Microbiol 1989; 135:2357-64. Med Microbiol Immunol 2004; 193:189-93.
52. Wood SA, Cole ST. A rapid method for detection of potentially 69. Martinez AN, Britto FPCC, Nery JAC et al. Evaluation of real
viable Mycobacterium leprae in human biopsies: A novel time and conventional PCR targeting complex 85 genes for
application of PCR. FEMS Microbiol Lett 1989; 65:305-10. detection of Mycobacterium leprae DNA in skin biopsy samples
53. Hackel C, Hourd S, Portaels F et al. Specific identification of from patients diagnosed with leprosy. J Clin Microbiol 2006;
Mycobacterium leprae by polymerase chain reaction. Mol Cell 44:3154-59.
Probes 1990; 4:205-10. 70. Sharma R, Lavania M, Katoch K et al. Development and
54. Plikaytis BB, Gelber RH, Shinnick TM. Rapid and sensitive evaluation of Real-time RT-PCR assay for quantitative estimation
detection of Mycobacterium leprae using nested primer gene of viable Mycobacterium leprae in clinical samples. Indian J
amplification assay. J Clin Microbiol 1990; 28:1913-17. Lepr 2008; 80: 315-21.
55. Cox RA, Kempsell K, Fairclough L et al. The 16S ribosomal RNA 71. Shepard CC. The experimental disease that follows the injection
of Mycobacterium leprae contains a unique sequence which of human leprosy bacilli into foot pads of mice. J Exp Med 1960;
can be used for identification by polymerase chain reaction. J 112: 445-54.
Gen Microbiol 1991; 30:284-90. 72. Musser JM. Antimicrobial agent resistance in mycobacteria:
56. Pattyn SR, Uris D, Iven M et al. Polymerase chain reaction Molecular genetic insights. Clin Microbiol Rev 1995; 8: 496–514.
amplifying DNA coding for species specific rRNA of 73. Honore N and Cole ST. A method for rapid detection of rifampicin-
Mycobacterium leprae. Int J Lepr 1992; 60:234-43. resistant isolates of Mycobacterium leprae. Lepr Rev 2001;72:
57. Misra N, Ramesh V, Misra RS et al. Clinical activity of LSR/A 15 441-48.
gene for Mycobacterium leprae detection in leprosy using 74. Williams DL, Spring L, Harris E. Dihydropteroate synthase of
polymerase chain reaction. Int J Lepr 1995; 63:35-41. Mycobacterium leprae and dapsone resistance. Antimicrob
58. Donoghue HD, Holton J, Spigelman M. PCR primers that can
Agents Chemother 2000; 44:1530-37.
detect low levels of Mycobacterium leprae DNA. J Med Microbiol
75. Cambau E, Carthagena L, Chauffour A. Dihydropteroate
2001; 50:177-82.
synthase mutations in the folP1 gene predict dapsone resistance
59. Jadhav RS, Kamble RR, Shinde VS et al. Use of reverse
in relapsed cases of leprosy. Clin Infect Dis 2006; 42: 238-41.
transcription polymerase chain reaction for the detection of
76. Williams DL, Waguespack C, Eisenach K. Characterization of
Mycobacterium leprae in the slit-skin smears of leprosy patients
Indian J Lepr 2005; 77:116-27. rifampicin resistance in pathogenic mycobacteria. Antimicrob
60. Phetsuksiri B, Rudeeaneksin J, Supapkul P et al. A simplified Agents Chemother 1994; 38:2380-86.
reverse transcriptase PCR for rapid detection of Mycobacterium 77. Zhang L, Namisato M, Matsuoka M. A mutation at codon 516 in
leprae in skin specimens. FEMS Immunol Med Microbiol 2006; the rpoB gene of Mycobacterium leprae confers resistance to
48:319-28. rifampicin. Int J Lepr Other Mycobact Dis 2004; 72: 468-72.
61. Sharma RK, Katoch K, Shivannavar CT et al. Detection of 78. Sapkota BR, Ranjit C, Macdonald M. Reverse line probe assay
M. leprae by gene amplification-ethidium bromide staining and for the rapid detection of rifampicin resistance in Mycobacterium
hybridization. Int J Lepr 1996; 64:409-16. leprae. Nepal Med Coll J 2006; 8:122-27.
CHAPTER
15
79. Drlica K, Xu C, Wang JY et al. Fluoroquinolone action in leprosy patients using Touch-Down (TD) PCR. FEMS Immunol
mycobacteria: Similarity with effects in Escherichia coli and Med Microbiol 2003; 36:27-32.
detection by cell lysate viscosity. Antimicrob Agents Chemother 82. Cardona-Castro NM, Restepo-Jaramillo S, dela Ossa MG et al.
1996; 40: 1594-99. Infection by Mycobacterium leprae of household contacts of
80. Takiff HE, Salazar L, Guerrero C et al. Cloning and nucleotide lepromatous leprosy patients from a post-elimination leprosy
sequence of Mycobacterium tuberculosis gyrA and gyrB genes region of Columbia. Mem Inst Oswaldo Cruz, Rio de Janeiro
and detection of quinolone resistance mutations. Antimicrob 2005; 100: 703-07.
Agents Chemother 1994; 38:773-80. 83. Geluk A, Spencer JS, Bobosha K et al. From genome to leprosy
81. Kim SK, Lee SB, Kang TJ et al. Detection of gene mutations diagnosis: from in silico predictions to ex vivo verification. Clin
related with drug resistance in Mycobacterium leprae from Vaccine Immunol 2009; 16: 352-59.
16 Differential Diagnosis of
Dermatological Conditions
Nand Lal Sharma, Vikram Mahajan
INTRODUCTION may present with leg edema, nasal stuffiness, crusting

and epistaxis. Madarosis, i.e. absence of eyebrows or
The clinical presentation of leprosy is highly variable and
eyelashes may add to the suspicion index. Erythema
in all its stages it can mimic a great variety of other lesions.
nodosum leprosum cases often land up with general
Its diagnosis can be made easily, as in the case of practitioners or physicians for complaints of fever, malaise,
lepromatous leprosy, as soon as the patient enters the arthralgia, etc. A thorough examination of morphology of
clinic while on the other extreme, there are few cases so lesions and nerves may clinch the diagnosis.
subtle that even the most experienced clinician may get Leprosy shows lesions of varied morphologies: Macules
confounded. The benefit of doubt for the diagnosis in such (erythematous or hypopigmented), infiltrated lesions,
cases may go in favor of a therapeutic trial of antileprosy plaques, nodules, noduloplaques, and subsequent to
treatment. However, the diagnosis of leprosy should not autonomic neuropathy, produces scaliness and dryness
be solely on the basis of therapeutic trial as stigma for over the lesions. Infiltrative lesions produce destruction of
leprosy is still important. If the clinical diagnosis is in doubt, hair follicles and sweat glands leading to loss of hair and
the lesion is perhaps too early as in case of indeterminate dryness of skin. Dryness of skin can be more generalized
leprosy, or it is not leprosy. Thus, the differential diagnosis due to widespread disease or the administration of anti-
of cutaneous lesions is so wide that one has to exclude a leprosy drugs. Acute inflammatory lesions occur and
variety of dermatological conditions before making the edema of the limbs gets accentuated in leprosy reactions.
diagnosis. Similarly, neurological symptoms of leprosy can So, the differential diagnosis would include many diverse
simulate a number of neurological disorders. Leprosy diseases which can mimic lesions of leprosy.
reactions too need to be differentiated from a number of Tables 16.1 to 16.5 give the differential list of diagnosis
systemic illnesses. However, along with characteristic skin of majority of the cutaneous lesions which need to be
lesions, the presence of other cardinal signs of leprosy differentiated from the lesions of leprosy. The exhaustive
viz. anesthesia (lesional or in glove and stocking list of diseases given in the tables is indicative of a wide
distribution), thickened nerve trunks (at the sites of array of skin lesions, of which the commoner ones are
predilection) and acid fast bacilli in slit-skin smears, are described.
useful in diagnosing leprosy.
A high index of clinical suspicion for leprosy is always PITYRIASIS ALBA
rewarding, especially if the lesions are non-pruritic, evolving This entity is commonly seen in children, and resembles
slowly, mostly asymptomatic and non-responsive to indeterminate leprosy to a great extent. The lesions vary
routine treatment. A combination of skin lesions and neural from single to ten in number and occur usually overface or
involvement should always arouse a strong suspicion for occasionally on upper trunk. The lesions are erythematous
leprosy. The diagnosis becomes more certain if there is or hypopigmented, ill-defined, round to oval, slightly scaly
sensory impairment, decreased sweating and hair growth. hypopigmented patches (Fig.16.1). They often show
Occasionally in the absence of frank skin lesions, patient seasonal variation and self-resolution. The lesions do not
CHAPTER
16
NEVUS ACHROMICUS/NEVUS
ANEMICUS
Nevus achromicus is a circumscribed area of
hypomelanosis usually present at birth, sometimes have
bizarre shapes and show a variable degree of
hypopigmentation. The lesion is usually single or
occasionally multiple and has feathery, serrated well-
defined borders (Fig.16.4). The texture and character of
the skin is otherwise normal. It does not disappear on
diascopy.
Fig. 16.1: Pityriasis alba: Often confused with indeterminate leprosy

(Photo courtesy: Prof HK Kar, PGIMER, Dr RML Hospital, New Delhi)
show loss of sensation, impairment of sweating or

peripheral/ lesional nerve thickening. Biopsy is rarely
required which will show changes of spongiotic dermatitis.
Treatment with emollients or mild steroids will resolve the
condition, which is likely to recur.
POLYMORPHIC LIGHT ERUPTION

Fig. 16.2: Polymorphic light eruption- hypopigmented lesions, usually
This photodermatosis presents hypopigmented lesions, over sun-exposed areas, may be slightly itchy. No sensory impairment.
which may be asymptomatic or slightly itchy, mainly Mimics indeterminate leprosy (Photo courtesy: Prof HK Kar,
located overexposed parts. The hypopigmented lesions, PGIMER, Dr RML Hospital, New Delhi)
especially over face may be confused with indeterminate
leprosy (Fig.16.2).
VITILIGO
Another common dermatosis that may be confused with
leprosy. Although complete loss of pigment, as in vitiligo,
is never due to leprosy, the lesions of vitiligo will show
hypopigmentation when they are in the incipient stage or
being treated (Fig.16.3). However, in such a scenario, the
lesions will not show sensory impairment, hair loss, or
decreased sweating. Similarly, the skin texture in vitiligo
lesion will be normal except for some of the lesions which
have been partially treated and the surface may show
atrophy or thickening depending upon nature of the
treatment. History, absence of cardinal features of leprosy
Fig. 16.3: Vitiligo: The hypopigmented lesions. No sensory impairment
and rarely skin biopsy may be required to help in (Photo courtesy: Dr Pankaj Sharma, PGIMER, Dr RML Hospital, New
differentiating these cases. Delhi)
CHAPTER
16
Differential Diagnosis of Dermatological Conditions 199
Fig. 16.4: Nevus achromicus (Photo courtesy: Prof HK Kar,

Nevus anemicus on the other hand is a vascular Fig. 16.5: Localized scleroderma (Morphea) (Photo courtesy:
Dr Pankaj Sharma, PGIMER, Dr RML Hospital, New Delhi)
anomaly where the vasculature in a circumscribed area is
pharmacologically abnormal and produces a hypo-
pigmented area. Nevus anemicus disappears on diascopy.
Some of these birth marks may fade slowly over years,
but unlike leprosy, characteristically they do not change
their appearance or extent.
ACQUIRED HYPOMELANOSIS
There are numerous causes of acquired hypomelanosis.
Endocrinal abnormalities, nutritional and chemical factors
may produce hypopigmented lesions. Frequently,
hypomelanotic lesions may follow some inflammatory
conditions like psoriases (Fig.16.17), eczema (Fig.16.14)
syphilis, pinta, yaws, lichen planus, lupus erythematosus
or sarcoidosis. Long-term use of potent topical corticos-
teroids or their intralesional administration (Fig.16.16) can Fig. 16.6: Tinea lesion over footcentral hypopigmentation,
scaling and peripheral erythema
sometimes produce cutaneous hypomelanosis and
atrophy. A careful history and morphology of lesions may
elicit their origin.
A number of chemicals can produce hypopigmented
to depigmented lesions, which may mimic leprosy lesions.
Chemicals often used in rubbers, footwears, cosmetics or
apparels may produce hypopigmentation or depigmentation
called contact leukoderma that occasionally simulates
leprosy lesions. However, in contact leukoderma
distribution of the lesions depends upon the site and type
of contact with the chemical, for instance, they are on the
hands in occupational leukoderma or when due to latex
gloves, and on feet in case of footwear contact leuko-
derma, and on the forehead in case of “Bindi” or vermilion
Fig. 16.7: Tinea corporis resembling TT leprosy (Photo courtesy:
contact leukoderma.
Dr Pankaj Sharma, PGIMER, Dr RML Hospital, New Delhi)
CHAPTER
16
Table 16.1: Differential diagnosis of hypopigmented macular lesions

1. Pityriasis alba Hypopigmented asymptomatic scaly patches usually over the face of children. No
sensory changes/nerve thickening (Fig.16.1).
2. Vitiligo Almost milky white macules of variable size and shape (Fig.16.3). Only loss of pigment
without any skin/ hair/sensory changes. Early lesions which are not completely white
may be misleading.
3. Progressive symmetric leukopathy Persistent punctuate leukoderma over shins and arms.
4. Idiopathic guttate hypomelanosis of Ito Ivory white small macular lesions without sensory changes, usually on the legs and
arms in the middle aged.
5. Halo nevus Central melanocytic nevus with a surrounding white halo, appears like vitiligo after the
melanocytic part has lost its pigment.
6. Albinism/Albinoidism Hereditary generalized absence of skin/iris pigment, photophobia, no hypoesthesia/
nerve thickening
7. Lichen sclerosus et atrophicus (LSA) Hypopigmented mildly atrophic plaque may show hair loss, no hypoesthesia/ nerve
thickening. Biopsy is diagnostic
8. Localized scleroderma/ Morphea Sclerotic or atrophic plaque without sensory changes (Fig.16.5).
9. Achromic onchocerciasis Hypo- and depigmentation, atrophy and infiltration, skin biopsy required for confirmation.
10. Tinea corporis Annular scaly lesions, definitive active border (Figs 16.6 to 16.8). Demonstration of
fungus in KOH is diagnostic.
11. Post Kala-azar dermal leishmaniasis (PKDL) History of past febrile episodes of Kala-azar, hypopigmented macules, noduloplaques,
papular or nodular infiltrations (Figs16.9 to 16.13). Giemsa stained slit-skin smears
show amastigotes (Leishman Donovan bodies), no acid fast bacilli on Ziehl-Neelsen’s
(ZN) stain.
12. Acquired hypomelanosis (postinflammatory ) Usually preceding history of primary dermatosis, no hypoesthesia, nerve thickening,
acid fast bacilli in slit-skin smears (Figs 16.14 to 16.17).
13. Incontinentia pigmenti achromicus Hereditary disorder having Blashkoid (whorled pattern) of hypomelanosis without
sensory changes
14. Seborrheic dermatitis Erythemato-scaly plaque, mostly involving scalp (dandruff), may spread around hairline,
postauricular area and on to the trunk. Isolated facial lesion might arouse suspicion of
leprosy but typical changes may be seen involving eyebrows, scalp. Sensory changes
of leprosy will be absent.
15. Pityriasis versicolor The lesions are usually small and numerous, hypopigmented, covered with fine
powdery scales. Scrapping from the lesion will show Malassezia furfur in characteristic
‘meatball and spaghetti’ appearance in KOH mounts.
16. Leukoderma syphiliticum Depigmented spots on a background of hyperpigmentation over back/sides of neck in
secondary syphilis. Lymphadenopathy and reactive VDRL serology are significant
findings
PITYRIASIS VERSICOLOR PSORIASIS

The lesions in pityriasis versicolor are small, smaller than Chronic plaque psoriasis characterized clinically by well-
leprosy macules, hypopigmented and show fawn colored demarcated, erythematous, infiltrated scaly plaques of
fine scaling. Lesions are asymptomatic and individual variable size and shape may mimic leprosy lesions,
lesions are discrete, but often fuse to form large lesions especially when in reaction. Following therapy or otherwise
mimicking leprosy. However, they do not show any resolving psoriasis lesion may leave hypopigmentation in
impairment of sensations or hair loss. A potassium a patchy pattern which may also be confused with
hydroxide (KOH) mount from scales will reveal short, hypopigmented leprosy lesions (Fig.16.17). The lesions
unbranched hyphae and spores in characteristic of psoriasis will have characteristic silvery scales which
arrangement. can be scrapped off with ease unmasking fine bleeding
CHAPTER
16
Table 16.2: Differential diagnosis of papulo-plaque lesions with or without annular configuration
1. Granuloma faciale Primarily facial asymptomatic, nodular lesions with smooth orange peel surface. Leukocytoclastic
histopathology is characteristic
2. Lymphocytoma cutis Asymptomatic, erythematous/violaceous nodules or plaques on face/head/ears. Biopsy essential.
3. Follicular mucinosis Follicular boggy pruritic papules or plaques over face /scalp without sensory changes. Histopathology
will show fenestrations, mucin deposits, no granulomatous inflammation or acid fast bacilli.
4. Kaposi’s sarcoma Commonly arises on hands and feet, the lesions bleed easily if injured. Classical histology and absence
of acid fast bacilli exclude leprosy.
5. Cellulitis / Erysipelas Acute inflammation following pyococcal infection, characterized by erythematous, warm, painful, tender
swelling. Pyrexia, malaise may be associated in severe cases. Needs differentiation from lesions in
leprosy reaction. Cardinal signs of leprosy are absent
6. Mycosis fungoides Cutaneous T-cell lymphoma is characterized by persistent, infiltrated plaques in tumor stage; early
stage may show scaling, erythema, annular plaques with active margins. Lesions mostly asymptomatic
(Fig.16.19). Lymphadenopathy may occur. Cardinal signs of leprosy are absent.
7. Urticaria Severely pruritic, evanescent, erythematous, edematous plaques are characteristic.
8. Erythema multiforme Erythematous, minimally infiltrated, target-like lesions may have a vesicle/bulla in the center of the
lesion. Mostly occur over acral parts or face following Herpes simplex infection or as an adverse drug
rash. The eruptions are sudden and no sensory deficit.
9. Sweet’s syndrome Plum colored erythematous, warm, tender noduloplaque lesions (Fig.16.20) with pseudovesiculation
over neck and hands, associated with fever, malaise, headache, conjunctival congestion and peripheral
polymorphocytosis. Histological evidence of neutrophilic infiltrate and edema in the upper dermis,
without evidence of leukocytoclastic vasculitis, like fibrin deposition, neutrophils within the vessel walls.
However, there may be swollen endothelial cells, dilated blood vessels and fragmented neutrophil
nuclei. No change in epidermis.
10. Syphilis Secondary syphilis manifesting as asymptomatic, erythematous, infiltrated, papular, papulosquamous
or papuloplaques with annular configuration, mainly over forehead (corona venereum) and upper trunk.
Positive Buschke-Ollendroff sign, lymphadenopathy and reactive VDRL serology are diagnostic findings.
11. Adenoma sebaceum Firm, discrete brownish red telangiectatic papules over face, associated other features of tuberous
sclerosis complex (Fig.16.21). Histopathology is characteristic.
12. Lichen myxedematosus Very uncommon disease. Numerous small firm papules often arranged in linear configuration against
the background of erythema and thickening of skin.
13. Granuloma annulare Usually skin colored beaded papules, often arranged in annular pattern, over dorsa of hands. Frequent
association with diabetes mellitus (Figs 16.22 and 16.23).
14. Lichen Planus Polygonal, purple, flat topped papules over flexures, often with Wickham’s striae. Annular lichen planus
plaque have atrophic pigmented center and active bluish lichenoid margin. May appear similar to a
tuberculoid leprosy lesion. Lesions are usually pruritic; as against those of leprosy.
15. Nummular Eczema Discoid plaque of papulovesicles with oozing and crusting, intensely itchy. Recurrent nature.
16. Necrobiosis lipoidica Yellowish red edematous plaque, mostly over shins, no sensory loss. Frequent association with
diabetes mellitus.
17. Cutaneous sarcoidosis To be distinguished from lesions of tuberculoid leprosy. Lesions are granulomatous infiltrated papulo-
plaques. Scalp lesions may attain annular/arcuate shape, no sensory loss. Additionally, signs of
systemic sarcoidosis or erythema nodosum may be present. Histologically, compact, naked epithelioid
granulomas without caseation necrosis are characteristic (Figs16.28 to 16.34).
18. Erythema annulare Arcuate/circinate lesions, advancing red border, trailing scales (Fig.16.24) usually on trunk. Few
centrifugum (EAC) lesions attain large size.
19. Granuloma multiforme Small noduloplaques or circinate lesions of varying size, few with fine infiltrated borders, slightly
erythematous or skin colored, rarely hypopigmented. Usually affect adults, lesions mostly distributed
over face, trunk and arms. The lesions do not show impairment of sensation or sweating and heal
slowly and spontaneously.
20. Psoriasis Erythemato-scaly plaques of variable size and shape, may have annular shape, present over extensors
or trauma prone sites. Individual lesion may mimic tuberculoid leprosy or subsiding type1 reaction
(Figs 16.25 to 16.27). Positive Auspitz sign and absence of cardinal signs of leprosy are differentiating
features.
Contd…
CHAPTER
16
Contd…
21. Lupus vulgaris Common over face, has variable morphology and has to be differentiated from tuberculoid leprosy.
Characterized by chronic reddish brown granulomatous plaque, causing significant tissue destruction
and scarring. Lesions tend to heal at one edge and spread from another (Fig.16.37).
22. Tuberculids A heterogeneous group of cutaneous eruptions secondary to an internal focus of tuberculosis in an
individual with a moderate to high degree of immunity to Mycobacterium tuberculosis. Papulonecrotic
tuberculid, the most common form of tuberculid occurs as recurrent crops of asymptomatic or itchy,
symmetric, firm, erythematous papulonodular lesions with central crusting which heal spontaneously
leaving hyperpigmentation. The lesions can be differentiated from papulonodular leprosy lesions by the
absence of cardinal signs of leprosy.
23. Discoid lupus erythematosus Erythematous infiltrated lesions with adherent scales and scarring, discoid lesions may simulate
tuberculoid leprosy lesions.
24. Malignant atrophic papulosus Crops of pink/red 2-5 mm necrotic /umbilicated papules with central white porcelain like scar, usually on
the dorsal aspects of lower limbs.
25. Onchocerciasis Characterized by lichenified dermatitis, hypopigmentation, atrophy and infiltration. Skin biopsy required.
Fig. 16.8: Tinea faciei resembling tuberculoid leprosy (Photo

courtesy: Prof H K Kar, PGIMER, Dr RML Hospital, New Delhi)
Fig. 16.10: Papulonodular lesions of PKDL overface. Mimics nodular
lesions of LL leprosy (Photo courtesy: Dr V Ramesh, VM Medical
College and Safdarjung Hospital, New Delhi)
Fig. 16.9: Leishmaniasis: Macular hypopigmented lesions of PKDL Fig. 16.11: Papulonodular lesions of PKDL overface (Photo
(Photo courtesy: Prof H K Kar, PGIMER, Dr RML Hospital, New Delhi) courtesy: Prof H K Kar, PGIMER, Dr RML Hospital, New Delhi)
CHAPTER
16
Fig. 16.15: PIH developing after healing at trauma site
Fig. 16.12: PKDL: Papules and Infiltration overface; and hypopigmented

lesions over neck and upper chest (Photo courtesy: Dr V Ramesh,
VM Medical College and Safdarjung Hospital, New Delhi)
Fig. 16.16: PIH at the site of infiltration with corticosteroids

Fig. 16.13: PKDL: Papules and nodules over nape of the neck. Also
note the earlobe infiltrations, overall picture mimicking lepromatous
leprosy (Photo courtesy: Dr HK Kar, PGIMER, Dr RML Hospital,
New Delhi)
Fig. 16.14: Postinflammatory hypopigmentation (PIH): After healing Fig. 16.17: PIH after the healed lesions of psoriasis
of lesions of Atopic dermatitis in a child (Photo courtesy: Prof HK Kar, PGIMER, Dr RML Hospital, New Delhi)
CHAPTER
16
Table 16.3: Differential diagnosis of

acquired ichthyotic lesions
1. Nutritional/ Lipid and vitamin deficiency leads to
malabsorption ichthyotic lesions, other signs of
ichthyosis deficiency present.
2. Ichthyosis secondary Most common with Hodgkin’s
to malignancies lymphomas, others are hypothyroidism,
sarcoidosis. See for other signs of
disease
3. Drug-induced Clofazimine, cholesterol lowering drugs,
ichthyosis INH can produce ichthyotic skin. Elicit
history of longterm drug intake.
Fig. 16.20: Sweet’s syndrome: Targetoid plaques lesions

resembling BB leprosy
Fig. 16.18: Lupus miliaris disseminativa facii. The papules and nodules
overface mimic lesions of lepromatous leprosy, and also those of
erythema nodosum leprosum (ENL) (Photo courtesy: Dr HK Kar,
PGIMER, Dr RML Hospital, New Delhi) Fig. 16.21: Adenoma sebaceum (Tuberous sclerosis): Papular lesions
overface mimicking LL leprosy (Photo courtesy: Dr HK Kar, PGIMER,
Fig. 16.22: Granuloma annulare: These asymptomatic lesions look

Fig. 16.19: Mycosis fungoides-annular plaques of variable like tuberculoid leprosy (Photo courtesy: Picture on Right: Dr HK Kar,
morphology resembling borderline leprosy PGIMER, Dr RML Hospital, New Delhi)
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Table 16.4: Differential diagnosis of facial infiltration

1. Post Kala-azar Infiltration associated with hypopig-
dermal leishmaniasis mented macules, nodules, plaques
(PKDL) (Figs 16.10 to 16.13). Giemsa slit-skin
smear is diagnostic showing
amastigotes (LD bodies). Past history
of kala-azar, absence of cardinal signs
of leprosy, are helpful clues.
2. Rosacea Diffuse erythema and thickening,
telangiectases, papules and pustules
over central area of face.
3. Reticulohistiocytosis Firm brown or yellow papules/plaques
over extensors, face scalp hands with
mutilating shortening of fingers due to
arthritis. Biopsy is confirmatory.
4. Sarcoidosis Papulonodules, diffuse facial papular
eruption, plaques, diffuse or patchy
ichthyotic lesions all may also mimic
leprosy (Figs 16.28 to 16.34). Biopsy Fig. 16.24: Erythema annulare centrifugam (EAC)
will show sarcoid granulomas.
5. Disseminated Not seen often. Widespread plaques,
cutaneous papules, nodules on face, extensors
leishmaniasis limbs. Resembles lepromatous leprosy.
Slit-skin smear and biopsy helpful.
6. Lipoid proteinosis Uncommon disease. Beaded papules or
yellow-brown nodules, loss of eyelashes,
hoarseness of voice. Histology helps in
diagnosis.
Fig. 16.25: Psoriasis: Annular plaques
CUTANEOUS SARCOIDOSIS
It is a chronic multisystem disease of unknown etiology
characterized by variability of presenting lesions viz.
papules (Fig.16.28), plaques (Figs16.29 and 16.32), nodules
(Figs16.31 to 16.34), ichthyotic, psoriasiform or cheloidal
lesions, and some lesions taking annular or polycyclic
Fig. 16.23: Granuloma annulare: Two lesions overface. Note that half shapes (Fig.16.30). The disease may affect skin, eyes,
of the upper lesion is lying over hairy area (Photo courtesy: Dr HK heart, lungs, and nervous system. The lesions or
Kar, PGIMER, Dr RML Hospital, New Delhi)
sarcoidosis have almost similar morphology as that of
leprosy lesions. They are chronic mostly asymptomatic
papillae (Auspitz sign), normal sensations, normal hair, no and of granulomatous nature. Papules or plaques forming
nerve thickening or acid fast bacilli in slit-skin smears annular or polycyclic shapes closely resemble tuberculoid
(Fig.16.26). The Erythrodermic psoriasis can sometimes or borderline leprosy. Ichthyotic sarcoidosis may closely
lead to hairloss which may lead to confusion with hairloss mimic similar skin changes seen in leprosy. However, there
of leprosy, i.e. madarosis (Fig.16.27). is no loss of sensations or nerve-thickening. Skin-slit smear
CHAPTER
16
Fig. 16.26: Psoriasis: Erythematous scaly papules and plaque, some

confluent; some discrete, resembling BL leprosy (Photo courtesy:
Dr HK Kar, PGIMER, Dr RML Hospital, New Delhi)
Fig. 16.29: Sarcoidosis: Atrophic plaque mimics tuberculoid leprosy
Fig. 16.27: Psoriasis: Madarosis in a case of psoriatic erythroderma,

mimicking LL leprosy (Photo courtesy: Dr Pankaj Sharma, PGIMER,
Fig. 16.30: Sarcoidosis: Annular plaque may be confused with
tuberculoid leprosy
Table 16.5: Differential diagnosis of madarosis

1 Hypothyroidism Loss of lateral third of eyebrows, associated
with puffiness of face, yellowish thickening
of skin. Hormone assays are essential.
2 Follicular mucinosis Follicular boggy pruritic papules or
plaques over face/scalp/eyebrow with
hair loss. Biopsy confirmatory.
3 Alopecia areata Involvement of eyebrows and eyelashes
simulate madarosis of leprosy. Alopecia
areata lesions over scalp, beard, etc.
presence of ‘exclamation sign’ hair in the
patches, and absence of cardinal signs
of leprosy are differentiating features.
Fig. 16.28: Sarcoidosis: Papular lesions
CHAPTER
16
examination will show no acid fast bacilli and histology
shows compact well-circumscribed granuloma, devoid of
lymphocytic rim (naked granuloma) and absence of central
caseation.
GRANULOMA ANNULARE
It is a disease of unknown etiology that is characterized
by a ring of small, smooth flesh colored papules. Most
commonly occurs in young adults in their thirties. The
commonest variant is seen over dorsa of hands as
asymptomatic, skin colored, non scaly, annular plaque with
beaded margins and centrifugal extension (Figs16.22 and
16.23). The disseminated variety has multiple such lesions. Fig. 16.31: Sarcoidosis: Multiple erythematous papules and plaques,
Localized annular variant needs differentiation from the with tendency towards symmetry, can be confused with BL leprosy
tuberculoid or borderline tuberculoid leprosy; and the
generalized variant from lepromatous leprosy. There is no
sensory deficit or nerve-thickening. Biopsy will help in
making the diagnosis.
LEISHMANIASIS
Leishmaniasis is a chronic protozoal parasitic disease with
a wide spectrum of presentation. Immunity of the individual
as well as the nature of infecting parasite decides the
morphology and course of disease. There are numerous
forms of leishmaniasis which can present real difficult
situations in differentiating leprosy. Some countries
have both the diseases and similar epidemiological
distribution. Fig. 16.32: Sarcoidosis: Lupus pernio (Photo courtesy:
Cutaneous leishmaniasis may be of localized or Prof HK Kar, PGIMER, Dr RML Hospital, New Delhi)
disseminated variety. In localized form, there are slowly
progressive chronic granulomatous lesions. Morphology
may be like furuncle, atrophic plaque, infiltrated plaques
overface and ear lobes, nodular or nodulo-ulcerative
(Figs 16.10 to 16.13), lupoid (Fig.16.35) or occasionally
crateriform lesions are seen (Fig.16.36). The crateriform
lesions have to be differentiated from the tuberculoid or
borderline tuberculoid forms. The lesions of leishmaniasis
do not show any abnormality of sensation or nerve-
thickening. Giemsa stained slit-skin smears will show
amastigotes (Leishman Donovan bodies). Histology will
show nerve involvement in all forms of leprosy.
Disseminated cutaneous form of leishmaniasis will
show nodular or plaque lesions and may even produce
leonine facies. History of visiting endemic area, absence
of nerve thickening or impairment of cutaneous sensitivity
Fig. 16.33: Sarcoidosis: Erythematous infiltrated papules and plaques,
and demonstration of amastigotes in smears will help note the earlobe infiltration (Photo courtesy: Prof HK Kar, PGIMER,
differentiation. Dr RML Hospital, New Delhi)
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16
CUTANEOUS TUBERCULOSIS
Lupus vulgaris is a form of postprimary tuberculosis of
variable morphology that occurs in patients with high degree
of immunity. Usually starts as a reddish-brown papule or
nodule which tend to heal at one edge and spread from
another evolving into a plaque which may attain annular
shape (Fig.16.37). Tissue destruction and atrophic scarring
are the hallmarks of this disease. Such lesions may closely
resemble the tuberculoid or borderline tuberculoid forms
of leprosy. Absence of nerve involvement and impairment
of sensations helps in differentiating the two conditions.
Tuberculids represent immunologic reactions to active
infection with or dead Mycobacterium tuberculosis or
antigenic fragments deposited in the skin and
subcutaneous tissue. The cutaneous lesions are a
Fig. 16.34: Sarcoidosis: Erythematous infiltrated papules and heterogeneous group and comprise true tuberculid where
plaques overface M. tuberclosis play significant role, viz papulonecrotic
tuberculid, lichen scrofulosorum, and facultative tuberculid,
i.e. erythema induratum of Bazin which has the bacillus
as one of the triggers. Papulonecrotic tuberculid lesions
are asymptomatic or itchy, firm, erythematous,
papulonodules occurring in crops and have central adherent
crust. There are usually no systemic symptoms and it
subsides spontaneously with hyperpigmentation and
varioliform scar. Histopathology usually shows
leukocytoclastic vasculitis, lymphocytic or granulomatous
vasculitis with or without fibrinoid necrosis. Papulonodular
lesions of lepromatous leprosy or erythema nodosum
leprosum may sometimes mimic papulonecrotic tuberculid.
Absence of cardinal signs of leprosy, histology of
vasculitis, response to antituberculosis treatment are the
differentiating features.
Fig. 16.35: Leishmaniasis: Lupoid lesions (Face) LUPUS MILIARIS DISSEMINATIVA

FACIEI
Lupus miliaris disseminativa faciei (LMDF) is an
Post Kala-azar dermal leishmaniasis (PKDL), a late uncommon, chronic, inflammatory dermatosis charac-
complication of visceral form of leishmaniasis seen in India terized by red, yellow or brown papules over the face,
and Africa, where leprosy is also endemic. It has particularly on and around the eyelids. The lesions may
hypopigmented macules over trunk, noduloplaque lesions occur singly or in crops. Once considered a tuberculid
or diffuse infiltration of face and other body parts and even because of the histology, many authors now consider
nodulation of pinna of ear, closely simulating or even being LMDF to be a variant of granulomatous rosacea. Others
wrongly treated as lepromatous leprosy. However, lesions believe it is a distinct entity because of its characteristic
in PKDL are mostly distributed towards midline and histopathology and occasional involvement of noncentral
commonly involve orogenital mucous membranes. Cardinal facial areas. The lesions can sometimes cause confusion
signs of leprosy will help differentiation in most cases. with lepromatous leprosy or ENL lesions (Fig.16.18).
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16
Fig. 16.36: Crateriform cutaneous leishmaniasis
Fig. 16.38: Subacute cutaneous lupus erythematosus:

Annular and polycyclic plaques
lesions of leprosy (Figs 16.39A to D). General physical

examination, hepatosplenomegaly, lymphadenopathy,
hematological findings would help arriving at the diagnosis.
CONCLUSION
To avoid misdiagnosis the clinician also need to be familiar
with normal range of skin color (erythema may not be very
obvious in dark skin), local customs to treat skin diseases
Fig. 16.37: Lupus vulgaris: Annular plaque with central atrophy
(cauterization of skin lesions can cause ulcers/scarring),
local occupations (manual labor causes calluses or
DISCOID LUPUS ERYTHEMATOSUS thickening of palmar skin) and social attitudes (social
ostracism of leprosy patients often leads people to hide
Early lesions of discoid lupus erythematosus (DLE) over-
leprosy) as all these may be altering the clinical picture
face can resemble tuberculoid leprosy plaque especially
and increase the difficulty in diagnosing leprosy or prevent
before atrophy and scarring appears, but unlike leprosy,
patients to seek treatment.
DLE lesions have adherent scales and follicular plugging.
Two or more diseases presenting together may also
(Fig. 16.38).
pose diagnostic problem, e.g. patients with cutaneous
leishmaniasis may get leprosy and the skin lesions at first
MALIGNANCIES
look appear confusing. It will be prudent to wait and watch
The malignant conditions like leukemias and lymphomas in doubtful cases instead of treating for leprosy. A wrong
can sometime present with nodular infiltrated cutaneous diagnosis may cause social problems and difficulty in
lesions which are difficult to differentiate from nodular rehabilitation of these patients.
CHAPTER
16
A B
C D
Figs 16.39A to D: Acute myeloid leukemia: Multiple generalized nodular lesions involving face, limbs, and trunk regions. The extensive
infiltrated lesions over the face producing the “leonine facies” and can be confused with LL leprosy. This patient died of the disease within two
weeks of the diagnosis (Photo courtesy: Dr HK Kar, PGIMER, Dr RML Hospital, New Delhi)
BIBLIOGRAPHY 2. Hastings RC, Opromolla DVA. Leprosy, 2nd edn. Edinburgh,

1. Burns T, Breathnach S, Cox N, Griffiths C. Rook’s textbook of Churchill Livingstone, 1994.
Dermatology 7th edn, Massachusetts, USA. Blackwell Publishing 3. Yawalkar SJ. Leprosy for Medical Practitioners, 5th edn. Basle,
Company, 2004. Switzerland, Ciba Geigy Limited, 1992.
17 Differential Diagnosis of Neurological
and Other Conditions
Prafulla K Sharma, Pankaj Sharma
PERIPHERAL NEUROPATHY periarteritis nodosa), the mononeuritis multiplex may be

the presenting feature initially, which may progress to
The disease processes of peripheral nerves (affecting
polyneuropathy later, as a result of involvement of multiple
axons and Schwann cells in nerves and nerve roots) are
small nerves.
commonly referred to as peripheral neuropathy which is a
In general, the polyneuropathies affecting mainly small
broad term encompassing neural insults as a result of a
nerve fibers predominantly affect pain and temperature
number of factors (like nutritional, genetic, metabolic,
sensations, while in case of involvement of large nerve
malignant, toxic or nutritional, etc.). However, this term is
fibers, the predominant symptoms are areflexia, sensory
frequently used interchangeably with peripheral neuritis
ataxia, with minimal cutaneous sensory deficit. The
(which in real sense, refers to the inflammatory disorders
thickening of nerves may also clinically manifest differently
of nerves).
in various clinical conditions, e.g. it is fusiform in leprous
The peripheral nerve disease can manifest clinically
neuritis, beaded in amyloid neuropathy and the uniform
with disorder related to one or more of the following functions
thickness in hereditary neuropathies. The polyneuropathies
(a) sensory, characterized by loss or alteration of
with long evolution time (over 3-5 years) are likely to be
sensations, which may be restricted to the area supplied
genetically determined, especially if the features are distal
by one or more nerves or it could be in ‘glove-stocking’
weakness/ muscular atrophy and minimal sensory features.
pattern, pain, muscle cramps, burning hands and feet, etc.
Diabetic polyneuropathy also evolves over 5-10 years
(b) motor, characterized by muscular weakness, paralysis
period.
or atrophy of muscles, restricted to the distribution of one
It may also be noted that thickening of peripheral nerves
or more nerves (c) reflex functions abnormalities like
may also be observed as an association of generalized
fasciculation, areflexia, hyporeflexia, trophic changes and
muscular development, e.g. in wrestlers or persons
finally (d) autonomic dysfunctions (dysautonomia)
engaged in occupations involving hard work. Also, localized
characterized by orthostatic faintness (postural
thickening of nerves may be observed, e.g. thickening of
hypotension), abnormalities of sweating and salivary
great auricular nerve in persons accustomed to carry heavy
secretions, sphincter disturbances and impotence. Many
weights on head1 (Table 17.1).
of these clinical features could be accompanied by
clinically palpable thickened nerves.
The functional deficit in polyneuropathy is generally BASIC CONSIDERATIONS OF NERVES
symmetrical, the symptoms and signs are more distal than In leprosy, mainly small calibre nerve fibers are afflicted
proximal. In mono or multiple neuropathies (sometimes which carry sensations of temperature and pain and so
referred to as mononeuritis and mononeuritis multiplex) these sensations are first to be affected though, according
the deficits are in distribution of one or more nerve trunks, to Cochrane, sensory loss is in the order of first thermal
respectively. In diabetes mellitus, it could be a combination then tactile, followed by pain and pressure.2 Three types
of both, for example, symmetric distal polyneuropathy and of damage to the neural structures are recognized which
localized deficits in one or several nerves. Also, (e.g. in may produce different types of functional loss.
CHAPTER
17
Table 17.1: Classification of neuropathies based on distribution areas and mode of onset
Asymmetric neuropathies
Mononeuropathy, Multiple mononeuropathy
(Syn. Mononeuritis, Mononeuritis multiplex)
Acute onset Chronic course
Trauma Leprosy
Bell’s palsy Diabetes mellitus
Polyarteritis nodosa
Allergic granulomatosis
Sarcoidosis
Chronic hepatitis
Chronic compression (entrapment) neuropathies
HIV infection (sometimes)
Symmetric polyneuropathies
Acute onset Chronic course
Guillain-Barre syndrome Familial (inherited) polyneuropathy
Acute intermittent porphyria A. Hereditary sensorimotor neuropathy (HSMN)
Porphyria variegata i. HSMN Type I (Peroneal muscle atrophy)
Toxic neuropathy (e.g. Thallium) ii. HSMN Type II (Charcot-Marie-Tooth disease – axonal form)
Corynebacterium diphtheriae infection iii. HSMN Type III (Dejerine Sotta’s disease)
iv. HSMN Type IV (Refsum’s syndrome)
B. Hereditary sensory neuropathies (HSN)
i. HSM Type I (Perforating foot ulcer disease)
ii. HSM Type II (Congenital sensory neuropathy)
iii. HSM Type III (Dysautonomia of Riley-Day)
Hereditary amyloid polyneuropathy
Toxic: Heavy metals, Organophosphorous compounds, Radiation exposure
Nutritional: Vitamin B1, B6, B12 deficiencies
Malignancy: Lymphomas, Multiple myeloma, Waldenström’s macroglobulinemia
Infections: HIV (Sensorimotor type: the most common presentation)
Developmental anomalies: Syringomyelia, Spina bifida
Wallerian Degeneration Demyelination

The axonal fragmentation due to crushing or transaction Segmental demyelination involves loss of myelin sheath
injuries causes degeneration of nerve segment distal to of the axons whereby Schwann cell processes retract from
the affected site leading to secondary demyelination. Toxic nodes of Ranvier. This results in delay in action potential
and metabolic neuropathies cause this in scattered axons. generation and slowing of nerve conduction velocity,
The nerve conduction velocity and compound action ultimately leading to conduction block. The axons remain
potential remain within the normal range until the very last, intact and there is no change in the neuronal body. With
as some axons are spared. The recovery after Wallerian recurrent episodes the segmental demyelination, the
degeneration takes more time. process may become irreversible. Schwann cell population
in such nerves is markedly increased, along with interstitial
Distal Axonopathy
collagen fibers. All of them are arranged concentrically
In this type of nerve damage, the degeneration of axon along demyelinating axons to form lamellated structures
and myelin takes place first, in the most distal part of the called “onion bulbs” called so, because of their characteristic
neuronal cell which eventually leads to axonal death in histopathological appearance. Such nerves are indurated
retrograde progression (dying back). This causes the typical and clinically enlarged. The recovery time is less in
distal (Stocking-glove) sensory loss or weakness. demyelination, as compared to Wallerian degeneration.
CHAPTER
17
Differential Diagnosis of Neurological and Other Conditions 213
SYMPTOMS OF NERVE DAMAGE nerves. This neurotropism has been implicated to be due
to (a) the specific binding site for M. leprae at alpha-
When a nerve is compressed or injured, different types of
dystroglycan in the G domain of the alpha-2 chain of laminin
injury can take place which have their own time course of
in the basal lamina of the Schwann cell–axon unit4 and
recovery. A simple compression will recover very rapidly
(b) the thermo sensitive nature of M. leprae makes it
(in a few minutes to hours), and if the myelin sheath is
multiply at temperatures 7-10°C lower than the core body
destroyed it may take several weeks for a new insulating
temperature of 37°C.5-7 Theses two factors account for
sheath lining to regrow. If the axon itself is disrupted, then
various clinical presentations typical to leprosy.
the regeneration will be from the cut point all the way, to
Further, the intracutaneous nerve endings and the
the skin or muscle, at a rate of 1-4 millimeters per day. If
some nerve segments are placed at cooler surfaces of
the conduit itself (the tube pipe tunnel comprising of
the body which on involvement produce sensory deficit
perineurium and epineurium) is destroyed, then a regrowing
first, on the cooler areas of the body (e.g. dorsal surfaces
nerve may never find its way past the point of injury, leading
of hands, dorsomedial surfaces of the forearms, dorsal
to permanent functional loss.
surface of the feet, ventrolateral aspects of the legs, the
pinnae of the ears, helices and earlobes) in patients of
Neurapraxia
lepromatous leprosy. With progression of the sensory loss,
This is the mildest grade of nerve damage which involves the warmer areas of the body (scalp, anterior aspect of
a reduction or complete block of conduction across a neck, attachment creases of the ear to the head, sternum,
segment of a nerve with axonal continuity preserved. A skin over the paraspinal muscles, the perineum and the
person’s foot “falling asleep” after his legs have been intergluteal folds, the antecubital and popliteal fossae, and
persistently in crossed position for some time, is an toe webs) are able to escape the sensory impairment.
example of a functional loss without abnormal change. So, in a case of distal neuropathy, the proximal and
cooler areas of the body should always be searched for
Axonotmesis the sensory loss. The deep tendon reflexes (DTR) in
This is a more severe grade of nerve injury (as compared lepromatous leprosy are preserved even though, the
to neurapraxia) as a result of damage to the axons, with sensorimotor nerves of the affected areas are involved,
preservation of the neural connective tissue sheath and the patients have claw hand/claw toes/or foot drop.
(endoneurium), epineurium, Schwann cell tubes, and other This differentiates it from other causes of neuropathies
supporting structures. The internal architecture thus where DTRs are diminished or absent.
preserved can guide proximal axonal regeneration to re- However, there is always a possibility that anyone of
innervate distal target organs. the clinical conditions detailed below, may be confused
with leprosy or vice versa. The following is an account of
Neurotmesis most of these conditions which could pose a problem in
diagnosis of leprosy, though the list may not be complete.
It is the most severe grade of peripheral nerve injury
involving damage to the axon, myelin sheath, and
METABOLIC CONDITIONS
connective tissue components, where recovery is not
The causes of metabolic polyneuropathies include diabetes
possible through axonal regeneration. This grade of injury
mellitus, hypoglycaemia, uraemia, biliary cirrhosis and
includes the nerve lesions in which external continuity is
hypothyroidism. Paresthesias and sometimes sensory
preserved but axonal regeneration is blocked due to
symmetric distal polyneuropathy occurs in myxedema.
intraneural fibrosis.
Diabetes Mellitus (DM)
DISEASES CAUSING PERIPHERAL
This is one of the most common causes of peripheral
NEUROPATHY
neuropathy in clinical practice which needs to be
Leprosy is a great imitator.3 Mycobacterium leprae is the differentiated. Particularly likely are the cases with
only bacterial pathogen that consistently invades peripheral undiagnosed DM and adult onset (Type II) DM which
CHAPTER
17
frequently involve lumbosacral plexus. Poor diabetic control Differentiation

is another important contributing factor. Ironically, repeated The metabolic conditions can be differentiated from leprosy
severe hypoglycemia may also contribute to the nerve by their respective metabolic abnormalities and absence
damage and peripheral neuropathy.8 Proximal leg weakness of cardinal signs of leprosy.
and pain in the thigh are the initial symptoms, besides
sensory loss may be present in few areas of the thigh. VASCULITIC CONDITIONS
Knee and ankle reflexes may be diminished or lost. The
Polyarteritis Nodosa
involvement may be unilateral or bilateral. The neural
symptoms are possibly due to occlusions or infarction of Collagen vascular disorders and polyarteritis nodosa affect
the vasa nervorum. More severe diabetic affliction can vasa nervorum and cause infarcts due to arteritis which
cause painful dysesthesias in the legs, distal leg muscle lead to loss of axons and myelin sheath. The resultant
wasting and weakness and trophic ulcerations in the feet. neuropathy could be single or multiple mononeuropathy,
distal asymmetric polyneuropathy or symmetric poly-
Differentiation neuropathy. Diagnostic aid can be obtained from biopsy
studies on sural nerve and skin which show necrotizing
Leprosy can be easily differentiated by the absence of
arteritis, perivascular inflammatory infiltrate, hemosiderin
hypopigmented patches or infiltrative plaques with sensory
deposition and neovascularization in epineural arteries. The
impairment. Also, absence of enlarged nerves in DM, along muscle biopsy shows vasculitis and dennervation atrophy.
with presence of diminished DTR and raised blood sugar At the site of infarct the nerve conduction is slowed and
level can give further aid in differentiation. nervous excitability is diminished distal to it. There is
sudden onset of nerve deficit in one or several nerves.
Porphyrias
Patients of acute intermittent porphyria (a hereditary hepatic Allergic Granulomatosis
porphyria) and sometimes of porphyria variegata and In allergic granulomatosis of Churg and Strauss, mono or
hereditary coproporphyria may present with acute polyneuropathy may be the part of syndrome which includes
symmetrical polyneuropathy similar to acute idiopathic asthma, eosinophilia (>10%), transient (non-fixed)
neuritis. Barbiturates could be the precipitating cause in pulmonary infiltrates, abnormalities of paranasal sinuses
these cases. The recovery from these episodes is slow as and extravascular eosinophils on biopsy.9 The polyneuro-
the polyneuropathy is due to Wallerian degeneration, as pathy is most often in glove and stocking distribution and
compared to the demyelination mechanism in acute loss of visual field is another feature.
idiopathic polyneuropathy. Deficiency of axonal heme/
Differentiation
protein required for survival of axons and/or neurotoxic
The vasculitic conditions can be differentiated from leprosy
properties of delta aminolevulinic acid and porphobilinogen
by the absence of typical leprosy skin patches or infiltration
have been implicated.
and absence of AFB (leprosy bacilli) on slit-skin smear
examination. Moreover the characteristic lesions of
Hypercholesterolemia
vasculitis e.g. purpura and ecchymosis, erythema
Accumulation of sterols (in biliary cirrhosis and hyper- multiforme like lesions, etc. would not be seen in leprosy.
lipidemia) can cause sensory neuropathy in the peripheral
nerves. ACUTE TRAUMA AND CHRONIC
COMPRESSION (ENTRAPMENT)
Uremia NEUROPATHIES
Sensory symmetric distal polyneuropathy associated The type of neural damage or neuropathy occurring due to
with slowed nerve conduction may also be a feature of compression or trauma depends upon severity and
uremia. chronicity. Segmental demyelination is seen in case of
CHAPTER
17
moderate compression of chronic duration wherein the
axons are spared. In case the compression is severe,
fragmentation of axons occurs, leading to Wallerian
degeneration. Herniated disc or exophytic bony spurs may
trap lumbosacral and cervical nerve roots. Pelvic
malignancies may invade and compress lumbosacral
plexus, while carcinoma of the lung or breast could involve
the brachial plexus. Intramuscular injection, if not given
with proper precautions, can damage sciatic nerve in the
sciatic notch and radial nerve in the spiral groove.
Some nerves could be damaged because of trauma
during their superficial course. Some examples are median
nerve in the carpal tunnel, ulnar at the elbow, common
peroneal nerve at the neck of fibula. Nerves such as
posterior tibial nerve in the tarsal tunnel and medial and
lateral plantar nerves in the foot lie confined in the fascial
canals close to the body surface at the pressure points. A
description of some common nerve palsies is given here.
Fig. 17.1: Sensory area distribution of ulnar nerve
Ulnar Nerve
account of the deposition of fibro-fatty tissue around
Fracture and/or dislocation following trauma at the elbow
fascicular tunnels housing the nerves. However, it may be
joint may lead to ulnar nerve palsy. Delayed type ulnar
noted that the vast majority of CTS cases are idiopathic.
nerve palsy can occur due to cubitus valgus deformity of
the joint. The paralysis is because of stretching of the
Radial Nerve
nerve and produces the typical picture of “ulnar claw hand”,
involving the 4th and 5th digit. Rarely, aponeuritic arch The radial nerve may be injured in axilla due to crutches
linking the two heads of the flexor carpi ulnaris entraps (“crutch” palsy) or in the midarm due to trauma when the
ulnar nerve at the elbow. Deep palmar branch of the ulnar nerve winds around the humerus. Sensations are impaired
nerve may get damaged at the base of the palm due to over posterior aspect of the forearm and a small area over
prolonged pressure. This results in weakness of hand the radial aspect of the dorsum of the hand besides inability
muscles without sensory loss (Fig. 17.1). to extend the elbow and paralysis of supination of the
forearm and wrist and finger drop (wrist drop).
Median Nerve
Common Peroneal Nerve
May be injured in axilla due to shoulder dislocation, or
during its course in upper arm and/or forearm by stabs or This nerve may be afflicted by pressure or sleep palsy
gunshot or at wrist by Colle’s fracture. Compression of the due to compression during its course over the head of the
median nerve (the classical description of carpel tunnel fibula. Fractures involving the upper end of the fibula,
syndrome- CTS) causes wasting of the thenar eminence operations on the knee, diabetic neuropathy and
of the flexor pollicis brevis, adductor pollicis, opponens polyarteritis nodosa can involve the nerve. As a result,
pollicis, abductor pollicis brevis. These all add up to make the dorsiflexion of the foot, toes and the everters of the
the clinical picture of the “Median claw hand”, involving foot may be paralysed (“foot drop”) and sensations to the
the first three digits. The sensory loss in the distribution of dorsum of foot and lateral aspect of the lower half of the
the median nerve, distal to the transverse carpal ligament, leg are lost.
is observed. The carpel tunnel syndrome may be caused
by systemic conditions like hypothyroidism, amyloidosis, Trigeminal Nerve
multiple myeloma, rheumatoid arthritis, pregnancy, The sensory supply of whole of the skin of the face and
acromegaly, mucopolysachharidoses, etc. mainly on half of the vertex of the skull (except the area over the
CHAPTER
17
parotid gland and the angle of the mandible—supplied by Meralgia Paresthetica

the great auricular nerve) is by the three branches of the (Syn. Bernhardt’s Syndrome)
trigeminal nerve, namely, ophthalmic, maxillary and
This condition entails the compression of the lateral femoral
mandibular shown as 1st, 2nd and 3rd branches
cutaneous nerve at the lateral end of the inguinal ligament
respectively in the Figure 17.2. The motor supply from
trigeminal nerve is to masseter and pterygoid masticatory where it enters the fascia lata. This results in paresthesia
muscles, which remain unaffected in leprosy. Hypesthesia and sensory impairment over anterolateral aspect of thigh
or anesthesia results from involvement of the sensory (Fig. 17.3). This condition is frequently seen in association
supply by the lesions of tuberculoid, borderline or with amyloidosis and hypothyroidism which predispose to
lepromatous leprosy. pressure palsies on account of fibro-fatty depositions, as
Trigeminal neuralgia (Tic Douloureux) presents with mentioned in section on carpal tunnel syndrome.
paroxyms of pain in the cheek region, typically lasting for
few seconds or minutes. The pain distribution is usually
localized to maxillary or mandibular (sometimes both)
regions. In some cases there may be a feeling of numbness
and paresthesias over cheeks. The pain sensations are
triggered by activities like face washing, shaving, chewing
and cool breeze, etc. The diagnosis is made by patient’s
history alone.
Sensory loss in the face, with or without weakness,
may also be found in tumors of middle cranial fossa,
Schwannomas of trigeminal nerve and metastatic tumors
of base of the skull. First and second divisions of the
trigeminal nerve may be affected by lesions of the
cavernous sinus, while ophthalmic division is affected if
the pathology is at superior orbital fissure.
Fig.17. 3: Meralgia paresthetica: Areas of sensory disturbance

(shaded region)
Facial Nerve Paralysis

Facial nerve is the motor nerve supplying the muscles of
facial expression. The facial nerve paralysis is not so
infrequent and has been reported with variable incidence
of 3%, 19.8% and 20.4% in leprosy in three studies.10-12
There is patchy facial paralysis of medial forehead
elevators and all muscles of facial expression. There is
Fig.17. 2: Three divisions of trigeminal loss of skin folds and creases and dropping of the angle of
nerve sensory distribution areas the mouth, the forehead is unfurrowed and the eyelids can
CHAPTER
17
not be closed. The lower eyelid sags and the punctum Differentiation of Leprosy
retracts away from the eyeball leading to spilling of tears The facial nerve involvement in leprosy in unlikely to be
over the cheek. Bell’s phenomenon (upward rotation of the encountered in absence of a visible skin patch over cheek
eyeball upon attempted closure of the eyelids) can be or adjoining neck area (or earlobe infiltration), more likely
observed on the paralyzed side. Lesions involving middle the patch being in a reactional state with accompanying
ear portion cause ipsilateral taste loss over anterior two neuritis. Also likely to be observed is a thickened palpable
thirds of the tongue. There may be numbness in the face nerve in the vicinity of the patch. Other than in TT and BT
but no sensory or taste loss is demonstrable. An associated leprosy cases, a slitskin smear examination would settle
deafness, tinnitus or dizziness is due to lesion in the internal the issue in BB, BL and LL cases.
auditory meatus affecting auditory and vestibular nerves.
Abducent nerve and corticospinal tracts are involved if Cervical Rib
the lesion is in the pons.
This refers to the abnormally enlarged transverse process
of the 7th cervical vertebra, which is unattached anteriorly.
Bell’s Palsy
The abnormal bone segment presses upon the adjoining
This condition refers to an idiopathic facial nerve paralysis branches of the brachial plexus. The main features are
(Bell’s palsy) which has an abrupt onset with pain behind thinning of thenar eminence which may be flattened or
the ear, followed by paralysis in 24 to 48 hours. Taste depressed. The symptoms are pain and tingling sensation
sensation may be lost and hyperacusis may be present. along the forearm and hand, over the distribution of ulnar
nerve. Wasting of intrinsic hand muscles may occur,
Ramsay-Hunt Syndrome leading to claw-hand. This condition can easily be
It results from involvement of the facial and auditory nerves differentiated on the basis of X-ray of cervical spine.
by varicella zoster virus (VZV). Herpetic inflammation of
the geniculate ganglion is felt to be the cause of this ACUTE AND CHRONIC INFLAMMATORY
syndrome. In this syndrome an acute facial paralysis DEMYELINATING POLYRADICULOPATHY
develops associated with pain in the ear, loss of taste (AIDP AND CIDP)
sensation in anterior two third of tongue, dryness of mouth
and eyes. Also there is eruption of erythematous vesicles
Guillain-Barre Syndrome
in the pharynx and external auditory canal. Eighth nerve
(Acute Idiopathic Polyneuritis)
may also be involved with it. With early treatment with oral It is a cell mediated immune disease and is the most
steroids and acyclovir, full recovery is usual in over 75% common cause of rapidly progressive symmetric
cases. polyneuropathy (characterized by areflexia and absence
Facial nerve paralysis may also be observed in other of fever) that usually follows viral infection or immunization.
conditions like: (a) Guillain-Barre disease where bilateral About 75% cases experience a symptom complex 1-3
involvement may occur in almost half the patients, (b) in weeks before neuropathy sets in, commonly referred to
sarcoidosis (Heerfordt’s syndrome, the triad of facial palsy, as antecedent events. The commoner (20-30% cases)
uveitis and parotitis), (c) lesions in the pons (due to infarcts among these events are respiratory or gastrointestinal
or tumors), (d) tumors that invade temporal bone (carotid infections (Campylobacter jejuni, human herpes virus,
body, cholesteatoma and acoustic neuromas). CMV, Epstein-Barr virus, Mycoplasma pneumoniae, etc).13
The supranuclear facial palsy must be distinguished It begins as weakness in the legs, arms, bulbar, or
from the nuclear and peripheral nerve paralysis. In the extraocular muscles and areflexia. The impairments are
former, there is less involvement of the frontalis and mainly motor (without sensory impairment); the weakness
orbicularis occuli muscles since upper facial muscles are is more prominent in the proximal group of muscles. Facial
innervated by both motor cortices whereas nerve fibers diaparesis is observed in as many as 50% cases. Senses
from opposite hemisphere innervate lower facial muscles. of proprioception and DTRs disappear in first few hours
Associated paralysis of arm and leg or aphasia will further indicating the major involvement of large sensory fibers.
differentiate it. In contrast sensations of pain and temperature remain more
CHAPTER
17
or less unaffected (indicative of minimal involvement of sensory and motor nerve conduction (typically <38-40
small nerve fibers). As the bulbar and respiratory muscles meters/second). Segmental demyelination is confirmed by
can be involved early in the disease, the suspicion of this nerve biopsy and nerve conduction studies.
disease at an early stage is necessary. Laboratory
diagnosis is aided by isolation of Campylobacter jejuni HSMN Type II
from stool culture and demonstration of antiganglioside (Syn. CMT2, Axonal form of Charcot-Marie-Tooth disease)
antibodies GM1 (in up to 20-50% cases).14 Most of the Autosomal dominantly inherited disorder, less common
patients are sick and require hospitalization, about one than type I, there is relative preservation of myelin sheath
third need ventilatory support. Over 85% patients recover and nerve conduction velocity (NCV) is nearly normal. The
fully over a period of months to years, the main treatment course is chronic, slowly progressive, less involvement of
options are intravenous immunoglobulins and plasma- intrinsic hand muscles. Clinically no nerve enlargement is
pheresis. seen.
Differentiation of Leprosy HSMN Type III

The rapidly evolving paralysis with areflexia (with (Syn. Dejerine-Sottas disease, Hypertrophic interstitial
preservation of pain and temperature sensations) over a neuropathy)
few weeks, coupled with a history of antecedent events This is a rare, severe, recessively inherited, chronic
(respiratory and GIT infections) can easily point to the GB symmetric demyelinating polyneuropathy of early onset in
syndrome, these features not observed in leprosy. infancy, marked by short stature, scoliosis, pes cavus
ataxia and severe weakness, often resulting in claw-hand.
HEREDITARY (FAMILIAL) The nerves are enlarged, show slow conduction (typically
NEUROPATHIES <10 m/s). The neural histopathology shows typical “onion
bulb” appearance and the CSF proteins are raised.15
The hereditary neurological conditions may be either
sensorimotor or pure sensory neuropathies, of each HSMN Type IV
category, three types are recognized: (Syn. Refsum’s Syndrome)
This rare autosomal recessive condition (only about 60
Hereditary Sensorimotor Neuropathy (HSMN) cases reported worldwide so far) comprises an association
HSMN Type1 of HSMN Type III with ichthyosis, neural deafness and
(Syn. Peroneal muscle atrophy, hypertrophic form of retinitis pigmentosa.16 Presentation is in late childhood or
Charcot-Marie-Tooth disease, CMT-1) adolescence (but can also be in early childhood, the
An autosomal dominantly inherited motor and sensory infantile form) and the polyneuropathy is progressive,
motor neuropathy may present with or without sensory sensorimotor, symmetric and distal. The clinical
defects, distal muscle weakness and foot deformities (Pes manifestations include weakness in the arms and legs,
cavus, Fig. 17.4), and hypertrophy of peripheral nerves. cerebellar ataxia, anosmia (loss of smell sensation),
tinnitus, cardiomyopathy and cataracts. A characteristic
The chief pathology is neural demyelination and reduced
shortening of 4th toe has been reported (Fig. 17.5).17 The
sensory disturbances present as numbness and burning
sensation and loss of reflexes. Night blindness is the usual
presenting feature, with parental complaints of the child
frequently colliding with household articles (table, sofa or
wall etc) after dark. There is a deficiency of enzyme
phytanic acid oxidase, responsible for alpha-oxidation of
branched-chain fatty acids (leading to accumulation of
Phytanic acid in the blood and tissues). The diagnosis is
by demonstration of increased levels of phytanic acid in
serum and urine. The CSF proteins are typically raised.
Fig.17.4: Pes cavus. High arched foot in a case of
Charcot Marie-Tooth disease The treatment is primarily preventive, i.e. avoidance of
CHAPTER
17
Fig.17.6: Hereditary sensory neuropathy in a 15 years old boy. The

symptoms of sensory loss over hands and feet, recurrent ulcerations
Fig.17.5: Refsum’s disease. Note the shortening of the 4th toe were present for 5-6 years. Recurrent infections lead to loss of digits
(Reproduced with permission)
This is slowly progressive, recessively inherited

dietary sources of phytanic acid (the rich sources include disease which presents in infancy. The common
beef, lamb, full cream, milk, butter and cheese). It is features are ulcers of the hands and feet, paronychia,
important to be careful to maintain weight, as loss of weight whitlow and limb fractures. Diminished tendon reflexes
can lead to release of stored phytanic acid from fat tissues, are associated with sensory loss, which is more to
touch than to pain perception, in distal regions of all
thereby causing an increase in plasma phytanic acid levels,
four limbs. Cutaneous myelinated nerves are completely
and can lead to a worsening of symptoms. Another option
lost.
for reducing the serum phytanic acid is plasmapheresis
3. HSN Type III (Syn. Dysautonomia of Riley-Day): This
(replacement of the plasma). Histopathologically, there is
condition inherited in a recessive fashion, is seen more
wide spread segmental demyelination and the onion-bulb
commonly in Jewish infants and children.
formation is a regular feature, but the clinical finding of
Histopathologically there is reduction in unmyelinated
enlarged peripheral nerves is not that usual.
fibers in the sural nerve. The common features are
insensitivity to pain, areflexia, corneal insensitivity and
Hereditary Sensory Neuropathy (HSN)
absence of filiform papillae over tongue. The poor
Three types described are as follows: feeding and vomiting lead to failure to thrive, pulmonary
1. HSN Type I (Syn. Mutilating acropachy, acrodystrophic infections and ultimately death. The autonomic
neuropathy, perforating foot ulcers disease, insensitive disturbances include defective lacrimation, poor
feet disease, hereditary sensory radicular neuropathy) temperature control, excessive perspiration,
This is an autosomal dominantly inherited, sensory hypertension and postural hypotension.
radiculopathy marked by severe distal sensory loss
more over feet and legs, than over hands. The Hereditary Amyloid Polyneuropathy
symptoms appear in the second decade of life in the (Syn. Sensoriautonomic Neuropathy)
form of glove stocking anesthesia, chiefly to pain and This autosomal dominant condition presents in adult life
temperature, diminished reflexes and foot ulcers with progressive sensory peripheral neuropathy and early
(Fig.17.6). On histopathology, cutaneous nerves show involvement with autonomic deficits. Pain and temperature
loss of most of the unmyelinated, and some of the sensations are diminished or absent. Cardiomyopathy,
myelinated nerve fibers. The nerve conduction is usually postural hypotension and gastrointestinal symptoms are
unaffected and life expectancy is near normal. other features. Extensive amyloid deposits are observed
2. HSN Type II (Syn. Congenital sensory neuropathy, in multiple organs and the condition is also associated
congenital absence of pain) with trophic ulceration of the feet.
CHAPTER
17
TOXIC/NUTRITIONAL CONDITIONS polyneuropathy. Radiotherapy administration in the

cumulative dose of 6,000 rads and above can cause fibrosis
Heavy Metals
in the exposed peripheral nerve plexuses and neuropathy
Lead, mercury, thallium and arsenic. due to loss of axons and myelin.
Drugs
INFECTIONS
1. Nitrofurantoin, Isoniazid, Diphenyl hydantoin
Corynebacterium Diphtheriae
2. Organophosphorous compounds.
This infection involving fauces or skin may cause
The toxic substances (few examples mentioned above)
segmental demyelination by its toxin. The exotoxin blocks
cause severe sensorimotor neuropathy by distal axonal
myelin protein synthesis by Schwann cells and causes
degeneration, commonly termed as “dying-back”
rapidly progressive sensorimotor neuropathy in the limbs,
neuropathy. Nerve biopsy reveals axonal ballooning with
several weeks or months after the infection. The bulbar
demyelination of these segments and slowing of nerve
dysfunctions (palatal and pharyngeal muscle paralysis,
conduction velocity. Lead (both, inorganic salts and organic
compounds) induces symmetric polyneuropathy and the difficulty in swallowing, nasal voice, regurgitation of fluids
characteristic motor weakness of extensor muscles of through nose, occulomotor and ciliary nerves paralysis
wrists and fingers. Persons working with lead paints or etc.) typically develop in first 2 weeks of illness. The
lead fumes are prone to it. Thallium poisoning causes an peripheral neuropathy develops 1-3 months after onset of
acute symmetric polyneuropathy in the form of mild infection. There is proximal weakness of limbs initially
sensory deficits and severe spontaneous pain and which spreads distally. Paresthesias develop in glove and
dysesthesias in legs. stocking distribution. Polyneuritis usually resolves
completely over several months.
Vitamin B Complex Deficiency
Differentiation of Leprosy
Deficiency of vitamin B complex (especially B1, B6 and
History of acute throat infection 1-3 months prior to onset
B12) induces symmetrical polyneuropathy. The sensory
of neuropathy (characterized by pseudomembrane in
deficits with painful feet syndrome are usually more
prominent than muscle weakness. Other features of tonsillar or surrounding areas), lack of skin lesions of
Vitamin B deficiencies can be noticed alongside. Dying- leprosy.
back pattern (the distal sensory loss) of Wallerian
degeneration is present and the nerve conduction velocity
HIV Associated Neuropathy
is within the normal range. Vitamin B1 (Thiamine) deficiency Early in the course of HIV-1 infection, there may sometimes
is seen as beriberi syndrome following intake of diets be mononeuritis simplex, a primarily motor neuropathy
deficient in thiamine (polished rice eaters), and in chronic involving progressive weakness, areflexia and minimal
alcoholism as part of Wernicke’s syndrome. Vitamin B6 sensory impairments. The cause is of vascular origin
(Pyridoxine) deficiency though rare, can occur in patients (necrotizing arteritis) and the condition may improve
taking isoniazid. Deficiency of Vitamin B 12 (Cyano- spontaneously.
cobalamine) is seen more commonly in pure vegetarians A much more common multiplex form (demyelinating
due to lack of this vitamin in vegetables. The condition polyneuropathy and lumbosacral polyradiculopathy) also
produces megaloblastic anemia, degeneration of the dorsal occurs late in the course of HIV illness. This presents with
and lateral columns of the spinal cord, dementia and multiple peripheral and cranial nerve involvement with focal
diminished/absent ankle deep tendon reflex. weakness, and distal sensory loss. The patient has painful
burning feet sensations, stocking type of sensory loss to
Malignancies and Radiation Toxicity touch, pain and temperature. Motor involvement is mild
Polyneuropathies of distal sensorimotor type can be found (limited to intrinsic foot muscles). This multiplex form of
in 5% cases of the malignancies. Multiple myeloma and neuropathy may be due to autoimmune phenomenon or
Walderstrom’s macroglobulinemia often have associated as a result of cytomegalovirus virus infection.18
CHAPTER
17
Chronic Hepatitis Table 17.2: Differential diagnosis of claw-hand
deformity and neurotrophic ulcers
The patients with raised levels of Australian antigen may
sometime develop mononeuritis or mononeuritis multiplex Claw hand Neuropathic ulcers
as a consequence of immune complex disease. 1. Progressive muscular atrophy 1. Diabetes mellitus
2. Congenital flexion of fingers 2. Planter corns and
callosities
DEVELOPMENTAL DISORDERS 3. Dupuytren’s contracture 3. Yaws
4. Trauma (Ulnar and Median 4. Tabes dorsalis
Syringomyelia nerves)
(Cystic Cavitations of Spinal Cord) 5. Syringomyelia 5. Raynaud’s disease
6. Cervical rib 6. Buerger’s disease
This can be congenital (nearly 70% cases; the most 7. Dejerine Sotta’s disease 7. Spina bifida
common cause being Arnold Chiari’s malformations) or 8. Sclerodactyly 8. Syringomyelia
9. Ainhum 9. Amyloid neuropathy
acquired (as a result of local trauma to spinal cord, tumors,
10. Hereditary sensory
local hemorrhage). The cavitations in the spinal cord lead neuropathy
to neuronal damage. It may result in a lower motor neuron
deficit (progressive weakness in arms and legs), loss of CONDITIONS PRODUCING CLAW-HAND
hand sensations, a dissociated form of sensory loss (loss DEFORMITY
of pain and temperature, and preservation of touch and See Table 17.2.
vibration) over the nape of the neck. In the legs there may
be upper motor neuron signs marked by spastic paralysis. Progressive Muscular Atrophy (PMA)
Spina Bifida This is a disorder of lower motor neurones with bilaterally

symmetrical affliction. The main features are muscle
This may result from incomplete closure of the spinal canal atrophy; fasciculation and muscular weakness which may
due to failure of fusion of the posterior arches of the produce typical claw hands (often bilateral). There are no
vertebrae. Spina bifida occulta is recognized by the sensory impairments and no thickened enlarged nerves.
X-rays, presence of dimple or a tuft of hair in the lumbar
region and absence of neurological signs. Tethering of the Congenital Flexion of Fingers
spinal cord occurs in spina bifida cystica and results in The condition is usually bilateral and limited to little finger
various neurological deficits in the lower limbs, trophic involvement. There is no sensory loss.
ulcers and sphincter disturbance depending upon the site
of traction injury. Dupuytren’s Contracture
This condition involves fibrous proliferation of palmar fascia
PSYCHIATRIC DISORDERS of unknown etiology and resultant flexion deformities of
Hysteria hand. In severe involvement the condition may sometimes
be confused with the claw-hand deformity but the differen-
This neurosis, observed more commonly in women than tiating point is that the deformity entails flexion at meta-
in men, and may lead to simulation of symptoms of almost carpophalangeal (MCP) joints, as against the hyperflexion
any of the organic illness. Weakness and paralysis of deformity at interphalangeal (IP) joints and hyperextension
muscles groups (usually accompanied by altered at MCP joints. The condition can easily be differentiated
sensitivity) are common, especially involving touch, pain by absence of other cardinal signs of leprosy.
temperature and sense of position. Particularly
characteristic is the “glove and stocking” distribution of Sclerodactyly
motor and sensory symptoms, when these affect the limbs
This condition (meaning “hard fingers and toes”) is usually
but the notable feature is that the distribution is determined found in clinical conditions of scleroderma, Raynaud’s
by the body-image concept of a functional arm and leg, as disease, mixed connective tissue disease and also as a
per patient’s perception, rather than the dermatomal part of CREST syndrome (Calcinosis, Raynaud’s
innervation of the area affected. phenomenon, esophageal dysmotility, sclerodactyly and
CHAPTER
17
Telangiectasia). The fingers become fixed and sometimes (Treponema pertune) of skin, bones and joints leading to
may look like claw hand and there may be small painful large scale tissue and bone destruction. Ulceration of hands
ulcers on fingertips. The condition can be differentiated on and feet may be observed and diagnosis is based on
basis of presence of features like intermittent blanching laboratory tests of dark ground examination from tissue
and cyanosis of fingers and toes, especially on exposure smears, VDRL and RPR tests, etc.
to cold water and winds, and on absence of cardinal signs
of leprosy. Tabes Dorsalis
Ainhum This is a slowly progressive degenerative form of
neurosyphilis which affects the posterior columns and
(Syn. Bankokerend, Dactylolysis spontanea, and posterior roots of the spinal cord. The main features are
Sukhapakla)19
loss of pain sensation and peripheral reflexes, impairment
This is a painful constriction of unknown etiology usually of vibration and position senses, and progressive ataxia.
affects the base of the fifth toe (in the form of a constricting Other common features are bladder incontinence, loss of
fibrous ring) which may frequently result in amputation of libido, Argyll Robertson pupil and lightening pain (appears
the affected digit later on. The disease occurs suddenly, spreads rapidly and disappears). The sensory
predominantly in black Africans and may sometimes look impairments may lead to neurotrophic ulcers later. The
like partial ulnar claw-hand.
differentiation of leprosy can be differentiated easily based
on VDRL, slit-skin smear examinations.
CONDITIONS PRODUCING
NEUROPATHIC ULCERS Raynaud’s Disease
Mentioned in Table 17.3, not described earlier in the text. In longstanding cases there may be development of finger-
tip ulcers, as has been mentioned in the sclerodactyly
Planter Corns heading. However, there is no nerve thickening or
The punched-out cavities left after the scraping the callus tenderness.
may resemble the neuropathic ulcers of leprosy.
Buerger’s Disease
Yaws
(Syn. Thromboangiitis Obliterans)
(Syn. Non-venereal Syphilis) The sensory loss is seen in the area limited to gangrenous
This condition (mainly encountered in Africa, South affliction. The neuropathic ulcerations may occur in feet.
America and Southeast Asia) is a spirochete infection Buerger’s disease almost exclusively occurs in smokers
and the most common complaint is intermittent
Table 17.3: Common causes of palpably enlarged nerves claudication.
Physiological
1. Generalized: Strenuous physical exercises, Wrestlers REFERENCES
2. Localized: Carrying heavy weights over head (Great
auricular nerve thickening) 1. Jopling WH. Differential diagnosis. In: Handbook of leprosy. 3rd
ed. (1st ELBS reprint), London, William Heinemann Medical
Pathological Books Ltd. 1987; 118-21.
1. Leprosy 2. Sabin TD, Swift TR, Jacobsen RR. Leprosy. In: Dyck PJ,
2. Amyloidosis Thomas PK, Griffin JW, Low PA, Podusco JF (editors). Peripheral
3. Sarcoidosis neuropathy. 3rd ed. Saunders, Philadelphia; 1993; 1354-79.
4. Neurofibromatosis 3. Fasal P. Leprosy: the great imitator. Presented at the first congress
5. Guillain-Barre syndrome of the International Society of Tropical Dermatology, Naples,
6. Refsum’s disease Italy, June 8, 1964. Quoted in, Medical Clinics North America
7. HSMN Type I (Charcot-Marie-Tooth disease) 1965;49:801-16.
8. HSMN Type III (Dejerine Sotta’s disease) 4. Rambukkana A, Salzer JL, Yurchenco PD et al. Neural targeting
of Mycobacterium leprae mediated by the G domain of the
Other less common causes
laminin-alpha 2 chain. Cell 1997;88:811-17.
1. Tubercular nerve abscess
5. Shepard CC. Temperature optimum of Mycobacterium leprae in
2. Cysts and trauma
mice. J Bacteriol 1965;90:1271-78.
CHAPTER
17
6. Brand PW. Temperature variation and leprosy deformity. Int J Lepr Guillain-Barré syndrome: A case-control study. Neurology 1998;
1959;27:1-7. 51:1110-15.
7. Hastings RC, Brand BW, Mansfield RE et al. Bacterial density in 14. Yuki N, Wim Ang C, Koga M, et al. Clinical features and response to
the skin in lepromatous leprosy is related to temperature. Lepr treatment in Guillain-Barré syndrome associated with antibodies
Rev 1968;39:71-74. to GM1b ganglioside. Ann Neurol 2000; 47:314-21.
8. Mohseni S. Hypoglycaemic neuropathy. Acta Neuropathol 2001; 15. Warner LE, Garcia CA, Lupski JR. Hereditary peripheral
102:413-21. neuropathies: Clinical Forms, Genetics, and Molecular
9. Masi AT, Hunder GG, Lie JT, et al. The American College of Mechanisms. Annu Rev Med 1999; 50: 263-75.
Rheumatology 1990 criteria for the classification of Churg- 16. Zalewska A, Schwartz RA. Refsum’s disease. Available at http:/
Strauss Syndrome (Allergic granulomatosis and angitis). Arthritis /emedicine.medscape.com/article/1114720-overview (last
Rheum 1990; 33:1094-1100. updated January 16, 2007).
10. Diwan VS. A survey of deformities in leprosy (with special 17. Willis AJ. Manning NJ and Reilly MM. Refsum disease (Review)
reference to face). Lepr Rev 1962; 33:255-62. Q J Med 2001; 94:403-06.
11. Reichart P. Facial and oral manifestations in leprosy. Oral Surg 18. Moore RD, Wai-Ming EW, Jeanne CK et al. Incidence of
1976; 41:385-99. neuropathy in HIV-infected patients on monotherapy versus
12. Sehgal VN, Sharma PK. Pattern of deformities/disabilities in urban those on combination therapy with didanosine, stavudine and
leprosy. Indian J Lepr 1985; 57:183-92. hydroxyurea. AIDS 2000; 14:273-78.
13. Jacobs BC, Rothbarth PH, van der Meche FGA, Herbrink P, 19. James WD, Berger T, Elston D. In: Andrews’ Diseases of the Skin:
Schmitz PIM, et al. The spectrum of antecedent infections in Clinical Dermatology. (10th ed.). Saunders, Philadelphia. 2005; 607.
Section
4 Disease Complications
(Nerve Involvement, Neuritis
and Reactions)
18 Structure and Electrophysiological
Studies of Peripheral Nerve
Sujai K Suneetha, P Narasimha Rao
INTRODUCTION
Leprosy is essentially a disease of the nerves. Most of
the disabilities associated with the disease are due to
involvement and damage to peripheral nerves. In this
context an understanding of the structure and function of
the nerve is in order.
STRUCTURE AND FUNCTION OF

PERIPHERAL NERVES
A peripheral nerve is composed of two cellular elements,
the neuron and the Schwann cell, both of which are derived
from embryonic ectoderm.1 Neuron is the functional unit
of the nervous system and is involved in transmitting nerve
messages to all parts of the body. Neurons are basically
made up of a cell body, dendrites and an axon. The cell
body contains organelles that maintain its life. Dendrites
are short processes from the cell body and are responsible
for receiving information and passing it on to the cell body.
Dendritic processes almost always undergo branching (Fig.
18.1). The axon passes information away from the cell
body. Axons remain unbranched for a long length and only Fig. 18.1: Structure of neuron
undergo branching towards the end of their process. A
nerve fascicle is formed when multiple axons are grouped
together, and many such fascicles constitute a peripheral The cell body of the axons in a peripheral nerve is
nerve. located in the dorsal root ganglion for sensory nerves; in
the ventral horn of the spinal cord or brainstem for
Structure of the Axon motor nerves and in the autonomic ganglion for autonomic
The axon is a long tubular extension of the neuron. The nerves.
axon is covered by the neurolemmal membrane and
Schwann Cells and Myelination of Nerves
contains fluid axoplasm. The axon carries information from
the cell body to the periphery. Each neuron has only one Myelin is a sheath of lipid that covers an axon. The myelin
axon. Sensory neurons have long dendrites and a short sheath protects the axon as well as speeds up the impulse
axon, motor neurons have the opposite. along the length of the axon. Myelin is produced by the
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228 Disease Complications (Nerve Involvement, Neuritis and Reactions)
Schwann cell that encircles the axon. Schwann cell is vital Structure of a Nerve
for the life and the function of an axon. Schwann cells
A peripheral nerve is formed when multiple axons – both
have an electron dense basal lamina which closely
myelinated and unmyelinated are grouped together into a
encircles the axon on its surface. Successive Schwann nerve fascicle. Greater the number of axons in a fascicle
cells cover an axon right from its origin in the spinal nerve and greater the number of fascicles in a nerve, greater is
root almost to its periphery. Mature Schwann cells produce the diameter of the peripheral nerve. On light microscopy,
myelin in response to a stimulus from the axon. Schwann the axon can be visualized only by silver impregnation
cells are also capable of utilizing degraded products of staining. Electron microscopically, the cytoplasm of the
myelin breakdown to re-synthesize fresh myelin. The axons contain neurofilaments, mitochondria, longitudinally-
Schwann cell membrane encircles the axon in a spiral oriented endoplasmic reticulum, neurotubules, and small
fashion to produce multiple layers of the membrane like vesicles and granules containing neurotransmitters and
an onion peel. Thus the myelin sheath is formed from the neuropeptides.4
lipid and protein of the cell membrane of the Schwann cell. The axons are long processes and since their terminal
The outermost layer of the myelin sheath is the Schwann ends are distant from the cell body, they are insulated
cell with its nucleus, cytoplasm and its outer cell membrane from other axons by endoneurial connective tissue
called neurolemma. consisting of type I and type II collagen fibrils, fibroblasts,
Along the length of a nerve multiple Schwann cells a few mast cells, macrophages and endoneural fluid.
surround the axon. The neurolemma of two adjoining A number of axons are grouped together to form a
Schwann cells dips down to the axon to produce short fascicle and each such fascicle is surrounded by dense
gaps where the axon is not enclosed by myelin. These are connective tissue called perineurium (Fig.18.2). The
called Nodes of Ranvier. These points are the places where perineurium is made up of multiple layers of perineural
the myelin sheath of one Schwann cell ends and the next cells, type I and type II collagen fibrils and elastic fibers,
begins. This is also the point at which any collateral in circumferential, oblique and longitudinal orientation. Each
branches of the axon leave the main axon. layer of perineural cells has a basal lamina containing
The axons covered by a myelin sheath and individual laminin and fibronectin. The innermost layer of perineural
Schwann cells are called myelinated nerves. There are cells have tight intercellular bridges that maintain the blood
unmyelinated nerves where multiple axons are sub served nerve barrier and preserve the endoneurial environment.
by one Schwann cell with the multiple axons embedded in
invaginations of the Schwann cell. These axons are not
enclosed beyond the initial stage of enfolding and
therefore, are enclosed by only a single or a few layers
of Schwann cell plasma membranes without the formation
of a thick lipoprotein sheath constituting myelin.2 Since
multiple layers of myelin are not present around each
such axon they are less protected and more importantly
they conduct electrical impulse along the axon much
slower than myelinated axons. Although the Schwann
cells of myelinated and unmyelinated nerves are similar
in many aspects, the Schwann cells of unmyelinated axon
lack lysosomes and that could be the reason why M. leprae
survive and are present in large number in unmyelinated
nerves.3 Myelination of a nerve is an important event for Fig. 18.2: Structure of a nerve
both protection of axon as well as for the quick conduction
of nerve impulses. Myelin predominantly contains Many nerve fascicles are enclosed together in a
glycolipids, galactocerebrosides and sulphatides. connective tissue covering called epineurium. The
Gangliosides and myelin p zero (P0) are specific for epifascicular epineurium encircles the entire nerve and the
peripheral nerves. interfascicular epineurium separates the different fascicles.
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Structure and Electrophysiological Studies of Peripheral Nerve 229
The epineurium consists of type I and type III collagen Axons that carry information from the CNS to produce
fibrils, fibroblasts, elastic fibers and mast cells. Even if effects in the periphery, such as contraction of a muscle
the sensitive living axons are damaged in the nerves, the are called efferent nerves or motor nerves.
conduit made up of epineurium and perineurium will often Nerves (axons) are also classified according to their
survive and provide a pathway for their regrowth. conduction velocities. The conduction velocities are directly
Axons often remain within the same fascicle throughout related to the size of the fibers, i.e. the larger fibers
their course. Sometimes they leave one fascicle and enter transmitting the impulse faster than the smaller fibers. The
another fascicle and continue their course in the adjacent conduction velocity is also dependent on the myelination
fascicle. The interchange of axons between fascicles may of the axons – with myelinated fibers transmitting faster
help to minimize the functional deficits caused by partial than unmyelinated fibers.
destruction of a few fascicles. When a peripheral nerve is stimulated electrically and
The axon may give off branches along its course and the electrical activity recorded, a wave is generated. The
at its termination. It either forms a synaptic junction with size of the wave generated reflects the number of axons
dendritic process of adjoining neurons or with the effector in the nerve and the shape of the wave reflects the type of
cells of muscles and glands. In the skin, the axon terminates axons present. The wave form produced by a mixed
as sensory nerve endings. A nerve contains bundles of peripheral nerve that has all type of fibers reveals three
nerve fibers, either axons or dendrites, surrounded by principals peaks – A, B and C.6 The A wave is the quickest
connective tissue. The fascicles of a nerve trunk divide to appear after stimulation and is produced by the rapidly
and reunite repeatedly to produce nerve plexuses along conducting axons which conduct the impulse in the range
the length of a nerve. This results in mixing of constituent of 12-120 m/s-1. These are called ‘A’ fibers. The A wave is
fibers of different groups at successive levels producing actually made up of 4 smaller peaks Aα, Aβ, Aγ and Aδ
eventually cutaneous, and trunk nerves and sensory, motor waves, each of which represents a smaller sub group of
and mixed nerves.5 Sensory nerves contain afferent fibers rapidly conducting axons (Fig. 18.3).
(towards the CNS), long dendrites of sensory neurons. Motor
nerves have efferent fibers (from the CNS), long axons of
motor neurons. Mixed nerves contain both types of fibers.
A nerve also has blood vessels enclosed in its
connective tissue wrappings. The blood supply to a nerve
(vasa nervorum) is from arteries that enter the epifascicular
epineurium and then traverse into the interfascicular
epineurium. A few of these divide into arterioles which
penetrate the perineurium obliquely and enter the
endoneurium. In the endoneurium they divide into smaller
capillaries that are longitudinally oriented. These capillaries
have tightly interlocked endothelial cells that maintain the
blood nerve barrier. Venules drain the blood and return it to
the heart. There are no lymphatics in the endo and
perineurium. Lymphatics are present only in the epineurium.
Types of Nerves
Nerves that supply the skin and other structural tissues
such as muscle and bone are called ‘somatic nerves’. Fig. 18.3: Neurogram of peripheral nerve
Nerves that supply visceral organs such as the lungs,
heart, liver and kidney are ‘visceral nerves’. These nerves The B wave is produced by slightly slower conducting
are largely autonomic in function. Axons that carry axons classified as ‘B’ fibers which have a conduction
information from the periphery to the CNS are called velocity in the range of 4-70 m/s-1. This is followed by the
‘afferent nerves’ or ‘afferent fibers’ or ‘sensory nerves’. ‘C’ wave which is produced by slowly conducting axons or
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18
‘C’ fibers with conduction velocities in the range of 0.5-2 The cutaneous nerves contain sensory or autonomic
m/s–1. nerve fibers. The sensory nerves carry afferent impulses
A and B fibers are myelinated axons of different from the periphery to their cell body in the dorsal root
diameter and differing conducting velocities. Larger ganglia, or, for the face, to the trigeminal ganglion.
myelinated axons carry impulses faster than smaller Cutaneous sensory neurons are unipolar; one branch of a
myelinated axons. ‘C’ fibers are unmyelinated, of small single axon extends from the cell body toward the periphery,
diameter and with slow conduction velocities. and the second one extends towards the central nervous
Functionally Aα, Aβ fibers represent motor fibers to system. As many as a thousand afferent nerve fibers may
voluntary muscles and few sensory fibers that transmit innervate 1 sq cm of the skin. The sensory supply follows
position sensation from skeletal muscle. Aβ fibers mediate well-defined dermatomes; however, an overlapping
touch, vibration and pressure sensation from the skin. Aδ innervation may occur. Autonomic nerve fibers are
fibers are sensory fibers that carry pressure, pain and distributed along with the sensory nerves until they branch
temperature sensation from skin. out into the terminal autonomic plexus, which supplies
C fibers are unmyelinated sensory fibers that arise in skin glands, blood vessels, and arrector pili muscles.
all tissues of the body and carry pain, temperature and In routine histology sections the nerves appear as wavy
pressure sensations. Because Aβ fibers have large structures with slender Schwann cell nuclei. Axons and
diameters they are sometimes called large diameter afferent myelin require special stains like silver impregnation and
fibers and Aδ and C fibers are called small diameter afferent solochrome cyanine stain for morphological study.
fibers.
Another way of classifying nerves relates specifically Nerve Endings
to sensory fibers. In this system sensory fibers are grouped Nerve endings can be differentiated into 3 types: (1) Free
into group I, II, III and IV depending on their conduction unexpanded endings (2) Expanded tips, e.g. Merkel’s
velocities. The group I-IV fibers have conduction velocities discs, (3) Encapsulated tips, such as Pacinian and
corresponding to Aα, Aβ, Aδ and C fibers respectively. Meissner corpuscles. All autonomic and many sensory
Group III and IV fibers mediate pain and temperature nerve fibers terminate as free endings, which consist of
sensations while Group II fibers mediate pressure and axons surrounded by Schwann cell processes. The basal
touch. laminas of a few of these Schwann cells are in contact
with the outer layer of the epidermis. Only in case of certain
Nerve Supply to the Skin pathological conditions and trauma, these nerve endings
The skin is innervated by cutaneous branches of have been seen to penetrate the epidermis.
musculocutaneous nerves that arise segmentally from the There are differences in the arrangement of nerves in
spinal nerves. In skin of the face, branches of the trigeminal hairy and nonhairy skin. In hairy skin, most nerves
nerves are responsible for the cutaneous innervation. The terminate either as free endings in the epidermis or as
main nerve trunks enter the subcutaneous tissues, divide, endings associated with hair follicles, which may be free
and form a branching network at the dermal-subcutaneous or encapsulated.8 In nonhairy skin, free nerves endings
junction. This deep nerve plexus enters the dermis from as well as sensory end-organs, such as the Meissner
the subcutaneous tissue and travels along with the blood corpuscles are present. They are touch receptors present
vessels in the neurovascular bundles. As they traverse in the dermal papillae, especially at the tips of fingers,
the dermis they become thinner and give off fine branches which consist of layers of flattened Schwann cells. Pacinian
to the skin adnexal structures like sweat glands, hair corpuscles are pressure-sensitive organs present in sub
follicles, smooth muscle, sebaceous glands and sensory cutis. Muco-cutaneous junction contains similar muco-
receptors. Most of these fibers are unmyelinated nerves. cutaneous sensory organs. All these sensory end-organs
Subsequently, the nerve fibers reorganize into small nerve are innervated by myelinated nerve.
bundles, which ascend along with the blood vessels and Millions of sensory receptors detect changes which
lymphatic vessels to form a network of interlacing nerves occur inside and outside the body. The receptors on the
beneath the epidermis, the superficial nerve plexus of the skin monitor sensations such as light touch, pain and
papillary dermis.7 temperature (hot and cold). Deep receptors monitor
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18
vibration, joint position and deep pain. In the internal bulb.’ These are formed by the association of proliferation
environment, receptors detect variations in pressure, pH, and rearrangement of Schwann cells with degeneration of
carbon dioxide concentration, and levels of important axons, proliferation of fibroblasts and fibrosis.
metabolites. All of this gathered information is the sensory
input or sensory function. Sensory input is converted into Axonal degeneration:Axonal damage and degradation of
electrical signals called nerve impulses that are transmitted myelin as a result of trauma produces myelin debris that
to the brain. There the signals are brought together to create need to be eliminated. This is accomplished by
sensations, to produce thoughts, or to add to memory. phagocytosis by Schwann cells.
Decisions are made based on the sensory input.
Compartmentation:Regeneration of neural tissue leads to
Based on the sensory input and integration, the nervous an altered configuration of the fascicles where the larger
system responds by sending signals to muscles, causing
fascicles get replaced by smaller ones by a process known
them to contract, or to glands, causing them to produce
as compartmentation. In this, Schwann cells and
secretions. Muscles and glands are called effectors
endoneurial fibroblasts elongate and resemble perineural
because they cause an effect in response to directions
cells.
from the nervous system. This is the output or motor
function. Mycobacterium leprae and Neural Predilection
Damage to Peripheral Nerves M. leprae survives and proliferates in the cooler parts of
the body- in macrophages in the skin and in peripheral
Damage to neural tissue due to trauma or during neuropathy nerves as they traverse superficially. A diagnosis of leprosy
elicits certain responses, which in the peripheral nerve is made based on the presence of M. leprae in the skin
largely affects Schwann cells function. There are mainly 3 and demonstrable nerve involvement and damage.
pathological responses:(1) Segmental demyelination (2) There are believed to be different ways in which
Wallerian degeneration and (3) Axonal degeneration. M. leprae may reach peripheral nerves.
Segmental Demyelination:This affects only the myelin that M leprae may enter the respiratory tract as a droplet
is present between two nodes of Ranvier, while the denuded infection and inhabit the nasal mucosa. They may be carried
axons remain unaffected. Demyelination produces delay by macrophages into the vascular sinuses in the nose
in nerve conduction and directly affects the integrity and and from there spread to the nerves at the sites of
function of the axons they subserve. predilection via the blood stream.
M. leprae may enter the skin at points of micro-
Wallerian degeneration:This involves degeneration of the ulcerations and enter naked nerve endings and traverse
whole nerve fibers distal to the site of injury or inflammation. centripetally up the nerve; Khanolkar referred to this as
Proliferation of Schwann cells in the form of long columns, “like fish swimming against the stream”.9 When the
known as bands of Bungner, leads to the repair of neural organism reaches the peripheral nerve it may enter the
tissue. These columns guide the regenerating axon to grow endoneurial blood flow and then ultimately parasitizes the
distally from the site of lesion. Within 4 weeks, the newly Schwann cells. Alternatively they may be engulfed by the
formed axon gets encapsulated completely by myelin. perineural cells and then pass inwards into the endoneurium
However in case of severe damage to axon and myelin, and Schwann cells.10
they fail to regenerate and the gap instead gets filled with Among bacteria, M leprae has the unique ability to infect
connective tissue. The first sign that characterizes Schwann cells and axons. The nerve in general is an
Wallerian degeneration is that the sheath cell nuclei and immune protected site. The lack of lymphatics and the
the Schmidt-Lanternann clefts in the myelin become more presence of blood nerve barrier within the nerve provide
prominent. high degree of protection from immune surveillance.11 A
In addition to the longitudinal orientation of the near perfect host parasite relationship is observed between
proliferating Schwann cells, another type of development, the M. leprae which are nontoxic bacilli with a long
found especially in chronic neuropathies, is noticed. It generation time and the ability to achieve dormancy and
involves a concentric arrangement of the Schwann cell the Schwann cells which are ideal host for their survival
processes and connective tissues around a center of and multiplication. Schwann cells are not functionally akin
myelinated fibers. This arrangement is known as an ‘onion to macrophages and have low ability to process and present
CHAPTER
18
antigen to T lymphocytes which enhance killing of the occurring in localized areas due to action exerted by
engulfed M. leprae. However, it should be noted that inflammatory cells; a secondary demyelination occurring as
although the phagocytic potential of Schwann cells is a sequel to atrophic changes in axonal compartment. 20
relatively low, they are able to ingest mycobacteria and This secondary demyelination is considered by some as
destroy them more rapidly than polymorphonuclear cells. the cause for silent nerve damage observed in leprosy.
They tend to retain the organism and antigen for long time Fibrosis in leprosy nerves was reported by many
and only in the presence of a local inflammatory response, authors and was reported in as high as 73% of nerve
is there a bacterial killing and accompanying damage to biopsies in pure neural leprosy patients.21 It was observed
nerves.12-15 to involve all the three compartments of nerve, the
Recent studies have revealed that M. leprae gains entry epineurium, perineurium and endoneurium, in varying
to peripheral nerves via the terminal sensory ‘C’ fiber degrees. While some studies detected increased type-I
Schwann cells and a further vertical spread occurs along collagen replacing type III collagen normally seen with
the Schwann cell column. M. leprae binds to the G domain lamellated periaxonal fibrosis surrounding both myelinated
of the laminin α2-chain (LN-α2), which is expressed on and unmyelinated fibers;22 others associated the fibrosis
the surface of the Schwann cell-axon unit.16 One of the of leprosy nerves with M. leprae induced alterations of
main causes of nerve damage among several other fibroblasts.23 All these changes lead to nerve fiber loss in
pathogenic mechanisms is the mechanical damage due leprosy. Thus the reasons for ensuing nerve fiber loss in
to the large influx of cells and fluid, and/or immunological leprosy could be explained either as a consequence of the
damage. A likely immunopathogenic mechanism of inflammatory process in the nerve resulting in fibrosis and/
Schwann cell and nerve damage in leprosy is that infected or of demyelination due to functionally impaired and M
Schwann cells process and present antigens of M leprae leprae infected Schwann cell.
to antigen-specific, inflammatory type I T-cells and that
these T cells subsequently damage and lyse infected ELECTROPHYSIOLOGICAL STUDY OF
Schwann cells.17 Diminishing levels of neuropeptides and PERIPHERAL NERVES IN LEPROSY
changes in the cytokine profile will affect the cortisol-
sensitivity of infiltrating T cells, and modulate the cortisol– The study of the electrophysiological activity of resting
cortisone shuttle so that the inflammatory site becomes and contracting skeletal muscle with the help of
resistant to physiological levels of anti-inflammatory Electromyography (EMG) and the conduction of the nerve
adrenocortical steroids.18 It would be useful to understand impulse along the peripheral nerve, also called Nerve
the mechanisms involved in inflammatory responses to Conduction Study have become most useful diagnostic
M. leprae particularly in the context of nerve damage and tools in the assessment of nerve function in leprosy, as
also the relationship between infection, inflammation and well as in other peripheral nerve disorders. These studies
the nature of damage to nerve fibers to help identify drugs were responsible for a complete reappraisal of
specifically directed at these mechanisms. neuromuscular diseases as these provide vital information
Studies of early untreated leprosy have shown that M. to confirm or alter a clinical diagnosis and prevent a serious
leprae are primarily seen in the Schwann cells of non- diagnostic error. It is only possible to learn these techniques
myelinated fibers. The reason for such preferential by practical experience; however, it is worthwhile to
lodgement is not known, but could be related to lack of understand the theory behind them. Hitherto EMG and
lysosomes in these Schwann cells. Once enclosed, a nerve conduction studies required large and sophisticated
vertical spread along abundant overlapping of cell instrumentation that necessitates high levels of expertise.
processes occurs. Studies have shown that segmental More recently, these have become commonly performed
type of demyelination independent of bacterial load bedside/outpatient procedures in many neurological
predominates in both tuberculoid and lepromatous leprosy centers. Nonetheless, these instruments are still not in
which is the main cause for the functional deficit.19 routine use in regular leprosy clinics.
Demyelination in leprosy is usually not conspicuous, being
Electrophysiological Study by EMG
better detected by the examination of teased fibers. Teased
fiber studies have affirmed the two distinct types of EMG helps in detection and recording of the electrical
demyelination, a primary segmental demyelination activity from a portion of a muscle by recording of motor
CHAPTER
18
unit potentials. Needle EMG is the usual method followed abnormal EMG indicating neuropathy, findings include
in the study of leprosy patients. It is carried out by insertion fibrillation, fasciculation, giant motor unit potentials and
of a twin core needle electrode into the muscle. The incomplete interference or reduced recruitment pattern.
electrical potentials in the muscle are observed on an Motor nerve conduction variables and sensory nerve
oscilloscope at four points; during the insertion of needle, conduction variables can also be measured and recorded
with the muscle at rest and during minimal and full muscle by EMG. It should be stated that in cases of myopathy (in
contraction. The muscle to be sampled is selected contrast to neuropathy) the EMG demonstrates motor unit
depending on the clinical diagnosis. The muscles usually potentials that are lower in amplitude and shorter in duration
examined in leprosy are, abductor pollicis brevis for testing than normal, and there is a reduced interference pattern.
the function of the median nerve, abductor digiti minimi for
testing the ulnar nerve and extensor digitorum brevis for Principle of Nerve Conduction Studies25,26
testing the lateral popliteal nerve. EMG is to be performed The basic requirements for motor nerve conduction studies
separately for each muscle to be tested.24 are that a suitable muscle be available and that its nerve
In the normal EMG, complete electric silence is supply can be stimulated at two points along its course.
observed at rest. With minimal voluntary contraction, The time taken for the stimulus to travel to nearest the
individual motor unit potentials are seen, which represents muscle is known as the distal latency and includes not
the summation of membrane action potentials of many only the time taken for the impulse to travel down the
muscle fibers. With increasing active contraction of the nerve but also the delay at the end-plate and initiation of
muscle, firing rate increases indicating increased motor contraction. If the nerve is then stimulated higher up, a
fiber recruitment, referred to as a complete interference second latency can be obtained, the difference in the time
pattern. taken being an accurate measurement of the time taken
If the nerve supply to a muscle is damaged by disease for the impulse to traverse a measured length of nerve.
of either ventral horn cell, nerve root or peripheral nerve, From this conduction velocity (meter/sec) is obtained. Most
the muscle is denervated to a variable extent and the commonly nerve conduction studies are performed in ulnar,
resulting EMG findings are known as ‘chronic partial median, peroneal and tibial nerves. In general, nerve action
denervation’ pattern. As each ventral horn cell and its potentials in upper limb are more easily elicited than in
axons supply a group of muscle fibers, called motor unit, lower limbs. The interpretation of electrophysiological
when such group of axons are damaged, as happens in functions of nerve trunks is usually based on the analysis
leprosy neuritis, a discrete and limited group of muscle of three basic criteria - velocity, latency and amplitude of
fibers cease to function. It has been shown that surviving the evoked response. Amplitude represents a summation
neurons are capable of branching and taking over adjacent of activity of the axons within a nerve trunk.
denervated muscle fibers over a period of time, at least Percutaneous stimulation for nerve conduction study
partially. The denervated muscle fibers are observed to is performed with surface electrodes placed at appropriate
be very irritable and show spontaneous electrical activity. anatomic locations along the course of nerve segment
On needle insertion in such muscles, in the EMG the being studied. The general principle of nerve conduction
normal brief injury potentials are greatly prolonged study is that the recording or active electrode is placed
(increased insertional activity) and occasionally continue over muscle or nerve segment to be studied. While the
in a burst of decreasing frequency and amplitude reference electrode for motor response is positioned off
(pseudomyotonic run). When the needle is held still in the and distal to the muscle being tested on a nearby bone or
resting muscle, fibrillation potentials occur in the partially tendon, whereas the reference electrode for sensory
denervated muscle which are usually monophasic and of response is placed distal to and on the nerve segment
longer duration. Occasionally, contractions of entire muscle being studied. The ground electrode which is usually a
producing fasciculation potentials are observed. When such metal plate that provides a large surface area of contact
a muscle contracts, gaps appear in the normal interference with patient serves as a reference zero potential and helps
pattern of the EMG readings. Sometimes large and to reduce stimulus artefacts. The ground electrode is usually
polyphasic potential are observed during active contraction placed on the body prominence between the stimulating
of a partially denervated muscle. In summary, in an and recording electrodes.
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18
Stimulating electrodes are usually two metal electrodes antidromic or orthodromic excitation and standardized
or felt pad electrodes placed 1.5-3.0 cm apart. However, variations for size of potential and latency. Moreover, multi
in conventional nerve conduction studies, mono-polar channel EMG machines, which are available widely, can
needle electrodes can be used, which has certain perform recordings for both Sensory nerve conduction
advantages which are: (a) smaller stimulus intensity is velocities (SNCV) and Motor nerve conduction velocities
required. (b) nerve can be stimulated more selectively and (MNCV).
(c) Nerves that lie anatomically deep can also be stimulated.
Application of Electrophysiological Studies in
Motor Nerve Conduction Study Leprosy
Peripheral nerve may be stimulated by passing electrical Peripheral nerve trunk involvement in leprosy is very
current through the skin, resulting in a synchronized muscle common. However, by the time it becomes clinically
contraction. When recorded by surface electrodes, this is manifest, the damage to the nerve fascicles present within
called the compound muscle action potential (CMAP). Motor the nerve is quite advanced. If the preclinical nerve damage
responses are recorded over muscle being studied. The can be detected early, the deformities and disabilities can
active (recording electrode -E1)) should be placed over be prevented to a large extent. A stage of functional
motor point of the muscle so that clear negative defection blockade of conduction of nerve impulse almost always
is recorded when electro-stimulation is applied to the nerve precedes visible pathological changes in the nerve.27
supplying that muscle. For example; E1 is to be placed on The role of electrophysiological evaluation of nerve
skin surface of abductor pollicis brevis for testing median function in the diagnosis and assessment of different
nerve motor nerve conduction potential. The reference neuropathies is well established. There are number of
electrode (E2) should be placed off the muscle on near by studies of motor and sensory nerve conduction which have
tendon or bone. Standard recording and reference electrodes shown that marked slowing of conduction may occur in
are about 1.0 cm in diameter. For standardization or leprosy affected nerves.28-30 In addition, a significant
comparisons, E1 and E2 used in CAMP recording should decline of motor nerve conduction velocities has also been
be of the same size. reported in clinically normal nerves in leprosy.
When sensory conduction velocity (SCV) was studied
Sensory Nerve Conduction Study in leprosy patients and normal subjects, slowing of
A compound nerve action potential produced by electrical conduction velocity was shown in all nerves of leprosy
stimulation of afferent nerve may be recorded over patients with no difference between tuberculoid and
peripheral sensory nerves in a number of areas. Sensory lepromatous patients. This study concluded that the SCV
nerve action potentials can be measured in two ways - in radial cutaneous nerve is reliable as an early diagnostic
orthodromically and antidromically. Here the main test for leprosy.31
requirement is a nerve near enough to the surface so that In a multi center study on 115 leprosy patients who
potentials can be picked up by a surface electrode and had nerve damage or a reaction of recent onset at diagnosis,
anatomically constant in position, allowing needle sensory and motor amplitudes and Warm Detection
electrodes to be inserted adjacent to it. The reference Thermal tests (WDT) were most frequently abnormal.
electrode usually is the same type as recording electrode, Among the nerves tested, the sural and posterior tibial
and in antidromic studies it is placed distal to the recording were the most frequently involved. WDT were much more
electrode. For orthodromic recording the reference electrode frequently affected than Cold Detection Thermal tests (CDT)
is placed proximal to the recording electrode. Recording in all nerves tested. The thresholds of all test parameters
and reference electrode used for sensory responses usually differed significantly between controls and patients, while
are surface electrodes with spring ring, disc or bar. These only some differed between patients with and without
different types of electrodes may be used inter-changeably reaction. Concordance between Voluntary Muscle Testing
for recording and stimulating purposes. (VMT) and motor conduction velocities was good for the
In recent years, due to improvements in the apparatus, ulnar nerve, but was low in a proportion of median and
very small action potentials in almost any cutaneous nerve peroneal nerves. However, a proportion of nerves with
can now be detected above background activity, using abnormal Semmes Weinstein (SW) Mono filament sensory
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18
test results tested normal on sensory nerve conduction and sensory testing with SW graded nylon filaments along
tests.32 This study concluded that nerve conduction studies with VMT is very useful, reliable and often comparable to
and WDT appear to be most promising for the early measurement of nerve conduction in detecting nerve
detection of leprous neuropathy as warm sensation was function impairment. In a recent study combining nerve
more frequently affected than cold sensation, indicating palpation with either SW monofilament testing or VMT,
that unmyelinated C fibers are more frequently affected increased the detection sensitivity of clinical tests by two-
than small myelinated A-sigma fibers. In another multi fold and was comparable to that detected by nerve
center study involving 188 MB patients, sensory nerve conduction studies.35 Many a times a direct relationship
conduction and WDT were found to be promising tests for between clinical sensory deficit and electrophysiological
improving early detection of neuropathy in leprosy patients, abnormality is not always found. However, clinically
as they often became abnormal, 12 weeks or more, before observed motor power loss usually correlates well with
an abnormal monofilament test. This study also concluded electrophysiological abnormalities.
that the changes in mono filament test and VMT score Nerve function assessment is important for the
diagnosis of leprosy as well as early diagnosis and
mirrored changes in neurophysiology, confirming their
prevention of NFI. Simple inexpensive clinical tests are
validity as screening tests.33
available for the assessment of nerve function in leprosy.
In a follow-up study of 17 MB and 15 PB leprosy
Under field conditions, combining clinical tests such as
patients on regular MDT therapy over a period of 1 year,34
nerve palpation and VMT with SW monofilament testing
it was observed that, overall, 13% of MB and 20% of PB
(described in detail in the Chapter-21 Neuritis:Definition,
cases showed signs of deterioration clinically and/or
clinical manifestations and proforma to record nerve
electrophysiologically. In further follow-up of these patients
impairment) could prove to be a practical as well as
no significant improvement in the sensory conduction in sensitive tool for diagnosing leprosy disease and detecting
both the MB and PB groups of nerves was observed, while nerve damage in these patients.36 Although electrophysio-
motor conduction showed a significant improvement at logical tests may not be available or can not be preformed
the first 6-monthly follow-up in the nerves of MB patients. in field conditions and in all leprosy clinics, they are be
It is generally observed that the nerves of lower recommended under special circumstances for further
extremity are more frequently and severely affected than confirmation and more detailed analysis or as a research
in the upper extremity in both PB and MB patients of tool for nerve function assessment in leprosy.
leprosy. Although as an individual test, nerve conduction In conclusion, it could be stated that electrophysio-
tests proved to be more sensitive, the combination of logical studies help in demonstrating and detecting the
physical palpation for nerve thickening and sensory testing integrity of nerve function in leprosy. They are useful not
with SW graded nylon filaments was closely comparable only in assessing nerve function at the time of diagnosis
to measurement of nerve conduction in detecting nerve but also in the follow-up study of leprosy patients
function impairment. and complement clinical tests for nerve function assess-
When electrophysiological functions of ulnar and median ment.
nerves were studied in leprosy patients at different stages
of disease, it was observed that the measurements show REFERENCES
a gradual insidious deterioration of function in the affected
1. Ridley DS. The structure of peripheral nerve. In:Pathogenesis
peripheral nerve trunk. In a study where electrophysiological of leprosy and related diseases. Wright London 1988;15-19.
studies were carried out in 53 early tuberculoid leprosy 2. Breathnach AS. Electron microscopy of cutaneous nerves and
patients to detect nerve damage before the onset of obvious receptors. J Invest Dermatol 1977;69:8-26.
3. Boddingius J. Mechanisms of nerve damage in leprosy.
functional deficit,35 no statistically significant difference
In:Immunobiologic aspects of leprosy, tuberculosis and
was observed between the nerve conduction (both motor leishmaniasis (DP Humber, (Ed)), Excerpta Medica, Oxford
and sensory) findings obtained from clinically thickened 1981;64-73.
and non-thickened nerves, indicating that nerve thickening 4. Winkelmann RK. Cutaneous nerves. In:Zelickson AV (Ed).
Ultrastructure of normal and abnormal skin. Lea and Febiger,
alone is not a reliable parameter in assessing nerve
Philadelphia 2002;203-27.
involvement in leprosy. Nonetheless, as already stated, 5. Sunderland S. The internal anatomy of nerve trunks in relation to
the combination of physical palpation for nerve thickening the neural lesions of leprosy. Brain 1973;96:865-88.
CHAPTER
18
6. Palastanga N, Field D, Soames R. Nervous System. In:Anatomy 22. Kajihara H, Parurusi IA, Saleh RM, et al. Light and electron
and human movement, 5th Edition. Butterworth Heinemann, microscopic study of peripheral nerves in patients with
Edinburgh 2006;5-10. lepromatous leprosy (LL) and borderline lepromatous leprosy
7. Sinclair DC. Normal anatomy of sensory nerves and receptors. (BL) Hiroshima J Med Sci 2000;49:83-92.
In:Jarrett A (Ed). The physiology and pathophysiology of the 23. Singh N, Birdi TJ, Chandrasekhar S, et al. In vitro studies on
skin:The nerves and blood vessels. Vol. 2. Academic Press, extracellular matrix production by M leprae infected murine
London 1973;347-98. neurofibroblasts. Lepr Rev 1998;69:246-56.
8. Miller MR, Ralston HJ, Kasahara M. The pattern of the cutaneous 24. Ramdan W, Mourad B, Fadel W, Ghoraba E. Clinical, electro-
innervations of the human hand, foot and breast. Adv Biol Skin physiological, and immunopathological study of peripheral nerves
1966;1:1-47. in Hansen’s disease. Lepr Rev 2001;72:35-49.
9. Khanolkar VR. Perspectives in pathology of leprosy. Indian J 25. Patten J. Neurological differential diagnosis. 2nd edition, Springer
Med Sci 1955;9 (Suppl 1):1-44 (India) Ltd, New Delhi 2005.
10. Boddingius J. Ultrastructural changes in blood vessels of 26. Lee JH, De Lisa JA. Manual of nerve conduction study and
peripheral nerves in leprosy neuropathy. II. Borderline, borderline- surface anatomy for needle electromyography (4th edn).
lepromatous and lepromatous leprosy patients. Acta Lippincott Williams and Wilkins, London, 2004.
Neuropathology 1977;40:21-39. 27. Hackett ER, Shipley DE, Livengood R. Motor nerve conduction
11. Ridley DS, Ridey MJ. Classification of nerve is modified by velocity studies of ulnar nerve in patients with leprosy. Int J Lepr
delayed recognition of M. leprae. Int J Lepr 1986;54:596-606. 1968;36:282-287.
12. Pearson JMH, Ross WF. Nerve involvement in leprosy- 28. Brown TR, Kovindha A, Wathanadilokkol U, et al. Leprosy
pathology, differential diagnosis and principles of management. neuropathy:Correlation of clinical and electrophysiological tests.
Lepr Rev 1975;46:199-212. Indian J Lepr 1996;68:1-14.
13. Rea TH, Ridley DS. Lucio’s phenomenon:A comparative 29. Ramkrishnan AG, Srinivasan TM. Electrophysiological correlates
histologic study. Int J Lepr 1979;47:161-66. of Hanseniasis. Int J Lepr 1995;63:395-408.
14. Barnetson RSC, Bjune G, Pearson JMH, et al. Antigenic 30. Samant G, Shetty VP, Uplekar MW, et al. Clinical and electro-
heterogeneity in patients with reactions in borderline leprosy. Br physiological evaluation of nerve function impairment, following
Med J 1975;iv:435-37. cessation of multidrug therapy in leprosy. Lepr Rev 1999;70:10-
15. Boddingius J. Mechanisms of peripheral nerve damage in 20.
leprosy:electron and light microscopic studies in patients 31. Sebille AJ. Respective importance of different nerve conduction
throughout the spectrum. In:Proceedings of the European velocities in leprosy. Neurol Sci 1978;38:89-95.
Leprosy Symposium 1981. Quaderni di Cooperazione Sanitaria 32. Van Brakel WH, Nicholls PG, Das L, et al. The INFIR Cohort
1982;1:65-85. Study:assessment of sensory and motor neuropathy in leprosy
16. Harboe M, Aseffa A, Leekassa R. Challenges presented by at baseline. Lepr Rev 2005;76:277-95.
nerve damage in leprosy. Lepr Rev 2005;76:5–13. 33. Van Brakel WH, Nicholls PG, Wilder-Smith EP, et al. Early
17. Spierings E, De Boer T, Zulianello L, et al. Novel mechanisms in diagnosis of neuropathy in leprosy - comparing diagnostic tests
the immunopathogenesis of leprosy nerve damage:The role of in a large prospective study (the INFIR Cohort Study). PLoS
Schwann cells, T cells and Mycobacterium leprae. Immunol Cell (Public Library of Sciences) Neglected Tropical Diseases 2008;2,
Biol 2000;78:349-55. (4), 1-12. (doi:10.1371/journal.pntd.0000212).
18. Rook GAW, Lightman SL, Heijnen CJ. Can nerve damage disrupt 34. Samant G, Shetty VP, Uplekar MW, et al. Clinical and electro-
neuroendocrine immune homeostasis? Leprosy as a case in physiological evaluation of nerve function impairment following
point. Trends Immunol 2002;23:18-22. cessation of multidrug therapy in leprosy. Lepr Rev. 1999;70:10-
19. Shetty VP, Mistry NF, Antia NH. Current understanding of leprosy 20.
as a peripheral nerve disorder:Significance of involvement of 35. Rao SP, Bharambe MS. Electro-neuro physiological studies in
peripheral nerve in leprosy. Indian J lepr 2000;72:339-50. early tuberculoid leprosy. Indian J Lepr 1993;65:181-87.
20. Jacobs JM, Shetty VP, Antia NH. Teased fiber studies in leprous 36. Khambati FA, Shetty VP, Ghate SD, et al. Sensitivity and
neuropathy. J Neurol Sci 1987;79:301-13. specificity of nerve palpation, monofilament testing and voluntary
21. Jardim MR, Chimeilli L, Faria SC, et al. Clinical, electroneuro- muscle testing in detecting peripheral nerve abnormality, using
myographic and morphological studies of pure neural leprosy in nerve conduction studies as gold standard;A study in 357
Brazilian referral center. Lepr Rev 2004;75:242-53. patients. Lepr Rev 2009;80:34-50.
19 Pathomechanisms
of Nerve Damage
Vanaja Prabhakar Shetty
INTRODUCTION 3. Significance of infection of Schwann cells by M.leprae.

4. Type of degeneration seen in leprous nerves.
Leprosy is a chronic infectious disease of the peripheral
5. Immunological aspects of nerve damage.
nerves and other tissues, arising from aberrant, rather than
6. Autoimmune type of nerve damage.
protective, immune responses to Mycobacterium leprae
7. Role of mycobacterial antigens in nerve damage.
(M.leprae). During the long course of the disease, the
8. Role of inflammatory cytokines in nerve damage.
peripheral nerves are under additional threat from acute, 9. Insidious nerve damage.
subacute or chronic intraneural immune-mediated events 10. Leprosy reactions and nerve damage.
known as “leprosy reactions”.
Maintenance of the peripheral nervous system is the
GENERAL FEATURES OF NERVE
result of a complex balance between the two functions of DAMAGE IN LEPROSY
the immune system viz. (1) defence against infection (2)
assistance in maintenance of nerve regeneration and Infection, host response and the functional impairments
physiology.1 Leprosy serves as a unique model where, of cutaneous nerves are the well established features of
due to insidious nature of the infecting organism (M.leprae) human leprosy. Some of the well documented works of
and its predilection for peripheral nerve Schwann cells, early 1980s describe how this might be taking place.
two functions of immune system coexists, at least during Carter, Professor of anatomy from Grant Medical
College, Mumbai, in a careful clinical observation and
initial stage. Although the earliest events in the encounter
histological studies on peripheral nerves obtained at post-
between the causative organism and the human body are
mortem, outlined several important characteristics of the
still unclear, there is no dispute that peripheral neural
nervous system involvement by M.leprae like:
involvement is inevitable once the infection progresses,
even before the disease manifests clinically. 1. The central nervous system (CNS) was unaffected
In this chapter various pathomechanisms involved in 2. Sensory fiber involvement was an important feature
peripheral nerve damage in leprosy are discussed. In 3. Cutaneous and nerve trunk enlargements followed a
elucidating the same, as far as possible, more recent and set pattern viz: thickening was maximal at superficial
sites, ceasing when the nerve pierced the deep fascia
relevant documented findings in both human and
4. Interfunicular plexuses existed within peripheral nerves,
experimental models are included. Besides, some of the
which possibly facilitated nerve damage
old documented findings that are invaluable; are also being
5. Nuclei (which we know today are the inflammatory cells)
referred to.
were present within leprous nerves viewed under the
The broad topics presented and discussed here are: microscope.2
1. The general features of nerve damage. It was further postulated by Dehio in 1953 that leprous
2. Entry of M.leprae and its spread. neuropathy is a centripetally ascending process,
CHAPTER
19
sequentially damaging the nerve structures. Motor fiber methods also asserts that nonmyelinated fibers are
involvement resulted from lateral spread of the pathology prominently involved in nerve injury in leprosy.14
within the mixed nerve trunk.3 Dehio opined that infection Clinical and operative correlative studies on neuropathic
did not descend centrifugally to the most distant intra- deformities by Thomas, supported the microbiological
muscular nerve terminals, but Dastur’s demonstration later maxim that M.leprae thrived in cool micro-environments
in 1978 of intramuscular neuritis with bacilli, belied Dehio’s which are also the sites of nerve enlargement. 15
assertion.4 Measurements of nerve temperature by Sabin and
Extensive histological studies of the central and associates confirmed that tissue temperatures around the
peripheral nervous systems by Ermakova in 1936, further ulnar nerve was lowest at the wrist and distal 1/3rd of the
confirmed that there was no pathology or bacillary invasion arm, which are also sites of maximum bacillary invasion.16
in the former; and that even in the latter the damage was Brand referred to the fact that neuropathy in the limbs in
not uniform.5 Limb nerves invaded with bacilli in their distal leprosy usually shows a stereotyped pattern, involving the
segments were normal at brachial and lumbo-sacral plexus ulnar nerve around the elbow and lower arm; the median
levels, with bacilli appearing in the related dorsal root nerve around the wrist and lower forearm; the tibial nerve
(sensory) ganglia. The uneven distribution of bacilli, around the ankle and the common peroneal nerve around
inflammatory response and fiber damage along peripheral the knee and distal thigh, with sparing of the nerves
nerves was well demonstrated in 1968 in postmortem supplying the girdle muscles.17
specimens by Job and Desikan.6 “Ganglionitis” in the form Motor nerve involvement occurs as a by product of
of focal round cell infiltration was reported by Tze-Chun damage to the mixed nerve, and is not a primary event. It
and Ju-Shi in 1984 from China in the autopsy material.7 was postulated that inter-funicular plexuses provided ready
However; this study did not provide information about the pathways for centripetal spread of infection from cutaneous
neurological status of these patients. A recent study funiculi to sensory-motor funiculi.18 In the ulnar nerve for
explored the involvement of CNS in 67 autopsy cases of example, sensory and motor branches which are in separate
clinically cured lepromatous leprosy patients. Paraffin funiculi at the wrist, undergo regrouping and mixing in the
sections of medulla oblongata and spinal cord were studied forearm so as to form one or two large funiculi at the elbow.
and vacuolar changes of motor neurons were seen in 67% The development of motor symptoms in a leprous ulnar
of cases. Using nested polymerase chain reaction (PCR) nerve therefore largely depends on the level in the forearm
approach, M. leprae specific genomic DNA was detected at which admixture of sensory and motor funiculi occurs
in a large proportion (23/27, 85.2%) of cases studied. in a particular case. A contributory factor maximising
However; no acid fast bacilli were detected in any of the damage at certain sites is the level-to-level change in the
Fite Faraco stained sections of these tissues. It is possible abundance of the investing epineurium. At the wrist, where
that the bacterial products may have seeped into the CNS ulnar nerve funiculi are small and numerous, compression
cavity. Interestingly, presence of vacuolar changes in the due to intraneural inflammatory edema might be mitigated
spinal cord showed a good correlation with deformity of by the large amount of yielding epineurium. At the elbow
hands and feet in this study.8 on the other hand, the funiculi are few and large and the
Studies of skin lesions by Khanolkar were among the epineurium comparatively unyielding; the nerve fibers are
first to focus on changes in dermal nerves and the sites of more liable to be damaged by compression. Palande,19
bacillary multiplication within them. He concluded that the Dastur20 and others speculated that the edematous nerve
organisms preferentially resided within axons, and were trunks themselves might be compressed as they traverse
carried centripetally in the axoplasm like “fish swimming unyielding osseo-fibrous passages such as the carpal and
upstream”.9 Electron microscopic studies of leprous nerves cubital tunnels. A study by Carayon indicated tissue anoxia
in the 1960s by Nishiura,10 Weddell and Palmer11 and from compressed perineurial arteries as the contributing
Lumsden12 showed that bacillation of the Schwann cells, factor for nerve fiber damage.21
rather than of the axon, was the dominant and characteristic Skin lesions tend to occur in areas of lowest
feature. Further studies that focussed on early nerve lesions temperature, e.g., extensor aspect of the forearm, elbow,
have delineated the preferential lodging of the bacilli in the hand, thigh, leg, knee, foot and on the cheeks. The
nonmyelinated fiber Schwann cells, signifying its early corresponding cutaneous innervation arising from the ulnar,
involvement.13 A recent clinical study using sophisticated median, common peroneal, tibial and trigeminal nerves
CHAPTER
19
Pathomechanisms of Nerve Damage 239
respectively, eventually implicates involvement of the nerve Schwannian relay, i.e distal sensory Schwann cells and
trunks. Weddell and Palmer pointed out that physiological cell to cell spread along the Schwann cell column. M.leprae
processes such as cutaneous terminal axon degeneration- were found in the terminal Schwann cells of dermal lesions
regeneration and Schwann cell turnover happen to be throughout the Ridley-Jopling classification. Several
particularly marked over these regions, which in turn might ultrastructural studies of nerves in leprosy across the
predispose these (dedifferentiated) Schwann cells to spectrum helped in ascertaining that Schwann cells are
ingress M.leprae.22 The in vitro studies using mouse dorsal the main hosts of M.leprae infection.13,26 Occurrence of
root ganglion cultures also revealed vulnerability of overwhelming M.leprae infection in the Schwann cells was
dedifferentiated Schwann cells to M.leprae infection which confirmed subsequently. 30 Other characteristic
is in consonance with the above observation.23 histopathological findings namely longitudinal involvement
of one or two fascicles, with sparing of others in a nerve
ENTRY OF M. leprae AND ITS SPREAD bundle, particularly in the tuberculoid leprosy is supportive
INTO THE NERVES of the evidence of spread of M.leprae along the Schwann
cell columns.30 In a recent large cohort study it was noted
The question of how M.leprae gains entry into the body, that skin lesions over lying major nerve trunks significantly
into the nerve, and into the Schwann cell in particular, is put the nerve at a greater risk for nerve function
important in the elucidation of pathomechanisms of nerve impairments, which also is an argument in line with the
damage. centripetal spread of infection.31
All routes - inhalation, ingestion, skin contact, and That the main bulk of M.leprae infection occurs in the
inoculation through abrasions and insect bites have been Schwann cells of unmyelinated fibers; was documented in
postulated over the years. 24 The current evidence a qualitative and quantitative electron microscopic study
implicates the nasal route as the more likely route of spread of nerve biopsies obtained from early untreated cases of
in more than one way.25 The question of the route of entry leprosy by Shetty and Antia (Fig. 19.1).32 Though it is not
is significant as it might also define the type of disease clear as to why there is such a preferential lodging of M.
which develops in a susceptible individual. Entry of the leprae in the Schwann cells of nonmyelinated fibers, it is
organism through the unbroken skin or mucosa (such as reasoned that a longitudinal spread along the nonmyelinated
inhalation), might predispose to high cell mediated fiber Schwann cells is facilitated by the abundance of
immunity (CMI) type of response, while chance inoculation overlapping and continuous cytoplasm. Influx of
into the blood stream via mucosal skin abrasions and macrophages and presence of bacilli in the macrophages
wounds etc. might promote high bacilliferous type with weak and endothelial cells lining the capillaries within the
or absent CMI. endoneurium occurred in the chronic and more advanced
Entry of M.leprae into the peripheral nerve could
essentially be the first step in the induction of neuropathy
in leprosy. There are two main routes by which leprosy
bacilli might enter the peripheral nerves; (1) The first is via
the blood stream into the endoneurium through the
monocytes or vascular endothelial cells. The presence of
M.leprae in the endothelial cells lining the capillaries within
and around the peripheral nerve is documented in biopsies
from chronic longstanding lepromatous cases of leprosy.26
It is also established that in lepromatous leprosy there is
a continuous bacilleamia27 and that this persists for a period
even after treatment.28 This is a good evidence of the
vascular spread of M.leprae. Recent studies on peripheral
nerves in Armadillos have suggested that M. leprae first
aggregate in the epineural lymphatics and blood vessesls Fig. 19.1: Part of a sural nerve from an early lepromatous leprosy
patient observed under electron microscope. Note the presence of
and then enter the endoneural compartment through its large bacterial globi (arrow) in the unmyelinated fiber Schwann cells
blood supply.29 (2) The second route of spread is via the (X 15000).
CHAPTER
19
nerve lesions, whereas cells lining the lymphatics in the been demonstrated. Of relevance is the enhancement of
epineurial area seldom showed M. leprae. Study of dermal bacterial adherence by treatment of Schwann cells with
lesions also showed infrequent presence of M.leprae in trypsin. A recent study put forth that the ‘G’ domain of
the lymphatic endothelial cells.33 It was deduced from these laminin α-2 chain is a host derived bridging molecule. It is
findings that in man, the dissemination of infection from proposed that M. leprae interacts with host Schwann cells
the nerve to other parts of the body occur via the blood by the binding of the bridge to the α6β4 integrin
stream. (dystroglycan) which acts as a laminin receptor on Schwann
The neural predilection of M. leprae is promoted by cell surface.40 The authors suggested that presence of
immune suppression due to cool temperature, trauma to both α-2 laminin and a dystroglycan is responsible for
nerves causing capillary damage and bacterial stickiness.34 restricting leprosy infection to the peripheral nervous
Factors that protect the bacilli within the nerve are the system (PNS) as these molecules are absent in the CNS.
absence of lymphatics within the endoneurial spaces and Their observations imply an almost equal predilection of
the presence of two specialized barriers namely, tight M. leprae for Schwann cells of both myelinated and un-
junctions of endothelial cells and of the perineural cells myelinated nerve fibers. This finding though plausible, fails
which provide a higher degree of protection and seclusion to explain the well established observations of preferential
from immune surveillance.35 The barriers could also hamper entry of M.leprae into the Schwann cells of unmyelinated
the penetration of drugs into the nerve thus making the fibers. Laminin, a Type-IV collagen associated glycoprotein,
treatment less effective. The poor ability of Schwann cells is a component of the basal lamina in the Schwann cells
to present antigens to the lymphocytes could also be one of both myelinated and unmyelinated fibers in vivo implying
of the factors that hinder the killing of M.leprae.36 Schwann that there may be more than one molecule involved in the
cells are long lived and those of nonmyelinated fibers in preferential involvement of unmyelinated fibers.41
particular, are poorly equipped with killer enzymes.37 They Nerve growth factor (NGF) plays an important role in
thus make an ideal host for survival, multiplication and a the survival of sympathetic ganglia and is a regulator of
good repository for persister M. leprae.38 pain sensation.42 Down-regulation of NGF in leprosy skin
lesions was demonstrated by Karanth et al43 and Anand
INFECTION OF SCHWANN CELLS et al44 generating considerable interest in its therapeutic
BY M. LEPRAE possibilities. Singh and coworkers studied NGF production
and expression of p75 by Schwann cells, neuro-fibroblasts
The basis of nerve damage in leprosy is the unique ability and macrophage secretary products in response to M. leprae
of M.leprae to invade Schwann cells. Several of the in infection in two strains of mice.45 The results indicated
vitro studies have tried to delineate the steps involved in involvement of NGF in neuro-regenerative response as
its adhesion to and the invasion of, Schwann cells. Based well as a nonsupportive role for macrophages in nerve
on the studies utilizing murine dissociated Schwann cell repair in leprosy. In their opinion, different mechanism of
cultures early entry (within 6 hrs) is observed with viable nerve repair may be operational in Swiss White (SW) and
bacteria.39 In another study organized, the dorsal root C57BL/6 strains of mice representing lepromatous and
ganglion cultures were infected with freshly harvested M. tuberculoid spectrum of leprosy patients respectively. A
leprae; entry of M.leprae was seen only into the Schwann recent study findings indicate that down regulation of NGF
cells and neuro-fibroblasts but not into the cell body or at the lesion sites may lead to disturbance in the mitogen
axons. Other important findings were, the Schwann cells activated protein kinase (MAPK) pathway and thereby
were more vulnerable to M.leprae infection in their pre- quiescent nerve damage (vide infra).
myelin secretary phase. On infection with M. leprae,
Schwann cells lost their ability to proliferate and synthesize
TYPE OF DEGENERATION SEEN IN
DNA,23 which in essence could mean a restricted
LEPROUS NERVES
proliferation of Schwann cells and defective regenerating
response. Observation that nerve biopsy of a clinically While the type of disease is determined on the basis of
normal nerve in leprosy patients does not result in neuroma inflammatory response and bacterial load, the exact
formation, is in agreement with these findings (Antia incubation time or duration of the disease is impossible to
personal communication). determine in humans. The descriptions of mild, moderate
The importance of bacterial surface lipid and or severe involvement of nerves are normally in relation to
polysaccharides in mediating selective cyto-adhesion has the extent of damage which varies from site to site.
CHAPTER
19
Various approaches have been used to assess the type patients, using combinations of techniques, viz
of degenerative changes in leprous nerves in order to morphometry and teased fiber preparation, have shown
understand the pathomechanisms of nerve damage in the presence of two distinct types of demyelination in
leprosy. Qualitative and quantitative morphology using light leprous nerves; secondary demyelination occurring as
and electron microscopy, teased nerve fiber study by it sequel of atrophic changes in the axonal compartment
self or in combination, were used to describe the nature (Fig. 19.2); and primary segmental demyelination occurring
and severity of nerve damage along the spectrum.
at the sites of active inflammation (Fig. 19.3).13 The former
In advanced leprosy lesions, some studies have shown
has been linked to MAP kinase mediated changes in axonal
the predominance of segmental demyelination in the
cytoskeletal proteins.48,49 The later was ascribed to direct
lepromatous lesions and Wallerian or axonal type of
degeneration in the tuberculoid type of lesions.26,46 Some myelinolytic action of the inflammatory cells.50,13
other studies have shown the predominance of The end result is a severely involved nerve with total
demyelinating pathology along the entire spectrum of loss of fibers and replacement with connective tissue matrix
leprosy.47 Regeneration and remyelination are also seen (Fig. 19.4) which has been shown in several of the
concomitantly. Studies on nerve biopsies from leprosy studies.51,13
B D
Figs 19.2A to D: Depicts various features of atrophic changes recorded in a leprous nerve viz (A) teased fiber preparation showing two fibers
with wrinkled myelin but no widening of node (B) a single teased fiber arranged in consecutive rows from Lt to Rt. There is widening of nodes
or more extended paranodal demyelination (secondary demyelination -arrow) at multiple sites (C) One micron thick section of sural nerve
stained with toluidine blue showing several fibers with folded myelin sheath or having infolded loops of myelin within the axon (black arrows) and
atrophic fibers (yellow arrows). Several small fibers have axons which are small for the myelin sheath thickness (X 100) (D) two myelinated
fibers with highly infolded myelin sheath (blue arrow) and normal looking axon (yellow arrow), as seen under electronmicroscope.
CHAPTER
19
which is liable to fluctuate with the ebb and flow of the

conflict between host and invader during the long drawn
saga of a leprosy infection.
Says Denis Ridley in his opening remark in a chapter
on differential pathology of dermis and nerve in leprosy.52
The host’s immune response to M.leprae plays a pivotal
role in producing the various structural and functional
changes that characterise leprosy; and the bacillus per se
seems to produce no perceptible damage.25 Cell-mediated
(CMI) as well as humoral immunity (HI) are activated to
varying degrees, the former predominating when bacilli are
few (in tuberculoid and borderline tuberculoid forms); and
the latter in bacilliferous forms of the disease (borderline
Fig. 19.3: One micron thick section of part of median nerve from a mid
borderline leprosy patient. Inflammatory cells including lymphocytes, lepromatous to lepromatous forms), while a combination
macrophages, and few plasma cells are seen. Note the presence of of CMI and HI responses to the bacillary antigens occur in
totally denuded/remyelinated axons (primary demyelination) in the the mixed (borderline) type. Protective immunity in leprosy
middle of inflammatory cells (Red arrows). Fibers with normal myelin
also seen (yellow arrow) (Mag. X 100).
is also cell-mediated, being modulated by genes of the
HLA complex, particularly the HLA-DR2 loci.53 A major
susceptibility locus has recently been mapped to
chromosome 10p13 in Indian patients.
AUTOIMMUNE TYPE OF DAMAGE

As early as 1964, Lumsden had suggested that the
damaged nerves in leprosy may liberate autoantigens that
can later sensitize and damage other nerve trunks even in
the absence of bacilli or inflammatory cells.12 After the
initial damage, myelin proteins would be expected to be
released and exposed to immune system and since M.
leprae has a powerful adjuvant activity, autosensitization
to myelin proteins may be anticipated. Antibody response
to peripheral nerve antigens has been investigated by
several workers.
Through a functional assay Shetty et al demonstrated
presence of demyelinating antibodies in 20% of the
randomly chosen serum samples, after intraneural injection
of test serum in the mouse.54 The exact specificity of these
Fig. 19.4: Part of radial nerve from a longstanding lepromatous leprosy factors was not clear. Unlike the experimental allergic
patient under electron microscope. Denervated and totally attenuated neuritis (EAN) model, active participation of macrophages
Schwann cells surrounded by dense collagen (C) are seen. Large in myelin stripping was not seen in this study using the
number of solidly stained bacilli are seen within the Schwann cells
electron microscope. Mshana and co-workers did not find
(arrow) (X15000)
antibodies to bovine peripheral myelin protein P2 and were
unable to detect lymphocyte transformation in response
IMMUNOLOGICAL ASPECTS
to bovine P2 in lymphocytes from leprosy patients.55,56
OF NERVE DAMAGE
Eustis-Turf and co-workers demonstrated the presence of
There is only one species of M. leprae; and the human antibodies to intermediate neural proteins in the serum of
host knows only one way to respond to it; though that way some of the leprosy patients. No cross reactivity was seen
is modified greatly by the hosts immune state, a state between antibodies to M.leprae and nerve tissue antigen.
CHAPTER
19
It was deduced that the antibodies were produced as an antigenic cross reactivity between Bacille Calmete Guerin
autoimmune response to nerve fiber damage and were not (BCG) and M. leprae using this technique.66,67 Several
likely to play a primary role in nerve pathology.57 group of workers, (Mshana et al55; Barros et al68; Khanolkar
Thomas and Mukherjee using the ELISA technique et al69; Shetty et al38) demonstrated the presence of
reported the presence of antineural antibody directed mycobacterial antigen in the skin and nerve biopsies of
against human peripheral nerve sonicate (PNS) in high treated tuberculoid and lepromatous leprosy patients, in
titres and frequency along the spectrum of the disease. the absence of morphologically demonstrable bacilli. A
Their postulation was that these antibodies might be study by Shetty et al demonstrated the presence of BCG
playing a role in complement-mediated cytotoxicity.58 cross reactive antigens in the absence of acid-fast
Similar studies by two other groups, however, have failed organsims in 50-60% of tuberculoid nerve lesions.70
to consistently find antibodies against neural antigens.59 Experimental studies have shown that M. leprae antigens
One of the studies failed to reveal any relationship between
can evoke cell mediated hypersensitivity. 56 This
neuropathy in leprosy and the levels of serum anti PNS
corroborates with the finding of purified protein derivative
antibodies.60
(PPD) and M.leprae specific (T-cell) lymphocytes in
A qualitative and quantitative morphological study
granulomas of paucibacillary patients. Recent studies on
investigating the pattern of nerve degeneration in leprous
the other hand suggest that M leprae as well as its antigens
nerves along the spectrum also fails to support the
bring about deregulation of MAP kinases and
hypothesis of an autoimmunological basis for nerve
pathology in leprous lesions.50,13 These studies have shown dephosphorylation of high and medium molecular weight
that macrophages do not take any part in the myelin neurofilament proteins.71,72 Thus, it is plausible that the
stripping as is the case in experimental allergic neuritis persisting antigens may interfere with the functions of the
(EAN) and acute inflammatory demyelinating poly- regulatory enzymes leading to hypophosphorylation. This
radiculoneuropathy (AIDP). Further, it was opined that a may explain the manner in which nerve degeneration
marked difference in the degree of nerve fiber involvement continues to occur after treatment with anti-leprosy drugs65
between adjacent fascicles, a characteristic feature of and even after corticosteroids.
leprous nerves particularly in the borderline spectrum, is
also not consistent with an autoimmune process of the ROLE OF INFLAMMATORY CYTOKINES
EAN type.13 IN NERVE DAMAGE
The Schwann cell as an antigen presenting cell, has
been proposed and investigated by some.61 Studies using The influx of inflammatory cells in the secondary stage of
electron microscope failed to show major histocompatibility nerve damage is associated with the release of a variety
complex (MHC) Class II expression by the Schwann cells of tissue damaging cytokines. Transforming growth factor
both, in experimental leprous granuloma and human leprosy beta (TGF-β) is a potent immunosuppressive cytokine
lesions.62,63 A similar study by Atkinson and co-workers secreted by inflammatory cells such as epithelioid cells,
also revealed expression of (MHC) Class II antigen by giant cells, activated lymphocyte as well as Schwann cells.
endothelial and perivascular cells but not on Schwann cells TGF-β has the potential to influence all phases of the
in leprosy and other human peripheral neuropathies.36 pathogenesis of infectious disease as an important
regulator of development and modulator of inflammation,
ROLE OF MYCOBACTERIAL ANTIGENS and wound healing. However TGF-β can also be exploited
IN NERVE DAMAGE by the pathogen during entry, replication and persistence
Leprosy is effectively treated with combination of 3 drugs in the host. Increased levels of TGF-β have been reported
and it has been shown that a single dose of Rifampicin in all forms of leprosy and the levels increase from
kills over 99.9% of the bacilli.64 However, nerve damage tuberculoid to lepromatous.73 It has been suggested that
continues to occur even after the treatment completion TGF-β controls the influx of inflammatory cells by down
and killing of almost all M.leprae.65 regulation of TNF-α, INF-γ as well as through inhibition of
Advances in immuno-histochemistry techniques have inducible nitric oxide synthase (iNOS) induction by
made it possible to detect M.leprae by indirect methods macrophages which in turn promotes the bacterial
other than acid-fast staining. Harboe et al demonstrated multiplication.74
CHAPTER
19
Rook and co-workers have proposed that the nerve of atrophic changes in leprous nerves.13,49 Cytoskeletal
damage itself may interrupt normal endocrine feedback protein metabolism was also studied in the mouse sciatic
that can limit inflammation, thus allowing the local nerve model as an adjunct to human studies. It was noted
inflammation to persist.75 In consonance with this, down that inoculation into the footpad with both viable and heat
regulation of gene expression for the enzymes that convert killed M.leprae invoked structural and biochemical changes
cortisone to cortisole has been observed in skin lesions at in the axon-cytoskeletal proteins, similar to those seen in
the onset of type1 reaction where maximum damage to human nerves. While inoculation with heat killed M. leprae
the nerves occur.76 This implies that nerves may not only resulted in early onset but transient changes, with viable
be the targets of inflammation in leprosy, directly or bacilli; though changes occurred later; but were persistent.71
indirectly but their destruction may enhance the intensity These findings suggest the interplay between M. leprae /
or duration of inflammatory process. antigens and the host factors. In leprous neuropathy the
focus has always been on Schwann cells since they are
INSIDIOUS NERVE DAMAGE the main hosts for M. leprae. Results from the above studies
indicate that it is the axon that is the primary target for
In leprosy, neural dysfunction frequently commences and M.leprae driven changes. This also gives clues as to how
progresses so insidiously and painlessly, that the patient ‘insidious’ nerve damage might be occurring in leprosy.
is unaware of abnormality till it is quite advanced. Two recently published large cohort studies that applied
Srinivasan et al first drew attention to the frequency of sophisticated clinical and electrophysiological methods to
this phenomenon, where 80% of patients reported that detect nerve function impairment, further show the
motor deficit had progressed “quietly”.77,78 In a longitudinal magnitude of such problem and confirm that leprous
study by van Brakel and Khawas in Nepal, “silent neuropathy is more diffuse than envisaged.14,80
neuropathy” (defined clinically as demonstrable nerve
function impairment (NFI) using monofilament (MF) and
LEPROSY REACTIONS AND NERVE
voluntary muscle testing (VMT) was reported in 7% of 536
DAMAGE
new patients, and in 21 months of follow-up, the annual
incidence rate of “silent nerve damage” was 4%, most In leprosy, the peripheral nerve is damaged not only by
commonly during the first year of chemotherapy.79 “silently occurring neuropathy”, but also as a result of
On the other hand using more sensitive test like nerve immunologic episodes known as “leprosy reactions”.
conduction study (NCS) parameters, NFI was detected in Patients with MB leprosy are more prone to these
91% of MB patients with no history of neuritis or reaction complications. Reactions may be cutaneous or neural or
in the past.80 So it is plausible that most part of the nerve combined cutaneous-neural. An acute inflammation in a
damage in leprosy is insidious in nature and episodes of pre-existing nerve lesion results in a rapid and severe nerve
reaction/ neuritis add more severity to the ongoing process. damage. Reactions are divided into two main types namely;
The question of when and how the nerve damage occurs type1 (T1R) and type 2 (T2R) on the basis of clinical and
in leprosy has been addressed in several of the immunological characteristics, but they have shown
morphological and functional correlative studies in leprosy. commonalities such as episodicity; sometimes progressing
As early as 1980, morphological abnormalities were to chronicity, induction of nerve pain/ tenderness and nerve
described in nerve, at a distance from skin lesions in all function impairment.
types of leprosy, which were unrelated to the presence of The relationship of leprosy reactions, both T1R and
M.leprae or of significant cellular infiltration.13 This is in T2R, to nerve damage is well recognized, although the
agreement with the insidiously occurring nerve damage trigger for reaction is unknown. 79 High levels of
discussed above. One of the frequent abnormalities inflammatory cytokines are associated with poor clinical
recorded, and was common to both tuberculoid and response to steroid treatment and recurrent episodes of
lepromatous nerves, were axonal atrophy (Fig. 19.2). type1 reaction. Manandhar et al and Sarno et al have tried
Underlying causes of these atrophic changes in the nerve to correlate nerve damage, reaction and cytokine
fibers have been further investigated by the same group. levels.81,82 They noted that MB patients with predominant
Alteration in the axonal cytoskeletal proteins in the form nerve reactions presented with elevated serum
of hypophosphorylation was demonstrated as the cause concentrations of TNF-α. Similar observations were made
CHAPTER
19
in MB patients with skin reactions even in the absence of such damage might be occurring? Though it requires further
neurological complaints. Elevated levels of TNF-α were probing, most logical explanation seems to be that; through
also detected in patients whose neurological grades M.leprae induced deregulation of MAP kinases that
worsened in the course of MDT. Evidence suggests synergy produces dephosphorylation of axonal cytoskeletal
between the elevated levels of both interferon gamma proteins, it results in axonal atrophic changes and slow
(IFN-γ) and TNF-α in skin lesions of both T1R and T2R. progressive secondary demyelination. Inflammation,
There is evidence, for example, of the expression of episodes of reactions and other secondary factors such
activation molecules as a consequence of induction of as anatomical and physiological dispositions add further
genes that are normally induced by these cytokines to the severity and magnitude of ongoing nerve damage.
including intracellular cell adhesion molecule (ICAM-1) and
HLA-DR; the later expressed on keratinocytes and ICAM- Suggested Reading
1 on endothelial cells. It is now widely accepted that over 1. Antia NH and Shetty VP (Eds). The peripheral nerve in
expression of integrins on endothelial cell surface is one leprosy and other neuropathies, Delhi; Oxford University
of the first step in immunoinflammatory cascade. These Press 1997.
events in association with the expression of activation 2. Pandya SS, Shetty VP. The neuropathy of leprosy. In :
molecules in circulating leukocytes; that are also induced Wadia Noshir H (Ed). Neurological Practice: An Indian
by the IFN-γ and TNF-α, determine at least partially the Perspective: Elsevier.
characteristics of the inflammatory cells present in the
lesions. Why neutrophils are preferentially activated during ACKNOWLEDGMENTS
T2R is not yet clear. Besides enhancing the pro-
inflammatory activity of leukocytes and endothelial cells, I am grateful to my mentor (Late) Dr NH Antia. He was
always; and will remain a source of inspiration for me.
TNF-α has been implicated as cytotoxic or myelinotoxic
I would like to thank Ms Fatema Khambati for her help in
in experimental systems and diseases of the nervous
organizing this manuscript.
system such as multiple sclerosis.83
REFERENCES
CONCLUSION
1. Perry VH, Andersson PB, Gordon S. Macrophages and
Three main factors that contribute to nerve damage in inflammation in the central nervous system. Trends Neurosci
leprosy are (1) the infection (2) hosts immune response 1993;16:268-73.
2. Carter HV. On the symptoms and morbid anatomy of leprosy
and (3) special anatomical and physiological dispositions
with remarks. Trans Med Phy Soc Bom 1863; 8 (new series):1-
of the nervous system. The descriptions of sequence of 104.
events and pathomechanisms are indeed based on several 3. Dehio K. On the lepra anaesthetica on the pathogenetical relation
sound documentations and findings in humans and are of the disease appearances. Transl. Biswas MG. Lepr India 1952;
24:78-83.
also supported by the experimental findings, but is no where 4. Dastur DK. Leprosy (an infectious and immunological disorder
near perfect to explain all the events and their of the nervous system). In: Vinken PJ, Bruyn GW (Eds). Infections
consequences. of the nervous system. Amsterdam: North Holland Publishing
It is apparent that when the infection manifests as Company, 1978;1:421-68.
5. Ermakova N. Studies on Leprosy: The central, sympathetic and
disease there has already occurred damage to the
peripheral nervous systems. Int J Lepr 1936;4:325-36.
peripheral nerves. It is the sensory compartment of the 6. Job CK, Desikan KV. Pathologic changes and their distribution in
nerve that is largely affected in leprosy. The motor fiber peripheral nerves in lepromatous leprosy. Int J Lepr 1968; 36:257-
involvememt occurs as a byproduct of damage to the mixed 70.
7. Tze-chun L, Ju-shi Q. Pathological findings of peripheral nerves,
nerve. Infection of the Schwann cells of nonmyelinated
lymph nodes and visceral organs of leprosy. Int J Lepr
fibers by M.leprae, is one of the characteristic features, 1984;52:377-83.
but is not a prerequisite to the induction of nerve damage. 8. Aung T, Kitajma S, Nomoto M, et al. Mycobacterium leprae in
In order of sequence, nonmyelinated fibers are the first to neurons of the medulla oblongata and spinal cord in leprosy. J
Neuropathol Exp Neurol 2007;66:284-99.
show structural and functional abnormality but Nerve 9. Khanolkar VR. Studies in the histology of early lesions in Leprosy.
damage is not only confined to the site of M. leprae Indian Council of Medical Research Special Report Series.
infection, but is lot more diffuse than envisaged. How then No.19.New Delhi, 1951.
CHAPTER
19
10. Nishiura M. The electron microscopic basis of the pathology of 32. Shetty VP, Antia NH. A semiquantitative analysis of bacterial load
leprosy. Int J Lepr 1960;28:357-400. in different cell types in leprous nerves using transmission
11. Weddell AGM, Palmer E. Recent investigations into the sensory electron microscope. Ind J Lepr, 1996;68:105-08.
and neurohistological changes in leprosy. In: Cochrane RG, 33. Mukherjee A, Mishra RS, Meyers WM. An electronmicroscopic
Davey TF (Eds). Leprosy in theory and practice. Bristol: John study of lymphatics in the dermal lesions of human leprosy. Int J
Wright and Sons 1964:205-20. Lepr 1989;57:506-10.
12. Lumsden CE. Leprosy and the schwann cell in vivo and in vitro. 34. Hastings R, Brand PW, Mansfield RE, et al. Bacterial density of
In: Cochrane RG, Davey TF (Eds). Leprosy in theory and the skin in lepromatous leprosy as related to temperature. Lepr
practice. Bristol: John Wright and Sons 1964:221-50. Rev 1968;39:71-74.
13. Shetty VP, Antia NH, Jacobs JM. The pathology of early leprous 35. Ridley DS, Ridley MJ. Classification of nerves is modified by the
neuropathy. J Neurol Sci 1988;88:115-31. delayed recognition of Mycobacterium leprae. Int J Lepr
14. van Brakel WH, Nicholls PG, Das L, et al. The INFIR Cohort 1986;54:596-606.
study: Assessment of sensory and motor neuropathy in leprosy 36. Atkinson PF, Perry ME, Hall SM, et al. Immuno-electron-
at baseline. Lepr Rev 2005;76:277-95. microscopical demonstration of major histocompatibility class II
15. Thomas RE. An investigation into paralysis in the forearm and antigen: Expression on endothelial and perivascular cells but
hand in leprosy. Lepr Rev 1954;25:11-15. not schwann cells in human neuropathy. Neuropathol Appl
16. Sabin TD, Hackett ER, Brand PW. Temperatures along the course Neurobiol 1993;19:22-30.
of Certain Nerves often affected in lepromatous leprosy. Int J 37. Boddingius J. Mechanisms of peripheral nerve damage in leprosy:
Lepr 1974;42:38-42. Electron and light microscopic studies in patients throughout the
17. Brand PW. Temperature variation and leprosy deformity. Int J spectrum. Quad Cooperations Sanitaria (Bologna) 1982;65-84.
Lepr 1959;27:1-7. 38. Shetty VP, Suchitra K, Uplekar MW, et al. Persistence of
18. Sunderland S. The internal anatomy of nerve trunks in relation to Mycobacterium leprae in the peripheral nerve as compared to
the neural lesions of leprosy. Observations on pathology, the skin of multidrug treated leprosy patients. Lepr Rev 1992;
symptomatology, and treatment. Brain 1973;96:865-88. 63:329-36.
19. Palande DD. Surgery of ulnar nerve in leprosy. Lepr India 1980; 39. Choudhary A, Mistry NF, Antia NH. Blocking of M.leprae
52:74-88. adherence to dissociated Schwann cells by anti-mycobacterial
20. Dastur DK, Porwal GL, Shah JS, et al. Immunological implications antibodies. Scand J Immunol 1988;30:505-09.
of necrotic cellular and vascular changes in leprous neuritis: 40. Rambukkana A, Yamada H, Zanazzi G, et al. Role of alpha
light and electron microscopy. Lepr Rev 1982;53:45-65. dystroglycan as a schwann cell receptor for Mycobacterium
21. Carayon A. Investigations on the physiopathology of the nerve leprae. Science 1998;282:2076-79.
in leprosy. Int J Lepr 1971;39:278-94. 41. Save MP, Shetty VP. A critique on commentary “How
22. Weddell G, Palmer E. The pathogenesis of leprosy: an Mycobacterium leprae infects peripheral nerves” by Weinstein
experimental approach. Lepr Rev 1963;34:57-61. F, Freedman VH, Kaplan G. Lepr Rev 2001;72:102-05.
23. Mukherjee R, Antia NH. Intracellular multiplication of leprosy 42. Lindsay RM, Harmar AJ. Nerve growth factor regulates
derived mycobacteria in Schwann cells of dorsal root ganglion expression of neuropeptide genes in adult sensory neurons.
cultures. J Clin Microbiol 1985;21:808-14. Nature 1989;337:362-64.
24. Pallen MJ, McDermott RD. How might Mycobacterium leprae 43. Karanth SS, Springall DR, Lucas S, et al. Changes in nerves and
enter the body? Lepr Rev 1986;57:289-97. neuropeptides in skin from 100 leprosy patients investigated by
25. de Vries RRP. HLA and leprosy type. In: Chatterjee BR (Eds). immunocytochemistry. J Pathol 1989;157:15-26.
Leprosy: Etiobiology of manifestations, treatment and control. 44. Anand P, Pandya S, Ladiwala U, et al. Depletion of nerve growth
Calcutta: Statesman Commercial Press 1993:152-58. factor in leprosy. Lancet 1994;344:129-30.
26. Dastur DK, Ramamohan Y, Shah JS. Ultrastructure of 45. Singh N, Birdi TJ, Antia NH. Nerve growth factor production and
lepromatous nerves – neural pathogenesis in leprosy. Int J Lepr expression of p75 by Schwann cells and neurofibroblasts in
1973;41:47-80. response to M. leprae infection and macrophage secretory
27. Drutz DJ, Chen TS, Lu WH. The continuous bacteremia of products. Neuropathol Appl Neurobiol 1997;23:59-67.
lepromatous leprosy. New Eng J Med 1972;287:159-64. 46. Job CK. Pathology of peripheral nerve lesions in lepromatous
28. Chatterjee G, Kaur S, Sharma VK et al. Bacillaemia in leprosy leprosy- A light and electron microscopic study. Int J Lepr
and effect of multidrug therapy. Lepr Rev 1989;60:197-201. 1971;39:251-68.
29. Scollard DM, McCormick, Allen JL. Localization of 47. Swift TR. Peripheral nerve involvement in leprosy: Quantitative
Mycobacterium leprae to endothelial cells of epineurial and histologic aspects. Acta Neuropathol 1974;29:1-8.
perineurial blood vessels and lymphatics. Am J Pathol 1999; 48. Shetty VP, Shetty KT, Save MP, Antia NH. M. leprae-induced
54:1611-20. alterations in the neurofilament phosphorylation leads to
30. Antia NH. The significance of nerve involvement in leprosy. Plast demyelination in leprous nerves: A Hypothesis. Indian J Lepr
Reconst Surg 1974;54:55-63. 1999;71:121-35.
31. van Brakel WH, Nicholls PG, Das L, Barkataki P. The INFIR 49. Save MP, Shetty VP, Shetty KT, Antia NH. Alterations in
Cohort study: Investigating prediction, detection and neurofilament protein(s) in human leprous nerves: Morphology,
pathogenesis of neuropathy and reactions in leprosy. Methods immunochemistry and western immunoblot correlative study.
and baseline results of a cohort of multibacillary leprosy patients Neuropath Appl Neurobiol doi: 10.1111/j.1365-
in North India. Lepr Rev 2005;76:14-34. 2990.2004.00578.X.
CHAPTER
19
50. Jacobs JM, Shetty VP, Antia NH, et al. Teased fibre studies in 68. Barros U, Shetty VP, Antia NH. Demonstration of M. leprae antigen
leprous neuropathy J Neurol Sci 1987;79:301-13. in nerves of tuberculoid leprosy. Acta Neuropathol.1987;73:387-
51. Job CK. Nerve damage in leprosy. Int J Lepr 1989;57:532-39. 92.
52. Ridley DS. Differential pathology of dermis and nerve in leprosy. 69. Khanolkar VR, Mackenzie CD, Lucas SB, et al. Identification of
In: Antia NH, Shetty VP, (Eds). The peripheral nerve in leprosy and M. leprae antigens in tissues of leprosy patients using monoclonal
other neuropathies, Delhi: Oxford University Press;1997: 138-50. antibodies. Int J Lepr 1989;57:652-58.
53. Siddiqui MR, Meisner S, Tosh K, et al. A major susceptibility 70. Shetty VP, Uplekar MW, Antia NH. Immunological localization of
locus for leprosy in India maps to chromosome 10p13. Nat mycobacterial antigens within the peripheral nerves of treated
Genet 2001;27:439-41. leprosy patients and their significance to nerve damage in
54. Shetty VP, Mistry NF, Antia NH. Serum demyelinating factors leprosy. Acta Neuropathol 1994;88:300-06.
and adjuvant-like activity of M. leprae possible causes of early 71. Save MP, Shetty VP, Shetty KT. Hypophosphorylation of NF-H
nerve damage in leprosy. Lepr Rev 1985;56:221-27. and NF-M subunits of neurofilaments and the associated
55. Mshana RN, Harboe M, Stoner GL, et al. Immune responses to decrease in KSPXK kinase activity in the sciatic nerves of Swiss
bovine neural antigens in leprosy patients. I. Absence of antibodes white mice inoculated in the foot pad with Mycobacterium leprae”.
to an isolated myelin protein. Lepr Rev 1983a;54:33-40. Submitted to Lepr Rev 2008.
56. Mshana RN, Humber DP, Harboe M, et al. Immune response to 72. Save MP, Shetty VP, Shetty KT. Study of phosphokinase activity
bovine neural antigens in leprosy patients. II. Absence of in vitro in the sciatic nerves of S/W mice inoculated in the hind foot pads
lymphocyte stimulation of peripheral nerve myelin proteins. Lepr with viable M. leprae, heat killed M. leprae and M. leprae antigens
Rev 1983b;54:217-27. MLSA and PGL-1. Submitted to Lepr Rev 2008.
57. Eustis-Turf EP, Benjamins JA, Lefford MJ. Characterization of 73. Khanolkar Young S, Snowdon D, Lockwood DN.
the anti-neural antibodies in the sera of leprosy patients. J Immunocytochemical localization of inducible nitric oxide
Neuroimmunol 1986;10:313-30. synthase and transforming growth factor-beta (TGF-b) in leprosy
58. Thomas BM and Mukherjee R. Antineural antibodies in sera of lesions. Clin Exp Immunol 1998;113;438-42.
leprosy patients. Clin Immunol Immunopathol 1990;57:420-29. 74. Naafs B. Treatment of reaction and nerve damage. Int J Lepr
59. Ghaswala PS, Mistry NF, Antia NH. Serum antibodies of normals 1996;64:S21-S28.
and leprosy patients show equal binding to peripheral nerve. Int 75. Rook GA, Lightman SL, Heijnen CJ. Can nerve damage disrupt
J Lepr 1989;57:690-92. neuroendocrine immune homeostasis? Leprsoy as a case in
60. Chujor CS, Bernheimer N, Levis WR, et al. Serum IgA and IgM point. Trends Immunol 2002;23:18-22.
antibodies against M. leprae derived phenolic glycolipid - I: A 76. Anderson AK, Atkinson SE, Khanolkar Young S, et al. Alterations
comparative study in leprosy patients and their contacts. Int J in the control-cortisone shuttle in leprosy type1 reaction patients
Lepr 1991;59:441-49. in Hyderabad, India. Immunol 2007;104:72-75.
61. Wekerle H., Schwab M., Linington C, et al. Antigen presentation 77. Srinivasan H, Rao KS, Shanmugam N. Steroid therapy in recent
in the peripheral nervous system: Schwann cells present “quiet nerve paralysis’ in leprosy. Report of a study of twenty
endogenous myelin auto antigens to lymphocytes. Eur J Immunol five patiens. Lepr India 1982;54:412-19.
1986;16:1551-57. 78. Srinivasan H, Gupte MD. Experiences from studies on quiet
62. Cowley SA, Butter C, Verghese S, et al. Nerve damage induced nerve paralysis in leprosy patients.In: Antia NH, Shetty VP, (Eds).
by mycobacterial granulomas in guinea pig sciatic nerves. Int J The peripheral nerve in leprosy and other neuropathies. Delhi:
Lepr 1988;56:283-90. Oxford University Press, 1997:30-35.
63. Cowley SA, Butter C, Gschmeissner SE, et al. An immunoelectron 79. van Brakel WH, Khawas IB, Lucas SB. Reactions in leprosy: An
microscopical study of the expression of major histocompatibility epidemiological study of 386 patients in West Nepal. Lepr Rev
complex (MHC) ClassII antigens in the guinea pig sciatic nerve 1994;65:190-203.
following induction of intraneural mycobacterial granuloma. J 80. Khambati FA, Shetty VP, Ghate SD, et al. The effect of
Neuroimmunol 1989;23:223-31. corticosteroid usage on the bacterial killing, clearance and nerve
64. Grosset JH. Progress in the chemotherapy in leprosy. Int J damage in leprosy. A prospective cohort study: Part 1 - study
Lepr 1994;62:268-77. design and baseline findings of 400 multibacillary patients. Lep
65. Croft RP, Nicholls PG, Richardus JH, et al. Incidence rates of Rev 2008;79:1-21.
acute nerve function impairment in leprosy: A prospective cohort 81. Manandhar R, Shreshtha CR, Butlin CR, et al. High levels of
analysis after 24 months. (The Bangladesh Acute Nerve Damage infalmmatory cytokins are associated with poor clinical response
Study). Lepr Rev 2000;71:18-33. to steroid treatment and recurrent episodes of type 1 reactions
66. Harboe M, Closs O, Bjorvatn B, et al. Antibodies against BCG in leprosy. Clin Exp Immunol 2002;128:333-38.
antigen 60 in mycobacterial infections. Brti Med J 1977;2:430-33. 82. Sarno EN, Sampaio EP. Role of inflammatory cytokines in the
67. Harboe M, Mshana RN, Closs O, et al. Cross reactions between tissue injury of leprosy. Int J Lepr 1996;64:S69-S74.
mycobacteria. II: Crossed electrophoretic analysis of soluble 83. Selmaj KW, Raine CS. Tumor necrosis factor mediates myelin
antigens of BCG and comparison with other mycobacteria. Scand and oligodendrocytes damage in vitro. Ann Neurol 1988;23:
J Immunol 1979;9:115-24. 339-46.
CHAPTER
20
20
Methods of Nerve Examination
BK Girdhar
INTRODUCTION acute, it may result in further and even permanent damage

to the nerve.
Leprosy is considered to be primarily a disease of the
Thus, thickening of nerves, with or without tenderness
nerves and it is the Schwann cell which plays a host to
on palpation, is an important clinical feature of leprosy.
M leprae. In leprosy the nerve damage is largely limited
Indeed, nerve thickening is one of the three cardinal signs
to the peripheral nerves and it is because of damage to
for diagnosis of leprosy. Therefore, in leprosy examination
the nerves that disabilities, deformities and stigma results.
of commonly affected nerves, as also their functional
All the three functions of the nerves, viz. sensory, motor
assessment is important for evaluation and taking decision
and autonomic can get affected. Damage to the nerves about diagnosis, classification, type of leprosy and the
(due to inflammatory response and/or bacilli) results in line of treatment. This is more so for the diagnosis of pure
varying degrees of sensory and motor deficit in the region neuritic leprosy, where the diagnosis is totally based on
supplied by the affected nerve(s). Because of nerve finding of nerve function deficit and thickened nerves.
damage, secondary manifestations such as deformities, Equally important is the examination of nerves for
trophic changes, ulcers, blisters, etc. are seen on the skin. classification of leprosy patients into PB/MB groups as
Despite being a generalized infection, not all the nerves also in assessing the risk of deformities and planning
get affected in leprosy. Only the peripheral nerves bear preventive measures.
the brunt of damage and this in turn appears to be limited
to certain segments of the nerve. It has been observed NERVE EXAMINATION
that the so called sites of predilection of nerve damage
Before one starts nerve examination, it is essential to have
correspond to the sites where the nerves are most some knowledge of the surface anatomy of peripheral
superficial, without the cover of the muscle mass and hence nerves. All cadres of medical and paramedical workers,
cooler. This is possibly due to the localisation of M. leprae involved in leprosy work are expected to know where and
in these segments having relatively lower temperature. how to palpate greater auricular, ulnar, radial, median,
Another possible reason for nerve damage at these sites common peroneal (lateral popliteal), superficial peroneal
is that here, the nerves lie near or across the joints and and posterior tibial nerves. In addition to above, the medical
hence prone to frequent microtrauma due to stretching. officers working in leprosy are required to know the surface
Further, at these sites, the nerves pass through tough location of other important nerves. These include
fibro-osseous tunnels. Any inflammation here, presses supratrochlear and supraorbital nerves in the forehead,
upon the blood supply of both affected (damaged) and facial and its zygomatic branch on the side of face,
unaffected nerve fibers to result in nerve ischemia and supraclavicular nerves over the clavicle, radial cutaneous
damage. Local inflammation results in nerve thickening. and dorsal cutaneous branch of ulnar at the wrist, three
Sudden increase in inflammation and inflammatory edema antebranchial cutaneous nerves in the upper limb, the three
in the nerve may give rise to varying degrees of pain and cutaneous nerves in the thigh, infrapatellar nerve at the
/or nerve tenderness on palpation, and if the process is knee and the sural nerve in the lower leg posteriorly.
CHAPTER
20
Methods of Nerve Examination 249
Apart from the above named nerves, areas around and
in particular, proximal to the patch or loss of sensation,
must be examined for any thickened named or un-named
cutaneous nerves.
For ease of nerve examination, the patient should
preferably be seated on a stool. Nerve palpation should be
done by the pulp of fingers and not by the tip of the digits.
The two sides should be compared to detect any difference
and abnormality. Initially, a gentle palpation is done, if no
tenderness is observed, mild pressure could be applied
on the nerves. While palpating the nerves, following points
are noted:
1. Tenderness—if present, its severity.
2. Thickness—whether normal or thickened: if thickened, Fig. 20.1: Examination of ulnar nerve
the degree of thickness.
3. Consistency—soft, normal, firm or hard.
4. Regularity—smooth or regular. If swelling is present its
extent, nature-uniform, sausage shaped or beaded,
whether the swelling is solid or fluctuant.
PALPATION OF NERVE TRUNKS

Ulnar Nerve
To palpate ulnar nerve, the elbow is flexed at 70-80o. For
right ulnar nerve, holding the patient’s hand/wrist in the left
hand, right hand is placed on the elbow and with the fingers
coming from below, medial epicondyle of the humerus is
located with little and ring finger. Palpation of ulnar nerve
can be made, in line above the epicondyle with the Fig. 20.2: Examination of median nerve. The patient can be asked to
remaining fingers (Fig. 20.1). For left ulnar nerve, patient’s flex the hand forcefully at wrist joint, which makes the tendon of palmaris
longus prominent. The nerve is palpated just medial to the tendon
hand is held in the right hand and palpation made as above
with the left hand. In our experience, palpating the ulnar
nerve is easier from the medial side. However, some
workers find it more convenient to palpate the nerve with
Radial Nerve
their fingers coming from the lateral side of elbow. With elbow partially flexed and the arm held in position
with shoulder internally rotated, radial groove at the insertion
Median Nerve of deltoid muscle is identified. For right radial nerve, fixing
In leprosy, the median nerve may also get inflamed and the flexor muscle mass with left thumb, the pulp of the
thickened. This occurs little above or at the wrist. To fingers is pressed deep in the radial groove to palpate the
examine the nerve, palmaris longus tendon is located by radial nerve (Fig. 20.3). The left radial nerve is palpated
asking the patient to flex the wrist against resistance. with the right hand in the similar manner. Tingling down
Median nerve lies slightly deeper and medial to above the course or local tenderness can be taken as guide.
tendon (Fig. 20.2). As this muscle is absent in almost
30% of the individuals, nerve can be located in line with
Common Peroneal (Lateral Popliteal) Nerve
the ring finger just above the creases of the wrist. Tingling/ With patient sitting on the stool and knees bent or standing
tenderness can be used in confirming palpation of the with knees slightly bent, both the nerves can be
nerve. simultaneously palpated by the examiner sitting in front of
CHAPTER
20
Fig. 20.3: Examination of radial nerve Fig. 20.5: Examination of posterior tibial nerve
is to put both the thumbs on the side of the nose and the
index fingers in front of the ear lobule and bring the fingers
anteriorly across the zygoma. Thread like structures in the
middle of arch and a twitching of corresponding eyelid
confirms the nerve.
PALPATION OF CUTANEOUS NERVES

Superficial cutaneous nerves more often get thickened if;
there is a lesion in the distribution/region of their sensory
supply. Thickening of one or more cutaneous nerves may
be the only confirmatory sign of leprosy. In general, when
thickened, the nerves are visible and / or palpable especially
Fig. 20.4: Examination of common peroneal nerve
when the skin over them is tightened. The normal nerve
may also be visible in muscular individuals, e.g. in
him. The thumbs are placed on the tibial tuberosities and sportsmen and laborers.
the fingers on the lateral aspects of the knees. Fibular
head is located and the nerves are palpated just below it Great Auricular Nerve
both posteriorly and winding round insertion of biceps To assess the status of this nerve, the head is turned to
femoris muscle on the neck of the bone (Fig. 20.4). the opposite side as much as comfortably possible to
stretch the sternomastoid muscle (Fig. 20.6). The nerve
Posterior Tibial Nerve is seen to cross the upper third of the muscle. In thin
With the ankle in the neutral position, the nerve can be individuals and those with very little fat, the nerve is visible
palpated at the midpoint between medial malleolus and as such. The nerve may also be visible in healthy muscular
the tuberosity of calcaneum (Fig. 20.5). individuals.
Facial Nerve and its Zygomatic Branch Supratrochlear, Supraorbital and

Infraorbital Nerves
The facial nerve can be palpated just below and front of
the ear lobule. On pressing the site, tenderness of the These branches of trigeminal nerve provide sensory supply
nerve is felt by the patient, if the nerve is affected and to the forehead and the frontal region of the scalp, and
enlarged. The zygomatic branch can be palpated over the area below the eyes. The nerves can be palpated running
middle of the zygomatic bone of the cheek. An easy way vertically up from the junction of medial third and lateral
CHAPTER
20
Methods of Nerve Examination 251
Fig. 20.6: Examination of great auricular nerve Fig. 20.8: Examination of zygomatic branch of facial nerve
two-thirds of the eyebrows (supratrochlear) and at the are visible and/or palpable in borderline (BT) patients
junction of medial two-thirds and lateral one-third (supra- especially when there are lesions in the forearm or hands.
orbital) (Fig. 20.7). The zygomatic branch of facial nerve The medial cutaneous nerve is seen or palpated running
can be palpated below the eyes, lateral to the nose down from the medial side of insertion of biceps towards
(Fig. 20.8). Most often their thickening is associated with the middle of the forearm, often branching and leading into
lesion(s) in the forehead region. When significantly the lesion, if present. The posterior cutaneous starting
thickened, these nerves are mostly visible. almost from the same point, immediately winds round
posteriorly. The lateral cutaneous nerve on the other hand
Supraclavicular Nerves is seen or felt right down the lateral border from mid arm to
The three supraclavicular nerves their branches, when the mid forearm.
thickened can be seen and or palpated going down the
medial, middle and the lateral third of the clavicle on to the Radial Cutaneous Nerve
pectoral area of the chest. This terminal sensory branch of the radial nerve that carries
sensations from lateral half of dorsa of hand, lies at the mount
Cutaneous Nerves of the Forearm of the wrist. The nerve can be palpated easily just above the
The three cutaneous nerves of the forearm—the medial, anatomical snuff box when the hand is held in slight flexion
posterior and the lateral cutaneous nerves, when thickened and the forearm in semiprone position (Fig. 20.9).
Fig. 20.7: Examination of supratrochlear nerve medially over Fig. 20.9: Examination of radial cutaneous nerve
eyebrows. Similarly supraorbital nerve can be palpated laterally
CHAPTER
20
Cutaneous Branch of the Ulnar Nerve

The nerve lies at the base of the fifth metacarpal, just
below the styloid process of the ulna as it comes from
medial to the lateral side and supplies medial half of the
dorsum of hand.
Cutaneous (Medial, Anterior and Lateral)

Nerves of the Thigh
When thickened, the nerves can be palpated in front of
the thigh starting 5-7 cm below the inguinal ligament and
running vertically down the inner side of the thigh, middle
of the thigh and anterolateral aspect of the thigh,
respectively. These nerves are often thickened in borderline Fig. 20.10: Examination of musculocutaneous nerve (superficial
peroneal) nerve. Note the prominent TT leprosy patch in type1 reaction
(especially BT) patients with lesions on the thigh. and the foot drop
Superficial Peroneal Nerve

(Musculocutaneous Nerve)
This nerve carries sensations from greater part of the
dorsum of the foot (with the exception of the adjoining
area between the first and second toe, which is supplied
by medial branch of the deep peroneal nerve from below).
When thickened, the nerve can be seen and palpated in
front of ankle coming towards the 2nd and 3rd toe. Gently
medially rotating and planter flexing the foot makes the
nerve stand out when thickened, especially in nonobese
patients with lesion(s) on the dorsum of the foot
(Fig. 20.10).
Sural Nerve Fig. 20.11: Examination of sural nerve
This cutaneous nerve provides sensory supply to the

ACKNOWLEDGMENT
lateral side of the foot and heel. The nerve may get
thickened if there is lesion in this area. With patient sitting The author thankfully acknowledges the gesture of
straight or standing, the nerve can be palpated running Department of Dermatology, Venereology and Leprology,
along the lower fourth of tendo-Achilles on the back of Dr Ram Manohar Lohia Hospital, New Delhi, for adding the
the leg (Fig. 20.11). clinical photographs in this chapter.
21 Neuritis: Definition, Clinical
Manifestations and Proforma
to Record Nerve Impairment
P Narasimha Rao, Sujai K Suneetha
INTRODUCTION Neuritis Associated with Reactions

Most important consequences of leprosy are due to the Reactions are acute inflammatory episodes which occur
direct result of involvement of peripheral nerves. But for during the course of leprosy and are of two types: Type 1
the involvement of peripheral nerves and consequent or reversal reaction and type 2 or ENL reaction. Although
deformities, leprosy would have been a simple disease neuritis can occur at any time during the course of leprosy;
and definitely; a disease without its stigma. it is more common and severe during these phases of
leprosy reactions and more so during type 1 reactions.
DEFINITIONS Overall the neuritis, that occurs as a consequence of
type 1 and type 2 reactions together; accounts for a
Neuritis/Neuropathy
significant proportion of neuritis and nerve damage
The literal meaning of neuritis is inflammation of nerves. occurring in leprosy.
Although ‘neuritis’ is a pathological term, in parlance of
leprosy it also denotes the clinical involvement of peripheral Neuropathic Pain
nerves. The terms neuropathy and neuritis are used
interchangeably in the leprosy literature and denote the Neuropathic pain (NP) or nerve pain is defined as pain
same process. Neuritis in leprosy is usually a subacute, ‘initiated’ or ‘caused’ by a primary lesion or dysfunction in
demyelinating and nonremitting event involving cutaneous the peripheral or central nervous system. It is caused by
nerves and larger trunks. Invasion of Schwann cells and excessive firing of pain mediating nerve cells that are
axons by M. leprae leads to demyelination and axonal insufficiently controlled by segmental and nonsegmental
degeneration.1,2 inhibitory circuits. It includes a wide spectrum of symptoms,
including paresthesia, dysesthesia, hyperesthesia and
Nerve Damage/Nerve Function allodynia along the nerve and in its area of distribution
Impairment (NFI) which can be quite debilitating. Importance of neuropathic
Nerve function impairment (NFI) and nerve damage are pain in leprosy is being increasingly recognized: (This entity
often used interchangeably to denote the sensory, motor is discussed in detail in the chapter 31 “Management of
and autonomic nerve deficits or a combination of these, Neuritis and Neuropathic Pain”).
those occur as a result of the pathological processes
resulting from infection of the nerve with M. leprae. NEURITIS IN LEPROSY
Silent Neuritis/Quiet Nerve Paralysis Pathological Basis of Neuritis in Leprosy

Silent neuritis or quiet nerve paralysis is defined as Mycobacterium leprae has the unique ability to invade
progressive sensory or motor impairment in the absence peripheral nerves and a special affinity for Schwann cells.
of symptoms such as pain, paresthesia or tenderness of A recent advance in the understanding of pathogenesis of
the nerve and no obvious signs of reaction. leprosy has been the identification of host Schwann cells
CHAPTER
21
proteins that bind to M. leprae. These binding proteins inflammatory cells. The precise mechanisms of axonal
mediate the entry of the organism into the nerve as the damage at the tuberculoid end may differ from those at the
first step in the pathogenesis of the disease. It has been lepromatous end of leprosy.9 Furthermore these changes
shown that the organism binds to the G domain of the are accentuated by leprosy reactions when they occur.
laminin alpha-2 chain which is expressed on the surface
of the Schwann cell-axon unit3 through a receptor on Mechanisms of Neuritis Across the Clinical
M. leprae which was shown to be a 21 kDa histone-like Spectrum of Leprosy
protein.4 This protein, LBP21, coded by the ML1683 gene, It should be noted that involvement of nerves by formation
is a major surface exposed antigen on M. leprae, and of granuloma within them is observed across the leprosy
probably serves as an adhesion for its interaction with spectrum. At the lepromatous end (LL), the granuloma is
peripheral nerves. In addition, a 25 kDa phosphorylated of the typical macrophage type, whereas at the tuberculoid
glycoprotein of human peripheral nerve has been shown end (TT) the granuloma is like that of delayed hyper-
to bind to M. leprae.5 Similarly, the terminal trisaccharide sensitivity type with predominance of epithelioid cells. The
of phenolic glycolipid 1 (PGL-1) which is a surface exposed granulomas consisting of epithelioid cells, Langerhans giant
M. leprae specific antigen, was shown to bind to laminin- cells and lymphocytes infiltrate the nerve followed by
2, indicating that PGL-1 also plays a role in the invasion of destruction of nerve tissue and in some instances there is
M. leprae into Schwann cells.6,7 caseous necrosis.10 In between, in one-third to one-half of
Schwann cells are also found to be actively phagocytic the borderline leprosy cases there may be discordance as
and able to engulf M. leprae. Intact acid-fast bacilli are to the type of granuloma seen in nerves.11 In other words,
found within swollen Schwann cells of unmyelinated nerve when some patients with a histological diagnosis of BT
fibers of lepromatous leprosy patients.8 It is not clear leprosy in the skin were studied, the granuloma in the nerve
however, whether Schwann cells are involved in presenting biopsies showed histopathology of lepromatous leprosy
M. leprae antigens to T cells in vivo, although there are with presence of AFB. In general nonetheless, the cellular
suggestions that they might be able to do so in vitro. infiltrate of granuloma within the peripheral nerves usually
In all forms of leprosy neuropathy, bacilli are first seen mirrors the type of cellular infiltrate seen in the granulomas
lying in Schwann cells without producing any cellular of the skin. When the lesion is paucibacillary, there is
response. Subsequently, they alter the interior milieu of typical epithelioid cells granuloma in the nerve with
the cell producing metabolic and functional changes. The presence of high proportion of CD4 lymphocytes. Where
sequence of events that follows is Schwann cell the lesions are multibacillary, T lymphocytes are less
proliferation, segmental demyelination of the nerve and evident with lowered CD4/CD8 ratio.
ultimately axonal degeneration. Influx of inflammatory cells The cellular infiltrate and the size of granuloma vary
to this site of M. leprae infection, granuloma formation and with the type of leprosy. In the nerve, the cellular infiltrates
accompanying edema, all additively contribute to the in tuberculoid and borderline tuberculoid leprosy are
process and severity of nerve damage. greater than in lepromatous leprosy. The infiltrate and the
The sequence of nerve damage in leprosy is as follows, accompanying edema causes compression of the nerves
M. leprae infection of the Schwann cells triggers the at ‘sites of predilection’ and in fibro-osseous canals causing
immune system resulting in influx of lymphocytes and severe nerve injury, equivalent to crush injury, resulting in
macrophages to the nerve. Release of cytokines and other Wallerian degeneration of the nerve. This explains the more
mediators of inflammation and accompanying inflammatory severe nerve damage observed in tuberculoid leprosy as
edema produce segmental demyelination of the nerves. compared to lepromatous leprosy. Even in lepromatous
The inflammatory cells make an attempt to form granuloma. leprosy extensive segmental demyelination, Wallerian
The volume of the granuloma as well as the intra- and degeneration and axonal degeneration can take place
perineural edema plays a crucial part in causing pressure insidiously. However, concurrently there is some
on the axons and producing axonal damage. The initial regeneration of Schwann cells and small nerve fibers within
axonal damage is predominantly due to the formation of the areas of fibrosis. With passage of time the severe
granuloma within the nerve and subsequently; due to the endoneural fibrosis leads to permanent damage to nerve
release of pharmacological mediators produced by the function. Vascular changes in the nerves are found early
CHAPTER
21
Neuritis: Definition, Clinical Manifestations and Proforma to Record Nerve Impairment 255
in lepromatous leprosy and include development of Mechanism of Neuritis during Reactions
fenestrations (gaps) between endothelial cells of capillaries,
As already explained, type 1 reactions occur due to an
thickening of basement membrane and rarely may progress
enhanced CMI response to the organism or its antigens.
to endarteritis with partial or total occlusion of capillaries.12
The benefit is the containment and localization of infection.
The nerve damage in leprosy is substantiated by
However, there are deleterious effects also in the form of
evidence of some reduction of myelin sheath and loss of
immune mediated damage to the tissues and nerves.
unmyelinated axons in nerves of BT and BL leprosy
During a reaction there is exacerbation of the inflammatory
patients, compared to controls. Also, on the basis of
granuloma in the nerve with marked increase in
immunohistochemistry studies it was observed that there
inflammatory cells infiltrating the nerve and accompanying
is almost a total absence of sensory and autonomic
edema. Damage to smaller cutaneous nerves is mainly
neuropeptide immunoreactivity in nerve fibers across the
due to compression of the nerve fibers due to edema and
leprosy spectrum. Although nerve damage as a result of
neuritis can occur at any time throughout the course of the expanding granuloma, although more complex damage
the disease; it is more severe during the phases of leprosy due to inflammatory mediator release is also implicated in
reactions, especially during type 1 reactions.13 case of larger nerves. The edema which occurs during
The effects of neuritis occur very early during leprosy; reactions increases the pressure inside the larger nerves
they continue during the phase of active disease and could however; the nerve cannot expand much due to the
cause secondary effects long after the disease has been encircling fibrous sheath of perineurium. This leads to the
arrested. compression of the axons in the endoneural fascicles,
Based on the type of pathology, neuritis in leprosy has leading to demyelination, damage to the axons and
been described by Ridley12 as: consequent loss of nerve conduction. If the edema persists,
1. Intrafascicular: Mainly as a result of Schwann cell it causes pressure effects on the vasa-nervorum traversing
involvement. obliquely through the perineurium, compressing the
2. Extrafascicular: Mainly due to reactional episodes. venules, which leads to the dilatation of capillaries within
3. Extraneural: As a result of compression in the fibro- the endoneurium causing further edema. In effect, the
osseous canals due to swelling and edema of the nerve. endoneural blood flow is compromised leading to relative
Essentially, peripheral nerve trunks carry sensory, anoxemia and additional damage.
motor and autonomic nerve fibers within them and when Type 2 or ENL reaction is an immune complex reaction
they are involved, the effects of nerve damage observed wherein, the antigen-antibody complexes are deposited in
clinically are either motor, sensory or autonomic various tissues of the body including the nerves. The
impairments or combination of these, depending on the immune complexes could be formed in the nerve directly
severity of involvement. Nerve function impairment (NFI) with the mycobacterial antigen released locally; or may be
is the term used to denote the outcome of such from the immune complexes in the circulation. The
involvement. inflammation is initiated by the direct activation of alternate
complement pathway by the breakdown products of
Neuritis during Reactions in Leprosy M. leprae and the deposited immune complexes.15 Such
Reactions are acute inflammatory episodes which occur activation leads to migration of polymorphoneuclear
during the course of leprosy. Reactions principally are of neutrophils (PMN) to these sites resulting in increase in
two types; type 1 reaction, also referred to as upgrading edema and inflammation, and further nerve damage.
(reversal) reaction; and type 2 reaction or erythema However, during type 2 reactions, the nerve damage is
nodosum leprosum (ENL) reaction. During type 1 reaction, usually patchy, limited to sites where PMN leukocytes
the inflammatory response in the nerve is due to the infiltrate in significant numbers. In addition, in areas where
increased immunological activity secondary to the nerves are already damaged, the metabolites, free radicals
increased delayed type hypersensitivity (DTH) or cell and cytokines (released due to continued antigen-antibody
mediated immune (CMI) response to mycobacterial deposition and activated PMN leukocytes) play a significant
antigens. During type 2 reaction the inflammatory response part in keeping the inflammation smouldering, leading to
is secondary to circulating immune complexes.14 the chronicity and recurrence of neuritis.
CHAPTER
21
Clinical Presentations (Types) cutaneous component, or the nerves. In a follow-up study

of Neuritis in Leprosy of leprosy patients in Nepal, type 1 reaction was cutaneous
Neuritis or neuropathy in leprosy can broadly be classified in 43% of patients, neural in 24% patients and mixed (both
into four clinical types based on their period of occurrence cutaneous and neural) in 33% of patients.20
and type of presentation. However, it should be noted that Although majority of the patients have single episode
they are not mutually exclusive and can overlap one of neuritis, recurrent episodes of neuritis are known to occur
another. and can cause severe nerve damage. Nerve damage
1. Neuritis associated with the disease. occurs during reactions at various levels: First at the level
2. Neuritis associated with reactions, which are usually of cutaneous nerve endings, second, at the level of sub-
acute and severe. cutaneous nerves, and third, at the level of nerve trunks.
3. Silent neuropathy/quiet nerve paralysis. Damage to the cutaneous and subcutaneous nerves leads
4. Neuropathic pain in leprosy. to increase in the area of loss of sensations; and loss of
autonomic nerve functions such as sweating. Damage to
Neuritis Associated with the Disease nerve trunks is seen as enhanced autonomic effects such
Neuritis in leprosy begins very early in the disease process as increased xerosis and fissuring over the skin of an
with subperineurial edema and some loss of unmyelinated extremity, apart from new motor deficits. Such effects when
axons.8 Clinically, neuritis associated with the disease is they occur in major nerve trunks carrying all three types of
usually chronic and low grade and is due to the presence nerve fibers; sensory, motor and autonomic, such as in
of granuloma and the resulting inflammatory response in posterior tibial, ulnar, median, lateral popliteal and facial
the nerve. It is clear from available pathological evidence nerves, the result is considerable NFI involving all the
that extensive neuropathy is already present before the components—sensory, motor and autonomic.
patient notices any signs and symptoms of neural The type 1 reactions occurring in skin patches at certain
impairment.16 sites, such as face, need special attention as these are
The peripheral neuropathy of leprosy has been associated with a higher frequency of ocular NFI (Fig. 21.1).
neurologically classified by many workers as ‘mononeuritis The significance of facial patches in type 1 reaction for
multiplex’ as it is widespread, but not homogeneous or the development of facial nerve damage in leprosy has
systemic in nature.17 One part of the nerve may show been demonstrated in a study on a large group of PB
extensive destruction, while a nearby section of the same patients.21 Other risk factors for neuritis include large skin
nerve may have an almost normal appearance. Similarly,
among adjacent fascicles some may be affected, others
may appear normal. Since nerves progressively give off
branches in their proximal to distal course, the more
proximal the nerve damage, greater is the likelihood of a
more extensive nerve deficit and sensory loss.18 Apart
from ‘mononeuritis multiplex’, mononeuritis affecting single
nerve trunk without skin lesions is also observed
occasionally in patients of leprosy, categorized under ‘Pure
Neuritic Leprosy’ which is not an uncommon clinical type
of leprosy in India.19
Neuritis Associated with Reactions

Neuritis associated with reactions can occur during both
type 1 and type 2 reactions. However; it is usually more
frequent and severe in type 1 reactions, as compared to
type 2 reactions, for the reasons already explained. Type 1
reactions can have changes both in cutaneous lesions Fig. 21.1: BT patch on face in type 1 reaction. Such patients should
and nerves as its feature; or can only be limited to the be followed-up for NFI of facial nerve
CHAPTER
21
patches on the limbs, overlying nerve trunks, skin and Such a silent fibrosis of a nerve is possible as it has been
nerve involvement of more than one body area, previous shown that in a nerve involved in tuberculoid leprosy, a
history of type 1 reaction or neuritis.22 In general, the NFI fairly normal appearing nerve fascicle can be seen alongside
effects are more extensive and pronounced during type 1 the fascicle infiltrated by granuloma.
reaction than in type 2 reaction. Nonetheless, chronic and
recurrent type 2 reactions in LL and BL patients can lead Neuropathic Pain in Leprosy
to considerable NFI in the long run, as more and more The importance of neuropathic or nerve pain (NP) in leprosy
number of nerve trunks are involved in these forms of was recognized only in the last two decades. Neuropathic
leprosy. pain is defined as ‘pain initiated or caused by a primary
lesion or dysfunction in the peripheral or central nervous
Silent Neuritis/Quiet Nerve Paralysis system’.26 Since leprosy is known to cause severe sensory
Silent neuritis/neuropathy is “quiet” in the sense that the loss leading to hypoanesthesia, it is generally assumed
patient does not complain or give history of pain or that pain is uncommon in leprosy. However, peripheral nerve
tenderness of the nerve associated with the recent event pain or neuropathic pain can complicate leprosy both, during
of motor and/or sensory deficit. May be for this reason, it and after treatment. During active disease, patients who
has also been referred to as ‘quiet nerve paralysis’ by some usually complain of neuropathic pain are patients of pure
workers. It does not refer to the chronic insidious destructive neuritic leprosy and those at the tuberculoid end of the
neuropathy of lepromatous leprosy, but rather to the leprosy spectrum with type 1 reactions, although
episodes of neuropathy that cause clinical nerve damage lepromatous patients with recurrent and severe type 2
within a relatively short period of weeks to months.23 It reactions can also have bouts of intense nerve pain
has also been defined as sensory or motor impairment involving multiple nerve trunks associated with other
without skin signs of reversal reaction or ENL, without symptoms.
nerve tenderness or complaints of nerve pain or pares- Neuropathic pain which is often debilitating is being
thesia.24 Although it has been observed across the increasingly recognized not only in patients with active
spectrum of leprosy, it is probably more common in the disease and reactions, but also in patients who have
borderline group. completed their MDT. It could be the chief complaint in
Silent neuritis has been observed in three clinical some patients who have been ‘released from treatment’
settings: (1) The patient who comes to the leprosy clinic and it could last for months to years. It includes a wide
with only skin lesions without reference to nerve pain or spectrum of symptoms, including paresthesia, dyses-
deficit but is found to have sensory and/or motor deficit. thesia, hyperesthesia and allodynia along the nerve and in
(2) The patient who during or after MDT, develops new its area of distribution. The occurrence of paresthesia could
sensory or motor deficit insidiously without clinical features be as high as 24% of the patients as observed in an Indian
of type 1 or type 2 reaction. (3) The patient who presents study.27 Although neuropathic pain can be present at rest,
with an obvious motor paralysis and/or sensory deficit it is appreciated more during or after a strenuous and
(usually presenting as neuropathic ulcers) of recent onset, repetitive physical activity of the limb involved, such as
but without apparent skin lesions of leprosy or history of along the ulnar nerve in a weaver, or along the sural nerve
reactions.17 The third pattern is usually observed in pure or lateral popliteal nerve in a tailor. It is usually described
neuritic type of leprosy, although it can also be seen in BT as ‘shooting’, ‘dragging’, ‘pulling’ or ‘electric shock like’,
leprosy. and also as Jhum Jhum in nature and can force the patient
The exact mechanism of silent neuritis is not known. to keep the limb in a position of rest.28 Neuropathic pain
Some workers consider it as a mild reversal reaction limited can be moderate or severe, and continuous or intermittent.
to the affected nerve. Others disagree, as they point out When it is severe, it could even disturb sleep.
that the patients with silent neuritis can have episodes of In patients who have completed their treatment,
obvious reversal reactions also, hence argue that it cannot neuropathic pain can occur due to continued damage to
be a manifestation of a mild reaction. It has also been the peripheral nerves, probably due to the persistence of
suggested that fibrosis following inflammation of nerve mycobacterial antigens and associated low grade
tissue can insidiously produce silent nerve impairment.25 inflammation and its sequelae. It was observed that a
CHAPTER
21
majority of patients with neuropathic pain have nerve the medial malleolus are such sites. Of these, the ulnar
tenderness and their nerve biopsies showed evidence of nerve is most accessible and easily palpable for a longer
on-going inflammation. Neuropathic pain is caused by part of its course in the arm. Other nerves are accessible
excessive firing of pain mediating nerve cells that are for palpation for a shorter part of their course and hence
insufficiently controlled by segmental and nonsegmental need more expertise to appreciate the changes in their
inhibitory circuits. Some workers have found severely thickness. Although these are the common sites of early
impaired perception of tactile stimuli and mechanical and involvement clinically and pathologically, nonetheless, the
thermal pain, indicating damage of Aβ, Aδ and C fibers at whole length of the nerve could be involved in severe forms
the painful site. Others have suggested that it could be a of the disease as observed in lepromatous leprosy.
small fiber sensory neuropathy (SFSN) which Apart from these main peripheral nerves, any
predominantly affects small nerve fibers and their functions cutaneous nerve near or supplying an area of a skin lesion
with painful paresthesia as the commonest effect of its of leprosy (e.g. great auricular nerve, ulnar and radial
occurrence.29 cutaneous nerves, digital nerves and for that matter any
There are no controlled trials to assess the efficacy of other cutaneous nerve) could be involved and thickened
simple analgesics in this condition. Tricyclic antidepre- (Fig. 21.2). These cutaneous nerves could be palpated
ssants and several antiepileptic drugs have a good efficacy along their course against a taut muscle.
in various neuropathic states, however; no studies are The main risk factor for nerve involvement is the
available as yet in patients with neuropathic pain due to presence of skin lesions overlying nerve trunks. Such a
leprosy.30 presence increases the risk of NFI by three to four times
compared to those nerves without overlying skin lesions.27
CLINICAL MANIFESTATIONS Type 1 reaction in these skin lesions further increases
OF NEURITIS this risk six to eight times. Hence, patients with skin lesions
overlying peripheral nerve trunks should be carefully
Nerve thickening is the main presenting feature of peripheral monitored periodically for the development of NFI,
nerve involvement in leprosy which can be clinically especially during reactions.
appreciated in most leprosy patients. In a study investi- Nerve function impairment as a result of damage to
gating the pathogenesis of neuropathy in North India, 94%
nerves includes autonomic, sensory and motor nerve
of patients had nerve enlargement as the most common
functions, depending on the type and severity of the nerve
sign of leprosy.27 This is often accompanied by mild to
involved. In a developing skin lesion of leprosy, loss of
moderate nerve tenderness. Although nerve swelling could
rarely occur in other conditions, the nerve enlargement
due to leprosy is fusiform and less circumscribed, as
compared to the swelling observed in chronically
traumatized nerve due to other causes.31 The associated
skin lesions corroborate to confirm leprosy as the cause
of nerve thickening in most cases.
Major peripheral nerves most frequently affected in
leprosy are the posterior tibial nerve, followed by the ulnar,
median, lateral popliteal and facial nerves.32 These nerves
are involved at the most superficial locations of their course,
at their specific sites of predilection. The sites of predilection
of major nerve trunks in leprosy are at their most superficial
and cooler sites where they are also prone to trauma. The
ulnar nerve in the upper arm just above the elbow; median
nerve at wrist behind the flexor retinaculum; radial nerve in
the upper arm in the radial groove; lateral popliteal nerve
behind the knee as it winds round the neck of the fibula Fig. 21.2: Thickening of great auricular nerve with skin
and posterior tibial nerve at the ankle below and behind patch on ear lobule
CHAPTER
21
sweating precedes the loss of temperature sensation, which METHODOLOGY TO RECORD NERVE
is followed by impairment of pain and lastly the touch INVOLVEMENT
sensation. Motor paralysis never occurs independent of
Examination of Peripheral Nerves
sensory impairment in leprosy.18 Early manifestations of
neuritis are xerosis of skin secondary to reduced sweating, Examination of peripheral nerves in leprosy patients is an
mild hypoesthesia and muscle weakness. Late manifes- integral part of the clinical examination (Table 21.1).
tations include severe xerosis, anesthesia of the skin, Nerve thickening: Confirmation of nerve thickening by
motor paralysis, wasting of the muscles supplied by the palpation is important as it is one of the clinical criteria for
involved nerve and deformities (Fig. 21.1). It is to be noted the diagnosis of leprosy in a patient. Proper technique of
that the wasting of muscles encountered in leprosy patients clinical examination of peripheral nervous system is
with neuropathy is secondary to neurogenic atrophy and mandatory to assess with reasonable accuracy the extent
not due to direct muscle involvement. In leprosy, deep of its involvement based on the symptoms and signs
tendon reflexes are normal as the central nervous system elicited. While palpating a peripheral nerve, thickening
is not involved, as a rule. However, in severe neuritis a should be assessed by palpating the affected nerve and
small proportion of patients can show abnormal tendon comparing it with the corresponding contralateral nerve.
reflexes and joint position sense.27 However, when thickening of nerves occurs bilaterally,
In a study of childhood leprosy in India, it was observed which is rather infrequent, it would be difficult to correctly
that about 24% of them had associated type 1 reaction at assess the grade of nerve thickening. The peripheral nerves
the time of initial examination and neuritis was the commonly palpated in a leprosy patient are greater
presenting symptom in 65% of these reactions, auricular, ulnar, radial, radial cutaneous, lateral popliteal,
emphasizing the importance of careful neurological
posterior tibial, sural and superficial peroneal nerve. Median
examination at the time of diagnosis and appropriate use
nerve at the wrist is behind the flexor retinaculum and
of steroids in children to prevent deformities.33 Trials in
hence, is very difficult to palpate normally. Apart from
prevention of disability using corticosteroid therapy indicate
these, any visibly thickened nerve can be palpated and
that nerve function recovers spontaneously and that
assessed, such as supraclavicular nerves, ulnar cutaneous
prednisolone is safe, but there are limits to its usefulness.34
The best way to prevent disabilities occurring as a result Table 21.1: Nerve function impairment (NFI)
of nerve damage is early diagnosis and treatment of leprosy
Early manifestations Late manifestations
and leprosy reactions.
The methodology and proforma for testing of peripheral Sensory: Sensory:
Altered heat and cold Hypoesthesia and anesthesia
nerves in a patient is given later in the section. In this
sensitivity, Hypoesthesia. leading to neuropathic ulcers.
context, it is important to be familiar with the sensory and
Motor: Motor:
motor supply and distribution of major peripheral nerves to
Mild motor weakness., Severe motor weakness progressing
accurately diagnose their involvement by appropriate
VMT score 4 to paralysis. VMT score 0-3
testing.
Autonomic: Autonomic:
Decreased sweating. Severe dryness with fissuring of
Manifestations of neuritis the skin.
1. Nerve thickening
2. Nerve tenderness
3. Nerve pain Clinical assessment of neuritis
4. Nerve function impairment (NFI) 1. Palpation of peripheral nerves
a. Sensory NFI 2. Grading of nerve thickening, tenderness and pain
– Altered heat and cold sensitivity 3. Assess nerve function impairment (NFI)
– Hypoesthesia and anesthesia a. Tools to assess sensory NFI
b. Motor NFI- Motor weakness – Semmes Weinstein monofilaments
– Motor paralysis – Sensory ENMG
c. Autonomic NFI b. Tools to assess motor NFI
– Loss of sweating – Modified MRC scales for VMT
– Xerosis and fissuring of skin – EMG
5. Secondary sequelae of NFI: c. Tools to assess autonomic NFI
a. Deformities and ulcers – Sweat test
CHAPTER
21
nerve, cutaneous nerves of forearm and thigh and digital Table 21.2: Grading of nerve thickness
nerves of fingers. These can be felt, more readily when Grade Degree Description
they are involved, under the surface of the skin along their
0 Not thickened Nerve not thickened and feels normal*
anatomical course against a taut muscle or bone. 1 Mild thickening Thickened compared to contralateral
Proper examination for nerve thickening by physical nerve
palpation cannot be over emphasized. Although nerve 2 Moderate Thickening is rope like
conduction studies proved to be sensitive in detecting NFI, 3 Severe Nerve thickened and also nodular or
beaded
the combination of physical palpation for nerve thickening,
voluntary muscle testing (VMT) and use of graded nylon *Normal nerve feels soft to firm, flattish and slightly compressible.
for sensory testing was closely comparable to the nerve
conduction studies in detecting neuritis.35 Table 21.3: Grading of nerve tenderness
Nerve tenderness: It is elicited by applying mild to firm Grade Degree Description: Patient’s response
pressure on the nerve during palpation. Repeated/ 0 None Says palpation is not painful even when
overzealous palpation of tender nerves should be avoided. asked about it.
Good amount of expertise in clinical examination is 1 Mild Says palpation is painful only when asked
necessary for making these judgements as these are about it.
2 Moderate Indicates palpation is painful by wincing
comparative in nature.
during palpation or says so.
Clinical Grading of Nerve Thickening, 3 Severe On palpation, tries to withdraw the limb; or is
clearly distressed by any pressure on the
Tenderness and Pain
nerve.
There is no objective clinical grading available to assess
thickening and tenderness of the nerves as they are
subjective in nature. High resolution ultrasonography has and technique described under nerve palpation. Palpate
recently been used objectively to measure the thickness each nerve for at least 5-10 cm of its length to also detect
of nerves.36 A clinical grading of thickness and tenderness beading or nodularity.
of nerves based on subjective assessment would help in
Grading of Nerve Tenderness
recording the extent and severity of nerve involvement by
the disease process. Such a clinical grading of thickening This is a highly subjective assessment, but reasonable
and tenderness is useful not only in the initial assessment grading could be made by an experienced examiner. A
but also during the follow-up of such patients for clinical four-grade scale (0-3) is used to grade tenderness
improvement. Moreover, a standardized grading of clinical (Table 21.3). Only apply mild to moderate but firm pressure
parameters of neuritis could be a means of communication on the nerve while palpating it. While palpating the nerve,
between leprosy workers, form a basis for its recording look for the patient’s response (wincing, expression of
and provide a parameter for the institution of appropriate distress on face or pulling away of limb), to evaluate the
therapy and evaluation. Although such a clinical grading grade of tenderness. Repeated palpation of tender nerves
of nerve thickening was practiced in a few research should be avoided.
studies;33 it is not widely practiced in leprosy clinics.
Grading of Neuropathic Pain
Recently however, one such grading of nerve thickness,
tenderness and pain was detailed in a leprosy website.37 Neuropathic pain, also called ‘nerve pain’ is increasingly
Given below is the clinical grading of nerve thickening, recognized as a symptom associated with the severe
nerve tenderness and nerve pain as practiced at Blue Peter involvement of peripheral nerves in leprosy. It is observed
Research Center (BPRC) in Hyderabad, Karnataka. not only in patients with active disease and reactions, but
also in patients who have completed MDT. Such pain is
Grading of Nerve Thickening complained more often after strenuous physical activity.
A four-grade scale (0-3) is used to grade nerve thickening Patients describe the pain usually as ‘shooting’ ‘dragging’
(Table 21.2). The nerves are palpated at their most ‘pulling’ or ‘electric shock like’ in nature. The grading of
superficial locations and sites based on the methodology nerve pain is based on the symptoms of the patients and
does not need palpation of the nerve. A four-degree scale
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21
Table 21.4: Grading of neuropathic pain measure both diminishing and returning cutaneous
Grade Degree Description sensations. These are nylon monofilaments made from
polyhexamethylene dodecanediamine, better known as
0 None Does not complain of nerve pain; says ‘no nerve
pain’ even when asked about it. nylon 612, which absorbs very little water (less than 3% in
1 Mild Complains of nerve pain even when not asked 100% humidity) and can be cleaned by alcohol. They have
about it. indefinite shelf life. 39 SW monofilaments provide a
2 Moderate Complains of severe nerve pain and points to
the areas of its radiation. The pain does not
repeatable instrument stimulus with a small standard
interfere with sleep. It is aggravated by deviation in contrast to other handheld test instruments,
repeated use of the limb such as manual labor, making them an optimum choice for objective sensory
tailoring, etc.
testing of NFI in leprosy patients.
3 Severe Says ‘pain is severe’, and that it interferes with
sleep. The patient keeps the limb in a position Sensory NFI is usually tested using a standard set of
of rest and avoids/restricts its movement. Semmes-Weinstein (SW) monofilaments. These nylon
monofilaments are precisely calibrated and are of equal
(0-3) is used (Table 21.4). length. The monofilaments are calibrated so as to produce
a force of 0.05 gm (green) 0.2 gm (blue), 2 gm (purple),
Application of Clinical Grading 4 gm (red), 10 gm (orange) and 300 gm (light red) of
When nerve tenderness and neuropathic pain is ≥ grade 2; pressure on the surface of the skin on application. A color
it requires immediate institution of corticosteroid therapy coded six-monofilament set is used to test normal,
along with other measures to prevent further nerve function diminished light touch, diminished protective sensation,
impairment (NFI). NFI associated with neuritis should be loss of protective sensation for hands, loss of protective
assessed periodically in these patients with the help of sensation for feet and for deep pressure sensation, in that
specific tests mentioned in later part of this chapter. order (Fig. 21.3). Each filament is mounted on holders (such
as needle bottoms or small plastic bases) and they should
Tools for Testing Neuropathy in Leprosy be applied perpendicularly to each specified site with mild
In leprosy as in other diseases of the peripheral nervous pressure until the filament gets bent forming a ‘C’ curve
system, identification of neuropathy in a patient is (Fig. 21.4). The standard sites tested are; on the hands,
dependent upon the results of the tests employed and the 3 sites each for the ulnar and median nerves, and 1 for
criteria for abnormality used. It is very important that the radial nerve; on feet, 7 sites on the sole for the posterior
tests performed should be relevant to the population group tibial nerve, and 1 site on the dorsum of the foot for deep
being examined. Keeping note of this is very relevant peroneal nerve (Fig. 21.5). Application should be started
because, the touch sensibility thresholds when tested with
SW filaments and recorded in a large group of healthy
normal Indians were not only higher than those reported in
populations of developed nations but also showed an
increased deterioration with aging.38 It was also observed
that women (compared to men) had higher sensibility in
palms. Many a times in a given patient, the worsening of
test score may reflect the onset of neuropathy, but the
test score may still be within the range of normal value.
These factors should be kept in mind while performing
tests for evaluation of neuropathy in a leprosy patient.
Some of the tests mentioned below are such that they
can be performed very easily in all leprosy and general
clinics with minimal facilities and are reproducible.
Tools to Assess Sensory NFI

Sensory Testing by Monofilaments Fig. 21.3: Standard set of Semmes-Weinstein (SW)
monofilaments of various calibers
Semmes-Weinstein (SW) monofilaments are used to
CHAPTER
21
with the finest (the green) filament and built-up to the orange
one. The details of the score should be recorded on a hand
and foot examination card-form of the patient. Testing should
be done once a month for the first 6 months and
subsequently once in 3 months.40
Criteria for Sensory Impairment

The reference value for normal sensation level/threshold
for population of Indian subcontinent for all sites on the
hand is 0.2 gm pressure and for the foot is 2 gm pressure,
as felt by the graded SW filaments.41,42 0.05 gm pressure
is the threshold for facial skin sensation. Sensory
impairment is diagnosed in the following situations:
(a) When the monofilament threshold sensation is increased
by 3 or more levels at any one site or (b) when threshold is
Fig. 21.4: The ‘C’ curve produced during examination with SW increased by 2 levels in one site and 1 level in another site
filaments. (Reference values to which normal individuals are expected
to respond are: 0.05 gm for the face, 0.2 gm for the hand and 2 gm for or (c) when it is increased by 1 level in all 3 sites for a
the foot) nerve tested.
Indentation of the skin quantifiable by Semmes-
Weinstein monofilaments is an accepted method of
measuring perception of touch. Silent neuropathy is a well
defined entity that can be accurately detected with the
help of SW monofilaments.40 Periodic examination for
nerve function assessment, at least during their first year
of treatment, with the help of SW fibers and voluntary
muscle testing (VMT), which could easily be performed in
an out-patient leprosy clinic, would enable us to detect
early occurrence of such a silent impairment. Regular
assessment of nerve function is essential as early detection
and treatment with steroids limits impairment and eventual
disabilities associated with it.
Sites for Testing

The sensory testing with SW filaments is being practiced
widely to diagnose various types of peripheral neuropathies,
including those secondary to diabetes and leprosy. The
pertinent sites of testing for sensation on hands and feet
of importance are given in Table 21.5 and depicted in
Figure 21.5. While testing for sensation with SW filaments,
subjects should be placed in a chair in a quiet room, made
comfortable and explained about the methodology of
testing. During testing, they should keep their eyes closed
to avoid a visual influence. The SW filaments are tested
on hands at 7 sites and on the feet at 8 sites starting from
right to left, using the staircase method.
A series of monofilaments in decreasing order are
Fig. 21.5: Sites for sensory testing on dorsal and ventral aspects of
hand and foot representing areas supplied by ulnar, median and radial, applied starting with the highest (usually 300 gm) target
nerves on hand and posterior tibial and deep peroneal nerves on foot force until the approximate threshold is determined. A
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21
Table 21.5: Sites for testing with SW filaments on hands and feet (Refer Figure 21.5)
7 sites for testing on hand 8 sites for testing on feet
Sites in the distribution of ulnar nerve Sites in distribution of deep peroneal nerve
1. Distal phalanx of little finger 1. Dorsum of the big toe
2. Head of 5th metacarpal Sites in the distribution of posterior tibial nerve
3. Hypothenar eminence 2. Plantar surface of the distal phalanx of the little toe
Sites in the distribution of median nerve 3. Head of 5th metatarsal
4. Distal phalanx of index finger 4. Lateral border of foot
5. Head of 2nd metacarpal 5. Plantar surface of the heel
6. Distal phalanx of thumb 6. Medial border of foot
Sites in the distribution of radial nerve 7. Head of 1st metatarsal
7. Dorsum of the thumb 8. Plantar surface of the distal phalanx of the big toe
minimum of five monofilaments should be selected and leprosy are, abductor pollicis brevis for testing the function
used sequentially in three cycles of ascending and of the median nerve, abductor digiti minimi for testing the
descending order. The lowest target force consistently ulnar nerve and extensor digitorum brevis for testing the
detected in three threshold crossings should be considered lateral popliteal nerve. For each muscle EMG is to be
as the threshold force. Rapid and repeated testing at or recorded in three phases: During insertion of needle, at rest
nearby sites should not be done to avoid spatial and and at full volition.
temporal summation of stimuli. To prevent false positives, In the normal EMG, complete electric silence is
subjects are also given mock exercises, without the probe observed at rest and with minimal voluntary contraction,
touching the skin. individual motor unit potentials represent the summation
of membrane action potentials of many muscle fibers. With
Testing for Hot and Cold Sensibilities increasing contraction, firing rate increases indicating
Hot and cold sensibilities are tested using instruments increased motor fiber recruitment, referred to as a complete
that can test both faculties one after the other. The WHO interference pattern. In an abnormal EMG indicating
has designed one such small pen-shaped battery operated neuropathy, findings include fibrillation, fasciculation, giant
instrument for thermal testing in the field. Some workers motor unit potentials and reduced interference or
prefer test tubes with hot and cold water for testing the recruitment pattern. Motor nerve conduction variables and
same. However, in most clinical settings, testing for hot sensory nerve conduction variables can also be measured
and cold sensibilities is seldom practiced. and recorded by EMG.
In cases of myopathy EMG demonstrates a motor unit
Laboratory Tools to Test for Sensory Impairment potential that is lower in amplitude and shorter in duration
than normal, and there is reduced interference pattern.
Nerve Conduction Studies
Tools to Assess Motor NFI
Formerly, electromyography (EMG) and nerve conduction
studies (NCS) required large and sophisticated Voluntary Muscle Testing (VMT)
instrumentation which required high levels of expertise. Motor NFI is assessed by VMT using the modified Medical
More recently however, these are becoming bedside Research Council (MRC) scale of 0-5.44 VMT score is
procedures with much smaller “Laptop” kind of instruments recorded using a modified version of the scale that was
to assess motor and sensory nerve conduction. However, first introduced by MRC of United Kingdom in 1940s and
these instruments are still not in routine use and such is known as MRC scale. It has six levels that are easily
tests are performed mostly in neuroscience laboratories. assessed during clinical examination. The modified MRC
grading score used for VMT is given in Table 21.6.
Electrophysiological Study by Needle
Different muscles are tested for each of the motor
Electromyography (EMG)43
nerves commonly affected by leprosy.
Electromyography helps in detection and recording of the The movements tested for the muscles for each of the
electrical activity from a portion of a muscle by recording of nerves are:
motor unit potentials. The muscles usually examined in 1. Ulnar nerve: Abductor digiti minimi (ADM)—little finger
CHAPTER
21
test can be performed on the suspected area of skin.

Table 21.6: Grades of VMT for voluntary muscles
VMT score Description of motor power Starch Iodine Test
Grade 5 Normal power. Full strength in all movements Absence of sweating can be established by injecting 0.2 ml
against normal degree of resistance. of 1 in 1000 solution of pilocarpine nitrate into the lesion to
Grade 4 Full range of movements but less than the normal be tested and paint the injection site with tincture iodine
strength. Movement against gravity but not of
and then dust with starch powder. Sweating causes bluish
normal degree.
Grade 3 There is full range of movements sufficient discoloration of the starch powder due to its reaction with
to overcome gravity but not against added iodine in the presence of moisture, absence of which
resistance. indicates anhidrosis.45
Grade 2 There is some contraction of the muscle but the
range of active movement is incomplete, effective Examination of Eyes for NFI
neither against gravity nor resistance.
Grade 1 Perceptible contraction of muscle(s) not resulting Assessment of NFI is never complete without examination
in joint movement. of the eye, as the eye is an important organ affected by
Grade 0 No movement or power representing total neuritis in leprosy. Involvement of the eye could occur
paralysis.
either directly as a result of invasion of M. leprae into ocular
structures as happens in lepromatous leprosy or more
commonly as an indirect result of neuritis of the zygomatic
abduction. branch of the facial nerve or the ophthalmic branch of the
2. Median nerve: Abductor pollicis brevis (APB)— trigeminal nerve. The strong association between the
abduction of thumb. frequency of eye involvement in leprosy and the presence
3. Radial nerve: Extensor muscles of wrist—wrist of type 1 reactional facial patches has been demons-
extension; extensor pollicis brevis (EPB) and extensor trated.21 Existing eye involvement in leprosy is further
pollicis longus (EPL) causing extension of thumb. exacerbated during both type 1 and type 2 reactions.
4. Lateral popliteal nerve: Tibialis anterior, peroneus Whereas reduction in the corneal sensation and its
longus and brevis—dorsiflexion of the foot and big toe. sequelae are observed more often due to type 2 reactions;
5. Facial nerve: Orbicularis occuli—forced closure of eyes. decrease in the motor function of orbicularis occuli leading
to lagophthalmos and its effects are observed more often
Criteria for Motor Impairment in type 1 reaction. VMT scoring for orbicularis occuli
If the VMT score for any muscle or group of muscles is muscle17 is slightly different from that of other voluntary
equal or less than 4 on the MRC scale, it is considered as muscles and is given in Table 21.7. Note that lid gap when
motor impairment. present, is indicative of advanced motor deficit and is not
an early sign.
Tools to Assess Autonomic NFI
Disability in Leprosy and its Grading
Damage to autonomic nerve supply of the sweat glands in
the dermis results in reduced or absent sweating. However, Unattended, neuritis in leprosy can result in a wide range
in tuberculoid leprosy, sweating could also be reduced due of NFI especially of hands, feet and eyes, ultimately
to the direct infiltration and destruction of sweat glands by leading to anesthesia, muscle weakness, deformities,
granulomatous inflammation. Table 21.7: Grading of VMT for orbicularis occuli
Sweat Test VMT score Description of motor power for eye
A simple method is to observe the suspected area of skin Grade 5 Normal forced eye closure
Grade 4 Full closure against reduced resistance
lesion for presence of moisture and/or sweating after mild Grade 3 Full closure without resistance
exercise. The typical tuberculoid patch looks very dry and Grade 2 Partial closure (lid gap present)
wrinkled due to xerosis secondary to diminished sweating. Grade 1 Muscle flicker with no closure
Grade 0 Complete paralysis
However, to confirm the absence of sweating, starch iodine
CHAPTER
21
neuropathic ulcers and resultant disabilities. The WHO Table 21.8: WHO disability grading with its modifications47
proposed disability grading of these impairments in 1988.46 Hands and feet
Periodic grading of such disabilities in a leprosy patient
Grade 0 No anesthesia, no visible deformity or damage
(Table 21.8) would assist in providing appropriate care and Grade 1 Anesthesia present but no visible deformity or damage
attention required for them. Grade 2 Visible deformity or damage present.
The best ways to prevent disabilities which are the Eyes
result of nerve damage is early diagnosis and prompt Grade 0 No eye problem due to leprosy, no evidence of visual
treatment of leprosy and leprosy reactions. Simple ways loss.
Grade 1 Eye problem due to leprosy present, but vision not
to care for insensitive hands and feet, and the need for
severely effected (Vision 6/60, can count fingers at
eye care and protection should be explained and taught to 6 meters).
the patient. Daily self-care by the patient to minimize the Grade 2 Severe visual impairment (Vision worse than
6/60, inability to count fingers at 6 meters. Also includes
effects of NFI is very important in preventing the lagopthalmos, iridocyclitis and corneal opacities).
progression of the existing disability.
Each limb and eye should be assessed and classified separately. If
any disability is found in the patient due to causes other than leprosy,
PROFORMA TO RECORD NERVE that fact should be noted. To record overall disability grading for the
patient, the highest leprosy disability grade for any part of the body
FUNCTION IMPAIRMENT (NFI) should be taken.
Form for Sensory Testing of Hands and Feet
Area of testing Site SW filament*
Score/Grade
Right Left
Hand
Ulnar nerve 1
2
3
Median nerve 4
5
6
Radial nerve 7
Foot
Deep pereneal nerve 1
Posterior tibial nerve 2
3
4
5
6
7
8
* The SW monofilaments are calibrated so as to produce a force of 0.05 gm (green), 0.2 gm (blue), 2 gm (purple), 4 gm (red), 10 gm (orange) and
300 gm (red) of pressure on the surface of the skin on application. The SW filaments could be numbered/ graded from 1 to 6 or as A to F
CHAPTER
21
Reference values of threshold pressure by the graded SW filaments

The reference value for normal sensation threshold for all sites on the hand is 0.2 gm pressure and for the foot is 2 gm pressure.
Sensory impairment is diagnosed in the following situations
1. The monofilament threshold is increased by 3 or more levels in any one site or
2. By 2 levels in one site and 1 level in another site or
3. By 1 level in all 3 sites for a nerve tested.
Motor Function Assessment of Important Nerves by Voluntary Muscle Testing (VMT)

Nerve Muscles to be tested VMT score
Right Left
Ulnar nerve Abductor digiti minimi
Median nerve Abductor pollicis
Radial nerve Wrist extensors and extensors of thumb
Lateral popliteal nerve Tibialis anterior/peroneous longus
– Dorsiflexion of foot
Extensor hallucis longus
– Dorsiflexion of big toe
Facial nerve Orbicularis occuli (VMT)
Lid gap on light closure (in mm)
Lid gap on strong closure (in mm)
Proforma for Recording NFI in the Eye

VMT Grade
Right Left
Eyelid # power in upper eyelid muscles:
try to open on forceful closure
Blink
Lid gap on light closure (in mm)
Lid gap on strong closure (in mm)
Obvious lagophthalmos
Conjunctiva Redness
Conjunctival congestion
Ciliary congestion VMT score # description of motor power for eye
Watering of eyes Grade 5 Normal forced eye closure
Grade 4 Full closure (against reduced resistance)
Cornea Corneal sensation
Grade 3 Full closure (without resistance)
Corneal ulcer Grade 2 Partial closure (lid gap present)
Grade 1 Muscle flicker with no closure
Corneal opacity/leucoma Grade 0 Complete paralysis
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Proforma to Record Clinical Grading of Nerve Involvement in Leprosy
Nerves Grade of thickening Grade of tenderness Grade of nerve pain
Ulnar nerve Right
Left
Radial cutaneous nerve Right
Left
Lateral popliteal nerve Right
Left
Posterior tibial nerve Right
Left
Sural nerve Right
Left
Great auricular nerve Right
Left
Median nerve Right Not applicable
Left Not applicable
Other nerve
Other nerve
Proforma to Record Disability, Deformities and Ulcers

WHO grade of disability (0/1/2) Type of deformity Ulcer(s)
Right hand
Left hand
Right foot
Left foot
Right eye
Left eye
Highest disability for any part should be taken as its disability grade. Mention the type of deformity; when present. Mention the number, location
and type of ulcers when present.
REFERENCES 9. Turk JL, Curtis J, De Blaquiers G. Immunopathology of nerve

involvement in leprosy. Lepr Rev 1993; 64:1-6.
1. Job CK. Nerve damage in leprosy. Int J Lepr 1989; 57:532-39. 10. Chandi SM, Chacko CJG, Fritchi FP et al. Segmental necrotising
2. Suneetha LM, Vardhini D, Suneetha S et al. Biochemical aspects granulomatous neuritis of leprosy. Int J Lepr 1980; 48: 41-47.
of Mycobacterium leprae binding proteins: A review of their role 11. Ridley DS, Ridley MJ. Classification of nerves is modified by the
in pathogenesis. Int J Lepr and Other Mycobact Dis 2001; 69:341- delayed recognition of Mycobacterium leprae. Int J Lepr 1986;
48. 54: 596-606.
3. Rambukkanna A, Yamada H, Zanazzi G et al. Role of alpha 12. Ridley DS. Pathogenesis of leprosy and related diseases.
dystroglycan as a Schwann cell receptor for M. leprae. Science London, Butterworth and Co. Publishers. 1988.
1998; 282:2076-79. 13. Lienhardt C, Fine PEM. Type- reaction, neuritis and disability in
4. Shimoji Y, Vincent NG, Matsumara K et al. A 21-kDa surface leprosy. What is the current epidemiological situation? Lepr
protein of Mycobacterium leprae binds peripheral nerve laminin- Rev 1994: 65: 9-33.
2 and mediates Schwann cell invasion. Proc Natl Acad Sci 1999; 14. Ramu G, Desikan KV. Reaction in borderline leprosy. Indian J
96:9857-62 Lepr 2002: 74: 115-28.
5. Suneetha LM, Satish PR, Korula RJ et al. Mycobaterium leprae 15. Ramanathan VD, Curtis J, Turk JL. Activation of the alternate
binds to a 25-kDa phosphorylated glycoprotein of human pathway of complement by Mycobacteria and cord factor. Infect
peripheral nerve. Neurochem Res 1998; 23:907-11. Immun 1980; 29:30-35.
6. Rambukkanna A. How does Mycobacterium leprae target the 16. Pearson JMH, Ross WF. Nerve involvement in leprosy–pathology,
peripheral nervous system. Trends Microbiol 2000; 8:23-28. differential diagnosis and principles of management. Lepr Rev
7. Harboe M, Aseffa A, Leekassa R. Challenges presented by 1975; 46:199-212.
nerve damage in leprosy. Lepr Rev 2005; 76:5-13. 17. van Brakel WH. Peripheral neuropathy in leprosy—the
8. Shetty VP, Antia NH, Jacobs JM. The pathology of early leprous continuous challenge. Thesis University Utrecht. Utrecht.1994.
neuropathy. J neurol Sci 1988; 88:115-31.
CHAPTER
21
18. Job CK, Chandi SM. Differential diagnosis of leprosy—a guide Bangladesh (The Bangladesh Acute Nerve Damage Study).
to histopathologists. Karigiri leprosy education programme. Lepr Rev 1999; 70: 140-59.
SLRTC, Vellore. Chummy printers, 2001. 33. Jain S, Reddy RG, Osmani SN et al. Childhood leprosy in an
19. Suneetha S, Arunthathi S, Kurian N et al. Histological changes in urban clinic, Hyderabad, India: Clinical presentation and the role
the nerve, skin and nasal mucosa of patients with primary neuritic of household contacts. Lepr Rev 2002; 73:248-53.
leprosy. Acta Leprologica 2000-2001;12:11-18. 34. Croft R. Editorial. Lepr Rev 2003; 74:297-99.
20. Roche PW, Theuvenet WJ, Le master JW et al. Contribution of 35. Samant G, Shetty VP, Uplekar MW et al. Clinical and
type 1 reaction to sensory and motor function loss in borderline electrophysiological evaluation of nerve function impairment
leprosy patients and the efficacy of treatment with prednesolone. following cessation of multidrug therapy in leprosy. Lepr Rev
Int J lepr 1998; 66:340-47 1999; 70: 10-20.
21. Hogeweg M, Kiran KU, Suneetha S. The significance of facial 36. Beekman R, Visser LH. High-resolution sonography of the
patches and type 1 reaction for the development of facial nerve peripheral nervous system–a review of the literature. Eur J Neurol
damage in leprosy. A retrospective study among 1226 2004; 11: 305-14.
paucibacillary leprosy patients. Lepr Rev 1991; 62:143-49. 37. Srinivasan H. Nerve thickening standards. AIFO leprosy mailing
22. Suneetha S. Key issues in the management of reactions and list archives. http://www.aifo.it/english/resources/online/
relapse in leprosy. Proceedings of round table conference- lml-archives/2008/210908-3.htm, accessed on 15th February,
Ranbaxy science foundation, Agra. 2002:103-17. 2009.
23. Srinivasan H, Rao KS. Steroid therapy in quiet nerve paralysis in 38. Jain S, Muzzafarullah S, Peri S et al. Lower touch sensibility in
leprosy. Indian J Lepr 1982; 54: 412-19. extremities of healthy Indians: Further deterioration with age.
24. van Brakel WH, Khawas IB. Silent neuropathy: An epidemiological J Peripheral Nervous Sys 2008; 13:47-53.
description. Lepr Rev 1994; 65: 350-60. 39. Bell Krotoski JA. Pocket filaments and specifications for Semmes-
25. Cheroskey CB, Gatti JC, Cardama JE. Neuropathies in Hansen’s Weinstein monofilaments. J Hand Ther 1993; 3:26-29.
disease. Int J Lepr 1983; 51:576-86. 40. Santhanam A. Silent neuropathy: Detection and monitoring using
26. Hietaharju A, Croft R, Alam R et al. The existence of chronic Semmes-Weinstein monofilaments. Indian J Dermatol Venereol
neuropathic pain in treated leprosy. Lancet 2000; 356:1080-81. Leprol 2003; 69:350-52.
27. van Brakel WH, Nicholls PG, Das L et al. The INFIR Cohort 41. Malaviya GN, Hussain S et al. Sensory functions in the normal
Study: Investigating prediction, detection and pathogenesis of persons and leprosy patients with peripheral trunk damage.
neuropathy and reactions in leprosy. Methods and baseline results Indian J Lepr 1994; 66:157-64.
of a cohort of multibacillary patients in North India. Lepr Rev 42. Kets CM, van Leerdam ME, van Brakel WH et al. Reference
2005; 76: 14-34. values for touch sensibility thresholds in healthy Nepalese
28. Lemaster JW, John O, Roche PW et al. Jhum-Jhum – a common volunteers. Lepr Rev1996; 67:28-38.
paresthesia in leprosy. Lepr Rev 2001; 72: 100-01. 43. Ramdan W, Mourad B, Fadel W et al. Clinical, electrophysio-
29. Haanpaa M, Lockwood DNJ, Hietaharju A et al. Neuropathic logical, and immunopathological study of peripheral nerves in
pain in leprosy. Lepr Rev 2004; 75: 7-18. Hansen’s disease. Lepr Rev 2001; 72: 35-49.
30. Lund C, Koskinen M, Suneetha S et al. Histopathologial and 44. Brandsma JW. Basic nerve function assessment in leprosy
clinical findings in leprosy patients with chronic neuropathic pain: patients. Lepr Rev 1981; 52:161-70.
a study form Hyderabad, India. Lepr Rev 2007; 78: 369-80. 45. Jopling WH, McDougall AC. Handbook of leprosy 5th edn. New
31. Martinoli C, Derchi LE, Bertolotto M et al. US and MR imaging of Delhi, CBS Publishers and Distributors. 1996.
peripheral nerves in leprosy. Skeletol Radiol 2000; 29:142-50. 46. WHO expert committee on leprosy. Sixth report. Technical report
32. Croft RP, Richardus JH, Nicholls PG et al. Nerve function series 768. Geneva WHO, 1988.
impairment in leprosy: Design, methodology, and intake status 47. Rao PN. Recent advances in the control programme and therapy
of a prospective cohort study of 2664 new leprosy cases in of leprosy. Indian J Dermatol Venereol Leprol 2004;70:269-76.
22
Leprosy Reactions
INTRODUCTION leprosy (LL).1 In some patients, the reactions are confined

only to the skin or the nerves only. In others, both skin
Reactions in leprosy constitute the main complication of
and nerves may be affected. Even when only skin is
the disease which can lead to serious consequences like
affected not all lesions may show acute increase in swelling
nerve damage and deformities. Leprosy reactions are
and redness. In some patients, however, there may be
immunologically mediated episodes of acute or subacute
sudden appearance of inflamed, new lesions and/or new
inflammation which interrupt, the relatively uneventful usual
nerve affection; with or without impairment of nerve
chronic course of disease affecting the skin, nerves,
function.
mucous membrane and/or other sites. Reactions may
occur in any type of leprosy except the indeterminate type. Upgrading or Reversal Reaction
Unless promptly and adequately treated, they can result If there is increase in the immunity, the shift is from
in deformity and disability. borderline spectrum towards the tuberculoid pole and is
Reactions constitute an important problem both for the called upgrading or reversal reaction (RR). The term,
patients and for the treating physician. Although with the “Reversal reaction” is because of the natural tendency for
introduction of MDT, the prevalence of leprosy has come subpolar tuberculoid and borderline leprosy to downgrade
down drastically, the potential risk of nerve damage in the slowly towards the lepromatous pole, without treatment,
affected person and community continues to be great. This which is reversed with treatment.
upsets the patients, especially those who are regular in
treatment. To the patients, the appearance of reactions Downgrading Reaction
not only indicates worsening of the disease, but also raises On the other hand, if there is sudden shift towards the
doubts about curability of the disease. Repeated attack of lepromatous pole with reduction of immunity, it is called
reactions also affects drug compliance. as downgrading reaction. However, there are conflicting
opinions regarding the existence of this form of type 1
TYPES reaction. There were two explanations proposed in the past
to explain the concept of downgrading reactions. One is
Three types of reactions recognized are classified as
that, during an upgrading reaction, the immunity is directed
follows:
against antigenic determinants that are essential for the
bacterium to survive and during a downgrading reaction
Type 1 Reaction (T1R)
the reaction is directed against the antigenic determinants
The type 1 reaction is associated with sudden alteration of secreted antigens, remnants of dead or dying bacteria
of cell-mediated immunity associated with a shift in the or against antigenic determinants of the host that has in
patient’s position in the leprosy spectrum. The type 1 common with M. eprae. The other concept that in both
reaction is usually observed in borderline spectrum of the upgrading and downgrading reactions, the same antigenic
diseases expect very rare reports in lepromatous components may be involved is the one most likely. This
CHAPTER
22
is not unlikely, that it is the orchestration of the cytokines countries; 28% in a hospital-based study from Nepal,4
resulting from immunological events that are responsible 16.5% from Ethiopia.5 and 24.1 % in one center from India.6
for the final effect, up- or downgrading. Different antigenic Probably, it reflects a variable proportion of PB/MB cases
determinants induce different cytokine profiles in different and the mixed case definitions used.6 Figures for the
individuals depending on their genetic make-up and percentage of patients manifesting RRs at any time vary
immunological history, including their contact with from 3.5% among PB cases in Malawi7 to 47.5% among
environmental microorganisms. MB cases in Zaire.3
In clinical practice, this distinction is clearly evident An attempt was made by the Indian Association of
and the laboratory tests to confirm the upgrading or Leprologists (IAL) in 2003 to find out the incidence of
downgrading of immunity may not be helpful. Moreover, reactions in leprosy collecting, both hospital (9 centers)
as the management is same, no distinction is and field (4 centers) based data of previous 10 years from
recommended to be made and all type 1 reactions are different zones of India.8 The cumulative crude incidence
labeled as reversal reactions (RRs). Henceforth, in this rates from hospital and field samples for both types of
text, the term RRs will be used for all types of type 1 reactions were found to be 24.4 and 3.7 per 100 patients
reactions. respectively and the corresponding crude annual incidence
rates were 2.4 and 0.37 per 100 patients respectively
Type 2 Reaction (T2R) Or Erythema Nodosum (Table 22.1).
Leprosum (ENL) Table 22.1 also shows that in both field and hospital
This type is usually associated with immune complexes situations, type 1 reaction rates are significantly higher
and observed in lepromatous leprosy and rarely in than type 2 reaction. Late type 1 and type 2 reactions
borderline lepromatous (BL) leprosy. Occasionally, both after completion of multidrug treatment (MDT) have been
type 1 and type 2 reactions are observed in BL spectrum observed among 1.5 and 0.6% of patients with fixed
of the disease, very rarely they may occur simultaneously duration treatment (FDT)-6, 12 months and MDT till
in the same person. inactivity, respectively. Neuritis without skin manifes-
tations of reactions is observed in quite appreciable
The Lucio Phenomenon number. Combining both type 1 and type 2 reactions, 30%
of the cases suffered more than one episode of reaction.
This is a type of reaction observed in untreated, uniformly About 34% had two to three episodes and few (5%) even
diffuse shiny infiltrative, non-nodular form of LL which is had four or more episodes or recurrent reactions which
chiefly encountered in Mexicans, called as Lucio leprosy. points to the need for longer duration of follow-up.8
This is associated with necrosis of arterioles whose At a fully-monitored field control unit (Koraput Leprosy
endothelium is massively invaded by M. leprae.2 Eradication Project- KORALEP), the data showed that
type 1 reaction occurred in 3.9% of borderline cases and
EPIDEMIOLOGY type 2 reaction in 23.7% of LL and BL cases. Majority of
Published reports indicate that the frequency of RRs at them were of mild or moderate degree and could be treated
the time of diagnosis varies between 2.6 and 6.4%.3 as outpatients. Of the borderline cases, BB type showed
However, higher figures were reported from different maximum rate of reactions. The BL type can present with
Table 22.1: Incidence of reactions, according to type of reaction

Sample No. of Type 1 Type 2 Combined Only neuritis Total No.
cases reaction reaction type 1 and type 2 No. (%) (%)*
registered No. (%) No. (%) reaction No. (%)
Hospital 6017 1132(18.8) 287(4.8) 12(0.2) 38(0.6) 1469(24.4)*
Field 26403 708(2.7) 196(0.7) 0(0.0) 75(0.3) 979(3.7)*
Total 32420 1840(5.7) 483(1.5) 12(0.03) 113(0.4) 2448(7.6)*
* Cumulative crude incidence rate calculated for approximately 10 years is 7.6 and the annual incidence rate is 0.76/ 100 patients
(hospital: 2.4/100 patients and field: 0.37/100 patients)
CHAPTER
22
Leprosy Reactions 271
both type 1 and type 2 reactions with a total incidence of
12.8%. While BT type constituted 74% of the total cases,
type 1 reaction occurred in only 3.1% of cases. Reactions
also occurred in 0.8% of RFT cases.9 At PGIMER,
Chandigarh (INDIA) 30.9% of cases presented with reaction
at the time of first visit, late RR occurred in 9.5% of all
cases and was noted up to 7 years after treatment.6 Overall
33% of all patients in the above study developed RR at
sometime during treatment and follow-up, including those
A B
with a reaction at presentation. Fig. 22.1A and B: RR in BT leprosy. Note the existing lesions on face
Reversal reactions usually occur during the first six become erythematous, shiny and swollen, in both patients. Also note
months of therapy in BT and BB patients, but longer a new lesion on the right cheek (B)
intervals have been seen in BL patients. Data on time of
onset of the reaction collected by Indian Association of Risk Factors
Leprologists (IAL) in 2003, both from the field and hospital
1. Borderline group of patients (BT, BB and BL) are the
combined, shows that 42% of all type 1 reaction cases
most vulnerable group with the highest risk of
present at the time of registration and initiation of therapy,
33% develop within first 6 months after starting multidrug developing type 1 reaction,16 amongst this group again
therapy (MDT), 16% developed in between 7-12 months BL and BB patients have a higher risk than BT
after starting therapy and 10% after release from treatment patients.17 Reactions occur earlier in BT patients.5
(RFT) called late reversal reaction.8 2. Patients who have one episode of reaction are more
ENL reactions were reported to occur in more than 50% likely to develop a second episode of reaction.
of lepromatous leprosy (LL) cases and in about 25% of 3. Female gender carries a higher risk than men.6 This
borderline lepromatous (BL) cases in the pre-MDT era.10 could be due to hormonal fluctuations.18 Pregnancy
Since the introduction of WHO-recommended MDT which and delivery carry an increased risk which is found to
includes clofazimine, the prevalence of ENL seems to have be the highest in the first six months after delivery
decreased.11 Of the two hospital-based studies, the one (postpartum).
from Nepal reported high incidence of ENL reactions 4. Older age group is at a higher risk than the younger
(28.6%) in LL, but only 7.5% in BL cases,12 whereas the age group.
other study from north India reported 47.4% in LL cases 5. Patients with multiple and disseminated patches
and 10.5% in BL cases.6 The result of field studies from involving larger body areas and multiple nerve involve-
Bangladesh and Ethiopia reported comparatively lower ment are at increased risk of developing RR.4, 6, 19
incidence of ENL, such as 12% in LL and 3.6% in BL from 6. Patients with large facial patches and lesions near
Ethiopia,13 and 2.1% of all MB patients from Bangladesh.14 the eyes are at risk of developing lagophthalmos due
The higher institutional figures may be related to the referral to a reaction.20
of cases particularly with severe, chronic or recurrent 7. Neuritis or previous history of nerve pain.
episodes of reaction from peripheral health care facilities. 8. Starting of treatment may precipitate reaction due to
increased breakdown and release of bacterial antigens.
TYPE 1 REACTIONS Increased bioavailability of antigens triggers the DTH
response.
These acute inflammatory events may accentuate the 9. Reaction may be present at the time of presentation
chronic course of the disease in the total clinical spectrum or develop during treatment and even after release
of this disease. Type 1 reactions (Figs 22.1 to 22.5) usually from treatment (RFT).6, 21
occur in borderline leprosy (BT, BB and BL), and very 10. Incidence of RRs is observed to be relatively higher
rarely in lepromatous leprosy.15 The difference of reactional among BB, BL, LL types of leprosy patients when
states between type 1 reaction and type 2 reaction can be MDT is administered combined with immunotherapy
conceptualized as representing fundamentally different (Mycobacterium w) as compared to those under MDT
dynamic events occurring in the lesions of the patients. alone.22, 23
CHAPTER
22
11. Hepatitis B or C may be risk factors for developing with evidence of macrophage activation. Although there is
reversal reactions.24 a fall in lesional cytokine mRNA levels with corticosteroid
therapy, there is still increased expression of some
Immunopathomechanisms cytokines at 6 months. Using mRNA based PCR and in situ
Reversal reactions are caused by increased cellular hybridization, it was observed that a higher percentage of
immune responses (delayed type hypersensitivity reaction- cells expressed IFN-γ (Th1 type of response) in reversal
DTH) to M. leprae antigens in the skin and nerves that is reactions than in ENL lesions.31 In addition to the above, it
presented by macrophages in the skin; and Schwann cells was also noted that higher signals for human serine esterase
in the nerves. This is marked by infiltration of activated (a cytotoxic T-cell marker) in the lesions of reversal
CD4 T lymphocytes, especially of Th1 class, with increased reaction than in those of ENL. In general, in reversal
expression of adhesion molecules on endothelium of blood reactions, the cytokine responses are of Th1 type and in
vessels resulting local DTH. Associated with it is the raised ENL the responses are of Th2 type. The production of
IL-2 receptor and IFNγ with resultant increased cellularity other Th1 responsive interleukins like IL-2 and TNF-α were
(lymphocytes) in the skin and nerves. Clinically, it also increased, which confirms a shift to the Th1 subtype
manifests as localized inflammatory lesions of the skin during a reversal reaction.32-34 Possibly, due to this shift
and nerve; producing neuritis and nerve damage. It is not the humoral immunity during RR seems to be diminished.34
known as to which antigen(s) or antigenic determinant(s) However, there also may occur a shift to Th2 activity in
of M. leprae are involved in the causation of RR. Again, the course of a reaction since there is an mRNA for IL-4 in
the role of autoimmunity is not clear, though it has been some of the lesions.28-30 In a recent study from Brazil for
shown that human nerve and skin have a number of identification of potential markers for reactions, the plasma
antigenic determinants in common with M. leprae. levels of CXC-Chemokine-10 (CXCL10/IP10) and IL-6 were
Although this is primary mechanism, there could be found to be elevated in type 1 reaction, which may serve
alternate immune-mediated pathways for inflammation, as potential laboratory marker tools.35
triggered by host-derived antigens or by the process of The finding of high levels of antibodies against stress
molecular mimicry.25, 26 proteins in patients with RRs, especially to 18 kDa antigen,
along with a heightened lymphoproliferative response to
Histopathological Features Mycobacterium leprae soluble extract (MLSE), is
suggestive of a coexistence of cell-mediated and humoral
The lesions show all characteristics of a delayed type
immunity in leprosy patients during type 1 reaction.36 During
hypersensitivity reaction. At initial stage only mild
the reaction and when it subsides, the relative number of
extracellular edema with some proliferation of fibroblasts
CD8+ (suppressor/cytotoxic) cells increases. 37 The
may be seen with increased number of lymphocytes in
regulatory interleukin, IL-12 was noted in higher percentage
the leprosy granuloma. Later, there is further increase in
of patients of reversal reactions as compared with those
the edema and a change in the cellular composition in and
having ENL.38 Further, Th1 type of response may persist
around the epithelioid cell granuloma, due to influx of
in patients for 6-7 months after the onset of reactions.39 In
lymphocytes that are mainly of CD4 subtype, especially
summary, in RR there is an influx of CD4 T cells into the
of the Th1 class.27-30
granuloma and a mantle of CD8, with increase in Th1 type
Inflammatory edema and infiltration within the nerves
cytokine pattern with increased expression of IFN-γ, IL-2
results in the destruction of Schwann cells by CD4
and TNF-α.
lymphocytes, as also ischemia resulting in pain and
Changes in plasma cytokine levels are not consistently
functional loss.
associated with RRs, however IFN-γ and TNF response
of peripheral blood lymphocytes to M. leprae antigens are
Immunological Studies
increased in RRs, which fall with therapy, but rise again
In last five years, various studies have demonstrated as corticosteroids are withdrawn. It has been shown that
the increased expression of pro-inflammatory cytokines, during RR the peripheral blood lymphocytes show an
TNF-α, IL-1b, IL-6, IFN-γ and IL-12, and immunoregulatory increased immune response to M. leprae antigens as
cytokines, TGF-β and IL-10 in reactional skin lesions, along demonstrated in vitro using lymphocyte migration inhibition
CHAPTER
22
tests (LMIT). These immune responses decrease with 1. Acute: Symptoms persisting up to or less than 1 month.
subsidence of reaction. 2. Subacute: Symptoms persisting for more than 1 month
However, it is still not known which antigens or antigenic up to 6 months.
determinants are responsible for RRs.34, 37 Since M. leprae 3. Chronic: Symptoms persisting for more than 6 months
are very difficult to find in paucibacillary patients especially or recurrence within 3 months of stopping treatment
in those with RR, the autoimmune phenomena have been for reaction.
incriminated by some to play a role in the reactional 4. Recent: Covers both acute and subacute types.
process. It has been shown that human nerve and skin 5. Recurrent/ Repeated reactions: Episodes recurring after
have a number of antigenic determinants in common with 3 months of stopping anti-reaction treatment.
M. leprae.40- 42 Many of these epitopes are heat-shock 6. Late Reversal Reaction (LRR): (RR occurring anytime
proteins (HSPs). In animal models, it has been shown after completion of MDT).
that M. leprae-primed macrophages attack the Schwann Sometimes, reversal reaction develops after the
cells, not only in the presence, but also in the absence of full course of anti-leprosy treatment, any time with in
detectable M. leprae.43 It was also observed in vitro that first two years after release from treatment. This
T-cells that reacted with M. leprae also reacted with happens particularly in those individuals who used to
components of Schwann cells. develop repeated reactions during the course of
A recent study shows that Toll-like receptor 2 (TLC2) treatment or even before starting therapy. It is usually
polymorphisms are associated with reversal reaction in seen over the patches and plaques present over the
leprosy and provide new insights into the immunogenetics face and other exposed areas like forearms. It is
of the disease.44 The microsatellite and the 597C≥t frequently confused with relapse clinically. The
polymorphism both, influenced susceptibility of the host differentiating points are outlined in the Table 22.4.
to RR. Although the 597T allele had a protective effect, At times the differentiation between the two
homozygosity for the 280-bp allelic length of the conditions is so difficult; one may have to prescribe a
microsatellite strongly increases the risk of reversal course of oral steroids (1 mg/kg/day) for a period of 4-
reaction. These associations are consistently observed in 6 weeks. During this period the lesions of LRR would
the different ethnic groups.44 show some subsidence or may clear to a large extent.
If the lesions do not show any regression, the patient
Salient Features of RRs: should be considered as a case of relapse and be treated
Immunology and histopathology with a fresh course of MDT for PB or MB leprosy,
depending on the number of fresh skin and nerve
1. Increased cell mediated (Type IV) immune response lesions.
to M. leprae antigens 7. Type 1 reactions as a part of immune reconstitution
2. Activation of CD4+ lymphocytes (Th1 type) and inflammatory syndrome (IRIS) in HIV positive patients:
increased expression of adhesion molecules on In coexisting conditions of leprosy and HIV, a
endothelium, increased IL-2 and IFN-γ leading to phenomenon akin to type 1 reaction is observed after the
increased lymphocytic infiltration in skin and nerves
patient is put on highly active antiretroviral therapy
(clinically manifesting as inflammed skin lesions,
(HAART). The patient may be having active leprosy patches
neuritis, nerve damage).
which become inflamed and show features of type 1
3. Histopathological features show lymphocytic infil-
tration, extracellular edema in and around epithelioid reaction. Alternatively, the leprosy patches may appear
cell granuloma. It also manifests in nerves showing for the first time after starting HAART, in a situation when
Schwann cell destruction, ischemia of nerve fibers the patient may not be having any patch (subclinical
(clinically manifesting as neural pain and loss of infection). Usually this phenomenon occurs anytime within
function). 3 months (usually 3-6 weeks) after start of HAART start
and is frequently associated with a 2-3 fold rise in the
Clinical Features CD4+ counts (as of the pre-HAART level). (Fig. 22.3). A
detailed account of IRIS in leprosy is given in Chapter 24,
Clinical Terms
Leprosy and HIV Infection.
The various clinical terms used to describe the course of The possible underlying mechanisms for this
the reaction, under different clinical situations are as follows: phenomenon could be that HAART may provide the
CHAPTER
22
corresponding nerve. In the severe form of type 1

reaction nerve abscess may be formed.
5. Tinel sign may be positive, i.e. pressure exerted on
the nerve gives distally a tingling pain.
6. Sometimes loss of nerve function occurs suddenly
without other signs of inflammation, making it much
less obvious—the so called ‘silent neuritis, i.e. without
apparent neuritis, producing claw hand, foot drop, facial
A B palsy.
Figs 22.2A and B: RR in a case of BT leprosy, (A), RR in a case of
BB leprosy (B), note the shiny erythematous and edematous plaques Rare or Uncharacteristic Presentations
1. Tenosynovitis due to synovial inflammation manifested
immunological “trigger” to the antigens present leading to
with a moderately painful swelling over the dorsum of
development of subpolar tuberculoid form of disease.
one or both hands and very rarely over the dorsum of
Secondly, there could be a sudden unexplained switching-
on of Th1 type responses to M. leprae, induced by HAART,
even though HIV may not impair immune responses to
M. leprae. Thirdly, HIV co-infection could result in a degree
of suppression of host responses to M. leprae infection
which is reversed after commencing HAART.45
Clinical Manifestations
Symptoms
Patients may complain of burning, stinging sensations in
the skin lesions. They may have aches and pains in the
extremities and of loss of strength and/or sensory
perception. They may suddenly start dropping things from
their hands and/or stumble when walking.
Signs Fig. 22.3: Development of a single erythematous plaque of BT leprosy

with type 1 reaction in a HIV positive patient, 7 weeks after start of
1. Increased inflammation of some or all of the pre-existing HAART (IRIS). The CD4+ counts rose from 125 cells (pre-HAART
skin patches or plaques which become erythematous, level) to 333 cells / mm3 during this period
swollen and may be tender looking like erysipelas.
Necrosis and ulceration can occur in severe cases.
Lesions desquamate as they subside.
2. Crops of fresh inflamed skin lesions in the form of
plaques may appear in previously clinically uninvolved
skin. The pattern of these skin lesions are of upgrading
nature clinically as compared to the existing skin
lesions.
3. Edema of extremities or face, frequently accompanied
by nerve involvement.
4. Neuritis: Rapid swelling with severe pain/tenderness
of one or more peripheral nerves is common at the site
of swelling or along the course of the nerves. The
A B
peripheral nerve affected is usually close to the inflamed
Figs 22.4A and B: BB leprosy with reversal reaction. The plaques
skin lesion or situated over the area innervated by the are prominent with erythema and edema
CHAPTER
22
the feet (Fig. 22.5). It is commonly associated in BT accompanying edema of the hands, feet and face with or
and BL leprosy.46 without peripheral nerve involvement.
2. Very severe reaction may be characterized by necrosis
and deep ulceration. This is presumably the result of Criteria System
exaggerated hypersensitivity in type 1 reaction. A criteria system for clinical diagnosis of T1R has been
3. Systemic manifestations like fever, malaise, vomiting, proposed by Naafs and his team, which can be used for
epistaxis, and joint pain are unusual.46 research purpose or for operation under field conditions. It
includes presence of one major criterion or at least two
Grading minor criteria (without signs of ENL) for the diagnosis of
type 1 reaction, as shown in Table 22.2.47
RRs can be graded as mild or severe in form. This is
essential for management and for the purpose of referral
Table 22.2: Criteria for diagnosis of T1R
from primary health care level to middle or tertiary care
level, for admission and management by the specialists. Major 1. Pre-existing and/or new skin lesions become inflamed,
red and swollen.
1. Mild: Few skin lesions with features of reaction clinically; Minor 1. One or more nerves become tender and may be swollen
without any nerve pain or loss of function. 2. Crops of new (painless) lesions appear.
2. Severe: 3. Sudden edema of face and extremities.
a. Nerve pain or paraesthesia 4. Recent loss of sensation in hands and feet or signs of
recent nerve damage (loss of sweating, sensation,
b. Increasing loss of nerve function muscle strength) in an area supplied by a particular
c. Fever or discomfort nerve.
d. Edema of hand, feet
e. Mild reaction persisting for more than 6 weeks Histopathological Examination48
f. Reaction of skin lesion on the face Before the reaction is clinically apparent, there may be
g. Ulcerative skin lesion some diffuse extracellular edema in and around the
granuloma and in the superficial dermis and a diffuse
Diagnosis proliferation of fibrocytes in the dermis. However, when
Clinical the reaction is clinically apparent, the histological response
Usually RR is diagnosed clinically when a patient has is not altogether predictable, it varies greatly in degree.
erythema, tenderness and edema overall or some of the Edema and proliferation of fibroblast may be profuse or
existing skin lesions; with or without appearance of fresh barely significant. If the delayed type hypersensitivity
similar reacting skin lesions and/or neuritis. There may be (DTH) reaction upgrades further, the granuloma is
completely replaced by the epithelioid cells and giant cells.
Foreign body giant cells may appear at this stage and if
edema is profuse they acquire vacuoles due to intracellular
edema. These could be confused with lepromatous
vacuoles but they contain no AFB, and are not present
unless there is much extracellular edema. An important
feature of a severe reaction is the breakdown and dispersal
of the granuloma or even liquefaction necrosis and
ulceration. Small accumulations of polymorphs are
sometimes present, but unlike ENL they are associated
with the presence of epithelioid cells. Heavy granuloma
formation or even caseation may be seen in the small
nerve bundles of the skin. Fibrinoid necrosis, if present,
A B signifies strong upgrading to TTs (sub polar tuberculoid
Figs 22.5A and B: The same case as in Fig. 22.4. The reaction leprosy), and it is followed by fibrosis. More details are
may be associated with edema of hands and/or feet given in Chapter 9, Pathology Aspects.
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22
Lepromin Reaction necessary as treatment with steroids for the RRs could
Due to strong DTH response in RR, the positivity of lepromin promote multiplication of bacteria.49
will be stronger in BT and TTs and may become positive Recently, a new diagnostic criterion for multibacillary
from earlier negativity in BB and BL. relapses in leprosy has been proposed by Linder et al,
taking into account the time factor, risk factors and clinical
Other Laboratory Tests presentation at relapse using a scoring system (Table 22.4).
No laboratory criterion is available for the assessment of This scoring system needs further validation in a
reaction. Further research is needed for new markers, e.g. prospective study to confirm its superior sensitivity and to
neuropeptides, specific antigens, and recently reported evaluate the specificity of these criteria by using mouse
potential markers CXCL10 and IL-8 for early diagnosis of foot pad (MFP)-confirmation of patients presenting with
RRs.35 signs of activity after treatment including late RR.50
Table 22.4 shows the final ‘Linder score’ which (in
Differential Diagnosis contrast to and as the only difference to “essential score”)
includes primary PB cases, (negative BI of ≥ 2+) at relapse
Reversal reaction, particularly late RR, must be differen-
is sufficient to score.
tiated from relapse (Table 22.3) and the other skin
conditions like acute urticaria, erysipelas, cellulitis, and Course
insect bite.
The problem in the diagnosis of late RR in leprosy is The type 1 reaction, if properly and adequately treated,
how to differentiate relapse and reactions from each other. seldom persists for more than a few months. Recurrences
This is emphasized in a study by Shetty et al49 who usually indicate inadequate therapy.
investigated biopsies of 25 BT leprosy cases presenting
with recurrent lesions, 1-13 years after RFT. Although none TYPE 2 REACTIONS
of the cases showed overt signs of reaction, 13 cases Type 2 reaction (T2R) is an immune complex syndrome
were histologically characterized as type 1 reaction, (antigen-antibody reaction involving complement). It is an
whereas the others showed features of BT leprosy only. example of type III hypersensitivity reaction (Coombs and
However, mouse foot pad inoculations detected live Gell classification) or Arthus phenomenon. IgG, IgM,
bacteria in five and seven cases in both groups of patients complement (C3) and mycobacterial antigens are all
respectively. The differentiation of RR and relapse is identified at the site of ENL. Therefore, immune complex
Table 22.3: Criteria helping in distinguishing a relapse from a type 1 reaction

(Most of these adapted from “Global strategy for further reducing the leprosy burden and
sustaining leprosy control activities, 2006-2010, Operational Guidelines, WHO, 2006)
Criteria Reversal reaction Relapse
Type of leprosy Observed in BT, BB, BL and sub-polar leprosy Can occur in all types of leprosy after it
becomes inactive with treatment
Onset Sudden Insidious
Time Any time during treatment and within 3 years More than 3 years after RFT
after release from treatment (RFT)
Progression of signs and symptoms Fast Slow
Site of skin lesions Over old patches In new places
Pain, tenderness or swelling Present over skin lesions and nerves Not usually present, however, rarely
relapse may present with clinical
manifestation of RRs
Nerve damage Sudden onset Occurs slowly
General conditions May be there (inflammation), mild symptoms
like body-aches and fever may be present Not affected
Response to steroid Good, subsides Not effective, disease may progress
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22
Table 22.4: Diagnostic scoring system for MB-relapse in Immunopathomechanisms
leprosy (Linder et al)
Initially, there is minimal increase in the number of
Factor Parameter Score*
lymphocytes, especially perivascularly. The majority of
I Time factor (Time after ≤ 12 0 these cells are CD4+ Th2 cells.53 With the progression of
release from treatment- 13-24 1 reaction, the number of these cells increases further and
RFT) (Months) 25-60 2
surpasses the number of CD8 cells that normally form the
>60 3
majority in a lepromatous leprosy lesion.37 This goes in
II Risk factor Initial BI ≥ 3+ 1
parallel with an increase in mRNA for IL-4, IL-5, IL-13 and
III Clinical factor BI in a single lesion 1
perhaps IL-10 cytokines, which are indicative of a Th2
(presentation at ≥ 2+ higher than the
relapse) expected BI**
type of reaction.28,54 The reflections of both immune-
Average BI is ≥ 2+ higher 1 complex and enhanced T-cell reactivity are observed, both
than the expected BI** in the blood and tissues.
No signs of reaction*** 1 During early phase of ENL in the lepromatous
* Relapses are diagnosed with a score of ≥ 3; the maximal
granuloma, in between the foamy cells, the smaller cells
score = 7; the maximal score for the time factor = 3, the maximal like monocytes, become active macrophages and probably
score for the additional factors = 4, these scores are added to give destroy the inert foamy macrophages. Release of antigens
the final score. from these foamy macrophages can be presented by fresh
**Expected BI = Calculated BI with an assumed fall of 1 log-unit/
year. If the initial BI was negative, a positive BI at relapse is macrophages to the immune system and further stimulate
sufficient to score. CMI. Those antigens which could not be engulfed by
*** Clinical signs of inflammation of the nerve or the skin or macrophages; form immune complexes with the locally
erythema nodosum leprosum.
present antibodies.55
Immunology
formation is implicated in the pathogenesis of type 2
reaction. The major clinical lesions on the skin are of In addition to immune complex formation, the involvement
erythema nodosum type; hence the term “erythema of CMI is proved by observation that the number of IL-2
nodosum leprosum or ENL” is used as an alternative term receptors on the immune competent cells increases, as
does the HLA-DR expression, not only within the infiltrate;
for T2R.
but also on the keratinocytes of the overlying epidermis.37,53
Type 2 reaction (ENL) occurs mostly in lepromatous
In early ENL lesions CD4 Th2 lymphocytes (the helper
(LL) and sometimes in borderline-lepromatous leprosy (BL).
T-cells) influx has been observed, the number of which
Lepromatous leprosy patients with high bacillary index are
may exceed CD8, the suppressor T-cells. Within the lesions
more prone to get ENL.51
the plasma cells, which can be stimulated by the IL-4
Risk Factors producing cells, are able to produce antibodies. These
antibodies combine the ubiquitous antigens and form
1. Lepromatous leprosy with skin infiltration52 immune complexes.53, 56
2. Antileprosy drugs except clofazimine Mycobacterium leprae antigens, IgG, IgM antibodies,
3. Bacterial index (BI) of >4+52 complement (C3d) and IL-4 mRNA are all identified in ENL
4. Patients with < 40 years of age52 skin lesions. IL-4, known to be a B-cell stimulator, increases
5. Intercurrent infections—streptococcal, viral, intestinal the HLA-DR expression and is a growth factor for mast
parasites, filaria, malaria cells. In a full blown ENL lesion, polymorphonuclear
6. Trauma granulocytes dominate the picture; a few leu7-positive
7. Surgical intervention (natural killer) cells can be seen along with increased
8. Physical and mental stress number of mast cells.37, 57
9. Protective immunizations Evidence of involvement of both, immune complexes
10. A strongly positive Mantoux test and CMI, in ENL has been shown in the peripheral blood
11. Pregnancy and parturition also. During ENL there is an in vitro increase in the response
12. Ingestion of potassium iodide. of peripheral blood leukocytes to mitogens, indicating a
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22
generalized increase in the CMI. The complement factor is a local reduction in the bacterial load. Most of the
C3d is increased in the peripheral blood which indicates organisms are fragmented and granular. During healing
complement activation and is probably a spill-over phase the neutrophils are gradually replaced by
from the tissues and not a sign of a classic Arthus lymphocytes.
phenomenon. In neuritis associated with T2R, there is inflammatory
The most prominent cytokines present during ENL edema, and cellular exudates in the perineurium.
reaction are IL-4, IL-5, TNF-α, and IFN-γ are known to be
a pyrogen which may be responsible for the rise of Salient Features: Immunology and
temperature and further tissue damage during ENL Histopathology
reaction.58 A recent study from Brazil for identification of
1. Initial histopathological features are of LL or BL
potential markers of reactions has reported the elevated
leprosy.
levels of IL-7, platelet derived growth factor BB (PDGF
2. Dense infiltration of dermal and subcutaneous tissue
BB) and IL-6 could serve as the laboratory markers of
by neutrophils (sometimes forming microabcesses),
type 2 reaction.35
superimposed on existing lepromatous diffuse
Similar to type 1 reaction, during ENL auto-immunity
granuloma.
might also play a role in the tissue damage. Histopatho-
3. Vasculitis, damage to collagen and elastic fibers are
logical examination of ENL tissue shows an increase in
common features clinically manifesting as skin
neural cell adhesion molecules (N-CAM) and N-CAM-
necrosis and ulcerations.
positive CD8+ cells are isolated from the nerve tissue.
4. Increased expression of IL-4, IL-5, IL-13 and IL-10
During active ENL reaction, when peripheral blood
cytokines (Th2 type response) and TNF-α and INF-γ
monocytes (PBMC) are exposed to M. leprae, there is an
5. Local reduction of bacterial load, presence of M leprae
increase in cytolysis of N-CAM- expressing Schwann cells
debris and replacement of neutrophils by
by CD8+ N-CAM-positive cells. IL-15 which is capable of
lymphocytes are other histopathological features of
inducing N-CAM expression has been found in excess in
type 2 reaction.
leprosy tissue.59
6. Evidence of presence of both immune complex
mediated (type III) and cell-mediated (Type IV)
Nomenclature
immune response in ENL.
Since many sign and symptoms described above can occur
without classical ENL lesions, the term type 2 reaction is
used to describe this type of leprosy reaction rather than
ENL. However, ENL term is often used by the physicians Time of Onset
or dermatologists or leprologists for those patients who
Type 2 reaction occurs mostly during the course of
have clinical evidence of ENL with or without other signs
antileprosy treatment. A few cases present for the first
and symptoms of type 2 reaction.
time with features of reaction before leprosy is diagnosed
and treatment started. Data on time of onset of the
Histopathology
reactions collected by IAL in 2003 both from the field and
The ENL lesion initially shows features of either LL or BL hospital shows that 21% of all cases present as ENL
histopathology depending on the clinical spectrum the lesions at the beginning, 17.6 % present within 6 months
patient belongs to. Histopathologically, there is dense after starting MDT, 16.6% during second half of the year
infiltration of the superficial and/or deep dermis and/or of MDT, and 44.5% have the episodes even beyond one
subcutaneous tissue by neutrophils. They are year of therapy.8 Chandigarh study also showed similar
superimposed on an already existing lepromatous figures, 19.4% (in BL) and 20.1 % (in LL) at registration,
granuloma. Often the influx of neutrophils is so intense as 10.5% (in BL) 12.9% (in LL) within 6 months, 17.2% (in
to form microabscesses. Vasculitis is a predominant BL) and 17.4% (in LL) in second half of first year, 32.8%
feature in some cases. Damage to collagen and elastic (in BL) and 27.2% (in LL) in second year, 20% (in BL) and
fibers is common. In some variants known as necrotizing 21.8% (in LL) in third year and beyond.6A recent report
ENL, there is also necrosis and ulceration of skin. There from Nepal showed similar figure (30% of patients
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22
presented with ENL at time of diagnosis, 41% developed crops of ENL lesions usually appear in the evening when
during the first year of MDT.60 endogenous cortisol production is at its lowest.12 New ENL
lesions appear, as old lesions subside. An individual ENL
Mode of Onset
lesion after a period of 24-48 hours shows a change of
1. Rheumatic onset: In one third of the cases, pain and color from pink/red to bluish and brownish and finally dark,
swelling in the joints precede or are a component of in a week or ten days. ENL lesions may not uncommonly
other of other constitutional symptoms. The patient become vesicular, pustular, bullous and necrotic and break
may sometime gets admitted in the internal medicine down to produce ulceration called as erythema nodosum
department with suspicion of rheumatic or rheumatoid necroticans.62, 63 In certain cases, the lesions may be
fever. There are case reports of type 2 reactions with hemorrhagic resembling Lucio phenomenon.
manifestations mimicking systemic lupus erythematous The ENL lesions subside with desquamation or there
(SLE), polyarteritis nodosa (PAN), and Behçet’s may be peeling of the superficial skin (Fig. 22.10). Pustular
syndrome.61 lesions scab or leave shallow ulceration followed by
2. Cutaneous onset: There may be appearance of skin scarring of the involved skin. Erythema multiforme type of
lesions in the form of maculopapular, papular, nodular skin lesions are also described.64 There may be edema of
or plaque type of lesions before the appearance of the hands, feet or face. When the inflammatory edema on
constitutional signs and symptoms. the dorsum of the hand is associated with SCN and arthritis
3. Mixed onset: Fever, joint pain and other constitutional of the interphalangeal (IP) joints; it constitutes the clinical
signs and symptoms; and skin lesions develop together condition known as the “reaction hand”.
and fever immediately follows the appearance of skin
lesions.
Skin Lesions
ENL
In classical type 2 reaction, usually no clinical change is
noticed in the original clinical lesions of leprosy, in contrast
to the type 1 leprosy reaction, where the lesions become
more prominent, erythematous, edematous and sometimes
tender. However, ENL lesions may appear anywhere, deep
A B
in the dermis and subcutaneous tissue even though these
Figs 22.6: Type 2 reaction (ENL) in a case of LL leprosy. Note the
are not clinically apparent on the surface of the skin. shiny erythematous papules and nodules (usually tender) over face
There is sudden appearance of crops of evanescent and thighs. The lesions are evanescent and usually associated with
(lasting for few days) pink (rose) colored tender papules, systemic features like fever, malaise, joint pain, etc.
nodules or plaques variable in size. They are painful and
tender to touch (Figs 22.6 and 22.7). These lesions may
be present inside the dermis and visible clearly or may be
deep enough involving subcutaneous tissue forming
subcutaneous nodule (SCN) where they are palpable rather
than visible. The nodules are dome-shaped and ill-defined.
These skin lesions are known as erythema nodosum
leprosum (ENL). The common sites of appearance of ENL
are outer aspects of thighs, legs, and face. However, they
may appear anywhere on the skin except the hairy scalp, A B
axillae, groin and perineum, the warmer areas of the body. Figs 22.7A and B: Erythema nodosum leprosum (ENL) lesions in a
These may be few or multiple, if multiple they tend to be case of LL leprosy, few of the lesions show gangrenous changes and
breakdown (erythema nodosum necroticans) (A). The lesions healed
distributed bilaterally and symmetrically. They are tender, leaving behind depigmentation and scarring after subsidence, following
warmer, and blanch with light finger pressure. The fresh 4 weeks course of thalidomide along with MDT (B)
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22
Skin lesions sometimes tend to recur at the same sites.

If they do not subside completely; a chronic painful
panniculitis develops which may persist for months or
years. Large areas of inflamed skin and subcutaneous
tissues get fixed to underlying fascia, muscle, bone, and
may thus immobilize a hand or foot or even the face. This
fixed fibrous tissue is poorly vascularized and may ulcerate
with slightest trauma, and heals with difficulty.
Another peculiar form of ENL is also described by some A B
authors is “lazarine leprosy” the term which itself is a subject Figs 22.8A and B: The shiny papules and nodules over the back of
upper trunk back in a case of LL, resembling the lesions of Histoid
of nonconsensus. Cochrane described it as a chronic leprosy (A). Similar type of lesions over shoulder region showing
progressive form of ENL in which individual subcutaneous central necrosis and ulceration. This unusual presentation with acute
nodules tend to breakdown and ulcerate, and the patient’s exacerbation of leprous lesions are rare in type 2 reaction (B)
condition is very distressing.65 However, according to
Ramu and Dharmendra, lazarine leprosy is a rare form of
leprosy that occurs near tuberculoid end of borderline
spectrum of leprosy in debilitated patients, it is
characterized by extensive ulceration of the lesions, which
commonly involve the trunk and the extremities.64 The
features of lazarine leprosy are further discussed in the
section on lucio phenomenon.
Lepromatous Exacerbation A B
The term lepromatous exacerbation has been used in older Figs 22.9A and B: Type 2 reaction with presence of vesico-bullous
and crusted lesions (erythema nodosum necroticans), some of these
literature for certain type of reaction in LL. This type of
lesions are arranged in annular fashion, over the existing lesions of
reaction is characterized by exacerbation of the LL skin BL, a rare form of ENL
lesions; they are swollen, red, painful and tender. There
may be constitutional symptoms. Lesions may ulcerate histoid lesions and in other large hyperactive lesions,
and involve cartilage of pinna giving a rat-bitten appearance. nodular or otherwise, mimicking ENL histologically.66
Exacerbation may involve the mucosa, leading to nasal
stuffiness ands hoarseness of voice. Rarely laryngeal Unusual Pattern of Vesiculobullous
edema may require emergency tracheostomy. Type 2 Reactions
Acute exacerbation of the disease is mainly seen in Atypical bullous lesions in T2R arranged in an annular
very advanced lepromatous patients with nodular and fashion on the extensor aspects of arms and lower legs
plaque-like lesions. The author has recently noticed a have been described in a pregnant lady after ingestion of
similar clinical form, where some of the shiny papulonodular ofloxacin for urinary tract infection.67 The authors also
histoid looking LL lesions suddenly underwent central observed similar type of lesions in a young unmarried
necrosis and ulceration (Figs 22.8A and B). Histologically, female, an untreated case of BL leprosy who suddenly
there are small localized areas of necrosis in the middle of developed T2R with the appearance of papulovesicular
a large sheet of macrophages eliciting a localized infiltration lesions in an annular form over the inner margin of the BL
of neutrophils. Vasculitis is rarely seen. The macrophages plaques after taking a course of ofloxacin (a bactericidal
contain a relatively large load of AFB with many solid drug for M. leprae) for treatment of acute urinary tract
staining organisms which differentiate acute exacerbation infection (Figs 22.9A and B).
from ENL. This may be due to sudden burst of bacterial
multiplication which overgrows the macrophage population, Systemic Manifestations
resulting in localized cell necrosis and acute inflammation. In T2R, the systemic manifestations like fever, malaise,
However, Ridley and Job (1985) described ulceration in prostration, headache, muscle, joint and bone pain, usually
CHAPTER
22
confining to tibia are common, may precede the appearance b. Arthritis: In one third of the cases, T2R is heralded by
of ENL. The rise of temperature is usually of intermittent the rheumatic type of onset. The presenting features
type in the acute stage with the fastigium in the evening. consist of joint swelling, pain, tenderness, limitation of
As the reaction subsides, the temperature comes down. movements. Synovial effusions and bursitis are found
In very severe types, the fever may be remittent in nature and in certain cases joint effusions appear very rapidly.
with diurnal variations. The joints commonly affected are knee, metacarpo-
phalangeal, interphalangeal, wrist and ankle joints; in
Nerve Involvement order of frequency. In recurrent T2R, nonparalytic
deformities and limitation of movement at the joint and
Nerve damage may occur in T2R, but not as quickly as it
radiological changes may develop without or with
occurs in type 1 reaction. Due to inflammatory edema and
inadequate treatment.
cellular exudates in the perineurium; the nerve is unable to
accommodate the increase in its bulk contents. c. Nose involvement: The infiltration and nodules present
Compression of the vasa nervorum and of the nerve fibers, in the nasal septum and inferior turbinate may be
results in precipitation of acute symptoms. Added swollen with blocking of the nose leading to difficulty
compression is provided by points of entrapment of certain in breathing. It may be associated with pain and
sites, e.g. the ulnar groove, the median nerve in the carpal epistaxis. In severe cases the nodules may ulcerate,
tunnel, the lateral popliteal in the fibro-osseous canal at the cartilage may be involved resulting in perforation
the neck of fibula, and the posterior tibial nerve in the of the septum.
tarsal tunnel. In addition, the facial, radial and cutaneous d. Soft palate involvement: The soft palate, fauces, base
nerves may also be involved. of the uvula may be hyperemic and may ulcerate. The
In severe T2R, there may be swollen, painful, and tender repeated ulceration may lead to complete destruction
nerve trunks with loss of function. Careful nerve
e. Hard palate involvement: Similarly, hard palate may
examination is essential to detect recent nerve function
be hyperemic and swollen during reactive states.
impairment (sensory, motor and autonomic functions)
Erosion of these reacting lesions involves the bone
of the respective affected nerves during and after
with destruction and eventually a perforation of the
each episode of T2R. However, skin involvement may not
palate may result.
be always associated with the manifestation nerve
lesions. f. Larynx involvement: In presulphone era the
inflammatory reaction involving the larynx was a life-
Other Associated Features threatening complication. The edema of the epiglottis
or of the false vocal cords led to respiratory
The associated features of T2R are myositis, arthritis,
embarrassment which sometimes necessitated
synovitis, rhinitis, epistaxis, laryngitis, iridocyclitis,
tracheostomy as a life-saving procedure.
glaucoma and painful dactylitis. There may be periosteal
pain (particularly in tibia), tender and swollen lymph nodes g. Bone changes:
(especially inguinal and femoral groups), acute epididymo- • Osteoperiosteitis: Osteoperiosteitis particularly
orchitis, nephritis and proteinuria, renal failure, over the anterior aspect of the tibia is very common.
hepatosplenomegaly, anemia and amyloidosis. There is severe bone pains and soft tender swelling
of the anterior aspect of tibia. X-ray picture reveals
a. Acute myositis: Muscle involvement in T2R is not elevation of the periosteum at the site of swelling
uncommon which may be invaded by an extension of with soft shadow underneath. Repeated attack may
the process of SCN formation, from the subcutis to lead to laying down of new bone with thickening of
deep into the muscle through deep fascia. The entire the cortex and increased anterior curvature of the
involved region feels woody hard. In some cases bone looking like ‘sabre tibia’ of syphilis. Besides
painful, tender, firm nodular lesions occur in the muscle tibia involvement it may also involve the phalanges
fibers per se. The movement of the muscles is painful. (dactylitis) producing spindle-shaped swellings with
In both instances the histopathological features of tenderness. This can occur at the upper end of ulna,
myositis are observed. the lower end of fibula, and the calcaneum.
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22
• Osteoporosis: Osteoporosis may occur without the breast. Repeated attacks of reaction result in
accompanying arthritis. The phalanges and testicular atrophy and gynecomastia.
metacarpals are common sites of predilection. It m. Hematological changes: Occasionally, a hemolytic
has been observed in long bones and ribs. It may crisis may be encountered with a dangerous fall in the
occur in the form of demineralization or as punched RBC count and hemoglobin. There is sudden pallor;
out areas of rarefaction seen in the skiagrams. The the patient develops breathlessness on the slightest
rarefaction may result in pathological fractures. The exertion. The condition calls for prompt treatment with
pull of the contracting muscles over the rarefied steroids and blood transfusion. Megaloblastic anemia
phalanges may lead to subarticular collapse of the has been documented possibly because of toxic or
bones. The demineralization is an acute process depressive effect on bone marrow. Therefore, there
as evidenced by increased excretion of calcium in may be dimorphic anemia.
the urine during reaction phase.
h. Lymph nodes enlargement: During ENL episodes, Type 2 Reactions without ENL
there is often acute and painful enlargement of inguinal, It is possible that the manifestations of the reaction may
axillary, cervical and epitrochlear lymph nodes along not be confined to the skin, and the patient may develop
with constitutional signs and symptoms. Occasionally, neuritis or systemic involvement or both, depending upon
large abscesses are formed which break open through the target organs where immune complexes deposition
lymph node capsule and skin producing sinuses with occurs.
discharge of pus. On acid-fast stain the pus shows
numerous M. leprae inside the neutrophils and Severity of Type 2 Reaction
macrophages.
i. Liver changes: Hepatic enlargement below the costal Presence of one or more of the features mentioned under
margin is sometimes observed. The liver is soft and severe reaction (Table 22.5) is considered as severe type
tender. 2 reactions which need treatment with steroid; albeit in
j. Kidney changes: Acute glomerulonephritis in leprosy older times, it was graded as mild, moderate and severe.
may be associated with ENL, due to the immune In milder grade, the temperature does not raise above 100o
complex deposition involving antigens of M. leprae. F; and the reacting skin lesions (ENLs) are few, confined
However, in majority of cases the blood pressure is to one or two extremities. In moderate degree, the
not elevated. The routine examination of urine reveals temperature goes up to 102oF the skin lesions are more
albuminuria many times in T2R from a trace to 1+. The numerous, affecting all the 4 limbs, with few on the trunk,
microscopic examination of the sediments after face and perhaps occasionally vesiculation. Extra-
centrifuging the urine sample reveals plenty of RBC, cutaneous signs may also be present. In the severe grade,
pus cells, epithelial cells, casts (from RBC, pus cells) the temperature rises above 102oF, tends to be of remittent.
and granular casts. In few instances frank hematuria, Vesiculation and postulation are frequent. Visceral
and rarely oliguria is observed. Kidney involvement is involvement is not uncommon.
observed with repeated attacks of T2R, rarely ending
Reaction Severity Assessment System (RSS)
fatally. In others, repeated reaction favors the onset
and progress of the amyloidal process of which renal
(Table 22.6)
amyloidosis forms a part. A reaction severity score may play an important role in
k. Suprarenal involvement: The blood pressure remains making clinical decisions about reactions, the choice of
low due to hypofunction of the suprarenal gland during treatment and monitoring progress. Reaction severity
reactive phases. The treatment with corticosteroid assessment for both types of reaction (type 1 and type 2)
should be prompt in adequate doses to compensate can be calculated more accurately using reaction severity
for the decrease of the hormone. scale formulated and tested by van Brakel and his team.68
l. Acute epididymo-orchitis: There may be acute pain, This group assessed 21 items as the basis for a reaction
tenderness and swelling in the scrotum during T2R due severity scale. These included assessment of skin signs,
to acute inflammation of the testes and epididymis. fever, edema and forms of neuritis plus changes in sensory
There may be concomitant swelling and tenderness of and motor function assessed using monofilaments (200 mg,
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22
Table 22.5: Differentiation between mild and severe form of type 2 reaction
Clinical Feature Type 2 reaction (Mild) Type 2 reaction (Severe)
1. Skin lesions and extent of involvement Few lesions Multiple red, painful nodules in skin, with/
without ulceration
2. Ulceration/ necrosis of skin lesion Absent Present
3. Constitutional symptoms like fever, arthralgia or fever Absent Present
4. Neuritis Absent Pain and tenderness in one or more nerves
5. Edema of limbs Mild Marked edema of the hands, feet or face
6. Eye involvement (Pain/ tenderness of eye, with or Absent May be present
without loss of visual acuity)
7. Recurrent ENL Nil Four or more episodes in a year
8. Response to oral steroids Usually responds in 6 weeks Persists for long
9. Tender lymphadenopathy Absent Frequently present
10. Systemic involvement (like epididymo-orchitis) Absent May be present
2 g, 4 g, 10 g and 300 g) and voluntary muscle testing his team includes the major criterion or at-least three minor
(VMT) respectively. Monofilament assessment at each test criteria.47
point is scored 0 where the 200 mg monofilament is felt
Clinical Tests
through to 5 where the 300 g is not felt. Muscle testing is
scored using the standard Medical Research Council Certain clinical tests are used as a clue for diagnosis of
(MRC) grading, normal (5), full range of movement but T2R.
reduced resistance (4), full range of movement but no 1. Ryrie’s test: Stroking the sole of the foot with the back
resistance (3), movement but reduced range (2), muscle of a reflex hammer elicits a burning pain which also
flicker (1) and paralyzed (0). For the eye, any gap on strong may be noticed when watching the patient walk, which
closure was substituted for movement but reduced range. seems as if he is walking on hot coals.
2. Ellis’ test: Squeezing the wrist during ENL elicits a
Table 22.6 summarizes test points for hands and feet
painful reaction; this does not occur in RRs unless the
and the method of calculation of a severity score ranging
radial cutaneous nerve is tender.
from 0 to 70, higher score being associated with more
severe reactions. However, this scoring system requires Histopathological Features of the Skin from the ENL
formal testing for validation and reliability. Lesions
Originally, the scoring of the items in the ‘Section A’ of Classical histopathological features of active ENL lesions
the severity scale was weighted in such a way that a score of the skin are increased vascularity with dilated
of ‘3’ or more on any individual item would trigger the capillaries in the upper dermis, and in the lower dermis, an
diagnosis that the outcome event (reaction or nerve intense infiltration with neutrophils which have predilection
function impairment) was severe and required steroid for surrounding blood vessels and invading the walls. There
treatment. In section ‘B’ a score of ‘2’ or more triggered is edema of the endothelium of veins, arterioles and small
the diagnosis ‘severe’ arteries. In case of erythema necroticans there is
obliterative angiitis and endarteritis. Bacilli are few and
Diagnosis are mostly fragmented and granular. The acid-fast
bacilli are usually scanty However, it is possible to
Clinical demonstrate mycobacterial antigen by the immuno-
Classical ENL and rarer types of T2R with different peroxidase technique.
morphological patterns with or without other constitutional In bullous ENL, immunofluorescence studies have
features and associated manifestations are diagnostic. revealed IgG deposits at the basement membrane zone in
(Table 22.7). Criteria for diagnosis of T2R (ENL) may be occasional cases; only fibrinogen deposits in one case62,
used for research or in the field proposed by B. Naafs and while negative immunofluorescence in others.63
CHAPTER
22
Table 22.6: Reaction severity assessment 68

Section A: Score reaction signs and symptoms in the right hand column
Scoring 0 1 2 3 4 Score
A1 Number of raised and inflamed lesions None 1-3 4-10 >10
A2 Degree of inflammation of skin lesions None Erythema or Erythema, raised Ulceration
of nodules nodules plaques or nodules
A3 Peripheral edema due to reaction None Minimal Visible, but not Edema
affecting function affecting
function
A4 Fever due to reaction < 37.5 37.6-38.9 ≥ 39
A5 Involvement of other organs None Mild Definite
(eye, testes, etc)
A6 Nerve pain and/or paraesthesia None Intermittently, Sleep
not limiting disturbed
activity and/or
activity
diminished
A7 Nerve tenderness on gentle palpation None Absent if Present if Withdraws
attention is attention is limb forcibly
distracted distracted
Section B: Score sensory assessments in the right hand column
Scoring 0 1 2 3 Score
B1 Ulnar-left No recent worsening 1 to 2 points worse 3 to 8 points worse 9 to 16 points worse
B2 Ulnar-right No recent worsening 1 to 2 point worse 3 to 8 points worse 9 to 16 points worse
B3 Median-left No recent worsening 1 to 2 point worse 3 to 8 points worse 9 to 16 points worse
B4 Median-right No recent worsening 1 to 2 point worse 3 to 8 points worse 9 to 16 points worse
B5 Lat. Pop.-left No recent worsening 1 to 2 point worse 3 to 8 points worse 9 to 16 points worse
B6 Lat. Pop.-right No recent worsening 1 to 2 point worse 3 to 8 points worse 9 to 16 points worse
Section C: Score motor assessments in right hand column
Scoring 0 1 2 3 Score
C1 Facial-left No recent worsening 1 point worse 2 points worse 3 to 5 points worse
C2 Facial-right No recent worsening 1 point worse 2 points worse 3 to 5 points worse
C3 Ulnar-left No recent worsening 1 point worse 2 points worse 3 to 5 points worse
C4 Ulnar-right No recent worsening 1 point worse 2 points worse 3 to 5 points worse
C5 Median-left No recent worsening 1 point worse 2 points worse 3 to 5 points worse
C6 Median-right No recent worsening 1 point worse 2 points worse 3 to 5 points worse
C7 Lat. Pop.-left No recent worsening 1 point worse 2 points worse 3 to 5 points worse
C8 Lat. Pop.-right No recent worsening 1 point worse 2 points worse 3 to 5 points worse
Total score: Sections A + B+ C
Laboratory Tests 20,000 to 50,000 per cubic mm. The erythrocyte

1. There is need for development of laboratory tests to sedimentation rate (ESR) is markedly elevated.
assist in the assessment of severity and resolution C-reactive proteins appear in the blood. Megaloblastic
of ENL. Further research is needed on the evaluation anemia has been observed due to bone marrow
of recently reported laboratory markers IL-7, PDGF- depression. Occasionally, hemolytic crisis may be
BB and IL-6, as the indicators of type 2 reaction. observed with dangerous fall in the RBC count and
2. There is no definitive criterion for histopathological hemoglobin.
diagnosis. 4. Routine and microscopic urine examination is must for
3. Hematological changes: There is always a detection of albuminuria, RBC, pus cells, epithelial cells
leukocytosis during reaction; the count varies from and casts to exclude kidney involvement.
CHAPTER
22
Table 22.7: Criteria for diagnosis of T2R ENL is frequently associated with malaise, leg edema,
and arthritis or arthralgia.
Major 1. A sudden eruption of tender (red) papules, nodules or
plaques, which may ulcerate. Rheumatic fever, rheumatoid arthritis, collagen
Minor 1. Mild fever, the patient is unwell disorders like system lupus erythematosus; and drug
2. Tender enlarged nerves reactions are to be kept in mind and need to be excluded.
3. Increased loss of sensation or strength It is not unusual to notice both types reactions (type 1
4. Arthritis
5. Lymphadenitis
and type 2) observed in same individual with BL or subpolar
6. Epididymo-orchitis type of leprosy while under MDT.
7. Iridocyclitis or episcleritis
8. Edema of extremities or face LUCIO’S PHENOMENON
9. Positive Ryrie’s or Ellis’ test
This is a special type of reaction observed in uniformly
diffuse shiny infiltrative non-nodular form of LL, called as
5. Liver function tests: In certain number of cases, there Lucio’s leprosy which is chiefly encountered in Mexicans.
is mild rise of serum bilirubin of 1 to 2 mg/100 ml. Rise Its unique feature is that it is seen only in untreated cases.
in serum transaminases (SGOT and SGPT) indicates This form of leprosy and its unique form of reaction were
hepatic and muscular damage. described by Lucio and Alvardo in Mexico in 1852 and
later, by Latapi and Zamora in 1948. It has also been
Differential Diagnosis reported from other countries such as Costa Rica, the
USA, Hawaii, and Brazil. Few cases of Lucio’s leprosy
T1R must be differentiated clinically from T2R (Table 22.8).
have also been reported in the recent past from India.69,70
However, acute erythema nodosum (EN) can occur due to
The authors also diagnosed a case of Lucio leprosy with
other common causes like sarcoidosis, tuberculosis,
initial attack of Lucio’s phenomenon; subsequently after
streptococcal infections, intestinal infections and drugs.
starting MDT he developed classical ENL lesions
They are usually up to 10 lesions, but in severe cases
(Fig. 22.10).
many more may be found, more common in young adult The etiopathogenesis of this phenomenon is less well
women, bilaterally symmetrical, usually located on the understood. M. leprae are found unusually in large numbers
pretibial area and lateral shins. in the endothelial cells of superficial blood vessels, and
Table 22.8: Differences between type 1 and type 2 reactions

Features Type 1 Type 2
Type of immunological reaction Delayed type hypersensitivity reaction Antigen antibody immune complex reaction
(Arthus reaction)
Type of patients affected Borderline types (BT, BB ,BL, rarely subpolar LL) LL, rarely BL
Constitutional signs and symptoms None or rare Common
like fever, malaise, arthralgia, myalgia
Type of the skin lesions Existing skin lesions (few or many or all) Fresh red, painful, tender, cutaneous
suddenly becomes reddish, swollen, warm, nodules, plaques. The existing skin lesions
painful, tender remain unchanged
Nerve involvement Nerves close to skin lesions may be enlarged, Nerves may be affected but not as commonly
painful and tender due to acute neuritis with or as severely; as in type 1 reaction
loss of nerve functions (loss of sensation and
muscle weakness). Neuritis may also appear
suddenly
Eye involvement Corneal anesthesia and lagophthalmos Internal eye diseases like iritis, iridocyclitis,
(weakness of eyelid closure) may occur due to glaucoma, cataract, etc.
nerve involvement (5th and 7th cranial nerves)
Other organs affected Not affected May be affected (lymphadenitis,
epididymo-orchitis, painful dactylitis,
periosteal pain (tibiae), myositis, arthritis,
and glomerulonephritis, etc.
CHAPTER
22
Histopathological Features
Rea and Ridley have compared the histology of ENL and
lesions of Lucio’s phenomenon. They distinguish Lucio’s
phenomenon from ENL by ischemic epidermal necrosis,
necrotizing vasculitis of small blood vessels in the upper
dermis, severe focal endothelial proliferation of mid-dermal
vessel, and by presence of large numbers of bacilli in
endothelial cells.2 A comparative account of clinical features
A B of Lucio’s phenomenon and vasculonectrotic ENL has been
Figs 22.10A and B: The diffuse infiltration of face in a case of untreated presented by Leticia et al (Table 22.9)72
LL (A). The patient developed sudden red-bluish ill-defined painful
slightly indurated diffuse lesions and plaques over the limbs which
underwent exfoliation after a period of one week without blistering (B).
Such type of reactional phenomenon can be observed in Lucio’s
leprosy called Lucio’s phenomenon. This patient improved with starting
MDT. However, later on, developed classical pattern of ENL
this finding may be responsible for the serious vascular

complications seen during the reactive phase. There is
marked vasculitis and thrombosis of the superficial and
deep vessels resulting in hemorrhage and infarction of the
skin. Lucio’s phenomenon might be another unusual variant
of ENL, like necrotizing ENL.
1. The reaction begins with slightly indurated red-bluish
plaques on the skin with an erythematous halo, usually
on one of the limbs, but may also develop on other Fig. 22.11: Slightly indurated red-bluish plaques of irregular and
triangular shaped lesions in a case of lucio leprosy, reported from
areas of the body. The lesions are ill-defined, but painful India (Reproduced with permission from Dr DM Thappa, JIPMER,
and rarely palpable. The shape of lesions is irregular or Puducherry, India)
triangular (Fig. 22.11). After a few days they become
purplish at the center, a central hemorrhagic infarct
may develop with or without blister formation. Later,
this becomes a necrotic eschar, which detaches easily,
leaving an ulcer of irregular shape. The ulcer heals
leaving a superficial scar (Fig. 22.12).
2. Sometimes larger inflamed bullous lesions also develop,
which burst leaving a deep ulcer with jagged edges. It
heals slowly and secondary cellulitis may complicate
(Figs 22.11 and 22.12).
3. Usually, the patients have lesions that are at different
stages of evolution. It takes about three weeks for a
lesion to develop an ulcer from the initial lesion. It may
take many months to heal.
4. Patients remain afebrile.
5. However, later on few of them may develop typical Fig. 22.12: Bullous lesions leading to deep ulceration and necrosis,
ENL after starting antileprosy treatment (MDT). In one resulting into formation of eschar, which on falling leaves a deep ulcer
with jagged margins, as observed in a fatal case of lucio phenomenon.
report, out of 10 such patients 4 developed typical ENL (Reproduced with permission from Dr DM Thappa, JIPMER,
in 3 months to 3 years after starting dapsone therapy.71 Puducherry, India)
CHAPTER
22
Table 22.9: Differentiating features between Lucio’s phenomenon and

type 2 leprosy reaction with vasculonecrotic phenomenon
Lucio phenomenon Type 2 leprosy reaction with vasculonecrotic phenomenon

Occurs only in the diffuse form of leprosy when no nodules appear. Occurs in leprosy with plaques and nodules, vasculonecrotic
Erythematous spots appear without localized infiltrations (diffuse lesions with eschars are formed.
leprosy that never presents papules, plaques or lepromas in
the course of disease) and evolves into small superficial
ulcerations, generally triangular or angular, that heal leaving
atrophic and hypochromic scars.
Occurs in untreated individuals, a few years after onset of More frequent in the first months of treatment
disease and, disappears with treatment being sometimes
replaced by erythema nodosum
Reddish 0.5 to 1.0 cm spots that ulcerate Extensive and deep necrotic lesions, regular and round or oval
ulcerations overlying a nodule.
Burning sensation Ischemic pain
Usually afebrile, never appear to be acutely ill, except in severe Presents with fever and constitutional symptoms
cases of extensive necrosis.
Does not affect nerves It may be accompanied by neuritis
No general symptoms or visceral damage Arthralgia, iridocyclitis, orchitis, lymphadenopathy, nephritis, hepatitis
Positive Medina test* Negative Medina test
Histopathology shows colonization of the endothelial cell by acid Histopathology shows panvasculitis. It starts in the hypodermis,
fast bacilli, ischemic epidermal necrosis, necrotizing vasculitis where the affected vessels are of variable caliber, with larger
of the small vessels of the superficial dermis, endothelial necrosis resulting in fibrotic scars.
proliferation of the medium-sized vessels of the mid-dermis
with passive venous congestion, and neutrophilic infiltration.
Does not respond to thalidomide Responds to thalidomide
Resolution in 15 days Slow resolution
Small hypochromic scars with hyperchromic border Large deep ulcers result in fibrotic, hypertrophic and radiated scars
*Medina test: This test is similar to lepromin test except that the antigen is prepared from the lesions of Lucio’s-leprosy.
Diagnosis Salient Features of Lucio’s Phenomenon

1. Unique form of leprosy reaction, observed in Lucio’s
1. Geographical distribution, chiefly encountered in
Leprosy, mainly reported from Mexico, Costa Rica,
Mexicans.69 It is rarely reported in India.70,71 USA, Hawaii, Brazil and recently from India.
2. Observed in untreated long-standing Lucio’s-leprosy 2. Lucio’s leprosy characterized by diffuse skin infil-
(diffuse non-nodular form of lepromatous leprosy). tration, loss of facial skin creases (leading to youthful
3. Classical clinical picture: Appearance of erythematous appearance—beautiful leprosy) and absence of
diffuse or plaque type lesions which become purpuric, papules and nodular lesions. M. leprae are found in
then necrotic followed by black eschar formation. The abudance.
eschar falls off in a few days leaving behind big ulcers 3. Classical clinical picture of Lucio’s phenomenon:
of irregular shape. Usually afebrile, appearance of erythematous diffuse
or plaque type lesions which becomes purpuric,
4. Absence of constitutional symptoms
becomes necrotic followed by black eschar
5. Specific histopathological features: The clinical
formation. The eschar falls off in a few days leaving
diagnosis is confirmed by microscopic pathology behind big ulcers of irregular shape.
marked by ischemic epidermal necrosis, necrotizing 4. Specific histopathological features: Ischemic epi-
vasculitis of small blood vessels in the upper dermis, dermal necrosis, necrotizing vasculitis of small blood
severe focal endothelial proliferation of mid-dermal vessels in the upper dermis, severe focal endothelial
vessels, and by presence of large number of AFB in proliferation of mid-dermal vessels, and by presence
endothelial cells.73 of large number of AFB in endothelial cells.
6. With starting MDT, the condition improves. 5. With starting MDT, the condition improves.
CHAPTER
22
REFERENCES damage in leprosy: a retrospective study among 126

paucibacillary patients. Lepr Rev 1991;62:143-46.
1. Kar BR, Job CK. Very rare reversal reaction and Mitsuda 21. Rose P and Waters MFR. Reversal reaction and their
conversion in secondary lepromatous leprosy, a case report. management. Lepr Rev 1991;62:113-21.
Lepr Rev 2005;76:258-62. 22. Kar HK, Sharma AK, Misra RS et al. Reversal reaction in
2. Rea TH, Ridley DS. Lucio phenomenon: a comparative multibacillary leprosy patients following MDT with and without
histopathological study. Int J of Lepr 1979;47:161-66. immunotherapy with a candidate for an antileprosy vaccine,
3. Lienhardt C, Fine PEM. Type 1 reaction, neuritis and disability in Mycobacterium w. Lepr Rev 1993;64:219-26.
leprosy. What is the current epidemiological situation? Lepr Rev 23. Wilkinson RJ, Lockwood DN. Antigenic trigger for type 1 reaction
1994;65:9-33. in leprosy. J Infect 2005;50:242-43.
4. Van Brakel WH, Khawas IB, Lucas S. Reactions in leprosy: an 24. Rego VP, Machado PR, Martins I et al. Type 1 reaction in leprosy:
epidemiological study of 386 patients in West Nepal. Lepr Rev characteristics and association with hepatitis B and C viruses.
1994;65:190-203. Rev Soc Bras Med Trop 2007;40:546-49.
5. Saunderson P, Gebre S, Byass P. Reversal reactions in the 25. Shetty VP, Antia NH. Pathology of nerve damage in leprosy. In:
skin lesions of AMFES patients: incidence and reaction factors. The peripheral nerve in leprosy and other neuropathies. Ed.
Lepr Rev 2000;71:309-17. Shetty V, Antia NH (Eds). Oxford University Press, Kolkata
6. Kumar B, Dogra S, Kaur I. Epidemiological characteristics of 1997;79-137.
leprosy reactions: 15 years experience from North India. Int J 26. Fiallo P, Cardo PP, Nunzi E. Identification of sequence similarities
Lepr Other Mycobact Dis 2004;72:125-33. between Mycobacterium leprae and the myelin proteolipid protein
7. Becx-Bleumink M, Berhe D. Occurrence of reactions, and their by computational analysis. Indian J Lepr 1999;71:1-10.
diagnosis and management in leprosy patients treated with 27. Yamamura M, Uyemura K, Deans RJ et al. Defining protective
multidrug therapy: experience in the leprosy control programme responses to pathogens: cytokine profiles in leprosy lesions.
of the All Africa leprosy and Rehabilitation Training Center Science 1991;254:277-79.
(ALERT) in Ethiopia. Int J Lepr Other Mycobact Dis1992;60: 28. Yamamura M, Wang XH, Ohmen JD et al. Cytokine patterns of
1873-84. immunologically mediated tissue damage. J Immunol
8. IAL Workshop on Reactions in Leprosy, Jamnagar, Gujarat, 11- 1992;149:1470-81.
12 January 2003. In Indian J Lepr 2003;75:295-305. 29. Modlin RL, Yamamura M, Salgame P, Bloom BR. Lymphokine
9. Desikan KV, Sudhakar KS, Tulsidas I, Ranganadha Rao. patterns in leprosy skin lesion. In: Dermatology; Progress and
Observations on reactions of leprosy in the field. Indian J Lepr prospectives, WHC Burgdorff, SI Katz (Eds). London, Parthenon
2007;79:1-7. Publishing Group, 1993; 893-96.
10. Lockwood DNJ. The management of erythema nodosum 30. Verhagen CE, Wieringa EEA, Buffing AAM et al. Reversal reaction
leprosum: current and future options (editorial). Lepr Rev in borderline leprosy is associated with a polarized shift to Type
1996;67:253-59. 1 like Mycobacterium leprae T-cell reactivity in lesional skin: A
11. Post E, Chin-A-Lein RAM, Bouman C et al. Lepra in Nederland in follow-up study. J Immunol 1997;159:4474-83.
de periode 1970-1991. Ned Tijdschr Geneesk 1994;138: 31. Cooper CL, Mueller C, Sinchaisri TA et al. Analysis of naturally
1960-63. occurring delayed type hypersensitive reactions in leprosy by
12. Jopling WH, McDougall AC. In: Handbook of Leprosy, 5th edn. in situ hybridization. J Exp Med 1989;169:1565-81.
New Delhi: CBS Publishers;1996;10-47. 32. Khanolkar-Young S, Rayment N, Brickell PM et al. Tumour
13. Lockwood DNJ, Vinaya Kumar S, Stanley JNA, Macadam PWJ, necrosis factor alpha synthesis is associated with skin and
Colston MJ. Clinical features and outcome of reversal (type 1) peripheral nerve pathology of leprosy reversal reaction. Clin
reactions in Hyderabad, India. Int J Lep Other Mycobact Dis Exp Immunol 1995;99: 196-202.
1993;61:8-15. 33. Verhagen CE, van der Pauw Kraan TCTM, Buffing AAM et al.
14. Naafs B. Treatment of reactions and nerve damage. Int J Lepr Type 1- and Type 2—skin derived M. leprae-responsive T- cell
Other Mycobact Dis 1996;64:S21-28. clones are characterized by co-expression of IFN-γ / TNF-α
15. Ridley DS. Reaction in leprosy. Lepr Rev 1969;40:77-81. and IL4/IL5/IL13 respectively. J Immunol 1998;160:2380-2387.
16. Roche PW, Theuvenet WJ, Britton WJ. Risk factors for type 1 34. Verhagen CE, Faber WR, Klatser PR et al. Immunohistological
reactions in borderline leprosy patients. Lancet 1991;338: analysis of in situ expression of mycobacterial antigens in the
654-57. skin lesions of leprosy patents across the histopathological
17. De Rijk AJ, Gabre S, Byass P, Berhanu T. Field evaluation of spectrum. Am J Path. 1999;154:1793-1804.
WHO-MDT of fixed duration at ALERT, Ethiopia. The AMFES 35. Stefani MM, Guerra GK, Sousa ALM et al. Potential plasma
Project-II: Reaction and neuritis during and after MDT in PB and markers type 1 and type 2 leprosy reactions: a preliminary
MB leprosy patients. Lepr Rev 1994;65:320-32. report. BMC Infectious Diseases 2009;9:75.
18. Lockwood DNJ, Sinha HH. Pregnancy and leprosy: a 36. Mohanty KK, Joshi B, Katoch K, Sengupta U. Leprosy reactions:
comprehensive literature review. Int J Lepr Other Mycobact Dis humoral and cellular immune responses to M. leprae, 65kDa,
1999;67:6-12. and 18 kDa antigens. Int J Lepr Other Mycobact Dis 2004;72:
19. Ramu G, Desikan KV. Reactions in borderline leprosy. Indian J 149-58.
Lepr 2002;74:115-28. 37. Naafs B. Reactions in leprosy. In: Biology of mycobacteria,
20. Hogeweg M, Kiran KU, Suneetha S. The significance of facial G Ratledge, JL Stanford, JM Grange (Eds). London, Academic
patches in type 1 reaction for the development of facial nerve Press Ltd 1989;3:359-403.
CHAPTER
22
38. Sengupta U. Immunopathology of leprosy (Symposium paper) 55. Naafs B. Symposium paper “Current views on reactions in
Indian J Lepr 2000;72:381-91. leprosy”. Indian J Lepr 2000;72:97-122.
39. Sreenivasan P, Misra RS, Wilfred D, Nath I. Lepromatous leprosy 56. Variham G, Douglas JT, Moad J. Immune complexes and
patients show T- helper 1- like cytokine profile with differential antibody levels in blisters over human leprosy skin lesions with
expression of interleukin-10 during type 1 and type 2 reactions. or without erythema nodosum leprosum. Clin Immunol
1998;95:529-36. Immunopathol 1992;63: 230-36.
40. Naafs B, Kolk AHJ, Chin A lien RAM et al. Anti-Mycobacterium 57. Shetty VP, Antia NH. Pathology of nerve damage in leprosy. In:
leprae monoclonal antibodies cross-reactive with human skin. The peripheral nerve in leprosy and other neuropathies (1997).
An alternative explanation for the immune responses in leprosy. NH Antia, VP Shetty (Eds). Mumbai, Oxford University Press
J Invest Dermatol 1990;94: 685-88. 1997;79-137.
41. Van den Akker T W, Naafs B, Kolk AH et al. Similarity between 58. Sarno EN, Sampaio EP. The role of inflammatory cytokines in
mycobacteria and human epidermal antigens. Brit J Dermatol the tissue injury of leprosy. Int J Lepr 1996;64: S69-74.
1992;127:352-58. 59. Julien D, Sieling PA, Uyemura K et al. IL-15, an immunomodulator
42. Rambukkana A, Burggraaf JD, Faber WR et al. The myco- of T cell responses in intracellular infection. J Immunol 1997;158:
bacterial secreted antigen 85 complex possesses epitopes that 800-06.
are differently expressed in human leprosy lesions and 60. Feuth M, Brandsma JW, Faber WR et al. Erythema nodosum
Mycobacterium leprae infected armadillo tissues. Infect Immunol leprosum in Nepal: a retrospective study of clinical features and
1993;61:1835-45. response to treatment with prednisolone or thalidomide. Lepr
43. Stanley JNA. Pathological changes in the sciatic nerves of mice Rev 2008;79:254-69.
with leprosy neuropathy – an electromicroscopic study, 1988. 61. Danda D and Cherian AM. Rheumatological manifestations of
PhD thesis, Oxford, UK quoted by Naafs B in symposium paper leprosy and lepra reaction. Indian J Lepr 2001;73:58-62.
“Current views on reactions in leprosy” in Indian J Lepr 62. Sethuraman G, Jeevan D, Srinivas CR et al. Bullous erythema
2000;72:97-122. nodosum leprosum (bullous type 2 reaction). Int J Dermatol
44. Bochud PY, Hawn TR, Siddiqui MR et al. Toll-like receptor 2 2002;41:362-64.
(TLC2) polymorphisms are associated with reversal reaction in 63. Rai VM, Balachandran C. Necrotic erythema nodosum
leprosy. J Infect Dis 2008;197:253-61. leprosum. Dermatol Online J 2006;12:12.
45. Ustianowski AP, Lawn SD, Lockwood DN. Interactions between 64. Ramu G and Dharmendra. Acute exacerbations (reactions) in
HIV infection and leprosy. Lancet Infect Dis 2006;6:350-60. leprosy, Chapter 9. In: Leprosy (Volume1), Dharmendra (Ed).
46. Kar HK, Saxena AK, Jain RK, and Sharma AK. Type 1 (Reversal) Kothari Medical Publishing House, Mumbai 1978;108-39.
lepra reaction in borderline leprosy with unusual clinical presen- 65. Cochrane RG. Complicating conditions due to leprosy. In:
tations—a case report. Indian J leprosy 1987;59:219-22. Cochrane RG, Davey TF (Eds). Leprosy in theory and practice
47. Naafs B. Treatment and duration of reversal reaction: A (2nd edn). Bristol, John Wright and Sons Ltd 1964;152-82.
reappraisal. Back to the past. Lepr Rev 2003;74:328-36. 66. Ridley DS, Job CK. The pathology of leprosy. In: Hastings RC
48. Ridley D S. Chapter: Reactions. In: Ridley DS (Ed). Skin biopsy (ed.) Leprosy. (1st edn). Edinburgh: Churchill, Livingstone,
in Leprosy, third edition, CIBA-GEIGY Limited, Basle (Switzerland) 100-33.
1990;53-58. 67. Kamat VM, Shukla. Atypical bullous lesions in type 2 lepra reaction.
49. Shetty VP, Wakade A, Antia NH. A high incidence of viable Indian J Lepr 2007;79:231-37.
Mycobacterium leprae in post-MDT recurrent lesions in 68. van Brakel WH, Nicholls PG, Lockwood DNJ et al. A scale to
tuberculoid leprosy patients. Lepr Rev 2001;72:337-44. assess the severity of leprosy reactions. Lepr Rev 2007;78:
50. Linder K, Zia M, Kern WV et al. Relapses v/s Reactions in 161-64.
multibacillary leprosy: proposal of new relapse criteria. Trop 69. Saoji V, Salodkar A. Lucio leprosy with Lucio phenomenon. Indian
Med Int Health 2008;13:295-309. J Lepr. 2001;73: 267-72.
51. Saunderson P, Gebre S, Byass P. ENL reactions in the 70. Kumari R, Thappa DM and Basu D. A fatal case of lucio
multibacillary cases of AMFES cohorts in central Ethiopia: phenomenon from India. Dermatology online journal
Incidence and risk factors. Lepr Rev 2000;71:318-24. 2008;14(2):10.
52. Manandhar R, LeMaster JW, Roche PW. Risk factors for 71. Rea TH, Levan NE. Lucio’s phenomenon and diffuse non-nodular
erythema nodosum leprosum. Int J Lepr 1999;67:270-78. lepromatous leprosy. Archi Dermatol 1978;114:1023-28.
53. Naafs B. Leprosy reactions: New knowledge. Trop Geogr Med 72. Leticia F, Elemir MS, Maria LC, Paulo ENFV. Vasculonecrotic
1994;46:80-84. reactions in leprosy. Brazilian J Infect Dis 2007;11:378-82.
54. Modlin RL, Mehra R, Bloom BR, Rea TH. In situ and in vitro 73. Jopling WH, McDougall AC. Leprosy reactions (Reactional
characterization of the cellular immune-response in erythema States), In: Hand book of leprosy, 5th ed. CBS Publishers, New
nodosum leprosum. J Immunol 1986;123:1813-17. Delhi 1996;82-91.
Section
5 Systemic Involvement and

Special Situations in Leprosy
23
Systemic Manifestations
V Ramesh, Joginder Kumar
INTRODUCTION migrate to cooler areas of the body with temperature lesser

than 37oC, accounting for skin and peripheral nerves as
Leprosy is predominantly a disease of the skin and
peripheral nerves. Conventional workbooks and manuals the predominant sites of disease manifestations.2 In
avoid discussing the systemic components of the infection. multibacillary disease, the bacilli seem to override this
This does not mean that Mycobacterium leprae does not preference and occupy the warmer sites too. In most
spread to other areas of the body. It does happen but the individuals the disease is arrested at a relatively early stage
smouldering nature of the infection and lack of symptoms of entry into the axoplasm of the sensory nerves in the
mask these occurrences. Consequently systemic skin where the histiocytes transform into epithelioid cells
involvement has often been relegated to the pathologists and engulf the lepra bacilli, but in some patients with low
in research institutions; or as a part of some academic resistance the infection progresses where histiocytes
work. In recent times the effective use of multidrug therapy convert to lepra cells. Unchecked by treatment it becomes
(MDT) has also rendered it redundant. a systemic disease, and the organisms (either in the body
Systemic manifestations occur mostly toward the of the histiocytes or flowing freely in the blood or lymph
lepromatous pole of the spectrum and the number of such stream) are rapidly transported to distant parts of the body.3
patients is very small. Moreover, the early institution of As many as 5 × 108 lepra bacilli circulate at any point of
therapy halts the progression of systemic involvement. time in an untreated lepromatous leprosy patient and can
Nonetheless, awareness of systemic disease is important be grown from blood inoculated in the foot pads of mice.4
because apart from the paralytic deformities, some organs Yet the remarkable silent nature of the infection is
like the eyes and bones which bear the brunt of systemic
maintained as the bacilli do not secrete any toxins and so
infection can be damaged early, greatly impairing the quality
infection by lepra bacilli differs from other septicemic
of life. Patients of multibacillary leprosy, which include the
conditions which are characterized by fever, chills and
borderline, borderline lepromatous and lepromatous forms
coagulation anomalies.5 Lepra bacilli, though less often,
in the Ridley-Jopling classification in whom this could
have also been demonstrated in the blood in indeterminate
happen, will continue to be seen till eradication of the
disease occurs and one should remain alert to these and tuberculoid forms too.6 The frequency of bacillemia
systemic manifestations. The patient rarely ever presents observed by some authors appears to be similar in both
with symptoms pertaining exclusively to the involvement borderline and lepromatous forms of the disease, with
of internal organs though most of them are found to be the maximum number of bacilli seen at the lepromatous
affected at autopsy/necropsy in lepromatous leprosy. The end of the spectrum.7,8 The degree of bacillemia does
organisms disseminate to the internal organs through not correlate well with the bacterial load in the skin and
hematogenous route during the phase of bacillemia. often has been detected in patients with negative slit-
skin smears.
BACILLEMIA IN LEPROSY Histopathological studies demonstrating the presence
Taking nasopharyngeal route as the main gateway to of bacilli within or between the epithelial cells of the nasal
acquiring infection through inhalation,1 the bacilli quickly mucosa suggest this to be a possible site for the entry of
CHAPTER
23
294 Systemic Involvement and Special Situations in Leprosy
bacilli into the blood stream.9 An outstanding pathological hastens and aggravates the disuse osteoporosis.14 In the
observation in lepromatous leprosy is the invasion of hands, the slow resorption and atrophy start from the distal
endothelium of blood vessels and lymphatics by M. leprae end of the terminal phalanx and proceed proximally to
which accounts for further spread of infection.10 The study involve the middle and proximal phalanges. The
of M. leprae genome has led to identification of surface metacarpals and carpals usually remain uninvolved. It is
proteins called adhesions that appear to play a prominent in the feet that both tarsals and metatarsals are affected.
role in their dissemination by helping attachment of bacilli The metatarsals become thinned out distally, a change
to Schwann cells and endothelial cells. The bacilli referred to as ‘pencilling’ or a ‘sucked candy stick’ and the
disseminate to involve almost every part of the body11 tarsals disintegrate. Foot models have shown that when
(Fig. 23.1). Apart from the skin and peripheral nerves, the osteomyelitis and unsightly trophic ulcers develop, the
tissues that show significant infiltration resulting in clinical progression of bone lesions is due to the combined effect
manifestations include the bones, eyes, upper respiratory of high vertical stresses and osteoporosis.15 Concentric
tissues, kidneys, liver and testes12 (Table 23.1). resorption of phalanges has also been seen quite
frequently.16 The muscle weakness/paralysis also results
BONES, JOINTS AND MUSCLES in the realignment of muscle actions and redistribution of
pressure and traction forces and may contribute to the
Bone changes in leprosy are often the result of impairment deformity and the formation of calluses and corns. At times,
of sensations, or in some cases even complete one can see a rare manifestation in the form of dactylitis
anesthesia, which because of repeated trauma, leads to presenting as a fusiform swelling confined to the finger
osteomyelitis. Restricted movement of the affected limbs only, often of the right hand (Fig. 23.2).
leading to muscle weakness and trophic changes, It is important to realize that nonspecific changes can
secondarily lead to disuse atrophy and osteoporosis. occur even after the institution of treatment, usually due
Understandably, such changes take a long time to manifest to neglect in the care of insensitive hands and feet. As the
and occur particularly when the disease is of long duration, control of leprosy improves and proper education is given
and has been neglected or adequate protective care has to such persons to take good care of the extremities, the
not been taken. The bone changes may be specific or incidence of deformities is expected to come down.
nonspecific.13 The nonspecific ones are the most common The specific changes due to bacillary deposits in the
and include osteomyelitis, osteoporosis, atrophy and bones and their feeding vessels are less common and are
absorption of the bones. seen as osteitis, periosteitis, lytic lesions, erosions and
They result from compromised nerve function and bone cysts in phalangeal bones,17 though M. leprae specific
impaired blood supply caused by the infiltrating granuloma, osteomyelitis has also been described.18,19
disuse and constant trauma. In males the deficient Specific bone lesions have been seen in 5% of
testosterone production due to leprous testicular atrophy hospitalized patients in one study, described more often
Table 23.1: Sites affected in relation to clinical significance in multibacillary leprosy

Clinically May be clinically Clinically insignificant
significant significant
Skin Joints Autonomic nerve dysfunction of
cardiac and respiratory systems
Peripheral nerves Kidneys Breasts
Bones Larynx Central nervous system
Eyes Liver Endocrine organs
Nose Lymph nodes Female reproductive system
Oropharynx Muscles of face and limbs Gastrointestinal tract
Testicles Tongue Heart and big vessels
Lungs
Pancreas
Prostate
Urinary tract (ureters, bladder and urethra)
CHAPTER
23
Systemic Manifestations 295
Fig. 23.1: Sites affected in leprosy

CHAPTER
23
the extremities.26 These do not interfere with the function

of the muscle. The histopathological specimens may reveal
lepromatous granulomas between muscle fibers and
connective tissue coverings of the muscle. The fibers
surrounding the grauloma are degenerated. AFB can be
seen in the macrophages, lepra cells and even lying freely
between the muscle fibers. In various other studies changes
like loss of striations, hyaline, fatty and sarcolemmal
changes, necrosis, fibrosis and endomysial thickening have
been described.27 Nail changes in leprosy are generally
nonspecific and appear dystrophic. These are attributed to
many factors that include neuropathy, trauma, vascular
changes and infections.28, 29 Recurrent dermatophytic skin
infections in some patients of leprosy have been attributed
Fig. 23.2: Dactylitis in a woman who had faint to nail infection (onychomycosis) which had remained
macules on trunk on examination unsuspected.30
due to contiguous spread of infection from overlying EYES

tissues than via circulation.20 Radiologically, islands of
dense areas within the bones of hands, feet and rarely Prior to availability of effective antileprosy therapy the eyes
long bones, have been seen in bacilliferous patients were the common sites of affection. The outer structures
indicating reparative activity in response to the damage of the eye as well as the eye ball tissues can be involved.
due to presence of lepra bacilli.21 Madarosis or the loss of eyebrows usually involves the
The facial changes (obviously due to damage to facial outer third but there can be complete loss of eyebrows. In
bones) are the ones that carry the imprint of leprosy. The tuberculoid leprosy it may be unilateral and occurs only if
full description by the Danish physician Moller-Christensen there is a patch over that area; while lepromatous infiltration
constitutes ‘facies leprosa’ which includes a triad of lesions destroys the hair roots and is usually bilateral giving a
considered characteristic of leprosy, namely: (i) atrophy of striking look to the face. Eyelashes may be lost in a similar
the anterior nasal spine, (ii) atrophy and recession of the manner. The heavy infiltration of the eyelids may result in
maxillary alveolar processes, and (iii) endonasal its drooping (upper eyelid) or ectropion (lower eyelid)
inflammatory change.22 These lesions are not individually because of tissue weight.
diagnostic of leprosy but together they constitute a reliable Involvement of the eyes can also occur indirectly.
marker of leprosy in the study of ancient skull remnants. Considerable damage may also take place during
Atrophy of anterior nasal spine is the commoner of the reactionary episodes. The indirect mode of involvement is
two and contributes to nasal collapse. The atrophy of the the one seen more frequently31,32 and it is not due to the
maxillary alveolar process often leaves the central incisors spread of bacilli to the ophthalmic structures but results
uncovered by bone as a result of which they fall away, from involvement of nerves supplying the ophthalmic area,
with much less bone around all other teeth.23 namely the Trigeminal (5th cranial nerve) and facial (7th
The rheumatological manifestations of leprosy are not cranial nerve) nerves. The trigeminal nerve is responsible
usually severe enough to warrant specific treatment. An for sensory innervations to cornea, conjunctiva and ocular
incidence of 6% has been recorded in some of the leprosy adnexae; while the facial nerve supplies the orbicularis
clinics.24 The functional incapabilities do not arise except oculi muscles. In the affliction of the former, the corneal
during reactionary episodes. The arthritis resembles that reflex is impaired and there is conjunctival/corneal
of rheumatoid disease usually involving the smaller joints anesthesia or hypoesthesia; while involvement of the latter
of hands and feet.24, 25 The serology may be positive for affects lid closure. In both the instances, there is a grave
Rh factor and ANA. danger of corneal ulceration resulting from exposure
Skeletal muscle involvement is rare which clinically keratitis which becomes much greater when both the nerves
presents as pea sized nodules inside the muscle mass of are affected concurrently. The corneal ulceration may lead
CHAPTER
23
to iritis or iridocyclitis with their associated potentially leprosy lagophthalmos is generally bilateral while in
disastrous consequences. Conjunctivitis can also occur tuberculoid it is ipsilateral. In contravention of the common
in a manner similar to exposure keratitis. The conjunctivitis assertion that the lower lid is affected due to preferential
is usually restricted to the area corresponding to the involvement of zygomatic branch of the facial nerve as it
palpebral fissure and is more intense near sclero-corneal courses over the zygomatic process, some observers feel
junction. that the upper and lower facial muscles are affected in the
Direct spread results from lodgement of the lepra bacilli same proportion.36 Lagophthalmos in paucibacillary leprosy
in the eyes and occurs only in multibacillary leprosy. The depends on the location of the patches, the large patches
bacilli reach the ocular tissue through the bloodstream. also involving other branches of the facial nerve. In
The structures in the relatively cooler anterior compartment lepromatous leprosy lagophthalmos is due to diffuse
are usually involved. Here the cornea, ciliary body, part of infiltration of not only the nerve but also of the muscles.
the choroid and the walls of blood vessels are infiltrated Chronic uveitis should be suspected in those with small
by heavily bacillated macrophages. The posterior part of pupils and poor pupillary reaction.
the eye is usually spared though nodules in the retina have High-risk factors that can lead to loss of vision may be
been occasionally observed.33 present even after release from treatment. A recent study
Beading and opacification of the corneal nerves is an found corneal causes to be the major sight threatening
early indication and is seen universally in almost all factors which were related to the longer duration of
lepromatous leprosy patients. It is due to multiplication of disease.37 To prevent blindness or visual impairment it is
bacilli in or adjacent to the nerves and is best seen with essential to examine the patient for visual acuity,
slit-lamp broad beam.34 Whitish dots appear over the cornea lagophthalmos at monthly visits and check for any signs
giving rise to leprotic punctuate keratitis. These dots are of reaction on the face.38 Care of the eyes is essential,
microaggregates of M. leprae or miliary lepromata lying like that of anesthetic hands and feet, and is something
between the epithelium and Bowman’s membrane. This is that the patient should be well educated about and clearly
then followed by pannus which forms all round the cornea instructed to adhere, during and well after completion of
therapy (For details on eye involvement in leprosy and its
and eventually leads to sclerosing keratitis which resembles
management, refer to the respective chapters in the book).
arcus senilis. An important manifestation is chronic
iridocyclitis which can be so insidious that there is no
redness and minimal ocular discomfort. Just like quiescent OROPHARYNX, LARYNX AND UPPER
(silent) nerve paralysis, this too can lead to blindness if RESPIRATORY TRACT
left undiagnosed. Leprous iridiocyclitis is less common in Leprosy confines itself mainly to the upper part of the
India as compared to the other endemic areas.32 With slit- respiratory tract while the lower respiratory tract and lungs
lamp examination the lepromata are seen as iris ‘pearls’. appear to escape. The nose is the portal of entry for
These are located at the sites of autonomic nerve plexuses M. leprae and is the earliest site of involvement in
that supply the muscles of iris. Initially, they are seen near lepromatous leprosy. It becomes heavily bacillated
the pupillary margin as creamy spheres less than 0.5 mm remaining a potential source for the exit of M. leprae from
but later may appear elsewhere on the iris and coalesce to the body. Edema and mucosal thickening are the main
form larger lesions. The iridocyclitis runs a protracted course findings seen commonly in the anterior aspect of the inferior
and extensive iris atrophy may take place. turbinate and nasal septum.39 Chronic rhinitis can occur.
Secondary cataracts, glaucoma and ciliary body Though not discernible during examination, a standardized
herniation can also occur. The acute form of iridiocyclitis test in a study for odor showed, the lower scores for smell
is usually encountered during reactions. Ocular defects as compared to controls, indicating leprous affection of
are seen mostly in smear positive persons with long the 1st cranial nerve which could be reversed by therapy.40
standing disease which is often associated with other An important clinical clue is to ask for a history of epistaxis
deformities.34 Lagophthalmos, pterygium, impaired corneal which is often passed off by the patients as an unrelated
sensation, dry eye syndrome and cataracts are some of occurrence. Many times this history would be in the form
the common complications seen in newly diagnosed of brownish crusts which can be brought out by the patient.
lepromatous and near lepromatous cases.35 In lepromatous On examination when these crusts are cleared, one may
CHAPTER
23
be able to even see septal perforation in advanced cases LOWER RESPIRATORY TRACT
by shining a torch, through the other nostril. The
Various degrees of tracheobronchial involvement have
combination of anterior nasal spine collapse and septal
been described and M. leprae have been demonstrated in
destruction causes total collapse of the nose. The paranasal
the bronchial washings. However, the trachea, bronchi and
sinuses are also involved in majority of the patients with lungs have not been known to be directly involved.51-53
lepromatous leprosy.41 Exophytic lesions of leprosy
affecting the anterior nasal septum in absence of lesions
GASTROINTESTINAL TRACT
elsewhere have been observed.42 This observation must
be carefully interpreted since majority of the patients have Apart from affection of oral and oropharyngeal structures,
mild diffuse infiltration of the nasal mucosa, usually missed rest of the gastrointestinal tract is uninvolved. The
on routine examination, but can be unmasked by doing a esophagus, stomach, small and large intestines have been
nasal scrape or slit skin smear to reveal AFB. found to be free of disease, and so are the pancreas, gall-
Oropharyngeal lesions have been commonly recorded bladder and biliary tract.51-53
in lepromatous patients.43 They include involvement and Involvement of the liver is through hematogenous
ulceration of tongue, pharynx, hard and soft palate, tonsillar spread and has been noted in both tuberculoid and
pillars and the uvula. Later, perforation of the palate can lepromatous leprosy.54 The involvement is dependent upon
occur.44, 45 Perforations of the palate and nasal septum severity of the lesions on skin, and the frequency and
have been seen even in burnt out cases. Patients with intensity of bacteremia.55 The leprous granulomata are
bilateral blindness, destruction of facial bones and found throughout the parenchyma and are heavily bacillated
perforations in the oral cavity giving a grotesque in lepromatous leprosy. They do not have any specific
appearance are still being seen.18 Histopathologically, distribution pattern in relation to the portal triad or central
vein. Steatosis and Kupffer cell hyperplasia have been
granulomas consisting of epithelioid cells, plasma cells
noted.56 Hepatic dysfunction can also occur.57 Jaundice
and lymphocytes are seen in subepithelial zone around
occurring in ENL reaction and prolonged jaundice in
blood vessels, nerves and muscle bundles.46 The AFBs
lepromatous leprosy has been reported.58 The metabolism
are seen not only in histiocytes, nerves, connective tissue,
of drugs can be altered.59
muscles and mucosal epithelial cells; but also in the
salivary duct epithelium. The absence of clear submucosal
zone and the presence of AFB in epithelium is said to REPRODUCTIVE SYSTEM
allow the shedding of large number of bacilli even from Male Reproductive System: Testes
intact mucosa. Reactions can give rise to palatal palsy The testicular involvement occurs to variable degrees in a
presenting with nasal regurgitation of food.47 large proportion of lepromatous patients, particularly in
Laryngeal involvement is a late phenomenon and may those experiencing repeated attacks of epididymo-orchitis
present as ulceration, nodules and thickening which results during type 2 reaction. M. leprae are present in the testes
in fibrosis later. With the impaired mobility of the vocal in almost all multibacillary patients and in many of them
cords, the resultant hoarseness of the voice is the manifest oligospermia is demonstrable.60 The initial presentation is
symptom in all these conditions. Such patients are quite of testicular pain and swelling, gradually changing to typical
often very poor, and in the past their croaking jobs for picture of chronic epididymo-orchitis with testes feeling
alms have deeply moved the travellers and writers alike.48 firm to hard. However, more often they feel soft, reduced
Impairment of laryngeal sensations may insidiously result in volume and finally turn atrophic in the late stage. There
in aspiration of food and secretions into the lungs leading is significant lowering of fertility.61 Histologically, a few
to fatal pneumonia.49 foci of lepromatous granulomas consisting of foamy
Granulomas have been seen most frequently in the macrophages are present laden with AFB. During type 2
vocal cords and sometimes even in epiglottis. Bronchial reaction, edema and acute inflammatory exudates
hyporeactivity and impaired cough reflexes due to suddenly appear in those foci, resulting in testicular
involvement of postganglionic vagal fibers have been hypofunction. Both the seminiferous tubules (exocrine part)
documented.50 and the interstitial cells (endocrine part) are involved. The
CHAPTER
23
seminiferous tubules are involved first by the disease; proteinuria, microscopic hematuria, granular, hyaline and
these are obliterated by hyaline deposition on Leydig cells red blood cell casts; and the biochemical aberrations like
and the final stage is one of complete fibrosis. The atrophy increased serum urea, serum creatinine, altered distal
of the exocrine portion results in aspermatogenesis leading tubular functions and reduced glomerular filtration rate.
to sterility, with no loss of sexual potency. The atrophy of Renal amyloidosis has been seen to vary in Indian patients
the interstitial cells (Leydig cells) which occurs late, affects from 0-15%. A higher incidence of amyloidosis (up to 31%),
the production of testosterone, causing impotence. The has been reported in Latin American countries69 and has
testicular involvement is commonly bilateral and when been found to be a leading cause of death due to renal
marked, is associated first with azoospermia; and later failure, in the absence of routine investigations.70 The low
with impotence. Initially, endocrine functions are affected incidence of renal amyloidosis in India is attributed to dietary
with marked reduction in male sex hormones (testosterone) factors like vegetarian food habits.71 The involvement of
resulting in impotence, reduced testicular volume, altered kidneys, though occurring less frequently as compared to
hair pattern, lack of testicular sensation and gyneco- the other organs, should never be ignored.72 Acute renal
mastia.62, 63 Mean blood levels of gonadotropic hormones failure can occur during reactional states when all
(FSH, LH) are raised while that of testosterone is reduced. measures should be taken to restore normal kidney
The hormonal aberrations corelate well with the duration functions to ward off the critical situation. Long-standing
of disease. In reactional states, repeated attacks of renal disease like glomerulonephritis or amyloidosis can
epididymo-orchitis hasten testicular atrophy. cause chronic renal failure necessitating hemodialysis.73
The epididymis also shows leprous granulomata but The ureters, urinary bladder and urethra have not been
the prostate and seminal vesicles have not been found to found to be involved.53
be involved.52, 53
ENDOCRINE GLANDS48-50
Female Reproductive System
Adrenal glands have been found to be histologically
In contrast to the universal involvement of testes in males involved though no functional deficit manifests clinically.
in multibacillary disease, the female reproductive organs However, there is some evidence to suggest a functional
are not significantly involved in leprosy. Necropsy studies insufficiency of the adrenals during reactions in leprosy,
did not reveal any evidence of leprosy in these organs; and the function returning to normal on the subsidence of
neither in tuberculoid nor in lepromatous leprosy.51 The
acute reactional state.74 In severe cases of type 2
biopsy findings from endometrium did not reveal any
reactions, a fall in temperature and blood pressure below
involvement.64 The menstrual fluid was found to be free of
basal levels, along with hypoglycemia and increased serum
leprosy bacilli even in patients having bacillemia. The
potassium levels, should be viewed with caution, as it
menarche, menstruation and fertility remain unaffected.
indicates an adrenal crisis which is one of the causes of
The bacilli have been found occasionally in breast milk65
sudden death in type 2 reactions. This calls for prompt
and possibly can cross the placental barrier.66
treatment with corticosteroids in adequate doses which
may require lifelong maintenance.75, 76 The postmortem
KIDNEYS studies have shown adrenal involvement in lepromatous
Renal involvement in leprosy is a quite frequent finding. leprosy in the form of granulomas in the cortex as well as
The exact histopathological lesions in the kidneys and medulla, mainly in and around the corticomedullary zone.
their nature are not clearly defined. A wide variety of Amyloid deposits may also be detected.
histological changes in varying incidence have been The other endocrine glands, i.e. parathyroid, pancreas
reported from different geographic areas. Almost all types and pituitary glands remain free of disease. Data about
of glomerulonephritis have been observed in lepromatous involvement and dysfunction of thyroid is scanty. Increased
leprosy and they have been thought to have an uptake of radioactive iodine and high prevalence of thyroid
immunological basis, particularly during reactions.67,68 autoantibodies in leprosy has been reported, the
Functional abnormalities have been found to be more significance of which is not clear because no functional
common than the histopathological changes. These include abnormality has been observed.77
CHAPTER
23
LYMPH NODES, BONE MARROW, may continue to show organisms even when the skin
SPLEEN smears have turned negative after treatment.82
Experimental studies have suggested that reticulo-
Spleen
endothelial system gets involved early in the course of
the disease. In experimental leprous inoculation in The spleen is usually not palpable, either in tuberculoid or
armadillos, the bacilli initially reached the regional lymph in lepromatous leprosy. In the latter, the microscopy of
nodes, followed by colonization of other groups of lymph splenic tissue shows diffuse infiltration of sinusoids with
nodes, liver, spleen, and finally the other organs.78 foamy macrophages and lepromas in the red and white
pulp. M.leprae are present within the macrophages, lying
Lymph Nodes freely in the sinusoids and within the cells lining the
sinusoids. There may be thickening of the walls of medium
Clinically, appreciable enlargement of lymph nodes is and small sized arteries due to amyloidosis. Amyloid
uncommon in leprosy except during reactions. The deposits can also be seen in the centers of Malphigian
histopathologic findings of biopsy 79 and autopsy corpuscles and elsewhere in the pulp.50, 51
specimens,52, 53 however, suggest involvement of these
nodes throughout the leprosy spectrum from tuberculoid
CENTRAL NERVOUS SYSTEM
to lepromatous forms of the disease, including indeter-
minate leprosy, but is often significant in multibacillary Affections of V and VII cranial nerves in leprosy are well-
disease. The involvement is seen in the form of mild to known but the brain and spinal cord are said to escape the
moderate enlargement of the regional lymph nodes which infection. However, some recent studies refute this. Using
do not show any matting or suppuration. In tuberculoid brainstem auditory evoked potentials (BAEPs) and visual
leprosy, only the regional lymph nodes draining the affected evoked potentials (VEPs), abnormal conduction of auditory
cutaneous area are involved while in lepromatous leprosy, and visual pathways have been demonstrated.83 Perceptive
the involvement is more widespread and generalized deafness of cochlear type has also been reported.84
affecting even the visceral nodes, if the concerned organ Subclinical phrenic nerve involvement has been docu-
has leprous involvement, e.g. hepatic lymph nodes and mented.85 Autopsies conducted on some treated lepro-
splenic hilar lymph nodes in hepatic and splenic affection matous leprosy patients have shown vacuolar changes of
respectively. The size of the glands was found to be motor neurons of medulla oblongata and spinal cord.86
proportional to the duration of the disease.79 These vacuolated areas were found to be PGL-1 positive
In tuberculoid leprosy the lymph glands show leprous and PCR could detect M. leprae specific genomic DNA in
lesions with foci of epithelioid cells and formation of many of these cases. Dementia attributable to leprosy
granulomata. AFB can also be detected in some cases.80 has also been reported.87
Patchy fibrosis without any caseation can take place
replacing the normal tissue.79 The aspirates of lymph nodes CARDIOVASCULAR SYSTEM
in lepromatous leprosy, demonstrate lepra cells in a
Leproma of the heart has been reported though previous
reactive lymphoid background 56 while the biopsy
specimens reveal involvement of both, the cortex and the studies could not establish such an involvement
conclusively.51,53,88 Autonomic neural supply to the heart
medulla, by the bacilli laden foamy macrophages. Well
may be affected89 and may lead to dysautonomia.90 Aorta
formed typical lepromatous granulomas may be seen.
and other major vessels do not appear to be involved.53
Involvement of smaller vessels has been confirmed
Bone Marrow
by many studies.91 The vessels get infiltrated by M. leprae
Bone marrow aspirates from lepromatous leprosy patients during the phase of bacillemia. Use of special stains has
invariably reveal presence of lepra cells and there may be demonstrated the presence of these organisms in all the
a relative increase of plasma cells.56 Ziehl-Neelsen staining three layers of the vessel wall.92 All types of vessels
for AFBs show their presence within foamy macrophages including arteries, veins and capillaries in the dermis as
as well as lying freely in the interstitium.81 The bone marrow well as subcutaneous tissues have shown infiltration. The
CHAPTER
23
histopathological changes are observed throughout the
thickness of the vessel wall which include homogenization
of the vessel wall and fibrosis. Well developed lepromatous
garanulomata in the intima of the veins can be seen that
may distort the lumen.93 In addition, the vasa nervorum
also show mycobacteria. Experimental studies in
armadillos have demonstrated that the infection of the
endothelial cells of epineural blood vessels precedes the
infection of endoneurial lining, raising the possibility that
the neural involvement in leprosy could be routed through
the nutrient vessels of the nerve.92,94 Vascular involvement
may help in the dissemination of disease and could also
be a contributing factor for trophic changes seen in leprosy.
Fig. 23.3: Fever, fatigue and arthralgias in a man admitted to medical
The smooth muscle of the media of blood vessels may ward as lupus erythematosus with positive ANA, showing malar
remain a protected site for the microorganism.92 erythema (Left) and eruptions that appeared a week later (Right); slit-
skin smear revealed AFB 3+ and history disclosed incomplete anti-
leprosy therapy 5 years ago
HEMATOLOGY AND SEROLOGY
With time, the usually observed changes in other chronic atypical presentations, simulating other immune-complex
diseases make their appearance in leprosy also. Lower diseases like systemic lupus erythematosus characterized
levels of hemoglobin, a raised ESR, low serum iron by malar flush, alopecia, skin eruptions, fever and joint
levels and lower levels of serum albumin are often pains (Fig. 23.3). Such patients may have antinuclear
observed.95, 96 These abnormalities (not usually severe antibodies (ANA); antisingle stranded DNA, antineutrophil
enough to warrant any special attention) are seen more cytoplasmic antibodies and positive rheumatoid factor,99
commonly towards the lepromatous pole of spectrum. The but are negative for antidouble stranded DNA antibodies.103
chronicity of lepromatous leprosy and formation of immune They are thought to result from stimulation of B-cells by
complexes result in development of many autoantibodies. antigenic complexes of M. leprae plus autologous tissue.104
Lepromatous leprosy since long has been described as a Leprosy is not a fatal disease but it is a chronic,
cause for false positivity of anticardiolipin antibodies based crippling disease, if not diagnosed and treated early. Most
serological tests for syphilis (VDRL, WR, RPR, etc.). LE of the systemic complications and their disfiguring sequelae
cells can also be seen in some cases. Antispermatozoal
can be prevented by early diagnosis and treatment.105 In
antibodies are often present in the blood of lepromatous
the past, severe reactions accounted for high morbidity. A
leprosy patients.97 Other autoantibodies detected in
relatively better understanding of the reactions and its
lepromatous leprosy include antimitochondrial antibodies,
treatment using corticosteroids as well as access to
rheumatoid factor, antinuclear antibodies, antisingle
thalidomide and its availability in the open market have
stranded DNA antibodies, antineutrophil cytoplasmic
improved the scene. Recurrent reactions and prolonged
antibodies (more commonly c-ANCA, and also p-ANCA
and atypical ANCA), lupus anticoagulant antiphospholipid use of corticosteroids can increase susceptibility to
antibodies, anti-β-2 glycoprotein and antiprothrombin infections and their judicious use has helped in keeping
antibodies.98-101 Serum complement levels may also be the mortality well below acceptable levels.
raised.102
Taken individually, it is seen that almost every system REFERENCES
is involved in multibacillary forms of leprosy though in 1. Rees RJW, McDougall AC. Airborne infection with Myco-
practice, the classification and treatment of disease is bacterium leprae in mice. J Med Microbiol 1977;10:63-68.
based on a thorough examination of the skin and peripheral 2. Shepard CC. Stability of Mycobacterium leprae and temperature
optimum for growth. Int J Lepr 1965;33:159-64.
nerves. The importance of systemic evaluation assumes
3. Khanolkar VR. Pathology of Leprosy, In: Leprosy in Theory and
significance in reactional states when many systems can Practice, R.G.Cochrane, TF Davey: John Wright (Eds), Bristol,
be noticeably affected. Some of these can have very 1964:125-51.
CHAPTER
23
4. Lane JE, Balagon MV, Dela Cruz EC, et al. Mycobacterium 26. Convit J, Arnelo JJ, Mensoza S. Lepromatous myositis. Int J
leprae in untreated lepromatous leprosy: More than skin deep. Leprosy 1960;28:417.
Clin Exp Dermatol 2006;31:469-70. 27. Kaur S, Malik AK, Kumar B. Pathologic changes in striated muscles
5. Drutz DJ, Chen TSN, Lu WH. The continuous bacteraemia of in leprosy. Lepr India 1981;51:52-56.
lepromatous leprosy. N Eng J Med 1972;287:159-64. 28. Patki AH, Baran R. Significance of nail changes in leprosy: A
6. Karat AB, Rao PS. Haematological profile in leprosy. Part I. clinical review of 357 cases. Semin Dermatol 1991;10:77-81.
General findings. Lepr India 1977;49:187-96. 29. Kaur I, Chakrabarti A, Dogra S, Rai R, Kumar B. Nail involvement
7. Raval SN, Sen Gupta U, Ramu G et al. A study of continuous in leprosy: A study of 300 patients. Int J Lepr and Other Mycobact
bacillaemia in borderline and lepromatous leprosy. Lepr India Dis 2003;71:320-27.
1982;54:623-33. 30. Ramesh V, Misra RS. Nail changes in leprosy and recognition of
8. Desikan KV. Bacteraemia in leprosy, In: Leprosy, Dharmendra,
fungal nail infections. Ind J Lepr 1987;59:360-61.
(Ed): Samant, Bombay, 1985;78.
31. Gopinath DV, Thappa DM, Jaishankar TJ. A clinical study of the
9. McDougall AC, Rees RJ, Weddell AG, Kanan MW. The
involvement of cranial nerves in leprosy. Indian J Lepr 2004;76:
histopathology of lepromatous leprosy in the nose. J Pathol
1-9.
1975;115:215-26.
32. Samanta SK, Das D. Recent advances in ocular leprosy. Indian
10. Pessolani MCV, Marques de Melo MA, Reddy VM et al. Systemic
J Lepr 2007;79:135-50.
dissemination in tuberculosis and leprosy: Do mycobacterial
adhesins play a role? Microbes Infect 2003;5:677-84. 33. Ebenezer GJ, Daniel E. Pathology of a lepromatous eye. Int J
11. Klioze AM, Ramos-Caro AF. Visceral leprosy. Int J Dermatol Lepr Other Mycobact Dis 2000;68:23-26.
2000;39:641-58. 34. Kim EC. Hansen Disease. E-article updated June 22, 2006
12. Kumar B, Rai R, Kaur I. Systemic involvement in leprosy and its (www.medscape.com).
significance. Indian J Lepr 2000;72:123-42. 35. Daniel E, Koshy S, Rao GS, Rao PS. Ocular complications in
13. Choudhuri H, Thappa DM, Kumar RH, Elangovan S. Bone newly diagnosed borderline lepromatous and lepromatous
changes in leprosy patients with disabilities/deformities (a clinico- leprosy patients: Baseline profile of the Indian cohort. Br
radiological correlation). Ind J Lepr 1999;71:203-15. J Opththalmol 2002;86:1336-40.
14. Ishikawa S, Mizushima M, Furuta M et al. Leydig cell hyperplasia 36. Lubbers WJ, Schipper A, Hogeweg M, de Soldenhoff R. Paralysis
and maintenance of bone volume: Bone histomorphometry and of facial muscles in leprosy patients with lagophthalmos. Int J
testicular histopathology in 29 male leprosy autopsy cases. Int Lepr Other Mycobact Dis 1994;62:220-24.
J Lepr Other Mycobact Dis 2000;68:258-66. 37. Rohatgi J, Dhaliwal U, Singal A. Factors associated with sight
15. Patil KM, Jacob S. Mechanics of tarsal disintegration and plantar threatening lesions of leprosy in patients on multidrug therapy.
ulcers in leprosy by stress analysis in three dimensional foot J Indian Med Assoc 2004;102:297-303.
models. Ind J Lepr 2000;72:69-86. 38. Thompson KJ, Allardice GM, Rajan Babu G et al. Patterns of
16. Thappa DM, Sharma VK, Kaur S, Suri S. Radiological changes ocular morbidity and blindness in leprosy – a three centre study
in hands and feet in disabled leprosy patients: A clinico- in Eastern India. Lepr Rev 2006;77:130-40.
radiological correlation. Ind J lepr 1992;64:58-66. 39. Anonymous. The nose and leprosy (editorial). Lancet
17. Dave S, Nori AV, Thappa DM, Siddaraju N. Leprous osteitis 1976;1:1062.
presenting as bone cyst and erosions. Dermatol Online J 40. Mishra A, Saito K, Barbash SE, et al. Olfactory dysfunction in
2004;10:17.
leprosy. Laryngoscope 2006;116:413-16.
18. Job CK. Pathology of leprous osteomyelitis. Int J Lepr
41. Sharma VK, Bapuraj JR, Mann SBS, Kaur I, Kumar B. Computed
1963;31:26-33.
tomographic study of paranasal sinuses in leprosy. Int J Lepr
19. Moller-Christensen V. New knowledge of leprosy through
1998;66:201-07.
paleopathology. Int J Lepr 1965;33:603-10.
42. Gupta A, Seiden AM. Nasal leprosy: Case study. Otolaryngol
20. Kustner-Chimenos E, Pascual-Cruz M, Dansis-Pinol C, et al.
Head Neck Surg 2003;129:608-10.
Lepromatous leprosy: A review and case report. Med Oral Pathol
Oral Cir Buc 2006;11: E474-79. 43. Scollard DM, Skinsnes OK. Oropharyngeal leprosy in art, history,
21. Carpintero P, Garcia-Frasquet A, Tarradas E, et al. Bone island and medicine. Oral Surg Oral Med Oral Pathol 1999;87:463-70.
and leprosy. Skeletal Radiol 1998;27:330-33. 44. Rao AG, Konda C, Jhamnani K. Palatal involvement in leproma-
22. Moller-Christensen V, Bakke SN, Melson RS, Waller E. Changes tous leprosy. Ind J Dermatol Venereol Leprol 2008;74:161-62.
in the anterior nasal spine of the alveolar process of the maxillary 45. Sharma VK, Kumar B, Kaur S, Dutta BN. Involvement of tongue
bone in leprosy. Int J Lepr 1952;20:335-40. in leprosy. Indian J Lepr 1985;57:841-44.
23. Blau S, Yagodin V. Osteoarchaeological evidence for leprosy 46. Kumar B, Yande R, Kaur I, Mann SBS, Kaur S. Involvement of
from western Central Asia. Am J Phys Anthropol 2005;126:50- palate and cheek. Indian J Lepr 1988;60:280-84.
158. 47. Pavithran K. Palatal palsy in a case of lepromatous leprosy. Lepr
24. Mandal SK, Sarkar RN, Sarkar P, et al. Rheumatological Rev 1994;65:248-52.
manifestations of leprosy. J Indian Med Assoc 2008;106:165- 48. Mehta V. Reflections: “Gaze of Lazarus”, In: Portrait of India,
66. Farrar, Straus and Giroux, New York, 1970:437-41.
25. Gibson T. Bacterial infections: The arthritis of leprosy. Baillieres 49. Bretan O, De Souza LB, Lastoria JC. Laryngeal lesion in leprosy
Clin Rheumatol. 1995;9:179-91. and the risk of aspiration. Lepr Rev 2007;78:80-81.
CHAPTER
23
50. D’souza GA, Jindal SK, Malik SK, Kumar B, Kaur S. Airway 75. Ramanaujam K, Dharmendra. Management of Reactions in
response to aerosol inhalation in leprosy. Indian J Med Res Leprosy, In: Leprosy, Volume 1, Dharmendra, (Ed), Kothari
1988;87:190-93. Medical, Bombay, 1978;512-34.
51. Powell CS, Swan II. Leprosy: Pathologic changes observed in 76. Jopling WH, McDougall AC. Other Aspects of Treatment, In:
fifty consecutive necropsies. Am J Pathol 1955;31:1131-47. Handbook of Leprosy, CBS Publishers, New Delhi 1996;118-34.
52. Desikan KV, Job CK. A review of postmortem findings in 37 77. Yumnam IS, Kaur S, Kumar B, Rastogi GK. Evaluation of thyroid
cases of leprosy. Int J Lepr 1968;36:377-83. functions in leprosy. Lepr India 1977;49:485-91.
53. Liu T-C, Qiu J-S. Pathological findings on peripheral nerves,
78. Job CK, Drain B, Truman R, et al. The pathogenesis of leprosy in
lymph nodes and visceral organs of leprosy. Int J Lepr 1984;
the nine-banded armadillos and the significance of IgM antibodies
52:377-83.
to PGL-1. Indian J Lepr 1992;64:137-51.
54. Kaur S, Chakravarti RN, Wahi PL. Liver pathology in leprosy.
79. Kar HK, Mohanty HC, Mohanty GN, Nayak UP. Clinico-
Lepr India 1974;46:222.
55. Chen TS, Drutz DJ, Whelan GE. Hepatic granulomas in leprosy. pathological study of lymph node involvement in leprosy. Lepr
Their relation to bacteremia. Arch Pathol Lab Med 1976;100:182- India 1983;55:725-31.
85. 80. Apte DC, Zawar M, Mehta MC, Zawar PB, Chawhan RN. Regional
56. Singh N, Bhatia A, Lakra A et al. Comparative cytomorphology lymph node involvement in tuberculoid leprosy. Lepr India 1983;
of skin, lymph node, liver and bone marrow in patients with 55:680-85.
lepromatous leprosy. Cytopathology 2006;17:257-61. 81. González-Villarreal MG, Gómez-Almaguer D, Salazar-Riojas
57. Nigam PK, Gupta GB, Khare A. Hepatic involvement and hepatitis R, Marfil-Rivera LJ. Bone marrow involvement in leprosy. Rev
B surface antigen (HbsAg) in leprosy. Indian J Dermatol Venereol Invest Clin 1991;43:192-94.
Leprol 2003;69:32-34. 82. Sen R, Sehgal PK, Singh U et al. Bacillaemia and bone marrow
58. Kumar B, Koshy A, Kaur S, Kaur I, Rajwanshi A. Leprosy, liver involvement in leprosy. Ind J Lepr 1989;61:445-52.
and jaundice. Indian J Lepr 1987;59:194-202. 83. Kocher DK, Gupta DV, Sandeep C, Halwai M, Kumawat BL.
59. Kumar B, Narang APS, Koshy A et al. In vivo and in vitro drug Study of brainstem auditory-evoked potentials (BAEPs) and
metabolism in patients with leprosy. Lepr India 1982;54:75-81. visual-evoked potentials (VEPs) in leprosy. Int J Lepr 1997;
60. Singh N, Arora VK, Jain A, et al. Cytology of testicular changes
65:157-65.
in leprosy. Acta Cytol 2002;46:659-63.
84. Mann SBS, Kumar B, Yande R, Kaur S, Kaur I, Mehra YN. Eighth
61. Kumar B, Raina A, Kaur S et al. Clinicopathological study of
nerve evaluation in leprosy. Indian J Lepr 1987;59:20-25.
testicular involvement in leprosy. Lepr in India 1982;54:48-55.
85. Dhand UK, Kumar B, Dhand R, Chopra JS, Kaur S. Phrenic
62. Abraham A, Sharma VK, Kaur S. Assessment of testicular volume
in bacilliferous leprosy: Correlation with clinical parameters. Indian nerve conduction in leprosy. Int J Lepr and Other Mycobact Dis
J Lepr 1990;62:310-15. 1988;56:389-93.
63. Saporta L, Yuksle A. Androgenic status in patients with 86. Aung T, Kitajima S, Nimoto M, En J, Yonezawa S, Arikawa I, Goto
lepromatous leprosy. Br J Urol 1994;74:221-24. M. Mycobacterium leprae in neurons of the medulla oblongata
64. Sharma SC, Kumar B, Dhall K et al. Leprosy and female and spinal cord in leprosy. J Neuropathol Exp Neurol 2007;
reproductive organs. Int J Lepr 1981;49:177-79. 66:284-94.
65. Girdhar A, Girdhar BK, Ramu G et al. Discharge of M. leprae in 87. Goto M, Kimura T, Hagio S, et al. Neuropathological analysis of
milk of leprosy patients. Lepr India 1981;53:390-94. dementia in a Japanese leprosarium. Dementia 1995;6:157-61.
66. Survey RB, Hardas UD, Chakravarti D. Leprosy complicating 88. Holla VV, Zawar PB, Deshmuckh SD, et al. Leproma of the heart.
pregnancy and puerperium. Lepr India 1974;46:234-37. A case report. Indian Heart J 1983;35:111-13.
67. Kaur S. Renal manifestations of leprosy. Indian J Lepr 1990; 89. Ramachandran A, Neelan PN. Autonomic neuropathy in leprosy.
62:273-80. Indian J Lepr 1987;59:277-85.
68. Kirsztajn GM, Nishida SK, Silva MS, et al. Renal abnormalities in 90. Khattri HN, Radhakrishanan K, Kaur S, Kumar B, Wahi PL.
leprosy. Nephron 1993;65:381-84. Cardiac dysautonomia in leprosy. Int J Lepr Other Mycobact
69. Nakayama EE, Ura S, Fleury RN, Soares V. Renal lesions in Dis 1978;46(2):172-74.
leprosy: A retrospective study of 199 autopsies. Am J Kidney 91. Chopra JS, Kaur S, Murthy JMK, Sodhi KS, Kumar B,
Dis 2001;38:26-30. Radhakrishnan K, Suri S, Sawhney BB. Vascular changes in
70. da Silva Junior GB, Daher Ede F. Renal involvement in leprosy: leprosy and its role in the pathogenesis of leprous neuritis. Lepr
Retrospective analysis of 461 cases in Brazil. Braz J Infect Dis India 1981;53:443-53.
2006;10:107-12.
92. Coruh G, McDougall AC. Untreated lepromatous leprosy-
71. Gupta JC, Panda PK. Amyloidosis in leprosy. Lepr India
histopathological findings in cutaneous blood vessels. Int J Lepr
1980;52:260-66.
1979;47:500-11.
72. Gupta JC, Diwakar R, Singh S, et al. A histopathologic study of
93. Mukherji A, Girdhar BK, Malviya GN, et al. Involvement of
renal biopsies in fifty cases of leprosy. Int J Lepr Other Mycobact
subcutaneous veins in lepromatous leprosy. Int J Lepr 1983;
Dis 1977;45:167-70.
51:1-5.
73. Lomonte C, Chiaruli G, Cazzato F et al. End-stage renal disease
94. Scollard DM, McCormick G, Allen JL. Localization of
in leprosy. J Nephrol 2004;17:302-05.
Mycobacterium leprae to endothelial cells of epineurial and
74. Dash RJ, Sriprakash ML, Kumar B, Singh S, Sharma BR, Kaur
perineurial blood vessels and lymphatics. Am J Pathol 1999;
S. Adrenal cortical reserve in leprosy. Indian J Med Res
154:1611-20.
1985;82:388-92.
CHAPTER
23
95. Karat AB, Rao PS. Haematological profile in leprosy. Part I – 100. deLarrañaga GF, Forastiero RR, Martinuzzo ME, Carreras LO,
general findings. Lepr Ind 1977; 49:187-96. Tsariktsian G, Sturno MM, Alonso BS. High prevalence of
96. Kumar B, Sehgal S, Ganguly NK. Total and differential antiphospholipid antibodies in leprosy. Lupus 2000;9:594-600.
serum proteins and globulins in leprosy. Lepr India 1982; 54: 101. Sehgal S, Kumar B. Circulating and tissue immune complexes in
263-69. leprosy. Int J Lepr 1981;49:294-301.
97. Gupta SC, Chhabra B, Mehrotra TN, Bajaj AK. A study of 102. Kumar B, Ganguly NK, Kaur S et al. Complement profile in leprosy.
antispermatozoal antibodies in leprosy. Int J Lepr 1982; 50: Lepr India 1980;52:217-22.
43-46. 103. Danda D, Cherian AM. Rheumatological manifestations of leprosy
98. Guedes Barbosa LS, Gilbrut B, Shoenfeld Y, Sheinberg MA. and lepra reaction. Indian J Lepr 2001;73:58-60.
Autoantibodies in leprosy sera. Clin Rheumatol 1996;15:26-28. 104. Azulay RD. Autoaggressive Hanseniasis. J Am Acad Dermatol
99. Pradhan V, Badakere SS, Shankar KU. Increased incidence of 1987;17:1042-46.
cytoplasmic ANCA (cANCA) and other autoantibodies in leprosy 105. Chatterjee G, Kaur S, Sharma VK et al. Bacillaemia in leprosy
patients from Western India. Lep Rev 2004;75:50-56. and effect of multidrug therapy. Lep Rev 1989;60:197-201.
24
Leprosy and HIV Infection
Archana Singal
INTRODUCTION active antiretroviral therapy (HAART) has been reported

to develop in patients with leprosy-HIV co-infection due to
Leprosy still continues to be a significant public health
restoration of immunity.
problem in India. As the prevalence rates of human
immunodeficiency virus-1 (HIV-1) infection are escalating,
one might expect increased numbers of co-infected PREVALENCE AND DIAGNOSIS
patients. Co-infection with the HIV has a major effect on The relationship between leprosy and HIV co-infection is
natural history of many infectious diseases, notably not yet fully understood; as not much is known about the
tuberculosis (TB) and other mycobacterial diseases. natural history of the co-infected patients. It is a matter of
Leprosy being a mycobacterial disease, it is imperative to debate whether HIV infection increases the risk of acquiring
expect changes in its presentation and clinical course as leprosy. It is difficult to carry out case-control or prospective
well, when co-infected with HIV. Immunosuppressive effect cohort studies of the incidence of leprosy in HIV positive
of HIV on the prevalence and clinical manifestations of patients and HIV negative controls due to long incubation
leprosy has been a subject of much speculation and period and low incidence of leprosy. Studies in Malawi,2
epidemiological investigations. However, studies on South India3 and Brazil4 found no association between
epidemiological and clinical aspects of leprosy suggest HIV infection and leprosy. However, few studies have
that unlike other mycobacterial diseases; the course of demonstrated small increase in HIV sero-prevalence
leprosy is not markedly modified by the HIV pandemic.1 among leprosy patients.5-7 This increase is substantially
There are conflicting reports regarding clinical lower than that observed in tuberculosis or diseases due
presentation, rate of reactions and relapse; and also the to Mycobacterium avium complex (MAC).
disease management outcomes in patients with co- However, there are major drawbacks in these studies
infection. HIV co-infection may have impact on the following such as small number of co-infected patients; non-
aspects of leprosy: consideration of immunosuppression (blood CD4 counts)
1. Prevalence and diagnosis and other confounding factors like age, sex, sexual
2. Predominance of multibacillary (MB) or paucibacillary behavior, urban/rural setup and socioeconomic status.
(PB) type There are also concerns regarding the reliability of HIV
3. Complications, reactions, relapse and outcome of the diagnoses in some of these studies. Leprosy might affect
disease the specificity or sensitivity of some serological assays
4. Response to treatment (anti-leprosy treatment and for diagnosis of HIV because patients with lepromatous
treatment of reactions) leprosy have a polyclonal hypergammaglobulinemia that
5. Impact of leprosy on HIV disease, progression and can give rise to false positive results. Leprosy patients
anti-retroviral therapy also produce antibodies to mycobacterial cell wall antigens
In addition, a specific condition immune reconstitution which may cross react with HIV-1 pol and gag proteins in
inflammatory syndrome (IRIS) following initiation of highly certain assays. In a study from India, western blot (WB)
CHAPTER
24
analysis revealed that sera samples from HIV negative definite conclusions can be reached from these limited
leprosy patients across the spectrum showed high reactivity and contradictory data. It has been postulated that relatively
with p18, Gp41 and p55 resulting in high frequency of false long incubation periods for leprosy (2-5 years for tuberculoid
positive results.8 So there is a need for caution in reporting and 5-15 years for lepromatous disease) might bias towards
HIV infection among leprosy patients. paucibacillary disease, since patient might die of AIDS
Newer serological assays are more reliable; and related complications before manifesting lepromatous
indeterminate or non-confirmed results may be assessed disease.
by PCR. Conversely, HIV infection causing false positive Leprosy presents with skin lesions and peripheral nerve
serological assays for leprosy has also been reported, damage. Spectrum of skin lesions ranging from
though diagnosis of leprosy depends mainly on clinical, hypopigmented tuberculoid lesions to nodular lepromatous
bacteriological and histological indices. lesions have been described in HIV-infected patients.
Worsening of nerve damage might be expected in patients
PREDOMINANCE OF MULTIBACILLARY with dual infection as HIV infection may alter the immune
(MB) OR PAUCIBACILLARY (PB) TYPE response in nerves to M. leprae. HIV is itself neuropathic,
AND CLINICAL FEATURES so could also act synergistically. However, conclusive
evidence to support this hypothesis is lacking.
Though HIV-1 infection has been shown to be strongly
associated with the development of active tuberculosis9,10
COMPLICATIONS, REACTIONS,
and diseases caused by other mycobacteria; 11 its
RELAPSE AND OUTCOMES
association with leprosy is much less clear. In general, no
major interactions have been documented. As the cell- Many authors have evaluated HIV positivity as a risk
mediated immune response of an individual determines factor for various complications of leprosy. A study from
the type of leprosy that will develop, theoretically Uganda demonstrated significant increase in the incidence
predominance of multibacillary (MB) leprosy and a faster of type1 reaction in HIV seropositive MB patients as
clinical evolution of the disease can be expected in patients compared to HIV seronegative MB patients (9/12 vs 8/40,
with dual infection, because of reduced cell mediated p<0.0005). Further, development of acute neuritis was
immunity in HIV-1 positive individuals. Several case reports observed in significantly more number of HIV sero-positives
and small case series have been published to determine as compared to sero-negative MB population (8/9 vs 3/8,
this association. p<0.0005).15 However, no significant difference was
A weak association between HIV positivity and MB observed in the incidence of these complications in
leprosy has been suggested by few reports from East seropositive and seronegative PB patients.15
Africa.5,12 A case control study conducted in Tanzania Vreeberg reported early onset of severe neuritis in
observed that HIV prevalence was higher with MB cases patients with dual infection; along with many severe
(5/28, 18%), as compared to PB cases (4/65, 6%).5 Further, episodes of intercurrent infections that proved fatal in two
the clinical presentation and disability grade of HIV-1 patients, probably as a result of long established HIV-1
infected patients was similar to that of patients without infection with advanced immunological disturbances.16
HIV infection.5 A positive association of HIV infection with Though reversal reactions and neuritis, both acute and
leprosy was further established in a subsequent study from chronic, were not significantly influenced by HIV status; a
Tanzania itself (odds ratio 2.5; 95% C.I. 2.0-3.2) but the possible increase in recurrent reversal reactions in HIV
authors have not commented on the differential association positive cases was reported.14 On the other hand, neuritis
with MB and PB disease. This data also suggested that was not found to be more severe or different in character
the protective effect against leprosy by BCG vaccination in HIV positive cases and no association could be observed
is lessened by HIV infection.7 between HIV positivity and the degree of nerve function
In contrast, recent report from Brazil demonstrated impairment at the start of treatment, after completion of
predominance (78%) of paucibacillary disease among HIV treatment or 5 years follow-up thereafter.14 Three untreated
positive individuals.13 Others however, did not find any borderline leprosy patients with HIV-1 infection developed
significant difference between the ratios of lepromatous reversal reaction with neuritis and did not downgrade
and tuberculoid leprosy in HIV co-infected patients.14 No towards lepromatous pole.17
CHAPTER
24
Leprosy and HIV Infection 307
Erythema nodosum leprosum (ENL) reactions were not evolution and response to treatment with MDT is reported
reported in HIV positive individuals until recently and it to be similar in both HIV positive and HIV negative leprosy
has been suggested that HIV infection may decrease the patients.22 It has been recommended that HIV/leprosy co-
risk of this complication.18 However of late, case reports infected patients should be treated with standard MDT
of ENL in HIV positive leprosy patients have started to together with HAART.23
appear; albeit infrequently. In one study14, HIV positive As the relapse rates are rare after multidrug therapy
individuals were reported to have a higher risk of ENL both in tuberculoid as well as lepromatous patients, the
reactions (relative risk 5.2: 95% CI 1.7-15.9) though Nery role of HIV infection as an important co-factor in the slight
et al did not observe any enhanced risk of ENL among increase in relapse rate is difficult to assess. It may be
their patients.19 possible to ascertain this only, if mandatory HIV testing is
Reversal reactions and acute neuritis in leprosy occur included for all patients relapsing after multidrug therapy.
as a result of cell mediated, delayed type hypersensitivity,
and hence these may be expected to be reduced in HIV Treatment of Reactions
positive cases. Likewise, ENL reactions occur due to Patients with borderline leprosy and co-existent HIV-1
circulating immune complexes and their increased infection developing reversal reaction have been reported
prevalence (if it actually occurs in HIV positive cases) to respond adequately to steroid therapy.17 No difference
should be a paradox. Increased death rate amongst leprosy has been observed in the response to steroid therapy
patients with HIV co-infection has been reported.20 This among seropositive and seronegative leprosy patients, in
was seen particularly in those cases who developed the management of acute neuritis or reversal reaction.13,14
recurrent reversal reaction as a result of advanced However, poorer outcome to steroid therapy has been
immunosuppression.14 reported by others.16
Relapse in a case of BB leprosy with HIV co-infection Thalidomide has been used traditionally for the
has been reported by Rath and Kar. They described three management of ENL in immunocompetent leprosy patients.
HIV-positive leprosy cases; two BT cases with CD4+ It has been used with success in the management of
counts of 482 and 540 cells/mm3 and one BB case with severe, recurrent ENL, refractory to high doses of daily
CD4+ counts of 240 cells/mm3. Both BT cases responded steroid therapy in a patient with co-existent HIV infection.24
well to conventional WHO MDT (PB) for 6 months. The BB Recently it has also been reported to produce an anti-
case who had relapsed 3 months after completion of MDT retroviral effect without any negative effect on immune
(MB) for one year; also became inactive again following a competence, 25 possibly through inhibition of TNF
further one-year course of MDT (MB).21 production and by blocking TNF stimulated HIV
replication.26 Due to these properties it appears to be the
RESPONSE TO TREATMENT drug of choice for treating ENL in HIV positive leprosy
Management of co-infected patient is a challenge for want patients. However, the drug has to be used with caution in
of clear-cut guidelines or uniform consensus and is further view of some reports of increased viral counts caused by
confounded by the lack of information on the natural course thalidomide.27
of dual infection.
IMPACT OF LEPROSY ON
Antileprosy Treatment HIV PROGRESSION AND
ANTIRETROVIRAL THERAPY
It has been postulated that HIV infection might affect the
efficacy of multidrug therapy for leprosy; with HIV-positive Tuberculosis is known to accelerate the decline of immune
patients potentially taking longer to clear mycobacteria functions in HIV-positive individuals by augmenting the
from the lesions or experience a higher relapse rate. rate of HIV replication, resulting most likely from marked
However, HIV positive patients with leprosy have been pro-inflammatory cytokine drive in tuberculosis patients.
reported to respond adequately to antileprosy chemotherapy This issue has not been addressed in relation to leprosy
without the need for prolonged treatment courses; and they as this cytokine drive is not present in leprosy patients
also experience similar side effect profile.15,17 The clinical except during severe ENL reactions.
CHAPTER
24
Early institution of highly active anti-retroviral therapy comprising of macrophages and small number of almost
(HAART) is reported to provide an edge in improving exclusively CD8+ T cells. In vitro, cells from these patients
therapeutic outcome in patients with dual infection. In the do not respond to M. leprae, but produce high titres of M.
management of reactions, addition of HAART not only leprae specific antibodies.
improves the therapeutic response to lower doses of Immunologically driven inflammation is also responsible
steroids but also helps in complete withdrawal for much of the clinically apparent nerve injury. Nerve
subsequently.24 However, since most of the clinical signs function impairment is more rapid and severe in patients
of leprosy are dependent on cell mediated immunity, it with aggressive cellular immune response i.e. in tuberculoid
has been postulated that when HIV infected patients with disease and during reactional states, especially type1
latent leprosy receive HAART, their immune system reaction. As HIV principally affects cell-mediated immune
recovers and M. leprae antigens are recognized with responses, these pathogens may also have potentially
subsequent development of clinical leprosy and interesting immunologic interactions in the human host.
exacerbation of existing leprosy lesions. Talhari et al Unlike tuberculosis, where HIV infection affects
reported two such AIDS patients with very low CD4 count granuloma formation depending upon the degree of immune-
(71 and 6 cells per µL) on HAART for 1-2 months, who suppression as reflected by blood CD4+ counts, host
developed skin lesions of borderline lepromatous leprosy granulomatous response to M. leprae is preserved among
(BL).28 MBMDT was instituted in addition to HAART. Two individuals with HIV.29 Sampaio et al30 described 11
to three months later, their CD4 counts increased, and patients, [3 borderline lepromatous (BL) and 8 borderline
both patients presented with swollen lesions of BT with tuberculoid (BT)] with HIV co-infection and low blood CD4+
type1 reaction which was documented histologically and counts. They found that biopsy of skin lesions in patients
treated with systemic steroids. These cases probably with BT revealed well formed granulomas that on
represent the unusual presentation of BL leprosy as a result immunostaining demonstrated normal numbers of CD4+
of augmented immunity following HAART therapy; and lymphocytes; while BL and HIV infected patients revealed
subsequent shifting of BL to BT after institution of relatively higher number of CD8+ lymphocytes. This
MB-MDT. observation is intriguing since the predominant cell type
towards the tuberculoid end of clinical spectrum is CD4+
IMMUNOLOGY AND HISTOLOGY IN lymphocytes which are also the target cells for HIV. They
LEPROSY-HIV COINFECTION also demonstrated expression of human leukocyte antigen
(HLA)-DR by dermal cells adjacent to granulomas, as an
Leprosy is characterized by a wide spectrum of clinical evidence of local interferon-γ production. Absence of bacilli
and histological features. Immune status of the host plays in the lesion indicated good immunity. In addition, HIV
a vital role in all aspects of the disease including infection did not alter the lack of response to M. leprae
establishment of the infection, its clinical features, antigens either in vitro or in vivo in lepromatous leprosy.
complications like leprosy reactions and nerve damage, Similar observations have been reported by Pereira et
diagnostic tests as well as targets for therapeutic al31 on histopathological analysis and immunostaining on
interventions. nine MDT-naive (BT 6, TT 2 ad LL 1) patients with HIV
The clinical and histologic spectrum of leprosy depends co-infection. BT lesions were characterized by less
on specific host immunity. Patients with tuberculoid leprosy circumscribed epithelioid cell granulomas and a few
have adequate cell-mediated immune response to M. Langerhans CD68+ cells in the centre surrounded by CD3+
leprae. They have few skin lesions and histology consists lymphocytes, a few of them with the CD8+ phenotype.
of well organized, lymphocyte-rich granulomas comprising Nerve damage was observed in the histopathologic
of predominantly CD4+ T cells. In vivo these patients exhibit examination of five of six BT lesions and two were AFB
strongly positive lepromin test and in vitro cells from these positive. The TT leprosy lesions had well formed granulomas
patients respond strongly to M. leprae in the lymphocyte with CD68+, epithelioid, multinucleated Langerhans cells
proliferation assay. On the other hand, the patients with and macrophages in the center; surrounded by a
lepromatous disease have poor or absent cell mediated lymphocytic mantle of CD3+ T cells and few CD8+ T cells.
immunity resulting in uncontrolled growth of bacilli and The TT lesions were AFB negative and nerves were not
disseminated skin lesions. Histology reveals loose infiltrate visualized. The only leprosy skin lesion categorized as LL
CHAPTER
24
had a diffuse CD68+, vacuolated, histiocytic cell infiltrate infection may be responsible. In addition, delayed clearance
with few CD3+ lymphocytes, a high (3+) AFB positivity, of M. leprae antigen due to impaired phagocytic function
and nerve damage. of macrophages has also been implicated.29
In all histopathologic categories, few NK CD57+ cells
were observed. Similar characteristics on histopathology IRIS
and immunostaining were observed on seven skin lesions
(TT = 3, BT = 3, and indeterminate [I] = 1) collected from The immune reconstitution inflammatory syndrome (IRIS)
in HIV-infected/AIDS patients results from restoration of
co-infected patients on MDT, except for a lower level of
immunity to specific infectious or non-infectious antigens;
cellularity. Thus histological architecture and cell
following initiation of highly active antiretroviral therapy
phenotypes within the leprosy skin lesions are not much
(HAART). It presents with the manifestation or unmasking
changed by HIV.
of a previously subclinical co-infection; or the symptomatic
In a cohort of dually infected 22 patients, regardless of
deterioration of an opportunistic infection that had been
the clinical form of leprosy (MB or PB), histopathologic
responding to the treatment.33,34 Such reactions typically
classification, AFB positivity in lesions and MDT status,
occur during the first 2-4 months of treatment with HAART;
none including one lepromatous case, had detectable IgM
the most rapid phase of immune recovery. The exact
antibodies specific for M. leprae PGL-1. This finding is
incidence of IRIS is unknown, but is dependent on the
consistent with low sensitivity of anti-PGL1 serology in population studied and its underlying opportunistic
patients with PB leprosy, but not expected in a LL case, infectious burden.33 Approximately 10-25% patients who
as 90% of LL patients without HIV show positivity to commence HAART are reported to experience IRIS.35
antibody. However, as it was a single case, studies on IRIS was initially observed in cases of co-infection with
larger number of HIV co-infected LL patients are desirable mycobacteria (Mycobacterium avium complex and
to provide conclusive results.31 Mycobacterium tuberculosis) in 1998.36 Subsequently,
Recently Carvalho et al explored cellular immunity in association with viral (cytomegalovirus, herpes simplex,
patients co-infected with HIV-1 and M. leprae. 32 Twenty- varicella zoster, human papilloma virus and hepatitis B
eight individuals were studied, comprising four groups: (a) and C virus), fungal (Cryptococcus neoformans,
healthy controls, (b) HIV-1 and M. leprae co-infection, (c) Histoplasma capsulatum), and protozoal infections
HIV-1 mono-infection, and (d) M. leprae mono-infection. (Toxoplasma gondii, Leishmania donovani and
Peripheral blood mononuclear cells (PBMC) were analyzed Pneumocystis jeroveci) have been reported.35 In some
to evaluate T-cell subpopulations and their activation status, cases IRIS appears in the absence of opportunistic
dendritic cell (DC) distribution phenotypes and expression pathogens and manifests itself as an autoimmune or
of IL-4 by T cells. The co-infected group exhibited lower granulomatous disease, of which sarcoidosis is the most
CD4:CD8 ratios, higher levels of CD8+ cell activation, frequent.37 Diagnostic criteria of IRIS as described by
increased Vδ1:Vδ2 T cell ratios and decreased percentages Shelburne et al38 has been shown in Table 24.1.
of plasmacytoid DCs, as compared with HIV-1 mono- After initiation of HAART, there is numerical increase
infected subjects. Across infected groups, IL-4 production in circulatory CD4+ cells. Of these, activated memory cells
by CD4+ lymphocytes positively correlated with the (CD4+, CD45RO+) account for the early incremental phase
percentage of effector memory CD4+ cells, suggesting
Table 24.1: Proposed criteria for the diagnosis of IRIS
antigenically driven differentiation of this population of T (Shelburne et al)38
cells in both HIV-1 and M. leprae infections. Co-infection
1. HIV positive
with M. leprae may theoretically exacerbate the 2. Receiving HAART
immunopathology of HIV-1 disease. A T helper 2 (Th2) a. Decrease in HIV-1 RNA level from baseline
bias in the CD4+ cell response was evident in both HIV-1 b. Increase in CD4+ cells from baseline (may lag HIV-1 RNA
decrease)
infection and leprosy, but no additive effect was apparent
3. Clinical symptoms consistent with inflammatory process
in co-infected patients. 4. Clinical course not consistent with
The exact immunopathophysiological mechanism a. Expected course of previously diagnosed opportunistic
underlying the possible increase in frequency of leprosy infection
b. Expected course of newly diagnosed opportunistic infection
reactions is not clear. Dysregulation of the immune system c. Drug toxicity
and the heightened state of immune activation in HIV
CHAPTER
24
of CD4+ cell recovery. Recovery of lost responses to required addition of azathioprine for the control of reaction
specific antigens also occurs during this early phase, as it recurred on tapering the dose of steroids. Since then,
probably because of cellular redistribution rather than a there have been many reports39-49 (Table 24.2) mostly from
de-novo specific CD4+ cell proliferation. the parts of world which are considered endemic for both
IRIS has been thought to be a result of several factors: HIV/AIDS and leprosy, including India.
response to a high antigen burden, an excessive response IRIS in association with leprosy is characterized by
by the recovering immune system, exacerbated production the development of type1 reaction in unstable borderline
of pro-inflammatory cytokines or a lack of immune
leprosy. Most of the reported cases belong to borderline
regulation due to inability to produce regulatory cytokines.
tuberculoid (BT) leprosy except one case by Singal et al
Disease susceptibility genes for specific subset of IRIS
who described IRIS in a patient with borderline lepromatous
have been identified e.g. TNFA-308*2 for mycobacterial
(BL) leprosy.45 Clinically, leprosy as IRIS usually presents
disease and HLA-B44 for herpes virus related IRIS.39 In
as type1 reaction with the development of erythematous,
addition, a CD4+ cells subset (known as T-regulatory cells)
oedematous skin lesions which may develop unusual
(CD4+, CD25+ Fox P3+) has an intrinsic ability to down
regulate the immune response and may play a role in the ulceration and neuritis with nerve paresis/paralysis. Many
pathogenesis of IRIS. These T-regulatory cells are investigators have shown that patients with a low baseline
susceptible to HIV infection and their numbers also CD4+ count at the time of starting HAART are at the
decrease in AIDS. highest risk of developing IRIS. However, even a minimal
IRIS in association with leprosy was first described by decrease in viral load in the absence of a significant rise
Lawn et al in 2003.40 They described a 37 years old in CD4+ cell count can precipitate IRIS.50 Treatment of
seropositive male patient (CD4+ count of 10/mm3) from IRIS includes anti-inflammatory drugs, steroids, specific
Uganda, with pulmonary tuberculosis and on anti tubercular antimicrobial agents; along with the continuation of HAART.
therapy for three months. One month after initiation of As access to HAART is increasing in leprosy endemic
HAART, the patient developed histologically proven lesions countries including India, the number of IRIS cases due to
of borderline tuberculoid (BT) leprosy with type1 reversal leprosy is likely to increase in future. Recognition of leprosy
reaction on his face, with an increase in CD4+ count. He as an IRIS associated entity is important in order to institute
was treated with 40 mg prednisolone daily but subsequently timely intervention.
Table 24.2: Leprosy cases in HIV positive patients presenting with IRIS, after starting ART, CD4+ counts
before and after; and time interval
Authors, year Pt.’s Age Clinical presentation CD4 counts per mm3 Time Interval
(Ref. No.) and sex Before After
Narang et al 2005,39 28/ M BT-Type 1 reaction 125 280 2 months
Lawn et al 2003,40 37/ M BT-Type 1 reaction 10 70 1 month
Couppié et al 2004,41 54 M BT-Type 1 reaction 87 257 2 months
40/ M TT- Type1 reaction 130 278 5 months
39/ F TT- type1 reaction 31 171 3 months
Pignataro et al 2004,42 48 M TT-Type1 reaction 147 499 3 months
34/F Reversal reaction 37 200 1 month
Visco et al 2004,43 32/ M TT-Type 1 reaction 7 90 2 months
Pereira et al 2004,44 38/ F BT-Type 1 reaction 73 270 2 months
25/ M BT- Type1 reaction 35 100 6 months
Singal et al 2006,45 32/ M BL-Type 1 reaction 108 224 3months
Kharkar et al 2007,46 35/ M BT-Type 1 reaction 299 504 3 months
Talhari et al 2007,47 35/ M BT-Type 1 reaction 92 426 3 months
Batista et al 2008,48 32 M BT-Type 1 reaction 14 172 2 months
Kar et al 2009,49 32/ F BT Type 1 reaction 125 333 2 months
CHAPTER
24
REFERENCES 19. Nery JA, Sampaio EP, Galhardo MC, et al. M. leprae-HIV co-
infection: pattern of immune response in vivo and in vitro. Indian
1. Kar HK, Sharma P. Does concomitant HIV infection has any J Lepr 2000; 72: 155-67.
epidemiological, clinical, immuno-pathological and therapeutical 20. Lewis DE, Yang L, Luo W, et al. HIV-specific cytotoxic T
relevance in leprosy. Indian J Lepr 2007; 79: 47-62. lymphocyte precursors exist in a CD28-CD8+ T cell subset and
2. Pönnighaus JM, Mwanjasi LJ, Fine PE, et al. Is HIV infection a increase with loss of CD4 T cells. AIDS 1999; 13: 1029-33.
risk factor for leprosy? Int J Lepr Other Mycobact Dis 1991; 59: 21. Rath N, Kar HK. Leprosy in HIV infection: A study of three cases.
221-28. Indian J Lepr 2003; 75:355-59
3. Sekar B, Jayasheela M, Chattopadhya D, et al. Prevalence of 22. Jacob M, George S, Pulimood S, et al. Short-term follow up of
HIV infection and high-risk characteristics among leprosy patients with multibacillary leprosy and HIV infection. Int J Lepr
patients of south India; a case-control study. Int J Lepr Other 1996; 64: 391-95.
Mycobact Dis 1994; 62: 527-31. 23. Trindade MA, Manini MI, Masetti JH, et al. Leprosy and HIV co-
4. Andrade VL, Avelleira JC, Marques A, et al. Leprosy as cause of infection in five patients. Lepr Rev 2005; 76: 162-66.
false-positive results in serological assays for the detection of 24. Sharma NL, Mahajan VK, Sharma VC, et al. Erythema nodosum
antibodies to HIV-1. Int J Lepr Other Mycobact Dis 1991; 59: leprosum and HIV infection: A therapeutic experience. Int J Lepr
125-26. Other Mycobact Dis 2005; 73: 189-93.
5. Borgdorff MW, van den Broek J, Chum HJ. HIV-1 infection as a 25. Stirling DI. Thalidomide and its impact in dermatology. Semin
risk factor for leprosy; a case-control study in Tanzania. Int J Cutan Med Surg 1998; 17: 231-42.
Lepr Other Mycobact Dis 1993; 61: 556-62. 26. Ravot E, Lisziewicz J, Lori F. New uses for old drugs in HIV
6. Meeran K. Prevalence of HIV infection among patients with infection: the role of hydroxyurea, cyclosporin and thalidomide.
leprosy and tuberculosis in rural Zambia. BMJ 1989; 298: 364- Drugs 1999; 58: 953-63.
65. 27. Radomsky CL, Levine N. Thalidomide. Dermatol Clin 2001; 19:
7. van den Broek J, Chum HJ, Swai R et al. Association between 87-103.
leprosy and HIV infection in Tanzania. Int J Lepr Other Mycobact 28. Talhari C, Ferreira LC, Araújo JR et al. Immune reconstitution
Dis 1997; 65: 203-10. inflammatory syndrome or upgrading type 1 reaction? Report of
8. Hussain T, Sinha S, Katoch K et al. Serum samples from patients two AIDS patients presenting a shifting from borderline
with mycobacterial infections cross-react with HIV structural lepromatous leprosy to borderline tuberculoid leprosy. Lepr Rev
proteins Gp41, p55 and p18. Lepr Rev 2000; 78(2): 137-47 2008; 79: 429-35.
9. Long R, Scalcini M, Manfreda J et al. Impact of human 29. Ustianowski AP, Lawn SD, Lockwood DN. Interactions between
immunodeficiency virus type 1 on tuberculosis in rural Haiti. Am HIV infection and leprosy: a paradox. Lancet Infect Dis 2006; 6:
Rev Respir Dis 1991; 143: 69-73. 350-60.
10. Selwyn PA, Hartel D, Lewis VA et al. A prospective study of the 30. Sampaio EP, Caneshi JR, Nery JA et al. Cellular immune
risk of tuberculosis among intravenous drug users with human response to Mycobacterium leprae infection in human
immunodeficiency virus infection. N Engl J Med 1989; 320: 545-50 immunodeficiency virus-infected individuals. Infect Immun 1995;
11. Pitchenik AE. The treatment and prevention of mycobacterial 63: 1848-54.
disease in patients with HIV infection. AIDS 1988; 2 (Suppl 1): 31. Pereira GA, Stefani MM, Araújo Filho JA et al. Human
S177-82. immunodeficiency virus type 1 (HIV-1) and Mycobacterium
12. Orege PA, Fine PE, Lucas SB et al. A case control study on leprae co-infection: HIV-1 subtypes and clinical, immunologic,
human immunodeficiency virus-1 (HIV-1) infection as a risk and histopathologic profiles in a Brazilian cohort. Am J Trop Med
factor for tuberculosis and leprosy in western Kenya. Tuber Hyg 2004; 71: 679-84.
Lung Dis 1993; 74: 377-81. 32. Carvalho KI, Maeda S, Marti L et al. Immune cellular parameters
13. Sarno EN, Illarramendi X, Nery JA et al. HIV-M. leprae interaction: of leprosy and human immunodeficiency virus-1 co-infected
can HAART modify the course of leprosy? Public Health Rep subjects. Immunology 2008; 124: 206-14.
2008; 123: 206-12. 33. Murdoch DM, Venter WD, Van Rie A et al. Immune reconstitution
14. Gebre S, Saunderson P, Messele T et al. The effect of HIV status inflammatory syndrome (IRIS): review of common infectious
on the clinical picture of leprosy: a prospective study in Ethiopia. manifestations and treatment options. AIDS Res Ther 2007, 4: 9.
Lepr Rev 2000; 71: 338-43. doi:10.1186/1742-6405-4-9.
15. Bwire R, Kawuma HJ. Type 1 reactions in leprosy, neuritis and 34. Lawn SD, Lockwood DN. Leprosy after starting antiretroviral
steroid therapy: the impact of the human immunodeficiency virus. treatment. BMJ 2007; 34: 217-18.
Trans R Soc Trop Med Hyg 1994; 88: 315-16. 35. DeSimone JA, Pomerantz RJ, Babinkchak TJ. Inflammatory
16. Vreeburg AE. Clinical observations on leprosy patients with HIV- reactions in HIV-1 infected persons after initiation of highly active
1 infection in Zambia. Lepr Rev 1992; 63: 134-40. antiretroviral therapy. Ann Intern Med 2000; 133: 417-54.
17. Arunthathi S, Ebenezer L, Kumuda C. Reversal reaction, nerve 36. Race EM, Adelson-Mitty J, Kriegel GR et al. Focal mycobacterial
damage and steroid therapy in three multibacillary HIV positive lymphadenitis following initiation of protease-inhibitor therapy in
patients. Lepr Rev 1998; 69: 173-77. patients with advanced HIV-1 disease. Lancet 1998: 351:
18. Miller RA. Leprosy and AIDS: a review of the literature and 252-55.
speculations on the impact of CD4+ lymphocyte depletion on 37. Blanche P, Passeron A, Gombert B et al. Sarcoidosis and HIV
immunity to Mycobacterium leprae. Int J Lepr Other Mycobact infection: Influence of highly active antiretroviral therapy. Br J
Dis 1991; 59: 639-44. Dermatol 1999: 140: 1185.
CHAPTER
24
38. Shelburne SA III, Hamill RJ, Rodriguez-Barradas MC et al. Immune leprae co-infection: HIV-1 subtypes and clinical, immunologic,
reconstitution inflammatory syndrome: emergence of a unique and histopathologic profiles in a Brazilian cohort. Am J Trop Med
syndrome during highly active antiretroviral therapy. Medicine Hyg 2004; 71: 679-84.
(Baltimore) 2002; 81: 213-27. 45. Singal A, Mehta S, Pandhi D. Immune reconstitution inflammatory
39. Narang T, Dogra S, Kaur I. Borderline tuberculoid leprosy with syndrome in an HIV positive leprosy patient. Lepr Rev 2006; 77:
type 1 reaction in an HIV patient-a phenomenon of immune 76-80.
reconstitution. Int J Lepr Other Mycobact Dis 2005; 73: 203-05. 46. Kharkar V, Bhor UH, Mahajan S et al. Type 1 lepra reaction
40. Lawn SD, Wood C, Lockwood DN. Borderline tuberculoid leprosy: presenting as immune reconstitution inflammatory syndrome.
an immune reconstitution phenomenon in a human Indian J Dermatol Venereol Leprol 2007; 73: 253-56.
immunodeficiency virus-infected person. Clin Infect Dis 2003; 47. Talhari C, Machado PRL, Ferreira LC et al. Shifting of the clinical
36: e5-6. spectrum of leprosy in an HIV-positive patient: a manifestation of
41. Couppié P, Abel S, Voinchet H et al. Immune reconstitution immune reconstitution inflammatory syndrome? Lepr Rev 2007;
inflammatory syndrome associated with HIV and leprosy. Arch 78: 151-54.
Dermatol 2004; 140: 997-1000 48. Batista MD, Porro AM, Maeda SM et al. Leprosy Reversal Reaction
42. Pignataro P, Rocha AS, Nery JA et al. Leprosy and AIDS: two as Immune Reconstitution Inflammatory Syndrome in Patients
cases of increasing inflammatory reactions at the start of highly with AIDS. Clin Infect Dis 2008; 46: e56–e60.
active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 2004; 49. Kar HK, Sharma P. Borderline tuberculoid leprosy with upgrading
23: 408-11. type1 reaction in a HIV seropositive patient, after anti-retroviral
43. Visco-Comandini U, Longo B, Cuzzi T et al. Tuberculoid leprosy therapy: an Immune reconstitution inflammatory syndrome. Lepr
in a patient with AIDS: a manifestation of immune restoration Rev 2009; 80: 85-88
syndrome. Scand J Infect Dis 2004; 36: 881-83. 50. Shelburne SA, Montes M, Hamill J. Immune reconstitution
44. Pereira GAS, Stefani MMA, Araujo Filho JA et al. Human inflammatory syndrome: more answers, more questions. J Clin
immunodeficiency virus type 1 (HIV-1) and Mycobacterium Microbiol 2006; 57: 167-70.
25
Leprosy and Pregnancy
Neena Khanna
INTRODUCTION atrophies leading to sterility and later, when the endocrine

part (interstitial cells) atrophy occurs, patients complain
Leprosy though predominantly a disease of the skin and
of impotence. Several studies have shown that in LL
peripheral nerves, does spread to other areas and organs
patients the serum levels of follicle stimulating hormone
of the body—mostly in the highly bacillated patients. But
(FSH), leutinizing hormone (LH) and estrogen are elevated;
quiescent nature of the infection and lack of overt
while those of testosterone are depressed, often even in
symptoms mask these occurrences. Systemic
the absence of clinical manifestations of testicular
manifestations occur mostly towards the lepromatous pole.
dysfunction.3-5 The high serum levels of FSH in males at
However, the number of such patients is dwindling because
lepromatous end of the spectrum have been attributed to
of the early institution of therapy. Invasion of the endothelial
cells of blood vessels and lymphatics accounts for the damage to the seminiferous tubules due to infiltration.6
spread of infection. Surface proteins of M. leprae called
Females
“adhesions” play a prominent role in the dissemination of
infection by helping attachment of M. leprae to Schwann In contrast to plethora of studies on gonads and gonadal
cells and endothelial cells. Consequently, leprosy function in males afflicted with leprosy, there is a paucity
granulomata have been demonstrated in several internal of literature on the involvement of gonads in female leprosy
organs. The organs which show significant infiltration patients. Mitsuda described the occurrence of lepra cells
resulting in clinical manifestations include bones, eyes, in the endometrium, fallopian tubes and in capillaries of
upper respiratory tract, kidneys, adrenals, bone marrow, vaginal mucosa, but was emphatic that leprosy in women
liver and testes.1,2 does not result in sterility.7,8 In contrast, Fleger, et al9 found
The present chapter discusses the involvement of the that 54% of females with leprosy evaluated by them were
female reproductive system by leprosy and its effects on sterile and similarly, King and Marks10 also reported gross
maternal and perinatal outcome; and also the effects of menstrual abnormalities in women with leprosy. In neither
pregnancy on the course of the disease and episodes of of the two studies was the hormonal profile evaluated.
leprosy reactions. Bogush11 reported menstrual dysfunction in their patients
with leprosy and observed that early institution of therapy
GONADAL INVOLVEMENT IN LEPROSY could prevent this. He, however, did not comment on the
fertility status of his patients.
Males
Hardas et al12 noted that although obstetric events
Gonadal involvement in males with lepromatous leprosy could alter the course of the disease, leprosy itself had no
(LL) is not uncommon and manifests initially as leprous effect on gynecological events like menstrual cycle or
orchitis (due to acute inflammation and edema) and fertility in their patients. Interestingly, in only 18% of their
subsequently as testicular atrophy (due to fibrosis).2 patients, the endometrial biopsy taken in the premenstrual
Initially, the exocrine portion (seminiferous tubules) period showed secretory phase, indicating that though
CHAPTER
25
fertility was not affected, there was some hormonal • Metabolic changes during pregnancy and puerperium.
imbalance. Sharma et al13 in a study of 35 adult female • Altered secretion of steroids during pregnancy.
patients with MB leprosy, found that the infection had no • Altered immunological response during pregnancy.
direct effect on menarche, menstrual cycle, fertility and
menopause. Significantly, 3 (8.6%) of their LL patients had Metabolic Changes
never conceived. Several metabolic changes occur during pregnancy and
Khanna et al14 in a study of 86 women with MB leprosy include a state of relative (because of increased demand
in the reproductive age group, reported irregularity of of pregnancy) and absolute malnutrition; including
periods in more than a third of them; with the irregularity deficiency of protein, vitamins, iron and other minerals.
postdating the onset of leprosy in 30% of the patients. Of This malnutrition may partly be responsible for the
the 24 married women with irregular periods, 50% were depression of CMI seen in pregnancy, because malnutrition
infertile and about 30% of these patients had elevated is known to cause inhibition of rosette-forming
levels of FSH and LH; almost reaching the castration levels. T lymphocytes.24
The mean levels of LH, FSH, and prolactin were all An adequate intake of vitamins (B6, folate, B12, C,
significantly elevated in patients with MB leprosy vis-à- and E) and minerals (selenium, zinc, copper, and iron)
vis controls. Similar findings suggesting a primary ovarian results in a pro-inflammatory Th1 cytokine-mediated
failure have been reported by Arora et al.15 response which is necessary for effective protective
The exact mechanism of ovarian failure in patients with immunity. Likewise an inadequate intake of vitamins and
MB leprosy really needs to be further explored, but it could minerals results in an anti-inflammatory Th2 mediated
be due to autoimmunity since both cell mediated and immune response which is associated with an increased
humoral immune responses do play an important role in risk of infections. Supplementation with these
premature ovarian failure and autoimmune oophoritis, which micronutrients reverses the Th2 response to a pro-
manifest as irregularity of menstrual cycle and inflammatory Th1 response with enhanced innate
infertility.16,17 Autoantibodies to granulosa and theca cells, immunity.25 Malnutrition itself can cause worsening of
zona pellucida of the oocyte as well as antibodies to adrenal leprosy as demonstrated by observations on inmates with
and ovarian steroidogenic enzymes have been leprosy in Sungei Buloh Leper Hospital under Japanese
demonstrated in these women, indicating an important occupation, where several patients had a down hill course
pathogenic role of autoimmunity in causation of of their leprosy under conditions of near starvation.26
infertility.16,17 Similarly, the cellular infiltrate in the ovaries
Altered Secretion of Steroids
results in low oestradiol levels with a compensatory
increase in FSH levels. Interestingly the infiltrate spares The levels of free cortisol and 17-hydroxycorticosteroid
the granulosa cells resulting in normal to high levels of increase during pregnancy and may partly be responsible
inhibin A and B.18 for the depression of CMI seen in pregnancy.27 The
Since MB leprosy is itself associated with increased depressed CMI results in improvement of rheumatoid
production of autoantibodies like antineural antibodies,19 arthritis and ulcerative colitis (both of which are mediated
antinuclear antibodies,20 A-ANCA (even in absence of through cellular immunity).27 The increased levels of
erythema nodosum leprosum), 21 antimitochondrial steroids may also be one of the reasons for the
antibodies22 and antispermatozoa antibodies,23 it may be exacerbation of tuberculosis and leprosy which occurs
postulated that the ovarian failure in leprosy is due to during pregnancy. Though the specific influence of steroids
formation of autoantibodies against some components of on M. leprae is not known, Shephard et al 28 have
the ovary. demonstrated that in mice fed with hydrocortisone, the
viability of M. leprae in the mouse foot pad improved, even
COURSE OF LEPROSY IN PREGNANCY though the rate of multiplication of bacteria had not
increased.
Reasons for Altered Course
of Leprosy in Pregnancy Alterations in Immunological Response
Several diseases, including infections and disorders Pregnancy and the postpartum period are associated with
mediated immunologically, have an altered course during biphasic alterations in both, the humoral and cell mediated
pregnancy and puerperium because of: immunity (CMI).29
CHAPTER
25
Leprosy and Pregnancy 315
Humoral Immunity dependent manner but do not have any effect on the
Pregnancy is associated with a biphasic alteration of production of Th2 cytokine, IL-4. Based on these findings,
humoral response, a heightened humoral immunity during it has been hypothesized recently that PZP and PP14
pregnancy and a ‘relative’ suppression of this enhanced form a stable complex in the plasma of pregnant women
humoral response in the postpartum period. The exact and act together synergistically to selectively modulate
mechanism of the heightened humoral immunity during the T cell activation. Mechanistically, this activity appears
pregnancy is not known, but pregnancy is associated with to be independent of the PZP receptor (CD91) or PZP’s
shift from a Th1 to Th2 immunological response and this anti-proteinase activity.34
in turn, is influenced by the elevated levels of estrogen As a consequence of changes in CMI which occur
and progesterone which occur during pregnancy.30 during pregnancy and lactation, several autoimmune
The increased humoral immunity to some extent; is disorders show a modulation of disease activity during
responsible for aggravation of antibody mediated disorders this period. For rheumatic diseases, pathogenetically
like systemic lupus erythematosus in pregnancy. Similarly, associated with a predominance of a Th1 immune
in the postpartum period when the humoral response response, a shift to Th2 type immune response during
decreases, these disorders improve.31 pregnancy is beneficial and is associated with a clinical
improvement in disease activity.35 Similarly, due to a
Cell Mediated Immunity
depressed CMI, pregnant women are more susceptible to
Pregnancy is also associated with a biphasic alteration of infections in which Th1 response is important for protection
CMI but in contrast to the humoral immunity, there is a (like viral infections and those due to intracytoplasmic
depression of CMI during pregnancy because a successful pathogens like toxoplasma).36 The same should also hold
pregnancy can only occur when the maternal immune true for leprosy, but unfortunately there is a paucity of
system fails to attack the allogenic foetus. The reverse hard data (especially from the era of MDT) on the course
however, occurs in puerperium, wherein the woman regains of leprosy in pregnancy,37 even though it is well established
the suppressed CMI.32 CMI is mediated through cytokines that both cell mediated and humoral responses are aberrant
and though both, Th1 and Th2 type cytokines are important in leprosy and similarly, there is a biphasic alteration in
in different stages of pregnancy and puerperium; cell mediated and humoral immunity during pregnancy and
simplistically put, the Th2 cytokines are protective for lactation.
pregnancy and are needed for the success of pregnancy, Though some studies on pregnancy and leprosy have
while Th1 type cytokines are associated with failure of been published, there are several lacunae in the available
pregnancy. So pregnancy is associated with down- information:37
regulation of Th1 response resulting in decreased • Inadequate determinants of reactions in pregnancy and
production of not only Th1-associated cytokines (like IL-1, lactation: As a result, in a given pregnant patient with
IL-2 and IFN-γ); but also with a decreased production of leprosy, it is difficult to predict the risk of developing a
other pro-inflammatory cytokines like TNF-α and IL-12; and type 1 or type 2 reaction, either during pregnancy or
simultaneously an increased production of Th2-associated during lactation.
cytokines (like IL-4 and IL-10).29 • Lack of appropriate studies:
The pathogenesis of the depressed CMI in pregnancy – Inappropriate study design: Most studies are
continues to remain an enigma. The local and systemic retrospective or case reports, so the data provided
cytokine profiles and their expression during pregnancy, is often incomplete and sketchy.
are strongly influenced by neuroendocrine factors with – Inappropriate controls in studies: In many studies,
hormones being the powerful modulators of cytokine healthy contacts of patients were recruited as
expression.33 Two plasma proteins with immunoregulatory controls when ideally, nonpregnant women with
activities, pregnancy zone protein (PZP) and placental leprosy should have been recruited, because the
protein-14 (PP14; also known as glycodelin-A), increase use of such controls would have permitted the
dramatically during pregnancy. They individually and calculation of the relative risk of developing
synergistically inhibit T cell activation, (as measured by reactions (both type 1 and type 2) in all three
reduced T cell proliferation and IL-2 production) in a dose- trimesters of pregnancy; as also during lactation.37
CHAPTER
25
• Geographical localization of studies: Most studies are FIRST PRESENTATION OF LEPROSY

from Ethiopia and it may not always be possible to IN PREGNANCY
extrapolate the findings of these studies to populations
Twenty to thirty percent women develop signs and
in Asia, Latin America or even other parts of Africa.37
symptoms of leprosy for the first time in pregnancy or
The lack of any study from India on this problem is
shortly thereafter, and this has been attributed to depressed
surprising, particularly given the high load of patients
CMI in pregnancy resulting in an increased multiplication
and the rather successful vertical (now horizontal)
of M. leprae.37 In a study from the pre-sulfone era (way
leprosy control programme that could have easily
back in 1936), Tajiri38 reported that more than a fifth of
gathered this data.
their cohort of 240 Japanese females presented with
• Paucity of data from MDT era: The earlier studies10,38
leprosy for the first time during pregnancy. Similarly, King
were done in the pre-sulfone and sulfone era, while the
and Marks10 reported about 35% of their women patients
Ethiopian studies were done in the early eighties (the
who presented with leprosy for the first time; either during
‘bridge period’ between the era of dapsone monotherapy
pregnancy or shortly thereafter.
and era of MDT). Data from MDT era is scanty and
In a retrospective study from Nagpur, Hardas et al 12
only in the form of anecdotal reports. It may be difficult
observed that almost 10% of their 68 patients noticed the
to extrapolate the data from those eras to the present
lesions of leprosy for the first time in pregnancy and more
day MDT treated leprosy patients because:
than 50% of the patients first noticed their lesions in the
– It is possible that the current multibacillary (MB)
post partum period. The large number of women who first
drug regimen (with its clofazimine component) presented with leprosy lesions in puerperium could be
protects women against developing erythema attributed to the increased visibility of leprosy lesions due
nodosum leprosum (ENL) during pregnancy, or at to erythema and oedema of reversal reaction (RR) which
least it may protect them from experiencing severe may occur due to recovery of CMI in the postpartum period.
recurrent ENL that have been reported in the It might have been compounded by the increased bacillary
Ethiopian studies.37 Similarly, the bactericidal effect load occurring during pregnancy (vide infra). Duncan
of rifampicin (even after the 1st dose) may nullify et al39 reported a new case detection rate (NCDR) of 3% in
(even if partially) the effect of depressed CMI. This women attending antenatal clinic in Ethiopia, in contrast
in turn would prevent the increase in bacterial load, to 0.1% in the non-pregnant women from neighboring
further reducing the severity and incidence of ENL, villages. Though there are no controlled studies/ reports
both of which occur more often in the highly after the initiation of MDT, Lyde40 in 1997, reported 2 women
bacillated patients. in the US, who developed symptoms and signs of leprosy
– MDT by itself may have little effect on the incidence for the first time in pregnancy.
of type1 reactions because even after the
completion of MDT, M. leprae do persist in the skin
ACTIVITY OF LEPROSY
and peripheral nerves, capable of providing antigenic
stimulus. Thus, when the CMI is restored after Logically because of suppression of CMI during pregnancy
delivery, the previously unrecognized antigen (not and its recovery during puerperium, leprosy aggravates/
only from viable but also from non viable bacilli) downgrades in pregnancy and upgrades during lactation.
may precipitate a type 1 reaction. This has been supported by several observational studies.
– With these deficiencies in the available data on the In the pre-sulfone era, Tajiri38 noted aggravation of leprosy
interaction of leprosy and pregnancy, it is important in 48% of pregnancies and these findings were more than
that a cohort of women with leprosy on treatment confirmed by King and Marks 10 who also observed
with MDT or those RFT from MDT, be followed to worsening of leprosy during pregnancy in 78% of untreated
find out the risk of reactions in pregnancy and post patients, in contrast to aggravation of leprosy during
partum period. Also to find out, for how long the pregnancy in 22% of patients on treatment with dapsone
risk of post-partum reaction persists after the monotherapy. Unfortunately, in both these studies
completion of treatment; and to know about the ‘aggravation of leprosy’ was not defined. However,
clinical profile of reactions in pregnancy and subsequent studies have clearly demonstrated the
thereafter. increased clinical manifestations of leprosy, both in the
CHAPTER
25
form of disease progression towards lepromatous end of Though most of the reports on relapse in pregnancy
spectrum (appearance of new skin lesions and progressive belong to the era of dapsone monotherapy, more recently,
nerve function impairment) during pregnancy, and RR which Lyde40 reported a case of lepromatous relapse in a pregnant
occurs in the postpartum period41 (vide infra). In a patient who had taken 20 months of daily rifampicin and
prospective study of 114 Ethiopian pregnant women with dapsone, emphasizing at the possibility of relapse in
leprosy, almost half (48.2%) of them showed worsening of pregnancy even in the era of MDT. However, the problem
their leprosy status during pregnancy; with more than a of relapse in MDT era requires systematic evaluation; with
quarter (27.2%) developing the down hill trend during the particular attention to factors which predispose to a greater
third trimester of pregnancy.42 risk of relapse and their relationship to the phases of
pregnancy/ lactation.37
BACILLARY LOAD
There is an increase in the bacillary load during pregnancy, REACTIONS AND PREGNANCY
due to suppression of CMI. A compounding factor for this Types of Reactions
could be the reluctance of women to take medication during
Reactions in leprosy are acute immunologically mediated
pregnancy.37 In the era of dapsone monotherapy, Duncan
episodes in the chronic course of the disease. They can
et al39 reported that the increase in bacillary load was seen
broadly be classified as:
in about a quarter of paucibacillary (PB) patients [who
• Type 1 reaction: Which is due to alteration
converted from bacteriological index (BI) negativity to
(improvement or deterioration) of CMI, occurs in
positivity]; and in about half of the multibacillary (MB)
borderline leprosy and is characterized by erythema
patients. The increase in the BI occurred both in patients
and edema of pre-existing skin lesions, appearance of
who had not received any antileprosy therapy (ALT) as
new lesions as well as neuritis which may additionally
well as those who were on ALT and in 38% of the patients,
manifest with motor and sensory deficits. Constitutional
the increase was due to multiplication of dapsone resistant
symptoms are minimal or absent.
M. leprae.43 The high prevalence of dapsone resistance in
• Type 2 reaction: Which is due to immune complex
pregnant women was a reflection of the quantum of the
deposition, occurs in multibacillary leprosy and
primary low grade dapsone resistance already existing in
manifests as erythema nodosum leprosum, neuritis and
the community in Ethiopia.44 This process was further
constitutional and systemic symptoms.
compounded by the immunosuppression of pregnancy
Since the immunological changes during pregnancy
which predisposed for selection of drug resistant mutants
to multiply rapidly. are biphasic, being different during pregnancy and
The increased load of M. leprae is most frequently seen puerperium, the impact of pregnancy and lactation on the
in the 3rd trimester of pregnancy and fortunately in about two types of reactions is being discussed separately.
50% of the patients the increase in BI is temporary,
declining to the pre-pregnancy levels, as CMI is restored TYPE 1 REACTIONS
during lactation.39 a. Downgrading reactions: There are leprologists who do
not subscribe to the view of downgrading reactions and
RELAPSE OF LEPROSY equate them with the downhill course of untreated
Pregnancy associated-relapse is again due to decrease in leprosy.
CMI. It is believed that the persisters multiply during the b. Reversal reactions (RR): RRs are less frequent during
period of prolonged (9 months) ‘immunosuppression’ which pregnancy than lactation. In a prospective cohort study
peaks in the 3rd trimester.45 of 114 pregnant Ethiopian women with leprosy, Duncan,
In the era of dapsone monotherapy (pre-MDT era), et al42 reported that 40% of RRs occurred during
Duncan et al42 observed a relapse rate of 36% in pregnant pregnancy and 60% during lactation. Since the controls
women with PB leprosy, 3-36 months after RFT. In a in this study were non leprosy pregnant women, it is
subsequent study, Duncan et al43 noted that 38% of the not possible to ascertain whether there was a true
women who relapsed during pregnancy, harbored dapsone decrease in RRs during pregnancy (and an increase
resistant M. leprae.44 during lactation) or not.
CHAPTER
25
Though the peak incidence of new RRs occurs antigenic load (BI ≥ 4, so usually LL and BL); untreated
3-16 weeks after delivery, recurrent episodes may disease and those harboring drug resistant M. leprae. The
continue even late into lactation (late RRs).45 The skin reaction may be severe and recurrent37,40 and though
patients with BL and subpolar LL are at the greatest neuritis is frequently present (in 70% of women) in
risk of developing RRs.46 In RRs occurring during pregnancy, systemic symptoms are less frequent.51
pregnancy and early postpartum period, cutaneous Duncan and Pearson51 in a prospective study of a
manifestations are more frequent and conspicuous than cohort of 76 women with MB leprosy (LL 32, BL 44) followed
neuritis. In contrast, in RRs occurring during lactation, through pregnancy and lactation, observed that 38%
neuritis and nerve function impairment (including sudden developed ENL during the study period (BL, 22%; LL, 59%).
and severe motor damage like claw hand and foot drop) The first episode of ENL could occur as early as the 1st
are seen more frequently (in up to 90% of patients) trimester or as late as 15 months postpartum. In a
and the skin may not even be involved.46 However, retrospective multicentric analysis from USA, Maurus52
even when involved, the classical cutaneous reported that 32% of the 26 women with leprosy on
manifestations are relatively subdued during pregnancy treatment followed through 62 pregnancies had episodes
and lactation (in comparison to those of non pregnant/ of ENL. Interestingly, more than 65% of the women who
nonpuerperal state) except in those women in whom had a BI of ≥ 4+ in this cohort experienced ENL during
antileprosy treatment (ALT) has recently been pregnancy. However, there was no information on the
instituted.39,47 This has been attributed to the varied clinical features, the temporal relation of these episodes
antigenic expression of M. leprae due to fluctuations in with pregnancy/parturition, or presence of previous
the host CMI.48 When the CMI is low (as in pregnancy), episodes of ENL. Lyde40 reported that 70% of women who
only the surface antigens of M. leprae multiplying in developed ENL during pregnancy had neuritis, as compared
the skin are exposed, resulting in predominantly with 30% in the non-ENL group. Lucio phenomenon has
cutaneous lesions. As the CMI improves (in the also been reported from Brazil in a pregnant woman with
postpartum period), the cytoplasmic antigens in the BL disease. The reaction responded to systemic steroids
nerves are uncovered due to destruction of bacteria, and had little impact on the outcome of pregnancy.53
resulting predominantly in neuritis.48 With recovery of CMI and shift from a Th2 response to
Pathogenetically, M. leprae are probably not fully Th1 response during puerperium, it seems logical to expect
recognized during pregnancy, but with the recovery of CMI a decrease in type 2 reaction in the postpartum period.
during puerperium, they are attacked by primed immune Though patients with type 2 reaction present less frequently
cells resulting in RRs.49 Alternatively, the late reaction for the first time during lactation than in pregnancy, recurrent
may be caused by release of sensitized lymphocytes during ENL may last for more than a year after delivery.51 Duncan
puerperium which were trapped in the spleen for the period and Pearson51 in a study from Ethiopia reported that though
of pregnancy.50 first episodes of ENL occurred more frequently in
pregnancy than during lactation, recurrent ENL persisted
TYPE 2 REACTIONS throughout lactation, with 15% of the group experiencing
ENL for an 18 month period from the 3rd trimester to
Type 2 reactions being immune complex mediated, occur 15 months postpartum. Episodes of ENL in puerperium
in the presence of antigen and antibody excess (BL, LL are often associated with significant motor and/or sensory
and pregnancy, all being dominated by Th2 response). deficit involving multiple nerves and unlike in pregnancy,
Unlike type1 reactions, though type 2 reactions do not involvement of other systems like eyes, bones and joints
have a clear temporal association with delivery and is frequent.51
lactation,37 the general impression is that while the first
episodes of type 2 reaction can begin early in pregnancy
PREGNANCY AND LEPROUS
and peak in the 3rd trimester, the recurrent episodes may
NEUROPATHY50-55
continue long into the lactation period.
Type 2 reaction manifesting as erythema nodosum Women with leprosy (both PB and MB) are at a risk of
leprosum (ENL) occur throughout pregnancy, peaking in developing neuritis during pregnancy, with the nerve
3rd trimester. They are more frequent in patients with higher function deteriorating in about 50% of women. Any patient
CHAPTER
25
with leprosy irrespective of the status of treatment (whether The evidence of transplacental transmission of leprosy
untreated, on treatment or RFT), can develop neuropathy.50 in humans is however, more tenuous and is largely based
Women with BL disease developed neuritis more frequently on the serological evidence. The presence of IgA and IgM
during the first 6 months of lactation as compared to the anti-M. leprae antibodies in the cord blood of newborns of
pregnant state. In contrast, in BT/TT cases neuritis was leprosy mothers; probably indicates intrauterine
less common and did not show any relationship to the immunologic stimulation due to transplacental transmission
trimester of pregnancy. of M. leprae. Anti M. leprae IgA antibodies have been
Pathogenitically the nerve involvement can be due to: detected in 30% and IgM antibodies in 50% of the babies
• Worsening of leprosy status of the patient born to mothers with LL but in none of the babies born to
• RR and type 2 reaction.50 mothers with tuberculoid leprosy and healthy controls. In
• Occasionally, a combination of type 1 and type 2 sera taken 3-6 months after birth from babies born to
reaction. lepromatous mothers, there is a significantly higher
increase of anti-M. leprae IgA and IgM antibodies, as
Neuritis in RR compared to tuberculoid mothers and controls. In contrast,
As a manifestation of RR, overt neuritis is most frequently the levels of anti M. leprae IgG antibodies showed a
seen during puerperium and is due to recovery of CMI in continuous and marked decrease in sera of all babies, at
the postpartum period, seen most frequently in women 3-6 and 6-9 months and even 15-24 months after birth.59,60
with BL, but may also be seen in the newly diagnosed and There are anecdotal reports of intrauterine transmission
even in relapsed PB patients. of leprosy in humans. Duncan et al61 reported that of the
The possibly increased load of M. leprae, and their 38 bacillated pregnant leprosy women who delivered,
presence and persistence in peripheral nerves due to 2 children were diagnosed to have leprosy at the age of 9-
pregnancy related immunosuppression, results in further 17 months and the proof of suspected intrauterine infection
damage to the nerve and its function; either by the way of lay in the presence of IgA and IgM anti-M. leprae antibodies
a spreading granuloma or edema and compression due to in the cord sera associated with an early and significant
RR.56,57 increase in these antibodies after birth. A decrease in serum
IgG anti-M. leprae antibody activity was demonstrated in
Neuritis in Type 2 Reaction one of the babies after complete response to treatment.
When as a manifestation of type 2 reaction, overt neuritis
occurs in any trimester of pregnancy (most frequently, 1st IMPACT ON FETUS
and 3rd) or during lactation, it is due to development of
ENL lesions in the nerves. It is more severe when the In contrast to the significant impact of pregnancy on the
patient is highly bacillated (BL/LL patients); or when patient course of leprosy, only a few obstetric complications have
has not received any treatment or in the presence of drug consistently been reported in women with leprosy,
resistant M. leprae.50,55 irrespective of the disease spectrum. Though in the early
leprosarium based study, Maurus52 reported several
EFFECT OF LEPROSY ON FETUS complications including prematurity (22%) and fetal loss
(17%) in 26 women with leprosy followed through 62
Transplacental Infection pregnancies, subsequent studies from Ethiopia have not
Experimental Evidence confirmed significant obstetric complications in women with
There is evidence of transplacental transmission of leprosy.62
M. leprae in animal models. Job et al58 have reported However, leprosy does impact the growing foetus.
lepromatous placentitis in 3 pregnant 9-banded armadillos Babies born to mothers with LL weigh significantly less at
(Dasypus novemcintus) as shown by the presence of birth than babies born to mothers with tuberculoid leprosy
M. leprae in placenta (in decidual tissue and trophoblastic as well as normal healthy controls.62 This intrauterine
cells of the chorionic villi). AFBs were also present in the growth retardation has been attributed to fetoplacental
spleens of 3 of the 4 fetuses born to the infected mothers. inadequacy in women with LL.63 The lower mean estrogen
Since mother to fetus transmission of M. leprae clearly excretion (which is an index of fetoplacental function),64
occurs in the armadillo, it may be a possibility in humans. between 32-40 weeks of gestation, in pregnant women
CHAPTER
25
with lepromatous disease compared to controls, is evidence levels of secretory IgA, lactoferrin, albumin and total protein
to suggest fetoplacental inadequacy.65 There is also an in colostrum and breast milk samples in patients with LL
association between infant’s weight at birth and lowered were comparable to normal controls.69 Many of the
estrogen excretion, this association being most marked in antileprosy drugs are excreted in breast milk and may cause
women with LL leprosy. Though the definite cause of feto- some effect in the breast fed infants (vide infra).
placental dysfunction is not known, it is probably due to
decreased uteroplacental perfusion.65 DRUG THERAPY OF LEPROSY
DURING PREGNANCY
IMPACT ON PLACENTA
Drugs are best avoided in pregnancy, but the benefits of
Though the morphology and immunohistology of placenta treating leprosy during pregnancy far outweigh the risks of
in women with leprosy (even LL) is normal,66 the placental the drugs. WHO recommends that pregnant women with
weight and placental coefficient (ratio of baby weight to leprosy should continue to take standard MDT.70
placental weight) is lower in women with leprosy and this
is most marked in LL.62,66 The small placental size of DAPSONE
women with leprosy is due to a decrease in size of cells of
placenta and not due to reduced number of cells. Though Though there are no studies to evaluate its safety in
there is no morphological evidence of infection of the animals,71 it is a pregnancy category C drug.72 Based on
placenta with M. leprae, in a small number of patients, a extensive experience on its safety, WHO recommends that
few AFB have been demonstrated in the placenta.66 dapsone should be continued during pregnancy,
irrespective of the trimester. Though dapsone readily
IMPACT ON INFANTS, CHILDHOOD passes into breast-milk, it generally has no adverse effect
AND ADOLESCENCE on the newborn, except for anecdotal reports of hemolytic
anemia and hyperbilirubinemia in breast-fed infants of
Eighty percent of the babies born to lepromatous mothers mothers receiving dapsone, 73,74 requiring appro-
have been found to be severely underweight (as compared priate laboratory monitoring including G6PD levels of the
to the Boston standards) even at 12 months of age.62 infants.
These infants, especially those born to mothers with LL,
have a higher incidence of respiratory problems,63 . more
RIFAMPICIN 75
serious childhood infections and a higher infant mortality
rate67 as compared to children of non-leprosy mothers. Animal experiments indicate that rifampicin is not
The newborns of mothers on MDT may present intercurrent teratogenic and though a pregnancy category C drug, WHO
disease, such as exfoliative dermatitis in the first hours of recommends continuation of rifampicin in pregnancy, both
life due to dapsone and brownish discoloration of skin due for treating leprosy as well as tuberculosis.76 An association
to impregnation of clofazimine in the skin.44 between rifampicin and hemorrhagic disease of the new
The pubertal skeletal growth spurt, and in girls menarche born has been reported and so prophylactic parenteral
may be delayed in children born to mothers with LL as vitamin K is recommended in infants born to mothers who
compared to healthy controls, but the growth curve of these have taken rifampicin during pregnancy.77 Lactating
children caught up with controls by late teens.67 The mothers who are taking rifampicin can continue breast
impaired growth in utero has been attributed to placental feeding their infants as it is only minimally secreted in the
inadequacy64 but it is difficult to explain the delay in growth milk.
in adolescent children of mothers with LL.
CLOFAZIMINE78,79
IMPACT ON LACTATION Animal experiments indicate that clofazimine is not
M. leprae are secreted in breast milk, more so in patients teratogenic in animals and though a pregnancy category
with MB leprosy.68 The protective effect of breast milk of C drug,72 clofazimine has been used in all trimesters of
women with LL is similar to that of normal controls; as the pregnancy in a number of women with MB leprosy without
CHAPTER
25
any evidence of teratogenicity. Since there are anecdotal new drug, caution should be exercised until the effects of
reports of death of neonates born to women receiving this exposure, if any, have been studied.90
clofazimine, it is suggested that women receiving
clofazimine during pregnancy should be managed during CORTICOSTEROIDS93,94
labour at a perinatal center with adequate neonatal care
Corticosteroids need to be given in pregnant women with
facilities.80,81 Clofazimine crosses the placenta and may
leprosy if they develop reactions (both type1 and type2),
discolor fetal skin temporarily, the discoloration, gradually
especially in the presence of neuritis. The duration of
fading over the first year.80 There is some evidence that corticosteroids therapy could vary from 4-16 weeks.
oestrogen excretion may be decreased in pregnant women Commonly used systemic corticosteroids including
receiving clofazimine, but further studies are needed.82 prednisone, cortisone, and dexamethasone cross human
Clofazimine is secreted in breast milk and there are reports placenta resulting in a small but definite increased risk of
of the drug causing temporary coppery discoloration of oral clefts with first trimester exposure. The clefting can
the skin of breastfed infants.80 be detected by a Level-II ultrasound scan. Though
secretion of steroids in breast milk is minimal, if
QUINOLONES 83-87 administered in a single daily dose of more than 40mg
prednisolone equivalent, it is recommended that feeding
Ofloxacin and sparfloxacin are the second line drugs for be deferred for at least 4 hours after the dose.
treatment of leprosy. Animal experiments indicate that
though quinolones are not teratogenic, they are fetotoxic NSAIDs
and can cause increased incidence of arthropathies and
osteochondrosis in immature animals. In humans, they NSAIDs need to be given in pregnant women with leprosy
if they develop mild to moderate reactions (both type1 and
are a pregnancy category C drug. Since the safety of long
type2), and they often need to be combined with
term quinolones (as required in leprosy and tuberculosis)
corticosteroids especially in the presence of neuritis. The
has not been established, the use of ofloxacin during
therapy could last for several weeks.
pregnancy, especially during the first trimester, is best
NSAIDs are best avoided during pregnancy, particularly
avoided. Quinolones are excreted in breast milk and
in the 3rd trimester.95 Though not directly teratogenic, they
therefore should not be administered during lactation may trigger premature closure of fetal ductus arteriosus
because of potential risk of arthropathies in infants. If (causing pulmonary hypertension), cause renal adverse
however, the mother’s health warrants continuation of these effects (causing oligohydramnios) and are sometimes
drugs, she should stop feeding the infant. linked with premature birth. In addition, aspirin95 may
aggravate maternal anemia, cause congenital salicylism
MINOCYCLINE 88 and if given in high doses near term; cause bleeding
disorders in neonates, manifesting as depressed platelet
Minocycline is a second line drug for treatment of leprosy.
function and purpuric rash. Due to lack of safety data on
It is a pregnancy category D drug and should not be
first trimester use of ibuprofen,96 it is prudent to avoid its
administered during pregnancy. In contrast, according to use in this period. Though, paracetamol97 (acetaminophen)
American Academy of Paediatrics, it can be administered is regarded as safe and well-tolerated during pregnancy,
safely during lactation.89 there is risk of hepatotoxicity with large doses. During
lactation, analgesics such as paracetamol, ibuprofen,
CLARITHROMYCIN90-92 naproxen and codeine are safe as very little is secreted in
breast milk.
Clarithromycin is a second line drug for treatment of leprosy
and there are anecdotal reports of safe short-term use of
clarithromycin in pregnancy. Based on experience with other THALIDOMIDE 98
macrolides, the risk to a nursing infant from clarithromycin Thalidomide is very effective in ENL but is absolutely
in breast milk is probably minimal, but because this is a contraindicated in women in reproductive age. Its
CHAPTER
25
prescription in many countries is restricted and monitored Second Line Drugs in Pregnant
by the country’s health authorities, e.g. in the USA Woman with Leprosy
prescription and dispensing thalidomide is monitored by There is no consensus on the use of second line of ALT.
STEPS (System for Thalidomide Education and Prescribing They can probably be administered in patients who cannot
Safety) program and only registered practitioners can use standard WHO MDT and when benefits outweigh the
prescribe the drug.98 risks.
PRACTICAL MANAGEMENT REFERENCES

Woman with Leprosy Becomes Pregnant 1. Bernard JC, Vazquez CAJ. Visceral lesions in lepromatous
leprosy. Study of sixty necropsies. Int J Lepr 1973; 41: 94-101.
• The patient should be counseled to complete the course 2. Desikan KV, Job CK. Visceral lesions caused by M. leprae; a
of ALT during pregnancy and if needed, in puerperium. histopathological study. Indian J Path Bact 1970; 13: 100-08.
As many pregnant women are tempted to avoid drugs 3. Garg R, Agarwal JK, Singh G, Bajpai HS. Hormone profile in
leprosy. Indian J Lepr 1989; 61:428-39.
in pregnancy and lactation; emphasize on the safety 4. Koshy TS, Rolston R, Mathews M, Taylor PM. Hormone profile in
of these drugs. lepromatous leprosy. Int J Lepr 1981; 49: 31-36.
• She should be counseled about the possibility of 5. Morley JE, Distiller LA, Sagel J et al. Hormone changes associated
with testicular atrophy and gynaecomastia in patients with leprosy.
development of reactions during pregnancy and
Clin Endocrinol 1977; 6: 299-303.
lactation and advise them to seek medical help 6. Martin FR, Maddocks I, Brown JB and Hudson B. Leprous
immediately. Careful monitoring of nerve function for endocrinopathy. Lancet 1968; ii 1320-21.
new sensory and motor deficits at every visit is 7. Mitsuda K. The significance of the vacuole in the Virchow lepra
cells and the distribution of lepra cells in certain organs. Int J
important. Lepr 1936; 4: 491-98.
• It is suggested (if possible) that patients taking ALT 8. Mitsuda K, Ogawa M. A study of 150 autopsies on cases of
during pregnancy should be managed at a perinatal leprosy. Int J Lepr 1937; 5: 53-60
9. Fleger J, Biric B, Prica S. Importance of leprosy in gynaecology
center where adequate neonatal care facilities exist.81
and midwifery. Trop Dis Bull 1963; 60: 446-47.
Prophylactic parenteral vitamin K is especially 10. King JA, Marks A. Pregnancy and leprosy. Am J Obstet Gynecol
recommended in the infants born to mothers who have 1958; 76:438-42.
taken rifampicin during pregnancy.77 Also the mother 11. Bogush TG. The question of the menstrual function in women
with lepromatous leprosy before pubescence. Sci Works Lepr
should be informed about the possibility of skin Res Institute 1979; 9: 116-18.
discoloration in the infant if she is taking clofazimine. 12. Hardas U, Survey R, Chakravarty D. Leprosy in gynaecology
and obstetric. Int J Lep 1972; 40: 399-400.
Pregnant/Lactating Woman is Diagnosed to 13. Sharma SC, Kumar B, Dhall K, et al. Leprosy and the female
reproductive organs. Int J Lepr 1981; 49: 177-79.
Have Leprosy 14. Khanna N, Ammini AC, Singh M, Pandhi R K. Ovarian function in
• Appropriate ALT should be started and the patient must female patients with multibacillary leprosy. Int J Lepr 2003; 71:
101-05.
be counseled to comply with ALT during pregnancy 15. Arora M, Katoch K, Natrajan M et al. Study of hormonal profile in
and in puerperium. Emphasize on safety of these drugs. female leprosy patients. Indian J Lepr 2008; 80: 89.
• The patient should be advised to seek medical help 16. Nelson LM, Covington SN, Rebar RW. An update: spontaneous
premature ovarian failure is not an early menopause. Fertil Steril
early, if reactions develop. Monitor for all parameters
2005; 83:1327-32.
as for other patients on ALT. 17. Nandedkar TD, Wadia P. Autoimmune disorders of ovary. Indian
J Exp Biol 1998; 36:433-36.
Pregnant/ Lactating Woman with Leprosy 18. Welt CK. Autoimmune oophoritis in the adolescent. Ann N Y
Acad Sci. 2008;1135:118-22
Develops Type 1/Type 2 Reactions
19. Park JY, Cho SN, Youn JK et al. Detection of antibodies to human
Appropriate ALT must be continued. Careful monitoring of nerve antigens in sera from leprosy patients by ELISA. Clin Exp
Immunol. 1992; 87:368-72
nerve function impairment is imperative and NFI must be
20. Garcia-De La Torre I. Autoimmune phenomenon in leprosy,
managed according to standard guidelines with caveat of particularly antinuclear antibodies and rheumatoid factor. J
pregnancy. Do not give Thalidomide. Rheumatol 1993; 20:900-03.
CHAPTER
25
21. Freire BF, Ferraz AA, Nakayama E, Ura S, Queluz TT. Anti- 42. Duncan ME, Pearson JMH, Ridley DS et al. Pregnancy and
neutrophilic cytoplasmic anti-bodies in leprosy. Int J Lepr 1998; leprosy: the consequences of alteration of CMI and humoral
66:475-82. immunity during pregnancy and lactation. Int J Lepr 1982; 50:
22. Guedes Barbosa LS, Gilbrut B, Shoenfeld Y, Scheinberg MA. 425-35.
Autoantibodies in sera of leprosy patients. Clin Rheumatol 1996; 43. Duncan ME, Pearson JMH, Rees RJ. The association of
15:26-28 pregnancy and leprosy II. Pregnancy in dapsone resistant
23. Saha K, Gupta I. Immunologic aspects of leprosy with special leprosy. Lepr Rev 1981; 52: 263-70.
reference to the circulating antispermatozoal antibodies. Int J 44. Pearson JMH, Haille GS, Rees RJ. Primary dapsone resistant
Lepr 1977; 45:28-37. leprosy. Lepr Rev 1977; 48: 129-32.
24. Chandra RK. Rosette-forming T lymphocytes and cell mediated 45. Rose P, McDougall AC. Adverse reactions following pregnancy
immunity in malnutrition. Brit Med J 1974; 3: 608-09. in patients with BL leprosy. Lepr Rev 1975; 46:109-14.
25. Wintergerst ES, Maggini S, Hornig DH. Contribution of selected 46. Duncan ME, Pearson JM. Neuritis in pregnancy and lactation.
vitamins and trace elements to immune function. Ann Nutr Metab Int J Lepr Other Mycobact Dis. 1982; 50:31-38.
2007; 51:301-23. 47. Lopes VGS, Sarno EN. Hanseníase e gravidez. Rev Ass Med
26. Ryrie GA. Some impression of Sungei Buloh Leper Hospital Brasil 1994; 40: 195-201.
under Japanese occupation. Lepr Rev 1947; 18: 10-17. 48. Barnetson R, Bjune G, Pearson J et al. Antigenic heterogeneity
27. Scott JS. Immunological diseases in pregnancy. Prog Allergy in patients with reactions in borderline leprosy. Brit Med J 1975;
1977; 23: 321-66. 4:435-37.
28. Shephard CC, McRae DH. M. leprae in mice minimal infectious 49. Weddell AGM, Pearson JMH. Leprosy histopathological aspects
dose, relationship between staining quality and infectivity, and on nerve involvement. In: Topics in Tropical Neurology. Hornbrook,
effect of cortisone. J Bacteriol 1965; 89: 365-72. RK ed, Philadelphia Davis: 1975; 17-28.
29. Priddy KD. Immunologic adaptations during pregnancy. J Obstet 50. Bullock WE. Perturbation of lymphocyte circulation in experimental
Gynecol Neonatal Nurs 1997;26:388-94 murine leprosy. II Nature of defect. J Immunol 1976; 117: 1171-
30. Canellada A, Alvarez I, Berod L, Gentile T. Estrogen and 78
progesterone regulate the IL-6 signal transduction pathway in 51. Duncan ME, Pearson JMH. The association of pregnancy and
antibody secreting cells. J Steroid Biochem Mol Biol 2008; leprosy. III. Erythema nodosum leprosum in pregnancy and
111:255-61. lactation. Lepr Rev 1984; 55: 129-42.
31. Varner MW. Autoimmune disorders and pregnancy. Semin 52. Maurus JN. Hansen’s disease in pregnancy. Obstet Gynecol
Perinatol 1991; 15: 238-50. 1978; 52: 22-25.
32. Wegmann TG, Lin H, Guilbert L et al. Bidirectional cytokine 53. Heliner KA, Fleischfrasser I, Kucharski- Esmanhota LD et al .
interactions in the maternal-fetal relationship: is successful The Lucio’s phenomenon (necrotizing erythema) in pregnancy.
pregnancy a Th-2 phenomenon? Immunol Today 1993; 14: 353- Ann Bras Dermatol 2004; 79: 205-10.
56. 54. Sehgal VN, Sharma V, Sharma VK. The effect of antireactional
33. Stensen M, Förger F, Villiger PM. Cytokines and pregnancy in drugs on complement components in type 2 ENL reaction. Brit J
rheumatic disease. Ann N Y Acad Sci 2006; 1069:353-63. Dermatol 1988; 119:255-58.
34. Skornicka EL, Kiyatkina N, Weber MC, et al. Pregnancy zone 55. Duncan M E. Pregnancy and leprosy neuropathy. Indian J Lepr.
protein is a carrier and modulator of placental protein-14 in 1996; 68:23-34.
T-cell growth and cytokine production. Cell Immunol 2004; 56. Shetty VP, Suchitra K, Upelkar MW, Antia NH. Higher incidence
232:144-56. of viable Mycobacterium leprae within the nerve as compared to
35. Da Silva J, Spector TD. The role of pregnancy in the course and skin among multibacillary leprosy patients released from multidrug
aetiology of rheumatoid arthritis. Clin Rheumatol 1992; 11: 189- therapy. Lepr Rev 1997; 68:131-39.
94. 57. Antia NH, Shetty VP, Mehta LN. Study of evolution of nerve
36. Luft BJ, Remington JS. Effect of pregnancy on resistance to damage in leprosy. I. An assessment. Lepr India 1980; 52: 48-52.
Listeria monocytogenes and Toxoplasma gondii infections in 58. Job CK, Sanchez RM, Hastings RC. Lepromatous placentitis
mice. Infect Immunol 1982: 38; 1164-71 and intrauterine fetal infection in lepromatous nine-banded
37. Lockwood DNJ, Sinha HH. Pregnancy and leprosy: A armadillos (Dasypus novemcinctus). Lab Invest 1987; 56:44-
comprehensive literature review. Int J Lepr 1999; 67: 6-12 48.
38. Tajiri I. Leprosy and childbirth. Int J Lepr 1936; 4: 189-94 59. Melsom R, Harboe M, Duncan ME, Bergsvik H. IgA and IgM
39. Duncan ME, Melsom R, Pearson JMH, Ridley DS. The antibodies against Mycobacterium leprae in cord sera and in
association of pregnancy and leprosy. I. New cases, relapse of patients with leprosy: an indicator of intrauterine infection in
cured patients and deterioration of patients on treatment during leprosy. Scand J Immunol 1981; 14:343-52.
pregnancy and lactation results of 154 pregnancies in 147 60. Melsom R, Harboe M, Duncan ME. IgA, IgM and IgG anti-M.
Ethiopian women. Lepr Rev 1981; 52: 245-62. leprae antibodies in babies of leprosy mothers during the first 2
40. Lyde CB. Pregnancy in patients with Hansen’s disease. Arch years of life. Clin Exp Immunol 1982;49:532-42.
Dermatol 1997; 133: 623-27. 61. Duncan ME, Melsom R, Pearson JM, Menzel S, Bernetson RS.
41. Duncan ME. An historical and clinical review of the interaction of A clinical and immunological study of four babies of mothers with
leprosy and pregnancy: a cycle to be broken. Soc Sci Med 1993; lepromatous leprosy, two of whom developed leprosy in infancy
37:457-72 Int J Lepr Other Mycobact Dis 1983; 51:7-17
CHAPTER
25
62. Duncan ME. Babies of mothers with leprosy have small placentae, 81. Bhargava P, Kuldeep CM, Mathur NK. Antileprosy drugs,
low birth weights and grow slowly. Brit J Obstet Gynaecol 1980; pregnancy and fetal outcome. Int J Lepr Other Mycobact Dis.
87:471-79. 1996; 64:457-58
63. Morrison A. A woman with leprosy is in double jeopardy. Lepr 82. Duncan ME. Reduced estrogen excretion due to clofazimine?
Rev 2000; 71: 128-43. Int J Lepr Other Mycobact Dis 1983; 51:112-13.
64. Bhansali KG, Eugere EJ. Quantitative determination of 17 beta- 83. Floxin. Internet drug index. Available at: the Internat drug index.
oestradiol and progesterone in cellular fractions of term placentae http://www.rxlist.com/floxin-drug.htm. (accessed March 25, 2009).
of normal and hypertensive patients. Res Commun Chem Pathol 84. Norrby SR, Lietman PS. Safety and tolerability of fluoroquinolones.
Pharmacol 1992; 77: 161-68. Drugs 1993; 45(Suppl 3):59-64.
65. Duncan ME, Oakey RE. Estrogen excretion in pregnant women 85. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome
with leprosy: evidence of diminished feto-placental function. after prenatal quinolone exposure. Evaluation of case registry of
Obstet Gynecol 1982; 60: 82-86. the European Network of Teratology Information Services
66. Duncan ME, Fox H, Harkness RA, Rees RJ. The placenta in (ENTIS). Eur J Obstet Gynecol Reprod Bio 1996; 69:839.
leprosy. Placenta. 1984; 5:189-98 86. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following
67. Duncan ME, Miko T, Howe R, Hansen S, et al. Growth and gestational exposure to fluoroquinolones: a multicenter
development of children of mothers with leprosy and healthy prospective controlled study. Antimicrob Agents Chemother 1998;
controls. Ethiopian Med J 2007; 45: 9-23 42:133-69.
68. Girdhar A, Girdhar BK, Ramu G, et al. Discharge of M. leprae in 87. Sparfloxacin. The internet drug index. Available at: http://
milk of leprosy patients. Lepr India 1981; 53:390-94. www.rxlist.com/sparfloxacin-drug.htm. (accessed March 25,
69. Duncan ME, Samson RR, McGrath J, McClelland DB. Humoral 2009)
defence factors in the breast milk of Ethiopian women with leprosy 88. Minocin. The internet drug index. Available at http://
and healthy controls. Am J Clin Nutr 1983; 38:921-28. www.rxlist.com/minocin-capsules-drug.htm. (accessed March
70. WHO. The final push strategy to eliminate leprosy as a public 25, 2009)
health problem. Question and Answers. 2nd edn. Geneva 89. Committee on Drugs, American Academy of Pediatrics. The
2003:25. transfer of drugs and other chemicals into human milk. Pediatrics
71. Kahn G. Dapsone is safe during pregnancy. J Am Acad Dermatol 1994;93:13750
1985; 13: 838-39. 90. Biaxin. The internet drug index. Available at: http://www.rxlist.com/
72. Food and Drug Administration, Federal Register 1980; 44: 37434- biaxin-drug.htm. (accessed March 25, 2009).
67. 91. Einarson A, Philips E, Mawji F, et al. A prospective controlled
73. Sanders SW, Zone JJ, Foltz RL et al. Haemolytic anaemia multicentric study of clarithromycin in pregnancy. Am J Perinatol
induced by dapsone transmitted through breast milk. Ann Intern 1998; 15: 5235.
Med 1982; 96: 465-66 92. Jacoby EB, Porter KB. Helicobacter pylori infection and persistent
74. Thornton YS, Bowe ET. Neonatal hyperbilirubinemia after hyperemesis gravidarum. Am J Perinatol 1999;16:858.
treatment of maternal leprosy. South Med J 1989; 82:668. 93. Walker BE. Introduction of cleft palate in rats with anti-
75. Rifadin, Internet drug index. Available at: http://www.rxlist.com/ inflammatory drugs. Teratology 1971; 4: 39-42.
rifadin-drug.htm. Accessed March 24, 2009. 94. Park-Wyllie L, Mozzotla P, Pastuszak A et al. Birth defects after
76. Bothamley G. Drug treatment for tuberculosis during pregnancy. maternal exposure to corticosteroids: prospective cohort study
Drug Safety 2001; 24:553-65. and meta analysis of epidemiological studies. Teratology 2000;
77. Ribes B C, Rossich VR, Aramburo CA, et al. Life-threatening 62: 385-92.
hemorrhage in the neonate of a rifampicin-treated mother. Ann 95. Aspirin. The internet drug index. Available at: http://www.rxlist.com/
Pediatrics (Barc) 2006; 65:629-30. aspirin-drug.htm. (accessed: March 25, 2009).
78. Clofazamine, Internet drug index. Available at: http:// 96. Ibuprofen. The internet drug index. Available at: http://
www.rxlist.com/lamprene-drug.htm. (accessed April 01 2009). www.rxlist.com/ibuprofen-drug.htm. (accessed: March 25, 2009).
79. Lamprene® (clofazimine) prescribing information. Novartis East 97. Paracetamol. The internet drug index. Available at: http://
Hanover, New Jersey; 1998. www.rxlist.com/tylenol-drug.htm. (accessed: March 25, 2009).
80. Farb H, West DP, Pedvis-Leftick A. Clofazimine in pregnancy 98. Thalidomide. The internet drug index. Available at: http://
complicated by leprosy. Obstet Gynecol 1982; 59:122-23. www.rxlist.com/thalomid-drug.htm. (accessed: March 25, 2009).
26
Leprosy in Children
Rajeshwar Dayal, Sunil Sanghi
INTRODUCTION detected were above 10% in 10 States & Union territories

(UT) of the country. The top ten States and UTs with highest
Mycobacterium leprae, characterized by well recognized incidence of child leprosy are Daman & Diu (30%), Dadara
clinical, bacteriological and pathological changes. Besides & Nagar Haveli (19.88%), Tamil Nadu (16.87%), Bihar
affecting all the organs, it particularly affects the skin and (16.64%), Goa (15.38%), Andhara Pradesh (12.5%),
nerves. The damage to peripheral nerves results in sensory Maharashatra (11.87%), Karanataka (11.81%), Gujarat
and motor impairment with characteristic deformities and (11.75%) and Kerala (10.16%).
disability. Leprosy among children is a public health Leprosy is known to occur at all ages ranging from
problem, reflecting the active transmission of the disease early infancy to old age. Some experts believe that the
in the community. As the transmission declines, the children are more susceptible to Hansen’s disease than
disease is seen in older age groups.1,2 adults with similar exposure. Hansen’s disease is rare in
Leprosy in children forms an important link in the natural children younger than 2 years in most cases.5 In children
evolution and the epidemic profile of disease. Leprosy in it is mostly seen between 5-14 years of age, though in
children is considered important because of its potential very high endemic areas, prevalence in age group below 4
to cause progressive physical deformity with serious years is quite significant. The youngest age reported for
psychosocial impact on the child and the family. Disabilities occurrence of leprosy is 3 weeks in Martinique (a small
are recognizably major factors of stigma associated with island near West Indies).6 The new case detection rate is
leprosy and they may impact psychological development the most reliable information to estimate cases in children,
in children.3 as it is based on actual records. The proportion of children
among newly detected cases shows wide variation across
the globe, in African region it ranges from 0.82% in Niger
EPIDEMIOLOGY
to 30.95% in the Comoros. In the South-East Asia region
The global leprosy situation as described by WHO still the proportion of children ranges from 2.99% in Thailand
requires concerted efforts to make it a disease of the past. to 11.4% in Indonesia. In the Western Pacific region the
At the beginning of 2009 the registered prevalence of range is from 2.48% in China to 39.5% in the Federated
leprosy globally was 213,036 cases. The number of new States of Micronesia.4 In India the range varies from 4.5%
cases detected during 2008 was 249,007. During 2008 the to 17.3% depending on whether study was hospital based,
global detection of new cases declined by >9126 cases which reflects lower prevalence in comparison to contact
(3.54%) as compared to 2007. The scenario in India has based studies.
also changed; the number of new cases detected in 2008 Presence of household or neighbourhood contact of
was 134,184 which formed 53.9% of total new cases leprosy increases the risk of infection. The risk is increased
detected in world.4 The proportion of new child cases 9 times if the contact case is within the immediate
Note: The terms “leprosy” and “Hansen’s disease” have been used in the text interchangeably
CHAPTER
26
household. The higher risk of developing leprosy is had no known familial contact with leprosy. The
associated with the presence of multibacillary leprosy case investigators opined in favor of intrauterine infection as
in the family (Fig. 26.1). There is a higher attack rate when the likely mode of infection in infants developing leprosy
the index case is mother.7,8 In children, among whom at smaller age of few months.13
lepromatous leprosy is rare, the gender incidence is
approximately equal. School surveys followed by contact CLASSIFICATION
surveys form an important method of early detection of
leprosy cases in endemic areas.2,9,10 Several systems have been used to classify leprosy but
wide agreement is there on describing leprosy as a
spectrum between two polar forms, tuberculoid and
lepromatous. A five group clinico-histological classification
based on immunological status was first described by
Ridley and Jopling which is still most widely accepted.14
The revised Indian classification by IAL in 1981 divided
leprosy into five broad groups viz. indeterminate, borderline,
tuberculoid, lepromatous and polyneuritic. WHO simplified
the classification based on presence of M.leprae, where
paucibacillary = BI as 0 and multibacillary having
demonstrable bacilli on slit skin smear. Present
classification is based on the number of lesions; up to 5
(PB) and 6 or more (MB).
SPECTRUM OF CLINICAL
Fig. 26.1: Risk of transmission of leprosy is very high if the index
case is of multibacillary type, residing within the household, and as PRESENTATION IN CHILDREN
long as remains without MDT. A case of LL with his son, who also has
a leprosy nodule over right earlobe. (Photo courtesy: Dr DM Thappa,
Leprosy in the child reflects to some extent all the aspects
JIPMER, Puducherry, India) of the disease in the adults; with some additional features
of its own. The exposed parts in general and limbs in
TRANSMISSION specific are the commonest sites affected.15 Children
suffer from less severe disease form and their chances of
Although the bacteria responsible for the disease, was
developing deformities are also low, mainly due to less
discovered in 1873, the scientists still do not fully
frequent involvement of nerve trunks. Though rare but when
understand the exact mode of transmission. Inhaled
it occurs, neuritis and the possibility of ensuing deformities
droplets are considered as the likely mode of infection.
in childhood leprosy is a compounded tragedy. 16
Other factors that may influence transmission include
genetic susceptibility, extent of exposure and the Prevalence of various forms of disease in children is mostly
environmental conditions. Transplacental infection is derived from hospital based studies. Borderline tuberculoid
possible though rare; and infected breast milk may be the (BT) form is the commonest, the prevalence ranging from
source of infection.11,12 The report of child developing 55–78.7% of all child cases in various studies. Borderline
leprosy at the age of 3 weeks6 is an example where the lepromatous (BL) is seen in approximately 7.8% while
infection would have been intrauterine, since the infection lepromatous leprosy rates are very low, ranging from
from outside is not possible because of the long incubation 1.6–4.9%.7,17,18 Prevalence of indeterminate leprosy in one
period. study was estimated to be 10.1%.19
In the study reported by Brubaker et al, comprising 91 The character of skin lesions found in children, as in
infants with leprosy, mother was considered to be most adults, is determined by the type and stage of the disease.
probable source of infection in 29 (31.9%) children. The Most childhood leprosy at diagnosis is indeterminate
father or some other near relative or some unknown contact (Figs 26.2 to 26.4) or at the tuberculoid end of the spectrum
was considered probable source of infection in 43% children. (Fig. 26.5). The most common lesions of childhood leprosy
The youngest of the infant was about 3 months of age and in most series are hypopigmented macules and raised
CHAPTER
26
Leprosy in Children 327
A B
Figs 26.2A and B: Indeterminate leprosy. The presentation is of mildly hypopigmented ill-defined macules or of normal skin color patches, or
areas of sensory impairment. In children it is sometimes difficult to elicit sensory loss. Slit-skin smear examination is not much helpful and the
diagnosis rests on the dual evidence of clinical and histopathological evaluation (Photo courtesy: Dr Pankaj Sharma, Dr RML Hospital,
New Delhi).
Fig. 26.3: Indeterminate leprosy. A single ill-defined, hypopigmented Fig. 26.4: Indeterminate leprosy. A single faintly erythematous macule
patch on the nape of the neck in a girl of 11 year age (Photo courtesy: on right cheek of an 8-year-old girl (Photo courtesy: Dr H K Kar and Dr
Dr H K Kar, Dr R M L Hospital, New Delhi) Pankaj Sharma, Dr R M L Hospital, New Delhi)
plaques. The indeterminate form is an early presentation age group in endemic areas should arouse suspicion of
of leprosy and it may progress to, either the spontaneous leprosy.
cure or one of the subpolar forms.19 The early single lesions Borderline tuberculoid leprosy in children (Figs 26.6 to
in children are mostly found on the gluteal region, posterior 26.8) form the most important part of the spectrum with
aspects of arms and hands.20 Slight sensory loss may be regard to number of patients seen and the severity of nerve
present and generally there is no peripheral nerve damage. The lesions are greater in number than TT with
thickening. Any hypopigmented macule in the pediatric less infiltration, less prominent margins and presence of
CHAPTER
26
A B
Figs 26.7A and B: BT leprosy in two children (hypopigmented macular
(A) and raised erythematous plaque with type 1 reaction with few
satellite lesions (B). (Photo courtesy (Left): Dr Pankaj Sharma, Dr
RML Hospital, New Delhi)
Fig. 26.5: Well-defined, raised erythematous plaque of tuberculoid
leprosy (TT) with loss of eye brows on the forehead of a girl child
(Photo courtesy: Dr HK Kar, Dr RML Hospital, New Delhi)
A B A B
Figs 26.6A and B: BT leprosy with regressed type 1 reaction in two Figs 26.8A and B: BT leprosy with subsiding type 1 reaction. The
children. The plaque on left is hypopigmented with mild scaling and lesions show scaling and hypopigmentation. BT is an unstable form of
sensory impairment. The lesion on the right is a partially defined plaque leprosy with potential to move towards any side of the disease spectrum.
with scaling and a satellite lesion. The sensory impairment could not (Photo courtesy (A) Dr Inderjeet Kaur and Dr Sunil Dogra, PGIMER,
be elicited clearly due to small age of the child. (Photo courtesy: Dr Chandigarh; (B) Dr Pankaj Sharma, Dr RML Hospital, New Delhi)
Pankaj Sharma, Dr RML Hospital, New Delhi)
satellite lesions. Damage to the nerves is more widespread cases where leprosy is endemic. This form occurs less
and severe. The most striking feature is the speed with commonly in children (about 3.2% of all child cases) than
which type 1 reaction may occur. Nerve function may adults; and the nerve involvement is seen in approximately
deteriorate rapidly and irreversibly. The cutaneous signs 20% of the cases.
such as bilateral and symmetrical innumerable ill defined Reactions are much less frequent in childhood than in
macular hypoanesthetic lesions or diffuse infiltration of adults. The lower prevalence of reactions and associated
the face and ear lobes and bilateral loss of eyebrows are disabilities in children than the older group; is probably
uncommonly observed because of the rarity of BL and LL due to lower incidence of nerve involvement and lower
leprosy in children (Figs 26.9 and 26.10). prevalence of pure neuritic cases. Reactions are reported
Pure neuritic leprosy presents with nerve involvement more frequently in hospital based studies, seen in
without any skin lesions and forms a small proportion of approximately 25% cases.7,18,21-23
CHAPTER
26
A B
Figs 26.9A and B: BL leprosy in two children with innumerable hypopigmented patches progressing towards subpolar LL. The lesions are
tending to become bilateral and symmetrical. (Photo courtesy: Left: Dr Pankaj Sharma, Dr RML Hospital, New Delhi).
Deformities
Deformities occurring in children are more distressing both
socially and psychologically, as they have to live their
whole life with this stigma. Prevalence of deformities in
India varies from 2.5-10.5%. The various factors
responsible are increasing age of children, delay in
accessing health care, more number of skin lesions,
multibacillary disease, multiple nerve involvement and
reaction at time of presentation and smear positivity.
Children with thickened nerve trunk had 6.1 times higher
risk of developing deformities as compared to those without
nerve involvement (Fig. 26.11). Majority of deformities are
reported in upper limbs, only 10% in lower limbs.16
Fig. 26.10: LL in a child. Diffuse infiltration over face with papular/ DIAGNOSIS
nodular lesions over earlobes and peri-oral region. LL and BL forms
are not commonly observed in children (Photo courtesy: Dr BK Girdhar, The diagnosis, classification, monitoring response to
Consultant Dermatologist, Agra). treatment or applying control measures depend on limited
numbers of investigations. Accurate diagnosis in children
Evolution is very important, because of immense psychosocial
impact on the family. There are diagnostic difficulties in
The course of childhood Hansen’s disease is unpredictable. children as indeterminate and tuberculoid forms are
Progression or regression of lesions is common, and the common and clinical features maybe evolving. The
time course is variable. In children, spontaneous regression elicitation of sensory impairments over the lesions may
may occur in 33-75% of cases. The prognosis in children be quite difficult in children. Conventional methods of
with leprosy on regular treatment is excellent. laboratory diagnosis which include slit-skin smear
CHAPTER
26
evidence. The clinico-histopathological correlation in

childhood leprosy is variable ranging from 36–60.8% in
good hands. The positive correlation is seen more in
advanced cases.16,26
Newer Methods
The identification of M. leprae can be done in a more rapid
and specific way, both from clinical specimens and mouse
foot pad culture, by recombinant DNA technology. Based
on gene sequencing of M. leprae, several tests have been
designed which can be of immense help in early diagnosis.
Several gene amplification techniques like PCR for
amplifying M. leprae specific sequences from variety of
Fig. 26.11: Claw-hand deformity in a 9 years old female patient with
specimens, are reported to be highly sensitive and
pure neuritic leprosy. The patient had grossly enlarged ulnar nerve
(forming a nerve abcess) and short history of nerve pain. She presented specific.27,28 Estimation of serum beta glucuronidase levels
to the health facility for the first time with this deformity (Photo courtsey: may be another useful parameter to assess the activity
Dr HK Kar, PGIMER, RML Hospital, New Delhi) and extent of pathogenesis in leprosy.29
examination and histopathology are also applicable on TREATMENT

children with provisional diagnosis of Hansen’s disease.
In children, a skin biopsy is often indicated, particularly in The major goals of leprosy control programs are (1) early
non endemic areas, to exclude other dermatological detection of cases; (2) appropriate treatment; and (3)
conditions mimicking leprosy. adequate care for the prevention of disabilities and
rehabilitation.
Slit-skin Smear Examination There are several effective chemotherapeutic agents
against M. leprae. Dapsone (DDS), Rifampicin (RFN),
Smear of scrapings from skin lesions stained for AFB is Clofazimine (CLF), Ofloxacin (OFL) and Minocycline (MINO)
the standard technique used to estimate the number of constitute the back bone of MDT regimen, recommended
M. leprae if present, in the skin lesions (Bacillary Index- by WHO. Multi drug therapy (MDT) is the cornerstone of
BI) and the proportion of viable bacilli (Morphological Index the leprosy elimination strategy as it cures patients, reduces
-MI). The sites of examination are usually the most the reservoir of infection and interrupting its
infiltrated parts of the lesion. If no definite patches are transmission.30,31 MDT also prevents disabilities through
visible, smear should be taken from ear lobules and buttock. early cure. Fortunately intolerance to anti leprosy drugs in
Smears are positive in LL, BL and some BT cases. It is of children is low and most of the cases respond well to WHO
limited value in TT and indeterminate lesions and patients regimen of MDT. Clofazimine is easily accepted in children.
with early atypical clinical presentation. Hence, slit-skin The dosage of antileprosy drugs for children are shown in
smear is not very helpful in the diagnosis in children Tables 26.1 and 26.2.
because most of the cases are indeterminate, tuberculoid
or borderline tuberculoid, where smear is generally Table 26.1: Dosage of antileprosy drugs for children with
negative.18,24,25 paucibacillary leprosy
(PB-MDT)
Histopathology Age group Dapsone: daily dose, Rifampicin: monthly
The histopathological diagnosis in BT, BL and LL usually (Years) unsupervised (mg) dose,supervised (mg)
offers no problem. The common forms seen in children, 3-5 25 150-300
indeterminate and tuberculoid can sometimes pose 6-14 50-100 300-450
15 or above 100 600
difficulties. In these cases, the histopathological diagnosis
should always be made in combination with the clinical Duration: 6 months
CHAPTER
26
Table 26.2: Dosage of antileprosy drugs for children with multibacillary leprosy
(MB-MDT)
Dapsone Rifampicin Clofazimine
Age group Daily unsupervised, Monthly supervised Unsupervised Monthly supervised
(Years) dose (mg) dose (mg) dose (mg) dose (mg)
3-5 25 150-300 100 once weekly 100
6-14 50-100 300-450 150 once weekly 150-200
15 or above 100 600 50 daily 300
Duration: 12 Months
The management of reactions in children is on the same 6. Montestruc E, Berdonneau R. Two new cases of leprosy in
lines as in adults. The corticosteroids are the safest and infants in Martinique” (inFrench). Bull Soc Pathol Exot Filiales
1954; 47(6): 781-83.
the most effective to use, in proportionately smaller doses. 7. Vara N. Profile of new cases of childhood leprosy in a hospital
setting. Indian J Lepr 2006; 78:231-36.
Prevention 8. Jain S, Reddy RG, Osmani SN et al. Childhood leprosy in an
urban clinic, Hyderabad, India: clinical presentation and the role
Focus of National Leprosy Eradication Program for the of household contacts. Lepr Rev 2002; 73:248-53.
future has included situation analysis for proportion of child 9. Norman G, Joseph GA, Udaysuriyan P et al. Leprosy case
cases in priority districts under the program. Such exercise detection using school children. Lepr Rev 2004; 75 34-39.
will further demonstrate the true prevalence and disease 10. Sahoo A, Singh PC, Patnaik S, Singh N. Incidence of leprosy in
school-children and their family members in Berhampur. Indian
burden in this subset of patients.32
J Lepr 2002; 74:137-43.
11. Meyers WM. Leprosy. Dermatol clinics 1992; 10:73-95
CONCLUSION 12. Pedley JC. The presence of M. leprae in human milk. Lepr Rev
1967; 38;239-42.
Leprosy continues to be an important health problem in 13. Brubaker ML, Meyers WM, Bourland J. Leprosy in children one
children, especially in endemic areas. The early cases which year of age and under. Int J Lepr Other Mycobact Dis 1985;
form the major risk group for transmission and progression 53(4):517-23.
14. Ridley DS, Jopling WH. Classification of Leprosy according to
to disabilities can easily be missed. It is imperative that
immunology. A five group system. Int J Lepr 1966; 54: 255-73.
our goal should be to bring all cases of leprosy in children 15. Bechelli LM, Garbajosa GP, Gyi MM et al. Site of early lesions in
under treatment at the earliest possible stage. Reactions, children with leprosy. Bull World Health Org 1973; 48:107-11.
severe disabilities and intolerance to treatment are 16. Kar BR, Job CK. Visible deformity in childhood leprosy: A 10 year
study. Int J Lepr Other Mycobact Dis 2005; 73: 243-48.
fortunately uncommon in children. Parental education/
17. Kumar B, Rani R, Kaur I. Childhood Leprosy in Chandigarh: a
counseling and school surveys form an integral part of clinico histopathological correlation. Int J Lep other Mycobact
early detection and treatment to achieve the goal of Dis 2000; 68: 330-31.
eradication of leprosy. 18. Burman DK, Rijal A, Agarwal S. et al. Chilhood leprosy in eastern
Nepal: A hospital based study. Indian J Lepr 2003; 75:53-58.
19. Selvaseker A, Geetha AJ, Nisha K et al. Childhood Leprosy in
REFERENCES endemic areas. Lepr Rev 1999; 70: 21-27
1. Dayal R. Early detection of leprosy in children. J Trop Paediatr 20. Sehgal VN, Srivastava G. Leprosy in children. Int J Dermatol
1991; 37; 310-12. 1987: 26: 557-66.
2. Wesley SR, Nair G TV, Nair B KH. Leprosy among school children 21. Gupta R, Singal A, Pandhi D. Genital involvement and type1
in Trivandrum city. Indian J Dermatol Venereol Leprol 1990; 56: reaction in childhood leprosy. Lepr Rev 2005; 76:253-57.
286-88. 22. Imbiriba EB, Hurtado-Guerrero JC, Garnelo L et al.
3. Hammond PJ, Rao PS. The tragedy of deformity in childhood Epidemiological profile of leprosy in children under 15 in Manaus
leprosy. Lepr Rev 1999; 70; 212-16. (Northern Brazil), 1998-2005. Rev Saude Publica. 2008 ; 42:
4. World Health Organization. Global leprosy situation, beginning 1021-26.
of 2009. Weekly Epidemiological Record 2009; 84: 333-40. 23. Chen XS, Li Lu-Z, Jiang C et al. Leprosy in children: a
5. Kaur I, Kaur S, Sharma VK. Childhood Leprosy in Northern India. retrospective study in China,1986-1977. J Trop Pediatr 2000;
Paediatr Dermatol 1991; 8: 121-24. 46:207-11.
CHAPTER
26
24. Prasad PVS. Childhood Leprosy in a rural hospital. Indian J 28. Dayal R, Singh SP, Mathur PP et al. Diagnostic value of in situ
Pediatr 1998; 65:751-54. polymerase chain reaction in leprosy. Indian Paediatr 2005; 72:
25. Jayalakshmi P, Tong M, Singh S. Leprosy in children. Int J Lepr 1043-46.
1997; 65: 95-97. 29. Nandan D, Venkatesan K et al. Serum beta glucuronidase levels
26. Cortés SL, Rodríguez G. Leprosy in children. Association in children with leprosy. Lepr Rev 2007; 78:243-47.
between clinical and pathological aspects. J Trop Pediatr 2004; 30. Ishii N. Recent advances in treatment of Leprosy. Dermatology
20:12-15. online journal 2002; 9(2): 5.
27. Dayal R, Agarwal PK, Kalra K et al. Diagnostic value of gene 31. WHO. Chemotherapy of Leprosy for control programme.
Technical Report Series 675, WHO, Geneva,1982.
probes and its correlation with the clinical profile of leprosy in
32. Kishore J. National Leprosy Eradication Programme. In Kishore
children. Indian Paediatr 1994; 31: 1521-27.
J. National Health programs of India 2007;7th:303-20.
Section
6 Therapeutics (Medical and

Surgical), Prophylaxis
and Monitoring
27 Chemotherapy: Drugs Used in Leprosy
Including Newer Drugs
BK Girdhar
INTRODUCTION many patients, particularly at the lepromatous end who

had shown good response initially, no further improvement
Leprosy is not only a curable disease; but is on the decline
was seen; and in many of the disease arrested cases there
the world over, having been eliminated from many countries,
was deterioration/ relapse during the later part of treatment.
including India. This has been possible due to the availability
Likewise, the Caucasians as well as the other races did
and wide application of effective and clinically safe drugs.
not seem to respond. This was subsequently found to be
This is in contrast to the situation till the middle of the last
related to smaller doses used in them, less than the
century when we had practically nothing effective and
minimum required dose of 15 ml per week, including half
specific for leprosy. In the absence of knowledge of
of it to be given intradermally. Because of increasing
causation of leprosy and the myths surrounding the same dissatisfaction among the workers and poor acceptability
during the last many centuries, a very large variety of drugs among patients with its use; and coupled with the
and approaches had been used to treat and cure the introduction of sulphones in leprosy, the use of chaulmoogra
disease. Anecdotal reports, presentation of experiences oil was given up, although the studies in mice had
of the efficacy of various modalities have not been subsequently confirmed its anti-M. leprae effect.1
substantiated. This includes repeated injection of diphtheria Unlike many other infections, leprosy treatment has to
toxoid and/or anti-toxin, likely exception appears to be in be prolonged, having bearing to the very slow cell division
the use of chaulmoogra oil. of the causative organism (the prolonged generation time,
Chaulmoogra oil is obtained from the fruit (seed) of a about 11-13 days). This calls for proper counseling of the
tree native to costal regions (ghats) of South East Asia. patients to motivate them to continue treatment regularly
This oil - also called hydnocarpus oil and its esters were in addition, also enlightening them about disease
the main stay in treatment of leprosy during the first half causation, curability and deformity prevention.
of last century, i.e. till the introduction of sulphones. Leprosy is not a disease of skin and or nerves alone
Following the demonstration that with its use alone or in rather it affects several organ systems and also; the psyche
combination with camphorated oil (with added resorcin), of the patients. Therefore, the treatment of leprosy should
given orally and intradermally, there appeared a definite involve the patient as a whole; not just the killing of the
improvement in situation. Hopes were raised of reducing organisms. This means that in addition to specific
and removing leprosy burden from many countries with its chemotherapy, treating the skin and/or nerve
wide use. Thus, injections and oral administration of the manifestations, care of systemic affection if any, providing
oil became the common practice in treatment of leprosy in psychological support and education for his problems and
India and several other countries. Non-lepromatous cases means to over come these are equally important. An
appeared to respond better than those with more advanced understanding and sympathetic attitude of the treating
disease- the lepromatous type. doctor goes a long way in making the patient comfortable
During its wide spread use lasting several decades, and helping his sagging morale. Patients at risk of reactions
physicians and leprosy workers began to realize that in need to be made aware of the possibility of occurrence of
CHAPTER
27
336 Therapeutics (Medical and Surgical), Prophylaxis and Monitoring
apparent worsening and/or nerve problems and their likely and killing of resistant organisms that may be present. For
causative factors. They must be told about the need to this, based on theoretical considerations and the
urgently report about the episodic events, if these occur, experience in tuberculosis, combination of drugs, with
to the health facility. different modes and sites of action, have been
The causative organism of leprosy, M. leprae, was recommended and are being used in the management of
discovered in 1873, but not much could be learnt about it patients.
nor the drugs effective against it could be developed, till
the early fifties. The main reason being that there is no CHEMOTHERAPEUTIC DRUGS FOR
organism bearing a close bacteriological, pathological, LEPROSY IN COMMON USE
antigenic and chemical resemblance to M. leprae. As a
result, M. leprae has never been cultivated on any artificial Dapsone
medium. Even in tissue cultures, M. leprae seems to only Dapsone (4, 4 diamino diphenyl sulphone)—a sulpha drug
survive but not multiply. No animal model was available till was synthesized in 1908. It was tested for its antibacterial
1960 when mouse foot-pad was shown to support a regular activity only after sulphonamides had been found effective
but limited multiplication of M. leprae.2 Large numbers of against several other bacteria. Given in doses similar to
M. leprae (from growth and multiplication in armadillos) sulphonamides, the drug was observed to possess
became available for the study of metabolism, drug significant antibacterial effect but was found to be too toxic.
sensitivity, etc. only after 1971.3 This led to the development and testing of its derivatives
The mouse foot-pad model has played a significant to reduce its side effects. Some derivatives were found
role, not only in the confirmation of efficacy of drugs, in effective and at the same time less toxic. Promin was the
particular dapsone and clofazimine, but also in screening first derivative used in clinical leprosy by Faget in 1947
of other drugs and assessing their potential against M.
and found effective. 4 Subsequently, several other
leprae. This model has also been used to confirm
derivatives that could be given orally in treatment of leprosy
occurrence of dapsone resistance, its degree and the
were introduced. Towards the end of 1940’s, dapsone was
magnitude of problem in the community, when the drug
again tried in leprosy in smaller doses with the apparent
was being used alone. Like wise, the knowledge of spread
aim of reducing the cost of treatment! Initially given as
of dapsone resistant M. leprae in the community and
oily or aqueous injection and later orally, the drug was not
subsequent occurrence of primary (de novo) resistance,
only well tolerated but also found effective. It is now well
has been possible due to mouse model.
established that the parent compound, diamino diphenyl
Following the establishment of growth and multiplication
sulfone (DDS/ dapsone) is the active molecule. The earlier
of M. leprae in the mouse model and the availability of a
used substituted derivatives were all converted into this
large number of M. leprae from armadillo, rapid progress
has been made in leprosy research, especially in molecule (active metabolite) in the body and hence these
therapeutics. The mouse footpad has provided a sensitive are no longer used. Since the early sixties, dapsone has
and precise means of measuring the efficacy of drugs continued to be the main weapon against leprosy.
against M. leprae. Likewise, bacteriological monitoring of Dapsone has a weak bactericidal action against
response to drugs in patients has made it possible to test M. leprae.5 The drug acts by competitive inhibition of
newer methods of treatment of leprosy. Further, with the enzyme—dihydro folate synthetase, involved in conversion
development of in vitro assays that are able to quantitate of para amino benzoic acid (PABA) to dihydropteroate in
the metabolic potential of organisms (an index of viable folic acid synthesis. In case of M. leprae, the affinity of
bacilli); hundreds of new compounds have been screened DDS towards dihydrofolate reductase, the enzyme involved
for their action against M. leprae. These have resulted in in the subsequent step of folic acid synthesis, also
the introduction of potent drugs like rifampicin, thioamides, appears to be important. This is in addition to inhibition of
fluoroquinolones, minocycline, etc. in the treatment of dihydrofolate synthetase, which probably is the main mode
leprosy. of action. The extreme sensitivity of M. leprae to DDS
Over the last fifty years, the treatment of leprosy has may be on account of a very low concentration of
basically remained directed against killing of M. leprae, competing PABA, high degree of sensitivity of enzymes
including prevention of emergence of resistant mutants and accumulation of DDS within the bacterial cells.6
CHAPTER
27
Chemotherapy: Drugs Used in Leprosy Including Newer Drugs 337
Pharmacokinetic studies have shown that following oral damage especially in reaction patients. Neurological deficit
administration, the drug is completely absorbed from the and trophic ulcers are not much affected by dapsone.
gut and peak levels are reached in 4-6 hours. The half life The killing of bacilli in patients is rapid and is almost
of the drug in man is around 24 hours (16-29 hours). Further, complete in 3–6 months, as reflected by a fall in the
a single dose of 100 mg of DDS maintains the serum levels morphological index (MI) and loss of viability of M. leprae,
of the drug above the MIC, for fully sensitive leprosy bacilli, as tested in the mouse foot pad. The bacterial index (BI)
for over 10 days. on the other hand, takes very long to decrease. In
As mentioned above, dapsone was considered in the lepromatous patients, there is usually a gradual and slow
past to be a very toxic drug because, like other decline of 0.6–1 log unit per year in BI with the result that
sulphonamides, initially it was administered in very large patients with a bacterial load of 5+ or more take up to 5–8
doses. Following the observations that a dose of 100 mg years to become smear negative.
per day results in serum levels almost 500–600 times higher Clinical response in paucibacillary (TT and BT) patients
than MIC of M. leprae,7-9 some authors in the past have is quite variable; in about two-thirds there is complete
considered that 1-2 mg of dapsone per day should be recovery within about 6 months, but the remaining may
adequate for an average adult. However, in view of the take even more than a year to regress. The nerve deficit
chances of emergence of dapsone resistance, currently mostly remains unaffected with dapsone. Therefore, eyes
its recommended dose is 1-2 mg/kg body weight once a and limbs need to be cared for and protected from trauma
day. The drug acts rapidly against M. leprae, reducing the and burns.
viable counts to less than 1% of the initial values over a
period of 3 months.10 In the past, the drug used to be Adverse Effects
started in small doses and the dose gradually increased Millions of patients of leprosy and diverse dermatological
to the maximum in 4-6 months time. This was done to disorders have been treated and/or continue to receive
reduce the chances of precipitation of leprosy reactions. the drug without significant problems. Experience has shown
Following the observations that the frequency and the dapsone to be a very safe drug as serious side effects are
severity of the reactions were not influenced by the dose rare. Some minor problems are, however, not uncommon.
of the drug, and also that the drug has significant Of these, hemolytic anemia, which occurs in a significant
immunosuppressive action,11 currently the treatment is proportion of patients on dapsone, is important.13 This is
started with full dose. Dapsone has been shown to particularly seen in patients with G6PD deficiency.14 The
stimulate neutrophil motility –an effect opposite to that of cause of this short-lived fall in hemoglobin is the reduced
clofazimine, and thus may be one of the factors for ENL life span of red blood cells with dapsone. This is
precipitation.12 subsequently compensated by an increase in bone marrow
activity. Bone marrow suppression, resulting in
Clinical Effects agranulocytosis15,16 as also aplastic anemia17 have been
In multi-bacillary leprosy patients (borderline and observed.
lepromatous) the clinical response is apparent within 3–6 Dapsone induced liver damage may occur in a few
months of starting dapsone therapy. Complete clinical patients. 13 Urine and liver functions may show
regression, however takes much longer—usually 2-3 years. abnormalities on investigation. In a few, jaundice may ensue
Mucosal ulcers / lesions are often the first to heal, resulting with an enlarged liver. It is worth mentioning that liver
in clearing of nasal passages, subsidence of epistaxis damage in leprosy patients, especially lepromatous, may
and decrease in foul smell from the nose. Healing of the be related to the disease per se or due to viral hepatitis
oral and laryngeal lesions, results in return of normal voice. which itself is fairly common in leprosy-endemic areas.
Skin ulcers too heal early, often with scarring. Regression Dapsone induced neuropathy has remained a debatable
of nodules and skin thickening starts later and in most issue. Though no clinical effects (worsening) have been
cases only scars and shrivelled skin remain after 2-3 years seen in leprosy patients, some authors have, on
of therapy. Regression of nerve thickening is slow and retrospective analysis of records, reported increased
often incomplete. Other drugs (especially oral steroids) deformities in patients who took dapsone regularly.18
are required to prevent and reverse continuing nerve Electrophysiological changes have also been recorded
CHAPTER
27
following dapsone administration in tuberculosis patients.19 dapsone). Given as deep intramuscular injection,
This possibly is dose related as this has frequently been acedapsone was found effective in field in Karimui, Papua
seen in dermatological patients where the dose of dapsone New Guinea.24 The drug may, therefore, be incapable of
used was much higher than the recommended dose in killing mutants with even a low grade of resistance, and
leprosy. may in fact help in selecting and perpetuating the resistant
Dapsone has been reported to cause every defined strains. Such an occurrence has been found in Karimui
type of skin rash. In addition, there is a cross sensitivity (New Guinea) and Micronesia, where acedapsone had been
with other sulphonamides. Exanthemas, papulosquamous tried in the field conditions.25 The use of the drug, on
rashes and fixed drug eruption are relatively common. account of parenteral mode of administration, cost and
Serious problems, like bullous erythema multiforme, toxic risk of M. leprae developing resistance, has remained
epidermal necrolysis, exfoliative dermatitis, are fortunately restricted to studies on chemoprophylaxis of leprosy.
rare.
Methemoglobin formation occurs in a small proportion Dapsone Resistance
of patients on dapsone but rarely results in clinical During the late fifties and sixties, several patients, who
manifestations. In accidental/suicidal poisoning, however, initially had responded to dapsone therapy, were observed
the level may be so high that cyanosis and shock can to deteriorate. Though suspected to be on account of
result, with collapse of the individual. The condition development of drug resistance26 the proof became
responds to ascorbic acid infusion. Methylene blue can available only in 1964 when, Petit & Rees showed
also be used.20 M. leprae multiplication in foot-pad of mice, fed on varying
concentration of dapsone in diet. 27 Subsequently
Dapsone Syndrome occurrence of relapses due to emergence of dapsone
This hypersensitivity reaction,21 is occasionally seen in resistance have been reported from all parts of the world.
patients who had been under treatment for some months. Indeed, dapsone resistance is one of the major problems
Reports suggest that its frequency is on the increase as in several parts of the world including India.28 Dapsone
over 95% of the reported 108 cases have occurred in the resistance has been reported to occur in about one in 250
lepromatous patients by the British group29 and in one of
last 2 decades, almost all since the introduction of MDT.22
the 1000 patients by the American workers.30 When used
In its complete form, the patient develops fever, skin
as mono-therapy, M. leprae tend to develop resistance to
rash of usually maculopapular type or exfoliative dermatitis
the drug. Risk of relapse due to drug resistance has been
with lymphadenopathy and hepatitis, usually 4-6 weeks
reported to be around 2-3% among patients treated with
after starting dapsone. Continued dapsone administration
dapsone alone. With dapsone, all grades of resistance have
results in rapid deterioration. Fatal outcome has been
been observed and it appears to be on account of process
reported in 13 % of the cases with all symptoms. In contrast
of selection and (to an extent) related to dose of drug
to this complete syndrome, in almost half the patients one
administered. Clinical appearance of relapse, due to
or more manifestation/s may be missing. Recovery occurs
secondary dapsone resistance, takes a long time, any
in all cases of incomplete syndrome on stoppage of
thing from 5-15 years or more.
dapsone. In addition to discontinuing dapsone, short course
The genetic basis of this resistance lies in mutation of
of steroids and supportive therapy is required for abatement
folP gene of M. leprae. Mutation at codon 55 in folP is a
of the condition.
substitution of leucine for proline.31 The main factors
attributed to this increasing problem have been the long
Acedapsone
practiced monotherapy, irregular intake and the suboptimal
Acedapsone is a diacetyl derivative of dapsone. A 225 mg dosage of dapsone used. It has been observed that
injection (in benzyl benzoate), given deep intramuscularly dapsone compliance is often very poor; in some studies
once in 11 weeks releases dapsone into the body so slowly no more than 40% drug intake has been reported.32 A
that following a single injection, drug levels above the MIC reduction in the dosage or complete withdrawal of the drug
are maintained for over 200 days. However, the peak levels during reactions adds to the irregularity.
are only 8 times higher than the MIC23 (in contrast to the with the increase in the number of patients with dapsone
500–600 times higher MIC achieved with 100 mg of oral resistance, spread of resistant infection to other members
CHAPTER
27
of the community, as expected, has occurred. This has scientists have observed it to be a weak bactericidal
been seen in Ethiopia,33 India,34 Columbia,35 Malaysia36 drug.43
and many other countries. This widespread distribution It acts by selective inhibition of DNA-dependent RNA
shows that primary resistance is not restricted to small polymerase of bacterial (but not mammalian) origin. The
pockets but occurs in all countries where dapsone had drug forms an irreversible complex with RNA polymerase
been widely used as monotherapy. This was found to be a binding at α subunit. This results in blocking the synthesis
significant problem as was indicated by THELEP (WHO) of messenger RNA, and thus protein synthesis.44 Mutation
conducted studies in South India and Bomako37 in the of a single amino acid in this enzyme can result in
early eighties. resistance to rifampicin.45 Its antibacterial action is so
In view of this, currently dapsone is recommended to powerful that a single dose of 1500 mg or 3 to 4 daily
be used only as component of MDT, to be given in 50-100 doses of 600 mg of the drug, given to patients, appear to
mg daily dose and as far as possible without any kill over 99.99% of the viable M. leprae, as tested in the
interruption. mouse foot-pad.46 The drug is equally effective against
both the dapsone sensitive and resistant organisms. No
Persisters cross-resistance with any other group of antibiotics has
The other major problem faced in the treatment of leprosy been reported. Rifampicin is unique in having a very long
with dapsone, as also with all other commonly used drugs, post antibiotic effect despite the fact that the drug levels
is the persistence of drug-sensitive organisms despite long wane within 24 hours of drug ingestion.
years of continued therapy.38,39 It is possible that these
persister organisms remain dormant in some tissues Dosage and Clinical Effects
(smooth muscles, nerves and skin)39, 40 and hence are not The drug is quickly and completely absorbed on oral
affected by drug/s used for treatment period. Presently we administration, especially if the stomach is empty. With
do not have any drugs that are effective against these an oral dose of 600 mg, a peak level in serum is reached
persister organisms. It has been considered all along that in 2-3 hours and is around 6-8 µg/ml which is almost 45-70
following the killing and removal of large proportions of M. times the MIC, which is between 0.1 – 0.3 µg/ ml. The half
leprae with treatment, the remaining organisms (persisters) life of the drug is around 12 hours. Nearly 80-90% of the
are taken care of by the body itself. The problem of drug remains bound to plasma proteins and as such, is
microbial persistence, in dapsone treated leprosy patients,
not available for the killing of the bacilli. The drug is rapidly
is mixed with the problem of acquired drug resistance which
metabolized in the liver through deacetylation and oxidation
is more important.
reactions and the metabolites are excreted into the bile.
The excreted metabolites reabsorbed from the intestines
RIFAMPICIN prolong the drug action as they also have activity against
Rifampicin is a semi-synthetic derivative of rifamycin, an M. leprae. Excretion of the metabolites through the kidneys
antibiotic originally obtained from broth suspension of results in orange-red discoloration of the urine—it is
Streptomyces mediterranei. Though the drug has a very important to make the patients aware of this. Rifampicin
potent bactericidal action against a spectrum of both gram- is able to cross the blood brain barrier and the placenta.
positive and gram-negative bacteria; currently it is Because of its affinity for lipids, it crosses the cell
recommended to be used only against infections with membranes and is therefore, effective in killing intracellular
Mycobacterium tuberculosis and Mycobacterium leprae organisms.47
(M. leprae) as these organisms are particularly sensitive Since its introduction, several dosage schedules of
to this drug. Following the observation of Operamolla of its rifampicin have been tested so as to get the optimal effect
usefulness in leprosy patients, Rees et al. 41 presented with minimum cost and toxicity.48-52 This has been done
detailed reports of its efficacy in patients and showed it’s with the additional aim of making its supervised mass
bactericidal role against M. leprae. British workers have application feasible. Unlike many other chemotherapeutic
reported that 0.003% of rifampicin in mouse diet was able agents, the drug possesses significant activity; even when
to kill 99.99% of viable M. leprae.42 Although similar given intermittently. It has been observed that both the
observations were made by many workers, American serum concentration and the half life of rifampicin are
CHAPTER
27
reduced gradually, if the drug is given continuously. administration, all over the world, has shown it to be well
However, on interrupted administration no such decrease tolerated. The important and commonly seen adverse
in serum level is seen. Further, monthly administration of effects on continued administration include hepatotoxicity
the drug has been found to give results almost similar to and drug rashes. Though jaundice is not very frequent,
its daily intake.53 Therefore, this mode of supervised loss of appetite, nausea, vomiting and / or pain in abdomen
treatment is preferred and is recommended by WHO. Some are not uncommon especially when the drug is taken empty
leprosy workers in India have favored its supervised daily stomach. In alcoholics the frequent rise in serum enzymes
administration (600 mg per day) for the first two weeks (SGOT and SGPT) and bilirubin are often seen with use of
followed by monthly doses. Such a way of administration, rifampicin. Apart from erythematous maculopapular and
which was recommended even by the NLEP in the early urticarial rashes, purpura and erythema multiforme have
eighties, has the advantage from the disease control point occurred with its use. Acute renal failure due to interstitial
of view also. Even if the patient/s default soon after start nephritis has been reported with rifampicin administration.
of treatment, the transmission of the disease is arrested, On the whole, the drug has been found safe in pregnancy56
as they are rendered non-infectious with this intensive and lactation. Given in last trimester, it may result in
phase of treatment.54 However, this initial intensive increased risk of bleeding in the new born.
treatment with rifampicin did not find favor with public health In contrast to its daily use, if the drug is given at
personnel, planners and WHO, possibly on account of substantial intermissions and particularly when large doses
difficulties of supervision, cost, hepatotoxicities, etc. are administered irregularly, the side effects may be
The clinical effects of the drug are very rapid. In severe.57, 58 However, not many serious side effects have
lepromatous patients, the nasal symptoms regress within been encountered when the drug has been given weekly
2–3 weeks and skin lesions / infiltration begin to clear or monthly, in leprosy, in the usual doses.59,60 On interrupted
in 2–3 months time. As seen with dapsone, complete administration of large doses, respiratory syndrome
regression of infiltration takes long and nerve damage does resulting in dyspnea, cough and fever, flu like syndrome
not seem to be much affected. The response with its use (characterized by chills, shivering, fever headache, bone
in other leprosy (tuberculoid and borderline) patients is and joint pains), gastrointestinal problems – nausea,
similar to that seen with dapsone.55 Some reports indicate vomiting, diarrhea, pain in abdomen may occur. Some
that the drug may act as a heptan, stimulating antibody patients may get purpura (thrombocytopenic) while shock
production. Though, considered to be a mildly like manifestations and acute renal failure may occur in
immunosuppressive drug,56 in some patients it appears to others. Reactions occurring with the intermittent use of
aggravate neuritis and type 1 reactions, particularly when the drug have been suggested to be due to the presence
given daily. of antibodies to rifampicin in the serum,61 but several
The skin smears show a very rapid decline in MI. Solid workers have not been able to confirm this.
staining bacilli are no longer seen in smears taken 4–6 Rifampicin is a potent inducer of drug metabolising
weeks after start of rifampicin. M. leprae obtained from enzymes (CYP3A4) in the liver, resulting in accelerated
biopsies, taken 4-7 days after the start of treatment show degradation of the drug itself, as also of other drugs like
complete loss of viability, as tested in the mouse foot steroids, oral contraceptives, oral antidiabetics,
pad.51 Bacteriological clearance, however, is very slow and, anticoagulants and cardiovascular glycosides, requiring
in fact, is similar to that with dapsone. The main problems adjustment in their doses and use of additional methods
with the use of this drug are the adverse effects, of contraception.62 Daily administration of rifampicin has
development of resistance when given as monotherapy been seen to result in progressive fall in drug levels in the
and survival of drug-sensitive persister organisms. serum and reduced half life. This is possibly the result of
accelerated drug degradation due to increased induction
Adverse Effects of liver enzymes as stated above. This observation has
This drug, which is very effective in mycobacterial been one of the bases of its monthly recommendation as
diseases, and on the whole a very safe and well tolerated in WHO regimen. It also accelerates dapsone metabolism
by majority of the patients, of both leprosy and tuberculosis, to some extent, but this is not clinically significant.63
is not without side effects. Experience with its daily Clofazimine has been reported to reduce the absorption of
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27
rifampicin and also results in delayed attaining of peak The drug is not water-soluble and hence micronised
serum levels.64 crystals are suspended in an oil-wax base and
encapsulated in soft gelatin for oral administration. The
Rifampicin Resistance absorption from the gut, even in this form, is about 30-
Patients have relapsed when treated for several years with 50%.79 Its serum levels following 50 mg dose are around
rifampicin mono-therapy due to the emergence of 0.5 µg while 300 mg dose results in only double the
rifampicin-resistant strains of M. leprae.65 Resistance in concentration. In man, as in mice, the drug passes into
M. leprae has been shown to be due to mutations in the various organs and is stored as needle like crystals,
preferentially in macrophages and cells of the
rpoB gene (codon 531: TCG to TTC).66 Simultaneous
reticuloendothelial system. Its accumulation within the
rifampicin and dapsone resistance has also been found,67
macrophages is advantageous and results in inhibition of
as also with clofazimine.68 Reduced rifampicin penetration
multiplication of intracellular M. leprae. Large quantities of
into the bacterial cells has also been suggested to result
the drug accumulate in the skin, subcutaneous fat, liver,
in drug resistance.
lungs, adrenals, kidneys, lymph nodes and gastrointestinal
Persistence of drug-sensitive organisms despite long
tract.80 Its accumulation in the tissues results in coloration
periods of treatment with rifampicin is not uncommon. Drug
of the organs and the skin. The drug is very slowly excreted
sensitive persister M. leprae have also been isolated after
from the body, usually taking 6–12 months on an average.
combined treatment with daily dapsone plus rifampicin,69
Hence, it takes this long period for the patients to regain
and rifampicin followed by dapsone.70 Even continuous
their normal coloration. Small amounts of the drug have
treatment for 5 years with rifampicin, in combination with
been detected in human tissues more than 3 years after
thiosemicarbazones, has failed to eliminate persister M.
stoppage of clofazimine. This accumulation of clofazimine
leprae.71 This phenomenon of continued presence of viable
in the macrophages possibly interferes with the capacity
drug sensitive organisms despite prolonged administration
of macrophages to process and present antigens; thereby
of effective drugs, has been attributed to metabolic
preventing their mobilization and activation, IL-2 release
inactivity (hibernation) of mycobacteria in presence of
and clonal expansion. In contrast to dapsone, the drug
adverse condition of drug presence.
has some role in suppression of cytokine release (IL-1)
resulting in decreased lymphocyte movement to the site
CLOFAZIMINE of type 1 or reversal reaction.78
This synthetic iminophenazine dye has been in use in the Because of its very long half life of almost two months
treatment of leprosy for over 3 decades.72 Brown and and marked tissue storage, it retains its activity even when
Hogerzeil in 1962, showed the clinical and bacteriological given intermittently, although intermittent administration
improvement in lepromatous patients with its use.73 This is less effective than daily intake or taken on alternate
was soon confirmed by studies carried out in National days.81 Clofazimine is equally active against both dapsone-
Institute of Health (NIH), Bethesda, USA. The drug has a sensitive and dapsone-resistant M. leprae.82
mild bactericidal action against M. leprae, the effect being
slightly less than dapsone.74 Though, its exact mode of Dosage and Clinical Effects
action is not known, the drug possibly acts by blocking The clinical response with 50–100 mg daily dose of
the template function of DNA.75 Studies have shown that clofazimine is almost similar to that seen with 100 mg of
clofazimine accumulation within the macrophages, the site dapsone, although the effect is slightly slow. Almost all
of M. leprae location, results in generation of superoxide types of leprosy respond equally well, indicating the
and hydroxyl radicals locally. These products are inhibitory usefulness of the drug. However, the drug should not be
to the multiplication of M. leprae.76 used alone nor it is a replacement for the cheaper and
The advantage with this drug is its anti-inflammatory more effective drug dapsone. The drug is indicated in
action and its resultant efficacy in type 2 reactions. patients with type 2 reactions although its anti-inflammatory
Stimulation of PGE2 synthesis and inhibition of neutrophil action is very slow. It has a special role in the prevention
motility, together with selective suppression of TH-1 subtype and management of patients with chronic ENL reactions.
of T-helper cells, may also add to its role in type 2 Some workers have shown that clofazimine reduces the
reactions.77, 78 risk of even hypersensitivity type of reactions.83
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27
Clofazimine Resistance of action. However, no cross-resistance has been observed

with INH. A daily dose of 500 mg results in serum levels
Clofazimine resistance is uncommon. However, given
45–60 times higher than the MIC. The drug levels are
alone, M. leprae tend to develop resistance to it.84, 85
maintained above the MIC just for one day. These drugs
Therefore, like other antileprosy drugs, clofazimine should
are not effective when given intermittently.94 Although the
be used only as part of MDT and not alone.
bactericidal activity of the two drugs is identical, serum
levels achieved with ethionamide are a little higher, while
Adverse Effects
prothionamide has the advantage of being better tolerated.
The brownish-red discoloration, secondary to deposition It is generally believed that liver damage, gastric intolerance
of clofazimine in the skin, is fairly common.86,87 It is more and nausea associated with these drugs are dose
marked on the sun exposed areas including face and this dependent, but a trial showed that both the doses (500 mg
results in low acceptability among the fairer individuals/ and 250 mg daily) of prothionamide are equally well-
races. Xerosis of the skin and in later stages, acquired tolerated.95
ichthyosis with violaceous brown color on the extensors A good clinical response has been observed with their
and markedly localized to the lesions, (due to ceroid like use in leprosy patients.95-97 Strains of M. leprae exhibit
pigment) is frequently seen. In some patients true cross-resistance between ethionamide, prothionamide,
hypermelanosis may also occur. thiacetazone and thiambutosine.98 No cross-resistance
Other side effects are mostly seen in reaction patients, with dapsone or rifampicin is known. In contrast,
who are given a daily dose of 200–300 mg for long periods ethionamide was found effective against dapsone and
of time, and the effects are on account of clofazimine rifampicin resistant strains of M. leprae in the mouse foot-
deposition in reticuloendothelial cells of various organs.88,89 pad.99 Use of either of these drugs, as monotherapy is not
In women, this may result in abdominal problems, such recommended, as several patients have relapsed following
as pain and/or diarrhea, that in turn may lead to their use.100 These drugs should only be used as part of
malabsorption and cachexia. In severe cases hypokalemia MDT. Indeed, the German group had been using a
and death may occur. Reduced sweating and decreased preparation - ISOPRODIAN, a combination of isonicotinic
tears, possibly on account of its anti-cholinergic action, acid hydrazide, prothionamide and dapsone together with
adds to the dryness of skin and eyes, increasing the rifampicin (ISOPRODIAN-R) with the reported good results
difficulties of leprosy sufferers. This may be particularly in lepromatous patients.101
troublesome in patients with corneal xerosis and As mentioned above, both these drugs produce
lagophthalmos. Episclera may also get colored. Splenic gastrointestinal intolerance resulting in nausea and vomiting
infarcts and ceroid congestion of small intestines has also in a substantial proportion of patients. In this regard,
been reported,89 as also the reddish sputum due to prothionamide is slightly better tolerated. Other related
excretion of clofazimine crystals in the respiratory tract – symptoms are anorexia, salivation and metallic taste in
mimicking hemoptysis.90 The drug crosses the placenta the mouth. Abdominal pain and diarrhea occur less
and affects the complexion of the fetus. No teratogenic commonly. Hepatotoxicity is a serious adverse effect seen
effects are known.91 in a small but significant proportion of patients.102-104 Other
less common side effects include peripheral neuropathy,
ETHIONAMIDE AND PROTHIONAMIDE headache, depression, drowsiness, hypotension, visual
disturbances and acne.
In experimental studies in mice, both these drugs possess
a powerful bactericidal effect against M. leprae.92,93 A killing
THIACETAZONE
of 92–99% of viable bacilli is achieved in 4-5 days,
displaying an effect intermediate between that observed Thiacetazone, a bacteriostatic drug, had been in use in
with rifampicin and dapsone. The precise mode of action the treatment of tuberculosis and leprosy.105After a single
of these compounds is not known but is believed to be dose of 150 mg peak serum levels exceed its MIC against
similar to that of INH with which they have structural M. leprae by about 8-folds and the inhibitory concentrations
similarity. Inhibition of mycolic acid; and to some extent are maintained for about two days indicating a low effective
protein synthesis; appears to be an important mechanism ratio.106 Further, as the drug is essentially bacteriostatic,
CHAPTER
27
and as stated above, has a short half life, irregularity in its been shown to possess a marked anti-mycobacterial
regular self administration frequently results in leprosy effect.109
bacilli becoming resistant, resulting in relapses. Further, This group of drugs acts by blocking DNA gyrase,
M. leprae resistant to thiacetazone show cross-resistance thereby inhibiting the coiling and super-coiling of DNA.108,110
to thioamides. Because of their unique mode of action, no cross-
Its advantage lies in its being cheap drug that is well resistance with any anti-microbial drug has so far been
tolerated. It has been used in India and several parts of encountered. It appears that the this group of drugs has
Africa. In our country the drug had been used extensively some blocking effect on the synthesis of some new protein,
in combination with INH (a very popular brand in 1960-70s and this action can not be observed on co-administration
was Isozone® Dumex) and streptomycin in treatment of with other protein synthesis blocking agents such as
tuberculosis and in combination with INH and dapsone in chloramphenicol and rifampicin.111 The antimicrobial action
treatment of leprosy. However, in some African countries, of these compounds is extremely rapid, a thousand fold
its acceptability on account of serious side effects had decrease in viable colony forming units (CFU) is achieved
been low. Its main side effects include agranulocytosis, in 1-3 hours at serum levels very close to MIC. With
hepatotoxicity, and gastrointestinal symptoms like pain, continued usage drug resistance does develop, but is of
nausea, vomiting and loss of appetite. Severe drug rashes low frequency (less than 1 in 109 organisms). The resistance
have occurred with its use. With the availability of several to fluoroquinolones is on account of a single step mutation
potent and relatively safe drugs, and its cross-resistance in the highly conserved region of gene gyrA of DNA gyrase
with thioamides, it is no longer considered a useful drug in enzyme of micro-organisms. 112 Adaptive decreased
the treatment of leprosy. penetration of fluoroquinolones into the bacterial cells has
also been suggested as mechanism of drug resistance in
NEWER DRUGS FOR LEPROSY bacteria.113
A high bio-availability, on account of low serum protein
It is thus seen that out of several available drugs, only binding, and almost complete absorption following oral
rifampicin and to some extent thiomides are proved to be administration, long half life and high urinary excretion in
bactericidal. Dapsone and clofazimine though very useful an unchanged form,114 in addition to their wide spectrum
and relatively safe drugs, are basically bacteriostatic and of activity, all these qualities have made these compounds
take several months to kill M. leprae in patients. Further, if the drugs of first choice in the treatment of bacterial
these drugs are used alone there are chances of selection/ infections of several organ systems. With such unique mode
emergence of resistant bacteria. Thus, to prevent of action and useful pharmacokinetic properties,
resistance and treat infection due to possible resistant fluoroquinolones are currently one of the most prescribed
organisms, use of drugs in combination has been drugs, not only in respiratory infections but also in genito-
considered and recommended. However, it has also been urinary infections including sexually transmitted diseases.
realized that for the treatment to remain effective, pursuit Following the demonstration that this group of drugs
for new drugs that are bactericidal has to be continued. was useful in tuberculosis108 and against M. leprae in the
Following group of drugs/molecules have been found to mouse footpad, Saito et al were the first to show the efficacy
be very useful during the last two decades. of ofloxacin in preventing multiplication of M. leprae in
mice.115, 116 They further observed continued inhibition of
Fluoroquinolones
growth of M. leprae even after cessation of drug
Fluoroquinolones—the nalidixic acid derivatives,107,108 are administration, suggesting bactericidal effect. This was
effective against both gram-positive and gram-negative soon confirmed by workers in France and England.
bacteria. Following the demonstration of their potent Studies in lepromatous patients have demonstrated
antimicrobial activity, many analogues continue to be their remarkable efficacy. Over 99–99.99% killing of viable
synthesized. Pefloxacin, norfloxacin, ciprofloxacin, M. leprae was observed with less than 1 month of therapy,
ofloxacin, enoxacin, sparfloxacin, levofloxacin, gatifloxacin with only 22 doses given over 28 days’ time.117 This degree
and moxifloxacin are some of the most tested and of M. leprae killing suggests that with their use any naturally
commonly used molecules. Some of these compounds occurring rifampicin resistant mutants would be killed in a
(e.g. pefloxacin, ofloxacin, sparfloxacin, moxifloxacin) have month’s time. Response with 400 mg ofloxacin once a day
CHAPTER
27
was found to be comparable to that seen with pefloxacin daily.131 Extended studies in mice have shown that the
400 mg given twice a day.118,119 Of the several hundred drug is almost equally effective when administered once a
fluoroquinolones tested, sparfloxacin,120 temafloxacin,121 week and to an extent, even once a month.132
moxifloxacin,122 and sitafloxacin123 have shown even better A good clinical and bacteriological response has been
efficacy. observed with its use in lepromatous patients. After one
These anti-microbials are very safe when given for a week’s treatment; decrease in erythema and/or induration
short period of week to ten days, as used in respiratory has been reported. Complete clearance of erythema and
and genitourinary infections. Only minor side effects like induration was seen in six of the eight patients with
abdominal problems, joint pains, pruritus and noticeable improvement in the remaining.133 Apart from
photosensitivity have been observed.107 A much longer vertigo, no other significant side effects have been
course of treatment, lasting for months, is required in observed with its prolonged use. Mouse footpad studies
leprosy and their safety on long-term use has not been have shown complete killing of M. leprae with 4 weeks’
detailed. Long term impression indicates that these treatment.133 Nasal symptoms in LL patients have been
compounds are quite safe. To reduce or minimize the future found to respond well to minocycline.134
emergence of resistance, it is considered essential that Minocycline is a time-tested drug as far as its safety
these drugs are used only as a component of MDT and record is concerned. It has been administered continuously
never alone, at least for mycobacterial disorders. Used for long periods and in large doses of 200 mg daily, without
this way, not only these compounds may help in shortening any significant problems in acne patients. Systemic side
the length of treatment but also reduce the chances of effects noted include nausea, vomiting, dizziness,
selection of drug resistance. headache, loss of concentration and lupus erythematosus
like reaction. Bluish brown discoloration of the skin,
Minocycline localized to the sites of earlier inflammation or diffuse in
Tetracyclines have for long been used in the treatment of distribution with prominence over sun exposed areas on
diverse bacterial infections on account of their very broad its prolonged administration, has been seen in some
spectrum of activity. This group of drugs acts by binding patients.135
to the 30s ribosomal subunits of bacteria, thereby inhibiting
protein synthesis and eventually causing the death of the
Macrolides-clarithromycin
organisms. Basic drug, tetracycline is inactive against Macrolide group of drugs are particularly effective
M. leprae, as tested in the mouse footpad,124,125 and against (bactericidal) against a variety of gram-positive organisms.
M.tuberculosis in vitro because it does not penetrate This class of compounds acts by inhibiting protein
mycobacterial cells. In contrast doxycycline and synthesis by binding to 50s ribosomal subunits.
minocycline, being tremendously lipophilic at neutral pH,126 Erythromycin, the most commonly used member of the
easily enter the bacteria and result in inhibition of their group, has been shown to have anti-mycobacterial effect
protein synthesis. For this reason and their known action in test tube cultures of atypical mycobacteria.136 However,
against gram-positive bacteria, their activity against it was not found to be active against M. leprae in the mouse
mycobacteria was investigated. Minocycline was found footpad. Following the establishment of a reproducible in
effective in swimming pool granuloma127—an infection vitro system, it was observed that even at low
caused by M. marinum. Likewise, minocycline was concentrations, erythromycin had significant action against
observed to be most effective against M. tuberculosis and M. leprae.137 Its lack of effect in the mouse footpad, had
other slow growing mycobacteria.128 Gelber in 1987 later been found to be related to its poor gastrointestinal
reported activity of minocycline against M. leprae in mice. absorption.
In contrast to the marked bactericidal action of minocycline On account of its short half-life (requiring frequent
against leprosy bacillus, doxycycline was not able to kill administration), cost and toxicity – more likely because of
M. leprae in the mouse footpad128,129 and in vitro—using the need for prolonged administration, erythromycin has
radio-respiratory techniques.130 The MIC was observed to not been considered useful in the treatment of leprosy.
be 0.2 µg/ml, a level which is almost 10-20 times less Using in vitro and in vivo methods, several other macrolides
than what is obtained in patients taking 100 mg minocycline (azithromycin, clarithromycin, roxithromycin, etc.) were
CHAPTER
27
screened for activity against M. leprae. Clarithromycin, at called ansamycins, have been tested. Rifabutin has been
0.125 µg/ml concentration, was found to have potent anti- found to be more active than rifampicin against both
M. leprae activity, while roxithromycin and M-119-31 (a M. tuberculosis and M. leprae.149,150 Its MIC was observed
coded compound), were only moderately active against to be much lower than that of rifampicin.149 The drug was
M. leprae.136,137 Mouse foot pad studies have confirmed also reported to be effective against rifampicin resistant
the bactericidal action of clarithromycin.138,139 Further strains.151 This reported efficacy of rifabutin against
proportional bactericidal tests, in the mice, have shown rifampicin resistant strains of M. leprae has not been
that 20 doses of 12.5 mg/kg body weight clarithromycin, confirmed in the later investigations.152, 153
given daily, result in significant bactericidal effect. The Rifapentine (DL 473), isobutylpiperazinyl rifampicin (R-
activity further increases on enhancing the dose to 25–50 71-1) and a coded compound (R-76-1) have also been found
mg/kg body weight.140 In the mouse footpad the drug has to be more active against M. leprae than the parent drug
been found to be fully active when given three times or rifampicin, when compared on dose basis,150,154 the
once a week; but only partially active on once a month minimum effective dose being eight times less than
administration.141 rifampicin. Their advantage lies in having a relatively longer
These newer macrolides formulated as enteric coated half-life, which enables their intermittent use. A clinical
tablets; have the advantage of being acid stable, resulting trial using 150 mg per day of isobutylpiperazinyl rifampicin
in more reliable absorption and fewer abdominal side (R-71-1), conducted in 20 Chinese MB patients a third of
effects. On account of their much longer half life, 1-2 daily whom were resistant to dapsone, has shown marked
doses are adequate. Serum levels do not seem to parallel improvement with complete killing of M. leprae in 3.5–21
the high efficacy of macrolides as these drugs get days (median 9 days) time. Jaundice and severe ENL were
concentrated in the tissues; and also in the bacteria, the significant side effects.154 Lin (in Chinese literature)
ensuring greater activity against the pathogens.142 When has reported complete M. leprae killing in seven days time
given alone, development of plasmid mediated macrolide on administration of 3-rifamycin SV (RFD) to five patients.
resistance is not uncommon. Cross-resistance with Despite the above advantages, the future role of
clindamycin and lincosamides has been observed. rifampicin derivatives in the chemotherapy of leprosy
Using clarithromycin in leprosy patients, a rapid clinical remains doubtful. This is on account of their having the
improvement has been observed together with a significant same mode of action as rifampicin, and hence cross-
decline in the MI and more than 99% and 99.9% loss of resistance, together with severe side effects and high cost.
viable bacilli with 28 and 56 days of treatment
respectively. 140,143,144 Although, clarithromycin is Beta Lactamase Resistant Antibiotics
comparatively a safer drug as compared to erythromycin, This class of compounds called cephalosporins are
a significant proportion of patients have gastrointestinal derivatives of penicillins. However, because of the
problems with its intake. modifications in 6-aminopenicillinic acid nucleus, these
On account of the sequential action of minocycline molecules are resistant to the action of beta-lactamases
and clarithromycin in inhibiting protein synthesis, a marked produced by some of the organisms and hence unlike
synergism of action has been found against several penicillins, these drugs are effective against organisms
bacterial infections and toxoplasma infection in mice145 that produce this enzyme. Mycobacteria produce beta-
as also in experimental leprosy.146 Likewise, enhanced lactamase an enzyme capable of breaking the beta-lactam
activity of clarithromycin in combination with ethambutol ring of penicillin. Hence, basic penicillins are not effective
and rifampicin is equally relevant.147 Also important is the in killing mycobacteria. Cephalosporins, drugs that are
finding of its high intracellular concentration,148 which may similar in basic structure and properties including the mode
prevent the selection of resistant bacilli in leprosy. of action to penicillins but are not affected by beta-
lactamase, are active against several mycobacteria. These
ANSAMYCINS are grouped as first generation (cephalothin, cephaloridine,
Since the introduction of rifampicin in clinical medicine, cephalexin); second generation (cefuroxime, cefaclor,
attempts have been made to synthesize its more active cefoxitin, etc); third generation (cefotaxime, ceftizoxime,
analogues. Several semi-synthetic derivatives, together ceftriaxone) and the fourth generation cefpriome,
CHAPTER
27
cefeprime, etc. Though all these drugs are inhibitors of and, as expected, have shown synergy with dapsone. Trials
gram-positive organisms, their activity diminishes against in leprosy are already under way. Seydal, reporting the
gram positive bacteria; and increases against gram early results, mentions “convincing clinical and laboratory
negative organisms as one goes from first to the fourth efficacy after 3 months of treatment with 200 mg
generation. Of these, cephaloridine, cephaloglycine, 7- brodimoprim + 25 mg DDS daily”, and reported that “the
amino cephalosporanic acid and cefoxitin, have been found treatment (with a combination of 200 mg brodimoprim +
to inhibit M. leprae multiplication.155 However, in view of 25 mg DDS and 600 mg rifampicin daily) was completely
their high cost, mostly parenteral mode of administration stopped after 3 months because of excellent clinical
and short half life (requiring frequent administration), these results”.160 However, no details or confirmations of these
drugs are unlikely to find a place in the treatment of leprosy findings are available.
and therefore, no trials have been considered. Several other drugs have also shown promise.
Another approach has been to combine the commonly Derivatives of thiacetazone and thiosemicarbazones
used penicillins with compounds that are inhibitors of beta- (hydrozones) have been synthesized. PH-22 and PQ-22
lactamase (penicillinase) enzyme of micro-organisms. Per are not only much less toxic,161,162 but also more potent
se these molecules have minimal anti-microbial or anti- against atypical mycobacteria and M. leprae with the added
mycobacterial activity. These drugs allow penicillin to inhibit advantage of synergism with dapsone and rifampicin. No
the bacterial transpeptidase enzyme (which is responsible clinical studies have been undertaken so far.
for cell wall synthesis) leading to bacterial death. A
combination of clavulanic acid (a beta-lactamase inhibitor) Fusidic Acid
plus amoxicillin is effective against drug sensitive156 (and This steroidal antibiotic has been used both systemically
dapsone or rifampicin resistant) strains of M. leprae.157 and topically, mostly against resistant staphylococcal
Sulbactam and YTR-830H have been found to possess infections. Though the spectrum of action is small and
even stronger penicillinase blocking properties. However; limited to gram-positive organisms (mainly staphylococcus
frequent gastrointestinal side effects have been reported species and corynebacterium species), there has been a
with their use in combination with penicillins. Trials in lot of interest in the compound in recent years because (a)
leprosy are underway to assess the clinical utility of these it acts via inhibiting bacterial protein synthesis by
drugs in combination with ampicillin. preventing the translocation of elongation factor-G from
the ribosomes -yet another step in sequential blockage of
Dihydrofolate Reductase protein synthesis, (b) has high lipophilicity, with resultant
Combinations of sulphonamides and trimethoprim higher intracellular concentration; (c) attains high serum
(available as Septran, Bactrim, and Aubril etc.) inhibit the levels and has long shelf life and (d) its safety profile.
multiplication of several bacteria by acting sequentially in Fusidic acid has been found to be useful against
blocking folate synthesis. Here both the drugs are able to M.tuberculosis and M.avium complex.163,164 It’s efficacy
enter the micro-organisms and block both the steps of against M. leprae could not be tested because in mice it is
essential folic acid synthesis pathway. However, this poorly absorbed and achieves very low serum levels. In
combination is not useful against mycobacteria due to the contrast, there is complete gastrointestinal absorption in
inability of trimethoprim to enter mycobacterial cells. man. The in vitro radio-respiratory methods have
Therefore, even though the enzyme, dihydrofolate demonstrated its powerful action against M. leprae, which
reductase is sensitive to trimethoprim; killing or inhibition almost equals that of other important drugs including
of mycobacteria does not occur.158 rifampicin.165,166 Trials with a daily dose of 500 mg and
Attempts have been made to synthesize compounds/ 750 mg showed marked improvement in 3 patients and
derivatives of trimethoprim that are able to enter the moderate improvement in the remaining six. Nearly 99.5%
mycobacteria and suppress dihydrofolate reductase. Of of viable bacilli were killed in patients in 6 weeks with no
the several analogues tested, two derivatives -brodimoprim difference in response between the 500 and 750 mg
and K-30, have been found to easily penetrate bacterial doses.167 Further, in view of its immunosuppressive
cells and thus block the second step of folate synthesis. activity; there may be a simultaneous suppression of
Both are effective against M. leprae infection in mice159 reversal reactions, as was observed in the above trial. As
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27
the emergence of resistance in staphylococci with its use limited but regular multiplication of M. leprae, patients who
as monotherapy is common, the drug should not be used worsened while on treatment or relapsed after stoppage of
alone. Given with rifampicin its action is additive or dapsone were investigated. Pettit and his colleagues, using
synergestic.168 the mouse footpad model, were the first to demonstrate
the emergence of dapsone resistant strains of M. leprae.27
Deoxy Fructo Serotonin (DFS) Soon dapsone resistant cases were reported by other
This normal human metabolite is present in the serum. workers. Studies have confirmed that dapsone resistance
Both in test tube169 and in the mouse footpad,170 it has is a worldwide phenomenon and has been on the increase.
been shown to possess inhibitory effect on M. leprae. A There are two types of drug resistance; (1) Secondary
clinical study reported in French literature indicated its utility or acquired resistance which develops following inadequate
in lepromatous patients without any side effects.171 Antia and often irregular monotherapy and presents clinically as
and his group have confirmed its efficacy in Indian initial improvement followed by deterioration, despite
patients.172 Of the 6 patients, administered DFS, 5 showed continued treatment. (2) Primary resistance which occurs
not only clinical but also bacteriological improvement. in untreated patients and results from infection with drug
Histological improvement was also observed in all five resistant organisms that are spread/discharged into the
patients. Faster decrease in BI and the histological environment by patients who have relapsed with secondary
upgrading were possibly the outcome of immune stimulating resistance.
effect as had been reported earlier.173 One of the significant The genesis of this resistance in M. leprae is considered
finding was the killing of bacilli within the Schwann cells to be basically a selection of naturally occurring partially
and in macrophages. Protection of nerve damage and or fully resistant mutants—a normal phenomenon in any
decreased attachment/uptake of M. leprae by the cultured large population of organisms. With the administration of a
Schwann cells has also been observed with this drug, single drug, the susceptible population gets killed and
when added alone or in combination with rifampicin. eliminated but the surviving resistant mutants continue to
Diuciphon, a pyrimidine sulfone derivative, has been multiply, resulting in bacteriological and subsequently
used in Russia and found effective. The drug is reported clinical relapse. Unlike with some other chemotherapeutic
to have additional anti-inflammatory properties and agents, the resistance in M. leprae to dapsone is a multi-
produces T-cell stimulation. Details are not available.174 step phenomenon. Therefore, all grades or degrees of
resistance are encountered. Patients receiving regular
treatment in full doses relapse quite late and generally
DRUG-RESISTANCE AND
with a high degree of resistance. Relapses are, however,
MULTIDRUG THERAPY
more frequent among those given monotherapy, in low
Soon after streptomycin was introduced in the treatment doses and /or irregularly.
of tuberculosis, it was observed that tubercular bacilli It is thus clear that if dapsone monotherapy is
developed resistance very quickly, even though the drug continued, a large proportion of patients will ultimately
continues to be effective against the M. tuberculosis. The relapse with dapsone-resistant bacilli. Likewise, a similar
same thing happened with the use of INH alone. This led problem is very likely if, monotherapy with other drugs is
to the consideration that if the drugs are combined, the practiced. There are several reports of rifampicin resistance,
chances of emergence of drug resistance could be reduced. most of whom had been given rifampicin alone. Clofazimine
Following in vitro confirmation and subsequent application resistance too, has been confirmed. Monotherapy with
of combined drug treatment in tuberculosis, indeed the thioamides too, is well known to result in relapse due to
problem of emergence of drug resistance in tuberculosis emergence of drug resistance. However, the probability of
had been reduced. In leprosy however, dapsone and emergence of naturally occurring resistant M. leprae varies
subsequently other drugs were used as monotherapy for with each drug, being low with rifampicin (around 1 in 109)
long without such a realization. Though an occasional and relatively more frequent with dapsone (about 1 in 106).
patient was reported to have deteriorated while under To offset this problem of emergence of drug resistance
dapsone therapy, resistance could not be confirmed on and to treat suspected or unsuspected resistance,
account of non-availability of tools. Following the bactericidal drugs are recommended to be used in
demonstration in 1960, that the mouse footpad allowed a combination. This is based on observations in
CHAPTER
27
bacteriological studies with M. tuberculosis and the clinical commonly used drugs viz. rifampicin, clofazimine and
experience in pulmonary tuberculosis. The basis, of dapsone; indicate that mostly the side effects are minor
administration of chemotherapeutic drugs in combination, and transitory. Less than 1% of the patients need to
is that the naturally occurring resistant organisms to one discontinue intake of drugs due to side effects and/or
drug are likely to be killed by the other drug and vice versa. clofazimine discoloration. Acceptance of clofazimine is
Since the chances of naturally occurring or selected somewhat less among the fairer individuals on account of
resistant mutants to two drugs together is very small, a yellowish brown discoloration. Though some mutagenic
combination of 2 drugs suffices in most untreated patients, effect of the drugs, in particular rifampicin, have been
who have a predominantly drug sensitive bacterial observed in in vitro experiments using Bacillus subtalis,
population. De novo infection with resistant M. leprae in no problems have been observed in either experimental
the community (i.e. primary resistance) is already a animals or humans. Hence, the administration of MDT
significant problem. Therefore, if patients are given a could be continued even in pregnancy. However, as a safety
combination of two drugs, with the likelihood of a large measure, in the first trimester, it is better to withhold or
number of M. leprae being primarily resistant to one of the delay start of rifampicin. Continued clofazimine
drugs, they (patients) are really on monotherapy with the administration during pregnancy could result in coloring of
other drug and their M. leprae will most likely become the newborn. Likewise, excretion of the drug in milk of
resistant to the other drug as well. lactating mothers, on MDT, can result in staining of the
In practice it is not possible to identify who harbours infants. Whether, this excretion of drugs, dapsone and
drug sensitive or drug resistant bacterial population or what clofazimine in the milk, protects the infant from infection
is the proportion of drug resistant population in the total is not known but is a distinct possibility. These issues are
bacterial load. Therefore, for management purpose it is discussed in more details in the chapter on leprosy and
assumed that every patient, having a large number of pregnancy.
bacilli (MB patients), has a load of resistant organisms
and hence needs to be treated with a three drug REFERENCES
combination. Smear negative patients (PB), on the other
1. Desai AC, Bhide MB. Hydnocarpus oil as an anti-leprotic agent
hand, have only a few M. leprae, calculated to be less that in mouse foot-pad technique. Lepr India 1977; 49: 360-63.
a million. The probability of PB patients having naturally 2. Shepard CC. Experimental disease that follows the injection of
occurring drug resistant mutant/s is thus very small or human leprosy bacilli into foot pads of mice. J Exp Med 1960;
almost nil. Hence, the use of a combination of 2 drugs 112: 445-54.
3. Kirchheimer WF, Storrs EE. Attempts to establish armadillo
ensures the killing of resistant bacilli if any, even if the (Dasypus novemcinctus Linn) as a model for study of leprosy. I.
patient had been infected with bacilli resistant to any one Report of lepromatoid leprosy in an experimentally infected
drug. Based on these considerations, for control/ elimination armadillo. Int J Lepr Other Mycobact Dis 1971; 39: 693-702.
of leprosy separate regimens for multibacillary and 4. Faget GH. Chemotherapy of leprosy. Int J Lepr 1947; 15: 7-14.
5. Colman MD. Dapsone: mode of action, toxicity and possible
paucibacillary patients have been formulated. These are
strategies for increasing patient tolerance. Brit J Dermatol 1993;
detailed in the subsequent chapters. 129: 507-13.
Experience has shown that combination therapy, as 6. Seydel JK, Richter M, Wempe E. Mechanism of action of folate
used in leprosy and commonly spoken as MDT, is effective blocker diaminodiphenyl sulfone (dapsone, DDS) studied in E.
coli cell-free enzyme extracts in comparison to sulphonamide
in all cases and has been responsible for checking the
(SA). Int J Lepr 1980; 48:18-29.
emergence of drug resistance. The efficacy of the regimens 7. Ellard GA, Gamman PT, Rees RJW et al. Studies on the
is established and no further trials are needed to compare determination of minimal inhibitory concentration of 4, 4-diamino
the utility of MDT using placebo as control. However, are diphenyl sulfone (Dapsone, DDS) against M. leprae. Lepr Rev
1971; 42:101-17.
these regimens safe and how well these are tolerated had
8. Peters JH, Gordon JR, Murray JF Jr et al. Minimal inhibitory
been the concerns. World wide application of MDT, two concentration of dapsone for M. leprae in rats. Int J Lepr 1972;
drug combination for paucibacillary patients and three drug 40: 467-9.
regimen for multibacillary cases, has brought out that the 9. Levy L, Peters JH. Susceptibility of M. leprae to dapsone as
use of recommended combination of drugs, is on the whole determinant of patient response to acedapsone. Antimicrob
very safe and equally well accepted. Short and long-term 10. Shepard CC. A kinetic method for study of activity of drugs
observations with use of the combinations of the three against M. leprae in mice. Int J Lepr 1967; 35: 429-5.
CHAPTER
27
11. Barnetson RSC, Pearson JMH, Rees RJW. Evidence for leprae due to mutations in dehydroteroate synthase gene. FEMS
prevention of borderline leprosy reactions by dapsone. Lancet Microbiol Lett 1999; 177: 231-5.
1976; ii: 1171-72. 32. Ellard GA. Drug compliance in treatment of leprosy. Lepr Rev
12. Imkamp FMJH, Anderson R, Gatner EMS. Possible 1981; 52: 201-13.
incompatibilities of dapsone with clofazimine in treatment of 33. Pearson JMH, Haile GS. Primary dapsone resistant leprosy.
patients with erythema nodosum leprosum. Lepr Rev 1982; 53: Lepr Rev 1977; 48: 129-32.
148-49. 34. Girdhar BK, Sreevatsa, Desikan KV. Primary sulfone resistance.
13. Kaluarachchi SI, Fernandopulle BM, Gunawardane BP. Hepatic A preliminary report. Lepr India 1978; 50:352-55.
and haematological adverse reactions associated with the use 35. Londono F. Primary sulfone resistance. Lepr Rev 1977; 48: 51-54.
of multidrug therapy in leprosy – a five year retrospective study. 36. Waters MFR, Laing ABG, Rees RJW. Proven Primary dapsone
Indian J Lepr 2001; 73: 212-29. resistance in leprosy- A case report. Lepr Rev 1978; 49: 127-30.
14. De Gowin RL, Eppes RB, Powel RD et al. The haemolytic effects 37. Sub-committee on Clinical Trials of the Chemotherapy of Leprosy.
of DDS in normal subjects and in those with G6PD deficiency. THELEP Scientific Working Group of the UNDP/World Bank/
Bull World Health Organ 1966; 25: 165-79. WHO Special Programme for Research and Training in Tropical
15. Bhat RM, Radhakrishnan K. A case report of foetal dapsone Diseases. Characteristics of THELEP patients in Bomako and
induced agranulocytosis in an Indian mid-borderline leprosy Chingleput. Lepr Rev 1981; 58: 7-16.
patient. Lepr Rev 2003; 74: 167-70. 38. Vellut C. Ten year’s follow up of lepromatous leprosy patients on
16. Woodbury GR Jr, Fried W, Ertle JO et al. Dapsone associated DDS treatment. Lepr India. 1969; 40:111-14.
agranulocytosis and severe anaemia in a patient with 39. Ramu G, Desikan KV. A study of scrotal biopsy in subsided
leucocytoclastic vasculitis. J Am Acad Dermatol 1993; 38: 781-3. cases of lepromatous leprosy. Lepr India 1979; 51: 341-7.
17. Goulart IMB, Reis ACS, De Rezende TMN et al. Aplastic anaemia
40. Waters MFR, Rees RJW, McDougall AC et al. Ten years of
associated with multidrug therapy (dapsone, rifampicin and
dapsone in lepromatous leprosy: Clinical, bacteriological and
clofazimine) in a patient with lepromatous leprosy. Lepr Rev
histological assessment and the finding of viable leprosy bacilli.
2005; 76: 167-9.
Lepr Rev 1974; 45: 288-98.
18. Radhakrishnan S, Nair NGK. Association between regularity of
41. Rees RJW, Pearson JMH, Waters MFR. Experimental and clinical
dapsone treatment and development of deformities. Int J Lepr
studies on rifampicin in treatment of leprosy. B M J, 1970; 1: 89-92.
1987; 55: 425-34.
42. Colston MJ, Hilson GRF, Banerjee DK. The proportional
19. Sebille A. Dapsone-induced neuropathy compounds Hansen’s
bactericidal test; a method for assessing bactericidal activity of
disease nerve damage: an electrophysiological studying in
drugs against M. leprae in mice. Lepr Rev 1978; 49: 115-26.
tuberculoid patients. Int J Lepr 1987; 55: 11-22.
43. Gelber RH. The killing of Mycobacterium leprae in mice by dietary
20. Pannikar VK, Valarmathi, Vijaykumaran P. On “suicide with
concentrations of dapsone and rifampicin. Lepr Rev 1986; 57:
dapsone”. Indian J Lepr 1989; 61(2): 306.
347-53.
21. Leta G, Esther dos Santo M, Oliveira ML et al. Dapsone
hypersensitivity syndrome: systematic review of diagnostic 44. Winder FG. Mode of action of anti-microbial agents and
criteria. Abst. Int J Lepr 2002; 70: 94A. associated aspects of molecular biology of the mycobacteria.
22. Rao PN, Lakshmi TSS. Increase in incidence of dapsone In: The Biology of Mycobacteria. Vol. I. Ed. Colin Ratledge and
hypersensitivity syndrome –an appraisal. Lepr Rev 2001; 72: John Stanford.1982, Academic Press, London p.354.
57-62. 45. Kono K, Oizumok, Oka S. Mode of action of rifampicin on
23. Shepard CC, Tolentino JG, McRae DH. The therapeutic effects mycobacteria. II. Biosynthetic studies on the inhibition of
of 4,4 diacetyl diamino diphenyl sulphone (DADDS) in leprosy. ribonucleic acid polymerase of M. bovis BCG by rifampicin and
Am J Trop Med Hyg 1968; 17:192-202. uptake of rifampicin by M. phlei. Am Rev Respir Dis 1973;
24. Russel DA, Shepard CC, McRae DH et al. Acedapsone ( DADDS) 107:1006-12.
treatment of leprosy patients in Karimui, Papua New Guinea; 46. Shepard CC, Levy L, Fasal P. Further experience with rapid
status at 6 years. Am J Trop Med Hyg 1975; 24: 485-95. bactericidal effect of rifampicin on M. leprae. Am J Trop Med Hyg
25. Russell DA, Worth RM, Jano B et al. Prevention of leprosy by 1974; 23:1120-4.
acedapsone. Lancet 1975; ii: 771. 47. Mandell GL. Interaction of intra-leucocytic bacteria and
26. Wolcott RR, Ross H. Exacerbation of leprosy during present antibiotics. J Clin Invest 1973; 52: 1673-9.
day treatment. Int J Lepr 1953; 21: 437- 40. 48. Pattyn SR, Rollier R, Saerens EJ et al. Controlled trial on initial 3
27. Petit JMH, Rees RJW. Sulphone resistant leprosy: an months continuous and intermittent rifampicin therapy in
experimental and clinical study. Lancet 1964; 2: 673-74. lepromatous leprosy: Final analysis. Lepr Rev 1975; 46
28. Ji B. Drug resistance in leprosy-a review. Lepr Rev 1985; 56: (Suppl):129-39.
265-78. 49. Wilkinson FF, Gago J, Santabaya E. Therapy of leprosy with
29. Rees RJW. Drug resistance in M. leprae, particularly to DDS. Int rifampicin. Int J Lepr 1972; 40: 53-67.
J Lepr 1967; 35: 625. 50. Girdhar BK, Ramu G. Sreevatsa, Desikan KV. Introductory
30. Shepard CC, Levy L, Fasal P. The sensitivity to dapsone (DDS) rifampicin therapy in lepromatous leprosy: A six-month follow up
of M. leprae from patients with and without previous treatment. study. Lepr India 1978; 50:363-70.
Amer J Trop Med Hyg 1969; 18: 258-63. 51. Levy L. Shepard CC, Fasal P. The bactericidal effect of rifampicin
31. Kai M, Matsuoka M, Nakata, N Maeda S, Gidoh M, Maeda Y et on M. leprae in man: (a) single doses of 600,900 and 1200 mg;
al. Diaminodiphenyl sulphone resistance of Mycobacterium and (b) daily doses of 300 mg. Int J Lepr 1976; 44: 183-87.
CHAPTER
27
52. Girdhar BK, Sreevatsa, Desikan KV. Effect of single dose 76. Niwa Y, Sakane T, Miyachi Y et al. Oxygen metabolism in
rifampicin on infectivity of patients with lepromatous leprosy. phagocytes of leprotic patients: enhanced endogenous
Lepr India 1980; 52:359-65. superoxide dismutase activity and hydroxyl radical generation
53. Report of the WHO Study Group. Chemotherapy of leprosy for by clofazimine. J Clin Microbiol 1984; 20: 837-42.
control programmes. Geneva. Technical Report Series 1982; 77. Anderson R. Enhancement by clofazimine and inhibition by
No. 675 p.20. dapsone of production of prostaglandin E 2 by human
54. The Indian Association of Leprologists. Consensus on treatment polymorphonuclear leucocytes in vitro. Antimicrob Agents
of leprosy and problems of drug delivery. Indian J Lepr 1984; Chemother 1985; 27: 257-62.
56:158-59. 78. Gatner EMS, Anderson R. vanRensberg CE et al. In vitro and in
55. Warndorff J, Bourland J, Pattyn SR. Follow up of short course 2 vivo effects of clofazimine on the motility of neutrophils and
month’s rifampicin treatment of paucibacillary leprosy. Lepr Rev transformation of lymphocytes from normal individuals. Lepr
1982; 53: 9-17. Rev 1982; 53: 85-90.
56. Vijaykumaran P. MDT effect on pregnancy. Abst. XVI - IAL 79. Visher WA. The experimental properties of G30, 320 (B663).
Conference, Trichur India, 1989. Lepr Rev 1969; 40:107-10.
57. Poole G, Stradling P, Worlledge S. Potentially serious side effects 80. Hastings RC, Jacobson RR, Trautman JR. Long term clinical
of high dose twice weekly rifampicin. B M J 1971; 3:343- 47. toxicity studies with clofazimine (B663) in leprosy. Int J Lepr
58. Aquinas M, Allan AGL, Horsefall PAL et al. Adverse reactions to 1976; 44:287-93.
daily and intermittent rifampicin regimens for pulmonary 81. Pattyn SR, Rollier R, Saerens EJ et al. Initial three months’
tuberculosis in Hong Kong. B M J 1972; I:1765- 71. continuous and intermittent therapy in lepromatous leprosy. A
59. Girdhar BK, Desikan KV. Pulsed rifampicin therapy in leprosy. controlled clinical trial. Preliminary data. Ann Soc Belge Med Trop
Lepr India 1979; 51:47-8. 1974; 54: 43-8.
82. Pettit JHS, Rees RJW. Studies on sulphone resistance in leprosy.
60. Girdhar BK, Sreevatsa, Desikan KV. Intermittent rifampicin
1. Detection of cases. Int J Lepr 1966; 34: 375-90.
therapy in lepromatous leprosy. Lepr India 1980; 52: 89-96.
83. Arunthathi S, Satheesh KK. Does clofazimine have a protective
61. Riska N, Mattson K. Adverse reaction during rifampicin treatment.
role against neuritis? Lepr Rev 1997; 68: 233-41.
Scand J Respir Dis 1972; 53: 87-96.
84. Kar HK, Bhatia VN and Harikrishnan S. Combined clofazimine
62. Apocella G, Conti R. Inter-reaction of rifampicin with other drugs.
and dapsone- resistant leprosy: a case report. Int J Lepr Other
Tubercle 1980; 61: 171-80.
Mycobact Dis 1986; 54(3): 389-91.
63. Balakrishnan S, Sheshadri PS. Influence of rifampicin on DDS
85. Warndorff-van Diepen T. Clofazimine resistant leprosy: A case
excretion in urine. Lepr India 1979; 51: 54-9.
report. Int J Lepr 1982; 50:139-42.
64. Kenny M T, Strates B. Metabolism and pharmacokinetics of
86. Hogerzeil LM. Experience with the combination of clofazimine
antibiotic rifampicin. Drug Metab Rev 1981; 12: 159-62.
(Lamprene) and long term steroid therapy in treatment of leprosy.
65. Jacobson RR, Hastings RH. Rifampicin resistant leprosy. Lancet
Lepr India 1976; 48: 718- 21.
1976; ii:1304-5. 87. Ramu G, lyer CGS. Side effects of clofazimine therapy. Lepr
66. Honore N, Cole ST. Molecular basis of rifampin resistance in India 1976; 48(Suppl.): 722-31.
Mycobacterium leprae. Antimicrob Agents Chemother 1993; 37: 88. lyer CGS, Ramu G. An open trial with clofazimine in the
414-8. management of recurrent lepra reaction using thalidomide as
67. Sreevatsa, Girdhar BK, Ramu G et al. Parallel dapsone and control drug. Lepr India 1976; 48:690-94.
rifampicin resistance: A prospective study. Jap J Lepr 1984; 89. Desikan KV, Ramanujam K, Ramu G et al. Autopsy findings in a
53:28-31. case of lepromatous leprosy treated with clofazimine. Lepr Rev
68. Rao GS, Norman G, Ebenezer GN et al. Clinical profile of patients 1975; 46:181-4.
exhibiting drug resistance to MDT drugs. Int J Lepr 2002; 70: 90. Girdhar A, Venkatesan K, Chauhan SL et al. Red discoloration of
92A-93A. sputum by clofazimine simulating haemoptysis. Lepr Rev 1991;
69. Pattyn SR, Dockx P, Rollier MT et al. M. leprae persisters after 63: 47-50.
treatment with dapsone and rifampicin. Int J Lepr 1976; 44:154- 91. Morison NE, Marley GM. The mode of action of clofazimine. Int J
58. Lepr 1976; 44:133-4.
70. Sreevatsa, Girdhar BK, Desikan KV. Persister M. leprae after 92. Colston MJ, Ellard GA, Gammon PT. Drugs for combined
introductory rifampicin followed by dapsone therapy. Lepr India therapy: Experimental studies on the anti-leprosy activity of
1981; 53: 350-53. ethionamide and prothionamide and a general review. Lepr Rev
71. Waters MFR, Rees RJW, Person JMH et al. Rifampicin for 1978; 49:115-26.
lepromatous leprosy: nine years’ experience. B M J. 1978; I: 133- 93. Petit S R. Further data on effect of ethionamide and prothionamide
36. in experimental leprosy. Lepr Rev 1978; 49: 199-202.
72. Kumar B. Clofazimine – A review. Indian J Lepr 1991; 63: 78-92. 94. Colston MJ, Hilson GRF, Lancaster R. Intermittent
73. Brown SG, Hogerzeil LM. B663 in the treatment of leprosy. Lepr chemotherapy of experimental leprosy in mice. Am J Trop Med
Rev 1992; 33:6-10. Hyg 1980; 29:103-8.
74. Levy L, Shepard CC, Fasal P. Clofazimine therapy of lepromatous 95. Girdhar A, Girdhar BK, Sreevatsa et al. Effect of prothionamide
leprosy caused by resistant M. leprae. Am J Trop Med Hyg on the infectivity of lepromatous leprosy. Indian J Dermatol
1972; 21: 315-20. Venereol Leprol 1985; 51: 198-201.
75. Morrison NE, Morley GE. Clofazimine binding with 96. Bragina VS. Results of the treatment of leprosy patients with
deoxyribonucleic acid. Int J Lepr 1976; 44: 475- 81. prothionamide. Int J Lepr 1979; 47(Suppl): 437-8.
CHAPTER
27
97. Revankar R, Samant NJ, Ganapati R. Effect of prothionamide in 118. Grosset JH, Ji B, Guelpa-Lauras CC et al. Clinical trials of
leprosy- clinicobacteriological observation. Indian J Dermatol pefloxacin and ofloxacin in treatment of lepromatous leprosy. Int
Venereol Leprol 1983; 49: 61-4. J Lepr 1990; 58: 281-95.
98. Pattyn SR, Colston MJ. Cross resistance amongst thiambutosine, 119. Ji B, Grosset JH. Ofloxacin in the treatment of leprosy. Acta
thiacetazone, ethionamide and prothionamide with M. leprae. Leprol (Geneva) 1991; 7: 321-26.
Lepr Rev 1978; 49: 324-6. 120. Chan GP, Garcia-lgnacio BY, Chavez VE et al. Clinical trial of
99. Jacobson RR, Hastings RH. Rifampicin resistant leprosy. Lancet sparfloxacin in lepromatous leprosy. Antimicrob Agents
1976; ii: 1304-05. Chemother 1994; 38: 61-5.
100. Gelber RH. US-Japan Cooperative Medical Science Programme: 121. Gelber RH, Murray L, Siu P et al. Bactericidal antibiotics of three
Workshop on Leprosy Chemotherapy. Int J Lepr 1976; 44: 369-73. different classes emerge to treat leprosy: recent development
101. Freerkson E, Rosenfeld M, Bonnici E, Depasquele G. Combined from the laboratory to patient. Int J Lepr 1991; 59:717-8.
therapy in leprosy – back ground and findings. Chemotherapy 122. Ji B, Grosset J. Combination of rifapentine-moxifloxacin-
1978; 24: 187 -201. minocycline (PMM) for the treatment of leprosy. Abstract. Asian
102. Cour HO, Binder HJ, Orr HD. Ethionamide induced hepatitis. Am Leprosy Congress, Agra. Nov.9-13, 2000. p.125.
Rev Respir Dis. 1964; 90: 303-18. 123. Dhople AM, Namba K. In-vitro activity of sitafloxacin (DU-6859a),
103. Cartel J, Millan J, Guelpa-Lauras C et al. Hepatitis in leprosy either singly or in combination with rifampin analogues, against
patients treated by a daily combination of dapsone, rifampin and M. leprae. J Infect Chemother 2003; 9:12-5.
thioamide. Int J Lepr 1983; 51: 461-65. 124. Gaugas M. Antimicrobial therapy of experimental human leprosy
104. Kar HK, Balakrishnan S, Vasantha Kumar G et al. Hepatitis and bacilli (M. leprae) infection in the mouse. Lepr Rev 1967; 38: 225-
multi-drug therapy in leprosy with special reference to 30.
prothionamide. Indian J Lepr 1985; 57(1): 78-89. 125. Shepard CC. A survey of drugs with activity against M. leprae in
105. Ryrie GA. Thiosemicarbazone in the treatment of leprosy. Lancet the mouse. Int J Lepr 1971; 39: 340-48.
1950; ii: 286-88. 126. Fair WR. Diffusion of minocycline into prostatic secretions of
106. Colston KJ, Hilson GRF, Ellard JA et al. The activity of dog. Urology 1974; 3: 201-13.
thiacetazone, thiambutosine, thiocarlide and sulpha- 127. Loria PR. Minocycline hydrochloride treatment for atypical acid-
methoxypyridazine against M. leprae in mice. Lepr Rev 1978; fast infection. Arch Dermatol 1976; 112: 517-18.
49: 101-13. 128. Tsukamura M. In vitro antimycobacterial activity of minocycline.
107. Girdhar BK. Fluoroquinolones and their adverse effects. Indian Tubercle 1980; 67: 37-38.
J Lepr 1993; 65: 69-79. 129. Gelber RH. Activity of minocycline in M. leprae infected mice. J
108. Wolfson JS, Hooper DC. The fluoroquinolones, structure, Infect Dis 1987; 156: 236-39.
mechanisms of action and resistance and spectra of activity in 130. Franzblau SG. Drug susceptibility testing of M. leprae in the
vitro. Antimicrob Agents Chemother 1985; 48: 273-89. BACTEC 460 system. Antimicrob Agents Chemother. 1989; 33:
109. Tsukamura M. In vitro antituberculosis activity of a new 2115-17.
antibacterial substance-ofloxacin (DL-8280). Am Rev Respir 131. Kelly RG, Allen SS. Pharmacokinetic studied on minocycline in
Dis 1985; 131:348-51. man. Clin Pharmacol Ther 1973; 14: 852-61.
110. Crumplin GC, Kenwright M, Hirst T. Investigations into the 132. Gelber RH, Siu P, Tsang M et al. Effect of low-level and intermittent
mechanism of action of the antibacterial agent norfloxacin. J minocycline therapy on the growth of Mycobacterium leprae in
Antimicrob Chemother 1984; 13(Suppl.B): 9-23. mice. Antimicrob Agents Chemother 1991; 32: 1758-62.
111. Stevens PJE. Bactericidal effect against E. coli of nalidixic acid 133. Gelber RH, Fukuda K, Byrd S et al. Clinical trial of minocycline in
and four structurally related compounds. J Antimicrob lepromatous leprosy. B M J. 1992; 304:91-92.
Chemother 1980; 6: 535-42. 134. Lalwani AK, Tami A, Gelber RH. Lepromatous leprosy : nasal
112. Williams DL, Gillis TP. Molecular detection of drug resistance in manifestation and treatment with minocycline. Ann Otol Rhinol
Mycobacterium leprae. Lepr Rev 2004; 75:118-30. Laryngol 1992; 101: 261-64.
113. Sanders CC, Sanders WE Jr, Goering RV et al. Selection of 135. Baster RSW. Minocycline related pigmentation. Arch Dermatol
multiple antibiotic resistance by quinolones, beta-lactams and 1985; 121: 608-10.
aminoglycosides with special reference to cross resistance 136. Molaui A. Weinstein L. In-vitro activity of erythromycin against
between unrelated drug classes. Antimicrob Agents Chemother atypical mycobacteria. J Infect Dis 1971; 123: 216-19.
1984; 22: 548-53. 137. Franzblau SG, Hastings RC. Rapid in vitro metabolic screen for
114. Lockley MR, Wise R, Dent J. Pharmacokinetics and tissue antileprosy compounds. Antimicrob Agents Chemother 1987;
penetration of ofloxacin. J Antimicrob Chemother 1984; 14:647-52. 31:780-3.
115. Saito H, Tomioka H, Nagashima K. In vitro and in vivo activities 138. Franzblau SG, Hastings RC. In vitro and in vivo activities of
of ofloxacin against M. leprae infection induced in mice. Int J macrolides against M. leprae. Antimicrob Agents Chemother
Lepr 1986; 54:560-2. 1988; 32:1758-62.
116. Grosset JH, Guelpa-Lauras CC, Perani EG et al. Activity of 139 Gelber RH, Siu P, Tsang M et al. Activities of various macrolide
ofloxacin against M. leprae in the mouse. Int J Lepr 1988; 56:259- antibiotics against M. leprae infection in mice. Antimicrob Agents
64. Chemother 1991; 35:760-63.
117. N’Deli L, Guelpa-Lauras CC, Perani EG et al. Effectiveness of 140. Ji B, Jamet P, Perani EG et al. Powerful bactericidal activities of
pefloxacin in treatment of lepromatous leprosy. Int J Lepr 1990; clarithromycin and minocycline against M. leprae in lepromatous
58:12-8. leprosy. J Infect Dis 1993; 168:188-90.
CHAPTER
27
141. Gelber RH, Murray LP, Sin P et al. Clarithromycin at very low 157. Prabhakaran K, Harris EB, Randhawa B et al. Reversal of drug
levels and on intermittent administration inhibits growth of M. resistance in M. leprae by ampicillin/sulbactam. Microbiol 1992;
leprae in mice. Int J Lepr 1992; 60: 485-87. 72:137-42.
142. Wollmer P, Pride NB, Rhodes CG et al. Measurement of pulmonary 158. Kulkarni VM, Seydel JK. Inhibitory activity and mode of action of
erythromycin concentration inpatients with lobar pneumonia by DDS in cell-free folate synthesizing system prepared from M. lufu
means of position tomography. Lancet 1982; I: 117-20. and M. leprae; a comparison. Chemotherapy 1993; 29:58-67.
143. Chan GP, Garcia-Ignacio BY, Chavez VE. Clinical trial of 159. Wiese R. New dihydrofolate reductase inhibitors (Abst). Int J
clarithromycin for lepromatous leprosy. Antimicrob Agents Lepr. 1993;61:313.
Chemother 1994; 38: 515-17. 160. Seydel JK. Brodimoprim-dapsone and brodimoprim-dapsone-
144. Gelber RH. Successful treatment of a lepromatous patient with rifampicin: in vitro and in vivo results (Abst). Int J Lepr 1993;
clarithromycin. Int J Lepr 1995; 63: 113-15. 61:315-6.
145. Derouin F, Caroff B, Chau F et al. Synergistic activity of 161. Schaper KJ, Seydel JK, Rosenfeld M et al. Development of
clarithromycin and minocycline in an animal model of acute inhibitors of mycobacterial ribonucleotide reductase. Lepr Rev
experimental toxoplasmosis. Antimicrob Agents Chemother 1992; 1986; 57 (Suppl 3): 254-64.
36: 252-55. 162. Schaper KJ, Seydel JK, Rosenfield M et al. Inhibition of
146. Ji B, Perani EG, Grosset JH, Effectiveness of clarithromycin mycobacterial growth by hydrozones (Abst). Int J Lepr 1993;
and minocycline alone and in combination against experimental 61:312.
M. leprae infection in mice. Antimicrob Agents Chemother 1991; 163. Hoffner SE, Olsson-liljequist B, Rydgard KJ et al. Susceptibility
35: 579-81. of mycobacteria to fusidic acid. Eup J Clin Microbiol Infect Dis
147. Rastogi N, Labrousse V. Extracellular and intracellular activities 1990; 9: 294-97.
of clarithromycin alone or in association with ethambutol and 164. Van Caekenberghe D. Comparative in-vitro activities of ten
fluoroquinolones and fusidic acid against mycobacterium
rifampicin against M.avium complex. Antimicrob Agents
species. J Antimicrob Chemother 1990; 26: 381-86.
Chemother 1991; 35: 462-70.
165. Franzblau SG, Biswas AN, Harris EB. Fusidic acid is highly
148. Yajko DM, Nassos PS, Sanders CA. Comparison of the
active against extracellular and intracellular M. leprae. Antimicrob
intracellular activities of clarithromycin against M.avium complex
strain in J774 cells and in alveolar macrophages from human
166. Franzblau SG, Harris EB, Hastings RC. Macrolides, fusidic acid,
deficiency virus type-1 infected individuals. Antimicrob Agents
lincosamide and quinolones (Abst). Int J Lepr 1993; 61:315.
Chemother. 1992; 36: 1163-65.
167. Franzblau SG. Clinical trial of fusidic acid in leprosy. Int J Lepr
149. Hastings RC, Jacobson RR. Activity of ansamycin against
1993; 61:519-20.
Mycobacterium leprae in mice. Lancet 1983; ii: 1979-80.
168. Collingnon P, Turnidge J. Fusidic acid in vitro activity. Int J
150. Pattyn SR. Rifabutin and rifapentine compared with rifampicin
Antimicrob 1999; 12(Suppl 2): S48-S52.
against M. leprae in mice. Antimicrob Agents Chemother 1987;
169. Jayaraman P, Mahadevan PR, Mester M et al. Inhibition of the
31: 134-36. incorporation of radioactive DOPA in M. leprae by
151. Hastings RC, Richard VR, Jacobson RR. Ansamycin activity deoxyfructoserotonin. Biochem Pharmacol 1980; 29: 2526- 28.
against rifampicin resistant M. leprae. Lancet. 1984; i: 1130 – 31. 170. Mester L, Balakrishnan S. DFS: First human metabolite with
152. Ji B, Grosset JH. Recent advances in chemotherapy of leprosy. anti-leprosy activity. Acta Leprol 1981; 83: 21-23.
Lepr Rev 1990; 61:1331-39. 171. Saint-Andre P, Baquillon G, Mester L et al. Bilan de neuf mois de
153. Yoder LJ, Jacobson RR, Hastings RC. The activity of rifabutin traitement par la deoxyfructo-serotonin des lepreux lepromateux.
against M. leprae. Lepr Rev 1991; 62: 280-87. Acta Leprol1982; 86: 189-97.
154. Ji B, Chen J, Lu X et al. Anti-mycobacterial activities of two 172. Antia NH, Ambrose EJ, Uplekar MW et al. Effect of deoxyfructo-
newer ansamycins, R-76-I and DL 473. Int J Lepr 1986; 54: 563- serotonin (DFS) on lepromatous leprosy. Lancet 1988; i: 619-22.
77. 173. Ambrose EJ, Antia NH, Tannaz JB. The action of deoxyfructo-
155. Shepard CC, VanLandingham RM, Walker LL et al. Activity of serotonin on intra cellular bacilli and on host response in
selected beta-lactam antibiotics against M. leprae. Int J Lepr lepromatous leprosy. Lepr Rev 1985; 56: 199-208.
1987; 55:322-7. 174. Goloschapov NM, Bazurov GI, Kharomova EB et al. Diuciphon
156. Gelber RH. The activity of amoxicillin plus clavulanic acid against and diuciphon in combined therapy of lepra (a 14-year follow up
M. leprae in mice. J Infect Dis 1991; 163:1374-77. study) (Abst.) Int J Lepr 1990; 57:147.
28 Development and Evolution of WHO MDT
and Newer Treatment Regimens
VV Pai, R Ganapati, Raghuram Rao
INTRODUCTION Clofazimine
Leprosy, considered to be one of the major disease of In 1962, based on the evidence of its efficacy in mouse
mankind, has been declared eliminated in many endemic foot pad, Brown and Hogerzeil first reported on the efficacy
countries (despite seemingly unsurmountable odds), of clofazimine in leprosy patients in Nigeria.4 The drug has
primarily due to the WHO multidrug therapy (MDT), political a mild bactericidal action on M. leprae and accumulation
will, donor agencies, NGOs and committed health workers. within the macrophages is advantageous and results in
Development and implementation of MDT has transformed inhibition of intracellular multiplication of M. leprae.
leprosy into a curable disease. As per WHO, 14.2 million Clofazimine is effective when given daily or on alternate
cases have been cured globally with MDT since 1985, of days. The clinical response to a 50-100 mg daily dose of
which 12 million are from South-East Asia, more than 10.8 clofazimine is almost similar to that seen with 100 mg of
million of them being from India.1 The seemingly great dapsone although, the effect is slightly slow.
success of MDT prompted the World Health Assembly in
1991 to call for elimination of leprosy as a public health Rifampicin
problem by the year 2000. The first results of treatment of leprosy patients with
rifampicin were reported in 1970.5,6 In the 1970s, there
SOME SIGNIFICANT LANDMARKS IN were wide differences of opinion about rifampicin dosage
THE TREATMENT OF LEPROSY AND (150-900 mg daily), dose-intervals (daily, twice weekly,
THE EVOLUTION OF MDT weekly or on 2 consecutive days every 4 weeks) and
duration (from a single dose up to 7 years) of treatment.
Until 1941, there was no truly effective antileprosy drug, Later, the recommended dosage of rifampicin was 450-
apart from hydnocarpus (chaulmoogra) oil which was in 600 mg daily.
use for centuries in India and China. The only remedy for Languillon et al were the first to report on the high
leprosy patients was isolation / segregation. efficacy, good tolerability and practicality of the supervised
once monthly (1200 mg oral-dose) schedule as a
Dapsone component of the combination therapy for lepromatous
In 1941, Guy Faget first used a di-substituted derivative of leprosy.7 Later, Yawalkar et al confirmed these findings on
dapsone (Promin) intravenously in treating leprosy at the the basis of Ciba-Geigy’s International, multicentric, single-
National Leprosarium, Carville, USA. It was first used for blind, comparative trial carried out in Brazil, India and
the treatment of leprosy by Cochrane in 1946, in India.2 Senegal.8 In this trial the clinical, bacteriological and
Later Lowe and Smith in 1949 reported on the successful histopathological effects of adding rifampicin in two
use of oral DDS.3 Dapsone is administered orally as a regimens (450 mg daily; or 1200 mg once monthly in a
daily dose of 1-2 mg/kg body weight and it shows clinical supervised single dose), to dapsone 50 mg daily, in
improvement within 3-6 months. It is remarkably well 93 patients with previously untreated lepromatous leprosy,
tolerated and side effects are rare. were practically identical.
CHAPTER
28
SEQUENCE OF SIGNIFICANT EVENTS IN continuing a decline that had started at least two decades
TREATMENT OF LEPROSY9 earlier and Freerkson declared the disease eradicated from
Malta in 2001.14
In 1964, the first confirmed case of dapsone resistance
was reported by Petit and Rees.10 In 1970, Rees et al
Persisters
demonstrated rifampicin as the most potent bactericidal
drug against leprosy.5 In 1972, Shepard suggested the use Persisters are viable, drug susceptible, leprosy bacilli that
of combined rifampicin and acedapsone therapy to reduce can be recovered from lepromatous patients, many years
drug resistance.11 In 1974, Waters et al demonstrated the after the apparently successful treatment with anti leprosy
existence of persisters (viable M. leprae) in lepromatous drugs.
patients treated with dapsone for 10-12 years.12 Approximately, 37% of 131 patients with lepromatous
In 1982, WHO Study Group recommended multidrug leprosy admitted into the THELEP controlled clinical trials
regimens for treatment of both, multibacillary and in Bamako and Chingleput were found to have dapsone
paucibacillary leprosy patients. resistant organisms, indicating primary dapsone
resistance.15 However, the primary objective of these
REASONS FOR SHIFT FROM THELEP controlled clinical trials was to compare several
MONOTHERAPY TO MDT combined drug regimens among previously untreated
lepromatous leprosy patients to detect persisting M. leprae.
Until 1982, the chemotherapy of patients with leprosy relied The results demonstrated that persisting M. leprae were
almost entirely on dapsone monotherapy. There were three detected in approximately 9% of all patients, without any
main disadvantages associated with prolonged dapsone relation to regimen and duration of treatment.
monotherapy, namely: (i) drug resistance, (ii) bacterial This study established the strong support to the
persistence and (iii) defaulting; due to which the need for a multidrug regimen recommended for treatment of
wholesome regimen arose. In addition, some of the other multibacillary leprosy.15 Another study in these THELEP
reasons in favor of introducing MDT were: trials reported persistence of viable bacilli in 7% of MB
a. To reduce the incidence of post-treatment relapse as patients. The significance of surviving drug sensitive
compared with monotherapy. persisters has remained debatable until recently. It has
b. To reduce the side effects been suggested that they die a natural death during
c. To increase the cost effectiveness by a shorter duration treatment and therefore are of no consequence. In the past,
of treatment leading to an earlier release of patients it had been thought that relapses were only due to the
from control. emergence of resistance. However, recent findings based
It is interesting to note that the first multidrug-
on long-term follow-up once again suggest the drug
combination project to treat MB leprosy patients was
sensitive bacilli to be a cause of relapse, as the relapsed
started in 1972 in Malta (a decade earlier than the launch
patients treated with same regimens showed good
of WHO MDT), by Professor Freerksen of Borstel,
response, indicating persisters as the probable cause.
Germany. All the registered patients with leprosy were
treated with a combined regimen, comprising initially a
Rifampicin-based Combined Therapy
daily oral administration of dapsone, prothionamide and
for MB Patients
isoniazid called “Isoprodian”. Later, dapsone, rifampicin,
prothionamide and isoniazid were given in a combined In a study, rifampicin was given in a single dose of 1500
tablet named “IsoprodianR”.13 Duration of treatment was mg in 12 untreated lepromatous leprosy patients, followed
dependent on the initial clinical, bacteriological and by dapsone 10 mg daily for four weeks and later, dapsone
histopathological status; the minimum treatment was for given in a dose of 50 mg daily. Subsequent mouse foot
5 months and the longest was 89 months.13 pad (MFP) inoculation studies of inoculum from these
A recent report on the follow-up investigation of the treated patients did not show multiplication of M. leprae.16
first multidrug therapy, in Malta project, indicates that the In another study of 17 untreated lepromatous leprosy
overall response to the therapy was excellent with an patients, rifampicin was administered in a dose of 600 mg
extremely low relapse rate. During the 30 years of the daily for a short period (duration not specified). MFP studies
project the incidence of leprosy steadily decreased, indicated no evidence of multiplication of M. leprae.17
CHAPTER
28
Development and Evolution of WHO MDT and Newer Treatment Regimens 355
These studies strongly indicated the powerful bactericidal the newly diagnosed cases. Further cases of resistance
effect of rifampicin against M. leprae paving the way for of M. leprae to rifampicin and thioamides had been reported
future investigations. In fact, during the decade between among patients receiving these drugs as monotherapy.
the mid 1970s and the mid 1980s, 12 rifampicin containing After reviewing the situation related to dapsone
combined regimens were tested among LL patients in the resistance, persisters, early development of resistance to
Institute Marchoux.18 In this study, out of 437 patients monotherapy even with potent drugs, and no consensus
enrolled, 384 were followed-up for more than 1 year, the on duration of therapy, WHO Study Group, in 1981
mean duration of follow-up being 63±30.3 months after recommended treatment with more than one drug for
completion of treatment. Relapse was confirmed by the 24 months or till smear negativity in multibacillary leprosy;
presence of viable M. leprae in skin biopsy specimens. and six months in paucibacillary leprosy.21 Because,
Relapses occurred late, about 5±2 years after stopping subsequently most data on the effects of limiting therapy
treatment, the shorter the duration of rifampicin adminis- to a 24 month course (rather than continuing until skin
tration the earlier the appearance of relapse. The total smear results are negative) were favorable, the WHO Study
relapse rates ranged from 2.9 to 27.8% (average 17.7%) Group on Chemotherapy of Leprosy recommended at its
and the relapse rates per 100 patient–years of observation meeting in 1994 that all multibacillary patients be given
ranged from 0.8 to 6.9. Among the 12 regimens tried, only the standard WHO MDT regimen for 24 months.
the WHO-MDT yielded an acceptable relapse rate.19
Multibacillary Leprosy
WHO STUDY GROUP ON For adults the recommended regimen is:
CHEMOTHERAPY OF LEPROSY20 1. Rifampicin (600 mg) once a month supervised.
2. Dapsone (100 mg) daily self-administered.
It is essential to know a little about the changing 3. Clofazimine (300 mg) once a month supervised and
classification of the disease because the definitions of 50 mg daily self-administered.
PB and MB leprosy have changed quite often over the 4. Duration: 24 months.
years.
In 1960, Ridley-Jopling classified leprosy based on the Paucibacillary Leprosy
clinical, bacteriological, histopathological and immuno-
For adults the recommended standard regimen is:
logical (Mitsuda reaction, T-cells and humoral response)
1. Rifampicin 600 mg once a month supervised.
status. In 1981, WHO recommended that patients be
2. Dapsone 100 mg daily self administered.
classified as paucibacillary leprosy (PB) leprosy with
3. Duration: 6 months.
bacteriological index (BI) of up to 2; and as multibacillary
Children should receive proportionately reduced doses
leprosy (MB) with BI more than 2 at any site in the initial
of the above drugs. Multibacillary patients should complete
skin smear. It was introduced to simplify disease
24 monthly doses within 36 months period; and
recognition and to ensure that patients were appropriately
paucibacillary patients 6 monthly doses within 9 months
treated with MDT.20 In 1988, it was recommended that a
period. It was recommended that patients receive their
positive smear at any site was sufficient to include the
drugs in monthly calendar blister packs.
case in MB category to include more patients in the MB
group to avoid under treatment of MB cases which were
classified as PB. Later the need for skin smear was
HISTORY OF MDT IN INDIA AND
dropped altogether and the current WHO classification
CONTROVERSY OVER INTENSIVE
TREATMENT WITH RIFAMPICIN22
includes any patient with 6 or more lesions under MB
category. Bombay Leprosy Project (BLP) as an NGO, initiated
When WHO study group on chemotherapy of leprosy rifampicin and clofazimine along with dapsone for the
control met in 1981, the Leprosy Control Programs faced treatment of smear positive leprosy cases (BL, LL types)
a variety of serious constraints. Widespread secondary for the first time in the slums of Mumbai in 1977-1978
dapsone resistance was reported in 19% of patients who during which time WHO coordinated THELEP trials were
were treated with dapsone monotherapy. Primary dapsone going on in Chingleput, South India and in Bamako, Mali.
resistance mostly of low degree was detected in 50% of Rifampicin was administered as a single dose of 1200 to
CHAPTER
28
1500 mg once a month; along with daily dapsone till Taking BI as a parameter of judgment, the results indicated
bacteriological negativity was achieved. Since then, several distinct improvement over the performance achieved
studies on rationalization of treatment have been taken up through dapsone monotherapy during earlier period.24
from time to time but at a slower pace. This contribution assisted the policy makers to shorten
Soon after WHO recommended MDT in 1981, BLP was the duration of treatment from “till smear negative” to a
one of the first to start WHO-MDT to treat leprosy patients fixed duration of 24 months. In spite of the WHO
in Mumbai. Initially, all the skin smear positive multi- recommendations, leprologists were hesitant to stop
bacillary (MB) leprosy patients were administered rifampicin treatment after 24 months. At the first meeting on this
daily for 21 days followed by monthly pulse doses. The issue called by the NLEP, in Delhi, selected leprologists
Indian Association of Leprologists (IAL) organized a were asked to stop treatment after 24 months on a trial
workshop in Karigiri in 1983 and recommended the use of basis, especially in cases with low BI.
rifampicin 600 mg daily for 21 days followed by the monthly It was only in 1990 that the NLEP introduced 24 months
pulse dose as recommended by WHO. National Leprosy MDT (FDT-24) in modified MDT district programs for the
Eradication Program (NLEP) accepted this recommen- convenience of the PHC doctors who were supposed to
dation initially and later changed over to 14 days intensive look after treatment of patients with leprosy. Later, since
therapy for their district MDT programs. 1992, the rest of the country started practicing FDT-24
The multidrug combination project on a mass scale irrespective of BI grading. 27 Some leprologists and
was implemented in Wardha (Maharashtra) in 1981. pathologists did have reservations in following the FDT-24
Intensive therapy for 14 days with rifampicin was practiced. regimen, especially in patients with high BI.
In a study conducted in 7 leprosy colonies in and around
Mumbai city, it was observed that after 21 days of initial Fixed Duration Treatment for 12 Months
intensive therapy; with continued MDT till bacteriological (FDT-12)
smear negativity; and after follow-up for 13 years of the BLP reported its findings as early as 1984, on smear
100 smear positive cases, no relapses were encountered. conversion in smear positive drop out patients after
This study of highly smear positive cases showed there receiving treatment for less than 12 months. Earlier BLP
was no bacteriological relapse or reaction over a period of had reported their observations on very low number of
13 years of post MDT follow-up.23 relapses in patients given FDT for 24 or even 12 months.
BLP observed 11 relapses in patients with initial BI of 3+
Fixed Duration Treatment (FDT) for 24 Months and above; over a period of 5 to 25 years of follow-up
BLP reported its findings in 1986 on the comparable among patients treated with, FDT-24 (6 relapses) and FDT-
outcome of conversion of smear positivity to smear 12 (5 relapses).28
negativity, with and without initial intensive therapy with It was again in 1991 that BLP reported its observations
rifampicin.24 This study indicated the equal efficacy of WHO on treatment with MDT for 12 months in skin smear positive
regimen and the regimen with daily rifampicin therapy. MB leprosy patients and provided follow-up data on 190
A key question for the study group was whether the patients which influenced policy makers to further reduce
WHO MDT regimen for multibacillary disease could now the duration of MDT from 24 to 12 months. WHO meanwhile
be fixed at 24 months. Most control programs started started double blind field trial of MDT-12 and other regimens
practicing WHO MDT for 24 months.25 Becx-Bleumink in 1992. The findings of this investigation were considered
reviewed the literature and recommended, that treatment (along with those collected by WHO worldwide on treatment
for multibacillary patients should be limited to 24 months of drop out patients), by the “WHO Expert Committee on
for operational reasons.26 Leprosy” in 1997 as an important authentic data to reduce
Analysis of BI of 584 MB leprosy patients who had the duration of treatment from 24 months to 12 months.
completed MDT as per recommendations of the WHO and In 1997, the WHO Expert Committee on Leprosy and
IAL, showed a smear conversion to negativity of 56% cases NLEP recommended Fixed Duration Treatment (FDT)-
at 24 doses and 66% at 36 doses. This study indicated 12 months for multibacillary leprosy and 6 months for
that daily initial administration of rifampicin for 21 days did paucibacillary leprosy in the program.21 This was not
not show any distinct advantage over the WHO regimen. accepted by all clinicians and they continued to treat MB
CHAPTER
28
patients with 24 doses. Even today, selected NGOs still better than) those who had taken 24 months of MDT. The
practice FDT-24 especially in high BI cases as their overall results in the three groups were comparable.30
organizational policy. Their fear is based on the report from In 1998, Skin smear was done away with as the reports
Bamako, Mali and JALMA, Agra, who reported high relapse from several field laboratories were not found to be
rates in patients with BI more than 4.0. This fear is still dependable in the sense that they would not match with
haunting many clinicians (and even policy makers) who the clinical diagnosis. There could be many causes for
do not favor stopping MDT at the end of 12 months. such problems pertaining to several operational factors
and skills of the field staff.
Rationale for Shortening the Duration of
MDT to 12 Months POST-TREATMENT SURVEILLANCE AND
RELAPSES IN LEPROSY
In 1997, the 7th WHO Expert Committee on Leprosy
The responsibility of health system towards the patient does
explored the possibility of further shortening the duration
not cease with the completion of chemotherapy. Surveillance
of MDT (MB) from 24 to 12 months, with a view to facilitate
has two main objectives, detection of relapse and the
better treatment compliance without significantly
recognition of reactive phenomenon occurring after
compromising the efficacy.21
completion of MDT. Patients should continue to have access
The rationale that rifampicin kills over 99.99% of the
to health facilities for detection and treatment of relapse and
viable organisms with three monthly doses and rifampicin,
management of leprosy reactions.31 Since many relapses
the resistant mutants are likely to be eliminated by 3-6
occur late, 5 years post-treatment follow-up may not be
months with dapsone and clofazimine. It was therefore adequate. Surveillance period of 8-10 years or even more
considered that the elimination of drug susceptible will be ideal. Stating reaction as a sign of activity has led to
organisms is almost entirely due to the bactericidal effect the interpretation that reaction warrants chemotherapy even
of the initial few doses of rifampicin. The major role of the after completion of MDT. In our experience, even macular
dapsone–clofazimine component in MDT is to ensure the lesions reappearing during surveillance respond to steroid
elimination of rifampicin resistant mutants from the bacterial therapy, which is generally recommended for classical
population. reversal reaction. Experience is to be gained with respect
The efficacy of standard and shorter MDT regimens to the further follow-up of such patients.32
for MB leprosy has also been compared in Malawi in which Biological factors influencing relapse following any
305 MB patients were treated with 18 or 30 monthly doses duration of MDT may be quite different from those
of MDT. No relapses were observed in either group after influencing decline of bacteriological index and attainment
treatment was completed. It was concluded that 18 monthly of negativity. Long-term observations to assess relapse
doses of MDT taken within 24 months may be sufficient after FDT for 12 months are required.32
for the treatment of multibacillary leprosy.21,29 The issue of relapses following WHO MDT is obviously
Information on the clinical and bacteriological progress of great significance and several studies have been initiated
of patients who fail to complete treatment, may shed some to provide estimates of the risk involved. The ultimate
light on the efficacy of MDT regimens of shorter duration test of chemotherapeutic effectiveness of any regimen is
than the standard WHO regimen. In a separate retrospective the relapse rate among patients who have completed the
study, 234 defaulters with multibacillary leprosy were prescribed course of treatment. As relapse in leprosy
examined at the time of retrieval after a mean period of occurs long after completion of treatment with any regimen,
7.5 years. Of these, 139 patients had taken treatment for a prolonged follow-up of treated patients is required. A
12 months or less; and 95 were treated with 13-23 monthly case of relapse is presented here in LL leprosy even 15
doses. These two group were compared with a group of years after attaining smear negativity, after extended MB
761 patients of MB leprosy who had taken 24 months of MDT (Figs 28.1 to 28.3).
MDT and had been followed up for a mean period of 4 years. Relapse rates after MDT for 24 months have been
The rates of skin smear positivity in the three groups at negligible. In early 1980s THELEP supported field
the time of retrieval were 1.04, 0.83 and 1.06 per 100 trials were carried out in MB patients at Karigiri and
person-years. In other words, the patients who took 12 or Polambakkam in South India; and in PB cases in Malawi
less doses of MDT performed as good as (in some cases and Indonesia. Most of the MB patients had previously
CHAPTER
28
A B
Figs 28.1A and B: Relapse in a case of LL leprosy (taken MB MDT till smear negativity) after an interval of 12 years
In a survey organized by WHO, the cumulative risk of

relapse was 0.77% for multibacillary leprosy treated for
24 months or till skin smear negativity and 1.07% for
paucibacillary leprosy, 9 years after completion of MDT.
Similar results have been reported in several leprosy
elimination programs and research projects thereby
indicating that the overall relapse rate was 0.1%.21
In a pilot survey in which 92,194 MB patients were
covered, 467 relapses were reported giving an overall
relapse rate of 0.23 per 100 person years. In the second
extended questionnaire survey, information was obtained
from 28 selected centers on patients treated with MDT for
24 months or till smear negativity between 1982 and 1990.
Fig. 28.2: Relapse in a case of LL leprosy who took 30 pulses of MB A total of 20,141 MB patients were observed of whom
MDT (March 1992 to August 1994) in Delhi. His initial BI was 4.0+ and 1414 were followed for 9 years. After stopping treatment,
was smear negative at the time of RFT in 1994. He presented with
these lesions over face and other body parts in April 2009 (15 years 67 patients were reported as relapse during a follow-up
after RFT). This time his BI was 3+, also note the enlarged great period of 80,000 person years giving a cumulative relapse
auricular nerve on left side. (Source: Department of Dermatology, Dr rate of 0.77%.33 It was also reported at a recent IAL
RML Hospital, New Delhi)
workshop on Cure of Leprosy held at Konark, Orissa that
taken prolonged dapsone monotherapy for several years. till March 2003, only 2563 cases have been diagnosed as
In the MB patients in Indian arm of the trails not a single relapse out of 7,43,224 cases cured with MDT.34 In a study
relapse was reported for at least 4 years among the 2000 by Jamet et al the overall relapse rate was reported to be
multibacillary patients whose treatment was stopped after as high as 20% in a group of 35 multibacillary patients
achieving smear negativity. In the study conducted in the treated with two years of MDT, after a mean period of 27 to
PB leprosy arm of the trial in Malawi, relapses were 84 months of follow-up.35
reported after 4 years of follow-up at the rate of 0.65/100 In our experience at BLP, true relapses in multibacillary
person years; and 0.12/100 person years after 5 years leprosy with bacterial positivity were observed as late as
follow-up from Indonesia.19 10 to 15 years after stopping the treatment and irrespective
CHAPTER
28
A B
Figs 28.3A and B: Relapse in a case of LL Hansens ( taken 24 months of MB MDT) after an interval of 8 years
of the treatment regimens. A total of 51 relapses were achieve clinical cure” was viewed against the conclusion
observed of which 16 relapses were among those treated of the few authors who observed that “persistence of
with MB MDT > 24 months; 14 among those treated with patches after six months of MDT warrant continuation of
MB-MDT 24 months; 7 among those treated with MB-MDT treatment”.
12 months and 6 relapses in those treated with ROM-1; In our own experience, only 17% of the patients with
and 8 in those treated with RO-28 days. All relapses were paucibacillary leprosy showed clinical activity after three
diagnosed in the clinic and not based on population and it years of surveillance, whereas 98.8% of patients with single
indicates that relapses occur in all types of regimen lesion healed at the end of two years of surveillance.39
irrespective of any combination of drugs.36 The occurrence of type1 reaction or appearance of new
In patients relapsed after WHO MDT, re-treatment with lesions during treatment or surveillance; seems to be yet
the same regimen showed a good response indicating another grey area. Experience is to be gained with respect
persisters or drug sensitive bacilli to be the cause of relapse. to further follow-up of such patients. It is not clear whether
In line with such relapses, Shetty and co-workers have determination of the duration of PB leprosy should be
found persisters (viable M. leprae) in 20% of skin and 30% influenced by episodes of reaction or appearance of new
of nerve biopsies of MB patients treated with 24 months lesions. However, follow-up of these cases is necessary
of MB MDT. The same workers have also reported to ascertain the long-term efficacy of such a regimen. This
persistence of viable bacilli in treated patients of is precisely the area where further research on FDT is
paucibacillary type of leprosy.37 needed.
The ultimate criterion of success of any regimen lies
in the prevention of relapses. Studies have shown that
CHEMOTHERAPY OF LEPROSY—
MDT is highly effective in this regard. Relapse rates below
FURTHER CHALLENGES38
1% have been reported by some workers in PB patients
PB leprosy in our view is the most ill understood aspect of while others have come across relapses in a larger number
the disease with respect to the rational management of of patients (3 to 10%).39
such cases. WHO determined regimen (1992) based on In a study at Malawi, Boerrigter et al reported 4.3
bacillary population seems to be improperly understood in patients with active skin lesions in 483 paucibacillary
general. The validity of several trials drawing conclusion patients after WHO MDT,40 while Katoch et al reported
that “continuation of chemotherapy is not necessary to 29.6% cases with activity (Personal communication).
CHAPTER
28
Some Problems with MDT Though MDT has been largely successful, some of
Multibacillary Leprosy the issues that need to be kept in mind are the frequent
changes in definitions of leprosy classification, operational
Though the success of multidrug therapy is well-known,
guidelines, change in schedules, rationale for micro-
some of the deficiencies and difficulties reported are slow
biological cure only, nerve involvement not considered in
fall of BI especially in those with high BI of more than or
classification of leprosy, delayed response in some
equal to 3. After the introduction of FDT, leprosy programs
patients as observed in a study from Thailand reporting
were doing away with slit skin smear investigations and
29% of patients being active after three years of follow-
even the clinical status of the patient as the treatment
up.42
was of fixed duration.
Paucibacillary Leprosy NEWER CHEMOTHERAPEUTIC AGENTS

A study by Boerrigter et al reported new or worsening of IN LEPROSY 48
disabilities in 2.5 % patients in a total of 499 paucibacillary The most crucial aspects in chemotherapeutics of leprosy
leprosy patients followed up over four years after MDT in
are the effective usage of new drugs to develop an ideal
Malawi.41 Another study from Thailand also reported
combination and ascertain the optimal duration of
worsening of nerve function impairment in 8 to 13% of
treatment. The reasons for efforts at development of newer
multibacillary and in 4 to 7%.42 of paucibacillary patients.
drugs and regimens are:
The development of new or worsening of disabilities is not
1. From the operational point of view the recommended
due to MDT as it is possibly triggered due to antigen related
duration of treatment (particularly for MB leprosy) is
nerve damage following neuritis (acute or chronic; with or
still too long.
without reaction). Therefore, early detection of NFI is the
key for timely institution of steroids, to prevent disability 2. Two of the components of currently administered drugs
development. for MB leprosy, i.e. dapsone and clofazimine are only
weakly bactericidal against M leprae. Hence, further
Drug Safety with MDT shortening the duration of treatment by this regimen
Drug safety has not been a major problem with MDT. In might result in higher relapse rate.
one large study from Tamil Nadu involving 10,426 patients 3. Administration of the daily components, dapsone and
with MB disease and 35,013 with PB disease, only clofazimine cannot be supervised.
17 patients had hepatitis, 3 had renal failure and 4 had 4. Patients who cannot tolerate any of the drugs in MDT-
cutaneous hypersensitivity reactions.43 Toxic reactions to MB need safer and effective alternatives.
rifampicin such as renal failure or thrombocytopenia are How the concepts on duration of treatment for MB and
rare. It has been reported that delayed type hypersensitivity PB leprosy have changed over the years is portrayed
reactions to dapsone are more common among patients (Table 28.1). It will be interesting to know that keeping
receiving MDT.44 In one program with 98,000 patients (PB antibacterial activity alone in mind; it is possible to reduce
and MB), there were 24 cases of adverse effects like the period of treatment in a drastic manner. How rational it
hepatitis, renal failures and hypersensitivity reactions is, to form impressions by attributing clinical improvement
observed over a period of 5 years. or deterioration, to the duration of administration of any
The commonest adverse effects reported were: antileprosy drug, is likely to be cleared when the long-term
1. Pigmentation with clofazimine. results of the regimens are available. Chemotherapy
2. Gastrointestinal side effects in (8.5%) with daily dose coupled with immunotherapy (the research on which is
of rifampicin and hepatitis in (0.8%) and allergic reaction still in its infancy) may alone be the answer for those who
in (0.2%) patients with monthly dose therapy.45 are eager to achieve the maximum clinical benefits with
In practice however, toxicity and side effects due to the shortest period of drug administration. MDT is very
MDT are not a major problem and one needs to ensure effective in the prevention and treatment of drug resistance
good patient compliance for early detection of any in leprosy, but it has not been possible to reduce the
problem.46 It has been reported recently that dapsone duration of treatment substantially in paucibacillary leprosy,
hypersensitivity syndrome (DHS) occurs in approximately though the duration in multibacillary leprosy has come down
2% of the patients in Nepal.47 considerably. To overcome this, several potent drugs that
CHAPTER
28
Table 28.1: Evolution of treatment regimens in leprosy
S. No Regimen Disease type Year of launch Duration
1. DDS monotherapy MB 1960s to 1980 Lifelong (continuous)
2. WHO-MDT (21 days intensive therapy, MB 1981 24 months or till skin smear negativity
subsequently reduced to 14 days)
3. WHO-MDT (Modified by IAL and NLEP) MB 1983 24 months or till skin smear negativity
4. WHO-MDT (FDT-24) MB 1994 24 months (daily)
5. WHO-MDT (FDT-12) MB 1997 12 months (daily)
6. WHO-MDT (FDT-6) PB 1981 6 months (daily)
7. ROM-12 MB 1995 12 months (monthly)
8. ROM-6 PB 1995 6 months (monthly)
9. RO PB/MB 1992 28 days (daily)
10. ROM-1 SSLPB 1997 1 day (single dose)
11. PMMX-1 MB 2000 1 day (single dose)
R—Rifampicin, O—Ofloxacin, M—Minocyline, P—Rifapentine, MX—Moxifloxacin
No. 1 – 4: Not in vogue; No.5 and 6: Universally recommended by WHO; No.7, 8, 9 and 11: Trials in progress; No.10: In vogue for sometime,
now given up.
can be administered in combination with rifampicin to 1651 MB smear positive patients (BI ≥ 2+) were recruited
achieve a better cure, have been tested. and equally divided into four different groups, viz. (1) MDT
The following are the various classes of drugs: –12 doses (2) MDT–12 doses + ofloxacin for 28 days
1. Fluoroquinolones:49 Ofloxacin, Pefloxacin, (3) rifampicin + ofloxacin (RO) for 28 days and (4) MDT –
Sparfloxacin, Temafloxacin, Moxifloxacin and 24 doses. Review of the results after 5 years showed that
Sitafloxacin. the BI fall in all the groups was comparable and no relapses
2. Tetracyclines: Minocycline. were encountered in group I, group II and group IV.
3. Macrolides: Clarithromycin. Similarly, 1815 PB leprosy patients were treated with RO
4. Ansamycins: Rifabutin, Rifapentine, R-76-1. for 28 days that need to be observed.51,52
5. Dihydrofolate reductase Inhibitors: Brodimoprim and A recent report by WHO shows that in Brazil there were
K-130. 19 relapses after five years of follow-up in the group treated
6. Fusidic Acid. with RO for one month indicating a high relapse rate of
7. Beta lactam antibiotics. 38.8%.53 This group was one of the comparative arms
with 12 months, 24 months MDT regimen and 12 months
SHORT COURSE CHEMOTHERAPY plus ofloxacin regimen which was a double blind control
IN LEPROSY study as referred to above.
In an “open trial” conducted by BLP, 56 MB smear
The recommendations of WHO 7th Expert Committee
positive patients were administered 28 days RO on the
(1997) regarding shortening of MB MDT to 12 doses were
basis of WHO protocol. During the follow-up period lasting
accepted by Government of India after scrutiny by an
for six years, BI fall in RO group was compared with BI fall
Indian Expert Group and implemented all over the country
in 24 doses (214 patients) and 12 doses (190 patients)
which helped to overcome logistic problems and save
WHO MB-MDT groups. In all the groups, the falls in BI
manpower.50
were comparable.51 The first case of relapse in multibaci-
llary leprosy following short course chemotherapy for 28
Recommendations for Research Trials
days was reported by Ganapati et al after seven years.54
RO trials (Continuous Treatment for 28 days) On follow-up of all patients, it was observed that RO
Trials were undertaken to reduce the duration of treatment group was associated with relatively far more risk of relapse
to 28 days in MB and PB leprosy with a combination of than expected however, the relapse rates were comparable
rifampicin (R) and ofloxacin (O). Double blind multicentric to those encountered in other mycobacterial diseases like
trials co-coordinated by WHO, was undertaken in which tuberculosis.55
CHAPTER
28
ROM Single Dose Regimen and 10 MB patients developed reaction (type1 and type 2)
A multicentric randomized, double blind controlled clinical during the first six months of treatment. Short-term
trial by WHO to compare the efficacy of ROM with that of observations showed BI decline and clinical regression in
the WHO PB-MDT in 1483 patients with one skin lesion a similar manner as seen with WHO MDT (PB and MB).
and no peripheral nerve trunk involvement was conducted Long-term results of intermittent therapy for PB and MB
in India. At 18 months follow-up of 1381 patients who leprosy are awaited in order to compare results with
completed the study, marked improvement was observed FDT-24, FDT-12 and FDT-6.
in 51.8% in ROM as against 57.3% in WHO group while
ROM Single Dose and WHO MDT PB (2-3 Lesions)
complete cure was observed in 46.9% of the ROM group
as against 54.7% in WHO PB-MDT. Six treatment failures In a multicentric double blind controlled clinical trial to
in each group were observed.56 No further observations compare efficacy of ROM administered as a single dose
were reported as ROM for single skin lesion leprosy was with that of standard WHO PB-MDT in a total of 236 smear
withdrawn from the program for operational reasons. negative untreated cases with two or three skin lesions
In another study, long-term follow-up of ROM treatment without nerve trunk involvement were enrolled. Clinical
was done for 310 SSL PB cases treated in Bangladesh improvement was seen in most patients in both regimens.
from 1998-2000 of whom 87% were retrieved having an Marked improvement at 18 months of follow-up was seen
average follow-up 6.3 years. Of these, 76% of patients in 46.2% and 53.4% of patients in ROM and standard WHO
had complete clearance of lesion and in 10 cases (3.6%) regimens, respectively.60
evidence of relapse (PB) was seen. None of them had But significant difference was noticed in favor of WHO
nerve function impairment. Possibility of higher rates of MDT-PB regimen in patients with 3 lesions and in patients
relapse in patients who receive ROM for single lesion with more than one body part affected. Reversal reactions
leprosy should be kept in mind.57 and adverse drug reactions were minimal in both the groups.
In another longitudinal study of 51 paucibacillary patients
ROM Trial (Intermittent Therapy) to compare efficacy of ROM administered as a single dose
WHO later initiated further clinical trials with intermittent with that of standard WHO PB-MDT and followed up for
drug regimens consisting of a combination of rifampicin 2 years showed good clinical and histopathological
(600 mg) + ofloxacin (400 mg) + and minocycline (100 improvement which was similar in both groups. It was
mg) (ROM) in both MB and PB leprosy. The supervised concluded in this study that the operational convenience
dose was given once a month without any treatment in and drug compliance with ROM could make it an acceptable
between. Short-term objective of such intermittent therapy regimen when the disease is localized to 2 or 3 skin
(for both MB and PB leprosy) was to study besides clinical lesions.61
response, any side effects and reactions (ENL and reversal) In another study, 93 PB leprosy patients with 2-3 skin
which might occur during and after the completion of lesions treated with a single dose of ROM showed good
treatment. The other objective was to make the chemo- clinical regression of which 5 (5.3%) patients developed
therapy of leprosy simpler and operationally feasible for reaction.62
mass programs; particularly in all difficult situations and A long-term follow-up study of patients treated with
to ensure better treatment compliance. single dose ROM in single skin lesion; and in those with
1500 MB patients and 1800 PB patients were enrolled 2-5 lesions, showed no correlation in the pattern of clinical
in a multicentric study in three countries, viz. Guinea, problems and the chemotherapy used in the two groups.63
Myanmar and Senegal. MB patients were given intermittent In the same study it was found that most of the clinical
therapy of 12 or 24 doses of ROM once a month. PB events including reaction were manageable.64 In the same
patients were given intermittent therapy of 3 or 6 doses of study the observations on the field implications showed
ROM once a month. The long-term results are awaited.51,58 that the relapses and treatment failures in both, the single
In 1995, a field trial was implemented in Senegal in skin lesion leprosy and those with 2-5 lesions, were not in
order to evaluate the efficacy of ROM intermittent therapy alarming proportions and could be well managed by field
in 102 PB and 118 MB patients.59 During the first year of workers.65
trial, none of the patients showed any side effects to these Similar trials were undertaken in Bombay by BLP where
drugs and patients tolerated the drugs well. Eleven PB 230 PB patients with 2-3 skin lesions and 43 patients having
CHAPTER
28
more than 10 lesions (smear negative) were treated with Moxifloxacin-based Regimens
3 and 6 doses of ROM, respectively. All the patients The flouroquinolone moxifloxacin has been shown to be
showed clinical improvement. Some of the patients (6.5%) the most powerful bactericidal agent against M. leprae. It
experienced leprosy reactions in both the groups.66 is a synthetic broad spectrum 8-methoxyfluoroquinolone
However, ROM therapy as single dose for single skin antibacterial agent. The bactericidal action of moxifloxacin
lesion and 2-3 lesions was withdrawn by WHO and NLEP results from inhibition of the DNA gyrase, required for the
from the program for operational reasons. bacterial DNA replication and is reported to have strong
Uniform MDT (U–MDT)53 bactericidal activity as shown in Table 28.2.
In this uniform MDT research project the patients are Table 28.2: Comparative bactericidal activity
provided six months MDT for all types of leprosy (both PB of various anti-leprosy drugs
and MB) and they are assessed for treatment response in Class Drug Bactericidal Bactericidal
term of relapse rates. This ongoing clinical trial has been activity in mice activity in human
launched with support from Special Program for Research
Fluoroquinolone Pefloxacin ++ ++
and Training in Tropical Diseases, in collaboration with Ofloxacin ++ ++
Global leprosy Program (GLP), for comparative evaluation Moxifloxacin +++ +++
of U-MDT with conventional WHO MDT regimens for MB Macrolide Clarithromycin ++ ++
Tetracycline Minocycline ++ ++
and PB leprosy. So far 3396 patients (2094 PB and 1302
Rifamycin Rifapentine +++ Not done
MB) have been included. An interim analysis available, as
of end of December 2008, showed that there have been 6
A combination of moxifloxacin with rifapentine and
relapse cases (4 among MB).
minocycline was recommended for human trials by Ji and
Another comparative study of U-MDT with a smaller
Grosset in 2000.29 However, no results of clinical trials
group of subjects was undertaken in South India, for using this combination are available at present. In a clinical
comparative evaluation of 6 months duration of U-MDT trial by Eleanor and Pardillo et al in 2008 moxifloxacin
with the existing WHO PB and MB regimen. Based on alone was proved to be highly effective in a group of 8 MB
clinical and histological parameters, 64 patients (32 PB patients.69
and 32 MB) available for follow-up (out of 127 inducted in Similar preliminary observations on 54 patients in an
the study) over a period of 24 months. The investigators open trial have recently been reported from Mumbai.70 The
concluded that U-MDT for 6 months was well tolerated schedule followed in this study was a combination
and appeared to exert a marginal beneficial effect in PB (Rifampicin 600 mg + Moxifloxacin 400 mg + Minocycline
leprosy, but was too short a regimen to adequately treat 200 mg) once in a month for 12 months in smear positive
MB leprosy.67 MB patients; and for 6 months in smear negative patients
(Figs 28.4 to 28.6). The highlights of the results are:
Accompanied MDT (A-MDT) 68
1. Remarkable clinical regression observed within 2-3
Accompanied MDT (A-MDT) was recommended by WHO months in all cases.
to address frequent problems in the field program by 2. No side effects seen with the drugs.
providing certain patients with a full course of treatment 3. Mild ENL was noticed in one patient and type 1 reaction
on their first visit to the leprosy clinics after diagnosis. in another patient.
WHO recommends, that A-MDT is user friendly, suitable These results are preliminary and long-term obser-
for mobile population, patients living in remote areas and vations are important to draw any conclusions.
in areas of civil strife. Though MDT coverage is reported
as 100% by all countries; there are still some underserved Other Regimens for Special Situations (WHO) 21
populations such as those living in hard to reach border Some special regimens are required for individual patients
areas, in urban slums or migrant labor. As an innovative who cannot benefit from rifampicin because of allergy or
approach to ensure that such underserved groups have inter current diseases such as chronic hepatitis, or who
access to MDT and other services, A-MDT is have been shown to be infected with rifampicin-resistant
recommended by WHO. M. leprae. Patients who refuse to accept clofazimine
For obvious reasons, both the field workers and experts because of the coloration it causes also require a safe
are not very enthusiastic about its implementation. and effective alternative.
CHAPTER
28
Initial 7 doses 9 doses

Fig. 28.4: Regression of lesions in a case of LL leprosy (BI 4.7+) after monthly regimen comprising rifampicin 600 mg,
moxifloxacin 400 mg and minocycline 200 mg
A B
Initial 6 doses
Figs 28.5A and B: Clearance of PB patch in a smear negative patient following 6 months treatment with monthly regimen
comprising rifampicin, moxifloxacin and minocycline
CHAPTER
28
A B
Initial 4 doses
Figs 28.6A and B: Regression of lesions in a MB patient (BI 3.7+) after 4 doses of same regimen as in Figs 28.3 and 28.4
For patients who do not accept clofazimine, while the 100 mg of minocycline or 400 mg ofloxacin) for at least
1993, WHO Study Group recommended using ofloxacin additional 18 months.
400 mg daily, or minocycline 100 mg daily as substitutes
Severe dapsone toxicity26
for clofazimine, the committee also suggested that they
If dapsone has any severe toxic effects in any pauci-
could also be treated by monthly administration of ROM
bacillary or multibacillary patients the drug should be
for 24 months. Patients harboring rifampicin-resistant M.
stopped immediately. No further modification is required
leprae are very often also resistant to dapsone and their
for patients with multibacillary leprosy. However, clofazi-
treatment depends almost entirely on clofazimine. Because
mine may be substituted for dapsone for a period of 6
daily treatment with the combination of ofloxacin plus
months in the dose employed in WHO MDT regimen for
minocycline shows promising bactericidal activity against
paucibacillary disease.
M. leprae in mice and in patients, multibacillary patients
who cannot benefit from rifampicin may be treated on a
daily basis with clofazimine in combination with ofloxacin CONCLUSION
and minocycline. It is remarkable that chemotherapy of leprosy has come a
WHO recommended the following regimen (for adults): long way and has shown a great promise and hope in the
management of leprosy. The evolution of WHO MDT
PB cases: Daily administration of (50 mg clofazimine + treatment regimens has undergone a sea change due to
400 mg of ofloxacin + 100 mg of minocycline or 500 mg of consistent research and painstaking follow-up, which is
clarithromycin) for 6 months, necessary in a chronic disease like leprosy to draw
MB case: Daily administration of any two drugs practical conclusions to understand the efficacy of several
(minocycline -100 mg, ofloxacin -400 mg, clarithromycin- drugs. In the absence of any kind of vaccine or immuno-
500 mg) along with clofazimine-50 mg daily for 6 months therapeutic agent, WHO MDT is still the main tool and the
followed by daily administration of (50 mg of clofazimine + strategy for the control of the disease.
CHAPTER
28
Newer drugs and the regimens hold a great promise 14. Jacobson RR, Gatt P. Can leprosy be eradicated with
chemotherapy? An evaluation of the Malta Leprosy Eradication
but have to be observed carefully for their long-term efficacy.
Project. Lepr Rev 2008; 79:410-15.
Further research is required into an important area to find 15. Subcommittee on Clinical trials of the Chemotherapy of Leprosy
a new drug or combination of drugs capable of eradicating (THELEP) Scientific Working Group of the UNDP/World Bank/
persisting organisms and eliminating the M. leprae derived WHO special Programme for Research and Training in Tropical
antigens causing adverse reactions and nerve damage. Diseases, Persisting M leprae among THELEP trial patients in
Bamako and Chingleput. Lepr Rev 1987; 58: 325-37.
16. Levy L, Shepherd CC, Faisal P. Death of M leprae following
ACKNOWLEDGMENTS treatment of leprosy patients with 1500 mg rifampicin in a single
dose. Int J Lepr; 1973; 41: 489-90.
The authors gratefully acknowledge the assistance provided 17. Faisal P, Shepherd CC, Levy L. Death of M leprae during treatment
by Mr Rahul Gupta and Mr Sanjay Kulkarni and all other of leprosy patients with 600 mg rifampicin daily. Int J Lepr; 1973;
clinical and secretarial staff of Mumbai Leprosy Project. 41: 489-90.
18. Marchoux Chemotherapy Study Group. Relapses in
The authors are also immensely thankful to the patients multibacillary leprosy patients after stopping treatment with
who helpfully participated in the various studies undertaken rifampicin containing combined regimens. Int J Lepr 1992; 60:
in last 30 years which helped to understand many facets 525-35.
of the disease. 19. Ellard G. The chemotherapy of leprosy. Part 2; Editorial; Int J
Lepr 1991; 59: 82-94.
20. WHO Study Group. Chemotherapy of Leprosy for Control
REFERENCES Programs, Geneva: World Health Organization; 1982; Technical
Report Series; 675.
1. WHO regional strategy for sustaining leprosy services and 21. WHO Expert Committee of Leprosy, Seventh Report; WHO 1998;
further reducing the burden of Leprosy 2006-2010. Indian J Technical Report Series; 874.
Lepr 2006; 78: 33-47. 22. Ganapati R, Revankar CR, Pai VV. History of MDT in India - Role
2. Dharmendra. Sulphone therapy General considerations. In: of Mumbai Leprosy Project. NLO Bulletin; April-June 2002;1-6.
Dharmendra (Ed). Leprosy, Vol 1, Samant D R, Mumbai 1985; 23. Naik SS, Shere SS, Ganapati R. Thirteen years of follow-up of
359-412. 100 smear positive leprosy cases after completion of multidrug
3. Lowe J, Smith M. The Chemotherapy of Leprosy in Nigeria. Int J therapy. Indian J Lepr 1995; 67: 483-84.
Lepr 1949 ;17:181-95. 24. Ganapati R, Revankar CR, Pai VV. Three year assessment of
4. Brown SG, Hogerzeil LM. “B 663” in the treatment of leprosy, multidrug therapy in multibacillary leprosy cases. Indian J Lepr
Preliminary Report of a Pilot trial. Lepr Rev 1962; 33:6-10. 1987; 59: 44-49.
5. Rees RJW, Pearson JMH, Waters MFR. Experimental and clinical 25. WHO Study Group. Chemotherapy of Leprosy. 1994; Technical
studies on rifampicin in treatment of leprosy. Br Med J 1970; 1: Report Series 847.
89-92. 26. Becx Bleumink M. Experience with WHO recommended
6. Leiker DL, Kamp H. First results of treatment of leprosy with multidrug therapy for multibacillary leprosy patients in the leprosy
rifadin. Lepr Rev 1970; 41:25-30. control program of the All Africa Leprosy and Rehabilitation
7. Languillon J, Yawalkar SJ, McDougall AC. Therapeutic effects of Training Centre (ALERT) in Ethiopia, appraisal of the recommen-
adding Rimactane 450 mg daily or 1200 mg once monthly in a ded duration of MDT for MB patients. Int J Lepr 1991; 59: 558-
single dose to dapsone 50 mg daily in patients with lepromatous 68.
leprosy. Int J Lepr 1979; 47: 37-43. 27. Proceedings of Annual Meeting of State Leprosy Officers, Delhi,
8. Yawalkar SJ, McDougall AC, Languillon J et al. Once monthly Leprosy Division, DGHS, Ministry of Health and Family Welfare,
rifampicin plus daily dapsone in initial treatment of lepromatous Nirman Bhavan, New Delhi 29-30th Dec 1995; 32.
leprosy. Lancet 1982; 1199-1202. 28. Ganapati R, Pai VV, Rao R. Leprosy: Control and Rehabilitation,
9. Ellard G. The Chemotherapy of Leprosy. Part 1, Editorial, Int J In: RG Valia, Amit Valia editors. IADVL Textbook of Dermatology,
Lepr 1990;58: 704-16. 3rd Edition, Vol 2, Bhalani Publishing House, Mumbai 2008; 2139-
10. Petit JHS, Rees RJW. Sulphone resistance in leprosy. An 54.
experimental and clinical study. Lancet(2)1964; 673-74. 29. Bohong Ji, Grosset J. Combination of Rifapentine–Moxifloxacin–
11. Shepard CC. Combinations of drugs against Mycobacterium Minocycline for the treatment of leprosy, Asian Leprosy
leprae studied in Mice. Int J Lepr 1972; 40:33-39. Congress, Agra, 2000.
12. Waters MFR, Rees RJW, McDougall AC et al. Ten years of 30. WHO Action Programme for elimination of leprosy. Shortening
Dapsone in Lepromatous Leprosy: Clinical, Bacteriological and duration of treatment of multibacillary leprosy. Weekly
histological assessment and the finding of viable leprosy bacilli. Epidemiological Record 1997; 72:125-28.
Lepr Rev 1974; 45: 288-98. 31. WHO Expert Committee on Leprosy. Sixth Report 1988,
13. Freerksen E, Rosenfeld M, Bonnici E et al. Combined therapy in Technical Report Series 768.
leprosy, background and findings. Chemotherapy 1978; 24: 32. Ganapati R, Pai VV. Field experience with Multidrug Therapy in
187-201. Leprosy. VNS Prescribers Monthly Guide, 1994.
CHAPTER
28
33. Isaac S, Christian M, Jesudasan K et al. Effectiveness of 53. WHO Report of the Tenth Meeting of the WHO Technical
multidrug therapy in multibacillary leprosy: A Long-term follow- Advisory Group on Leprosy Control, New Delhi, India, 23rd April
up of 34 multibacillary leprosy patients treated with 2009.
multidrug regimens till skin smear negativity. Lepr Rev 2003; 54. Ganapati R, Pai V V, Revankar CR et al. Relapse of Multibacillary
74: 141-47. leprosy after Rifampicin and Ofloxacin for 28 days; a case report.
34. PKB Patnaik. Recommendations of Seminar on “Cure of Int J Lepr 1998; 66: 56-58.
Leprosy” 14th Feb 2009, Konark, Orissa. 55. Ganapati R, Pai VV, Revankar C R et al. A Decade of experience
35. Jamet P, Ji Baohong. Marchoux Chemotherapy Study Group. with Ofloxacin in leprosy – An update, Abstracts, Dermacon 2003,
Relapse after long-term follow-up of multibacillary patients treated 31st National Conference of IADVL; Kolkata; 2003; 145.
by WHO Multidrug regimen. Int J Lepr 1995; 63: 195-201. 56. WHO Single Lesion Multicenter Trial Group. Efficacy of Single
36. Annual Report: Mumbai Leprosy Project, 2008. dose multidrug therapy for the treatment of single lesion
37. Shetty VP, Suchitra K, Uplekar MW et al. Persistence of M. leprae Paucibacillary leprosy. Indian J Lepr 1997; 69:121-29.
in the peripheral nerve as compared to the skin of multidrug 57. Alam K, Butlin CR, Pahan D et al. Long-term follow-up of ROM
treated leprosy patients. Lepr Rev 1992; 63: 329-36. treated cases. Lepr Rev 2007; 78: 160.
38. Pai VV. Chemotherapy of leprosy–Further challenges. Health 58. Pannikar VK. Milestones towards the Elimination of Leprosy. Int
Administrator, 2006; XVII: 72-76. J Lepr 1996; 64: S11-12.
39. Revankar CR, Karjivkar VG, Gurav VJ et al. Clinical assessment 59. Mane I, Cartel JL, Grosset JH. Field trial on efficacy of supervised
of paucibacillary leprosy under multidrug therapy—a three year monthly dose of 600 mg rifampicin, 400 mg ofloxacin and 100
follow-up study. Indian J Lepr 1989; 61: 355-59. mg minocycline for the treatment of Leprosy; First Results. Int J
40. Boerrigter G, Ponnighaus J, Fine P. Preliminary Appraisal of a Lepr 1997; 65: 224-29.
WHO recommended Multidrug Regimen in Paucibacillary leprosy 60. WHO Single Lesion Multicenter Trial Group. A comparative Trial
of Single dose Chemotherapy in Paucibacillary leprosy patients
patients in Malawi. Int J Lepr 1988; 56: 408-17.
with two to three skin lesions. Indian J Lepr 2001; 13: 131-43.
41. Boerrigter G, Ponnighaus J, Fine PM et al. Four year follow-up
61. Emmanuel M, Gupte MD. Lesional characteristics and
results of a WHO recommended Multidrug Regimen in
histopathology in Paucibacillary leprosy patients with 2 or 3 skin
Paucibacillary Leprosy patients in Malawi. Int J Lepr 1991; 59:
lesions, Comparison between ROM and PB-MDT regimens.
255-61.
Indian J Lepr 2005; 77: 19-25.
42. Dasanjali K, Schreuder P, Pirayavaraporn C. A Study on the
62. Pai VV, Revankar CR, Chavan RG et al. Single dose of rifampicin,
Effectiveness and Safety of the WHO/MDT Regimen in the
ofloxacin and minocycline for PB leprosy patients with 1-3
Northeast of Thailand; a Prospective Study, 1984-1996. Int J
lesions. Abstracts (No. P-25), 20th Biennial Conference of Indian
Lepr 1997; 65: 28-36.
Association of Leprologists, Bhopal,1997.
43. Ekambaram V, Rao MK. Changing picture of leprosy in North
63. Ganapati R, Revankar CR, Pai VV et al. Single dose treatment
Arcot district, Tamil Nadu after MDT. Indian J Lepr 1989; 61:
for paucibacillary leprosy: Feasibility of Long-term follow-up. Int
31-43. J Lepr 1999; 67: 308-09.
44. Richardus JH, Smith TC. Increased incidence in leprosy of 64. Pai VV, Bulchand HO, Revankar CR et al. Single dose treatment
hypersensitivity reactions to dapsone after introduction of for paucibacillary leprosy; Clinical Problems and Management.
multidrug therapy. Lepr Rev 1989; 60: 267-73. Int J Lepr 1999; 67: 310-12.
45. Reeve PA, Ala J, Hall JJ. Modification of multidrug treatment of 65. Revankar CR, Pai VV, Samy A et al. Single Dose Treatment for
leprosy in Vanuatu. Int J Lepr 1992; 60: 655-56. paucibacillary leprosy: Field Implications. Int J Lepr 1999; 67:
46. Gilbody JS. Impact of multidrug therapy on the treatment and 312-14.
control of leprosy. Editorial; Int J Lepr 1991; 59: 458-78. 66. Ganapati R, Pai VV, Chavan RG et al. Reactions after intermittent
47. Sapkota BR, Kancha S, Pandey B et al. A retrospective study of therapy with ROM in PB leprosy–Preliminary observations,
the effect of modified multidrug therapy in Nepali leprosy patients Abstracts (No. O-23), 20th Biennial Conference of Indian
following the development of adverse effects due to dapsone, Association of Leprologists, Bhopal, 1997.
Lepr Rev 2008;79: 425-28. 67. Rao PN, Suneetha S, Pratap DVS. Comparative study of uniform
48. Ganapati R, Pai VV. Newer Chemotherapeutic agents in Leprosy. MDT in Pauci and Multibacillary leprosy patients over 24 months
Indian J Dermatol 1996; 41: 1-4. of observation. Lepr Rev 2009;80:143-55.
49. Girdhar BK. Flouroquinolones and their adverse effects. Indian 68. WHO Regional strategy for sustaining leprosy services and
J Lepr 1993; 65: 69-79. further reducing the burden of Leprosy 2006-2010. Indian J
50. DDGHS (Leprosy), New Delhi. Modified guidelines on MDT Lepr 2006; 78: 33-47.
regimen to be followed under NLEP; Circular No. 19025/6/97 69. Pardillo FEF, Burgos J, Fajardo TT et al. Powerful bactericidal
dated 28-08-1997. activity of Moxifloxacin in human leprosy. Antimicrob Agents
51. WHO Meeting on Chemotherapy Research in Leprosy, Madras. Chemother 2008; 52: 3113-17.
Lepr Rev 1997; 68: 285-87. 70. Ganapati R, Pai VV, Khanolkar SA et al. Clinical Trials with
52. Ganapati R, Pai VV, Shroff HJ et al. Rate of decline in Moxifloxacin-based Regimen in Leprosy – A Preliminary
bacterial index in leprosy; Observations after three different Communication. Revista De Fontilles Leprologica; 2009; 27:
chemotherapeutic interventions. Int J Lepr 1997; 65: 264-66. 49-55.
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29 Recording, Reporting and Monitoring

of MDT and Post-treatment Follow-up
PR Manglani
INTRODUCTION Quarterly and Annual Performance Reports, and Indicators

Constituted SIS.
Leprosy is a chronic, infectious disease caused by Lepra
After achieving leprosy elimination at national level in
bacilli. Control of disease is mainly through ‘Secondary
December 2005, NLEP adopted the monitoring tools as
Prevention’, i.e. chemotherapy. Leprosy Eradication in India
per WHO operational guidelines for the implementation of
is a National Health Program. The ‘National Leprosy
the Global Strategy for further reducing the leprosy burden
Eradication Program’ (NLEP) was initially conceived as a and sustaining leprosy control activities, 2006-2010.
control program (National leprosy Control Program- NLCP) Special emphasis on Disability Prevention and Medical
and launched in 1954-55, the program was subsequently Rehabilitation (DPMR) in the 11th-Five-year plan, calls for
changed to NLEP in 1983. From the beginning, the program some additional information required.
was run through a vertical set up of specially trained staff; Monitoring can be defined as periodic collection and
and monitoring was an inbuilt component of the program. analysis of selected indicators. It is a process of measuring,
NLEP services are now integrated with ‘General Health recording, collecting and analysing data on actual
Care’ (GHC). Multi-drug Therapy (MDT) services are being implementation of the program and communicating it to
provided by general health care staff through PHC system. the Program Managers, so that any deviation from the
Health information is an integral part of any health planned operations is detected, investigation for causes
program. It is a mechanism for the collection, processing, of deviation is carried out and suitable corrective actions
analysis and transmission of information required for are taken. Implementation of planned activities, quality of
organizing and operating health services and also for services and impact of services can be assessed and
research and training. A WHO expert committee identified ensured through monitoring.
the following requirements to be satisfied by the health Data is the term used to describe basic facts and
information system which should: figures/statistics about activities of a project, which can
1. Be population based. be processed to produce information. Information is
2. Avoid the unnecessary agglomeration of data. obtained by assembling items of data into a meaningful
3. Be problem-oriented. form. Information is nothing but processed data. Processing
4. Employ functional and operational terms. is manipulation of facts, figures and statistics (data). The
5. Express information briefly and imaginatively. operation involved in the processing are—calculation,
6. Make provisions for the feedback of data. comparison, logic and decision taken.
After the integration of leprosy services into general Key Epidemiological Questions
health care, NLEP information system was simplified in What are the problems? Who is affected? How many are
2002 to suit to GHC system. ‘Simplified Information affected?
System’ (SIS) contained minimum data collection essential When did it take place? Where did it occur? Why did it
for monitoring the program. Case-card, Treatment Register, happen?
Drug Stock Register, Monthly Progress Report (MPR), How can we manage it? Which approaches are best?
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Recording, Reporting and Monitoring of MDT and Post-treatment Follow-up 369
Indicators The number of new cases indicates how much leprosy
Indicators show to what extent the targets are reached. burden there is in an area. This shows how much MDT
Types of indicators are: should be supplied to that area during the following year.
1. Input (resources) Given consistent procedures for case detection, figures
2. Process (transforming) for a period of several years will show whether there is an
3. Output 1: coverage increase or decrease in numbers, which may indicate
4. Output 2: quality whether activities aimed at controlling the disease are
5. Impact (health status) effective. If the population of the area is known, it is possible
to calculate the case detection rate (the number of new
Strengthening Evidence-based Decision-making cases per 100,000 people) which can be compared with
other areas.
1. From data to information
The proportion of new patients who complete their
2. From information to evidence
treatment on time is an indication of how well the leprosy
3. From evidence to decision-making
patients are being served by the health services. The
From Data to Information information required to calculate this indicator can be
Describe: collected either through the routine reporting system from
1. Ask key questions all health facilities or from a representative sample of health
2. Use at-risk populations and target populations facilities as part of supervision. The rate is calculated
3. From absolute to relative data (%, rates) separately for PB and MB patients, in what is known as a
4. Use defined indicators. ‘cohort analysis’. A cohort is simply a group of patients
who all started treatment in the same batch, usually in the
Analyze:
same year.
1. Use common sense
2. Compare indicators in time, place and with target The calculation of the completion rate is as follows:
3. Identify high-risk populations. 1. The report date will normally be at the beginning of a
new reporting year and the annual report will refer to
From Information to Evidence the year just completed (Year Y). For completion
Interpretation of data: statistics, the PB cohort will be from year Y-1; the MB
1. Relevance cohort will be from year Y-2.
2. Consistency 2. Identify all the PB patients who are new cases in the
3. Context. register and who started MDT in year Y-1. Note this
number.
From Evidence to Decision-making
3. From this cohort, count the number who completed
Using the information: treatment within 9 months of registration.
1. User perspective—Answer their information needs 4. The PB treatment completion rate is calculated as
2. Effective presentation—Use attractive presentation follows:
methods
3. Advocacy skills—Do social marketing, negotiating skills Number of new PB cases who completed MDT
 100
to convince decision makers Number of new PB cases who started MDT
5. Identify all the MB patients who are new cases in the

INDICATORS FOR MONITORING register and who started MDT in year Y-2. Note this
NLEP FUNCTIONS number.
Main Indicators 6. From this cohort, count the number who completed
treatment within 18 months of registration.
• The number of new cases detected in a given area 7. The MB treatment completion rate is calculated as
each year. follows:
• The proportion of patients who complete their treatment
on time as a proxy for cure rate. Number of new MB cases who completed MDT
 100
• Registered prevalence. Number of new MB cases who started MDT
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8. Note that each cohort includes all new cases that the ratio is higher, steps should be taken to ensure that
started treatment during the year, including any who women have adequate access to diagnostic services.
became defaulters or who died before completing
treatment. THE INDICATORS FOR PATIENT
For example, the report for the year Y= 2010, will include MANAGEMENT AND FOLLOW-UP
completion statistics for PB cases registered in 2009 (Year
The following indicators for quality of care and patient
Y-1) and for MB cases registered in 2008 (Year Y-2).
management may be collected, usually on a representative
sample basis, as part of an integrated supervision process.
ADDITIONAL INDICATORS FOR CASE
DETECTION The Proportion of New Cases
The following additional indicators for case detection may Correctly Diagnosed
be used. The information used to calculate these indicators The accuracy of diagnosis should be assessed through
is collected routinely. regular technical supervision. If there is any suggestion of
significant over-diagnosis, a sample of new cases should
Proportion of New Cases Presenting be reviewed within three months of the diagnosis being
with Grade 2 Disability made. The proportion of new cases included in the review
Because disability and deformity occur late in the disease, would depend on the total number of cases and the
the proportion of new cases with disability gives a rough resources available (staff and funds) for the review. This
would identify problem areas where additional training and
indication of how early, on average, leprosy cases are
supervision are needed, but would not impede treatment
coming forward for diagnosis. Recently, WHO has
at all.
introduced a new indicator giving rates of new cases with
grade-2 disability per 100,000 population per year. It is
The Proportion of Treatment Defaulters
given and indication on detection due to various reasons.
This only requires examination if the completion rate is
Proportion of Child Cases (Under 15 Years low. The proportions of patients who default and who are
of Age) Among New Cases transferred out are calculated in exactly the same way as
the cure rate. If transfer out is the main reason for non-
If the transmission of leprosy is being reduced in an area,
completion of treatment, the situation needs to be
it is expected that the proportion of children affected will
investigated to find out whether the transferred patients
decrease. Monitoring this indicator over several years, may are really continuing treatment at a new clinic, or whether
show a trend. It is also required for correctly replenishing in fact they just stop taking treatment.
the stock of child doses for MDT.
The Number of Relapses Reported
Proportion of Multibacillary Cases during the Year
Among New Cases
Relapse cases occur sporadically and are generally not
The proportion of Multibacillary (MB) cases is a useful part of any defined cohort, so these figures are difficult to
guide to the proportion of cases at risk of complications analyze. If high numbers are reported from any particular
and is needed for replenishing the stock of MDT correctly. area, further investigations must be carried out.
Proportion of Female Patients Among The Proportion of Patients who Develop New
New Cases or Additional Disability during MDT
Many programs diagnose leprosy more frequently in men Possible methods of calculating this indicator are given
than in women, but there is concern that women may have below:
less access to health care in some situations. Thus, a This indicator is a measure of how well new nerve
ratio of 2 males to every 1 female is commonly seen. If damage is detected and treated by the program. There are
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two ways in which information may be gathered in the 2. Data about new leprosy patients is entered into the
clinic in order to calculate this indicator, the eye-hand-foot Leprosy Treatment Register, which is essential for
(EHF) score and the Impairment Summary Form (ISF). planning, the calculation of essential indicators and
Both scoring systems can also be used after completion monitoring.
of treatment to monitor prevention of deformity (POD) Note that clinics with only occasional patients may not
activities. need a Leprosy Treatment Register; the treatment can be
1. The EHF score is calculated from data already being noted on the Patient Record Card. If no printed Record
recorded routinely. It is the sum of all the individual Card is available, a blank sheet of paper may be used.
disability grades for the two eyes, two hands and two However, at least some kind of record is essential for good
feet. Since the disability grade can be scored as either patient care, effective supervision and monitoring.
0, 1 or 2, it follows that the EHF score ranges from 0 to The Leprosy Treatment Register should list every patient
12. A score of 12 would indicate grade 2 disability of receiving MDT at a particular clinic.
both eyes, both hands and both feet. 1. The name of every patient who is started on MDT in
The EHF score has been shown to be more the Leprosy Register.
sensitive to change overtime than the Disability Grade 2. Treatment they are getting (PB or MB) and the dose
itself. The simplest way to use the EHF score to (adult or child).
measure the development of new or additional disability 3. The type of patient (New or Other).
during MDT, is to calculate the score at diagnosis (this 4. The disability grade.
examination is already done in the initial assessment 5. The date of starting treatment.
of Disability Grade) and then repeat the examination at 6. The date of attendance whenever the person comes
the time treatment is completed. The two scores can for MDT and the amount of treatment given (this will
then be compared. When the cure rate is calculated for indicate when the person is expected to attend again)
any cohort, the proportion in which the EHF score The register should record each visit of each patient to
increased can be calculated at the same time – an receive MDT. It should be easy to see from the register
increase in the score would indicate some new or when any patient is overdue for an appointment – in other
additional disability. words, when any patient has runout of MDT at home. Each
2. The Impairment Summary Form (ISF) may be used to month, examine the register, to find out which patients (if
monitor impairments and disabilities in patients, and any) did not attend during the last month to collect their
to calculate the proportion of patients who develop new
MDT. Remember to make a note if more than one month’s
or additional disability during MDT. The ISF contains
treatment has been given. Every effort should be made to
more detail about each individual patient’s impairments
help patients take treatment regularly.
and disabilities, so if used effectively it allows a higher
When a patient collects the last dose of MDT (the sixth
quality of care to be maintained.
dose of PB-MDT, or the twelfth dose of MB-MDT), mark
them as “Treatment Completed” and close their entry in
RECORDS USED IN CLINICS the Treatment Register. Tell them they are cured after
TREATING LEPROSY completion of this last dose and stress the importance of
Information about new leprosy patients is needed for two returning if there are any further complications. The other
reasons: treatment outcomes that may be recorded include:
1. Details about the individual are recorded in the Patient “Transferred out” (= a patient who has started treatment
Record Card/case-card; over the following months and and has been transferred to another reporting unit and for
years, any health worker treating that person will be whom the treatment outcome is not known at the time of
able to read the medical history, which is very important evaluation of the treatment results), “Defaulted” and “Died”
when considering how to manage a new problem. Good (= a patient who died for any reason during the course of
records are essential for quality health care. Good MDT).
records do not have to be very detailed – they may be The cohort analysis is carried out using the Leprosy
quite simple but they should be accurate and neat, in Treatment Register.
order to be useful to other health workers who will read Some countries prefer to keep a Master Register at
them. the district level with all details of patients being treated in
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29
the district (these include, in addition to the personal details, of spatial phenomena. Data flows through a GIS via a
such as name, address, sex, classification, and disability series of system functions. Data can be manipulated in a
status and treatment outcome). Such a register is usually GIS using a series of functional programs called “tools”
maintained by a district supervisor, who compiles the that operate on mapped data. Users can also elect a series
reports from this register. of output options for communicating the results of their
analyses to the users.
Monitor Drug Stock GIS can be used for planning and monitoring the health
At least three months drug stock for each category of services and health status of the community and find the
patient should be maintained at the district whereas at the cause of any discrepancy in the collected information.
health facility level at least one month buffer should be Some of the uses have been enumerated:
available. PHCs with no case in the last three months 1. Design the functions of health care services and
need not keep any stock. administrative services.
1. District leprosy office should estimate the amount of 2. Monitor health status and service need.
drugs of all categories required for the whole year taking 3. Set priorities for the allocation of health care resources.
into consideration the stock in hand (with expiry date) 4. Evaluate health program & health care outcomes, e.g.
and number of new cases expected. He can request changes in health status as a result of intervention on
the stocks for three months but assess the stores every health care program.
month. 5. Identify environmental, socioeconomic and other risk
2. Each health facility will prepare and submit monthly factors, which influence health, under serviced, poor,
progress report (LF 04) to the block level PHC which inaccessible areas and other geographic and
will compile the reports and send the consolidated demographic factors.
report to DLO. 6. Generate “thematic maps” (ranged color maps on
3. The district leprosy officer will compile all the block proportional symbol maps to denote the intensity of a
reports and send a consolidated report (LF 05) to the mapped variable).
SLO. The DLO will also prepare quarterly and annual 7. Allow for overlaying of different pieces of information.
performance assessment report (LF 06 and 07). 8. Create buffer areas around selected features (e.g. a
4. All the activities in the district are carried out under the radius of 10 km around a health center to denote a
guidance of District Health Society. catchments area).
9. Calculate distances between two points.
GEOGRAPHICAL INFORMATION GIS permit dynamic link between databases and maps
SYSTEM so that data updates are automatically reflected on maps
and also permit interactive queries of information contained
Geographical information system (GIS) is a computerized,
within the map, table or graph.
integrated system used for compiling, storing, manipulating
and mapping spatial data.
COMLEP
Conceptually, a GIS can be envisioned as a stacked
set of map layers, where each layer is aligned in relation Computerized information system for leprosy control
to all other layers. Typically, each layer contains a unique program are designed to facilitate monitoring of program
geographic theme or data type. By sharing mutual and individual patient also. Once the primary data related
geography, all layers in the GIS can be combined or overlaid to each patient is fed into computer, processing of these
in any user-specified combination. data becomes easy, quick and correct and report generation
A GIS provides a hybrid database that contains both is without delay and information can be used for decision
spatial and attribute data. Spatial data describe the location making in time. COMLEP software, designed by
of objects with respect to a known coordinate system, Netherlands Leprosy Relief (NLR) has been field tried and
while attribute data describe the nature or characteristics ready for wider use.
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29
Formats for Recording and Reporting

LF-01
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LF-03
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NLEP Monthly Reporting Form PHC / Block PHC Report MLF 04/A [Page 1]
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MLF 04/A [Page 2]
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Form – P IV
Prednisolone Card
(This card should be kept with the patient)
INSTRUCTIONS NATIONAL LEPROSY ERADICATION PROGRAM

• Take prednisolone tablets as single dose daily with milk / food
but never on empty stomach PREDNISOLONE – CARD
• Restrict salt intake till on prednisolone Name of the patient ………………………………………..…………
• Inform soon if you notice black stool (malena), pain upper Reg. No./ MDT No. ………………………
abdomen or vomiting
Type MB/ PB
• Inform immediately if discharge in planter ulcer, any focus of
infection, persisting cough, mild fever or any deterioration Date / Due date of RFT …………………………………………….
• Don’t stop prednisolone before completion of regimen, even if Indication for prednisolone therapy:
there is improvement or deterioration.
Date of starting Prednisolone……………….……………………..
• Report for review/check-up and next dosage, every fortnight.
Signature of MO / Supervisor………………………………………
Prednisdone Record
Other drugs issued ………………………………….……………….

……………………………………………………………..............…..
Progress / Remarks
Signature of
MO……………………………………..……………………..............
Name
………………………………………………………………………….
Place
…………………………………………………………………………..
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Form – P VI
Referral Slip
(to be used by peripheral health worker)
PHC District State
Name of the person to be referred:
Age and Sex:
Address:
Clinical finding:
Reason/indication:
for referring
Referred to:
Referred by:
(designation and place)
Signature and date:
Form – P VII
Referral Slip
(to be used by Medical Officer at PHC)
PHC District State
Name of the person to be referred:
Age and Sex:

Address:
Clinical finding:
Reason/indication:
for referring
Referred to:
Copy marked to district nucleus on: :
Action taken at referral centers:
Instructions for follow-up: :
Referred by:
(designation and place)
Signature and date:

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CHAPTER
30
30
Management of Leprosy Reactions
INTRODUCTION 2. The patients must be counselled, so also their family

members regarding importance of regular and complete
Leprosy Reactions are immunologically mediated episodes
of acute or subacute inflammation affecting the skin, treatment of leprosy.
nerves, mucous membrane and/or other sites which 3. Patients and the family members must be educated to
interrupt the chronic and placid course of leprosy. Unless identify early signs and symptoms of reactions and
promptly and adequately treated, these reactions can result neuritis and asked to report immediately on appearance
in deformity and disability. Occurrence of reactions is one of these.
of the characteristics of leprosy. All leprosy patients, 4. Early signs and symptoms: The early features which
whether with paucibacillary (PB) or multibacillary (MB) can give some clue to the reactions are given in Table
disease, have some risk of developing reaction. 30.1.
5. Defaulters should be retrieved
TYPES OF REACTION 6. Persons at higher risk should be examined frequently,
at least once a month
1. Type 1 Reaction (T1R) or Reversal reaction (RR) 7. Timely initiation of treatment for reaction is essential.
occurring mostly in BT, BB and BL patients.
2. Type 2 Reaction (T2R) or Erythema Nodosum Table 30.1: Early signs and symptoms suggestive of reaction
Leprosum (ENL), occurring in LL and BL patients. • Inflammation of skin (redness, pain, tenderness, swelling) of the
In addition, acute neuritis may develop in isolation or existing lesions
as a part of reactions. Lucio phenomenon is another rare • Sudden appearance of painful nodular swelling (nodules) on the
skin (especially face and thighs)
form of reaction observed only in Lucio leprosy.
• Numbness and tingling sensation in limbs
• Loss of sensation, weakness and paralysis of the muscles of
PREVENTION/EARLY DIAGNOSIS OF limbs
REACTION • Infrequent blinking of the eye.
• Incomplete closure of the eye lids
With the current level of understanding about leprosy • Red painful eyes
• Deterioration of vision
reactions it is neither possible to predict its occurrence in
• Development of painless wounds and ulcer
a patient, nor it is always possible to prevent it altogether. • Dry cracked skin
However, the following steps can be taken to prevent
occurrence of reactions, for early diagnosis and prompt
treatment of reaction (Table 30.1). TYPE 1 REACTION
1. Build capacity of the peripheral or primary level health
care staff to enable them to suspect reaction from its
PRINCIPLES OF MANAGEMENT
early signs and symptoms and refer them to the next
higher health care center for early diagnosis of reaction The Type 1 reaction is associated with sudden alteration
and prompt treatment. of cell-mediated immunity associated with a shift in the
CHAPTER
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Management of Leprosy Reactions 387
patient’s position in the leprosy spectrum. The Type 1 reaction The treatment of Type 1 reaction with varying severity
is usually observed in borderline spectrum of the diseases, and various treatment options are discussed bellow:
rarely in LL leprosy. The reactions may be confined only to
the skin or the nerves only or both may be involved. Even Treatment of Mild RR
when only skin is affected; not all lesions may show acute
Mild reaction can be treated with daily aspirin or
increase in swelling and redness. In some cases there
paracetamol given for few weeks. Reassurance is very
may be sudden appearance of inflamed, new lesions and/
important to the patient as well as to family members.
or new nerve affection with or without impairment of nerve
They should be educated that the development of reaction
function. The management should be on the following line:
is an indicator of bacterial kill, which is associated with
Anti-leprosy Treatment immunological upgradation.
The specific anti-leprosy treatment (MDT) has to be started Treatment of Severe RR and Acute Neuritis
or continued if started early unless there are
contraindications, since this is required for continuous Corticosteroid (prednisolone) is still the cornerstone therapy
killing of M. leprae to reduce the bacterial/antigenic load and considered to be the drug of choice for RR. This
from the skin and nerves. In addition, anti-leprosy drug compound acts by the dual mechanism of reducing the
dapsone in higher dose is known for its immunoinflammatory edema, and inducing immuno-suppression.
suppressive action, so also clofazimine for its anti- However, prednisolone has to be administered in very high
inflammatory action. Clofazimine has been observed to initial doses (1-2 mg/kg/day) and over a longer period of
have a role in the prevention of neuritis in higher doses. time; with slow tapering to produce a significant effect on
cell-mediated immune response. Steroids might also be
Treatment of Reaction able to reduce the chance of recurrence of RR.
There are several reports for justification of prolonged
Specific treatment has to be initiated depending on the
steroid treatment to treat T1R and to prevent its recurrence.
severity of the reaction (mild or severe type). Mild reaction
Thacker et al studied leprosy patients’ electro
is characterized by the presence of inflammation (marked
physiologically during and after reactions. Their patients
erythema, swelling, pain, tenderness) in few of the existing
were treated with prednisolone over a 6-week period.
skin lesions, other wised called as EEL (exaggerated
Although they observed significant improvement during
inflammation of the existing skin lesion). The severe
reaction is characterized by the presence of one or more treatment, but deterioration started after prednisolone was
of the following features. stopped.2 Duration of Type 1 reactions has been studied
• More number of EEL and as well as inflamed new lesions by Li- Huan Ying in a series of 86 patients (18 BT, 6 BB
• Nerve pain, tenderness or paraesthesia or increasing and 62 BL) and they were found to last up to 3 months in
loss of nerve functions 36.0% cases, up to 6 months in 54.6% and up to 12 months
• Fever, discomfort, arthralgia in 93.0% cases.3 Continuing Th1 cytokine (IFN-γ, IL-12,
• Edema of hands and/or feet and ions proteins) activity even 180 days after the start of
• Ulcerative skin lesions prednisolone (standard reducing course of steroids, starting
• Reaction persisting more than 6 weeks. at 30 mg daily) in T1R in some of the patients (3 out of 5
BL patients) at follow-up, also supports the need for
Specific Therapy prolonged treatment with prednisolone.4 Median levels of
IFN-γ and TNF-α levels fall during treatment with steroids;
Specific therapy aims to suppress the harmful delayed
however, TNF-α levels increase as the steroid dose is
type hypersensitivity (DTH) response to M.leprae antigen
reduced. Median IL-10 levels normally remain increased
with anti-inflammatory therapy – either non-steroidal anti-
inflammatory drugs (NSAID) for milder type of RR and through out steroid treatment period. Patients with high
steroids for severe type of RR. cytokine levels have (a) poor recovery of sensory or
The patient may also need a tranquillizer in spite of (or voluntary muscle nerve function, (b) higher risk of
in addition to) reassurance, as mental stress of worrying reactivation of symptoms during steroid treatment, and
about the reaction may itself lead to aggravation of the (c) a higher risk of another episode of T1R within few months
condition. of completing steroid regimen.5 Therefore, monitoring
CHAPTER
30
cytokine levels may be helpful for evaluation of the reaction Standard treatment schedule of Oral Prednisolone for
and the prognosis. management of type1 reaction (under field conditions)
A multicentric, double blind, randomized trial of three Dose Weeks of treatment
steroid regimens in the treatment of Type 1 reactions was
• 40 mg daily 1st and 2nd week
conducted at six centers in India. The prednisolone regimen • 30 mg daily 3rd and 4th week
comprised (a) high dose short duration i.e. 60 mg per day, • 20 mg daily 5th and 6th week
tapered over 12 weeks and 20 weeks in two groups and • 15 mg daily 7th and 8th week
• 10 mg daily 9th and 10th week
(b) low dose long duration regimen i.e. 30 mg per day,
• 05 mg daily 11th and 12th week
tapered over 20 weeks.5 At the end of 12 months, 46% on
the high dose short course regime required additional
steroids, as compared with 31% on the low dose long However, with the above standard steroid dose schedule
duration and 24% on the high dose long duration regimen. of WHO (1998) –the recovery does not seem to be
The two 20-week regimens were significantly better than sustained.6,10 Longer duration of steroid administration
the 12 week regimen. The high dose 20 weeks regimen is results in better recovery which is also longer lasting.10
marginally and non-significantly better than the low dose Steroids need to be given at the earliest and in sufficient
20 weeks regimen. To conclude, reactions in leprosy persist doses, not only to regain the sensory and motor functions
over many months and require to be managed with of the affected nerves, but also to prevent irreversible nerve
prolonged courses of steroids.6 damage. Steroids may be required to be given over several
The mechanisms of action of glucocorticoids have been months together with supportive measures like
explained in terms of genomic and non-genomic pathways, physiotherapy, along with standard MDT. The starting daily
the former involving hormone binding to cytosolic (classic) dose of prednisolone should be around 1 mg/kg body
receptors and subsequent modulation of gene expression weight.5, 11 Steroid should be given once a day in the
followed by protein synthesis. There is the recently morning after breakfast.
introduced (and a bit controversial) concept of non- Standard Dose Schedule at Referral Center
genomic pathways where the glucocorticoid actions are
Starting dose: 1mg/kg body weight –continue till
not mediated through genomic alterations but rather
improvement of skin lesion is visible/nerve tenderness and
through, yet poorly understood, receptors in cellular
pain subsides. Then the dose should be cut by 5 mg every
membranes and cytosol. The recent work on the relative
1-2 weeks. The crucial maintenance dose should be around
genomic and non-genomic potencies of glucocorticoids
15–20 mg for several weeks/months.9 In the follow up
suggests that glucocorticoids with a high ratio of non-
period, the dose should be cut by 5 mg every 2-4 months.
genomic to genomic activity (i.e. predominantly non-
Sensory testing and voluntary muscle testing can guide
genomic pathway actions) may be needed for early, high
the tapering off of prednisolone. Graded sensory testing
level of immunosuppression.7 Methylprednisolone, which
has been shown to be the most sensitive for this
has such a ratio may be a suitable drug for initiating the
purpose.10The duration should be long enough to cover
treatment.8 In addition to its effectiveness against both
the period that the antigen load is able to trigger CMI
skin and nerve manifestations of lepra reactions, it is also
response (BT: 4 to 9 months, BB: 6 to 12 months, BL: 6 to
useful in preventing and reversing the motor and sensory
24 months).
deficits.
Outcome of Timely and Adequate Corticosteroids
Dose and Duration of Prednisolone Administration
• Improvement in inflammation over the skin lesions,
Standard Dose Schedule for Field Purpose
both old and new
(WHO, 1998)
• BT lesions show better response than BB, BL lesions
WHO recommends a standard field regimen of 12 weeks • Improvement in nerve function impairment in 30 to 70%
therapy with prednisolone. The schedule for an adult patient patients, response is better with recent nerve damage,
is as follows9: and more in BT group than in others, especially when
CHAPTER
30
nerves are rested.13 Median nerve shows better the patient may die of adrenal shock unless adequate
response than ulnar nerve. doses of steroid are administered during crisis period.
As a precautionary measure, it is essential to check
Adverse Effects the patient for hypertension, diabetes, infections particularly
It is surprising that the adverse effects with corticosteroids tuberculosis, worm infestations, before the start, and during
during treatment of Type 1 reaction are not many in contrast course, of steroid treatment, as these may get worse with
to those observed while treating ENL with prednisolone. prolonged corticosteroid therapy.
This is particularly relevant in view of steroid dependency
and the associated metabolic problems.13 Treatment of Late RR
The adverse effects associated with prolonged use of Prednisolone with the usual starting dose (1 mg/kg BW
corticosteroid may produce numerous changes of the skin per day) for 4 to 6 weeks during which the lesions either
as well as profound effects on metabolism of many tissues, resolve or show some signs of subsidence evident by
leading to predictable and sometimes preventable decrease in infiltration/erythema. Steroids may be continued
complications. Injectable preparations are not a safer till complete subsidence of the lesions. If reactive skin
delivery method than oral administration. and nerve lesions do not show improvement within
Skin changes include striae, steroid acne, purpura, 3 months of steroid therapy, the case should be considered
ecchymosis, xerosis, persistent erythema of the skin in as relapse presenting in the form of T1R and MDT should
sun exposed area and erythromelanoses. Last three skin be restarted for another course and oral steroids continued
complications can also be observed due to clofazimine along with gradual tapering dose till complete subsidence
which is a component of MDT in multibacillary leprosy. of reactional features in the lesions.14
However, the most common change is Cushingoid features
due to the alteration in fat distribution like buffalo hump, Additional Measures for Neuritis/Nerve Function
facial fullness (moon face), increased supraclavicular and Impairment (NFI)
suprasternal fat, protuberant or pendulous abdomen, and In acute phase the inflamed nerves must be kept in resting
flattening of buttocks and gynecomastia (it can also occur position. Appropriate splinting and padding gives relief to
per se in LL, as a result of orchitis). In addition, there is these patients. When the acute phase is over, passive
hair loss, thinning of hair and brittle fracturing along hair and active exercises should be initiated. Oil massage and
shaft. There may be hair growth on the beard area, on the other electrical stimulations like short wave diathermy
arms and back, and coarsening of fine vellus hair, (SWD) or ultrasonic therapy (UST) help in restoring the
especially in women. motor function and preventing disability. Additional NSAIDs
Common systemic complications include gastro- may help in relieving pain.
intestinal side effects like hematemesis, peptic ulcer or
perforation, edema due to sodium retention, hypokalemia Other Immunosuppressive Drugs
due to increased potassium excretion, diabetes, The side effects associated with prolonged use with
hypertension, cataracts, glaucoma, osteoporosis, and corticosteroids sometimes warrant discontinuation of their
aseptic necrosis of the bone and pathological fractures. usage for genuine indications of flaring up of conditions
Some other metabolic complications are hyperlipidemias, like diabetes or hypertension. At least it becomes
secondary amenorrhea, decreased efficacy of necessary to reduce the corticosteroids doses to a minimal
anticoagulants and oral contraceptives. The prolonged use functioning level, for which a number of complimentary
of steroids may also result in CNS complications like medications have been tried, and some of them used
psychosis and pseudotumor cerebri. successfully.
The patient should carry a steroid card giving details
of the steroid dosing, with durations. The reason for carrying Methotrexate
such a card is that injury, intercurrent infection and surgical This compound has been used in leprosy for its anti-
operation demand extra supplies of endogenous cortisol, inflammatory properties. It was reported to be successfully
and these cannot be produced by an already atrophic used to reduce steroid dose in a patient of borderline
adrenal cortex due to prolonged steroid therapy. Rarely leprosy who was intolerant to steroids.15
CHAPTER
30
Cyclosporine A (CyA) (C3) and mycobacterial antigens are all identified at the
It inhibits transcription of IL-2, mRNA , thereby blocking site of ENL.
proliferation of T cells. It is found to be associated with Lepromatous leprosy patients with high bacteriological
decrease in anti-nerve growth factor anibodies.16 This drug index are more susceptible to develop Type 2 reaction or
ENL. These patients need close monitoring during treatment
is useful in chronic neuritis and can be tried in those cases
with MDT. The very first dose of MDT can lead to
who do not respond well to prednisolone. It improves the
precipitation of a reaction of mild nature, or sometimes
sensory impairment, muscular force and pain. CyA is
neuritis. It can continue to occur after completion of MDT.
administered up to 12 months with a starting dose of
This reaction is characterized by crops of tender
5 mg/kg per day followed by gradual reduction of dose.17
erythematous subcutaneous nodules, skin lesions, may
Azathioprine be accompanying neuritis, iritis, arthritis, orchitis, dactylitis,
lymphadenopathy, edema, fever and malaise.
Reduces requirement of steroid when given in To prevent such unforeseen events, the MDT in cases
combination.18 However, it acts much more slowly. It with high bacterial load should preferably be started, under
inhibits T-cells and B-cells proliferation, antibody synthesis the cover of oral steroids, which may be withdrawn after a
and TNF-α. period of 2-4 weeks. However, this view is not endorsed
by many leprologists and some other advocate the use of
Mycophenolate mofetil
steroid cover in situations of starting MDT when the patient
This is a reversible inhibitor of inosine monophosphate is susceptible and likely to undergo Type 1 reaction and
dehydrogenase, an enzyme essential for de novo purine neuritis.
synthesis that is needed for lymphocytes. Therefore, this
compound affects both T and B lymphocyte activity PRINCIPLES OF MANAGEMENT OF T2R
resulting in immunosuppression and should work both for 1. Look for severity of reaction.
Type 1 and Type 2 reactions theoretically. However, it was 2. Look for any precipitating causes.
not found to be useful in any of the type of reaction in 3. Continue taking MB MDT.
reducing and withdrawing the steroid dose after several 4. Untreated patients of LL/BL presenting with ENL should
months of its addition.19 be commenced on MDT along with the specific
treatment for ENL.
Surgical Decompression
5. Appropriate treatment of reaction.
In spite of the best efforts with medications and other 6. Management of other manifestations of T2R: Neuritis,
supportive measures, a few cases continue to have nerve acute iridocyclitis, acute epididymo-orchitis.
pain and tenderness and/or functional impairment in one
or few nerves. This is because of persistence of increased Identify Severity of T2R
intra-neural pressure leading to ischemia down the nerve. T2R may be of mild, moderate or severe type.
In such patients there is need for surgical intervention in Mild type is defined as the type of reaction when the
the form of nerve decompression which adds to the benefit patient has only a few ENL lesions and no signs of
of steroids in relieving pain and stops further deterioration involvement of organs other than skin, but the patient does
of sensory and motor functions. Surgical decompression feel uncomfortable.
involves exposing the affected nerve trunk at the point of In moderate type of T2R, there is mild fever less than
maximal thickness; and giving longitudinal incisions into 100°F and mild to moderate crops of ENL. There is
the nerve up to epineurium layers of nerve bundles. leucocytosis and some involvement of other organs except
Continuation of steroids during and after surgery prevents nerves, eyes or testes.
postoperative edema and decreases postoperative scarring. Severe type of T2R has the following signs and symptoms
a. High fever and severe malaise,
TYPE 2 REACTION (T2R) b. Pustular/ulcerative lesions of ENL,
c. Tender and enlarged lymph nodes,
Type 2 reaction (T2R) is an immune complex syndrome, d. Neuritis, arthritis, orchitis, iridocyclitis (presence of one
an example of Type III hypersensitivity reaction (Coombs or more features),
and Gell) or Arthus phenomenon. IgG, IgM, complement e. Persistent albuminuria with red cells in urine
CHAPTER
30
However, in the field conditions, for the treatment control the reaction within a week. The dose is then
purpose, it may be divided into three categories: Mild (single tapered to 250 mg twice a day for a week, followed by
episode ENL), Moderate or acute recurrent (multiple 250 mg daily. Maintenance dose of 250 mg every other
episodes of ENL for <2 years), and Severe or chronic day may be sufficient to maintain the control. However,
(continuous immunosuppression required).20 periodical attempt is made to discontinue the drug
because of chance of retinopathy. Regular check up of
Treat Precipitating Factors eye for evidence of retinopathy is essential. The patient
It is important (and sometimes rewarding also) to look for gets more relief when it is combined with aspirin. When
any precipitating factor which could be providing a trigger joints are involved, a combination of NSAIDs and
for reaction. It may be any intercurrent infection like sore chloroquine is effective. To prevent gastritis (a very
throat (streptococcal), viral (especially common one is common side effect) chloroquine should always be given
herpes simplex), intestinal parasites, filaria, or malaria after food. However of late, in view of inconsistent
which all need appropriate treatment. Another important results and availability of better alternatives, the use
factor is psychological stress which should not be of chloroquine for Type 2 reactions has taken a
overlooked and must be dealt with by counseling by the backseat.
doctor, nurses, or a trained counselor. 2. Antimonials: Sodium antimony gluconate (Stibophen)
is commercially available as a 10% aqueous solution
Continue Multi-drug Therapy (100 mg per 1 ml), given with an initial dose of 1.5 ml
intramuscularly (IM). If no adverse effect occurs, 3 ml
MDT has to continue uninterrupted, and if not started earlier I.M. is administered 2 days later, followed by 3-5 ml IM
should be started along with specific treatments for T2R. every alternate day. The total dose should not exceed
30 ml over a period of 3 weeks. Improvement is
Untreated Patients of LL/BL Presenting
expected after 5 to 6 doses. The course may be repeated
with ENL if necessary after an interval of several weeks (or 2-3
These patients should be commenced on MDT as well as months). It seems to inhibit complement activation.
specific treatment for T2R. This can be administered along with NSAIDs. Stibophen
is usually tolerated well; the common side effects are
TREATMENT OF T2R gastrointestinal disturbances, fatigue, fever, myalgia,
and arthralgia. Other important (though uncommon) side
Mild effects are electrocardiographic abnormalities, raised
Mild T2R can be managed easily with analgesics and anti- hepatic enzymes, renal toxicity. During dose
inflammatory drugs such as aspirin and other non-steroidal administration caution should always be taken about
anti-inflammatory drugs (NSAIDs). Aspirin is given in the occurrence of hypotension. Blood pressure should be
dose of 600 mg 6 hourly after food. These NSAIDs decrease measured before every dose administration.
prostaglandin synthesis and help in mild suppression of 3. Colchicine inhibits vascular injury by inhibiting the
Ag-Ab reaction and Ab production, and thus help to alleviate neutrophil chemotaxis and may be helpful in mild to
the reaction.21 moderate type of ENL. 22, 23. It is given orally in the
dose of 0.5 mg three times daily with a tapering course.
Moderate The adverse reactions in decreasing order of severity
When the reaction is of moderate nature, a number of are: bone marrow depression (aplastic anemia,
medications with anti-inflammatory properties have been agranulocytosis, thrombocytopenia) which may occur
used successfully. in patients receiving long-term therapy. Peripheral
1. Anti-malarials: Chloroquine is an anti-inflammatory neuritis, purpura, myopathy, loss of hair, and reversible
drug which acts by stabilizing lysosomal membranes, azoospermia have also been reported.
decreasing complement activity, inhibiting
prostaglandin synthesis, and enhancing the platelet Severe
activity and fibrin formation. It is administered in a dose Patients with severe reaction (high fever, extensive ENL
of 250 mg 3 times daily which should be sufficient to with or without pustular/necrotic lesions, neuritis, recent
CHAPTER
30
NFI, iridocyclitis, orchitis, and/or severe bone pain, etc.) Therefore, clofazimine in a higher dose and for longer
should preferably be admitted in the hospital for rest and duration should be added to steroids.24 This prevents
daily monitoring. requirement of frequent increment of the steroid dose to
control ENL reaction. It is administered in the dose of 300
USEFUL DRUGS FOR TYPE 2 REACTIONS mg daily orally in an adult for a period of 1 month followed
by 200 mg daily for 3-6 months and 100 mg daily for as
Oral Corticosteroids long as symptoms remain. Clofazimine does not relieve
Oral corticosteroids constitute the first line armamentarium acute manifestations of reaction. However, with the use of
in management of severe type2 leprosy reactions. WHO higher initial dose of clofazimine (300 mg) given over
(1998) recommends prednisolone for severe ENL with the several weeks, it is possible to reduce the dose or even
similar doses as prescribed for reversal reaction (a 12- withdraw the steroid under its cover. This also prevents or
week course of prednisolone).9 Prednisolone should be reduces the reoccurrence of reactions.
started with 0.5 mg to 1 mg/kg/day (40 to 60 mg) till clinical High dose of clofazimine for a long period may lead to
improvement, then taper every week by 5-10 mg over 6 to 8 a risk of chronic abdominal pain due to deposit of the drug
weeks. A maintenance dose of 5-10 mg may be needed for and its effect on the bowel wall mucosa. The pain may be
several weeks to prevent recurrence of ENL. (ILEP, 2007). severe and crampy. There may be diarrhea, nausea,
Steroids act by inhibiting both the early and late phases vomiting and weight loss. If clofazimine is continued there
of inflammation. It decreases chemotaxis of neutrophils may be partial or complete bowel obstruction. X-ray
and inhibits the enzyme prostaglandin synthetase. Steroid examination of the bowel may reveal edema of the small
administration is also associated with suppression of CMI bowel wall with effacement of the mucosa. Biopsy from
by depletion of T-cells, particularly B-helper T-cells with the bowel wall mucosa shows massive deposit of
consequent restoration of altered helper/suppressor T- cells clofazimine crystals. Gradually decreasing the dose should
ratio, and resultant decrease in the liberation of pro- prevent this, if it does occur, the drug should be stopped.
inflammatory lymphokines. No doubt, quick response to Other side effects include discoloration of the skin
prednisolone is observed in most of the cases with first (particularly in people with light skin) and ichthyotic changes.
attack of type2 reaction. However, in addition to usual side Discontinuation of the drug leads to clearance of most of
effects observed with steroid described earlier, steroid the pigmentation within 6-12 months, although traces may
dependence is a very important problem to handle. Relapse remain as long as 4 years or more.
of reaction is often associated while tapering the dose of
steroid. Thalidomide
Analgesics, like paracetamol are required to control Thalidomide, if available, should be the treatment of choice
fever and pain. Sedation with tranquilizers relieves stress for the management severe T2R. Thalidomide was
and strain, a precipitating factor for initiation and progression developed in 1954 and subsequently marketed in Europe,
of the signs and symptoms of reaction. Australia and Canada as a sedative and anti-emetic. The
drug was not approved in the USA by the Food and Drug
Clofazimine Administration because of concerns about safety and
Clofazimine is a rimino-phenazine dye which was first used neurotoxicity. In 1965, Sheskin reported the effectiveness
for the treatment of leprosy in the early 1960s. In addition of thalidomide in the management of ENL. In the aftermath
to its action and use against M.leprae and other of the worldwide criticism following serious teratogenic
mycobacteria, clofazimine is also effective in the effects (discussed below), but in view of its useful activity
management of T2R because of its anti-inflammatory in leprosy reactions, thalidomide was licensed in USA for
activities. But, its mechanism of action is not clearly use in leprosy on July 16, 1998.
understood. Clofazimine is slow to act and is not useful in Thalidomide is a racemic glutamic acid analogue
all patients and in all manifestations of ENL. With the use composed of two enantiomers R- and S- thalidomide
of larger doses of this drug for a longer period (several (stereoisomers that are mirror images of one another) which
weeks), it is possible to reduce the occurrence of reactions interconvert under physiological conditions. Two
and reduce or even withdraw steroids under its cover. enantiomers have different properties; one is a more potent
CHAPTER
30
suppressor of TNF release by stimulated peripheral blood The informed consent obtained (when an individual
mononuclear cells whilst the other is sedative. Thalidomide decides to take the drug) should form the basis of a
undergoes hydrolysis at pH 7 in aqueous solution and this contract.
degradation leads to the formation of more than 20 Thalidomide is able to suppress all clinical
products which are responsible for the activity. manifestations of T2R within 48 to 72 hours. Its action is
The exact mechanisms of action are not clear, but faster and more effective than aspirin, clofazimine and
TNF, interferon-γ, interleukins 10 and 12, cycloxygenase- pentoxyphylline. It quickly reduces the fever and number
2 and possibly the pro-inflammatory transcription factor of skin lesions. The effect on nerve and eye involvement
κB (NF-κB) are all affected. It may have varied mode of is less pronounced, but still deemed to be superior to that
anti-inflammatory actions: of aspirin.29 This drug also can be tried as a complimentary
a. It reduces chemotactic factors medication for withdrawing the steroid dose. This drug is
b. It inhibits IgM synthesis which is important in ENL.25 essentially non-toxic and well tolerated even during long-
c. Thalidomide causes significant reduction in CD4 + term administration. However, the side effects of this drug
lymphocytes and thus corrects the imbalance that must be kept in mind.
occurs during ENL.26 Dosage: In severe ENL, it is suggested to start
d. It reduces plasma soluble IL-2 receptor, a marker of thalidomide at a dose of 400 mg at bedtime (nocte Gk. at
night) or 100 mg 4 times daily. This dose easily controls
inflammation, but the mechanism is unclear
the reaction within 48 hours in most of the cases. Then it
e. It causes significant reduction of TNF-α. These
is tapered to 300 mg daily as soon as possible, usually
mechanisms of action seem to be important in
within a week. The dose is then reduced more slowly by
suppressing ENL. In vitro work has demonstrated that
100 mg each month.30 During this period the patient should
M.leprae induce activation of NF-κB in a Schwann cell
be assessed regularly to observe any deterioration, which
line leading to transcription repression mediated by TNF
should be treated by increasing the dose of thalidomide
is inhibited by thalidomide.27 Recurrence of the ENL
again for a few weeks. The patient should be stabilized on
after cessation of thalidomide is associated with an
the lowest dose that controls the disease and continue at
elevation in serum TNF levels.28
this dose for a period of 2-3 months.30 However in some
f. Thalidomide has effects on angiogenesis in addition to
patients, recurrence is quick, the ENL may become chronic,
those over immune function and inflammation.
and in that case it requires prolonged therapy. Instead of
Indications discontinuing the drug, a maintenance dose of average
100 mg daily (with a range of 100 mg on alternate days; to
WHO expert Committee advises that thalidomide should 100 mg two or more times daily) should be given for a
be used only in men or post-menopausal women who are sufficient period. Every 6 months attempts should be made
dependent on corticosteroids.9 The ILEP Technical Bulletin to discontinue the drug after gradual tapering of the dose.
acknowledges the effectiveness of thalidomide and states If again there is recurrence of reaction this drug can be
that it has fewer adverse effects than corticosteroids. restarted for another period of 6 months. This process is
Therefore, thalidomide is a good choice for men and post- repeated until reaction no longer recurs when the drug is
menopausal women with difficult to manage ENL, discontinued.
particularly for the patients with recurrent ENL and for If the patient is already receiving prednisolone for T2R,
steroid dependent cases. but difficult to control and needs to be switched over to
However, women of childbearing age should also not thalidomide, first prednisolone should be tapered to a level
be denied an effective and sometimes life-saving drug until the reaction recurs. Then at that level of corticosteroid,
provided that they and their physicians understand the thalidomide should be introduced with the initial dose of
risk associated with it and all precautionary measures are 400 mg daily (100 mg × 4 times daily). When this regimen
taken for administration of this drug prior to therapy. controls ENL, the dose of prednisolone should be furthered
Physicians must undertake a detailed assessment of the tapered within 6 weeks and finally discontinued and
risks as well as the benefits before prescribing thalidomide. subsequently the thalidomide dose is gradually tapered to
The patient and their partner should be educated about a maintenance level. As described earlier, at every 6 months
the drug and the adverse effects associated with it. interval attempt should be made to discontinue the drug.
CHAPTER
30
In few patients, the drug may have to be continued till phocomelia (Gk. Phok; seal, melos; limb) due to
skin-smear negativity is achieved.31, 32 resemblance of the limbs with that of seal (Fig. 30.1). The
However, controlling ENL by replacing steroids with other associated abnormalities with phocomelia are
thalidomide is more difficult than using thalidomide from deficient or absent ears, hearing loss, absent or extra digits,
the beginning. It may take some several weeks to reduce visual disturbances, cardiac, renal and GIT anomalies,
the steroids and obtain control with thalidomide alone. cleft palate, saddle nose, etc.
Therefore, switching to thalidomide from steroid should be During use of thalidomide in women of childbearing
done early. A further indication for replacing steroid with age it is absolutely mandatory to invoke contraception (with
thalidomide is early amyloidosis, especially persistent mild two reliable methods, unless total abstinence is ensured)
albuminuria, despite treatment with steroids. for a period of 4 weeks before stating the drug, during the
drug administration; and for 4 weeks after discontinuation
Adverse Effects of Thalidomide of the drug. Reliable contraception is indicated even where
Teratogenicity there has been a history of infertility, unless due to
Intrauterine exposure to thalidomide by the pregnant women hysterectomy or because the patient has been
leads to development of congenital anomalies in the limbs postmenopausal for at least 24 months.
and other organs in the children of those women who have Thalidomide appears to intercalate into guanine rich
taken thalidomide during pregnancy between days 20 and promoter sequences of insulin growth factor-1 (IGF-1) and
36 after conception. The tragic history dates back to late fibroblast growth factor (FGF) genes.33 IGF-1 and FGF
1950s and early 1960s when thalidomide was used as a act in combination to stimulate limb initiation and
sedative. The serious teratogenic adverse effects came thalidomide has been shown to suppress guanine rich
to light when all over the world 10,000-12,000 children were promoter sequences in myeloma cells.34 The drug is also
born with virtually absent limbs. Most of the surviving distributed into human semen after oral dosing.35 But there
victims are now in their 50s. The condition was called as is no report of teratogenicity so far caused through semen
exposure. However, it has been reported in experimental
rabbits via this route.36 Limb reduction of upper limb, to a
lesser extent in lower limbs is the most common
abnormality followed by abnormalities of the ears and eyes.
Drowsiness, a common side effect, can be avoided by
giving it at bed time.
Neuropathy
Peripheral neuropathy occurs in 20% of individuals during
first year of treatment.37 It is characterized by painful
paraesthesia and numbness in a glove and stocking
distribution. It affects the lower limbs initially followed by
the upper limb. It may be associated with weakness.
Neuropathy correlates with the daily dose administered,
but continues to progress for some time even after
cessation of therapy, then gradually shows improvement.
However, it remains permanent in 50% of the cases.
Nerve conduction studies reveal a sensory,
predominantly axonal, length-dependent neuropathy. Nerves
show loss of large myelinated fibers and little inflammation
when examined histopathologically. 38 The electro-
physiological features of thalidomide induced neuropathy
include reduction of sensory nerve action potential
amplitude and relative conservation of nerve conduction
Fig. 30.1: Phocomelia baby velocities.
CHAPTER
30
Thromboembolism • 400 mg nocte or 100 mg 4 times a day, for 3-7 days or
In thalidomide treated cases of multiple myeloma till reaction is under control followed by tapering within
thromboembolism has been reported in 3% of cases.39 3 to 4 weeks or taper slowly if recurrence occurs
This rate increased to 14% when it is combined with quickly:
dexamethasone. There have been two case reports from • 100 mg morning + 200 mg evening for 4 weeks
• 200 mg evening od for 4 weeks
India describing occurrence of iliac deep vein thrombosis,
• 100 mg evening od for 4 weeks
in a woman with ENL treated with a combination of
• 50 mg daily evening or 100 mg every alternate day
thalidomide, prednisolone, dexamethasone and
evening for 8 to 12 weeks
cyclophosphamide.40, 41
Somnolence Summary of Treatment of Recurrent

or Chronic ENL
It may be of severe nature in up to 11% of patients.39
Cutaneous adverse reactions: These have been
Option 1: (Clofazimine + Prednisolone)
reported in 3% of cases.37 Rare, but severe cutaneous
adverse effects are erythema multiforme (EM), The combination regimen (clofazimine and prednisolone)
erythroderma, toxic epidermal necrolysis (TEN).42 is always preferred.
Clofazimine should be given in a dose:
Other Side Effects
300 mg daily for 3 months followed by
Conditions like constipations, nausea, dizziness, peripheral 200 mg daily for 3 months followed by
edema, and hypothyroidism have also been reported. 100 mg daily as long as symptoms persists
Plus
SUMMARY OF TREATMENT FOR SEVERE Prednisolone in the dose of 30 mg daily for 2 weeks followed
T2R (FOR 1ST ATTACK OF SEVERE ENL) by
1st Option: (Prednisolone) 25 mg daily for 2 weeks
20 mg daily for 2 weeks
A short 6 to 8 week course, but in high initial dose (0.5 to 15 mg daily for 2 weeks
1 mg/kg body weight), 40 to 60 mg till clinical improvement, 10 mg daily for 2 weeks
then taper every week by 5-10 mg over 6 to 8 weeks. A 5 mg daily for 2 weeks, then stop
maintenance dose of 5-10 mg may be needed for several
weeks to prevent recurrence of ENL.43 Option 2: (Thalidomide)
200 mg bid for 3-7 days followed by
2nd Option: (Prednisolone + Clofazimine)
100 mg morning + 200 mg evening for 4 weeks
A combination of prednisolone (doses as above) and 200 mg evening o d for 4 weeks
clofazimine is given in the dose as mentioned below44: 100 mg evening o d for 4 weeks
Clofazimine alone does not control severe T2R. 100 mg evening alternate day for 8 to 12 weeks or
• 300 mg daily for 1 month more
• 200 mg daily for 3 to 6 months For any relapse or deterioration raise the dose
• 100 mg daily for as long as symptoms remain. immediately by 200 mg, then slowly reduce to 100 mg on
However, with the use of larger doses of clofazimine, alternate day or 50 mg daily for several months to manage
given over several weeks, it is possible to reduce the dose chronic ENL.30
or even withdraw the steroids under its cover. This also
prevents or reduces the recurrence of reactions. STEROID REPLACEMENT BY
THALIDOMIDE FOR ENL PATIENTS
3rd Option: (Thalidomide) ALREADY ON STEROIDS
Thalidomide should be considered as the third option. It Replacing steroids with thalidomide is much difficult than
can be given in the following doses: starting thalidomide from the beginning. Steroids should
CHAPTER
30
be reduced very gradually. The indications to consider groups), and also in the comparative study between BCG
replacing steroids with thalidomide for patients already on and Mw, done at Chandigarh49, with 20 patients each in
steroids are as below: BCG, Mw and the control groups. But these results could
• Steroid dependence. not be reproduced in the final detailed analysis of data
• Recurrent ENL not under control with steroid. comprising 157 and 147 patients in the vaccine and control
• Steroid sparing in chronic ENL with DM, TB or group respectively.50
hypertension.
• Early amyloidosis especially associated with persistent Other Drugs/treatment Modalities Tried in ENL
mild albuminuria, despite treatment with steroid.
i. Pentoxifylline: This is a methyl xanthine derivative
used in the management of peripheral vascular
Alternate Therapies for T2R
diseases. It has been shown to inhibit the production
of TNF both in vivo and in vitro.51 One double blind
Betamethasone Pulse Therapy
trial study from Brazil shows that in ENL pentoxifylline
Slow infusion of 40 mg Betamethasone daily in 5% 1200 mg daily is not as effective as thalidomide in a
dextrose for 3 consecutive days every 4 weeks for recurrent dose of 300 mg daily. There are several small case
ENL. Though well tolerated, it does not offer significant studies showing a limited response in ENL to
advantage over conventional way of managing ENL/chronic this drug at daily dose regimen from 1200 to
and recurrent ENL. However, side effects of steroid were 2400 mg. 52-54 It could be a good option for patients
not progressive in contrast to progressive side effects
with HIV co-infection where long-term steroids are
observed in daily steroid regimen.45
contraindicated.53 However, there is relapse of
Dexamethasone Pulse Therapy with Azathioprine reaction within one month of stopping the drug.
ii. Cyclosporine-A: Cyclosporine-A has been used
This regimen may be considered in ENL as a daily steroid
because of its immunosuppressant action. It inhibits
sparing regimen for steroid dependent chronic ENL
Th cells and restores the Th: Ts cells balance.
reaction. It is given in a dose of 100 mg dexamethasone in
However, in short series of clinical trials it has
500 ml glucose IV infusion on 3 consecutive days every
provided ambiguous results with controversial
month along with 50 mg daily azathioprine.46 This pulse
therapy may help in reducing the steroid requirement. outcome.
iii. Plasma exchange: Plasma exchange removes Ag,
Azathioprine Ab and immune complexes. It may be helpful in
Azathioprine can be tried in preventing recurrence of difficult cases when this facility is available and cost
reaction in patients with recurrent ENL.47 It has been factor is not a hindrance.
reported effective in weaning a female patient of iv. Methotrexate: Methotrexate acts by increasing the
thalidomide. It is administered in the dose of 2 mg/kg/day adenosine levels, reducing pro-inflammatory
for 6 to 8 months. cytokines and increasing the levels of anti-
inflammatory cytokines.55 It was found to be effective
Immunotherapy in Chronic and Recurrent ENL as a steroid sparing agent in a case of steroid
resistant ENL.56
Several immunomodulaters along with MDT have been
tried in the past in patients with multibacillary leprosy for v. Mycophenolate mofetil: It is an inhibitor of de novo
faster clearance of dead bacilli from the body. Theoretically purine synthesis in T and B lymphocytes. But the
it is expected to prevent T2R and may even be helpful in results so far have not been promising, as discussed
treating the reaction through its effectiveness by quick in the section on Type 1 reaction.
bacterial clearance. These are BCG + M.leprae, M. vaccae, vi. Cyclophosphamide: This drug is worth for a long-
ICRC bacilli and Mw vaccine. The last one of these, Mw term series trial.
vaccine was found to show a slightly lower incidence of vii. Zinc: Oral zinc (220 mg per day) has been tried in
type2 reactions (in those administered vaccine, as India. It has been claimed to reduce steroid
compared to controls) in the preliminary study at Delhi48 requirements but it is not possible to make any
(reported with 45 and 41 patients in vaccine and control definite conclusions about the clinical effect.30
CHAPTER
30
Newer Drugs in ENL Management Management of Other Manifestations: Neuritis,
Acute Iridocyclitis, Acute Epididymo-orchitis
a. Leukotriene inhibitors (Zafirlukast, Montelukast):
Zafirlukast has been tried in an open phase II cohort For acute epididymo-orchitis in addition to oral prednisolone
using an initial dose of 40 mg twice daily. It was found scrotum should be supported by a suspensory bandage.
effective in 6 patients of ENL, but end points are not (Please refer to individual chapters for the management of
defined.57 neuritis and acute iridocyclitis).
b. Thalidomide derivatives (Revimid, Actimid): These
immunomodulatory drugs are even more potent than LUCIO PHENOMENON
thalidomide and do not appear to have any adverse This refers to the unique reactional form of lucio leprosy
effects. However, these molecules require clinical trial. which is encountered in certain parts of the world like
c. Infliximab (TNF α antibody): This chimeric monoclonal Mexico. The details have been discussed in the chapter
antibody suppresses the biological activity of TNF by on leprosy reactions. This form of reaction typically occurs
specially binding to it. It has been reported to be in untreated patients, and the patients remain afebrile
effective in a single case of recurrent ENL. It could be through out. The patients respond excellently well when
another approach for chronic ENL. However, because MDT is started. They also respond to oral steroids but
TNF-α blockade carries an increase risk of thalidomide is of no value. However, after initial good
M.tuberculosis and fungal infections, one needs to use response to MDT, many of these patients may develop
infliximab with great care.58 the classical ENL.
30
CHAPTER
30
Conclusion 8. Lockwood DNJ. Steroids in leprosy type 1 (reversal) reactions;

mechanisms of action and effectiveness. Workshop proceedings.
Borderline leprosy patients have to be monitored very Lepr Rev 2000; 71: S111-S114.
closely for RR and neuritis, both during treatment and 9. WHO Expert Committee on leprosy. Technical Report Series,
thereafter. Adequate initial dose of steroid is the key to 1998; 874:1-48.
control reactions and even reverse the nerve damage. 10. Naafs B. Current views on reactions in leprosy. Indian J Lepr
2000; 72:99-122.
Sufficient duration of steroid therapy is the key to prevent
11. Naafs B. Treatment duration of reversal reaction: a reappraisal,
recurrence and nerve recovery. back to the past. Lepr Rev 2003; 74:328-36.
As per the severity of ENL, the choice of suitable drugs 12. Girdhar A, Chakma JK, Ravinderan A et al. A comparative study
has to be made. Recurrent and chronic ENL pose a difficult of high v/s low dose corticosteroid therapy in reversal reactions
problem for the physician to manage. Repeated ENL in leprosy. Indian J Lepr 2005; 77:350-51.
13. Girdhar BK, Girdhar A, Chakma JK. Advances in the treatment
reactors need thalidomide therapy in addition to short course
of reactions in leprosy. Indian J Lepr 2007; 79:121-34.
of steroids. 14. Kar HK, Sharma P. New lesions after MDT in PB and MB Leprosy:
The reactions are the basis for neuritis; and neuritis is A report of 28 cases. Indian J Lepr 2008; 80:247-55.
the basis for deformities, disabilities and the stigmatising 15. Biosca G, Casallo S, Lupez-Velez R. Methotrexate treatment for
figure of leprosy patient. So the identification and treatment type1 (reversal) reactions. Clin Infect Dis 2007; 45:e7-9.
16. Sena CBC, Salgado CG, Tavares CMP, et al. Cyclosporine A
at the earlier stage is important. At the current juncture,
treatment of leprosy patients with chronic neuritis is associated
there is a need to enhance the research for newer drugs in with pain control and reduction in antibodies against nerve growth
the management of reactions. There should be a good factor. Lepr Rev 2006; 77:121-29.
patient monitoring scheme. Quality of life studies in patients 17. Chin-A-Lien, RAM, Faber WR, Naafs B. Cyclosporine A treatment
with ENL would help to determine the social and financial in reversal reaction. Trop Geogr Med 1994; 46:123-24.
impact of these conditions. 18. Marlowe SNS, Hawksworth RA, Butin CR, et al. Clinical outcomes
in a randomized controlled study comparing azathioprine and
prednisolone and prednisolone alone in the treatment of severe
Summary leprosy type1 reaction in Nepal. Trans R Soc Trop Med Hyg
The flow chart (See Page 397) for managing moderate to 2004; 98: 602-09.
19. Burdick AE, Ramirez CC. The role of mycophenolate mofetil in
severe ENL (modified and simplified from the original
the treatment of leprosy reactions. Int J Lepr Other Mycobact
Algorithm is given from the review article by Steven L et Dis 2005; 73: 127-28.
al. 2007).30 20. Pre-congress workshop on reactions and neuritis. Chaired by
Lockwood DN and Scollard D as rapporteur. Proceeding
published in Lepr Rev 2008; 79:216-20.
REFERENCES
21. Naafs B. Reactions in leprosy. In: Biology of Mycobacteria, Vol 3
1. Arunthathi S, Satheesh KK. Does clofazimine have a prophylactic Eds Ratledge G, Stanford JL, Grange JM. London, Academic
role against neuritis? Lepr Rev 1997; 68: 233-41. Press Ltd, pp 359-403.
2. Thacker AK, Chandra S, Mukhija RD et al. Electro-physiological 22. Sarojini PA, Mshana RN. Use of colchicines in the management
evaluation of nerves during reactions in leprosy. J Neurol 1996; of ENL. Lepr Rev 1983; 54:151-53.
243:530-35. 23. Kar HK, Roy RG. Comparison of colchicines and aspirin in the
3. Li Huan-Ying. Analysis of reversal reactions in leprosy patients treatment of type2 lepra reaction. Lepr Rev 1988; 59:201-203.
following fixed duration MDT. Paper at the Asian Leprosy 24. Schreuder PAM, Naafs B. Chronic recurrent ENL, steroid
Congress in Agra, 2000. dependent long-term treatment with high dose clofazimine. Lepr
4. Little D, Khanolkar-Young S, Coulthart A et al. Rev 2003; 74:386-89.
Immunohistochemical analysis of cellular infiltrate and gamma 25. Shannon EJ, Miranda RO, Morales MJ et al. Inhibition of de novo
interferon, interleukin-2, and inducible nitric oxide synthease
IgM antibody synthesis by thalidomide as a relevant mechanism
expression in leprosy type 1 (reversal) reactions before and
of action in leprosy. Scand J Immunol 1981; 13:553-62.
during prednisolone treatment. Infect Immun 2001; 69:3413-17.
26. Gad SM, Shannon EJ, Krotoski WA et al. Thalidomide induces
5. Manadhar R, Shrestha N, Butlin CR et al. High levels of
imbalance in T-lymphocyte subpopulation in the circulating blood
inflammatory cytokines are associated with poor clinical
response to steroid treatment and recurrent episodes of type 1 of healthy males. Lepr Rev 1985; 56:35-39.
reaction in leprosy. Clin Exp Immunol 2002; 128:333-38. 27. Pereira RM, Calegari-Silva TC, Hernandez MO et al.
6. Sundar Rao PSS, Sugamaran DST, Richard J et al. Multi-centre, Mycobacterium leprae induces NF-kappaB-dependent
double blind, randomized trial of three steroid regimens in the transcription repression in human Schwann cells. Biochem
treatment of type1 reactions in leprosy. Lepr Rev 2006; 77:25- Biophys Res Commun 2005; 335:20-26.
33. 28. Sampaio EP, Kaplan G, Miranda A et al. The influence of
7. Lipworth BJ. Therapeutic implications of non-genomic thalidomide on the clinical and immunologic manifestation of
glucocorticoid activity. Lancet 2000; 356:87-88. erythema nodosum leprosum. J Infect Dis1993; 168: 408-14.
CHAPTER
30
29. Iyer CG, Languillon J, Ramanujam K et al. WHO co-ordinated 43. Shannon EJ, Sandoval E. Thalidomide is agonistic to synthesis
short-term double-blind trial with thalidomide in the treatment of of IL-2 and it can be agonistic and antagonistic to the synthesis
acute lepra reactions in male lepromatous patients. Bull World of TNF-α. Int J Lepr Other Mycobact Dis 1995; 63:654-56.
Health Organ 1971; 45:719-32. 44. ILEP. How to recognize and manage leprosy reactions,
30. Walker SL, Waters MFR and Lockwood DNJ. The role of chapter three, ILEP, Learning Guide two, Pub, ILEP, 2002;
thalidomide in the management of erythema nodosum leprosum. page: 33-34.
Lepr Rev 2007; 78:197-215. 45. Girdhar A, Chakma JK, Girdhar BK. Pulsed corticosteroid therapy
31. Pai VV, Rao R, Bansode S et al. Maintenance therapy with in patients with chronic recurrent ENL: a pilot study. Indian J
thalidomide to minimize recurrence in type2 lepra reactions. Lepr 2002; 74:233-236.
Indian J Lepr 2005; 77:44. 46. Mahajan VK, Sharma NL, Sharma RC et al, Dexamethasone pulse
32. Villaherrmosa LG, Fajarado TT, Abalos RM et al. A randomized, therapy with azathioprine in ENL. Lep Rev 2003; 74;171-74
double-blind, double dummy, controlled dose comparison of 47. KK Verma, Srivastava P, Minz A et al. Azathioprine and recurrent
thalidomide for treatment of erythema nodosum leprosum. Am J ENL. Lepr Rev 2006; 77:225-29
Trop Med Hyg 2005; 72:518-26. 48. Zaheer SA, Misra RS, Sharma AK et al. Immunotherapy with
33. Stephens TD, Blunde CJ, Fillmore BJ. Mechanism of action in Mycobacterium w vaccine decreases the incidence and severity
thalidomide teratogenesis. Biochem Pharmacol 2000; 59:1489- of type2 (ENL) reactions. Lepr Rev 1993; 64:7-14.
99. 49. Narang T, Kaur I, Kumar B et al. Comparative evaluation of
34. Drucker L, Uziel O, Tohami T et al. Thalidomide down regulates immunotherapeutic efficacy of BCG and Mw vaccines in patients
transcript levels of GC- rich promoter genes in multiple myeloma. of borderline lepromatous and lepromatous leprosy. Int J Lepr
Mol Pharmacol 2003; 64:415-20. Other Mycobact Dis 2005; 73:105-14
35. Teo SK, Harden JL, Burke AB et al. Thalidomide is distributed 50. Sharma P, Kar HK, Misra RS et al. Reactional states and neuritis
into human semen after oral dosing. Drug Metab Dispos 2001; in multibacillary leprosy patients following MDT with/without
29:1355-57. immunotherapy with Mw anti-leprosy vaccine. Lepr Rev 2000;
36. Lutwak- Mann C, Schmid K, Keberle H. Thalidomide in rabbit 71; 193-205
semen. Nature 1967; 214:1018-20. 51. Sampario EP, Moraes MO, Nery JA et al. Pentoxifylline decreases
37. Bastuji-Garin S, Ochonisky S, Bouche P et al. Incidence and in vivo and in vitro tumour necrosis factor-alpha (TNF-alpha)
risk factors for thalidomide neuropathy: a prospective study of production in lepromatous leprosy patients with erythema nodosum
leprosum (ENL). Clin Exp Immunol 1998; 111:300-08.
135 dermatologic patients. J Invest Dermatol 2002; 119:1020-
52. Dawlah ZM, Cabrera A, Ahern K et al. A phase-II open trial of
26.
pentoxifylline for the treatment of leprosy reactions. Int J Lepr
38. Chaudhry V, Cornblath DR, Corse A et al. Thalidomide-induced
Other Mycobact Dis 2002; 70:38-43.
neuropathy. Neurology, 2002; 59:1872-75.
53. Chatterjee M, Jaiswal AK. Does pentoxifylline find a place in the
39. Glasmacher A, Hahn C, Hoffmann F et al. A systematic review
armamentarium of leprologists in type II reaction? Indian J Lepr
of phase-II trials of thalidomide monotherapy in patients with
2002; 74:329-34.
relapsed or refractory multiple myeloma. Br J Haematol 2006;
54. De Carsalade GY, Achirafi A, Flageul B. Pentoxifylline in the
132:584-93.
treatment of erythema nodosum leprosum. J Dermatol 2003;
40. Sharma NL, Sharma V, Shanker V et al. Deep vein thrombosis: a 30:64-68.
rare complication of thalidomide therapy in recurrent erythema 55. Swierkot J, Szechinski J. Methotrexate in rheumatoid arthritis.
nodosum leprosum. Int J Lepr Other Mycobact Dis 2004; 72:483- Pharmacol Rep 2006; 58:472-92.
85. 56. Kar BK, Babu R. Methotrexate in resistant ENL. Int J Lepr Other
41. Vetrichevvel TP, Pise GA and Thappa DM. A case report of Mycobact Dis 2004; 72:480-488.
venous thrombosis in a leprosy patient treated with corticosteroid 57. Vides EA, Cabrera A, Ahern KP et al. Effect of zafirlukast in
and thalidomide. Lepr Rev 2008; 79:193-95. leprosy reactions. Int J Lepr Other Mycobact Dis 1999; 67:71-75.
42. Wu JJ, Huang DB, Pang KR et al. Thalidomide: dermatological 58. Faber WR, Jensema AJ, Goldschmidt WF. Treatment of recurrent
indications, mechanisms of action and side effects. Br J Dermatol erythema nodosum leprosum with infliximab. N Eng J Med 2006;
2005; 153:254-73. 355:739.
CHAPTER
31
31 Management of Neuritis and

Neuropathic Pain
INTRODUCTION 2. Damage mediated by inflammatory and immune

mediated processes.
Neuritis, literally translated means inflammation of the
3. Damage due to edema and mechanical compression.
nerve. Mycobacterium leprae (M. leprae) is the only bacillus
which is able to invade the peripheral nerves, produces Neuritis and nerve function impairment (NFI) can occur
inflammation in the nerve (neuritis) and consequent nerve in the setting of immunological reactions but occur more
function impairment (NFI) with attendant deformity and commonly independent of them because of the disease
increased risk of stigma. per se. Some patients develop neuropathy after completion
A patient with leprous neuritis can have any of the of multi drug therapy (MDT) in the absence of reaction or
following symptoms viz. spontaneous nerve pain, visible leprous activity.3 All leprosy patients do not develop
tenderness, paresthesias, sensory, motor or autonomic neuritis and NFI. The BANDS study (aphorism for the cohort
impairment. Different clinical types of leprosy produce study conducted in Bangladesh by Danish Bangladesh
different patterns of nerve involvement. Nerve inflammation Leprosy Mission) identified the bacillary status and nerve
can be acute, chronic, acute on chronic or smouldering function loss (NFL) at presentation as the significant risk
type. Neuritis is not always symptomatic, and can have factors for further development of the NFI.4 Leprosy
minimal symptoms and even the damage can go on silently patients were divided into three risk groups based on the
(silent neuropathy). presence of these risk factors. Paucibacillary (PB) leprosy
A neuron is the building block of the nerves. Neuron patients with no NFL at presentation had 1.3% risk (low
has a cell body and multiple cytoplasmic projections risk) of developing NFI within two years of follow up; PB
including axons and dendrites. Each axon has an insulating leprosy patients with NFL and multibacillary (MB) leprosy
lining of myelin formed of a fatty material inside the patients without NFL had 16% risk; and the MB patients
Schwann cells. Nerve fascicle is made up of a group of with NFL at the time of presentation had a 65% risk of
axons encased by perineurium; bathing together in development of new NFI within 2 years of registration.
endoneurial fluid. Between the fascicles is a fatty material Clinician should be aware of the varied presentations
called the interfascicular epineurium. The nerve is then of leprous neuritis to individualize therapy and
wrapped in the main epineurium. Even if the sensitive living prognosticate the patient. The different clinical
axons are damaged, the conduit made up of epineurium presentations are:
and perineurium will often survive and provide a pathway
Acute neuritis—patient presents with acute neuritic pain
for regrowing of the nerve fibers.
or nerve tenderness and/or swelling due to nerve abscess
Nerve damage in leprosy occurs by three distinct
and/or recent onset neurological deficit of usually less than
mechanisms:
6 months duration. This mostly occurs in the setting of
1. M. leprae directly damages neurons via mechanisms
type 1 (T1R) or type 2 (T2R) leprosy reactions and should
involving Schwann cells1 and by contact demyelination,
be treated vigorously as the clinical deterioration is fast. It
as described by Rambukkana.2
shows good response to treatment.
CHAPTER
31
Management of Neuritis and Neuropathic Pain 401
Chronic neuritis—patient presents with long standing (>6 1. Nerve palpation is done to look for tenderness,
months duration), gradually progressive neurological deficit thickening, consistency and abscess formation.
with nerve tenderness or pain. It shows poor response to 2. Nerve function assessment
treatment. a. Sensory function evaluation in the distribution of
nerves for touch, pain and temperature.
Recurrent neuritis—an episode of neuritis recurring after
b. Voluntary muscle testing (VMT) and grading the
a symptom free interval of at least three months and it
power.
indicates poor prognosis and the NFI deteriorates further.
c. Autonomic function evaluated from skin dryness,
Silent neuropathy—patient has only neurological deficit hair loss, skin colour and temperature.
which is mostly progressive in the absence of nerve pain
and tenderness with no evidence of reaction. Investigations
Catastrophic paralysis—patient develops sudden Specialized investigations include nerve fine needle
paralysis. It’s an emergency which needs urgent attention. aspiration cytology (FNAC), nerve biopsy, nerve
electrophysiological studies (NES) and laser Doppler
Completely destroyed nerves—when patient has no
fluxometry. These investigations are done only in selected
residual nerve function and electrophysiological studies
cases.
show no conduction.
1. Nerve FNAC—It is a simple, quick, less invasive
procedure which does not affect the nerve adversely,
DIAGNOSIS AND MONITORING and therefore can be done from any accessible nerve
When patient presents in the clinic, detailed examination which seems to be affected clinically. It provided
should be done to make note of the extent of nerve function diagnostic aspirate in 67-92% patients in different
impairment if any, at the time of presentation. Patients at studies.7,8 The diagnostic aspirate from cases towards
high risk of development of NFI or having it at presentation tuberculoid pole comprised good cellular infiltrate with
should be put on close follow up. Risk factors for cohesive epithelioid cell granuloma with fair amount of
development of new NFI are MB leprosy,4 NFI at diagnosis4 lymphocytes; while towards the lepromatous end it
and those with detectable PGL-1 antibodies.5 This would comprised of fair to poor cellular infiltrate, mainly foamy
help in detecting the fresh nerve function loss at the earliest macrophage and very few lymphocytes. This
and also in gauging the efficacy of the treatment. investigative method is mainly useful in establishing
An international workshop on neuropathology in leprosy, the diagnosis of pure neuritic leprosy.
held at Soesterberg, Netherlands in June 2007, concluded 2. Nerve biopsy—It is an invasive procedure done on
that the nerve function assessment should be performed superficial cutaneous sensory nerves. Tissue can be
at different times and frequencies according to the type of used for histopathological examination and PCR for M.
leprosy, presence of NFI and the context of the case:6 leprae. It is useful in establishing the diagnosis of pure
• At start and end of treatment with MDT in all types of neuritic leprosy.
disease. 3. Nerve electrophysiological studies (NES)—
• If NFI is present at diagnosis then nerve function Electrodiagnostic findings early in the disease reveal
assessment (NFA) is done at every visit- 3 monthly demyelinating features, such as slowing of conduction
approximately. velocity and prolongation of latencies, but as the disease
• In MB patients, assessment should continue after progresses, secondary axonal damage ensues. These
completion of MDT, every 3 months for 2 years. studies are the most sensitive. They help in early
Assessment of patient includes clinical examination detection of NFI and provide a baseline and an objective
and the specialized investigations. measure for gauging the response to therapy.
4. Laser Doppler fluxometry—It measures the cutaneous
Clinical Examination blood flow in fingertips and toes using laser light. This
technique is utilized to measure vasomotor reflex
Nerve examination includes nerve palpation and nerve
in leprosy patients with prominent autonomic nerve
function assessment:
lesion.
CHAPTER
31
MANAGEMENT mediated via steroids cytoplasmic receptors and via non-

specific physiochemical activity. Steroids with relatively
Early detection and appropriate treatment of neuritis and
high non-genomic potencies like methylprednisolone would
leprosy reactions is the key issue in the leprosy
be needed for early and greater immunosuppression.11
management. The principles of management of neuritis
Steroids also reduce the postinflammtory scar formation
are:
during the prolonged healing phase which is very important
1. Continuing the treatment of leprosy (MDT)
for the improvement of nerve function after the reaction is
2. Treating complicating reactional states, i.e. type 1 and
controlled.12
type 2 leprosy reactions
Use of corticosteroids is recommended when there is
3. Effective and prolonged anti-inflammatory therapy
neuritis or NFI of less than six months duration. WHO
4. Surgery when indicated
recommended corticosteroid regimen for treating nerve
5. Physical therapy and rest during the phase of active
damage starts with 40 mg prednisolone daily and tapered
neuritis
over the next 12 weeks, as follows:13
6. Physiotherapy during recovery phase
Recovery of NFI depends on several factors like degree Dose once a day Weeks of treatment
of damage, severity of reaction, duration of NFI, age of
40 mg 1, 2
the patient, general health condition, type of leprosy and
30 mg 3, 4
the adequacy of treatment.
20 mg 5, 6
MDT should be continued or started, if the patient has
15 mg 7, 8
not received it before. Though MDT does not improve
10 mg 9, 10
neuritis but is still an important part of treatment as it
5 mg 11, 12
would kill the bacilli and reduce the bacterial antigenic load
responsible for the reactions and neuritis. Those patients Earlier the treatment is started, higher are the chances
at greater risk of developing neuritis should be educated of reversal of nerve function impairment.14,15 Recovery of
regarding their occurrence at the start of MDT as patients nerve function loss is more likely when the duration of NFI
tend to panic and default when they develop new NFI while has been less than 6 months.12,14 But doubts have been
on MDT. expressed about the need for treatment of very early nerve
damage with steroids.16
ANTI-INFLAMMATORY THERAPY The optimal dose and duration of therapy for neuritis
has not been established. Rao et al17 in a optimal steroid
Corticosteroids are the most commonly used anti-
dose finding study compared three steroid regimens in
inflammatory agents for the management of leprosy
leprosy patients with type1 reaction and they concluded
neuritis. Other agents include clofazimine, azathioprine,
that prolonged duration of therapy was more effective than
thalidomide and cyclosporine.
the high dose therapy. In another randomized clinical trial
by Garbino et al,18 it was found that the higher dose (2 mg/
Corticosteroids
kg/day) of steroids produced better results than the lower
Corticosteroids with dual anti-inflammatory and dose (1 mg/kg/day) during the first month of treatment for
immunosuppressive actions form the mainstay in the ulnar neuropathy.
treatment of leprous neuritis. Steroids produce rapid Various studies have found that prolonged prednisolone
improvement in most but not all the patients; by quickly treatment may be more effective in the treatment of severe
reducing the oedema and number of inflammatory cells reactions and reversing the nerve damage and the WHO
and bringing down the intraneural pressure considerably. recommended 12 weeks therapy is inadequate.14,19,20
Its action is via both, genomic9 and non-genomic10 effects. The best strategy is to tailor the therapy to the individual
Genomic effects are produced by binding to steroid nuclear patient’s response. There have been no randomized
receptors which in turn alter the production of various controlled trials (RCTs) comparing the standard regimen
cytokines. These effects take time while the non-genomic and patient tailored steroid regimen with nerve function
effects are responsible for the immediate action and are impairment as primary outcome.
CHAPTER
31
Efficacy of Steroids in Acute Neuritis nerves have been demonstrated in long standing cases of
leprosy.26 Therefore some clinicians still believe in giving
Many studies report spontaneous improvement in the nerve
a trial of treatment with corticosteroids, even in long
function in leprosy patients over a period of time and this
standing cases of neuritis. Acute neuritis shows better
is a big confounding factor for steroid dose efficacy
response while the patients with recurrent and chronic
studies.21,22
neuritis respond poorly to the steroids. So earlier the
In a RCT, mild sensory impairment of less than 6 months
treatment is started; higher are the chances of reversal of
duration was treated with tapering doses of steroids for 16
nerve function impairment.
weeks starting at 40 mg/day.16 Sensory improvement at
Though the steroids are the most efficacious drugs
the end of one year was seen in 80% of cases in
among all anti-inflammatory agents for the treatment of
prednisolone group and 79% in placebo group.
leprous neuritis; there are few drawbacks and limitations.
In another retrospective cohort study, 35% of patients
Steroids are not uniformly effective in all patients and a
having complete anesthesia and 67% with moderate
significant number of patients do not respond to
sensory impairment, improved to good function in 3 months
steroids.21,27,28 Variability of response to steroids is due to
after the start of corticosteroid treatment.23 Among cases
different processes of nerve damage working in different
with complete motor paralysis or moderate motor
combinations in different patients.
impairment, 11% and 55% patients in the two groups
It is not known if steroids interfere with the killing of
respectively, recovered to good function.
bacilli and clearance of antigen from the body. So there is
Data from Ethiopia ALERT MDT Field Evaluation Study
a concern regarding potential of growing of leprosy bacilli
(AMFES) showed that the patients with acute neuropathy
in patients on long term steroids and increasing the
when treated with steroids had full recovery in 88% cases,
chances of relapse and late reactions. Therefore, the
while the patients with recurrent or chronic NFI had poor
patients of neuritis or chronic reactions who have completed
prognosis with only 51% of involved nerves showing full
MDT but are on steroids, should be given some antileprosy
recovery in the long term.21
treatment. Clofazimine given alone is considered a better
Data from non-randomized studies show that the
option because of its additional anti-inflammatory
steroids are effective in acute neuritis though the recent
properties. However, we have to keep in mind the rare
RCT does not support it.16
chance of development of drug resistance to clofazimine
Efficacy of Steroids in Chronic when given alone, against the existing viable M.leprae.
and Recurrent Neuritis Steroids have minor and major side effects and these
side effects become all the more significant in patients
TRIPOD 3 study investigated the role of steroids in patients with leprous neuritis who receive steroids for long periods.
with long standing neuritis.24 In a multicentric randomized, Data from three TRIPOD trials, in which standardized
double-blind placebo-controlled trial conducted in Nepal regimens of corticosteroids for prophylaxis and treatment
and Bangladesh, patients with untreated NFI between 6 of nerve function impairment were given, was evaluated
and 24 months duration were randomized to either tapering for incidence of adverse events with prednisolone.29 It
doses of prednisolone starting at 40 mg/day for 16 weeks, revealed minor adverse events in 20% and major adverse
or to placebo. Assessment was done at 4, 6, 9, and 12 events in 2% of the test group which received prednisolone.
months from the start of treatment. There was no Minor adverse events included acne, fungal infections and
demonstrable additional improvement in nerve function, gastric pain. Major adverse events were peptic ulcer,
or in preventing further leprosy reaction events in the diabetes and infections like bacterial sepsis.
prednisolone group. Overall, improvement of nerve function To minimize the side effects, steroids can be given in
at 12 months was seen in about 50% of patients in both combination therapy with other anti-inflammatory agents
groups. The trial concluded that it is not advisable to treat like clofazimine.
long-standing NFI with prednisolone.
Saunderson found the use of steroids to be
OTHER ANTI-INFLAMMATORY AGENTS
disappointing in recurrent neuritis.25
All nerve fibers are not destroyed even in badly Treatment of leprosy reactions and neuritis is largely
damaged nerves and axon sprouting and regeneration of dependent on the steroids. Clofazimine and thalidomide
CHAPTER
31
are other anti-inflammatory agents with well established is a 50% decrease in the sensory nerve action potential
role in the management of leprosy reactions. All of these (SNAP) amplitude, with relative conservation of nerve
drugs have significant adverse effects when given for long conduction velocities on nerve electrophysiological studies
duration and also, all patients do not show good response. (NES).
So there is an ongoing hunt for new agents. Reaction patients with neuritis when treated with
thalidomide should be monitored closely, both clinically
Clofazimine and with NES.
Clofazimine is a phenazine derivative with both anti-leprosy Lastly, it goes without saying that the potential
and anti-inflammatory properties. It acts by reducing the teratogenic threats must be kept in mind when using this
granulocyte chemotaxis and stabilizing the lysosomal drug in female patients in reproductive age group, as has
membrane. It has limited role in the management of acute been discussed in the chapter on treatment of leprosy
stage of type 1 reaction but has been found to reduce its reactions.
incidence30,31 and that of neuritis32 as well. It is a steroid
sparing drug in the treatment of recurrent and chronic ENL
Azathioprine
reactions.33,34 Azathioprine has immunosuppressive and anti-
As clofazimine acts slowly, it should be used in inflammatory effects. Its active metabolite 6-thioguanine
combination therapy with steroids. Later steroids can be is structurally similar to endogenous purines adenine and
gradually withdrawn while patient continues on clofazimine guanine. It gets incorporated into the DNA and RNA,
alone. There is an added advantage with clofazimine that subsequently inhibiting cell division. It affects the function
its addition to therapy takes off any fear of growing bacilli of both the T as well as the B cells.
when patients with reaction or neuritis are on prolonged Azathioprine is used as steroid sparing agent in various
immunosuppression with steroids. immune mediated cutaneous disorders. This has led to
It is given in doses of 300 mg daily in three divided clinical trial of azathioprine under the ILEP co-ordinated
doses; for a maximum period of 12 weeks. Dose is then nerve function impairment and reaction research program
reduced to 200 mg daily and after few months to 100 mg to find its efficacy as a second-line treatment for severe
daily, which may be continued for more months. type1 reactions (T1R).36 The trial concluded that a 12-week
The drug accumulates in the body especially in the course of azathioprine at 3mg/kg/day plus an 8 week
skin, mucous membrane, reticuloendothelial system and reducing course of prednisolone starting at 40 mg/day is
tissues with large number of macrophages. The side effects as effective as a 12 week reducing course of prednisolone
are dose-related and are more common and severe at starting at 40 mg/day and that the combination therapy is
higher cumulative dose. Most important side effects are well tolerated in leprosy patients with severe T1R.
gastrointestinal disturbances and cutaneous pigmentation.
The significant adverse effects of azathioprine are
pancytopenia, liver toxicity and gastrointestinal intolerance.
Thalidomide
Further studies are needed to establish its role in the
Thalidomide is a non-polar glutamic acid derivative. It is management of neuritis.
an anti TNF-α agent with immunomodulatory, anti-
inflammatory and hypnosedative effects. It is the drug of Cyclosporine
choice for type 2 reactions and there are reports of
Cyclosporine is a potent immunosuppressant which acts
satisfactory response of neuritis in the patients.35
directly on CD4+ T cells. The drug inhibits calcineurin and
But the problem with thalidomide is that it itself produces
this leads to decreased activity of transcription factor
peripheral neuropathy which most commonly presents with
NFAT-1, inhibiting the IL-2 production. Reduced IL-2 level
symmetrical painful paresthesias of the hands and feet;
result in decreased activation of T-cells; and thereby the
frequently associated with a lower limb sensory loss. Mild
proximal muscle weakness can occur but severe motor B cells and antibody production.
impairment and proprioceptive failure occurs only Cyclosporine has been used in the management of
occasionally. The cardinal sign of drug related neuropathy chronic ENL37 and reversal reactions.38 It has been found
CHAPTER
31
to produce pain relief in chronic neuritis patients along CHRONIC NEUROPATHIC PAIN
with the recovery of the neural functions.39 Cyclosporine
Nerves carry the pain sensation, but when some primary
was given in a 12 month reducing course starting at 5 mg/
lesion or dysfunction of the nerve itself produces pain, it
kg per day. The author proposed that the mechanism of
is termed as neuropathic pain. Leprosy related chronic
action of cyclosporine was through reduction of anti-nerve
neuropathic pain has received scant attention in literature.
growth factor (NGF) autoantibody titres. NGF is trophic to
It is a common late complication of leprosy. Its diagnosis
the neurons and anti-NGF autoantibodies deplete the NGF
is made when patient after completion of MDT presents
in leprosy patients.
with pain in the absence of leprosy reaction and absence
Marlowe et al40 in an open prospective trial treated 41 of new nerve function impairment. It is predominantly of
patients of severe type1 reaction with cyclosporine (5- continuous burning type with glove and stocking
7.5mg/kg/day) for 12 weeks with good response of skin distribution.45,46
lesions as well as the nerve function. Different pathophysiological mechanisms possibly
The significant adverse effects like renal dysfunction, leading to leprosy related neuropathic pain are small fiber
hypertension, electrolyte imbalance, neurological side neuropathy and persistent intraneural inflammation.45
effects, gum hyperplasia and the high cost are important
limiting factors with cyclosporine. Medical Treatment
Analgesics Simple analgesics like NSAIDS are usually ineffective.

Though there are no randomized controlled trials but in
Aspirin, ibuprofen, paracetamol and other NSAIDs can be corollary with the management of neuropathic pain of other
used in full doses for the pain control in patients with acute etiologies like postherpetic neuralgia and diabetic
neuritis. However, care should be taken while using them neuropathy, tricyclic antidepressants, anticonvulsants and
concurrently with steroids. opioids can be tried.
Intraneural Administration of Drugs Tricyclic Antidepressants (TCA)

Some workers have tried giving drugs via intra- or peri- There is no major difference between different drugs of
neural injections in patients whose acute severe neuritic this group. Amitriptyline and nortriptyline are the most
pain was not controlled with medical therapy alone. Various commonly used drugs. The drug is started at doses of 10-
drugs given via this route include the vasodilator drugs 25 mg and dose escalation is done every 3-7 days till
like isoxsuprine (Duvadilan) or tolazoline (Priscol), adequate pain relief is attained. The common side effects
spreading factor hylase and the corticosteroids. As the of TCA are sedation, tiredness, dry mouth, constipation,
intraneural injections are very painful, the drug was disturbances of micturition and orthostatic hypotension.
combined with local anaesthetics. Garrett41 was first to Less common side effects are disturbances of sexual
use this technique. functions and arrhythmias.
Results of this technique have been inconsistent. While
Anticonvulsants
Sepaha et al42 recommended the use of this technique,
Ramanujam43 reported results to be unsatisfactory. Carbamazepine is effective in neuropathic pain of varied
Recently Nashed et al44 reported successful treatment of etiologies.47 Dosage regimen is similar to that in epilepsy.
right claw hand deformity in a 60 year old male with monthly Drug is started at a dose of 100 mg daily and escalation of
intraneural injection of corticosteroids over a 6 month drug dose by 100 mg after 3 to 5 days. Adequate pain
relief is usually attained at doses of 400-600 mg daily.
period.
The common side effects are tiredness, vertigo and
This mode of drug administration has not been very
hyponatremia. Total blood cell counts and liver enzyme
popular because of two reasons. First, the pain during and
assay should be done at start of therapy.
(for few minutes) immediately following the injection is
Gabapentine is another anticonvulsant found to be
extremely severe and second, there is a potential danger
effective in management of neuropathic pain. It is started
of damaging the nerve fibers.
at dosage of 300 mg daily at bed time. The dose is
CHAPTER
31
escalated by 300 mg every 1-3 days till a maximum dose edema in the rigid fibro-osseous channels with limited
of 3600 mg. The most common adverse effects are vertigo, space, resulting in increased external pressure. Also the
tiredness and edema. perineurium does not give way to the swollen inflamed
Pregabalin received FDA approval for treating epilepsy nerve, again compromising the function of nerve axonal
and neuropathic pain in 2004. Pregabalin increases neuronal cylinders. Basis of nerve surgeries is to relieve the
GABA levels by producing a dose-dependent increase in mechanical compression, restoring the blood flow and
glutamic acid decarboxylase activity. It is given in a dose functioning of the nerve axonal cylinders.
of 150 mg daily at bed time and the maximum dose can As with steroids, early intervention with surgery results
be up to 450 mg per day. Dizziness, drowsiness, ataxia in complete recovery or arrest of progression of damage.48
and peripheral edema are uncommon side effects. Rarely The different surgical procedures are-
neutropenia has been reported.
1. Extra-neural Neurolysis
Opioids This is a decompression surgery in which constricting
Tramadol is a weak opioid with proven efficacy in fibrous bands and ligaments are excised and rigid fibro-
neuropathic pain. It produces little dependence and osseous channels opened. This procedure relieves the
tolerance. external pressure only. Fibro-osseous channels in relation
to the important nerve trunks are-
Surgery Ulnar nerve: The cubital tunnel at elbow, medial
There are two broad groups of surgeries which are done intermuscular septum, aponeurosis of flexor carpi ulnaris
for leprosy patients. One is the surgery of the nerves done muscle.
primarily to improve its function. The other group of surgeries Median nerve: The carpal tunnel at wrist
is done when nerve function cannot be improved and
reconstructive surgery needs to be done on muscles, Radial nerve: The spiral grove of humerus
tendons and bones to improve the disability. We would Common peroneal nerve: The retrofibular tunnel at neck of
confine our discussion to the former set of indications for fibula
nerve surgeries.
All the vessels supplying nerve should be carefully
There is a consensus regarding the validity of nerve
saved and the nerve should not be subjected to undue
surgeries but there is no uniformity of opinion on its
trauma or tension or traction or displacement from its bed.
indications, achieved benefits and the timing of surgery.
Surgery should be done under corticosteroid coverage as 2. Intra-neural Neurolysis or Longitudinal
the two modalities are complimentary and not competitive. Epineurotomy
While steroids would overcome the inflammation, surgery Longitudinal incisions are given in the sheath of the nerve
would help steroids to reach the target tissues in adequate trunk i.e. epineurium taking care not to injure the vasa
concentration. Indications for surgery are not well defined nervorum. This procedure has to be preceded by extra-
but are based on common practice. neural neurolysis.
The important indications are:
1. No improvement or deterioration while on steroids 3. Interfascicular Neurolysis
2. Corticosteroids are either contraindicated or not It is a meticulous and delicate procedure in which individual
tolerated due to adverse effects nerve bundles are dissected and separated. This procedure
3. Nerve abscess is now almost abandoned as it damages the nerve tissue
4. Intractable pain despite vigorous immunosuppressive and its vascularity, producing fibrosis which is far more
therapy crippling than the advantage it offers.
5. Sudden paralysis
It is believed that axonal damage is due to the 4. Nerve Abscess Drainage
inflammatory response of the body against M.leprae and A nerve abscess should always be drained. Longitudinal
ischemia. Ischemia is the result of increased intraneural incision is given over the abscess and all the caseous
pressure compromising the blood flow in vasa nervorum. liquid material is drained. If there is subcutaneous collection
The affected nerve is swollen and is unable to accommodate of the material then a collar stud extension into the nerve
CHAPTER
31
must be anticipated. The whole procedure should be done GENERAL MEASURES
meticulously to avoid trauma to the surviving nerve fibers.
Acutely inflamed nerve should be put to strict rest as any
After complete drainage, the skin is closed by sutures of
kind of trauma would further aggravate the inflammation.
suitable material.
In addition, rest also reduces the reactive fibrosis. This is
5. Nerve Transposition by Means of Medial done by immobilizing the limb in semi relaxed functional
Epicondylectomy position using padded splints.
Graduated exercises are to be done as the clinical
This procedure is done for the ulnar nerve at elbow. The
improvement occurs.
objective is to avoid stretching of the nerve with movement
Heat therapy in the form of short wave diathermy,
of the elbow joint, to increase the blood supply and
ultrasonic therapy and transcutaneous nerve stimulation
protecting it from injury by burying it into the muscles.
are different physical modalities which can be used for
Which surgery to be done; is the decision of operating
pain control, not fully responding to immunosuppressants.
surgeon based upon the gross appearance of the nerve at
Hand and foot care advice is given to the patient to
dissection and extent of its damage. prevent the development of nerve deficit related deformities
Evidence from randomized controlled trials for the and complications. Patient should be explained that the
effectiveness of decompressive surgery is scarce. The anaesthetic area will gradually contract with time; as the
most consistently reported benefit is the relief of nerve other nerve fibers supplying in neighbouring areas will take
pain and tenderness while nerve function improvement is over the function.
also frequently reported. Correct counselling of the patient is important. It should
Response to surgery depends on several factors and be emphasized that the reversal of NFI is highly
surgery results will be better in cases of: unpredictable and the duration of therapy is likely to be
A. Partially damaged nerve prolonged. Many patients tend to default from MDT when
B. Duration of neuritis before surgery less than six months. their long standing NFI does not improve or when they
Trial by Pannikar et al49 and Ebenezer et al50 compared develop new NFI while on MDT. The importance of
the added benefits of medial epicondylectomy and external continuation of MDT should be emphasized to ensure
decompression over corticosteroids for participants with compliance.
ulnar neuritis of less than six months duration. They did
not find any added benefit with surgical intervention as PREVENTION
compared to steroid therapy alone in the treatment of early
ulnar neuritis. Only the early diagnosis of leprosy and regular treatment
Boucher et al51 carried out a randomized controlled can prevent the nerve damage by killing all lepra bacilli
before they infect the nerves. The goal could be partially
trial of medical versus medico-surgical treatment of leprous
achieved by increasing awareness about the early signs
neuritis. They performed longitudinal epineurotomy for ulnar,
and symptoms of leprosy among the general public, and
median, common peroneal and posterior tibial nerve
removing the barriers (like social stigma) which prevent
involvement of less than six months duration. There was
people from reporting for treatment. Much of the nerve
no significant statistical difference between the two groups
damage occurs during reactions. Therefore patients at
with respect to the nerve involved, duration of the deficit,
higher risk of reactions should be educated about these
the form of leprosy and the type of antileprosy treatment.
reactional episodes in detail and emphasized to present
However, the medico-surgical treatment had a significantly early for treatment.
better result on pain; and on major but incomplete nerve Patients who are at increased risk of reaction and
involvement. Malaviya52 suggested that surgery should neuritis can be identified and put on prophylactic treatment.
be considered as add-on therapy to the steroids as they TRIPOD 1 trial53 investigated the role of low dose steroid
remove the external compression and improve the in the prevention of type1 reactions in MB patients. One
circulation so that steroids can reach the target tissues group of patients received 20 mg of prednisolone during
faster and lead to rapid improvement of nerve function. initial four months of MDT while the other group received
Complications of decompressive surgery include painful placebo. Incidence of type1 reaction was lower in the trial
scars, wound problems, hematoma, infection and damage group during the four months but the difference was not
to nerves, arteries or tendons. significant at the end of one year.
CHAPTER
31
Arunthathi et al54 tested the usefulness of clofazimine CONCLUSION

as a prophylactic agent against neuritis and nerve damage. Early and appropriate management of leprous neuritis is
Sixty five patients received high doses (300 mg daily) of the key to prevention of disabilities in leprosy patients.
clofazimine for initial three months of MB-MDT and the Our understanding of pathogenetic mechanisms involved
control group received only MB-MDT. Patients were in nerve damage is incomplete and more research is needed
followed for two years and the incidence of neuritis was for development of new principles in therapy and
significantly lower in the test group (5.66%) as compared prophylaxis.
to control group (26.1%).
ACKNOWLEDGEMENT
NEWER APPROACHES OF TREATMENT
The authors thankfully acknowledge the help of Dr Savita
Till now we largely rely on anti-inflammatory agents for the Yadav, Senior Resident, Department of Dermatology,
treatment of leprosy related neuritis. With the advancement PGIMER, Chandigarh in the preparation of this manuscript.
in the knowledge of pathophysiology of leprosy infection
and leprosy related neuritis, newer approaches of treatment REFERENCES
are designed which are in experimental stages - 1. Spierings E, De Boer T, Wieles B et al. Mycobacterium leprae-
a. Drugs and vaccines blocking the attachment of specific, HLA class II-restricted killing of human Schwann cells
Mycobacteria to the Schwann cell-axon unit: With the by CD4+ Th1 cells: a novel immunopathogenic mechanism of
identification of neural targets on Schwann cells and nerve damage in leprosy. J Immunol 2001; 166: 5883-88.
2. Rambukkana A, Zanazzi G, Tapinos N et al. Contact-dependent
the specific bacterial component responsible for neural demyelination by Mycobacterium leprae in the absence of
tropism, agents blocking the attachment of the two immune cells. Science 2002; 296: 927-31.
can be designed.55 These agents would prevent the 3. Rosenberg NR, Faber WR, Vermeulen M. Unexplained delayed
entry of bacilli into the nerve. nerve impairment in leprosy after treatment. Lepr Rev 2003; 74:
357-65.
b. Neruotrophic factors (NTFs): Schwann cells play
4. Croft RP, Nicholls PG, Steverberg EW et al. A clinical prediction
significant role in the maintenance and regeneration of rule for nerve-function impairment in leprosy patients. Lancet
axons of the neurons in the peripheral nervous system. 2000; 355: 1603-06.
These cells are regulated by neurotrophic factors. NTF 5. Roche PW, Theuvenet WJ, Britton WJ. Risk factors for type-1
reactions in borderline leprosy patients. Lancet 1991; 338:
have been found to increase the transmission of
654-57.
impulses between fibers of collateral axons blocked 6. Van Brakel WH, Saunderson P, Shetty V et al. International
by mycobacterial antigens in the axoplasm.56 These workshop on neuropathology in leprosy—consensus report.
NTFs could be the drug molecules of future promoting Lepr Rev 2007; 78: 416-33.
the nerve regeneration and conduction in existing fibers. 7. Vijaikumar M, D’Souza M, Kumar S et al. Fine needle aspiration
cytology (FNAC) of nerves in leprosy. Lepr Rev 2001;72:
171-78.
HIV AND LEPROUS NEURITIS 8. Jayaseelan E, Shariff S, Rout P. Cytodiagnosis of primary neuritic
leprosy. Int J Lepr Other Mycobact Dis 1999; 67: 429-34.
Presently, co-infection with HIV-1 and M.leprae is a rare 9. Barnes PJ. Anti-inflammatory action of glucocorticoids: molecular
event in India. With increasing HIV prevalence, in future mechanisms. Clin Sci 1998; 94: 557-72.
10. Buttgereit F, Wehling M, Burmester GR. A new hypothesis of
we are likely to get more number of cases suffering from
modular glucocorticoid actions: steroid treatment of rheumatic
both ailments. HIV per se produces neuropathy and so diseases revisited. Arthritis Rheum 1998; 41:761-67.
would aggravate it in leprosy patients. Steroids have to be 11. Lipworth BJ. Therapeutic implications of non genomic
given cautiously in these patients with strict monitoring glucocorticoid activity. Lancet 2000; 356: 87-88.
for adverse effects. 12. Britton WJ. The management of leprosy reversal reactions. Lepr
Rev 1998; 69: 225-34.
Leprous neuritis and type1 reactions were found to be 13. WHO action Programme for the Elimination of Leprosy. A guide
more common in HIV seropositive MB cases; as compared to eliminate leprosy as a public health problem. 1995.
to HIV seronegative MB cases, while the same did not 14. Becx-Bleumink M, Berhe D, Mannetje W. The management of
hold true for PB cases.57 HIV seronegative and seropositive nerve damage in the leprosy control services. Lepr Rev 1990;
61:1-11.
patients showed a similar response to steroid therapy for 15. Naafs B. Treatment of reactions and nerve damage. Int J Lepr
the management of acute neuritis. Other Mycobact Dis 1996;64:S21-28.
CHAPTER
31
16. Van Brackel WH, Anderson AM, Withington SG et al. The 36. Marlowe SN, Hawksworth RA, Butlin CR, et al. Clinical outcomes
prognostic importance of detecting mild sensory impairment in in a randomized controlled study comparing azathioprine and
leprosy; randomized controlled trial (TRIPOD 2). Lepr Rev 2003; prednisolone versus prednisolone alone in the treatment of
74: 300-10. severe leprosy type 1 reactions in Nepal. Trans R Soc Trop Med
17. Rao PS, Sugamaran DS, Richard J et al. Multi-centre, double Hyg 2004; 98:602-09.
blind, randomized trial of three steroid regimens in the treatment 37. Miller RA, Shen JY, Rea TH et al. Treatment of chronic erythema
of type-1 reactions in leprosy. Lepr Rev 2006; 77: 25-33. nodosum leprosum with cyclosporine A produces clinical and
18. Garbino JA, Virmond Mda C, Ura S et al. A randomized clinical immunohistologic remission. Int J Lepr Other Mycobact Dis 1987;
trial of oral steroids for ulnar neuropathy in type 1 and type 2 55: 441-49.
leprosy reactions. Arq Neuropsiquiatr 2008; 66: 861-67. 38. Chin-A-Lien RA, Faber WR, Naafs B. Cyclosporin A treatment in
19. Naafs B, Pearson JM, Wheate HW. Reversal reaction: the reversal reaction. Trop Geogr Med 1994; 46:123-24.
prevention of permanent nerve damage. Comparison of short 39. Sena CB, Salgado CG, Tavares CM et al. Cyclosporine A
and long-term steroid treatment. Int J Lepr Other Mycobact Dis treatment of leprosy patients with chronic neuritis is associated
1979; 47: 7-12. with pain control and reduction in antibodies against nerve growth
factor. Lepr Rev 2006; 77: 121-29.
20. Naafs B. Treatment duration of reversal reaction: a reappraisal.
40. Marlowe SN, Leekassa R, Bizuneh E et al. Response to
Back to the past. Lepr Rev 2003; 74: 328-36.
cyclosporine treatment in Ethiopian and Nepali patients with
21. Saunderson P, Gebre S, Desta K, et al. The pattern of leprosy-
severe leprosy Type 1 reactions. Trans R Soc Trop Med Hyg
related neuropathy in the AMFES patients in Ethiopia: definitions,
2007; 101: 1004-12.
incidence, risk factors and outcome. Lepr Rev 2000; 71: 285-
41. Garrett AS. Hylase (Hyaluronidase) injection for lepromatous
308.
nerve reactions. Lepr Rev 1956; 27: 61-63.
22. Schreuder PA. The occurrence of reactions and impairments in 42. Sepaha GC, Sharma DR. Intraneural cortisone and priscol in
leprosy: experience in the leprosy control program of three treatment of leprosy. Lepr India 1964; 36: 264-68.
provinces in north-eastern Thailand, 1987–1995 [correction of 43. Ramanujam K. A note of the use of intra-neural corticoids in
1978–1995]. III. Neural and other impairments. Int J Lepr Other acute leprous neuritis. Lepr India 1964; 36: 261-63.
Mycobact Dis 1998; 66: 170-81. 44. Nashed SG, Rageh TA, Attallah-Wasif ES et al. Intraneural
23. Van Brakel WH, Khawas IB. Nerve function impairment in leprosy: injection of corticosteroids to treat nerve damage in leprosy: a
an epidemiological and clinical study – Part 2: Results of steroid case report and review of literature. J Med Case Reports 2008;
treatment. Lepr Rev 1996; 67: 104-18. 2: 381.
24. Richardus JH, Withington SG, Anderson AM et al. Treatment 45. Lund C, Koskinen M, Suneetha S et al. Histopathological and
with corticosteroids of long-standing nerve function impairment clinical findings in leprosy patients with chronic neuropathic pain:
in leprosy: a randomized controlled trial (TRIPOD 3). Lepr Rev a study from Hyderabad, India. Lepr Rev 2007; 78: 369-80.
2003; 74: 311-18. 46. Hietaharju A, Croft R, Alam R et al. Chronic neuropathic pain in
25. Saunderson P. The epidemiology of reactions and nerve damage. treated leprosy. Lancet 2000; 356: 1080-81.
Lepr Rev 2000; 71: S106-10. 47. McQuay H, Moore A. An evidence based resource for pain
26. Miko TL, Maitre CL, Kinfu Y. Damage and regeneration of relief. Oxford University Press, Oxford 1998.
peripheral nerves in advanced treated leprosy. Lancet 1993; 48. Husain S, Mishra B, Prakash V et al. Results of surgical
342: 521-25. decompression of ulnar nerve in leprosy. Acta Leprol 1998; 11:17-
27. Croft RP, Nicholls PG, Richardus JH et al. The treatment of 20.
acute nerve function impairment in leprosy: results from a 49. Pannikar VK, Ramprasad S, Reddy NR et al. Effect of
prospective cohort study in Bangladesh. Lepr Rev 2000; 71: epicondylectomy in early ulnar neuritis treated with steroids. Int
154-68. J Lepr Other Mycobact Dis 1984; 52: 501-05.
28. Lockwood DN, Vinayakumar S, Stanley JN et al. Clinical features 50. Ebenezer M, Andrews P, Solomon S. Comparative trial of steroids
and outcome of reversal (type 1) reactions in Hyderabad, India. and surgical intervention in the management of ulnar neuritis. Int
Int J Lepr Other Mycobact Dis 1993; 61: 8-15. J Lepr Other Mycobact Dis 1996; 64: 282-86.
29. Richardus JH, Withington SG, Anderson AM, et al. Adverse 51. Boucher P, Millan J, Parent M et al. Randomized controlled trial
events of standardized regimens of corticosteroids for of medical and medico-surgical treatment of Hansen’s neuritis.
prophylaxis and treatment of nerve function impairment in leprosy: Acta Leprol 1999; 11: 171-77.
52. Malaviya GN. Shall we continue with nerve trunk decompression
results from the ‘TRIPOD’ trials. Lepr Rev 2003; 74: 319-27.
in leprosy? Indian J Lepr 2004; 76: 331-42.
30. Ross WF. Does clofazimine have any value in the management
53. Smith WC, Anderson AM, Withington SG, et al. Steroid prophylaxis
of reversal reaction? Lepr Rev 1980; 51: 92-93.
for prevention of nerve function impairment in leprosy:
31. Imkamp FM. Clofazimine (lamprene or B663) in lepra reactions.
randomized placebo controlled trial (TRIPOD 1). BMJ 2004;
Lepr Rev 1981; 52: 135-40.
328: 1459-62.
32. Pfaltzgraff RE. The control of neuritis in leprosy with clofazimine.
54. Arunthathi S, Satheesh KK. Does clofazimine have a prophylactic
Int J Lepr Other Mycobact Dis 1972; 40: 392-98. role against neuritis? Lepr Rev 1997; 68: 233-41.
33. Ramu G, Girdhar A. Treatment of steroid dependant cases of 55. Rambukkana A. Molecular basis of the interaction of
recurrent lepra reaction with a combination of thalidomide and Mycobacterium leprae with peripheral nerve: implications for
clofazimine. Lepr India 1979; 51: 497-504. therapeutic strategies. Lepr Rev 2000; 71: S168-69.
34. Schreuder PA, Naafs B. Chronic recurrent ENL, steroid 56. Anand P. Neurotrophic factors and their receptors in human
dependent: long-term treatment with high dose clofazimine. Lepr sensory neuropathies. Prog Brain Res 2004; 146: 477-92.
Rev 2003; 74: 386-99. 57. Bwire R, Kawuma HJ. Type 1 reactions in leprosy, neuritis and
35. Theophilus S. Treatment with thalidomide in steroid dependency steroid therapy: the impact of the human immunodeficiency virus.
and neuritis. Lepr India 1980; 52: 423-28. Trans R Soc Trop Med Hyg 1994; 88: 315-16.
CHAPTER
32
32 Leprosy Vaccines
and Immunotherapy
Kiran Katoch
INTRODUCTION IMMUNOPROPHYLAXIS
Leprosy is a unique chronic infectious disease with a long The principle of immunoprophylaxis is based on enhancing
and variable incubation period. The disease manifests the host immunity and is perhaps, the most effective
clinically in the skin, peripheral nerves or both. The means of controlling infectious diseases. The global
manifestations of disease depend to a large extent on the eradication of smallpox could be achieved mainly because
immune response of the host. The diagnosis of the disease of the availability of a cheap and effective vaccine which
is mainly by clinical criteria and there is no definitive test successfully enhanced the specific host immunity.
(especially in the early stages) when the disease is Generally vaccines have the capacity to provoke an
evolving. Due to immunological alterations evoked by the immune response which enables the host to effectively
organism in the susceptible host; the patient suffers from deal with the infecting organism and protect the host from
immunological reactions which are the main cause of disease.
The issue of the need of a vaccine to prevent leprosy
morbidity due to the disease.
has been, and is still being debated. With changing profile
Besides the live pathogen which triggers the immune
of the disease, curability of the disease with effective and
response; it is believed that the dead bacilli and/or their
widely available chemotherapy (multi-drug therapy, MDT)
products also trigger immune responses which are linked
coupled with low incidence rates of the disease; vaccine
with pathology of the disease; especially reactions and
development has taken a back stage by most research
nerve damage. Although the prevalence of the disease
groups and funding agencies. Moreover, with limited
has decreased markedly due to successful implementation knowledge of the transmission dynamics of the disease,
of MDT, new cases continue to occur which indicates a vaccine for use in the general population is not the real
continued transmission in the community. need, especially in the post elimination era, but may still
Therefore besides chemotherapy, which primarily be required for specific groups like close family contacts.
targets the live organism, immune modulators are required With the increased survival of AIDS patients and
to modulate the immune response which damages the manifestation of the immune reconstitution syndrome
host. These (immunomodulators) are the substances which (IRIS) with the wide spread use and availability of anti-
help to regulate the immune system and optimize the retroviral therapy (ART), the debate on immunoprophylaxis
immune response. The immune response is essential not is still alive and needs even more attention. Vaccines are
only for recovery from the infection; but also for prevention normally antigenically similar to the pathogen; which are
from the development of disease. Over the last four capable of evoking an immune response in the host. They
decades, considerable data on immunoprophylaxis and are mostly of the following categories:
immunotherapy related aspects of the disease have a. Killed organisms that have lost their infectivity but have
become available. This information is being discussed in retained their antigenicity. The residual ‘protective’
the light of current needs. antigens can evoke an immune response.
CHAPTER
32
Leprosy Vaccines and Immunotherapy 411
b. Live attenuated organisms are also used that are able + killed M. leprae. On the other hand, protection was up to
to provoke a protective response in the host against 60% in household contacts who received a single dose of
the pathogen by active multiplication in the host, the killed Mw as compared to BCG (Gupte et al, unpublished
process similar to that of natural disease evolution, reports). In immunoprophylactic trials undertaken by Convit
but does not cause the disease per se. et al BCG + killed M. leprae did not provide significant
c. Related non-pathogenic organisms that antigenically additive effect over the use of BCG alone.5
cross-react with the pathogen and evoke an immune For assessing the use of the vaccine in a selected
response in the host and act as a vaccine. population, another large field based, double blind,
d. More recently, the immunogenic ‘subunit / (s)’ of the controlled clinical study was undertaken in the family
organism are also used which evoke a protective contacts of index leprosy cases, in Ghatampur district of
response. Kanpur, using 2 doses of killed Mw administered at an
Vaccines have been developed from each of the above interval of 6 months. On follow-up of the household contacts
four categories (a, b, c and d) and have been shown to a protective efficacy of 68% and 60% was observed after
provide variable degrees of protection. The protective effect a follow-up of 3 and 6 years respectively. However, this
of vaccination in the host can vary for several reasons efficacy decreased to 39.3% 10 years after vaccination,
which include, indicating a need for a second booster after around 8-10
i. route of administration years later.6 Long-term results of the use of ICRC vaccine
ii. age at the time of vaccination in contacts are not available. It would be noteworthy to
iii. coverage of vaccination in the area mention here that of these vaccines only BCG and Mw
iv. duration of follow-up are available commercially.
v. related endemic diseases
vi. nutrition and genetic susceptibility of the population IMMUNOTHERAPY
vii. other similar antigenically related bacteria prevailing Although the present day chemotherapy has helped in
in the local environment reducing the prevalence and incidence of the disease and
All the above factors are known to influence the outcome achieving elimination goal at the national level, some
of the vaccination. problems do remain.
The use of BCG as an anti-leprosy vaccine has i. relatively long duration of treatment schedule,
produced widely varying results in different populations. It ii. adherence to the treatment regimen,
is an attenuated strain of M. bovis. Calmette, during early iii. persistence of disease activity after stoppage of
part of the 20th century, described its prophylactic role in therapy,
cattle. Later on, it was found to be useful in the humans in iv. occurrence of reactions and nerve damage during
prevention of tuberculosis. This has been widely used as well as after stoppage of therapy;
throughout the world and has been reported to offer v. occurrence of relapses,
significant protection against leprosy also.1 In a large scale All above issues call for a better and more efficient
prospective study in South India, the prophylactic effect management of the disease. Addition of immunotherapy
was very limited; with no protection against the smear has been tried and shown to improve the treatment outcome.
positive forms of disease.2 Other case control studies The addition of immunotherapy to chemotherapy aims at:
showed that BCG could be of value in preventing borderline i. Achieving more efficient killing of viable bacilli,
leprosy.3 In the comparative leprosy vaccine trial in South including the persistor organisms,
India four vaccines; namely (1) BCG, (2) BCG + killed ii. Faster clearance of dead bacilli and their components
M. leprae, (3) Mw and (4) ICRC were administered to about from the body,
1,71,000 subjects from general population. The protective iii. Reducing the incidence and severity of reactions and
efficacy after 5 years of follow-up was observed to be the nerve damage
highest for ICRC (65.5%), BCG + killed M. leprae provided iv. Restoration of effective immunity in the host which
64% protection, while BCG and Mw provided 34.1% and helps in reducing relapse and re-infection.
25.7% protection respectively.4 However, with a longer The immunomodulators being used in leprosy can be
follow-up, this protection decreased considerably with BCG broadly classified into:
CHAPTER
32
i. Antigenically related mycobacteria which share et al in 198516 and Waters et al in 1993 reported beneficial
antigens with M. leprae. effects of this vaccine.17
ii. Drugs acting as immunomodulators
Mycobacterium w (Mw): Mw is a rapid growing, non-
iii. Other miscellaneous agents and components of
pathogenic, saprophytic cultivable mycobacteria belonging
M. leprae
to Runyon group IV of classification of mycobacteria. It
shares several antigens with M. leprae (65 Kd, 18 Kd & 13
Antigenically Related Mycobacteria
Kd) and M. tuberculosis. 18 It is administered as an
Mycobacteria which share some antigens or show cross autoclaved heat killed vaccine in the dose of 5 x 109 bacilli/
reactivity with M. leprae have been studied for their 0.1 ml of physiological saline intradermally in the first dose,
immunomodulatory potential in animals and in humans. and subsequently in the half dose, i.e. 5 x 10. 8 Its
Mycobacteria which have been tried in humans include immunomodulatory effect has been tested in vitro, in
BCG, BCG + killed M. leprae, Mycobacterium w, ICRC experimental animals19 and also in humans.20-25 It is well
bacillus, Mycobacterium vaccae and Mycobacterium tolerated and safe, the only minor side effect being (seen
habana. in about a third of cases) the formation of blister/nodule at
Mycobacterium bovis (BCG): This was one of the first the site of inoculation. The blister appears at 3-4 weeks
mycobacteria to be tried in humans and has shown both, and heals on its own by 6-8 weeks. The results with Mw in
non-specific as well as specific immunomodulatory effect multibacillary patients have shown an earlier achievement
against mycobacteria. It is used as a live vaccine. of smear negativity, a more rapid bacterial clearance and
Fernandez in 1939 demonstrated lepromin conversion in rapid killing of viable bacilli in patients receiving Mw +
30% to 100% individuals vaccinated with BCG.7 Convit et MDT as compared to MDT alone. Mukherjee et al reported
al in 1974 and 1982 reported lepromin conversion and a significantly higher percentage of patients showing
enhanced bacterial clearance in treated lepromatous leprosy upgrading and/or enhanced clearance of dermal granuloma
patients after BCG vaccination.8,9 Immunotherapy with in Mw vaccinated + MDT group; as compared to the MDT
BCG showed enhanced bacterial killing and clearance in alone group.26 Natrajan et al observed similar results with
BL/LL smear positive patients treated for 2 years with a more rapid granuloma clearance and histological
upgrading in Mw + MDT group; as compared to MDT +
standard MB MDT.10 Subsequently BCG was given with
placebo.12 In the studies undertaken at JALMA, Mw was
MDT from the beginning of treatment and subsequently
given along with MDT every 6 months in highly bacillated
every 6 months; till the end of treatment. The vaccine was
BL/LL patients till 24 months.10,11,12,27 To summarize the
well tolerated and there was a blister/nodule formation at
effects, Mw was well tolerated and there were no side
the site of vaccination which healed on its own.10,11 There
effects except for blister/nodule formation at the local site
was a faster bacteriological attainment of smear negativity,
of injection, which appeared in 2-4 weeks and regressed
faster fall in BI, more rapid killing of viable bacilli (as
within the next 1 to 2 months with a small scar. The fall in
observed by mouse foot pad inoculation and estimation of
BI and incidence of reactions in the Mw + MDT and MDT
ATP from the tissue biopsies). The severity and incidence
+ placebo group is shown in the following Figure 32.1.
of reactions was not increased and rather in patients
The fall in BI was as a result of killing of viable bacilli
receiving MDT alone the reactions persisted for a longer
as measured by mouse foot pad inoculation and measuring
duration. Natrajan et al reported faster granuloma clearance
the ATP in the tissue biopsies of these patients.11,27 The
and histological upgrading in these patients.12
patients in Mw + MDT group became smear negative in
BCG + killed M. leprae: Shepard et al observed the 32 months; while patients in the MDT + placebo group
protective effect of BCG + killed M. leprae in mice13 and took 52 months to attain smear negativity. Besides, the
this was subsequently tried in humans by Convit et al in granuloma fraction also decreased more rapidly and there
1982 9 and later in 1993. 14 He reported beneficial was more lymphocytic infiltration in the Mw group as
immunological changes in indeterminate leprosy patients, compared to MDT+ placebo group.12 There was no increase
Mitsuda negative close contacts and lepromatous leprosy in the incidence of reactions (both reversal and ENL), rather
patients. Meyers et al in 1988 reported histological the reactions stopped earlier in the Mw + MDT group; as
upgrading in patients receiving this therapy15 while Samuel compared to MDT + placebo group. Kar et al observed a
CHAPTER
32
Besides the related mycobacteria discussed above,
there are a few more mycobacteria which have some
antigenic similarity with M. leprae and show some degree
of cross sensitization (Table 32.1). These include
Mycobacterium habana,37,38 Mycobacterium phlei and
Mycobacterium gordonnae.19
Immunomodulator Drugs
Levamisole
This is a broad spectrum anti-helminthic which acts by
influencing the host defences by modulating the cell
mediated human response, as seen by in vitro and in vivo
experiments.39,40 It is believed to have an immuno-
Fig. 32.1: Reactional episodes and bacteriological decline in the highly modulatory effect on defective T lymphocyte function and
bacillated patients in the two sets of patients receiving MDT with or has been tried in lepromatous leprosy patients. Martinez
without Mw vaccine
and Zaias in 1976 used levamisole as an adjunct to
slightly increased incidence of reversal reaction (RR) in dapsone therapy and reported clinical improvement in the
BL/LL patients given Mw + MDT (Mw given at 3 month lesions and decrease in incidence of reactions as compared
interval); as compared to MDT alone. This RR was of mild to the placebo.41 In another study, 150 mg of levamisole
nature, short lasting and not leading to any significant was given twice a week for 6 weeks in persistently skin
morbidity. In fact, it comprised a protective defence smear positive, lepromatous leprosy patients who had
mounted by the host to the antigenic challenge.23 received continuous dapsone treatment for 5 years. Most
of the patients became skin smear negative by 1 year of
ICRC bacillus : This organism was isolated from leprosy
treatment.42 Sher et al administered levamisole daily for
patients and showed cross reactive antigens to M. leprae
2 consecutive days every week, for 6 weeks in a group of
in the in vitro and in vivo experiments;19,21,28 as well as in
lepromatous patients. Although there was no significant
human studies.29-32 The authors reported that when killed
clinical improvement at the end of 6 weeks; there was a
ICRC vaccine along with chemotherapy; was given in
significant change histologically in the biopsies and in the
lepromatous leprosy patients; reversal reactions and
E and EAC rosettes of those who took levamizole.39
lepromin convertibility was observed. They also reported
The use of levamisole as an adjunct to MDT has been
a significant and rapid fall in the BI of this group.
reported by Kar et al. There was no conversion of Mitsuda
Mycobacterium vaccae: This mycobacteria also shares reactivity and no change in leucocyte migration inhibition
some antigens with M. leprae and has been shown to induce in both, controls (only MDT) and the experimental group
in vitro and in vivo immune reactivity in leprosy patients. (MDT+ Levamisole). In both the groups, statistically
Its beneficial effects have been reported in leprosy patients significant clinical and bacteriological improvement and
when combined with BCG.17,33-36 increase of EAC rosette counts was found at the end of
Table 32.1: In vitro and in vivo effects of the various mycobacteria

Agent LMIT LTT Lepromin response Tuberculin response Protection in mice
BCG + + + + +
BCG + killed M. leprae + + + + Not done
Mw + + + + +
ICRC + + + + +
M habana + + + + +
M vaccae + + + + Not done
M phlei + + + Not done +
M gordonnae + + + Not done Not done
CHAPTER
32
one year. However, the bacteriological improvement in the formation of epithelioid granuloma and occurrence of
trial group showed statistically significant difference when reversal reaction in some cases.47-50 Enhanced bacterial
the improvement was compared with that of control group. clearance at the local site has also been observed by
No adverse effects due to levamisole were encountered.43 Sivasai et al.51 The administration of Interleukin-2 has also
been reported to produce similar effects.52
Zinc
Zinc has also been tried as an immunomodulator in Aceto Acetylated M. leprae
treatment of lepromatous leprosy. When given in therapeutic This is a carrier modified M. leprae and a single injection
dosages, it inhibits the complement dependent immune was observed to produce a positive lepromin response in
complex formation and polymorphonuclear leucocyte 7 out of the 13 patients who were repeatedly lepromin
chemotaxsis.44 It has also been tried in recurrent ENL negative.53
reaction and it was observed that after giving zinc therapy;
steroids could be withdrawn completely; and the duration De-lipified Cell Components
and severity of reaction could also be reduced.45 Cases of M. leprae (DCC)
treated with zinc showed faster clinical improvement,
re-growth of the eyebrows and rapid fall in BI of the skin Mahadevan and Robinson observed that defective
macrophages of leprosy patients were able to recognize
and in the granuloma as seen histologically. Histopatho-
DCC as an antigen which led to production of desired
logical upgrading occurred in 6 of the 15 cases (40%)
lymphokines.54 Mice vaccinated with DCC could mount a
treated with zinc + dapsone, as compared with 1 out of
10 cases (10%) with dapsone alone. Five out of six patients CMI response and control the growth of M. leprae.55
who showed upgrading in the treated group, became
Soluble Protein Component Obtained from
lepromin positive while only one patient (a BL case) showed
Cell Wall of M. leprae
lepromin conversion in the control group.44 However, the
effect of zinc with MDT has not been documented. The soluble cell wall component acts as antigen, causes
stimulation of T cell and shows protection in mice.56-58
Other Drugs Immunotherapy leads to systemic changes in the host
Various other drugs like corticosteroids, thalidomide, high in the form of improved cell mediated immune responses,
doses of clofazimine (300 to 400 mgs daily), colchicine, better killing/ clearance of organisms/ related pathology
and cyclosporine have been used by various workers for and ultimately the faster clinical recovery (Table 32.2).
treatment of neuritis and ENL reactions. However, the major limitations of IL-2 and IFN-γ are;
the effects are seen locally, only at the site of injection
and last for a limited period, whereas the effects of the
OTHER IMMUNOMODULATORS
related mycobacteria are longer lasting and are observed
Transfer Factor in other parts of the body, besides the local area of
This was used by Hastings and Job and was shown to inoculation.
induce lepromin conversion, granuloma formation and
increased influx of lymphocytes locally when injected. CONCLUSION
However, these effects were short lived and not seen Most of the studies cited above were undertaken in times
systemically.46 when the disease profile was different from that of now
and several highly bacillated patients were reporting for
Cytokines/Interleukins
treatment and were also being detected in field conditions.
The use of gamma interferon (IFN-γ) has been shown to The treatment was for a longer duration and several patients
activate macrophages and cause intracellular killing of were reporting with reactions.
M. leprae. However, it had to be injected and the results The disease profile has since changed, more smear
were confined locally and for a short period. Intra-lesional negative cases are detected and fixed duration treatment
injections of recombinant IFN-γ have demonstrated a is now used for treating patients. However, the reactions
distinct fall in the bacteriological index at the local site, do continue to occur in patients and are a cause for
CHAPTER
32
Table 32.2: Systemic effects of immunotherapy as used in leprosy
Agent Lepromin conversion Histological Clinical Bacterial Clearance Reactions
used response killing of bacilli
contacts Indet. BL Upgrading Non RR ENL
leprosy leprosy specific
BCG + + + + + Good + + ±
BCG + + + + + Good +
killed M. leprae
Mw + + + + + Good + + ± ±
ICRC + + + Good + + +
BCG + M vaccae + + + Good + +
IL-2 + + Good + + +
IFN-γ + Good +
continued morbidity due to the disease. Understanding the and in vitro studies, experimental animals; as well as large
beneficial effects of combining immunotherapy with scale studies (both under hospital based and field settings)
chemotherapy may help in reducing reactions, faster with long follow up of 10-15 years.
granuloma clearance and may help further in reducing the
duration of treatment by helping in both, killing of viable REFERENCES
bacilli and clearance of dead bacilli. Despite effective MDT,
1. Bagashawe A, Scot GC, Russel DA et al. BCG vaccination in
persisting viable organisms are a significant problem in a leprosy: final results of the trial in Karinaul Papua New Guinea.
section of leprosy patients.59 Immunotherapy is a good Bull WHO 1989; 67:389-99.
option to overcome this problem.27 2. Gupte MD. Vaccine trials against leprosy. Int J Lepr 1998; 66:
The whole genome of Mw has been mapped and 587-89.
3. Mulyil JP, Nelson KE, Diamond EL. Effect of BCG on the effect of
sequenced; and the mycobacteria has been renamed as leprosy in endemic area: a case control study. Int J Lepr 1991;
Mycobacterium indicum pranii.60 Further studies can be 59: 229-36.
planned to identify parts of the genome which impart the 4. Gupte MD, Vallishayee RS, Ananathramanan DS et al.
immunomodulatory properties to the organism. Comparative leprosy vaccine trial in South India. Indian J Lepr
1998; 70: 369-87.
Immunotherapy combined with chemotherapy is a good
5. Convit J, Smith PG, Zuniga M et al . BCG vaccination protects
and viable option to overcome the problems with present against leprosy in Venezuela: a case control study. Int J Lepr
day MDT.27 Agents like BCG and Mw (Immuvac(R)) can be 1993; 61: 185-91.
used as immunotherapeutic adjuncts on case to case 6. Sharma P, Mukherjee R, Talwar P et al . Immunoprophylactic
effects of anti-leprosy vaccine in household contacts of leprosy
basis as they are safe, well tolerated and also available
patients: clinical field trials with a follow-up of 8-10 years. Lepr
commercially. Rev 2005; 76: 127-43.
Although, leprosy elimination has been achieved (in 7. Fernandez JMM. Use of BCG in immunoprophylaxis of leprosy.
most countries); eradication probably can not be achieved Rev Arg Dermatol 1939; 23:435.
by MDT alone.61,62 The issue of using mass vaccination 8. Convit J, Pinnardi ME, Rodriguez OC et al. Elimination of
Mycobacterium leprae by other mycobacteria, Clin Exp Immunol
in selected endemic pockets and situations, is also worth 1974; 17: 821-26.
consideration. 63 Both BCG and Mw have potential 9. Convit J, Aranzazu N, Ulrich M et al. Immunotherapy with a
immunoprophylactic role against tuberculosis and leprosy. mixture of Mycobacterium leprae and BCG in different forms of
The role of BCG against adult pulmonary TB in India was leprosy and Mitsuda negative contacts. Int J Lepr 1982; 50:
415-24.
not considered significant,64 although there is some amount
10. Katoch K, Natrajan M, Narayan RB et al. Immunotherapy of
of protection imparted against leprosy. However, Mw has treated BL/LL cases with BCG: histological, immunohistological
the advantage of being potentially useful against both and bacteriological assessment. Acta Leprol 1989; 17: 153-55.
leprosy6 and tuberculosis65 and may be a better option. It 11. Katoch K, Katoch VM, Natrajan M et al. Treatment of bacilliferous
BL/LL cases with combined chemotherapy and immunotherapy.
merits consideration and in-depth investigations, especially
Int J Lepr 1995; 63: 202-12.
in view of resurgence of tuberculosis in the era of HIV 12. Natrajan M, Katoch K, Bagga AK et al. Histological changes with
pandemic. These agents besides being safe and well combined chemotherapy and immunotherapy in highly bacillated
tolerated; have been shown to be beneficial in both in vivo lepromatous leprosy. Acta Leprol 1992; 8: 79-86.
CHAPTER
32
13. Shepard CC, Van Landinghaun R, Walker LL. Search among 31. Bhakti WS, Chulawala RG, Bapat CV et al. Reversal reaction in
mycobacterial cultures for anti-leprosy vaccines. Infect Immunity lepromatous leprosy patients induced by a vaccine containing
1980; 29: 1034-39. killed ICRC bacilli – A report of 5 cases. Int J Lepr 1983; 51: 466-
14. Convit J, Smith PG, Zunigha M et al. BCG vaccination protects 72.
against leprosy in Venezuela: a case report. Int J Lepr 1993; 32. Bhakti WS, Chulawala RG. Immunotherapeutic potential of ICRC
61:185-91. vaccine – A case control study. Lepr Rev 1992; 63: 358-64.
15. Meyers W, McDougall AC, Flurry RN et al. Histological responses 33. Stanford JL, Stanford CA, Ghazi Saudi K et al. Vaccination and
in sixty multibacillary patients inoculated with autoclaved skin test studies on children of leprosy patients. Int J Lepr 1989;
Mycobacterium leprae and live BCG. Int J Lepr 1988; 36: 302- 57: 38-44.
09. 34. Stanford JL. Rook GAW, Bahr GM et al. Mycobacterium vaccae
16. Samuel NM, Neopani K, Louden J et al. Vaccination of leprosy in the immunoprophylaxis and immunotherapy of leprosy and
patients and healthy contacts. Indian J Lepr 1985; 57: 288-96. tuberculosis. Vaccine 1990; 8: 525-30.
17. Waters MFR, Filley E, Stanford JL. Annual immunotherapy in 35. Ghazi Saudi K, Stanford JL, Stanford CA et al. Vaccination and
treated lepromatous leprosy with three BCG based vaccines: A skin test studies in children living in villages of different endemicity
six years assessment. Int J Lepr 1993; 61: 103A. of leprosy and tuberculosis. Int J Lepr 1989; 57: 45-53.
18. Mustafa AS. Identification of T-cell activating recombinant 36. Ganapati R, Revankar CR, Lockwood DNJ et al. A study of
antigens shared among three candidate anti-leprosy vaccines; three potential vaccines of leprosy in Bombay. Int J Lepr 1989;
killed M.leprae, M.bovis BCG and Mycobacterium w. Int J Lepr 57: 33-37.
1988; 56: 265-273. 37. Singh NB, Lowe C, Rees RJW et al. Vaccination of mice against
19. Mustafa AS, Talwar GP. Five cultivable mycobacterial strains M. leprae infection. Infect Immun 1989; 57:633-55.
giving blast formation and leukocyte migration inhibition of 38. Singh NB, Srivastava A, Gupta HP et al. Induction of lepromin
positivity in monkeys by a candidate anti-leprosy vaccine
leukocyte analogous to Mycobacterium leprae. Lepr India 1978;
M. habana. Int J Lepr 1991; 59: 317-20.
50: 488-508.
39. Sher R, Wade AA, Jaffer M et al. The in vitro and in vivo effects
20. Talwar GP, Zaheer SA, Mukherjee R et al. Immunotherapeutic
of levamisole in patients of lepromatous leprosy. Int J Lepr 1981;
effects of vaccine based on saprophytic cultivable Mycobacterium
59: 317-20.
w in multibacillary patients. Vaccine 1990; 8: 121-39.
40. Shepard CC, Van Landinghan R, Walker LL. Effect of levamisole
21. Govil DC, Bhutani LK. Delayed hypersensitive skin reaction to
in Mycobacterium leprae in mice. Infect Immun 1977; 16: 564-67.
lepromin and antigens prepared from other mycobacteria. Lepr
41. Martinez D, Zaias N. Levamisole as an adjunct to dapsone in
India 1978: 50:550-54.
lepromatous leprosy Lancet 1976; 2:209.
22. Chaudhari S, Fotedar A, Talwar GP. Lepromin conversion in
42. Ramu G, Sengupta U. Preliminary trial of intervention levamisole
repeatedly lepromin negative BL/LL patients, after immunization
leprosy in persistently bacteriologically positive lepromatous
with autoclaved Mycobacterium w. Int J Lepr 1983; 51: 159.
leprosy. Lepr India 1983; 55: 64-67.
23. Kar HK, Sharma AK, Mishra RS et al. Reversal reaction in
43. Kar HK, Bhatia VN, Kumar V et al. Evaluation of levamisole, an
multibacillary leprosy patients following MDT with and without immunopotentiator, in the treatment of lepromatous leprosy. Indian
immunotherapy with candidate anti-leprosy vaccine J Lepr 1986; 58: 592-600.
Mycobacterium w. Lepr Rev 1993; 64: 219-26. 44. Mathur NK, Bumb RK, Mangal HN et al. Oral zinc as an adjuvant
24. Zaheer SA, Mukherjee R, Beena KR et al. Combined multidrug to dapsone in lepromatous leprosy. Int J Lepr 1984; 52: 331-38.
therapy and Mycobacterium w in patients with multibacillary 45. Mathur NK Bumb RK, Mangal HN. Zinc in recurrent erythema
leprosy. J Inf Dis 1993; 67: 401-10. nodosum leprosum reaction. Lepr India 1983; 55: 547-52.
25. Sarkar AD, Kaur I, Radotra BD et al. Impact of combined 46. Hastings RC, Job CK. Reversal reaction in lepromatous leprosy
Mycobacterium w vaccine and one year MDT on multibacillary following Transfer factor therapy. Am J Trop Med Hyg 1978; 27:
leprosy patients. Int J Lepr 2001; 60: 187-94. 995-1004.
26. Mukherjee A, Zaheer SA, Sharma AK et al. Histological monitoring 47. Nathan CF, Kaplan G, Lewis WR et al. Local and systemic effects
of a immunotherapeutic trial with Mycobacterium w. Int J Lepr of intradermal recombinant interferon gamma in patients with
1992; 60: 28-34. lepromatous leprosy. New Engl J Med 1986; 315: 6-15.
27. Katoch K, Katoch VM, Natrajan M et al. Ten to 12 years follow-up 48. Samuel NM, Grange LM, Samuel S et al. A study of effect of
of highly bacillated BL/LL leprosy patients on combined intradermal administration of gamma interferon in lepromatous
chemotherapy and immunotherapy. Vaccine 2004; 22: 3049-57. leprosy patients. Lepr Rev 1987; 58: 389-96.
28. Bapat CV, Modak MS, De Souza NGA et al. Reversal reaction in 49. Kaplan G, Mathur NK, Job CK et al . Effect of multiple interferon
lepromatous leprosy patients to M. leprae lepromin and to ICRC gamma injection in the disposal of Mycobacterium leprae. Proc
in antigen from cultivable acid fast bacilli isolated from lepromatous Natl Acad Sci USA 1989; 86: 8073-77.
nodules. Lepr India 1977; 49: 472-84. 50. Mathur NK, Mittal A, Mathur D et al. Long term follow-up of
29. Deo MG, Bapat CV, Chulawala RG et al. Potential anti-leprosy lepromatous leprosy patients receiving intralesional gamma
vaccine from killed ICRC bacilli – a clinicopathological study. interferon. Int J Lepr 1992; 60: 98-100.
Indian J Med Res 1981; 74: 164-67. 51. Sivasai KSR, Prasad HK, Mishra RS et al. Effect of recombinant
30. Deo MG, Bapat CV, Bhale Rao V et al. Anti-leprosy potential of interferon gamma administration on lesional monocytes/
ICRC vaccine: A study in patients and healthy volunteers. Int J macrophages in lepromatous leprosy patients. Int J Lepr 1993;
Lepr 1983; 51: 540-49. 61: 259-69.
CHAPTER
32
52. Kaplan G, Britton WJ, Hancock GE et al. The systemic effect of 59. Shetty VP, Wakade AV, Ghate SD et al. Clinical, histopathological
recombinant interleukin-2 on manifestation of lepromatous and bacteriological study of 52 referral MB cases relapsing after
leprosy. J Exp Med 1991; 173: 993-1006. MDT. Lepr Rev 2005; 76: 241-52.
53. Talwar GP. Vaccines against leprosy. Lepr India 1983;55: 60. Ahmed N, Saini V, Raghuvanshi S et al. Molecular analysis of a
525-30. leprosy immunotherapeutic bacillus provides insights into
54. Mahadevan PR, Robinson P. An antigen complex that restores Mycobacterium evolution. PLoS One, 2007; 10: e968.
ability of leprosy patients to kill M. leprae: The probable molecular 61. Gillis T. Is there a role for a vaccine in leprosy control? Lepr Rev
events identified by in vivo experiments. Trop Med Parasitol 2007; 78:338-42.
1990; 41: 310-13.
62. Jacobson RR, Gatt P. Can leprosy be eradicated with
55. Damle A, Mahadevan PR. The in vivo effect of de-lipidified cell
chemotherapy? An evaluation of Malta Leprosy Eradication
wall component of M. leprae in relation to infection of leprosy
Project. Lepr Rev 2008; 79: 410-15.
bacteria in mice. Indian J Lepr 1993; 65 : 271-78.
63. Katoch VM, Gupta UD. Vaccines against leprosy. In: Adult
56. Gelber RH, Hunter SW, Brennan PJ et al. Protection of mice by
Immunization, SK Sharma and others (Eds), API publication,
cell wall of M.leprae. Infect Immun 1990;58:711-18.
57. Gelber RH, Breenar DJ, Hunter SW et al. Effective vaccination 2009.
of mice against leprosy disease with sub-unit of M.leprae. Infect 64. Tuberculosis prevention trial of BCG vaccines in South India
Immun 1990; 58: 711-18. for tuberculosis prevention. Indian J Med Res 1979; 70: 349-
58. Gelber RH, Murray L, Sui P, Tsang M. Vaccination of mice with a 63.
soluble protein fraction of M. leprae provides consistent and 65. Katoch K, Singh P, Adhikari T et al. Potential of Mw as a
long term protection against M. leprae infection. Infect Immun prophylactic vaccine against pulmonary tuberculosis. Vaccine
1992; 60: 1840-44. 2008; 26: 1228-34.
CHAPTER
33
33
Chemoprophylaxis
BK Girdhar
INTRODUCTION AND THE NEED the onset of pathological process in response to the
presence of bacteria in the body or later; killing of the
All efforts at elimination of leprosy, during the last 50 years
pathogen and allowing the pathological changes to reverse,
or so, have been directed at early detection and treatment
or the subclinical disease to heal, or both. In leprosy, as
of patients with the aim of reducing the pool of infection in
the incubation period is very long, both the mechanisms
the community and thus preventing spread of infection to
may be involved, though the later one appears to be more
the uninfected members of the society. Such an approach,
relevant.
though likely to be effective, is sure to take long to result
in perceptible reduction in incidence rate. For effective
Who Needs Chemoprophylaxis?
outcome, in other words for disease elimination and zero
incidence in the near future, the efforts based only on An issue of significant importance appears to be, who
chemotherapy of known patients alone may not be needs protection—the entire community or a select group.
sufficient and call for raising the herd immunity of the In theory, every one who lives in an endemic area should
community so that the individuals are no longer susceptible get protection. In leprosy, providing protection to the entire
to the infection, even if the causative organism is present community, apart from reducing the pool of infection, does
in the surrounding environment. However for this, as of not seem cost effective and/or feasible–as the disease
now, we do not have any reliable and effective tool – affects only a small fraction of the society. If it is not
vaccine. possible to cover all the individuals in an endemic area,
Consequent to the spread of any infection in the can the efforts be limited to any group in whom the disease
community, by active case detection or voluntary reporting, is likely to occur more frequently.
manifest disease is detected only in a proportion of In tuberculosis transmission, ‘stone-in-the-pond’
population. In contrast, individuals with sub-clinical infection concept has been suggested, meaning that the risk of
remain unidentified and if left alone, some of them may infection gradually decreases as one moves away from
later develop disease. It has long been considered that the open case.1 Familial contacts are at greater risk than
prophylactic treatment of the individuals, who are exposed neighbors who in turn are at increased risk than their
to infection and might be incubating the disease, may be neighbors and so on. This implies that as we move away
helpful. Such an approach has remarkably been effective from the pool of infection, the index case, the risk of
in containing yaws. Similar reduction in occurrence of infection decreases. Indeed, the available data indicates
tuberculosis, by giving isoniazid to the familial contacts of that the risk of contracting leprosy, too, decreases with
‘open’ cases, had led to the thinking in leprosy that increasing physical distance from the patient or the intensity
chemoprophylaxis could be useful in reducing the incidence of contact. This increased risk of infection determines the
rates in leprosy. need for prophylaxis.
The mechanism by which chemoprophylaxis works It is a common observation that only 30% patients
possibly involves killing of the causative organisms before have an index case in the family and the rest neither have
CHAPTER
33
Chemoprophylaxis 419
any known case of leprosy in the family nor in the Younger children have been observed to be more
neighborhood or at place of work. The former group, on susceptible to leprosy, there being a strong relationship
account of closeness of contact are at higher risk than the between the risk of developing clinical leprosy and the
noncontacts. Thus, among the small number of familial or age at exposure, the risk decreasing with increasing age.6
close contacts, a third of the total patients occur. Thus, for Bimodal distribution of the disease has been observed in
leprosy chemoprophylaxis, focus had long been on the several studies, though this may suggest that the infection
contact population, i.e. on those who are at higher risk of can occur later in life as well. Disease attack rates are
acquiring the infection and disease. In the endemic areas higher in the males possibly on account of increased
the remaining population, with no known contact with any exposure. Are there any biological factors to account for
leprosy patient, accounts for rest of the cases. Even though this increased risk in the males is not clear. Less
the prevalence rate in this population is very low, the total occurrence of the disease in the educated class, as also
number of patients who appear in this population is not those with better housing conditions and less crowding
small as 70 % of the patients belong to this category. In indicates that individuals with poor socioeconomic
view of this, work has also been undertaken to find ways conditions are at a greater risk of infection and disease.7
to prevent disease in the general population. This could possibly be on account of several factors, such
as poor personal hygiene, over crowding, poor nutrition,
The High-risk Group poor sanitation, etc.
In both tuberculosis and leprosy, examination of the Delayed detection or diagnosis and consequent delayed
contacts has received a considerable importance. Based start of treatment of leprosy patients, especially the smear
on the above mentioned ‘stone-in-the pond’ concept, positive ones, exposes the community to the increased
familial contacts of the index case have been considered chances of infection. Many individuals in endemic areas
to be the most important group. Household contacts in may already be infected in the family or neighborhood,
particular have been the focus of attention. Workers have before the index case is put on treatment for leprosy. Thus,
defined household contacts in greatly varied fashions even when only a few patients are detected and diagnosed
taking the social structure of the society into consideration. in the field, there are several in the community who may
However, all seem to agree that a person with prolonged, already be infected but have not developed disease
frequent or close contact with an infectious case is at a manifestations, because of the long incubation period of
greater risk. It has also been observed that the risk of the disease.
disease among the contacts not only depends upon the Based on the above understanding studies were
closeness of contact, but also the type of disease in the initiated in the sixties to see, if chemoprophylaxis reduces
index case, risk being 6 to 8 times greater in contacts of the risk of developing the disease among both the contacts
MB cases than those of PB patients who in turn are at and general population.
twice the risk than noncontacts. Even the contacts of low
smear positive cases are at a much higher risk of getting DAPSONE CHEMOPROPHYLAXIS
infected as compared to the contacts of skin and nasal
During the last fifty years, workers have been involved in
smear negative cases.2,3
testing the efficacy of various drugs that could be used for
Apart from the increased exposure, the susceptibility
chemoprophylaxis. Expectedly, initially dapsone (DDS) was
of the individuals also seems to play some role.4 Higher
tested in this regard.
prevalence among the familial contacts has been
suggested to be due to similar genetic make-up. In this
Studies in Contacts
regard, observations of more than twice the risk of leprosy
in monozygotic twins, as compared to dizygotic twins, is Early work in this regard was carried out in India and Africa.
relevant. HLA (DR2) and non HLA genes appear to In the trial undertaken at Mumbai,8 none of the 51 contacts
contribute to genetic susceptibility to either leprosy per se who received dapsone chemoprophylaxis developed
or the type of disease. Locus on chromosome 6q25 appears leprosy in contrast to leprosy manifesting in 9.35 % of 524
to control part of the susceptibility. Studies from India have contacts who had not been administered dapsone. Working
shown that locus on chromosome 10p13 is linked to the with children of leprosy parents, Lew and Kim9 reported
increased risk with paucibacillary leprosy.5 that only 2 of the 325 (0.61%) DDS administered familial
CHAPTER
33
contacts developed disease. This is in contrast to 31 of group, all the healthy individuals below 25 years of age
the 425 (7.3%) contacts not given DDS, developing the received DDS twice a week for four and a half years; where
disease during the same 2 years period. Similar effect as similar persons in the other 27 villages were given
was observed by the authors on long-term (3-10 year) placebo tablets for the entire duration of observation. Yearly
follow-up in larger familial contact population.9 Work assessment carried over four and a half years, showed
undertaken in Philippines, showed a reduction of 44 % in reduction in the incidence in the prophylaxis group to the
occurrence of leprosy over a period of 3 years in child tune of 49%; more than that in the control group –wherein
contacts of leprosy patients who had been given DDS as a decrease of 41% had been observed, possibly
compared to those without the drug.10 Observation made consequent to reducing load of infection in the community.
in Vietnam also indicated marked efficacy of dapsone in Continued DDS administration beyond this period was found
children.11 Contacts staying with their lepromatous parents, to have lesser protective role. Like in contact studies,
who received dapsone, had less leprosy as compared to benefit of disease protection was more among the younger
those not given the drug. age group.
Two systematic investigations have been made on the Whereas mass chemoprophylaxis as above, appears
utility of DDS prophylaxis in the familial contacts. One effective in reducing new leprosy cases, its application to
study was undertaken in South India.12,13 In this placebo very large populations in the endemic countries does pose
controlled, randomized and double blind investigation, half challenges. Not only because large numbers of individuals
of the familial contacts were given a minimum of 3 years have to be given the drug, but also because of the long
DDS and the remaining received a placebo. Comparison duration for which the drug administration had to be
made over 5 years, revealed that there was an overall continued, especially to children. Since self administration
reduction of 52% in the treatment group as compared to of any drug, even for symptomatic diseases, over long
the control group—the difference being statistically periods of time is fraught with the risk of irregularity and
significant. In both the groups, most of the patients were the consequences thereof, self intake of drugs, for long
of tuberculoid type. Though no contact developed duration for prophylaxis, is even more likely to be erratic.
lepromatous disease in either of the groups, 3 patients in
the control group had skin smear positive leprosy. In Acedapsone (DADDS) for Chemoprophylaxis
contrast, only one patient had bacteriologically positive With the understanding that MIC of dapsone against
disease in the trial group. Similar observations were also M. leprae was very low and that even a small daily dose of
reported from Mali, Bomako.14 Of the 57 children, staying 1-2 mg resulted in drug levels that were almost 10 times
with their lepromatous parents and receiving DDS, for a higher than the MIC for M. leprae, an injectable depot
mean period of 30 months, none developed leprosy. In all preparation of dapsone, diacetyl diaminodiphenyl
the above studies the source or the index case had been sulphone—in short called acedapsone, was developed
treated side by side. (Details in chapter 27 on Chemotherapy). Injections of
With these observations of disease protection with acedapsone (225 mg) given deep intramuscularly every
dapsone and the knowledge that the numbers of contacts two and a half months (11 weeks) were advocated for
who develop disease, form a small percentage of the total leprosy. One shot of acedapsone gave serum levels above
incident cases, it was considered that, if chemoprophylaxis MIC for almost 3 months. As the drug had to be injected,
was limited to contacts alone, this might not help much in this supervised and ensured form of dapsone delivery was
the control of leprosy. With this in view, workers have been tested for its prophylactic value against leprosy, in
trying to assess, if chemoprophylaxis given to the entire Micronesia and later in Chingleput.
population would be useful in this regard. In the work undertaken in three villages of Ponape
district of Micronesia,17,18 which had high prevalence of
Dapsone Chemoprophylaxis in the Entire active disease, all the leprosy patients under treatment
Endemic Population were switched on to acedapsone from oral treatment and
Initial work, in this direction, was undertaken in Srikakulam the entire leprosy free population, more than 6 months in
district of Andhra Pradesh.15,16 The study was carried out age, was given acedapsone injections every 75 days for
in 54 villages divided randomly into two groups. In one 3 years. Yearly examination of the population revealed less
CHAPTER
33
than half the expected cases during the first year and no Bakker and his coworkers have undertaken controlled
new case in the next 2 years. Continued follow-up showed studies in five Indonesian islands.22 Comparing the
emergence of 5 cases in the subsequent 2 years, four outcome of two doses of rifampicin given 3 months apart,
among those who had not taken full course of acedapsone to all residents of 3 islands (the blanket group), with the
prophylaxis. In the two nearby villages, where acedapsone drug administered the same way to only the children and
administration had been better supervised, the results were neighborhood contacts in one island – the contact group
better as compared to the third village which was far away and no chemoprophylaxis in the fifth island, the authors
and thus had lesser supervision. This indicated have reported that the cumulative incidence after 3 years
considerable role of preventive treatment, when given to was significantly lower in the blanket group as compared
the entire population. The important issue here was the with control group. The protection afforded was to the tune
essentiality of continuing therapy of all known cases. A of 75%. On long-term follow-up of 6 years, the
double blind placebo controlled study undertaken in effectiveness of the rifampicin protection was reduced and
contacts of lepromatous patients in South India, has was not significantly more than in the control group. To
confirmed a significant protection with acedapsone prevent occurrence of one case of leprosy, the number
administration over 2 years period.19 needed to be treated at 3 years was 127 and it increased
In short, all the studies on the subject, controlled and to 244 at 6 years. The protection, in the spatially defined
uncontrolled, indicated that chemoprophylaxis with dapsone contacts, with rifampicin was not significantly different than
or acedapsone, especially when given to the entire in the control group.
population, afforded protection to the extent of 55-60% Placebo controlled, randomized double blind study
during the period of administration, with gradual loss of giving single dose of rifampicin to the contacts of leprosy
protection after stoppage of the drug. Further, to prevent patients (household and compound members, immediate
occurrence of a case of leprosy, the number of individuals neighbors and the neighbors of neighbors, and the close
that had to be treated was relatively small among the social and business contacts) has been conducted in
contacts and fairly large in the general population. The Bangla Desh.23,24 First follow-up made after 2 years
main problem with this mode of prophylaxis was that showed a significant reduction of 56% in incidence of
dapsone/acedapsone had to be given for long periods and leprosy in the rifampicin protected contacts as compared
hence the possibility of irregularity. Another cause of to the controls. However, the protection was no longer
concern had been the risk of increasing dapsone resistance significant in the third and fourth year. The protective
which had already been observed to be a world wide efficacy was observed to be more in the comparatively
phenomenon. less high-risk group, i.e. in neighbors of neighbors and
social and business contacts than among the family (close)
contacts. A possible reason suggested is that the load of
RIFAMPICIN FOR PROTECTION
M. leprae in the household contacts could be much higher
AGAINST LEPROSY
than among the noncontacts and thus relative inability of
Following the demonstration of potent bactericidal action one dose of rifampicin to kill the bacilli. Like in the earlier
against M. leprae and thus the efficacy of rifampicin in study, the numbers needed to be given chemoprophylaxis
treatment of leprosy, its utility in prophylaxis of the disease to prevent a case of leprosy was 272.
was considered. As the drug had been shown to kill over A similar multicentric, double blind, randomized and
99% M. leprae following a single dose, it had been placebo controlled trial in over 7500 household contacts in
considered that a limited administration of rifampicin may India has shown protection against leprosy.25 A significant
be useful for prophylaxis of the disease. In the initial work, decrease in new case occurrence, in the ensuing 4-5 years,
undertaken in southern Marquesas,20,21 wherein the entire was observed in contacts who received a single dose of
population was given rifampicin 25 mg per kg body weight, rifampicin (10 mg / kg body weight). However, the numbers
a protection of 40-50% was observed. As the superiority needed to be treated to prevent the occurrence of one
of giving bolus dose of 1500 mg rifampicin over efficacy case of the disease was 1556 – that is, a large population.
of 600 mg given only once or on two days had not been Utility of a combination of three drugs—rifampicin,
proved, this dose has not been used in any further trials. ofloxacin and minocycline (ROM) has also been looked
CHAPTER
33
into. Work undertaken in Micronesia with ROM has shown to be given prophylaxis to prevent a case of leprosy is
protective efficacy similar to that observed in studies using bound to increase, making chemoprophylaxis less and less
rifampicin alone.26 This is in line, with the findings in mice, cost effective as it requires very high direct and indirect
that ROM is no more bactericidal than single dose of costs for implementation. This apart from being difficult,
rifampicin alone.27 Further, in view of the small bacterial time and manpower intensive, may not be well accepted
load that may be present in the exposed individuals and by several healthy individuals in the community. Newly
thus very little possibility of de novo rifampicin resistance, diagnosed, concerned and understanding patients may
addition of accompanying drugs is sure to make it less indeed want to protect their household contacts but may
cost effective and possibly more toxic and hence has not not like their diagnosis/disease to be known to their contacts
found favor with the leprosy workers. and/or neighbors on account of stigma that has been
In short, the studies indicate that chemoprophylaxis, attached to the disease for long.29 Furthermore, many
particularly when given to the entire community, has a individuals, even educated ones, continue to believe that
significant protective effect in reducing the incidence of leprosy is a disease of the poor and thus may not accept
leprosy; and that the protective effect lasts for a limited prophylaxis.
period of time and wanes subsequently. In contrast to Despite the above mentioned reservations, rifampicin
prolonged intake of dapsone required, single or two doses chemoprophylaxis for leprosy could be useful in high
of rifampicin are better options. However, the important endemic pockets where clustering of cases is found,
need is simultaneous and still better earlier start of provided thorough screening for leprosy and tuberculosis
treatment of all the patients in the family and the is made before hand and the community is well educated
community. in health issues and understands that prophylaxis afforded
Concerns have been expressed regarding the by rifampicin is significant though not complete.
applicability and feasibility of chemoprophylaxis in the field, Chemoprophylaxis has shown a good protection among
i.e. need to administer the drug to very large populations the high-risk groups. Therefore, its application in protection
in the endemic countries. Possibility of selection of resistant of household contacts, in particular those of skin smear
bacteria of varied types, including M. leprae and positive patients, is more likely to be useful. Here, only a
M. tuberculosis, has been expressed. It is feared that this
small numbers of individuals, more often child contacts of
may pose problems in the treatment of leprosy and/or
index cases, are to be protected. As protection is more
tuberculosis. Therefore, it is essential that the contacts/
often asked by the family, not only the contacts are brought
healthy population be screened for both leprosy and
for examination to rule out pre-existing leprosy but also can
tuberculosis prior to consideration of chemoprophylaxis,
be thoroughly examined to rule out tuberculosis. It has been
which should only be given under supervision.
suggested that chemoprophylaxis would be more useful and
feasible in contacts of patients in low endemic and high
APPLICATION OF CHEMOPROPHYLAXIS resource countries.25 As stated earlier, for any protection
How should chemoprophylaxis be made use of, has been using chemoprophylaxis to be effective, the essential thing
the subject of discussion. Whether this would be cost is the treatment of the index cases side by side.
effective, in the program, in reducing the incidence rates Giving one or two doses of rifampicin has been another
of the disease in a community, depends upon the number issue. A second dose given the very next day is not likely
of individuals who need to be treated to prevent a case of to add to the efficacy. Whether repeating the dose 3 or 6
leprosy. For blocking the transmission at the community months later, and /or repeating the prophylactic dose to
level, large number of apparently healthy individuals in the the contacts after the index case has become skin smear
endemic areas need to be given the drug in supervised negative, would be of any benefit is not clear. Is their a
fashion. All the studies indicate, that to prevent a single subgroup, among the close contacts, who in turn is more
case of leprosy, hundreds and may be thousands of prone to develop the disease is also not clear, as we still
subjects need to be given chemoprophylaxis.28 With the lack tools, serological and others, to identify them. Whether
decreasing case load and hence reducing pool of infection combination of chemoprophylaxis and immunoprophylaxis,
and thus transmission, the number of individuals who need would be more useful, needs to be investigated.
CHAPTER
33
REFERENCES 17. Sloan NR, Worth RM, Jano B et al. Acedapsone in leprosy
chemoprophylaxis; Field trial in three high prevalence villages in
1. Veen J. Micro-epidemics of tuberculosis: The stone-in–the-pond Micronesia. Int J Lepr 1972; 40:40-47.
principle. Tuber Lung Dis 1992; 73:73-76. 18. Russell DA, Worth RM, Scott GC et al. Experience with
2. Moet FJ, Meima A, Oskam L et al. Risk factors for development acedapsone (DADDS) in the therapeutic trial in New Guinea
of clinical leprosy among contacts, and their relevance for and the chemoprophylaxis trial in Micronesia. Int J Lepr 1976;
targeted intervention. Lepr Rev 2004; 75:310-26. 44:170-76.
3. Bakker MI, Hatta M, Kwenang A et al. Risk factors for developing 19. Noordeen SK, Neelan PN, Manaf A. Chemoprophylaxis against
leprosy – a population based cohort study in Indonesia. Lepr leprosy with acedapsone– an interim report. Lepr India 1980;
Rev 2006; 77:48-61. 52:97-103.
4. Fitness J, Tosh K, Hill AV. Genetic susceptibility to leprosy. 20. Cartel JL, Chanteau S, Moulia-Pelat JP et al. Chemoprophylaxis
Genes Immun 2002; 3:441-53. of leprosy with a single dose of 25 mg per kg rifampin in the
5. Siddiqui MR, Meisner S, Tosh K et al. A major susceptibility south Marquesas; results after four years. Int J Lepr 1992;
locus for leprosy in India maps to chromosome10p13. Nat Genet 60:416-20.
2001; 27:439-41. 21. Ngyur LN, Cartel J-L, Grosset J H. Chemoprophylaxis of leprosy
6. Fine P E, Sterene JA, Ponnighaus JM et al. Household and in the South Marquesas with a single dose of 25mg/kg rifampicin.
dwelling contact as risk factor for leprosy in northern Malawi. Results after 10 years. Lepr Rev 2000; 71:S33-36.
Amer J Epidemiol 1997; 146:91-102. 22. Bakker MI, Hatta M, Kwenang A et al. Prevention of leprosy
7. Kumar A, Girdhar A, Yadav VS et al. Some epidemiological using rifampicin as chemoprophylaxis. Am J Trop Med Hyg
observations on leprosy in India. Int J Lepr 2001; 69:234-41. 2005; 72:443-48.
23. Moet FJ, Oskam L, Faber R et al. A study on transmission and
8. Figueredo N, Balakrishnan V. Risk of infection in leprosy. Part-
trial of chemoprophylaxis in contacts of leprosy patients: design,
2. Chemoprophylaxis. Lepr Rev 1967; 38:93-96.
methodology and recruitment findings of COLEP. Lepr Rev 2004;
9. Lew J, Kim YS. Chemoprophylaxis of leprosy contacts with
75:376-88.
DDS. Int J Lepr 1968; 36:620 (Abst).
24. Moet FJ, Pahan D, Oskam L et al. Effectiveness of single dose
10. WHO Expert Committee on Leprosy. WHO Tech Report Series
rifampicin in preventing leprosy in close contacts of patients
# 459:1970.
with newly diagnosed leprosy: cluster randomized controlled
11. Nhu TQ, Don TKM. Chemotherapy in children living in leprosy
trial. B M J 2008; 336:761-64.
institutions. 10th Leprosy Congress, Bergen 1973; Abstract 25. Oskam L, Bakker MI. Report of the workshop on use of
p.136. Int J Lepr 1973; 41:618. chemoprophylaxis in the control of leprosy held in Amsterdam,
12. Dharmendra, Noordeen SK, Ramanujam K. Prophylactic value the Netherlands on 2006. Lepr Rev 2007; 78:173-85.
of DDS against leprosy—a further report. Lepr India 1967; 39: 26. Diletto C, Blank L. Leprosy chemoprophylaxis in Micronesia.
100-06. Lepr Rev 2000; 71:S21-25.
13. Noordeen SK. Chemoprophylaxis in leprosy. Lepr India 1969; 27. Ji B, Sow S, Perani E et al. Bactericidal activity of single-dose
41:247-54. combination of ofloxacin plus minocycline, with or without
14. Louvey M, Saint-Andre P, Giraudeu P. Role of chemoprophylaxis rifampicin, against M. leprae in mice and in lepromatous patients.
in prevention of leprosy. Med Trop 1976; 36:153-57. Antimicrob Agents Chemother 1998; 42:1115-20.
15. Wardekar RV. DDS prophylaxis against leprosy. Lepr India 1967; 28. Noordeen SK. Prophylaxis–scope and limitations. Lepr Rev 2000;
39:155-59. 71:485-95.
16. Wardekar RV. Chemoprophylaxis in leprosy. Lepr India 1969; 29. Smith WCS. Chemoprophylaxis in prevention of leprosy. BMJ,
41:240-46. 2008; 336:730-31.
CHAPTER
34
34 Deformities of Face, Hands and Feet,

and their Management
Atul Shah, Neela Shah
INTRODUCTION considered suitable for treatment as multibacillary type to

prevent leprosy related disabilities and effectively control
The word leprosy is derived from the Greek word “lepros”
the disease.
which means ‘scaly’. The Indian word Kushtha is derived
from Sanskrit word “Kushnati” which means eating away.1
The abhorrent images often seen in the pictures and
CLINICAL MANIFESTATIONS
depictions about leprosy- affected individuals with eaten Leprosy affects skin as well as nerves. Disabilities due to
away fingers and toes are no longer a trend of the disease. skin infiltration are more obvious on the face with resultant
The incurability, transmission to other individuals because sagging of skin, wrinkled skin appearance, enlarged ear
of non-availability of the effective treatment, is also a lobules, loss of eyebrows, etc. Mucosa of the nose is also
chapter bygone. However, we cannot ignore the fact that affected in some cases leading to depressed or saddle nose.
among us, we have more than a million individuals with The effect on nerves may be limited to cutaneous nerve
leprosy related deformities and disabilities living in homes thickening in line with a cutaneous patch or may extend to
and colonies surrounding us. peripheral nerve trunk with or without its palpable thickening
Leprosy bacilli discovered by GA Hansen in 1873, are in its course. In majority of cases, presenting with
pleomorphic slightly curved rod shaped gram-positive disabilities like claw hand, the enlarged (thickened) nerve
organisms,2 seen in the slit skin smear lying singly; or in clinches the diagnosis of leprosy. Sometimes skin smears
clumps in cases of borderline to lepromatous leprosy, often are required for making a diagnosis or judging the
called multibacillary (MB) leprosy. It is this spectrum of improvement in the status while on MDT. The demonstration
the disease, which over a period tends to exhibit greater of Mycobacterium leprae in skin smears is one of the
disabilities. The other part of the spectrum, borderline to cardinal signs for the diagnosis of the disease.3
tuberculoid leprosy called paucibacillary (PB) leprosy, has
up to five patches on the body including peripheral nerve Episodes of Reactions
involvement, and may show evidence of deformity An acute episode of sudden inflammation during the chronic
associated with the affected nerve trunk. The development course of disease is defined as ‘reaction’. There are two
of different clinical types from indeterminate towards any types of reactions; the “Reversal Reaction” and “Erythema
side of the spectrum depends on susceptibility and Nodosum Leprosum” (ENL). The former occurs on account
resistance of the individual. Greater the immunity; better of enhanced cell mediated immunity whereby a skin patch
are the chances of the disease tending towards tuberculoid becomes pinkish and inflamed while the affected nerves
type manifestations. Pure neuritic (≥ 2 nerves involved) become painful and tender causing onset of loss of
type of leprosy seen in Indian subcontinent or any type, sensation or weakness in motor power. In the ENL reaction
which shows bacilli on laboratory examination, is (mediated as humoral response) the typical inflammatory
CHAPTER
34
Deformities of Face, Hands and Feet, and their Management 425
nodular eruptions, which may even ulcerate, and despite the fact that nerve damage is taking place within
constitutional symptoms like fever, joint pain, malaise, etc. the nerve trunk.
may be seen. When any of these reactions involve nerves,
they are classified as “severe” on account of their DISABILITIES AND DEFORMITIES IN
propensity to cause functional impairment in nerves and LEPROSY—TERMINOLOGY
deformities.
Next to inflamed skin lesions, acute neuritis is the most Development of a hypopigmented patch associated with
common manifestation of a reaction in leprosy.4 Early loss of sensations is considered essential for making a
identification of reactional episodes particularly in the field diagnosis of leprosy. Often the terms anesthetic patches
areas and early recognition of nerve damage, help or anesthetic extremities are used to describe decreased
tremendously to prevent the deformities or to bring about sensibility in the affected areas. The term anesthesia
the sensorimotor recovery with prednisolone therapy. WHO denotes the complete loss of sensations while the term
recommended dose of prednisolone therapy starting with hypoesthesia denotes impairment of sensations like
40 mg and gradually decreasing by 10 mg every 15 days touch, temperature and pain. Clinically, it is established
for 3 cycles and by 5 mg for further 3 cycles is considered that at first, the temperature sensation is affected followed
safe for use in the field. Figures 34.1A and B show recovery by touch and pain. Thus, early recognition often depends
in a case of lagophthalmos following this regimen. A good on testing with hot and cold test tubes. However, since
concept map for management of reactions is given in the this technique is not feasible in the field; loss of sensations
publication from Karigiri.5 It contains other drugs such as to touch is tested by the ballpoint pen and/or cotton wool
clofazimine and thalidomide recommended for use in such and pinprick, as a routine.
reactions. It is believed that effective management of the The term impairment is a scientific term denoting the
reactions can bring down the occurrence of disabilities to loss or abnormality of the anatomical or physiological
a great extent. Not all cases tend to exhibit signs of structure or function. Van Brakel and associates have
reactions. As per Srinivasan there is also an entity called popularized nerve function impairment (NFI) assessment
as “silent neuritis” or “quiet nerve palsy” wherein some cases to draw attention towards disability prevention. The most
deformity occurs gradually and without pain or tenderness, common term “deformity”, is defined as the visible
A B
Figs 34.1A and B: Recovery in lagophthalmos with steroid therapy
CHAPTER
34
alteration in the form, shape or appearance of body due to Table 34.1: WHO grading of disabilities in leprosy8
impairment produced by the disease like loss of eyebrows Grade Hands and Feet Eyes
or clawing of fingers.
Grade 0 No disability found No disability found
Disability on the other hand, is the lack of ability to Grade 1 Non-visible damage No grade 1 for Eye
perform an activity considered normal for a human being. (Loss of sensation)
Thus, in leprosy, slipping of pen or objects from the hands Grade 2 Visible damage (Disability, Inability to close, obvious
constitutes a disability even without an apparent deformity. wounds (Ulcers), deformity redness, visual
due to muscle weakness, impairment, blindness
It is due to deformity and precisely the disability that a loss of tissue (such as foot
person is not able to play the role of a normal individual drop, claw hand, loss or
and becomes handicapped. For example, he cannot earn partial resorption of fingers/
toes, etc.)
his living or cannot perform activities of daily living as a
result of the handicap caused due to leprosy.
the disability rate in the population if this effort continues.
People working in the field of leprosy often use the
Van Brakel has worked extensively on grading of
term “POD” which means “prevention of disabilities”. Any
impairment in leprosy and the eye, hand and foot (EHF)
activity, which is directed at the prevention of either primary
score. He advocates its use to assess the patient’s
or secondary disabilities, is included under this term. Some
condition after any service, which can be reported as stable,
people suggest more specific terms like POWD, which
improved, or worse.9
means “prevention of worsening of disabilities”. Technically,
in certain cases, it refers to activities at the field level,
more accurately in cases that may deteriorate unless cared NERVE INVOLVEMENT
for. The health services often use the term “deformity care Involvement of nerves produces loss of sweating, loss of
program” or “disability care program” whereby patients are sensations and motor power in its territory just distal to
examined to provide disability care services. These are the site of affection. It is imperative that palpation reveals
colloquial terms often used as synonyms and in general, the enlargement of the nerve and that clinical examination
include activities related to caring of the leprosy disabled of sensory and motor loss is charted in order to judge its
persons. These programs are aimed at prevention, recovery or downgrading.
correction and care of various disabilities witnessed in a Clinical examination of nerves starts from the greater
leprosy-affected person, with various aids and appliances auricular nerve in the neck, which shows thickening in
as well as selection for referral for reconstructive surgery. cases of facial patches.10 One must remember that the
In the holistic approach, it also includes socioeconomic greater auricular nerve is visibly enlarged in some normal
rehabilitation of the leprosy-disabled persons. individuals but in such cases, the enlargement is usually
Recently, the Government of India has rechristened bilateral. Unilateral thickening invariably points towards
the prevention of disability (POD) as DPMR, which means diagnosis of leprosy. It is followed by examination of radial
‘Disability Prevention and Medical Rehabilitation’. It cutaneous nerve at wrist. Similar to the greater auricular
includes all activities aimed at prevention and care for nerve, unilateral thickening is noted in cases with leprosy.
disabilities, reconstructive surgery for leprosy related The ulnar nerve is affected just proximal to the elbow
deformities and other rehabilitation measures. and is easily palpable behind the medial epicondyle. The
In their sixth report, World Health Organization (WHO) enlargement is just above the medial epicondyle and often
Expert Committee on Leprosy recommended that continues as a fusiform segment higher up in tuberculoid
“prevention and management of impairments and leprosy cases and as general thickening in lepromatous
disabilities, which have long been recognized as essential type. The median nerve is affected just above the wrist
components of leprosy control programs, should be but difficult to palpate unless grossly enlarged. In some
implemented effectively”. 6 The best way to prevent cases, tenderness on pressing firmly at the proximal wrist
disabilities (Table 34.1) is through the early detection of crease can be elicited. In case of the radial nerve, the
patients and their treatment with MDT7 which is provided main trunk is affected in very few cases and when affected
free of charge to patients throughout the world, donated it can be rolled as thickened cord in humeral groove, in the
by Novartis. Hence, it should not be difficult to bring down arm. In the legs and feet, the thickening of any superficial
CHAPTER
34
nerve is generally diagnostic and confirmatory for leprosy. technique utilized by physiotherapists, many points in the
Sural nerve can be palpated on the back of the leg, running palm have to be tested and results are to be noted down
along the lower portion of tendo-Achilles. Its thickening for future comparisons. For the ulnar nerve the little finger
almost confirms the diagnosis. The lateral popliteal nerve and for the median nerve the index finger is tested
at the neck of the fibula when affected can be palpated respectively as they generally do not have any overlapping
extending proximally towards popliteal fossa in its course. sensory supply by the adjacent nerve. Lateral popliteal
The posterior tibial nerve is palpated just behind the medial nerve supplies a minor area of the first web space and
malleolus and is occasionally found painful even in normal hence, generally does not require testing. For the posterior
individuals on exertion of deep pressure. Unless its tibial nerve, loss of sensations, occur in the sole of the
enlargement is unilateral and associated with anesthesia foot. The areas to be tested include first and fifth toe until
or deformity, it should not be considered as the sole criteria metatarsal head and heel in the center. It is necessary to
for diagnosis. The electromyography and nerve conduction remember that instep area and lateral side have sensory
velocity when available can serve as a tool in aiding the overlap hence, one need to be careful in deriving inferences.
diagnosis of the disease in difficult cases.
Surgery on Nerves
The common indications for surgery on nerves are obtaining
a biopsy of a funicle for establishing diagnosis in certain
cases, e.g. pure neuritic leprosy, or to evacuate a nerve
abscess to get back the sensory and motor recovery
through tunnel decompression. External entrapment is
relieved by de-roofing of the nerve tunnel while the internal
entrapment can be released by hemicircumferential
epineurotomy.11
Ideally, as a base for the diagnosis, biopsy of an
affected nerve is required to be done. However, one cannot
take the biopsy from the proximal nerve trunk due to fear
of causing damage where none may exist. Therefore,
superficial nerves are considered for biopsy, among which
radial cutaneous or its index branches and sural nerves A B
are preferred. Even in clinically uninvolved nerves, electron
Figs 34. 2A and B: Points for testing the sensation in hand and foot
microscopy can reveal the neural affection.
TESTING FOR NERVE DAMAGE Motor Testing

Deformities arise due to loss of power in certain muscles
The signs and symptoms of gradually progressive nerve
supplied by the affected nerve. The unopposed action of
damage frequently are tingling and numbness, altered
the normal muscles of the opposite group (extensors in
sensibility towards touch, temperature and pain sensations
case of flexor paresis) produces instability at the joints
and muscular weaknesses, which are noticed ultimately
giving rise to characteristic deformities like claw hand.
in the form of deformities.
A Quick Test to Assess Motor Damage
Sensory Testing in Hands
There are many different techniques to test the loss of The person should be asked to make a five finger pinch in
sensations in the hands and feet, however, a quick method the wrist-extended position with metacarpophalangeal (MP)
is to test the area supplied by the nerve with a ballpoint joints in flexion and interphalangeal joints in extension, as
pen or pinprick. Figures 34.2A and B show the points on shown in Figure 34.3 (called as “Beak Test”; after the shape
the hand and foot for quick testing. In the detailed testing attained by hand, looking similar to that of beak and the
CHAPTER
34
extended neck of a bird). If he is able to maintain this In the lower extremity, if lateral popliteal nerve affection
position for about 30 seconds, there is no motor damage is present the foot cannot be raised from the ankle (Foot
to the hand (after Fritschi) (Fig. 34.3A). drop). If a patient is explained properly, he can test the
For the Ulnar nerve, a simple test is to teach a patient weakness himself by keeping both feet on the table (or
to spread the fingers and apply pressure with one little ground) and the foot, which is weak, will be seen to be
finger to the other little finger. The weak one will give way lagging behind while actively taking the ankle upwards.
and turn towards the ring finger. For the median nerve, the Figure 34.5A shows the weakness on the right side, which
affection of the thumb is tested by asking the patient to is lagging behind in dorsiflexion. Patient will also notice a
raise the thumb. The weakness will be evident when slight limp while walking.
compared with the normal thumb. Figures 34.3 and 34.4 In facial nerve affection resulting in lagophthalmos, the
show the method of testing and the weakness of little finger weakness in closure of the eye is evident and the globe of
and the thumb. Similarly, in radial nerve affection there is the eye remains visible while attempting to close the eye.
a weakness in raising the wrist. However, the patient is unlikely to realise the same, as he
A B
Figs 34.3A and B: (A) The Beak Test (B) Testing for weakness in little finger and thumb
A B
Figs 34.4A and B: Testing for weakness in little finger and thumb – can be taught to patient
CHAPTER
34
A B
Figs 34.5A and B: (A) In lateral popliteal nerve palsy weakness does not allow foot to be lifted upwards at the level of the ankle, which can be
compared with the other side, (B) In facial palsy affecting eyelids, the eye does not close completely and eyelid can be lifted with ease as
orbicularis oculi is paralysed
cannot see when his eyes are closed. What he generally example being the claw hand, which is usually chronic
feels is heaviness and somebody else points out to him and not sudden like in a case who has injury to the nerve.
that his eyelids do not seem to close. Figure 34.5B shows
early weakness in eye closure on left side, with sclera Primary and Secondary Deformities
visible on the medial aspect. The weakness can be tested A deformity is the visible consequence of impairment. Loss
with the examiner’s hand trying to lift the eyelid and of sensation due to nerve damage is primary impairment
comparing it with the opposite side. One may also observe and is classified as a Grade 1 disability. Claw hand is also
the uneven blinks. In the lower facial palsy, which is quite a primary impairment and is called as claw hand deformity
uncommon nowadays, and affects the mouth, the patient due to it being a visible consequence and hence, it is
will notice that there is a change in his facial appearance classified as a Grade 2 disability. Secondary deformities
and it can be confirmed by asking him to show his teeth are joint stiffness and volar skin contractures in the hands
and ulcers due to anesthesia, injury and neglect of self-
and observing that the affected side does not move properly.
care. Absorption and shortening are the examples of
For all cases, a proper disability record of nerve function
secondary deformities in the hands and feet. In the eyes,
assessment is mandatory and Jean Watson12 gives a
corneal ulcers and loss of vision can occur secondary to
detailed format, while Brandsma13 offers an excellent
lagophthalmos. Figures 34.6A to D show various deformities
review on monitoring the nerve function. As he mentions, that occur in leprosy.
not all muscles innervated by the nerve at risk need to be
tested and that many muscles cannot be tested in isolation. DEFORMITIES OF HANDS
Clawhand
DEFORMITIES IN LEPROSY
Affection of ulnar nerve paralyses the small muscles of
Deformities in leprosy arise due to tissue infiltration and the hands, i.e. intrinsic muscles like interossei and
nerve damage. Loss of eyebrows, depressed nose and lumbricals. Extensors exert the force and pull
wrinkled skin of the face are deformities due to tissue metacarpophalangeal (MP) joints in extension bringing
infiltration. These are commonly seen in lepromatous about compensatory flexion at the proximal interphalangeal
leprosy. The nerve damage is due to the leprosy neuritis (PIP) joints. When it affects only ulnar nerve, both the ring
and reactions, which affects peripheral nerves at a particular and the little finger are involved and it is called ulnar claw.
site; resulting in paralysis, of which the most common When both ulnar and median nerves are affected, often
CHAPTER
34
A B C D
Figs 34.6A to D: Deformities in leprosy: Total clawhand (including thumb paralysis), a case of wrist drop, lagophthalmos and face of a
patient showing wrinkling, collapse of nose and loss of eyebrows
the median nerve is involved partially, i.e. thumb is not However, if a patient presents himself late with a mobile
involved, it is called ulnar and partial median claw hand or claw hand immediate reconstruction is advisable. This will
subtotal claw. When all fingers and the thumb are involved, also prevent the occurrence of secondary deformities.
causing Ape-thumb deformity along with claw of all fingers, Dryness of hands due to autonomic fibers involvement
it is called ulnar and median claw hand or ‘total’ claw hand. sometimes exhibits cracks in the palmar skin. The use of
The fitness of the hand for reconstructive surgery can oil at home generally takes care of the dryness. Only when
be assessed by Bouvier’s maneuver. When holding the cracks are infected and deep crevices are noticed that it
MP Joint in flexion and asking the patient to extend the IP requires dressings. Other secondary deformities following
joints, if he is able to extend completely, the hand is fit for unprotected use of anesthetic hands are burns and cuts
surgery. If PIP joints cannot be extended it is likely that or wounds, which need medical care with dressings.
there is damage to extensor expansion at the PIP level. It Untreated wounds become deeper with development of
may be associated with contracture of volar skin. In such osteomyelitis and eventually lead to resorption and/or
cases it is necessary to make such hands fit with amputations.
preoperative exercises and splinting. Other deformities of Physical Measures
hands include swan-neck deformity, which is very rare and
occurs generally in reactions. Similarly, wrist drop (Fig. A mobile claw hand is one where there is no stiffness and
34.11) is rare but may occur and needs reconstructive range of movement is not affected. This type represents a
hand that needs reconstructive surgery at the earliest.
surgery.
However, if such facility is not available or surgery is
Management of Hand Deformities deferred to a later date, then exercises are advocated to
prevent stiffness. The best exercise is to put all joints
A clear understanding of the duration of the disease, neuritis through their range of movement several times a day with
and the deformity is necessary. The best treatment would the help of the normal hand. Specific exercise for clawed
be to operate on the nerve within six months of onset of fingers is aimed at movement of PIP joint to prevent its
symptoms of neuritis in order to get sensory and motor stiffness. Patient is taught to hold his clawed fingers with
recovery. One must remember that reconstructive surgery his thumb and index finger in total flexion at MP joint and
cannot get the sensations back. It is only when you can move PIP joints up and down (flex and extend). Mostly,
reverse the effects of the damage caused by operating on the patients do not continue the exercises for long.
the nerves, that you get both sensory and motor recovery. Therefore, it would be advisable to give finger loop splint
CHAPTER
34
to carry out exercises.14 The aim is to prevent secondary Physiotherapy is very useful in the management of
complications like stiffness, skin contracture and extensor deformities and is essential in both preoperative as well
hood damage (Figs 34.7A to C). as postoperative care of patients with deformity.
Reconstructive surgery requires the patient to use a
different muscle in place of the paralyzed muscle.
Therefore, the intelligent cooperation of the patient and
the active involvement of the physiotherapist trained in
leprosy are essential before the surgery is performed.15
Splints
Four main types of splints have been used by the authors
in the field areas. The health workers deliver these on their
routine rounds. These prefabricated lightweight splints have
been the mainstay in the management of deformities in
leprosy. These are Adductor Band Splint, Finger Loop Splint,
Opponens Loop Splint and Gutter Splint (Figs 34.8A to D).
Splints prevent deterioration and render the hands fit
for reconstruction.16 In early cases of abduction deformity
or in splayed fingers before or after reconstruction, an
A adductor band splint helps to keep fingers together and in
case of ulnar claw hand indirectly allow common extensors
to act on the paralyzed fingers. In late cases with stiffness,
dynamic gutter splints made of elastic materials are very
helpful in stretching out the skin contractures and relieve
the joint stiffness. Gutter splints are of two types: (i) static
splints, those made of rigid materials and (ii) dynamic
splints made up of flexible materials. Authors prefer to
use elastic materials like a hosepipe split in to half to
make the dynamic gutter splint. On account of its elasticity,
it tends to exert antagonistic pressure on the contracture
or stiff joint and gradually stretches it out. Another method
is to give plaster cylinder to each individual finger. Wax
bath may be offered to loosen out the stiff joints wherever
B available. Finger loop splint not only maintains the lumbrical
position but also help strengthen the small muscles of the
hands. Figures 34.9A to C show a patient who recovered
from the deformity with corticosteroid therapy and splintage.
Grip-aids
In the advanced deformities of hands like absorption and
amputations, Grip-aids may be required for activities of
daily living, which minimizes the dependency on others
for day-to-day tasks. Epoxy-resin Grip-aids (Modulan®)
applied on articles of work help patients to hold the objects
C and increase his/her efficiency in the working
Figs 34.7A to C: A single most important exercise for a clawhand is environment.17 However; it takes time to make an epoxy
to hold MP joint and move the PIP joints of the fingers several times in resin grip-aid and is not easy to use it in the field area.
a day. Finger loop splint helps to carry it out with better efficiency. Recently, Neela Shah demonstrated the quick solution with
CHAPTER
34
A B
C D
Figs 34.8A to D: (A) Prefabricated Opponens Loop, (B) Finger Loop, (C) Adductor Band and (D) Gutter Splints
These have been incorporated in the disability care program in the field areas
C
Figs 34.9A to C: A patient with reactions in nerves and
developing clawhand was put on corticosteroid and splints
with exercises which resulted in total recovery from
B deformity
CHAPTER
34
an Instant Grip-Aid Kit for immediate benefit in eating, finger to the thumb, split into two and inserted at the
drinking, combing and other activities of daily living.18 It adductor tendon by routing over the neck of metacarpal
has caught the attention of many rehabilitation specialists and the other slip in to the extensor pollicis longus at the
and has been provided free of cost across India and Africa distal interphalangeal joint level. Swan neck deformity is a
by Novartis Foundation. Figures 34.10A to C show how it rare occurrence. For the wrist drop correction, generally,
facilitates eating, drinking water and brushing the teeth pronator teres is transferred to extensor carpiradialis longus
almost as soon as it is applied. and brevis at the forearm, palmaris longus is transferred
to thumb extensors, and flexor digitorum superficialis of
Reconstructive Surgery ring finger is transferred for the extensor digitorum
Reconstructive surgery of the clawhand is a complex communis. All reconstructive procedures are followed by
subject and the very fact that there are many procedures proper re-education exercises for maximization of the result
described, shows that there is no uniformity and that no and the improvement.
single technique is the best. However, following extensive
work on the Zancolli’s Lasso procedure, Lasso as done by DEFORMITIES OF FEET
many surgeons is considered simple and effective with
The common deformities seen in the feet are foot drop
minimal rehabilitation requirements. Shah described Lasso
and claw toes, besides plantar ulcers. If neglected, these
in 1984-85.19-21 Currently, Shah advises 1:4 Lasso for
deformities can worsen with time and make a person
subtotal or total claw (Figs 34.11A to C) and TRAC
dehabilitated. Therefore, empowering a person with proper
(transverse arch correction) operation for ulnar clawhand.22
knowledge and supplementing the care with required
When one does not want to sacrifice the sublimis of any
materials is the only solution for deformity prevention and
finger, indirect lasso can be done using palmaris longus
better foot care.
as motor. The contraindication for lasso would be PIP joint
stiffness. In such cases, it is better to insert the transferred
Foot Drop and Claw Toes
slip into the extensor expansion like original Stiles-Bunnel23
or Antia’s Palmaris longus four finger many tail24 operation. Foot drop occurs when the lateral popliteal nerve, near the
In some instances, Brand’s extensor carpiradialis longus knee joint is affected. Patients cannot lift the foot from the
(ECRL) transfer and Fowler’s operation are also useful. ankle in the upward direction and it affects the normal gait.
Ape thumb deformity, i.e. thumb paralysis is corrected by In addition, paralysis of the muscles causes uneven
transfer of flexor digitorum superficialis (FDS) of the ring distribution of loads and stresses in the foot. Unsupported
A B C
Figs 34.10A to C: Instant Grip-Aid Kit contains rubber Velcro strap to tie it on shortened or amputated stump of the hand, a spoon, a glass, a
toothbrush and a comb holder. Patients can do activity of daily living like eating, drinking water or tea, brushing teeth, etc. almost immediately
CHAPTER
34
A B C
Figs 34.11A to C: Atul Shah’s Lasso procedure is done under vision with FDS slip divided in to two or four and inserted to itself after
forming a loop (Lasso) around A1 pulley. Photographs show clawhand before and after reconstruction
or uncorrected foot drop in the long run cripples the patient Plantar Ulcers
by contracture of tendo-Achilles and equinus deformity. Ulcers on the sole of the feet occur due to injuries from
Strengthening of weak dorsiflexion is carried out by outside or due to body weight itself, coupled with other
tying gradual load on the foot and asking the patient to factors as internal injury forming a swelling under the intact
dorsiflex the foot. The tightening effect of strong tendo- skin, which later on bursts open. Another cause is dry
Achilles is counteracted by stretching exercises in which skin, which cracks and gets infected thus developing in
A bandage cloth is tied in such a way that the patient to an ulcer. It may be true that an anesthetic foot is
himself can dorsiflex the foot by pulling it. Standing on a more likely to get an external injury and thus prone to
slope by which the foot is everted outward will nullify the ulcerations. Therefore, all persons with anesthetic feet are
inversion effect of the posterior compartment muscles. advised regular use of padded or microcellular (MCR)
A foot drop splint is provided at the earliest sign of footwear.
weakness in the leg to support the foot. So far, the common The common sites of ulcerations on the sole of the
splint used was a spring splint attached to the MCR feet are the weight bearing areas like metatarsal heads in
footwear. The spring action can be offered at ankle or by a the forefoot followed by heel and lateral border (Refer to
splint tied at the knee with an elastic strap. A simple solution Fig. 36.6 in the Chapter 36 on Nursing Care for Leprosy
has evolved recently with the use of polymers in the form Patients). On examination, the ulcer may be found to have
of prefabricated foot ankle arthrosis. The advantage is that purulent discharge or be dry with unhealthy granulations in
it is permanent and will be useful for a lifetime. If the patient the base. The former needs to be treated with systemic
does not want to get operated, the foot drop splint serves and/or local antibiotics and the latter needs more of the
as the next best solution. local antiseptic measures to promote healing. On movement
Claw toes generally do not cause any problem to the of the toes or on pressing the ulcer site, if serosanguinous
patient except sometimes rubbing against the footwear discharge is seen coming out it can be said to be a deeper
and/or development of ulcers on the tips. They are ulcer affecting probably the joint space. True plantar ulcer
correctable by reconstructive surgery with long flexor to is also called trophic ulcer as it is devoid of proper nutrition.
extensor transfer. It has a typical punched out margin, which is thickened as
CHAPTER
34
a result of the body’s protective response to further weight practicalities of self-care. These groups are often
bearing and continued walking on the painless foot. surprisingly supportive and can be very motivating for the
members. In addition, these groups also advice on how to
Management care for feet even without a kit, replacing with the home
If ulcer is present, rest is essential. All simple ulcers will made materials when materials in self-care kit are over.
heal, if given sufficient rest. The decision of what advice On the other hand, Hugh Cross advises reliance more on
and reference to be given depends on some simple criteria. the self-care with available materials at home and teaching
The first and foremost is the depth of the involvement. patients what to do on a daily basis.26
Deep ulcers are less likely to respond to conservative The most important instructions in use of the kit are:
treatment and will need scraping (pairing) or scooping 1. Do not use the scraper on the dorsal surface.
surgically followed by dressing and in case of non-healing 2. Do not scrape as to cause bleeding.
ulcer skin replacement with graft or flaps. However, majority 3. Do not use too many gauze pieces for dressing.
of cases need only self-care at home. 4. Do not tie the bandage too tight to cause swelling
Author’s work over a decade in obtaining healing with distally.
self-care kit has been well recognized and adopted by the 5. Not to use more than four rounds of the bandage, so
government and non-government organizations making as to keep the ulcer area in good aeration.
their own self-care kits. A typical self-care kit contains The plastic tub and MCR footwear forms an integral
scraper to scrape gently the thick margin of the ulcer, an part of the materials to be given in these camps.
antiseptic cream, an antiseptic solution to pour into water As per the author’s experience, nearly 40% of cases
at the time of soaking the feet, sterile gauze pieces to are able to heal their ulcers with the use of the self-care
cover the ulcer after ointment application, a bottle of kit. Figure 34.12A shows the sample of the self-care kit
Vaseline or any oil or cream which is used to hydrate the designed by authors and Figures 34.12B and C show the
skin or retain hydration in the skin and bandage with healing of ulcer with its use. Empowerment happens when
scissors and sticking plaster. individuals or group of people recognize that they
A typical session of empowerment of patients in the themselves can change their situation and then begin to
rural area is carried out as group therapy with instructions do so.27 Although 85% feet improve considerably well, it
and demonstrations on every step. Self-care groups have is the cardinal rule that those cases in which ulcers do not
been started in some communities. A number of people heal in about 4 months time, are referred for reconstructive
with self-care needs meet together to discuss the surgery. The cases with Grade1 disability with anesthetic
Figs 34.12A to C: Self-care kit and result in healing

of ulcer in about 3 months. Patient is empowered to
carry out self-care at home in a training session at
DPMR camp B C
CHAPTER
34
feet, dryness and cracks who were given only the effective to provide skin cover over the region and can be
moisturizing cream or oil and taught to keep their feet easily carried out by a general surgeon.
hydrated; were also able to prevent worsening of disability.
In some cases with ichthyosis on legs, improvement was Footwear
noticed with the application of moisturizing cream. Microcellular rubber (MCR) footwear is considered the best
Furthermore, all these cases are also supplied MCR for evenly spreading out the body weight as well as
footwear at the disability care program. preventing external injuries with a hard sole.31 Considering
the paucity of its availability, a criteria for its distribution
Surgery for Plantar Ulcers was standardized by the authors as a first priority to those
About 10 to 15 % cases of plantar ulcers need reconstruc- with ulcers and healed ulcers for next three years, secondly
tive surgery. If there is deeper tissue infection or bone to those with cracks and history of infection and swelling
involvement, one of the three procedures are performed. in the feet off and on; followed by all other cases. If
These are: (1) sesamoidectomy, (2) subtotal metatarsectomy specialized footwear is not available, the insole of
and, (3) transmetatarsal amputation.28 Besides split skin microcellular rubber also can be used in patients own
graft in cases with large raw areas, a flap cover is required footwear, as an alternative. Finally, it is necessary to
for the chronic heel ulcers and metatarsal head ulcers as explain to the patient that any footwear, which will prevent
these are weight-bearing areas. Shah has described an injury, has to be used by him or her and they need to
advanced myocutaneous flap for chronic heel ulcers.29 learn to diagnose the initial symptoms of impending
However, often local transposition flaps suffices. His original ulcerations by looking at their feet, palpating for increase
technique of Neurovascular Island flap to first and second in temperature in certain areas and any unusual swelling,
metatarsal region offers sensory skin and often prevents on regular day-to-day basis.32 To overcome the stigma
or delays the recurrence.30 However, it can only be associated with conventional MCR footwear, some
performed by a specialist plastic surgeon. Alternately, the designer (and fancy!) MCR footwears have also been made
author advocates a distally based flap for 1st metatarsal available for use. The pictures of some designer footwear,
head ulcers (Figs 34.13A and B) which is simple and prosthesis and splints made commercially available at
A B
Figs 34.13A and B: Distally based flap to provide skin cover for 1st metatarsal head ulcer with exposed tendon
CHAPTER
34
subsidized cost by ALERT, an NGO are given at the end flaps are inserted horizontally, giving bulk to the nose and
of this chapter. it generally does not require any prosthesis to be held for
prevention of contracture, as for inlay. In both procedures,
DEFORMITIES OF FACE a cantilever bone graft can be performed after six months
to give a better dorsal line. In the inlay, at that time, the
The common deformities of face are wrinkling of face giving oral incision is closed and prosthesis discontinued. In cases
an aged appearance, saddle nose changing the personality where one finds adequate lining, either a silicone implant
of the person, loss of eyebrows making him an obvious or a bone graft may be put to correct the dorsum of the
notable person with an unusual face in the crowd. These are depressed nose. Behavior of silicone implant is
generally due to tissue infiltration and can be corrected once unpredictable and it may come out after a period varying
the chemotherapy treatment is completed satisfactorily. from few days to few years. But it is an easy procedure
and bone graft can always be done later on, if required.
Depressed Nose (Collapsed Nose) Figures 34.14A and B show a patient in whom silicone
It occurs due to destruction of anterior nasal spine and implant was put offering quick correction without any
loss of cartilaginous support to the nose following mucosal associated morbidity. It remained for few months and was
infiltration, secondary infection and destruction of cartilage. extruded due to infection. However, he did not need any
The lining of the nose shrinks inwards, pulling the end of further surgery.
the nose upward.33 The upper lip then seems unusually
long. Destruction of anterior maxillary spine and later lack Wrinkled Face
of support to upper central incisors may also be noted in Nasolabial face-lift has been the standard as generally
advanced cases. Replacement of mucosa is invariably there is greater laxity in these areas making it an obvious
required with either skin graft or nasolabial flaps. choice.35 However, the disadvantage is the visible incisions,
Replacement of mucosa described by Antia as inlay graft; at least for sometime. Shah has also performed the typical
is one of the standard procedures when there is a snarl plastic surgery face-lift procedure when the patient is
present on the nose. Shah has modified Antia and Buch’s34 relatively younger and when one wants to avoid the scars
approach and prefers to insert the nasolabial flaps as lining on the face (Figs 34.15A and B). Sometimes, enlarged ear
wherever possible with a U-shaped incision. The nasolabial lobules also need to be tackled with triangular excision.
A B
Figs 34.14A and B: Depressed nose in which silicone implant was inserted to shape the dorsum of the nose
CHAPTER
34
thickness hair graft, which initially looks as if it has necrozed

but the thin line of hair eventually remains and grows. The
flap cover also needs a secondary procedure for trimming
the bushy growth, which is not liked by the patients.
Lagophthalmos
Lagophthalmos generally occurs due to involvement of the
zygomatic branch of the facial nerve. It is important to
recognize this complication early and if possible treat it
with prednisolone therapy to get motor recovery. In the
established cases, reconstruction by the temporalis
musculofascial sling is carried out (Figs 34.16A and B).36
Lateral tarsorrhaphy though a simple procedure; often shows
an unsatisfactory outcome in terms of the eye closure.
Ectropion
In the old age; and in patients from colonies with long
standing disease, one also comes across the ectropion of
A
the lower eyelid, which may need correction with full
thickness skin graft and/or by triangular excision of the
everted eyelid margin.
RECONSTRUCTIVE SURGERY (RCS) IN

DPMR—A GOVERNMENT OF INDIA
(GOI) INITIATIVE
It is estimated that around one million leprosy patients
with disabilities exist in the country.25 There is a greater
need to introduce reconstructive surgery at all medical
colleges and district hospitals. Authors have been closely
associated with RCS mega-camp experiment in Gujarat
where nearly 5000 operations have been performed. The
Government of India labeled it as the Gujarat Model and
asked other states to follow it, to reach the benefits to a
majority of disabled cases. DPMR (disability prevention
B and medical rehabilitation) initiated by GOI and
Figs 34.15A and B: Wrinkles on the face corrected with enthusiastically implemented by the National Leprosy
standard face-lift procedure
Program Manager, has RCS built in for all DPMR institutes,
Government Medical Colleges and District Hospitals. All
patients undergoing RCS are likely to get an incentive for
Loss of Eyebrows loss of wages, travel, sustenance, etc. a sum of Rs. 5000/-.
Reconstruction is undertaken with superficial temporal Similarly to create RCS facility in the existing department
artery flap (either pedicle or Island). In the former case, of government colleges, a similar amount for each operation
the flap is divided after 15 days and the extraportion performed, would be given to the government hospitals. In
discarded. When island flap is done occasionally, necrosis the year 2008 itself, this has resulted in more than 3000
in medial portion may occur and need secondary RCSs being performed. However, load of RCS is so
reconstruction with free full thickness hair graft from the extensive that it will take many years to reach these
occipital area. Some surgeons prefer directly the full services to all those in need.
CHAPTER
34
A B
Figs 34.16A and B: Temporalis sling was performed on both sides in this patient for correction of lagophthalmos
ECONOMIC REHABILITATION selling second hand clothes, and presiding at provision

stores”.39 Yo Yuasa claims that the final goal is not only
Leprosy handicapped persons form a very distinct entity
the healing of leprosy as a disease; but total restoration of
even for the rehabilitation strategy.37 Often leprosy
leprosy patient as a whole person in community.40
sufferers, especially those with stigmatizing signs and
The publicity provided at public functions is of great
deformities, are not accepted well even within their own
help in increasing awareness about leprosy as a disease,
families. Fortunately, instances of dehabilitation leading
and the plight of the sufferers, which sensitizes the
to social ostracism are now on decrease following
community regarding their restoration in the community.
extensive education about leprosy and the availability of a
One can also equate this activity as community based
cure in the form of multidrug therapy. Nonetheless, some rehabilitation (CBR). CBR is a strategy, which targets social
of the patients lose their self-esteem and find it difficult to inclusion, and aims to overcome activity limitations and
earn money, causing a strain on the family income. Often participation restrictions and thus improve the quality of life
they do not have the means and resources to get back to for persons with disabilities.41 The impact of the economic
work. As mentioned in the ILEP SER guidelines, “although rehabilitation with articles of income generation for the
many people are resilient enough to cope with the effects disabled individual and their families is dramatic and it
of leprosy, others need help if they are to resume their has transformed the quality of lives of hundreds of people.
previous way of life. These individuals are the focus of On account of integrated approach of disability
socioeconomic rehabilitation (SER) programs”.38 prevention, correction and care including rehabilitation, this
The leprosy workers identify such people who are in approach by authors Atul Shah and Neela Shah for Novartis
need of economic rehabilitation, try to understand what Foundation has been hailed as a successful “Model” of
they can do and in consultation with them and their family, the holistic approach.42 The enhanced strategy for 2010 to
identify what could best serve them and for their betterment, 2015 by WHO has endorsed the goal of reducing grade 2
as an appropriate economic rehabilitation, e.g. sewing disabilities by 35% from the baseline level of 2010.43
machines, handcarts, kits for bicycle repair, carpentry, Improving the quality of services for prevention of
masonry work, agricultural tools, etc. After this assessment, disabilities and rehabilitation are also the objectives of the
the project personnel provide the required aids (Figs 34.17A enhanced strategy.
to C). In the account on leprosy sufferers, i.e. “Don’t Fence In the end, authors have to reiterate the fact that
Me In”, Tony Gould writes from the expedition of Dr Tonkins “leprosy is curable, do not fear it or its consequences but
that “despite the repulsive appearance, the public have no face them and fight back to emerge happy and victorious
active objection to it. I have frequently seen them tailoring, in life”.
CHAPTER
34
A B C
Figs 34.17A to C: (A) Economic rehabilitation program, a person followed up was selling toys and earning good amount (B) Leprosy affected
persons at the regular community gathering to discuss their health and social problems (C) While another was using farming equipment to earn
more
HEALTH EDUCATION TO A PERSON AFFECTED WITH LEPROSY
Advice to Patients on Completion of MDT

1. Skin patches will take much longer time to disappear or get back the original color and texture.
2. Skin color will return to normal within few months of MB MDT when dark coloration of the skin is due to clofazimine.
3. Reactions in the skin or nerves may occur in a few instances even after completion of the treatment (after being
cured). If the skin patches become reddish, if there is loss of sensation in the hands or feet or weakness in the
muscles, report back immediately for a check up.
4. Tingling, numbness or heavy feeling is the initial signs of neural damage. Do not neglect it and report for a check
up.
Advice to Patients with Loss of Sensation in Hands and Feet (Fig. 34.18)
1. Daily inspection of hands and feet for signs of injury.
2. Keep the hands and feet moist- use water to wet hands and feet often; rub a few drops of oil or use moisturizing
creams.
3. Do not exert undue pressure while working, for this can cause friction on the skin.
4. Do not touch any hot objects without wrapping a cloth on your hands.
5. Use wooden handles while cooking food at home and never lift the cooking vessels with bare hands; use thick
cotton cloth for the same or use cotton glooves.
6. Do not walk barefoot particularly on tar roads. Walk a small distance at a time, walk slowly and take rest
frequently. If possible, use of cycle is much safer than walking on anesthetic feet.
7. Use comfortable footwear without nails and check your feet daily for injuries or burns.
Advice to Patients who have Deformities

1. Follow advice for loss of sensations.
2. Carry out simple physiotherapy exercises at home to keep the joints mobile.
3. Deformity is a consequence of the disease and is reversible or correctable.
4. Deformity is not contagious and cannot transmit the disease.
5. Do not allow deformities to worsen; get the specialist’s advice as soon as possible.
CHAPTER
34
Fig. 34.18: Health education pamphlet shown above has been translated in various languages and used in many
countries to educate patients who have loss of sensations (Courtesy: Novartis CLC Association)
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34
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34
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34
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34
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34
REFERENCES 20. Shah A. Multiple Superficialis Motor for Opponens and Lumbrical
replacement: One stage correction of leprous clawhand. J Hand
1. Yawalkar SJ. Historical Background. In: Leprosy for medical Surg 1984; 9:285-88.
practitioners and paramedical workers, 7th Ed. Basle, 21. Shah A. One in four flexor superficialis lasso for correction of
Switzerland, Novartis Foundation for Sustainable Development, clawhand. J Hand Surg 1985;10: 404-06.
2002:2. 22. Shah A. A new technique for correction of reversal of transverse
2. Job CK, Selvapandian AJ, Rao CK. Aetiology, Pathogenesis and metacarpal arch and ulnar claw hand. In: Maneksha RJ (Ed.)
Pathology, In: Leprosy Diagnosis and Management, 4th edn. Transactions of IXth International Congress of Plastic and
New Delhi, Hind Kusht Nivaran Sangh, 1991:9-13. Reconstructive Surgery. New Delhi: Tata McGraw Hill, 1987:533.
3. Nilsson T, Sparell G. Skin smears for leprosy, 1st edn, ALERT, 23. Brand PW. Paralytic claw hand, with special reference to paralysis
Addis Ababa, Ethiopia, printed by GLRA, Wurzburg, Germany, in leprosy and treatment by sublimis transfer of the Stiles and
produced under TALMILEP with financial support of CIBA-Geigy, Bunnell. J Bone Joint Surg Am 1958;40-B: 618-32.
Basle, 1989:3. 24. Antia NH. The Palmaris Longus Motor for Lumbrical
4. Ganapati R. Studies on leprosy, Bombay Leprosy Project, 1988:6. Replacement, The Hand. 1969; 1:139-45.
5. Baktha Reddy NB, Doris P. Schieffelin Leprosy Research and 25. Disability Prevention and Medical Rehabilitation 2007 –
Training Centre, Karigiri, 2000:12. Operational Guideline, Pub; Central Leprosy Division,
6. Prevention of Disability, Guidelines for Leprosy Control Government of India, New Delhi, 2007, vi.
Programs, published by ILEP, London, 1995:3. 26. Hugh Cross in “I can do it myself”. Tips for people affected by
7. Improving Access to Leprosy Treatment, pub; Novartis
leprosy who want to prevent disability, WHO, SEA/CLP/2007.2.
Foundation for Sustainable Development, 2005:47-51.
27. WHO/ILO/UNESCO CBR Guidelines, pub; WHO, 2007:5.
8. Workshop for Health Service Managers in Charge of Leprosy
28. Srinivasan H, Palande DD. Essential surgery in leprosy. WHO,
Control Programs, World Health Organisation, 2007, printed in
Geneva, 1997:24-28.
India Feb. 2008:90-91.
29. Shah A, Pandit S. Reconstruction of the heel with chronic
9. Van Brakel WH, Reed NK, Reed DS. Grading impairment in
ulceration with flexor Digitorum brevis myocutaneous flap. Lepr
leprosy, Leprosy Review 1999;70:180-88.
Rev 1985; 56:41-48.
10. Wheate HW, Pearson JMH. How to examine for enlargement of
30. Shah A, Saluja K. Rehabilitation in Hansen’s Disease. Disabil
nerves, In: A Practical Guide to the Diagnosis and Treatment of
Rehabil 1991;14:125-33.
Leprosy in the Basic Health Unit, 3rd Ed. Wurzburg, Germany,
31. Brand PW. Neuropathic ulceration, quaderni di cooperazione
1985:13-17.
sanitaria, Browne SG, Nunzi E. pub; Associazione Italiana “Amici
11. Fritschi EP. Etiological considerations in leprous neuritis and
di Raoul Follereau” 1981:93-107.
their implications in treatment. Proceedings of the workshop on
32. Mendis M. Physiotherapy in Leprosy. John Wright and Sons,
reactions in leprosy. Pub: Indian Association of Leprologists,
Bristol, 1965:73.
Sponsored by World Health Organisation and Government of
33. Pfaltzgraf RE. How to Diagnose and Classify Leprosy, A study
India, New Delhi, 1986:133-35.
Guide, New Jersey, American Leprosy Mission 1988:17.
12. Watson JM. Essential Action to Minimise Disability in Leprosy
34. Antia NH, Buch VI. Correction of nasal deformity with nasolabial
Patients, 2nd edn. TALMILEP, The Leprosy Mission International,
flaps. Indian J Plast Surg 1972; 5: 23-25.
1994:4-5.
35. Antia NH. Reconstructive Surgery of the face. In: Cochrane (Ed)
13. Brandsma JW. Monitoring motor nerve function in leprosy
Leprosy in Theory and Practice. Bristol; John Wright and Sons,
patients. Lepr Rev 2000; 71:258-67.
1964; 2nd edn, 497-508.
14. Shah A. Prevention and Correction of Claw Hand by Splintage—
36. Antia NH. The ‘Temporalis Musculofascial Sling” for the correction
A New Approach to Deformity Care. 1992, Ciba-Geigy Leprosy
of Lagophthalmos. Indian J Surg 1966; 28:389-96.
Fund - Comprehensive Leprosy Care Project.
37. Shah A, Shah N. Rehabilitation Surgery for leprosy handicapped
15. Shah A. Physiotherapy and Surgery. In: Leprosy A Concise Text.
at a rural leprosy colony. Int J Rehabil Res 1985; 8(3): 345-47.
Koticha KK, (Ed), Pub; Koticha DK, 1990:189-214.
38. Guidelines for the social and economic rehabilitation of people
16. Shah A, Shah N. Prevention and Care of Disabilities in Leprosy,
affected by leprosy. ILEP, London 1999:2.
Pub; Novartis Comprehensive Leprosy Care Association,
Mumbai, 2006:20-24. 39. Tony G. Don’t Fence Me In. Bloomsbury, 2005:229.
17. Shah A, Yawalkar SJ, Ganapati R. Modulan Grip-Aids for 40. Yuasa Y. International Seminar on leprosy control, Seoul, Korea,
Rehabilitation in Leprosy. 1993, Ciba Geigy Leprosy Fund, 1991, quoted in Annotated Bibliography on Leprosy pub: CASP-
Novartis Foundation for Sustainable Development, Basle, PLAN, Pune, 2001:395.
Switzerland. 41. Brochure on Community-based Rehabilitation, Towards An
18. Shah N, Shah A. Grip-Aid Kit – A simple method for instant Inclusive Policy, Dutch Coalition on Disability and Development,
benefit in activity of daily living in advanced hand deformities. 2007, http://www.dcdd.nl.
17th International Leprosy Congress. Hyderabad, 2008. 42. Gokhale SG, Sohoni N. Human Face of Leprosy, International
19. Shah A. Correction of Ulnar Claw Hand by a Loop of FD Leprosy Union 2001:168-69.
Superficialis Motor for Lumbrical Replacement. J Hand Surg [Br] 43. Report of the Global Program Managers Meeting on Leprosy
1984; 9:131-33. Control Strategy. New Delhi. WHO, April 2009:72.
35
Deformity/Disability Prevention
GN Malaviya
INTRODUCTION Types of Deformities

The main cause of socioeconomic dehabilitation in leprosy The deformities due to the direct result of disease process
is deformities. A considerable portion of disability load is and infiltration with Mycobacterium leprae are called
the result of failure to incorporate activities relating to specific. Deformities in this group are due to the
prevention of disabilities using simple technologies and mycobacterial load and its local damaging effect on the
patient motivation into the leprosy management. Where tissues, for example leonine faces, sagging of ear lobules,
leprosy is common, it is identified with deformities and loss of eyebrows, etc.
disability by the public. Failure of control program to master Deformities which are produced due to indirect effects
the problem of deformities is seen by public as failure to of disease, e.g. motor paralysis and recurrent ulcers due
control the disease. to anesthesia of extremities; are grouped separately as
Prevention of impairments and disability (POID) is paralytic and anesthetic deformities respectively.
integral to the success of management of leprosy affected Table 35.1 summarizes various deformities seen in leprosy
persons. The objectives of managing disabilities in leprosy, patients. Fortunately, the deformities which are difficult to
therefore, are to prevent (i) onset of new disabilities and treat can be easily prevented if little attention is paid to,
(ii) worsening of existing disabilities. The prevention of e.g. anesthetic deformities. The deformities, which are
disabilities is an essential component of the National difficult to prevent, are fortunately amenable to treatment;
Leprosy Eradication Program. In addition to any direct for example motor paralysis.
benefit to the patient, attention to disabilities has a favorable
influence on attendance at clinics and thus, on the leprosy GRADING OF DISABILITIES
control as a whole. Prevention of deformities increases AND DEFORMITIES
the confidence of the patients and their peers in therapy. Some form of grouping or grading of deformities is
The terms disability and deformity have been used necessary to assess the patients in field surveys, leprosy
interchangeably while referring to the physical problems in control programs and rehabilitation work. Different methods
leprosy patients. Deformity is an alteration in the of grading do offer some convenience to the field workers
appearance and is usually (but not always) associated but in a clinical set-up it is always better to record the
with some incapability especially if the limbs are actual disability/deformity.
involved. Disability is actually an incapability of the patient WHO in 1970 suggested one such grouping of
and it may exist even without any obvious disfigurement. disabilities (Table 35.2).1 The main drawback of this
In a nutshell to say, deformity refers to anatomical classification was the failure to recognize the significance
(physical) aberration and disability refers to a functional of individual defects which seem to have a lot of bearing
aberration. on the overall function of the part. In hand, for example,
CHAPTER
35
Table 35.1: Disabilities and deformities which can develop in leprosy patients
Sr. Organ Specific deformities Motor paralytic Anesthetic Miscellaneous
no. deformities deformities deformities
1. Face Nodulation; loss of facial hair in males; Lagophthalmos; facial Anosmia Paraesthesia; loss of taste;
nasal defects: full thickness loss of nasal palsy crocodile tear syndrome;
wall, depressed dorsal crest, alar nasal crusting and blockage
deformities and distortion,facial wrinkles
2. Eyes Loss of eyebrows Blurring due to Complicated cataracts;
corneal abrasions ectropion and entropion;
secondary to painful red eye, loss of
corneal anesthesia vision
3. Ears Sagging of ear lobules;
Rat bitten appearance of helix
4. Larynx Hoarseness of voice
5. Hard and Palatal perforation Nasal speech
soft palate
6. Hands Reaction hand, frozen hand, Ulnar claw hand; ulnar Anesthesia Paraesthesia, pain loss of
twisted fingers, intrinsic plus fingers median claw hand; wrist Ulcers Resorption grip power
drop; “z” thumb and weak
pinch; reversal of distal
transverse metacarpal
arch; interphalangeal
joint contracture of the
thumb
7. Legs and Frozen foot Clawing of toes, drop Ulcers, absorption, Warty outgrowths on the
feet foot partial or complete disorganization of dorsum of foot;
foot chronic lymphedema
8. Skin Scarring due to recurrent reactions Dryness of skin
9. Testes Testicular atrophy Gynecomastia;
gynecothelia, impotence,
sterility in later stages
Table 35. 2: WHO (1970) Grading of disabilities

Sr. no. Grade Hands Feet Eyes
1. Grade 1 Insensitive hand Insensitive feet Redness of conjunctiva
2. Grade 2 Ulcers and injuries and /or mobile Trophic ulcer and /or claw toes or Lagophthalmos and/or blurring of
claw hand, and /or slight absorption foot drop and/or slight absorption vision and /or inflammation of globe
3. Grade 3 Wrist drop and /or clawing of fingers Contracture and/or severe Severe loss of vision
with stiff joints and /or severe resorption of foot (1/5 of the sole
resorption of fingers area is lost)
the wrist drop is grouped with stiff joints and severe The need is being felt for a simple disability record for
absorption of fingers and toes. Wrist drop can be easily field use from which the problems can be immediately
corrected with surgery. Similarly, drop foot deformity has identified and appropriate action taken on a priority basis.
been grouped with ulcers. Drop foot is a severe disability A modified scheme for grading is shown in Table 35.4.
but it responds fairly well to surgical correction. The altered Here Grade 1 and Grade 2 deformities include anesthesia
gait mechanics of the drop foot predisposes to ulceration and ulcers, the problems which can be taken care of by
because weight distribution patterns are altered. In 1988, physiotherapists and other personnel participating in the
WHO grading was revised (Table 35.3).2 It considered only Leprosy Control Program. The Grade 3 disabilities are
three grades and appears to be meant for grading the paralytic deformities and can be corrected by surgery and
disabilities for statistical purposes and not for recording therefore should be referred to the centers offering surgical
the progress of individual patients from the point of services at the earliest. Grade 4 deformities are gross
rehabilitation. mutilations needing the attention of rehabilitation team and
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35
Deformity/Disability Prevention 449
Table 35.3: WHO (1988) Grading of disabilities
Sr no. Grade Hands and Feet Eyes
1. Grade 0 No anesthesia, no visible deformity or damage* No eye problems due to leprosy**
No evidence of visual loss
2. Grade 1 Anesthesia present but no visible deformity or damage Eye problems due to leprosy present but vision not
severely affected as a result of these (vision 6/60 or
better; can count fingers at 6 meters)
3. Grade 2 Visible deformity or damage present Severe visual impairment; (vision 6/60 or les; inability to
count fingers at 6 meters
*Damage in extremities means ulcer, shortening, stiffness, disorganization, and loss of part or all of the hand or foot.
** Eye problems due to leprosy include corneal anesthesia, lagophthalmos and iridocyclitis.
Each hand, foot and eye is to be assessed and classified separately.
If any disability, found in the patient, is due to causes other than leprosy, the fact should be recorded.
Table 35.4: Grading of disabilities according to their management

Sr. no. Grade Hands Feet Eyes
1. Grade 1 Insensitive hand Insensitive foot Redness of conjunctiva /conjunctivitis
2. Grade 2 Ulcer and injuries and/or Trophic ulcers and/or claw toes Blurring of vision and/or inflammation
slight resorption of globe
3. Grade 3 Mobile claw fingers and/or paralyzed Drop foot Lagophthalmos
thumb and/or wrist drop
4. Grade 4 Stiff finger joints and/or resorption Contracture and/or severe Severe loss of vision or blindness
of fingers resorption of the foot
social workers who then can organize the institutional or Type of disease and immune status: The immunity to
community care for them. disease varies with the type of leprosy, being the maximum
in tuberculoid variety and almost absent in lepromatous
FACTORS AFFECTING THE ONSET AND leprosy. The tissue damage, when it occurs, is severe in
PROGRESSION OF DISABILITIES patients with higher cell mediated immunity. The nerve
damage occurs fairly early in tuberculoid form of the
Existence of an effective Leprosy Control Program disease. The excessive cell mediated immune response
influences the deformity rate but all leprosy patients do in the nerves in tuberculoid leprosy results in rapid
not suffer from disability. The available reports quote that destruction of the nerves progressing to caseation and
4 to 10 % of patients suffer from some form of disability.3 often it is irreversible.
Age: The deformities are more commonly seen in 20-40 In lepromatous patients, multiple nerve trunks are
years age group probably because of the fact that self- involved but damage occurs quite late. However, the
limiting forms of disease occur in younger age groups and disease takes longer to be controlled. Due to widespread
the duration of disease is also shorter in them. The 20-40 nerve involvement, deformities are observed in larger
years age group is comparatively more active and thus proportion of lepromatous patients; there is slow fibrosis
forms a vulnerable group. in nerves with the result that over a period of several years
multiple nerves are affected. Since the nerve fibers are
Sex: The deformities are less common in females because
damaged even by intraneural fibrosis, deformities might
of lower incidence of disease, occurrence of milder forms
appear even in cases where the disease appears to be
and also lesser involvement of nerve trunks in them.
controlled clinically. Onset of leprosy reaction may also
Duration of the disease: It has been observed that damage the nerves rather quickly.
shorter the duration of active disease, lesser the number Borderline forms of leprosy are notorious because the
of deformities probably because of better control of immunity is unstable and fluctuating. In these patients,
disease with treatment and lesser degree of involvement reactional states produce acute nerve damage which at
of tissues. times, may recover fully under appropriate treatment.
CHAPTER
35
Occupation: Injuries (single or repeated) often cause Quiet nerve paralysis: Clinically, evident acute or subacute
damage to the anesthetic limb. Heavy manual labourers neuritis of nerve trunks is a sign of impending paralysis.
and specific occupations causing repeated trauma to an However, thickened nerve trunks quite frequently become
anesthetic part are more likely to cause ulcerations which paralyzed without manifest nerve pain and the damage is
may progress to mutilation if not attended to. Females recognized only after it is physically manifest. The use of
suffer damage to the fingers due to burns in their role as corticosteroids in substantial doses (please see WHO
homemakers. recommended schedule for neuritis management) over a
period of 3 to 6 months, is reported to facilitate the recovery
Attitude of the patient: Living with anesthetic extremities
in high proportion of such cases where the disease is treated
is difficult. Patients, who do not have clear concepts about
before the nerve is completely paralyzed.9
the value of sensations and its protective function in
preventing tissue damage, suffer more and develop serious
deformities; even due to minor trauma occurring in routine CAUSATION OF DEFORMITIES
activities of life. Due to extreme emotional upset, The deformities can develop due to (a) direct result of
sometimes the patients develop apathy towards their infiltration of tissues by M. leprae, (b) muscle imbalance
disease and ignore their injuries. Such cases also suffer secondary to motor paralysis and (c) secondary effects of
severe mutilations. analgesia and anesthesia. These factors operate singly or
Treatment: Effectiveness of the treatment in preventing in combination in various patients but to identify the individual
the occurrence of deformities is still debated. An attempt contributions of each, these are discussed separately.
has been made to establish an association between
dapsone treatment and development of deformities.4 A Effects of Infiltration of Tissues By M. leprae
possible neurotoxic effect of dapsone was suggested Nerve Damage
because it was observed that deformities were common Involvement of major nerve trunks of extremities results
in patients who had regular dapsone therapy.4 However; a in sensory-motor deficits. Sensory loss almost always
report on military personnel where treatment was precedes motor paralysis. The sites and sequence of nerve
supervised, said that only 1.5% of patients developed trunk involvement in leprosy follow a definite pattern but
deformities after they were put on therapy.5 In another the causes for such specificity of nerve involvement have
report, where workers have emphasized the need of anti- not been fully understood. It has been suggested that the
inflammatory drugs together with dapsone during reactional tissues in a more superficial position where core
states, none of the patients developed deformity after temperature is less, favor the growth of M. leprae.10 The
starting the therapy.6 nerves which commonly get involved pass through a
Srinivasan and Noordeen did report higher deformity narrow osseofascial tunnel across the joint. During
rates in patients taking regular treatment as compared to movements of these joints nerve trunks suffer minor
the group who had not taken any treatment. 7 They damage due to stretching. The inflammatory process starts
suggested that under field conditions the treatment is at these sites and is perpetuated by the presence of
carried out on a mass scale and on a routine basis where infection. The reactionary edema and infiltration add to
facilities for individualizing treatment for management of the swelling of the nerve, which is further accentuated by
complications and satisfactory follow-up are not adequate, the pre-existing external compressive forces. The
as in an institutional setup. This probably could explain to unyielding fibrous epineurium adds to the compression.
some extent the contradictory reports from various centers. The end result is ischemic, inflammatory nerve damage.
Regularity of treatment could be taken as indicative of Brand suggested three chief factors which determine
the clinical symptomatic state of the patients.8 Furthermore whether an infected nerve will be paralyzed or not.11 These
dapsone given in doses for treatment of leprosy is not factors are:
neurotoxic; at least in experimental situations. (i) The number of nerve fibers in the nerve trunk,
Availability of medical care: Areas where adequate (ii) The depth of location of the nerve from the body
medical attention is available, the deformities tend to be surface
lesser in number and milder in form. (iii) Immunological status of the patient.
CHAPTER
35
Higher the immunity; more severe is the nerve damage. Skin Damage
More the number of nerve fibers in a nerve trunk; more is Most of the obvious lesions in leprosy occur in skin and a
the susceptibility of nerve to damage because intervening lower temperature than the body core has been put to
areolar tissue is less and compression can occur more blame. The cooler epithelium of nasopharynx favors growth
easily. The nerve trunks or the parts of nerve trunk which of M. leprae. Some of the most marked infiltrations occur
are superficially located (nearer to the skin or body surface) around the face, other regions are also affected but the
are affected more probably because of the lower core sparing of axilla and groin is far from clear. The axilla has
temperature.10 A lower temperature favors the growth of a much lower temperature than oral cavity.
M. leprae. When the skin and subcutaneous tissues are infiltrated,
The most commonly involved nerve is ulnar at the level the collagen and elastic fibers, which maintain the shape
of elbow just above the medial epicondyle. Posterior tibial and form of skin, are largely replaced by granulation tissue.
and common peroneal nerves are involved at the ankle The skin, first of all, looks swollen and shiny but later
and just behind the neck of fibula respectively. Median when the disease subsides it becomes atrophic, wrinkled
nerve is involved at the level of wrist. The radial nerve is and loose. The skin appendages are also destroyed leading
involved in the upper arm but is usually not damaged to the loss of hairs and reduced or absent sweating.
enough to manifest clinically particularly in the Indian Recurrent reactional episodes with pustulation/ulcerations
population. produce scarring on the body surface.
The sequence of paralysis is also characteristic. The
usual paralysis is high ulnar (at the elbow) followed by Oro-nasal Defects
combined high ulnar- low median type. The least common The nose is affected because of its lower temperature.
combination is high ulnar - high median and radial paralysis. Granulomas have been shown to be present in the nose
Isolated paralyzes of these nerves have been reported even before the disease manifests clinically.12 Nasal
but those are rather uncommon. Lateral plantar component stuffiness develops first, followed by superficial ulcers in
of posterior tibial nerve is more commonly affected and so nasal mucosa due to trauma while picking the nose. These
is the deep peroneal component of common peroneal nerve get secondarily infected and repeated inflammatory
which innervates tibialis anterior and extensor muscles of episodes lead to the destruction of nasal cartilage and
the toes. The zygomatic branch of the facial nerve is more subsequent scarring. The nasal tip is pulled backwards
commonly involved producing lagophthalmos, complete presenting as typical nasal deformity with depressed dorsal
facial paralysis being uncommon. crest and anteriorly facing nostrils. The alar cartilage can
Accompanying sensory loss is a major handicap. Since also be damaged and its margins show various forms of
anesthesia is generally irreversible, continued trauma can irregular outline. The excessive nasal discharges putrefy
result in ulceration, infection, osteomyelitis and absorption and dry up forming crusts that at times attract flies. The
of digits even after the disease is labeled as cured. In larvae of these flies hatch out and burrow deeper tunnels
addition to the sensory-motor damage, the autonomic fibers into local tissues producing intense cellulitis of face.
innervating the sweat glands and cutaneous vessels are Sometimes, destruction is so extensive that full thickness
also damaged; the capability of the vessels to respond to of the nasal wall is lost producing severe facial
inflammatory process therefore decreases. In the beginn- disfigurement.
ing, there occurs only partial ischemia of the nerves which Lepromatous nodules occurring over palate may
causes a reversible paralysis due to loss of conduction in ulcerate and an oronasal fistula can form making eating
the nerve. Later, Wallerian’s degeneration sets in which if and drinking difficult. The scarring around soft palate may
mild, recovers. This reversible stage of damage lasts up restrict its movements resulting in nasal speech.
to one year in majority of patients. After that paralysis is
considered as established and corrective measures can Gynecomastia and Associated Changes
be undertaken. The atrophy of testes can occur due to its complete
Table 35.5 depicts the effects of nerve damage and destruction by granulomatous infiltration, especially in
associated deformities. Deformities of the hands being more patients in the lepromatous spectrum. The resulting
common are seen in all types of leprosy followed by those hormonal imbalance leads to gynecomastia and impotence.
of the feet and face. Such patients may also develop sterility. Liver damage, in
CHAPTER
35
Table 35.5: Physical manifestations of nerve damage in leprosy

Sr.no. Nerve trunk Site Muscles paralyzed Deformity Sensory loss
1. Ulnar Palm All Interossei; lumbrical for ring Clawing of ring and little Ulnar side of ring finger and
nerve and little fingers; hypothenar fingers”Z” pinch complete palmar aspect of little
muscles; adductor pollicis and finger and hypothenar area
sometimes flexor pollicis brevis
Elbow All the above plus flexor carpi As above As above plus anesthesia on the
ulnaris and flexor digitorum dorsum of ring and little fingers
profundus of little and ring
fingers
2. Median Palm Thenar muscles Loss of abduction-opposition Palmar aspect of thenar
nerve of thumb; thumb lies in the eminence, index and middle
plane of palm fingers
Forearm Long flexors of fingers and Loss of active flexion of As above
thumb fingers; deformity becomes
obvious while gripping an
object
3. Radial Upperarm Paralysis of wrist and finger Wrist drop; finger clawing if Overdorsum of thumbweb
nerve extensors and abductor pollicis present becomes less
longus obvious
4. Common Just behind Evertors and dorsiflexors of Drop foot Overdorsum of foot
peroneal the neck of the foot
nerve fibula
5. Posterior Just above Intrinsic muscles of the foot Clawing of toes Oversole of the foot
tibial nerve and behind
medial
malleolus
6. Facial nerve Over Orbicularis occuli Lagophthalmos Nil
zygomatic
bone;
In facial All the muscles of the facial Complete facial paralysis of Nil
canal expression the affected side
some patients, may also contribute to the hormonal Leprosy by itself does not cause gross bone destruction
imbalance. but it does cause the bone to become fragile by trabecular
absorption and decalcification, so that it is no longer able
Damage to Other Tissues to withstand normal strains. These changes are reversible
Infiltration in the larynx especially the vocal cords and recalcification takes place leaving functionally normal
manifests as hoarseness of voice. Nodules are also seen bones if adequate protection/support is given during acute
on the vocal cords. During reactional states laryngeal reactional episodes and other stresses to the limbs. The
edema may develop which is a medical emergency. granuloma has been found to occur in the subarticular
Scarring of vocal cords may occur resulting in permanent regions of small bones of the hands and feet in lepromatous
hoarseness of voice. Infiltration and scarring of soft palate patients which may gradually increase in size. During
can also lead to the problems of phonation and also reactional episodes these granulomata swell up.
difficulty in swallowing. Accompanying osteoporosis, torsion and improper
Infiltration of the facial skin results in loss of eyebrows movements of hands precipitate pathological fractures at
(madarosis) and other facial hairs (moustache and beard these sites. These fractures heal spontaneously, if not
in males). Hormonal imbalance may also be responsible splinted properly, in bizarre positions producing deformities
for sparse facial hairs in male suffering from lepromatous of the fingers. There are number of other abnormalities in
form of the disease. Extensive infiltration of the face may bones associated with trophic changes and accompanying
provide a look which is classically described as leonine sepsis. The secondary factors contributing to the bone
facies. Such patients are hardly seen these days, thanks damage are immobility during reactions and painful neuritis,
to MDT and better control of the disease. impaired blood supply due to vasculitis, effects of
CHAPTER
35
anesthesia which causes excessive stresses to the bones
especially small bones of the hands and feet, unrecognized
trauma due to absence of pain perception and sepsis.
Damage to the tendon sheaths and joint capsules also
occurs in leprosy. The synovial inflammation due to
infiltration might present clinically as cystic swellings over
dorsum of the hands.13 Damage to joint capsules during
reactional episodes may produce contractures. Invasion
of cartilage by inflammatory cells can also occur during
reactional states. There may be painful arthritis as the
joint capsules are infiltrated and swollen.14 The patients
keep their fingers in extended position relaxing the
ligaments. In due course, these ligaments contract A
producing stiffness of the joints and contractures. If the
fingers are kept partially flexed throughout the acute phase,
the healing and scarring will be in a functional position and
this will maintain the functional usefulness of the hand.
Effects of Motor Paralysis

The motor paralysis results in loss of function performed
by the paralyzed muscle (s). When some muscles around
a particular joint are paralyzed the normal balance of forces
acting on that joint is disturbed and a new equilibrium is
achieved in conformity with the new system of forces.
Achieving the new equilibrium involves adopting new
postures by the concerned joints and this postural alteration
is seen as deformity. The disturbed muscle balance across B
the joints produces a deformity, for example the clawing Figs 35.1A and B: Gripping by normal and intrinsic
of the finger results due to paralysis of small muscles of palsied fingers (A) Pinching, (B) Gripping
the hand —the lumbricals and the interossei.
Motor paralysis may also contribute to the resorption
damage to the hands and feet. The protective reflexes are
of fingers by altering the gripping patterns. When a patient
lost. With impaired/loss of pain perception many
tries to hold an object with his clawed hands, the tip of the
occupations becomes hazardous specially those requiring
fingers come in contact with the object, not the pulp of the
heavy manual work, requiring friction and pressure and
fingers (Figs 35.1A and B). Thus the actual strain of bearing
working with heated objects.
the weight of the object is confined to the tip of the fingers.
The loss of pain allows the patient to use his burnt or
The pressure exerted by the object per mm2 of contact
injured fingers as actively as if it were unwounded or
area will be much more as compared to the situation where uninfected. The reflex splinting action due to pain is absent
whole hand grasps the object. Furthermore due to in these patients and they need a conscious effort to avoid
anesthesia of hands and fingers, the amount of force further injuries to the already injured hand(s) /foot (feet). If
exerted by the patient in order to hold an object is neglected, these minor injuries have a cumulative effect
excessive. This adds to the traumatic forces and is one of leading to tenosynovitis and osteomyelitis and further
the causes of finger resorption in leprosy patients. destruction of small bones and joints.
Much of the deformities and mutilations that occur in
Effects of Anesthesia and Analgesia the anesthetic hands and feet in leprosy are due mostly to
Inability to appreciate the temperature and pain is one of the excessive and unreasonable strains which they have
the dangerous consequences of the disease and causes to bear. The denervated tissues are some what less able
CHAPTER
35
to bear even normal physiological strains. The response nerve pain and tenderness along with nerve function
of the tissues to inflammation and trauma is also not changes.
effective since denervation also affects the tissue repair.
The regeneration of nerve and/or continued low grade Role of Steroids
inflammation manifest as paraesthesia and dysthesia even Steroids have been used to treat NFI, reactive episodes
if the disease has been clinically cured. Sometimes and also as prophylactic agents against reactions.17-22 In
especially in cases with facial lesions, the regenerating a report it was concluded that 60 % of patients who were
trigeminal nerve branches communicate with facial nerve treated with steroids for NFI had useful recovery of
branches resulting in cross innervations. Such patients sensory-motor functions. If detected in early stages of NFI,
complain of lacrimation while eating, this phenomenon is patients can possibly have full recovery. However defining
also known as crocodile tear syndrome. early has its own problems – early in terms of duration of
Damage to cranial nerves has been also reported in clinical manifestations or early in terms of severity of clinical
leprosy. Commonly affected nerves are trigeminal and manifestations. Some studies have suggested that
facial. Loss of taste and somatic sensations have been steroids if given along with MDT can prevent NFI and
reported in patients having facial lesions and nerve reactions.20, 22 Optimal steroid regimens still need to be
involvement. worked out.
PREVENTION OF DISABILITIES Role of Nerve Trunk Decompression

To prevent the development of disabilities in a fresh case; The timing of nerve trunk decompression is not very clear.23-
and its progression in a case that has it at the time of 26 It has been reported that nerve damage of 3 months or
detection of disease, steps should be taken to start early lesser duration and with a muscle strength of MRC grade3
treatment of the disease and to continue it till recommended. or more has a favorable prognosis.24 Simple epineurotomy
Efforts should be made to recognize early signs of damage and laying open the fibro-osseous tunnel has been shown
to the nerves and eyes and supportive preventive to be effective. Surgery in combination with oral steroids
measures and treatment be given. Deformities are has been found to give better outcomes as compared to
corrected surgically if required. Attempts need to be made surgery alone.
to provide a life with dignity and fellowship for the severely
disabled regardless of their physical condition. Care of the Eyes
The impairment of vision is a devastating disability in
Anticipating Nerve Function Impairment (NFI) leprosy since it is most often associated with sensory
We need to anticipate the impending neural damage and loss in hands and feet. The eyes need special care because
thereby identify high-risk patients. These patients can then in the absence of sensory feedback from palm and sole,
be given extraattention and some form of prophylactic they take up the additional responsibility of warning the
treatment to bring down the numbers of those developing patient about imminent dangers from noxious stimuli. Basic
deformities. Risk factors have been identified which can screening of the eye functions is easy and quick. The eyes
help in pointing out cases that are more likely to develop should be examined initially in every patient and all
reactive episodes and NFI.15 Previous nerve damage, multibacillary patients should be re-examined at regular
clinical multibacillary (MB) disease especially borderline intervals.
leprosy, pregnancy and postpartum, inter-current illness In leprosy, eyes can be damaged either as a direct
like tuberculosis, multiple nerve trunk involvement, result of disease process or following nerve damage which
presence of facial lesions and presence of lesions over a affect the blinking and closure of the eyes. It is through
nerve—all can precipitate a reactive episode. Predicting tears and blink that the surface of the eye is kept moist
the onset of a reactive episode based on serological and clean. Blinking is an involuntary (reflex) process
changes have not been successful so far.16 Diagnosis of initiated by a feeling of dryness or irritation in the eye.
reaction is primarily a clinical exercise based on the Damage to the corneal sensory nerve endings results in
changes appearing in the skin lesions, neural swelling, impaired sensory perception which affects reflex blinking.
CHAPTER
35
Damage to facial nerve branches may result in paralysis starting the treatment. This base line information is helpful
of orbicularis occuli muscle so that the eyes can not be to assess the nerve functions in response to therapy.27 A
closed properly. Both these conditions individually complete examination is also carried out to find out the
predispose the eye to get damaged, effect being more condition of skin, nerve trunks, sensory-motor functions
severe if involvement of both the nerves coexists. The and the joints. It is convenient to record this information in
aim of management is to keep the eye clean, prevent its charts, containing outline drawings of hands and feet, so
dryness and protect it from injuries due to dust and wind. that these can be easily referred to in future. An account
It is, therefore, necessary to build up a habit to look of proformas to record the neural impairments is given in
after the eyes, regularly. One has to develop a habit of Chapter 21.
blinking regularly with a voluntary conscious effort, i.e. The skin of hands and feet is examined for texture,
“think and blink”. The patient must remember to often close mobility, sweating, fissures, ulcers and scars of previous
the eyes with effort from time-to-time. The eyes can be injuries. The nerve trunks (ulnar, median, radial, common
protected with spectacles or a shield while moving out in peroneal and posterior tibial) at the sites of their
open and in the sun. If lagophthalmos is there, the eyes predilection, are palpated. The swelling and tenderness, if
can be covered with an eye pad or head cloth while sleeping. found is noted down. Evaluation of sensory functions in
The eyes should be washed with clean water twice daily hands and feet is important. Methods to assess sensory
and mopped gently with a clean cloth. Patient is told not to and motor functions have been detailed elsewhere in the
rub his eyes and report to the nearest health facility book.
available if he notices any redness, irritation or pain in the Sensory system functions at subconscious level and
eyes. therefore we take it for granted. It is only when there is
sensory loss in palms and/or soles that we realize the
Management of Reactions importance of sensory inputs from these areas which
The crucial elements in the management of reversal perceive the environment around and keep the brain duly
reactions are early recognition and prompt treatment. informed. These sensory inputs help the brain to develop
Neuritis associated with reaction is an indication for starting a motor strategy to respond. If the stimulus is interpreted
corticosteroid therapy without delay. The dose of to be injurious, there is an immediate withdrawal. To
appreciate finer details of an object-texture, etc. intact
corticosteroids will depend on the severity of reaction,
sensory modalities are necessary. However, to appreciate
patient’s body weight and response to treatment. It should
noxious stimuli certain minimal sensory abilities are
be sufficient to relieve both nerve pain and tenderness.
enough. This is called “protective sensation” and is
Administration of corticosteroids should be continued for
presumed to be essential so that the neurally impaired
several months. The actual duration of steroid therapy
leprosy affected person can save himself from injuries
depends upon the individual circumstances.
and progressive damage to the tissues.
Monitoring and Self-reporting Average normal perception threshold for nylon filaments
at finger pulp is 0.217 gm/mm2 and levels of protective
The patients can be taught to recognize reportable events sensations are double the normal thresholds, i.e. 0.434
like changes in the vision, symptoms in the eyes, gm/mm2. For sole these values have been worked out to
sensorimotor functions, and nerve pain and to ask for help be 2.35 gm/mm2 and 5 gm/mm2 respectively.28, 29 Some
if required. But monitoring is still necessary in most cases other reports take responses to 10 gm as cut off point to
because many patients are not aware of ongoing changes define protective sensations on the sole.30,31 The sole has
as in silent neuropathy. a higher tactile threshold than hand due to thicker keratin
Plantar ulcers and their management are detailed in layers in the plantar skin. Callosities, occupation, use of
another chapter. footwear and also the type of footwear seem to affect the
plantar sensory thresholds and these factors should be
EVALUATION OF THE PATIENT AND kept in mind while interpreting the outcomes of testing.32,33
ASSESSMENT OF DISABILITY If sensations are lost, extracare is needed for this group
An assessment of disabilities and deformities in a patient of patients and they are to be educated and monitored for
is done at the time of his first visit and recorded before selfcare practices.
CHAPTER
35
The perception of touch decreases as a consequence ROLE OF PHYSIOTHERAPY

of decrease in receptor density in the glabrous skin that Physiotherapy is an integral part of management of leprosy
occurs with age.34 However, perception of pain remains the and is needed to prevent the onset of disabilities and
same with age indicating that nociceptive free nerve endings deformities and also to arrest the progression of those if
do not decrease with age. Testing for pinprick pain has already developed. It is required to relieve nerve pain and
been widely used. In its basic form, it is a non-graded test keep the integrity of muscle fibers intact if palsy has set
(yes or no replies). Modifications have been tried but have in till such time they are re-innervated. In lepra reaction, it
not been very popular.35 Since non-myelinated fibers are first also helps in the resolution of inflammation and edema of
affected in leprosy, testing for pinprick pain is essential. the extremities and keeps the joints mobile. Leprosy
Since a potential risk of transmission of HIV and hepatitis is affected persons can be managed better if physio-
there, reuse of pins is discouraged. therapeutic measures are added to the conventional MDT
Tip of ballpoint pen is used by majority of field workers and other medical management. If surgical intervention is
to evaluate sensory loss and these have been reported to required for correction of deformities, pre- and post operative
be comparable to monofilament nylons.36-39 The ball pen physiotherapy is mandatory.
test is universally available and simple to use. A light touch
with a ballpoint pen can generate pressure of 4 gm or more. Techniques of Physiotherapy as Applied to
Therefore it may not be very useful to detect mild sensory Leprosy Affected Persons
deficits especially on the palm. However, the reliability of
Commonly used physiotherapeutic methods in manage-
this methods have been found to be satisfactory37 and the ment of leprosy affected persons are—hydro-oleo therapy,
method is capable of detecting major sensory changes exercise, splinting, heat therapy and electrical stimulation.49
while monitoring sensory functions.39 Static two point These methods are simple and can be organized with very
discrimination, a test for innervation density, is reliable little inputs.
but slow to respond to changes as compared to
monofilament nylons. Testing for temperature sensation, Soaking in Water and Oil Application
though potentially important to detect early cases is crude Due to damage to autonomic nerves the sweating is
and not of much value in established cases of leprosy. affected. The skin becomes dry and can crack resulting in
A simplified version of the voluntary muscle-testing fissures. Soaking in water and subsequent oil application
(VMT) is often used to detect gross paralysis which can is done to make the skin supple and soft. It can be practiced
be suitably modified to quickly assess the muscle strength. at least twice a day but is not advised if the part is acutely
If any weakness is detected, the patients can be subjected inflamed, has injuries or blisters and there is secondary
to a detailed assessment.40 A rapid neurological evalua- infection.
tion41- 43 must test sensibility, mobility and trophicity. It is The hands and feet are soaked in water at room
performed on each side (only six main nerve trunks most temperature for 10 to 15 minutes in a suitable pot like a
commonly affected on each side), are to be tested in a plastic tub. After soaking, the skin is gently scrubbed with
sequence to save time. a thick cloth to rub off the dead keratin, taking special
Periodic assessment by voluntary muscle testing and care around the fissures and ulcers to prevent damage to
response to graded monofilament nylons can be used to the delicate tissues lying in the depth of fissure. Vegetable
monitor progress of the patients preferably by the same oil is then applied on wet skin and lightly massaged so
observer, as inter-observer variations do exist.44-47 Of the that it mixes well with the water on the skin and forms an
various testing methods compared, for their efficacy to emulsion film on the skin surface that helps to retain the
detect early nerve damage, nerve palpation and testing moisture longer. Mustard oil, neem oil or sesame seed oil
with 200 mg monofilament nylon were found better.48 In is preferred. To distract the insects and rats, some camphor
most situations a combination of ballpoint pen testing and can be added to the oil to give it a smell.
quick muscle testing appears to be a more practical option, While the oil is being applied and massaged, the finger
detailed testing being reserved for cases with doubtful nerve joints are passively stretched 10-12 times each. If cracks
function impairments. or fissures are present in the digital creases, care is taken
not to stretch them. The thumb web is also stretched by
CHAPTER
35
holding on to the head of first metacarpal and pulling it Table 35.6: Benefits of different exercises
away from the index metacarpal. These maneuvers prevent of the hand and foot
the development of contractures. Oil massage is also Refer to Figure Exercises and its benefits
preparatory to active exercises of the hands and feet. Number
Fig. 35.2A Finger abduction and adduction exercises
Exercises strengthens the interossei and opens up the
interdigital webspace
Active and assisted exercises are performed to increase
Fig. 35.2B Thumb MCP joint flexion with extended IP joint
the strength of the muscles and retain their tone. Active mobilizes MCP joint and prevents its contracture
exercises are most useful in cases with early and Fig. 35.2C Stretching of thumbweb
incomplete motor paralysis. The exercise can induce Fig. 35.2D Thumb approaches the pulp of individual fingers
and in the process rotates through full range of
hypertrophy of the remaining fibers increasing their power movement
of contraction and may compensate for the damaged Fig. 35.2E Helps in picking small objects and strengthens
muscle fibers. These exercises also prevent disuse atrophy pulp-to-pulp pinch between index finger and
of the remaining muscles in a palsied limb and help thumb
Fig. 35.3A Stretches the foot to prevent inversion
overcome the mild joint stiffness and contracture. Since contracture
weak muscles get fatigued early these should be exercised Fig. 35.3B Passive stretching of calf muscles and tendo-
for relatively shorter periods. Achilles to prevent its contracture
Assisted active exercises are performed to prevent
Splints and Splinting
damage to the anatomical structures by adaptive postures,
e.g. damage to extensor apparatus of the fingers due to Splints are external appliances which are worn over the
clawing and constant proximal inter-phalangeal (PIP) joint affected part of the body to hold it in a desired position.
flexion. These exercises are called assisted, because These can be made from different materials.50-52 Splinting
external support is used to stabilize the joints rendered is done to achieve different objectives individually or in
unstable by muscle palsies, e.g. exercising PIP joints of combination, viz to immobilize a part to relieve pain, to
fingers by supporting MCP joints in 90° flexion to prevent stabilize a joint, to retain the joint/part after release of
stretching and damage to extensor expansion. contracture in a particular position, to prevent its movement
Passive exercises, where joint movements are carried in a particular direction and also to provide continuous
out with full outside support (instead of by the muscles gradual stretching.52
which normally perform that movement), are aimed to put With innovative approaches, a variety of splints have
the joint through full range of movement so that contractures been developed to serve a specific purpose. These are
do not develop in opposite group of muscles and also in easy to carry, simple to apply and effective in preventing
the joints. Mild-to-moderate, established contractures can the progression of existing deformities.51
be overcome by forced passive movements. Such forced Claw Hand: The splints used to manage finger clawing
passive movements are gently performed in anesthetic can be static—that is to maintain the joint position; or
extremities so that internal tissues are gradually stretched dynamic where some form of mechanism is incorporated
and do not get inflamed ending up with further scarring. to exercise the fingers.53, 54 The splints can be made of
Different exercises for the fingers and thumb are shown in steel wire, 55 plaster of Paris, polyvinyl tubes 56 or
Figures 35.2A to E. thermoplastic materials. Pre-fabricated splints made of
The foot is massaged after properly cleaning the nails organic polymer, which have a screw mechanism
and interdigital spaces. The toe joints, subtalar joints and incorporated in them, are now available. The screw can be
ankle are gently moved through full range of motion both manually tightened (half a turn in a day) to stretch the
actively and passively (Figs 35.3A and B). If facial muscles contracture especially of PIP joint. Since leprosy affected
are weak eye closure exercises and blowing of the balloon hands are anesthetic, using these splints is little risky.
is performed, in 20 to 25 cycles two to three times a day, For this reason, these splints are not recommended to be
to strengthen these muscles. used as a routine.
Different exercises that are commonly performed Common splints in use for hand deformities are—gutter
for the hand and foot and their benefits are listed in splints, finger loop splints, opponens splints and adductor
Table 35.6. band (Figs 35.4 to 35.7). These splints can be easily
CHAPTER
35
B C
D E
Figs 35.2A to E: Exercises for fingers and thumb (A) Finger abduction and adduction exercises (B) Thumb MCP joint flexion with IP joint
extended (C) Stretching of thumbweb (D) Opposition of thumb to pulp of individual fingers (E) Pinching with index finger
fabricated at the local level. A simple spiral splint made Adductor band consists of a straight band of
out of 10 SWG galvanized steel wire sheathed with thick appropriate dimensions at either end of which Velcro
rubber sleeve is easy to fabricate and can be used by the fasteners are stitched (Fig. 35.5C).
patient anytime (Fig. 35.4C). It stabilizes all four fingers.55 Serial splinting involves repeated application of plaster
Gutter splint is in the form of a half-cut tube (made of of Paris casts to PIP joint (s) of the fingers at regular
thick, firm polyvinyl material) lined with felt and provided intervals to overcome the contractures gradually.50,54 The
with Velcro fasteners at its either ends (Figs 35.5A and B). contracted finger is passively stretched and held in that
It is a static splint. position by a plaster of Paris cast, made by wrapping a
Loop splint consists of a loop of rexin or other suitable wet plaster of Paris bandage (45 cm long and 5 cm wide)
soft material having an eyelet at its end. Through this eyelet so as to form 4 to 5 layers around PIP joint, which is held
opening a rubber band is threaded and tied to itself. The in desired position till the cast is dry. Care is taken to
other end of rubber band is tied to a wrist band at apply the layers with moderate tightness so as not to impair
appropriate tension (Figs 35.6A and B). This is a dynamic the blood circulation and also not to press on knuckles
splint and is used for exercising the finger(s). It helps in otherwise skin in that area may necrose. The finger tip is
strengthening the extensor systems of the finger(s). left exposed to monitor circulation (Fig. 35.8A). This cast
Opponens splint is similar to loop splint, the loop here is retained for a week. Then the cast is removed, wax
is wider to accommodate for diagonal movement of the therapy is given and the cast is reapplied with some more
thumb (Figs 35.7A and B). stretching. Minimum force is used while stretching so that
CHAPTER
35
Figs 35.3A and B: Exercises for foot (A) Stretching of foot to prevent
inversion contracture (B) Stretching of calf muscles and passive
dorsiflexion of foot
circulation is not compromised and soft tissues are not

C
injured. The process is repeated till the contracture is
overcome. The release so obtained, is then maintained by
gutter splints. For stretching the thumb web wedges of Figs 35.4A to C: Splints (A) Wrist drop splint (B) Knuckle duster
splint (C) Spiral splint
increasing angles, made of plaster of Paris, are applied at
regular intervals as above (Fig. 35.8B).
Where to use; which splint: When the palsy has just to exercise the fingers and gutter splints are used during
begun and little finger is not able to adduct, adductor band night to maintain the stretched position of the fingers. For
splint is used. For a hand with mobile finger clawing loop fingers with obvious contractures gutter splints are used.
splints are preferred. If the thumb is also paralyzed, then Similarly, for the thumb interphalangeal joint (IPJ), gutter
opponens splint is used in addition. If the fingers have splints are used.51 If it can be managed, serial splinting
mild stiffness, then loop splints are used during daytime gives better results in a shorter period of time.
CHAPTER
35
A
A
Figs 35.6A and B: Finger loop splint and its use

(A) Finger loop splint (B) Splint in use
C
A B
Figs 35.5A to C: Gutter splint and adductor band (A) Standard gutter
splint with Velcro fasteners (B) Gutter splint with “V” cut to accommo- Figs 35.7A and B: Splints for the thumb (A) Loop splint for opponens
date PIP joint in cases having PIP joint flexion (C) Adductor band in use (B) Static splinting of thumb in abduction using adhesive tape
CHAPTER
35
A B
Figs 35.8A and B: Commonly used plaster of Paris splints (A) Cylindrical splint (B) Thumbweb splint
If thumbweb has mild contracture, opponens splint will joint extension. The splints are not effective if the
take care of it. However, if the thumbweb has contracted, contracture has become fixed, i.e. it cannot be passively
it can be stretched with plaster of Paris wedges of gradually stretched by reasonable force. Such cases require a prior
increasing angles applied at periodic intervals. surgical release.
Duration of splinting: Even though it is difficult to predict Drop Foot: Splinting for drop foot is aimed to prevent
the duration of splintage required for a particular case, stretching of dorsiflexor muscles of the foot and prevent
majority of case have been observed to improve in 8 to 12 contracture of tendoachilles. A below knee slab of plaster
weeks time.50,51,57 The splints are used till the improvement of Paris, to keep the foot in neutral position, is adequate. It
reaches a plateau and continued thereafter to keep the is important to wear the splint during night time because
fingers mobile till the surgery is performed. If the patient is foot muscles can be unduly stretched by foot movements
not willing to undergo surgery, he can continue using static during sleep or while manoeuvring the quilt or sheet to
splints during night. cover oneself. Alternatively a “Y” strap with spring
(Fig. 35.9A) or single elastic strap (Fig. 35.9B) can be used
Precautions to be observed while splinting the fingers
to provide lift to the forefoot while walking, prevent
and thumb: The adjustment of tension while applying
stretching of the dorsiflexors of the foot and prevent
splints to fingers is critical. In contracted fingers do not try
contracture of tendo-Achilles. This splint can be used while
to open up the fingers fully on the first day itself. The fingers
waiting recovery of muscles and also if the patient is not
should be stretched gradually. If redness or blisters occur
willing for surgery.52, 56
on the dorsal aspect of the finger—discontinue the use of
splint (s) or loosen it (them). If a patient complains of pain Facial Palsy: The facial skin is appropriately splinted with
or swelling or bluish discoloration of nail or pulp occurs, hypoallergenic adhesive tape strips so that lower lid is not
the splint should be removed and its use discontinued till sagging due to gravity and the angle of mouth is not
the condition is settled. Reapplication is done at a lower deviated (Fig. 35.10). This is only a temporary measure
tension. and can be tried for few weeks if recovery is expected.
For loop splints the tension in the rubber bands is Splinting for Nerve Pain: The affected limb is placed in
adjusted in such a way that metacarpophalangeal (MCP) a splint made of suitable and easily available material so
joint is kept in 70–80° flexion. The rubber bands should as to prevent the movement/stretching of the nerve (read
not be over stretchable (beyond 10°) to prevent full MCP joint across which the nerve trunk takes its course) and
CHAPTER
35
A B
Figs 35.9A and B: Drop foot splints (A) “Y” strap with spring (B) Single elastic strap
should extend up to midarm, for median nerve up to mid

forearm, up to lower third of thigh for common peroneal
nerve and up to middle of the leg for posterior tibial nerve.
The splint should be well padded so that it does not press
on the inflamed nerve. The splinting is continued till the
pain subsides. When the pain has subsided the joint
position is gradually altered to gently stretch the nerve
trunk so that it gains some freedom to move with joint
movements. Total duration of splinting may vary from 3 to
4 weeks, i.e. until tenderness subsides. If heat therapy is
also given side-by-side, then the splint is removed for the
application of heat and then reapplied.
Heat Therapy
Superficial heating modalities like heating pads,
hydrotherapy and paraffin baths which heat by conduction,
are not able to transmit heat past a depth beyond 2 to
3 cm because of the factors like patient tolerance, tissue
Fig. 35.10: Splinting for facial palsy resistance to heating and the body response to local
heating. Of these, wax bath is the most commonly used in
provide rest to the nerve. The joint is immobilized in such leprosy because most of the tissues to be heated are with
a position that the nerve is relaxed. For ulnar nerve (behind in 2 cm from the body surface.
the elbow) the joint is kept at 110°, for median nerve the The physiologic effects of heat application are increased
wrist is rested in neutral position, for common peroneal collagen extensibility, decreased joint stiffness, relief of
nerve knee is kept in 35-40° flexion and for posterior tibial pain and relaxation of muscle spasm, increased blood flow
nerve pain, the foot is kept in 15-20° plantar flexion and resolution of inflammatory infiltrates, edema and
(Figs 35.11A to D). For ulnar nerve at elbow the splint exudates. At 45°C collagen is known to stretch irreversibly,
CHAPTER
35
splinting. It is also used before and after surgery of the
hand deformities. The hot wax permits sustained heating
of the part for a considerable period (up to 20 minutes or
longer depending upon the ambient temperature).60 In
addition, it makes the skin supple, stimulates the sweat
glands and improves blood circulation in the skin.
The heat of molten wax does not penetrate deep;
therefore wax therapy has only marginal value in treating
deep-seated pain. The main contraindication for wax
therapy is presence of blisters and open sores. The
A
temperature of the molten wax should be 42-45°C. The
melting point of commercially available wax is about 65°C.
It is lowered down by mixing wax with vaseline and liquid
paraffin in a ratio of 2:1:1. Portions of vaseline and liquid
paraffin are added to the molten wax and mixed till the
B desired melting point (42°C) is obtained.
The patients have to be careful not to touch the sides
and the bottom of the bath. The part to be treated is dipped
in the molten wax in such a way that a thick continuous
coat of wax covers the part like a sleeve or glove. It
requires about 6 to 8 dippings getting a complete glove or
else the molten wax can be poured over the part till it is
fully covered. The outer layer of wax cools down to form
an insulation preserving heat in deeper layers. After the
coat is formed, the part is wrapped in a thick towel and is
kept still for about 20 minutes. The coat is then peeled off
and returned to the wax tub. The patient can practice oil
massage and exercises after the wax therapy.
Electrical Stimulation
Electrical stimulating currents have low frequency and long
wavelengths and easily penetrate human tissues. Electrical
C D stimulation has been used for reduction of pain, stimulation
of neuromuscular function and to stimulate the bone and
Figs 35.11A to D: Splinting for nerve pain (A) Ulnar nerve at elbow
(B) Median nerve at wrist (C) Common peroneal nerve at knee soft tissue healing. Electrical stimulation of muscles has
(D) Posterior tibial nerve at ankle also been used to reduce edema and also to strengthen
and rejuvenate the muscle.61 Transcutaneous electrical
proportional to stress applied.58 Several mechanisms have nerve stimulation (TENS) has been widely used to treat
been postulated to explain the effectiveness of heat therapy acute and chronic painful conditions.62 It has also been
including cutaneous counter-irritant action, vasodilatation used in leprosy.63 High frequency, low intensity TENS
with flushing of pain mediators, endorphin mediated activates peripheral A beta fibers selectively which blocks
response and altered cell membrane permeability. Elevated or modulates the pain carrying inputs at the level of the
pain threshold has been documented with deep heating dorsal horn of spinal cord. Pain relief by TENS also occurs
modalities.59 by release of endogenous opioids into the brainstem
Wax bath is a method to give heat therapy where the cerebrospinal fluid. It is also likely that afferent nociceptive
part to be treated is covered with warm molten wax. It is inputs are blocked due to antidromic stimulation.
useful in the treatment of nerve pain and stiff joints.49 It is Physiologic tolerance to TENS may develop in due course
also used as an initiator before massage, exercises and of time.
CHAPTER
35
PREVENTION OF PROGRESSION OF psychological and social pressures come in their way. Also,
DISABILITIES there is an inherent desire in these patients to perform and
behave like normal persons. As a result they are likely to
The components of this activity include detection of nerve
damage their hands and feet. The patients are shy to use
damage (early in terms of duration and severity) and also
appliances. At times it is because of social compulsions
the care for existing disabilities. Of these, severity of nerve
(to hide their disease and avoid social embarrassment)
damage decides the actual clinical outcome. More severe
that they are not able to take protective measures.
damage of shorter duration some times has better
prognosis in contrast to a less severe damage of longer
duration viz silent neuropathy which is chronic and
Management
insidious type of nerve damage having variable response The patient needs to be properly examined and evaluated
to therapy.9, 64 before a tailored scheme for his rehabilitation can be worked
Problems faced by the patients having insensitive out.66 A need based program has better chances to
extremities (hands and feet) are:(i) problems of disuse or succeed. The evaluation includes, besides age and
under use, (ii) problems of misuse and overuse and (iii) occupation, assessment of residual sensory-motor
problems of accepting/ using protection. functions and psychological state to find out his reaction
Problems of disuse are seen in hands in patients having and attitude towards his problems. The sensory evaluation
unilateral palsies especially where non-dominant side is begins by asking the patient to outline the area of sensory
affected. Patients avoid using affected limb even if it is loss on his palm and sole. The presence or absence of
surgically restored until, it is absolutely essential for them protective sensations and use of hand by the patient for
to use that.65 This results in disuse atrophy of the muscles. daily activities is assessed. Since no single test can
In growing children disuse results in hypoplasia of the limb. completely assess the complexity of sensibility and
The neglected limb may also result in skin and joint dysfunctions, it is better to apply a battery of tests selected
contractures. after initial examination.
Problems of misuse and overuse are different in hands Proper counseling is done in several sittings and options
and feet. In hands, even if motor capability is there, the are suggested. It is for the patient to decide and choose
efficiency is reduced. The paralyzed hand adopts unnatural the one that suits him best under the circumstances. A
postures due to muscle imbalance and functionally constant feedback is obtained as it helps to check whether
convenient movement patterns for activities of daily living the patient understands his selfcare routine and is carrying
leading to contractures. The postures get somewhat fixed. it out or not. During visits the patient can be asked to
In median nerve palsy pinch is badly affected. Even with demonstrate his selfcare skills. Special checks are to be
simple ansthesia patients complain that they cannot hold made for “think-blink” and footwear.
the objects properly. They have a feeling that objects will Health education is an important component of the
fall down and therefore tend to use much force than what management scheme and is the key to success. It should
is actually required. This leads to gradual absorption of start from the day the patient is brought under MDT
their fingertips. Fine manipulative activities cannot be umbrella and continue until he is ready to be released from
performed. In cases with bilateral involvement, it is a severe control. Patient has to be told about the causation of injuries
handicap. and ulcers. The role of sensory loss in this context has to
Patients keep standing on the same foot without be made clear. The patient should be explained the cause
changing postures for quite some time and walk briskly of anesthesia and also the methods to protect their hands
over long distances without resting their feet. Even if they and feet. Simple and easy to follow instructions are
have plantar ulcers they walk and injure the foot further in important to ensure compliance. The patients must
the process. The absence of pain is the root cause for all understand their physical limitations due to disease and
such misadventures. Surgically restored limbs are also accept that. Once this has been achieved, they can be
prone to injuries because patients are likely to carry a empowered to adapt to the new situations.
false impression that their limbs have become normal and Self care is the responsibility of the individual who
do not require extracare any more. has nerve function impairment (NFI) and he/she is expected
Problems of accepting and using protection are peculiar. to carry this out on daily bases. The health care workers
Even if patients are aware of their deficiencies, are expected to educate and guide patients in selfcare
CHAPTER
35
practices. The hydro-oleo therapy and passive exercises identification of high-risk patients, prophylaxis, treatment,
are prescribed to keep the skin supple and mobile. Looking reconstructive surgery and rehabilitation.
for injuries, redness, blisters and impending ulcers in hands POID at the initiation and during MDT calls for proper
and feet on daily basis is essential. If found, promptly recording of baseline data and regular follow-up information
treating them, goes a long way in preventing mutilations. about nerve function, detection of high-risk cases and
The patients are taught “protected” use of hands and management of reactions. Diagnosis of leprosy clinically
feet. They are advised to use visual feedback while using is relatively simple but the value of detailed records should
their hands for different tasks and use both hands with not be undermined by presuming that a fixed duration MDT
conscious effort. Use of tools and appliances with is the answer for all the ills of leprosy. An initial record of
protective (molded) handles at home and at place of work disease when patient enters the MDT program is essential
can be suggested. Sensory re-education program can be to keep track of events. The deformities and condition of
tried in cases having some residual sensibility, especially the nerves should be carefully recorded so that we know
in younger patients. With some training protective
how the patient is progressing. If the patient develops any
sensibility can be sufficiently restored.
reactive episodes and/or painful tender nerves, he needs
Constant use of proper fitting protective footwear is
management preferably under supervision. Regular testing
desirable. It is not a must to go in for conventional micro
should include accurate measurement of function in the
cellular rubber (MCR) footwear since it is not easily available
eyes, hands and feet and recording of other disabling or
in the market. As a matter of fact any footwear will reduce
stigmatizing signs in face. This is more important because
the walking foot pressure to the extent of twenty-five
activity of disease in the nerves persists longer and may
percent. The appropriate footwear should have a tough outer
continue to exist even after skin is visibly free from disease
sole of 15-18 mm thickness, soft inner sole which is 18 to
22 mm thick and comparable firmness of 15 to 20 shore. and even after RFT.
In addition to forefoot straps, a heel strap should also be The physician must recognize the psychology of the
there so that the footwear does not slip out of anesthetic person who has lost sensations in their limbs. Even
feet. Ideally all the components of the footwear should intelligent patients continue to use their infected fingers
have been stitched with thread or glued and have Velcro and continue to walk on wounds destroying their feet. Many
fasteners. Iron nails and buckles are to be avoided. Many patients who feel stigmatized by disease and by their
commercial firms are making “Raja Model” now and it is deformity retain an immense desire to perform normally in
easily available. Earlier this “Raja Model” (its MCR version the society. They want to walk faster, do other activities
was prescribed to leprosy affected persons) carried a stigma with their hands rejecting protective appliances that identify
with it but now the design is very popular with the people them as disabled. They love to do things with their own
because of its comforts. Footwear is a cost effective hands and even succeed at times at the expense of more
intervention in preventing plantar ulcers and its recurrences injury and infection. With a low self image it is less likely
and along with selfcare practices has done wonders for for them to save their hands and feet. We have to spend
the patients. There might be some initial hesitation but some time to explain to them in simple language the
with time patients accept it realizing the benefits. physiology, pathology, mechanisms and psychology of their
Treating and preventing disability should be an integral deformities and encourage them to believe that their limbs
part of any control program and it is recommended that can be saved with some extracare.
patients released from MDT programs should be followed
up on a long-term basis with regard to appearance or REFERENCES
worsening of disabilities. Only 10% cases are deformed,
1. WHO Technical Report Series 1970, No 459:26-30.
which means that only one tenth of the total cases need 2. WHO Technical Report Series 1988, No 768:35.
continued attention. In addition to early detection and 3. WHO Leprosy disabilities: magnitude of the problem. WHO
provision of MDT the process of POID has to be addressed Weekly Epidemiological Record 1995; 70: 269-75.
at every level of care. 4. Gupte MD. Dapsone treatment and deformities: a retrospective
study. Lepr India 1979; 51:218- 35.
A comprehensive concept of POID needs to be 5. Tiwari VD, Mehta RP. Deformities in leprosy patients of Indian
developed involving all areas of leprosy control, viz. early armed forces treated/reviewed at military hospital Agra (a
detection, regular MDT, nerve function assessments, retrospective study). Lepr India 1981; 53:369-78.
CHAPTER
35
6. Kaur P, Singh G. Deformities in leprosy patients attending urban 29. Saltzman CL, Rashid R, Hayes A et al. 4.5 Gram monofilament
leprosy clinic at Varanasi. Indian J Lepr 1985; 57:178-182. sensation beneath both first metatarsal heads indicates
7. Srinivasan H, Noordeen SK. Epidemiology of disabilities in leprosy. protective foot sensation in diabetic patients. J Bone Joint Surg
Int J Lepr 1966; 34:170-74. 2004;86-A:717-23.
8. Wardekar RV. Sulphone treatment and deformities in leprosy. 30. Birke JA, Simm DS. Plantar sensory thresholds in the ulcerative
Lepr India 1968; 40:1-18. foot. Lepr Rev 1986; 57: 261-67.
9. Srinivasan H, Rao KS, Shanmugham N. Steroid therapy in recent 31. Hammond CJ, Klenerman P. Protective sensations in the foot in
“Quiet Nerve Paralysis”. Lepr India 1982; 54:412-19. leprosy. Lepr Rev 1988; 59:347-54.
10. Brand P. Temperature variation and leprosy deformity. Int J Lepr 32. Stratford CJ, Owen BM. The effect of footwear on sensory testing
1959; 27:1-7. in leprosy. Lepr Rev1994; 65:58-65.
11. Brand P. Deformities in leprosy—Orthopaedic principles and 33. Malaviya GN, Husain S, Girdhar A et al. Sensory functions in
practical methods of relief. In “Leprosy in theory and practice” limbs of normal persons and leprosy patients with peripheral
RG Cochrane (Ed), John Wright and Sons Ltd. London 1964; trunk damage. Indian J Lepr 1994; 66:157-64.
447-96.
34. Conomy JP, Barnes KL. Quantitative assessment of cutaneous
12. Chacko CJG, Bhanu T, Victor V et al. The significance of changes
sensory function in subjects with neurologic diseases. J Neuro
in nasal mucosa in indeterminate, tuberculoid and borderline
Sci 1976; 30:221-35.
leprosy. Lepr India 1979; 51:8-22.
35. Jain GL, Pasricha JS, Guha SK. Objective grading of the loss of
13. Malaviya GN, Ramu G, Mukherjee A et al. Synovial swellings
pain and touch sensations in leprosy patients. Int J Lepr 1986;
over wrist in Leprosy. Indian J Lepr 1985; 57:350-53.
54: 525-29.
14. Ramu G, Balakrishnan S. Arthritis in lepromatous leprosy : clinical
36. Brandsma JW. Basic nerve function assessment in leprosy
features and biochemical findings. Lepr India. 1968; 40:62-69.
patients. Lepr Rev 1981; 52:161-70.
15. Pearson JMH, Ross WF. Nerve involvement in leprosy: pathology,
37. Anderson AM, Croft RP. Reliability of Semmes-Weinstein
differential diagnosis, and principles of management. Lepr Rev
1975; 46:199-12. monofilament and ball pen sensory testing and voluntary muscle
16. Stefani MMA, Martelli CMT, Morais-Neto et al. Assessment of testing in Bangladesh. Lepr Rev 1999; 70: 305-13.
anti-PGL-1 as a prognostic marker in leprosy reaction. Int J 38. Birke JA, Brandsma JW, Schreuders T et al. Sensory testing
Lepr 1998; 65:356-64. with monofilaments in Hansen’s disease and normal control
17. Touw-Langendijk EMJ, Brandsma JW, Anderson JG. Treatment subjects. Int J Lepr. 2000; 68:291-98.
of ulnar and median nerve function loss in borderline leprosy. 39. van Brackel WH. Detecting peripheral nerve damage in the field
Lepr Rev 1984; 55:41-46. our tools in 2000 and beyond. Indian J Lepr 2000; 72:47-64.
18. van Brakel WH, Khawas IB. Nerve function impairment in leprosy: 40. Brandsma JW. Monitoring motor nerve function in leprosy
an epidemiological and clinical study – part 2: results of steroid patients. Lepr Rev 2000;71:258-67.
treatment. Lepr Rev 1996; 67:104-18. 41. Fritschi EP. Field detection of early neuritis in leprosy. Lepr Rev
19. Sugumaran DST. Steroid therapy for paralytic deformities in 1987; 58:173-77.
leprosy. Int J Lepr1997; 65:337-44. 42. Malaviya GN. Rapid neurological-evaluation of leprosy patients
20. Croft RP, Nicholls P, Anderson AM et al. Effect of prophylactic in field. Ind J Phys Med Rehab 1991;4:4-9.
corticosteroids on the incidence of reactions in newly diagnosed 43. Palande DD, Bowden REM. Early detection of damage to nerves
multibacillary leprosy patients. Int J Lepr. 1999; 67:75-77. in leprosy. Lepr Rev 1992; 63:60-72.
21. Lockwood DNJ. Steroids in leprosy type I (reversal) reactions: 44. van Brakel WH, Shute J, Dixon JA et al. Evaluation of sensibility
mechanism of action and effectiveness. Lepr Rev 2000; in leprosy: comparison of various clinical methods. Lepr Rev
71:S111-14. 1994; 65:106-21.
22. Anderson A. TRIPOD trial—prophylactic use of prednisolone, 45. Lewis S. Reproducibility of sensory testing and voluntary motor
results at 4 and 6 months. Int J Lepr 2001; 69:S146-S147. testing in evaluating the treatment of acute neuritis in leprosy
23. Ebenezer M, Andrews P, Solomon S. Comparative trial of steroids patients. Lepr Rev 1983; 54:23-30.
and surgical intervention in the management of ulnar neuritis. Int 46. Lienhardt C, Currie H, Wheeler JG. Inter-observer variability in
J Lepr 1996; 64:282-86. the assessment of nerve functions in leprosy patients in Ethiopia.
24. Malaviya GN, Ramu G. Role of surgical decompression in ulnar Int J Lepr1995; 63:62-76.
neuritis of leprosy. Lep India 1982; 4:287-302. 47. Brandsma JW, Van Brakel WH, Anderson AM et al. Intertester
25. Srinivasan H. Surgical decompression of ulnar nerve. Indian J reliability of manual strength testing in leprosy patients. Lepr
Lepr 1984; 56:520-31.
Rev 1998; 69:257-66.
26. Kazen R. Role of surgery of nerves in leprosy in the restoration
48. Prevention of disabilities. Lepr Rev 2002; 73 Suppl 1:S35-S43
of sensibility in hands and feet of leprosy patients. Indian J Lepr
(Editorial)
1996; 68:55-66.
49. Namasivayam PR. Physiotherapy in leprosy. Lepr India 1963;
27. Pearson JMH. The evaluation of nerve damage in leprosy. Lepr
35:65-73.
Rev 1982; 53: 19-130.
50. Selvapandian AJ, Menon MPA and Palani N. Use of splints in the
28. Malaviya GN, Husain S, Mishra B et al. Protective sensibility –
treatment of deformed hands in leprosy. Lepr India 1964; 36:
its monofilament nylon threshold equivalents in leprosy patients.
20-43.
Indian J Lepr 1997; 69:149-58.
CHAPTER
35
51. Shah A. Prevention, correction of claw hand by splintage—A 59. Lehmann JF, Brunner GD, Stow RW. Pain threshold
new approach to deformity care. Bombay: Ciba-Geigy Leprosy measurements after therapeutic application of ultrasound,
Fund and Hindustan Ciba-Geigy Limited; (1992). microwaves and infrared. Arch Phys Med Rehabil 1958; 39:
52. Brandsma JW. Splinting in leprosy. Indian J Lepr 2001; 73:37-45. 560-65.
53. Kulkarni VN, Mehta JM. Splinting of hand in leprosy. Lepr India 60. Allis JB. Use of paraffin in leprosy. Lepr Rev 1961; 32:167-74.
1983; 55:483-84. 61. Hamilton JM. The place of electrical stimulation in the
54. Kulkarni VN, Mehta JM. Special features of physical therapy in physiotherapy of leprosy. Lepr India 1977; 49:197-206.
the claw hand in leprosy. Lepr India 1983; 55: 694-96. 62. Long DM, Campbell JN, Gucer G. Transcutaneous electrical
55. Namasivayam PR. A spiral splint for claw fingers. Lepr India1976;
stimulation for relief of chronic pain. Adv Pain Res Ther 1979;
48:258-60.
3:593-94.
56. Theuvenet WJ, Ruchal SP, Soares DJ et al. Advantages,
63. Mehta JM, Nimbalkar ST, Thalayan K. A new approach in the
indications and the manufacturing of melted PVC water pipe
relief of pain of leprous neuritis. Lepr India 1979; 51:459-64.
splints. Lepr Rev 1994; 65:385-95.
57. Koulamban SL. The role of static and dynamic splints, 64. van Brakel WH, Khawas IB. Silent neuropathy in Leprosy: an
physiotherapy techniques and time in straightening contracted epidemiological description. Lepr Rev 1994; 65:350-60.
inter-phalangeal joints. Lepr India 1969; 39:323-28. 65. Malaviya GN Unfavorable results after claw finger correction
58. Lehmann JF, Masock AJ. Warren CG et al. Effect of therapeutic surgery as seen in leprosy. Indian J Lepr 1997; 69:43-52.
temperatures on tendon extensibility. Arch Phys Med Rehabil 66. Malaviya GN. Rehabilitation of insensitive hands. Indian J Lepr
1970; 51:481-87. 2002; 74:151-57.
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36
36
Nursing Care for Leprosy Patients
Vineet Kaur, Gurmohan Singh
INTRODUCTION NURSING: ASSESSMENT OF A LEPROSY

PATIENT
When one thinks of ‘leprosy’ today, the image that comes
to mind is of a person with one or few light colored skin Through Interview
patches with anesthesia/hypoesthesia, or an area of
i. Understanding of diagnosis: It must be reiterated that
anesthesia in a limb and in very rare cases, some
leprosy is a completely treatable disease that is
deformities. The old images of leprosy patients, with
acquired through close contact or air borne route over
deformed, mutilated and ulcerated limbs, saddle nose,
which the patient has hardly any control. It is neither
opaque cornea/s (blind eye) are fortunately quite rarer
hereditary nor the result of wrath of gods. The disease
today.
however has the potential to cause deformity in a
On the other hand, when one thinks of “nursing” it
small percentage of patients.
conjures up images of women (almost exclusively; at least
ii. Understanding of multi drug therapy (MDT): Once
in India) in white, on wards, going from bed to bed, looking
MDT has been instituted, it must be emphasized that
after sick patients. So what then is the common factor
between these images and nursing in leprosy? And yet, it is absolutely essential that it be continued without
those of us who have worked ‘hands on’ with patients of interruption for the prescribed period. The patient must
leprosy, know that caring for a leprosy patient involves in be instructed to report any perceived side effects
addition to compassion, a significant amount of nursing immediately. The nurse must also ensure that the
skill and care. In the following few pages, the invaluable patient has understood how the two/three drugs (as
role a nurse (read also any other allied health care per the leprosy type PB or MB) have to be taken.
professional) in improving outcome while looking after iii. Understanding of the course of disease including
patients of leprosy, right from diagnosis to the end of their reactions: After the diagnosis is understood by the
lives, will be highlighted. patient, the nurse must take the opportunity to assess
Although, we in India cannot yet boast of specialist if the patient also understands that the disease might
dermatology nurses, yet it is not impossible to train general pass through reactional phases, which may seem to
nurses to look after leprosy patients. At a stage that leprosy patient like worsening of the disease.
is practically eliminated from our country, and with the iv. Understanding of prognosis: The nurse must assess
National Leprosy Eradication Programme (NLEP) becoming if the patient understands what relief he/she can
part of the horizontal general health care services, the role expect from the treatment. The patient must accept
of a nurse will become even more useful. The role of that it may not be possible for whole of the sensory
nursing professional will be discussed under separate loss to be reversed; and in some cases residual
headings for convenience. deformity could remain.
CHAPTER
36
Nursing Care for Leprosy Patients 469
v. Communicability status of disease: Because of the the nurse should enquire and ascertain if any such
stigma attached to leprosy, the patient must be issues are operative in a particular patient.
assessed for his/her understanding of the non-
communicability of disease to those in close contact Post-assessment Nursing Intervention
with him, if regular treatment is taken. a. The nurse must explain that MDT is the global standard
vi. Effect on employment: Once a diagnosis of leprosy treatment for leprosy. She must reiterate that the patient
is made, the patient might have concerns about must not miss taking medication at any time and that
whether it will affect his employment. This must be the duration of treatment as prescribed by the
evaluated by the nurse and the patient guided about dermatologist is based on severity of the disease.
safety measures to be followed at the place of work. b. The patient must be explained that intake of Clofazimine
vii. Lifestyle changes: On initial assessment, it must be may turn the skin coppery and in lactating mothers,
ascertained if the patient is aware that a diagnosis of can also darken the breast milk color. Rifampicin causes
leprosy may warrant some changes in day to day the urine to be tinged orange, is an important fact that
lifestyle both, at home and at the work place. These must be explained to the patient since it can cause
may include using another mode of transport, e.g. unnecessary alarm. Rare side effects like “flu like”
cycling would be suitable, as against walking to the syndrome with rifampicin, jaundice with dapsone/
work place, using modified utensils in the kitchen, rifampicin and acute renal failure with rifampicin should
wearing special footwear etc. The patient should be also be flagged up.
able to understand that the aim is to prevent disability c. It must be explained that even after completing the
from setting in; and from worsening of the existing prescribed course of MDT, some anesthesia may
deformities, if present. remain. All patients (especially multibacillary cases),
viii. Family support: The success of treatment in leprosy must be explained about the possibility of occurrence
depends to a very large extent on the support of reactions while on treatment; and the fact that these
extended to the patient at home, at work place and do not necessarily indicate a worsening of the disease.
by the society at large. The nurse should pick up They should be explained how to recognize the features
clues that point towards these issues while of reaction and to report them to the health personnel
interviewing the patient. The effort should be made to at the earliest.
extract the requisite information from the patient by d. Those with existing deformity must be prognosticated
general talking and indirect questioning; eliciting with regard to the extent of likely recovery.
answers by direct questioning should be avoided, as e. Pregnant mothers on MDT should be reassured about
far as possible. This information will help the nurse to the safety and the usefulness of continuing MDT. They
gain the confidence of patient’s attendants and also, should be encouraged to breastfeed their newborns as
encourage and involve the family members in patient usual.
care. f. Lifestyle changes (e.g. use of special utensils to avoid
ix. Social rehabilitation: Once a diagnosis of leprosy is thermal injury, avoid sitting in front of the community
made, in some cases, especially in the villages, there fire in winters, use of protective gloves etc.) must be
might be problems with acceptance of the patient in impressed upon by the nurse and their significance
the community. This can be a major hurdle for some explained. This is specially so because patients without
patients with the diagnosis.1 This was indeed a very significant paralytic or anesthetic disabilities are unlikely
serious matter in most parts of the country, barely to realize the long term impact of these incapabilites.
30-40 years back, when the patients with leprosy had g. It is important that the patient and the nurse form a
no option but to leave the home, for a life of destitution close bond of confidence and the patient is able to
in secluded areas outside the village; or in various discuss his or her family problems related to the
leprosy colonies made for them. An account of such disease or its management. It is also important for the
instances has been in the chapter on case studies, nurse to involve at least one other family member in
at the end of the book. Although fortunately, this the ongoing care of the patient and to try and solicit
situation has changed considerably now, by all means, the family’s support in general.
CHAPTER
36
Through Examination
i. General examination of skin: The patient should be
exposed in good light to look for the clinical signs of
leprosy (hypopigmented macules, infiltrated lesions,
ENL lesions etc.) for record keeping and follow up,
and also the general condition of the skin, especially
dryness.
ii. Examination of sensory loss: The areas of sensory
loss should be mapped out and these areas should
be evaluated subsequently during follow up visits.
iii. Examination of motor function of commonly affected
nerves: Although there are many methods detailed
on testing for motor functions,2 the nurse must adopt
a quick check approach. This is important, and Fig. 36.1: Early ulnar nerve paralysis – inability to bring
enables one to identify the impending deformity at ring finger together with the others
the earliest.
The motor function of the six most commonly affected
nerves in leprosy is as follows:
a. Ulnar nerve
b. Radial nerve
c. Median nerve
d. Common peroneal nerve
e. Posterior tibial nerve
f. Facial nerve
To test the motor functions of first three together,
ask the patient to bring all the fingertips together with
the thumb, and then to fully dorsiflex the hand at the
wrist. In case of ulnar nerve paralysis, the little and
ring finger will lag (Fig.36.1). In case of median nerve
paralysis, there will be inability to join the index finger
(Fig. 36.2), and in case of radial nerve paralysis, there Fig.36.2: Early median nerve paralysis – inability to bring index
will be difficulty in dorsiflexion at the wrist. finger together with the others
To examine the common peroneal nerve, ask the
patient to dorsiflex the foot at the ankle, inability to
do this indicates nerve paralysis.
For the posterior tibial nerve, a quick test is to
ask the patient to fan out his toes; the paralysis of
this nerve will not allow the patient to do this (Fig. 36.3).
To test the facial nerve, ask the patient to close
his eyes tightly, an easy separation of the lids (done
by the examiner) or a lid lag (inability of the patient to
close the eye completely) will be observed.
All these quick tests can be carried out in a very
short time and are a useful tool in patient assessment
even during follow up.
iv. Examination for deformity: Any claw hand, wrist drop,
foot drop or lagophthalmos in the patient should be Fig.36.3: Inability to fan out toes of left foot – early paralysis of
posterior tibial nerve
CHAPTER
36
documented. Anesthetic deformities resulting from can be reviewed less frequently as compared to ‘high risk’
resorption of digits must also be noted. Impending ones who need to be seen more frequently.
deformity from a swollen and tender major nerve must This stratification is broadly based on:
be picked up as early as possible. a. Age of the patient
v. Examination for ulcers: The hands and feet are most b. Type of disease (multibacillary vs. paucibacillary)
likely to get ulcerated due to anesthesia. An ulcer c. Nerve/ organ involvement
should be examined for: d. Past or present reactional states
a. Location of the ulcer: this will give an idea of the e. Presence/ absence of disability and deformity
possible cause, e.g. is it at a pressure point? Is it
at a point of friction? Low Risk
b. Appearance of the ulcer: this will give an idea of Young patients with paucibacillary leprosy having no
the duration for which it has been present. Long significant damage to nerves and no reaction/disability can
standing ulcers will be deeper, with a thicker rim be included in this group. There is a very low likelihood of
of hyperkeratotic tissue around them. Infection of them going into reactional states in the future or of
the ulcer will indicate the level of care of an ulcer. developing deformity.
Nursing: Assessment During High Risk

Follow Up Visits
Patients with multibacillary leprosy, having past or present
i. Checking regularity of MDT: The nurse must enquire reactions; and those with nerve trunk involvement are
about how the patient is taking medication. Indirect included in this group. Patients with sensory loss to the
questioning about orange colored urine will reveal limbs and eye involvement, as also the pregnant mothers,
whether rifampicin is being taken by the patient.3 belong to this high risk group. They are more likely to
ii. Checking for side effects of MDT: The patient should develop deformity and must be followed up more closely
be asked for any fever, rash, discoloration of urine on and more frequently.
days other than when rifampicin is taken (indicating Note: Reassess the risk status of the patient at every
jaundice), loss of appetite, dryness/cracking of skin repeat visit because it is not unusual for the risk status of
(due to clofazimine), any newly observed muscular the patient to change.
weakness (indicating peripheral neuropathy).
iii. Re-examination of skin, nerves, ulcers, deformity: To NURSING: ASSESSMENT
be quickly repeated as described in sub-section OF ACTIVITIES OF DAILY LIVING
headings (ii), (iii) and (iv) of the previous section on
“through examination” discussed above. Since nerve involvement, reactional states and disability,
iv. Checking for exercises being performed: As described all directly or indirectly affect the daily activities of a leprosy
later in the section on deformities. patient, it is important to assess the patient’s ability to
v. Checking splints, footwear and assistance aids (if carry these out.
the patient is using any): As described later in the Nurses can easily be trained to use the Green Pastures
section on deformities. Activity Scale (GPAS)4 (Table 36.1) which comprises
patient’s assessment into various grades, on the following
parameters namely:
NURSING: ASSESSMENT OF THE ‘RISK’
a. Daily activities
STATUS
b. Interpersonal relationship
It would be helpful to broadly classify leprosy patients into c. Use of assistive devices
‘High risk’ and ‘Low risk’ after initial assessment. This is The daily activities include things like– comfort, mobility,
important to be able to prognosticate the patient as well seeing, brushing, bathing, dressing, combing, nail cutting,
as flag up issues that might warrant an immediate eating/drinking, defecating, preparing meals and other
consultation by a dermatologist. Also, ‘low risk’ patients routine activities in the house.
CHAPTER
36
Table 36.1: Green pastures activity scale (GPAS) for in good light. They must wash their hands with clean
assessment of daily routine of leprosy patients water at room temperature and then look for:
a. The daily activities are assessed in grading as: • Areas of redness
4. Not difficult • Blisters
3. A bit difficult • Swelling
2. Very difficult • Ulcers
1. Impossible
Once an injury has been identified, the nurse must
b. The interpersonal relationship can be scored as:
4. No problems reiterate the need to identify how it might have
3. Some problems occurred. This is necessary to prevent further injury
2. More problems from the same/similar cause/s.
1. No relation ii. Avoidance of injury: The patient should be trained to
c. For the use of assistive devices: think about possible injury in any activity. One of the
4. Not necessary
commonest injuries to anesthetic hands is thermal –
3. Not difficult
2. Difficult in women while cooking, and in men in rural areas
1. Very difficult who sit around fire in winter. The women patients must
be demonstrated the use of cotton oven gloves
Nursing Intervention (Fig.36.4) or simpler still, a piece of cloth wrapped
around utensil handles. The ideal solution is to have
Such a scoring system done at initial visit and then at
long wooden handles for all utensils (Fig.36.5) and
follow up can help the nurse to pick up early deformity and
moulded handles for deformed hands. They must also
steps can be taken to prevent further deterioration. Also,
be told not to cook chapattis directly on the fire
such information is required to optimize the assistive
because burns can be caused in this situation.
devices being used by the patient. Family support too can
Men should be instructed to cover up with extra
be tailored to the daily needs of the patient.
layers of woollen garments instead of sitting around
a fire. Likewise cigarette smoking is not only harmful
NURSING: ROLE IN THE CARE OF
to the lungs but can also burn the digits of an
ANESTHETIC LIMBS
unsuspecting hand in leprosy. Those working as
The nurse has a major role to play in helping to care for manual labourers in many different fields need to
anesthetic upper and lower limbs. protect their hands from trauma.
Anesthetic Upper Limb

Assessing the extent of anesthesia has been described in
the previous section on clinical examination (examination
of sensory loss). This assessment is a prerequisite for
advising on the care of such a limb. Once the extent of
sensory impairment has been established, the nurse can
proceed to advise the patient (and also the family members,
especially in case of a child patient) on the following aspects
of patient care:
Nursing Intervention
The success of a nursing intervention is that eventually
the patient learns self care. Various models around the
world emphasize transferring this skill to the patient.5
i. Teaching daily self examination: do not experience
pain and temperature, trauma goes unnoticed.
Therefore the patient has to be taught that in order to Fig. 36.4: Home made oven gloves, suitable
identify injury early, he should inspect his hands daily for patients with anesthetic hands
CHAPTER
36
- The bandage used to secure the splint must not be
too tight
- A part of the finger tip and nail must be kept exposed
so that any color changes in the digits can be
noticed.
iv. Nursing advice on follow up visits: The nurse should
enquire from the patient about his daily routine for the
care of hands. She should check for any raw areas,
blisters, ulcers etc and whether they are infected.
Any dressings applied by the patient must be assessed
for their correctness. The patient should be asked to
bring along any mittens (mittens: any fabricated piece
of cloth meant for use as glove) they might be using
to see if they are not worn out and are thick enough
Fig.36.5: Utensil with wooden handle to protect the hand from heat. Splints should also be
checked for any sharp edges.
Those patients with involvement of the eyes must
be instructed to always wear protective glasses and Anesthetic Lower Limb
use artificial tears. As in the upper limb, the feet also need similar attention
iii. Teaching self care: The patients who do develop care and guidance in protecting them from ulcers, disability
blisters or ulcers can be taught the basic steps of
and deformity. As compared to the upper limb, the lower
skin care as below:
limb is more difficult to protect and preserve, because of
a. Cleansing – The patient should wash their hands
its weight bearing role. As a result, in leprosy patients the
with soap water at room temperature to remove
foot is more prone to develop injury. The most important
all the dirt and mop them dry.
cause is the walking on anesthetic feet. Other causes like
b. Dressing – Any raw area should be covered with
injury from heat and from ill fitting footwear are also not
sterile gauze and a clean bandage or cloth. If the
uncommon.
wound looks infected (explain signs of infection
i.e. pus discharge, foul smell), an antiseptic Nursing Intervention
ointment should be applied and he should be seen
The nurse has an important role in explaining to the patient,
by the treating physician.
through demonstration, that his/her feet are anesthetic.
c. Care of the bandage – the patient should be
The patient should be made to understand clearly, that
instructed to keep the bandage dry and clean.
While engaging in any chores, the hand can be walking for a distance which might be a normal routine for
put in a polythene disposable bag. In case the others, can cause blistering and ulceration in a person
dressing gets wet, it must be changed. with anesthetic feet. These ulcers heal with scarring, which
d. Limb elevation – In case the hand is swollen, show remains a weak point in the foot and can break down again,
the patient how to elevate it by putting it in a sling. if subjected to unusual trauma. Repeated ulceration,
e. Splinting – It must be emphasized that only rest combined with weakness/paralysis of the muscles due to
can help the ulcer heal. Often splinting is required nerve involvement, finally causes deformity.
for this. The patient can be shown how to use i. Teaching daily self examination: The patient must be
materials such as cardboard, plastic, wood etc demonstrated the soaking of feet in water or soap
wrapped in cotton and then a bandage or cloth to water for 10-15 minutes. The areas between the toes
be used to support the hand. must be cleaned and any foreign bodies, thorns,
While explaining the use of a splint, the nurse must pebbles, dust sand etc. removed. After this the patient
ensure that the patient understands, that: must examine his feet in good light and look for:
- The edges of the splint must be smooth - Cracks/ fissures
CHAPTER
36
- New areas of redness or blistering • When callosities are present on the top of the feet
- Ulcers on the outer margin, they are most often a result of
The patient should be told how to examine the friction with ill fitting footwear. This can be avoided
footwear and look for worn out areas that might be by using footwear specially designed for that
causing friction. Very often the patient does not notice individual’s foot deformity
a nail sticking out of the footwear which may be the iii. Care of ulcers on the feet: The first requirement for
cause of repeated trauma and the subsequent treating ulcers on the feet is to teach the patient to
ulceration. recognize an early ulcer. The patient must be made
ii. Care of fissures and callosities: It must be explained to understand that the more superficial the ulcer, the
to the patient that because of anesthesia and faster it will heal. Deeper and infected ulcers may
decreased sweating, the sole becomes thickened at take up to weeks to months to re-epithelialize and
places where there is repeated pressure. This are the commonest cause of deformity. The nurse
localized area of thickening (callosity) is more prone must also judge if there is a need for referral to a
to cracking and secondary infection. The patient must higher center.
be shown the five most common sites of callosities The basic principles of care are the same as for
in the foot as shown in the Figure 36.6: the upper limb (discussed in previous sections) except
1. Tips of toes (especially if clawed) that since the lower limb is weight bearing, a much
2. Creases between toes and ball of the foot greater emphasis to be given upon the rest. If the
3. Area under the fifth metatarsal ulcer is uncomplicated, the patient may be allowed to
4. Margins of the heel carry out daily activities using crutches but if it is
5. Center of the heel deep, rest in bed, perhaps with limb elevation must
The aim of treating callosities is to prevent cracks and be ensured.
further infection. To achieve this aim, it is important that iv. Teaching self care: Since deformity depends on
the feet are kept supple and soft by soaking the feet in repeated injury to the limb, it is prudent to explain to
water and applying Vaseline/oil/cold cream. the patient that his efforts to look after his lower limb
The nurse should flag up the following points for will go a long way in preventing deformity. The patient
callosities in special situations: must carry out the following rituals on a daily basis
• Callosities on the lateral malleolus are mainly due before retiring to bed:
to pressure while squatting. This can be avoided • Soaking feet in water and then examining them for
by advising the patient to either change his posture any blisters or ulcers
or put a thick padding on it while squatting. • Applying petroleum jelly to moist the feet to prevent
cracks and fissures
• Changing any dirty bandage
• Examining footwear for any rough areas that might
be causing friction
v. Nursing care on revisits: A review visit is very
important in the nursing context. It is an opportunity
to reiterate what was discussed and taught to the
patient in the past. These visits must never be hurried
and it should not be presumed that the patient has
understood and is carrying out all the instructions
given so far.
The following could be a handy check list for the
nurse:
• Has the area of sensory loss increased?
• Is there any increase in motor deficit (has the
Fig.36.6: Areas of sole prone to develop callosities. patient developed a foot drop / has the foot drop
The numbers in figure refer to those in text worsened)?
CHAPTER
36
• Is the patient able to carry out his daily checking other injuries. The need for care is perhaps most important
routine at bedtime? here because the mind has to be retrained to do things
• Has he developed any new raw areas (blisters/ that are a reflex, differently.
ulcers) if yes, how do they look?
• Does the patient need special footwear? Nursing Intervention
• Is the footwear fitting correctly? The nurse must teach the patient to:
• Are any assistive aids like crutches required? • Recognize early signs of paralysis (As described in a
previous section on examination of motor functions)
NURSING: INTERVENTION IN LEPROSY • Recognize early areas of impending ulceration
DEFORMITY The patient must remember at all times that the aim is to:
The nurse has a two pronged role here. • Prevent ulceration/ nerve damage induced paralysis
a. To help prevent deformity • Prevent existing deformity from getting worse
b. To help existing deformity from worsening • Avoid stiffness of deformed hand
Deformity in leprosy primarily involves the hands, feet Once a deformity has been identified, the nurse should
and eyes. They could be a result of the disease itself take the patient through the care routines that he will then
(saddle nose), result from nerve damage or a consequence have to follow henceforth.
of repeated trauma to any anesthetic body part.
The nurse should first briefly explain to the patient the Massage and Exercises for Hands with
etiology of deformity. This information into the causes of Paralytic Deformity
deformity will go a long way in the patient being able to
Massage and Exercises for the Fingers
understand how to avoid injury and subsequent
damage. For the sake of simplicity, deformities can be The nurse must demonstrate to the patient the correct
divided into – paralytic and anesthetic. technique for massage. First take some oil and smear it
i. Paralytic deformity: Patients must be explained that on the fingers (both palmar and dorsal surfaces). The
because leprosy primarily involves the nerves, patient should rest the hand on the thigh and gently stroke
damage to these nerve trunks causes weakness and them with the flat of the opposite hand trying to straighten
sometimes paralysis of the muscles supplied by them. the fingers; without applying too much pressure. This should
In the upper limb this can result in partial claw hand, be repeated twice daily for at least twenty times each.
complete claw hand and wrist drop. In the lower limb, To exercise the fingers, the patient should keep the
the commonest deformity is foot drop. Lagophthalmos hand bent at the knuckles and press the back of the hand
(inability to completely close the eye on blinking) and against the thigh or a table top (Fig. 36.7). Then using the
subsequent exposure keratitis (dry eye) are common
deformities encountered in the eye.
ii. Anesthetic deformity: Loss of sensation to touch, pain
and temperature compounded by the loss of sweating
can cause the affected area to get damaged. It is
important for the nurse to make the patient understand
the relevance of this; so that he is able to take
measures at all times to protect such body parts. At
the same time, this also must be emphasized that
leprosy does not necessarily mean deformity and that
with proper care and prevention these are avoidable.
Deformity of Upper Limb

Since the hand is our body’s connection with the world,
being used all the time for picking, touching, feeling etc.,
it is the part most likely to be damaged by thermal and Fig. 36.7: Exercise for fingers
CHAPTER
36
hand to claw. Other than active stretching through

exercises, the use of splints for passive stretching specially
at night should be demonstrated.
Deformity of Lower Limb

Since the feet are weight bearing, and used all day for
walking, there are more chances of injury than perhaps on
any other body parts.
Nursing Intervention
As in the upper limb, the patient must be taught for early
paralytic deformity or anesthetic injury. A simple check
list can be discussed with the patient to be used both by
the patient and the nurse, as given below:
• Check if the toes are bent rather than straight
Fig.36.8: Another exercise for the hand
• Check if the tips of the toes (rather than the pads) are
making contact with the ground.
other hand he should attempt to straighten his fingers till
• Whether the heel and the ball of the big toe are in
the back of the fingers touch the thigh or table top (Fig.36.8).
contact with the ground.
Massage and Exercises for the Thumb • Check if fanning of the toes is possible.
Ask the patient to rest the edge of the palm on the table. The patient has a ‘foot drop’ gait rather than a normal ‘heel-
Then he should gently but firmly try to pull the thumb to to-toe gait’. Here the patient has to lift the leg high in order
straighten it. Too much force should not be applied while to clear the ground
stretching for fear of producing cracks. The patient must • To look for any breaks in the skin, blisters or ulcers on
be instructed that no massage is to be done if the hand the sole or dorsum
has blisters, raw areas, or is swollen. • Ask the patient to lift his toes and then his heels.
The patient should steady the thumb with the opposite Inability to do so or to sustain it for more than 30
hand. Then he should try to lift up the tip of the thumb in seconds signifies muscle weakness.
order to straighten it. It must be emphasized that deformities like foot drop
Taking a soft rubber ball and making a small hole in it and weakness of any muscle cause an uneven
to squeeze out the air can be a useful aid for exercising transmission of load in the foot leading to further friction
the hand muscles (Fig.36.9). In addition there are devices
such as the one shown here that are available locally at
very low costs to help exercise the hand.
Use of Splints for the Hand

In case where paralytic deformity is of recent onset, the
patient should be explained that it can be prevented from
getting worse. If it is not yet stiff, splints play a useful
role. The nurse must demonstrate the use of splints for
passive stretching after taking the patient through the full
range of movements of a normal hand. The principle in
paralytic deformities is that one set of muscles is not
working. So the muscles with opposite action act to create
an imbalance. e.g. in a claw hand, the extensors are
paralyzed so, the over action of the flexors causes the Fig.36.9: Hand exercise using soft ball
CHAPTER
36
and ulceration. This information will help elicit co-operation
from the patient in caring for the foot, recognizing early
paralysis and helping to prevent further deformity.
i. Care of anesthetic foot: This has been dealt with in
detail in previous section on anesthetic lower limb.
ii. Care of foot drop: Once early weakness is picked up,
the patient must be referred to the doctor for institution
of therapy in addition to MDT. The patient must be
informed about the side effects to watch for, while on
corticosteroids, and also about the precautions
needed to be taken. The nurse must monitor if the
patient is taking the prescribed additional drugs, doing
exercises and using splints etc as advised.
Fig. 36.11: Night time splint for foot drop
The nurse will have to teach the patient the
following:
iii. Splinting of knee: When there is acute neuritis of the
common peroneal nerve and foot drop, the knee and Ask the patient to stand straight in front of a wall,
ankle must be splinted to prevent repeated bending. keeping the feet about one foot away. Without lifting
This will allow rest to the inflamed nerve and result in the toes or bending the knees, he should lean forwards
quicker healing. A splint can easily be made at home supporting his body with his palms against the wall.
by taking a stiff board. This should be well padded He should stay like this for ten seconds and repeat
with a lump of extra cotton padding in the middle and this about ten times.
at the lower end (these parts will sit behind the knee v. Foot supporting devices: These devices help to
and the ankle). Bandage this splint to the leg at the support the dropped foot and prevent it from falling
knee (Fig.36.10). At night when the patient is in bed, when the patient walks. In addition, equal weight
the dropped foot should be supported to hasten distribution to the sole can also be ensured. Most of
recovery. Again a simple home made splint as shown these devices work on a simple principle – An above
can be used (Fig.36.11) ankle strap has a spring or an elastic band, the other
iv. Stretching the calf muscles: Whenever there is a foot end of which is attached to the sandal or the shoes at
drop, normal stretching of the calf muscles, as occurs the point of the third/ fourth toe. Each time a step is
during walking on heel-toes, does not occur. This leads taken, it pulls the front of the foot up and on setting
to development of contracture and the patient lands the foot down does not allow it to fall. Thus the high
up permanently walking on the toes which get stepping gait can be abolished. The nurse can show
damaged from overuse. In order to prevent this, the the patient the use of such a device and also suggest
nurse must show the patient simple calf stretching a place where one can be obtained or ordered.
exercises. vi. Use of protective footwear: Once there is a deformity,
whether anesthetic or paralytic, it is prudent to reiterate
the need for protection of such a foot at every follow
up visit. There is now sufficient evidence that regular
use of protective footwear and foot orthoses can help
plantar ulcers heal faster.4
The patient must be made to understand the
vulnerability of his feet. This alone will ensure that he
complies with the special footwear that will be required.
There is a wide variety of specialized footwear options
available for the patient; however the nurse must
ascertain the most suitable option for each individual
Fig. 36.10: Home made splint for knee case.6
CHAPTER
36
Wearing soft shoes with soft insoles but a hard ROLE OF THE NURSE IN THE CARE OF
sole are necessary. Although a variety of such WOMEN WITH LEPROSY
specialized shoes made from microcellular rubber
Gender inequalities in health have a significant impact on
(MCR) are available in some setups, there are simpler
women’s health.8 Being a woman puts a leprosy patient in
versions also that are readily available at ordinary
double jeopardy. Her status in the family, in society, and
shoe stores. The simplest thing to suggest is a soft
in special situations like pregnancy, puts her at higher risk
sports shoe. However, if there is significant scarring
for developing disability, deformity and social stigma. It is
and deformity, specially moulded shoes are essential.
important for the nurse to take these aspects into
Once the patient understands the function of such
consideration while following up and caring for a woman
protective shoes, he is more likely to comply with
leprosy patient.
their constant use, both inside and outside the house.
The challenge is far greater in getting women to
Status in the Family
comply because of the social taboo in rural areas
regarding women wearing shoes, more so in the For most unmarried girls, this might not be an issue but
cooking area of the house. It is better to suggest a once the woman is married, her treatment and care
protective sandal since it is more likely to be used. depends to a very large extent on her place in the family.
They too must be told to wear footwear at all times Using indirect clues, e.g. the delay in bringing the patient
both inside and outside the house. The patient must for treatment, the regularity with which she is taking
also be taught to take care of the footwear and MDT, the state of her hands and feet if anesthetic, her
examine it from time to time for worn out or rough footwear, etc. the nurse can assess her status. Then
areas, which may need repair or replacement. using this information, the nurse can foresee difficulties
she will encounter and should make efforts to find
Nursing Intervention: solutions to such problems with a sensitive and amicable
Care of the Eyes in Leprosy manner.
The eyes can get affected in leprosy. Estimates reveal
Status in Society
that at first presentation, 3.2% of patients have leprosy
related blindness.7 The two commonest complications Status of the woman with in the family directly influences
resulting from leprosy are lagophthalmos and exposure her place in society. Those who have no support at home
keratitis. The nurse can play a crucial part in preventing are ostracized by society and ill treated by all. Such
ocular complications and in preventing the damaged eye examples are still common despite the fact, that leprosy
from worsening. Her role includes: is curable and has been ‘eliminated’. The role of nurse is
• Informing patients considered ‘at risk’ on the first visit to support the patient, educate the family and bring about
itself to recognize early signs of lagophthalmos (explain a change in their attitude and finally influence the society
to the patient in simple terms that it manifests as for acceptance of such patients.
inability to close the eye completely).
• Equally important is to check for lagophthalmos through Leprosy and Pregnancy/Lactation
examination at every repeat visit. Hormonal changes during pregnancy can cause a variation
• If the patient has already developed lid lag, he should in the host immunity. The first appearance of disease, its
be explained that this can lead to dry eye and repeated reactivation and relapse in ‘cured’ patients is most likely
infections. to occur in the third trimester. It is well known that both
• Educate the patient regarding an ‘acute red eye’ (uveitis) type1 and type 2 reactions extend into the postpartum
that must be reported immediately. and lactation period. If the nurse is aware of these special
• Showing the patient the use of protective glasses at circumstances, she can look for any signs of worsening
all times and checking for the same at repeat visits. of disease and similarly educate the patient. The fact that
• Demonstrating and impressing upon the use of artificial MDT has to be continued throughout pregnancy must be
tears to be used at least twice daily. reiterated at every follow up visit. Clofazimine can some
• Early referral to a specialist in case of need. times be excreted through breast milk and this may alarm
CHAPTER
36
the patient. The nurse can allay any fears the mother might In the last, but not the least, the nurse can also play
have about the effect of leprosy on the unborn child or on an important role as a health educator. She has an
the breast fed baby. opportunity to communicate with the patient, his family
members, the people who come to visit the patients in the
ROLE OF THE NURSE: CARE OF hospital, on other issues (medical, rehabilitative,
INDOOR PATIENTS occupational, social, etc.) related to leprosy.
Leprosy patients sometimes need hospital admission due

CONCLUSION
to a variety of reasons. These most commonly include
reactions in leprosy, neuritis, trophic ulcers and for In this chapter, an attempt has been made to highlight the
reconstructive surgery for correction of deformity. invaluable role nurses can play in the eventual outcome of
During reactions in leprosy, the patient can be quite the management of a leprosy patient. In some settings
sick with fever, joints pain, nausea, vomiting, etc. The nurse they might be the only health care professionals available
plays an important role in looking after hydration, for advice to a leprosy patient and so their role must not
interventions like cold sponging for fever and helping to be underestimated. The combined efforts of all the
alleviate anxiety of the patient and relatives by explaining members of a dermatological team can ensure that some
that these reactions are not unusual. The nurse has a day we will live in a leprosy free world.
great role to educate the patients to continue MDT in spite
of getting reactions, after the MDT has been started. REFERENCES
Supervised administration of anti-leprosy treatment by 1. Scott J. The psychological needs of leprosy patients. Lepr Rev
nurse is mandatory for patients admitted in wards. 2000; 71: 486-91.
2. Brandsma JW, Schreuders TA. Sensible manual muscle
Splinting to immobilize the affected limb helps to strength testing to evaluate and monitor strength of intrinsic
prevent deformity due to neuritis. For those patients with muscles of the hand: a commentary. J Hand Ther 2001; 14:273-
non healing ulcers, the nurse helps in the daily cleansing 78.
3. Harries AD et al. Monitoring rifampicin compliance by visual
and dressing of the wound; as well as in teaching the patient
inspection of urine color. Trop Doct 1999; 29:243-44.
to take care for a trophic ulcer. Patients who undergo 4. Chitra W. Impairment of activities of daily living among leprosy
reconstructive surgery need her input not just for daily patients. Ind J Com Med; 2006; 31(2): 115.
dressings; but also for limb elevation and helping the patient 5. ALERT, Ethiopia. The experience of self care groups with people
affected by leprosy. Lepr Rev 2001; 72: 311-21.
to carry out daily functions while a limb is immobilized
6. Saunderson PR, Seboka G. Protective footwear for leprosy
after surgery. patients with sole sensory loss or ulceration of foot. Lepr Rev
While the patient is in hospital, the nurse should utilize 1995; 66: 237.
this opportunity to show the patient how important it is to 7. Ffytche TJ. The prevalence of disabling ocular complications of
leprosy: a global study. Indian J Lepr 1998; 70:49-59.
protect limbs from thermal injury even while carrying out 8. Le Grand A. Women and Leprosy: a review. Lepr Rev 1997; 68:
daily activities like feeding and drinking tea. 203-11.
Section
7 Miscellaneous Issues
in Leprosy
37
Relapse in Leprosy
Devinder Mohan Thappa, Sowmya Kaimal
INTRODUCTION or tender, after which antileprosy treatment was continued

for 3-5 years.1 With the advent of multidrug therapy (MDT)
Relapse of diseases, acute or chronic, caused by bacterial
such rigid clinical criteria for cure have lost their
infections is quite common. Usually relapse indicates a
importance. A leprosy patient is defined by the WHO, as
failure to treat the infection thoroughly and this is
the one who is found to have signs and symptoms of the
compounded by irregular treatment, particularly in chronic
disease and who requires chemotherapy. As of 1997, WHO
diseases.
recommended one year of MDT for MB patients (12 pulses
The treatment of leprosy, compared to other infectious
in 18 months) and 6 months (6 pulses in 9 months) for PB
diseases, is unique in terms of the fixed dose and duration patients. At any point of time during therapy, the patient
of regimens and also in terms of the definition of “cure”. should have ingested two-thirds of the pulses till that time.
Often, termination of treatment is based on the completion For operational purposes, once a patient receives adequate
of recommended duration of treatment; rather than the chemotherapy, he is considered “cured”. Histopathological
disappearance of clinical signs and symptoms which led resolution of the lesions and clinical subsidence of the
to initiation of treatment in the first place. disease may take months to years after antileprosy
Thus, the principal mode of assessing the efficacy of treatment is stopped.
therapeutic regimens in leprosy is the “relapse rate”. A
very low relapse rate over an adequate period of observation Several definitions have been proposed for relapse
indicates that the regimen used has been effective. The in leprosy.1
correct diagnosis of relapse and its differentiation from 1. Guide to Leprosy Control (WHO 1988):
late reversal reaction is very important, particularly in the “A patient who successfully completes an adequate
field conditions. course of multidrug therapy, but who subsequently
develops new signs and symptoms of the disease,
DEFINITION either during the surveillance period (2 years for PB
and 5 years for MB leprosy) or thereafter”.
The definition of “relapse” can be understood only in context 2. Becx-Bleumink lists several criteria for relapse,2
of the definition of “cure”. In the era of Dapsone which include:
monotherapy, a patient with multibacillary (MB) disease a. New skin lesions
was declared “disease arrested” when skin lesions resolved b. New activity in previously existing skin lesions
and when three monthly consecutive skin smears were c. Bacteriological index (BI) 2+ or more in two sets of
negative for acid-fast bacilli (AFB), after which antileprosy skin smears
treatment was continued for another 5-10 years or even a d. New nerve function loss
life time. A paucibacillary (PB) patient was declared e. Histological evidence of relapse in skin or nerve
“disease free” when all skin lesions resolved with no biopsy
infiltration and no erythema; and nerves no longer painful f. Lepromatous activity in the eye(s)
CHAPTER
37
484 Miscellaneous Issues in Leprosy
3. Relapse in paucibacillary (PB) patients: Surprisingly, there were no confirmed relapses in 502
a. Beorrigter et al3 – “Appearance of a new skin lesion patients who completed fixed-duration MDT in the AMFES
or increase in size of pre-existing skin lesion, (ALERT MDT Field Evaluation Study) cohort, a descriptive
provided there is either strong clinical or definite study of leprosy in Ethiopia,7 in a follow-up period of up to
histopathological evidence (or both) of leprosy in 8 years after completion of treatment, even in the 57 cases
such a lesion” with an initial average BI > 4.0, 20 of whom have been
b. Pandian et al4 proposed seven criteria for defining followed for more than 5 years after ceasing MDT. This
relapse in PB – “Extension of the lesion, infiltration, again indicates that the relapse rate after MDT is low.
erythema, occurrence of fresh lesions, pain and
tenderness of nerve, new paralysis of muscles and Microbiological Aspects
bacteriological positivity.”
The conventional method of confirming activity or relapse
Regardless of the definition used for a case of relapse,
in an infectious disease is demonstration and/or culture
it is important to remember that relapse in multibacillary
of the etiologic agent. These methods unfortunately have
(MB) cases is relatively easy to recognize clinically while
limited utility in leprosy because of the difficulty in
relapse in PB cases may be difficult to distinguish clinically
demonstrating bacilli in PB cases and absence of a
from reversal reaction occurring some time after therapy
method of in vitro cultivation of M. leprae. Unlike PB
is completed.
leprosy, where the criteria for relapse depend heavily on
clinical features, bacteriological parameters are useful in
Relapse Rate
MB leprosy.
There are wide variations in the estimates of relapse rates Reappearance of positivity for AFB after the case has
in different regions. This is probably due to variations in become negative, has been considered a feature of relapse
the definition of relapse, proportions of previously dapsone- in both PB and MB cases. Persisting high BI or increase
treated and untreated patients, range of skin smear in BI are also important parameters for diagnosing relapse
positivity in MB cases, and differing durations of follow- in MB leprosy. BI, persisting at the same level, an increase
up. The risk of relapse is very low, both for PB and MB in BI of 2+, appearance of new active lesions with high BI,
patients after completion of MDT, and this is at least 10 or BI becoming greater than what it originally was in the
times lower than with dapsone monotherapy.1 pre-existing lesion, are some of the criteria for diagnosing
The WHO has estimated a risk of relapse of 0.77% for relapse. However, an increase in BI of even 1+ should be
MB, and 1.07% for PB patients, nine years after stopping considered as adequate supporting evidence for diagnosing
MDT. Various other studies using person-years of relapse in patients who had earlier become negative, or
observation estimate the relapse rates varying from 0.65% were showing downward trend in BI after MDT.8
to 3.0% for PB, and 0.02% to 0.8% for MB leprosy.1 A number of in vivo and in vitro techniques are available
A retrospective study of data from the Central Leprosy for monitoring the progress of treatment in leprosy, which
Teaching and Research Institute (CLTRI), Chengalpattu, can also be used as additional objective criteria for confirming
Tamil Nadu, included 3248 leprosy patients who completed relapse.
WHO MDT during the period 1987-2003.5 The overall
relapse rates for MB and PB leprosy were 0.84% and 1.9% In vivo Techniques
respectively, while the rates for person-years of follow up (i) Mouse foot-pad studies:
were 0.86 and 1.92 per 1000 respectively. The majority of These methods measure the viability and include the
relapses occurred in the first 3 years after release from use of mouse foot-pads for cultivation of M. leprae.
treatment. If an individual does not relapse within the first
5-6 years, his/her risk of relapsing is negligible. In vitro Techniques for Assessing the Viability
In a recent retrospective analysis of relapse rate in (i) Morphological index
China after 24 months of WHO MB-MDT for 2374 MB (ii) Fluorescent diacetate ethidium bromide (FDA-EB)
patients, who were followed up for a mean duration of 8.27 staining
years per patient, 5 patients with relapse were identified (iii) Laser microprobe mass analysis (LAMMA)
with an accumulated relapse rate of 0.21/1000 person- (iv) ATP measurements
years, which is quite low.6 (v) Macrophage-based assays
CHAPTER
37
Relapse in Leprosy 485
Molecular Techniques a rise in levels of IFN-γ, IL-2 and IgG2 antibodies, in
(i) DNA and RNA targeting probes addition to a positive lepromin test. On the other hand,
(ii) Polymerase chain reaction (PCR) for gene when TT/BT patients relapse as BL/LL types, a Th2 type
amplification.8 of immune response is initiated, which should lead to a
A study conducted at the Schieffelin Leprosy Research rise in IL-4, IL-5, IL-6, IL-10 and IgG1 production, a
and Training Centre, Karigiri, India, tested biopsy samples concomitant fall in IL-2 and IFN-γ, and lepromin negativity.10
of lepromatous patients who completed 12 and 24 months
Molecular Assays
of MB-MDT for viable M. leprae by mouse footpad
inoculation.9 None of the skin or nerve biopsies from It may be possible to differentiate reinfection from relapse
patients who completed 24 months of MDT showed any by molecular typing of M. leprae, based on amino acid
growth, while a small percentage (3.3%) of patients with a sequencing, as well as to identify relapse at a very early
high BI were found to harbour viable bacteria in the skin stage using nucleic acid amplification techniques such as
after 12 doses of MDT. These patients need to be followed polymerase chain reaction.10
up for a longer period to ascertain whether or not they will
relapse. Histopathology
Ideally regular skin biopsies and skin smears, at least
Immunologic Tests for Relapse once in 6 months, from representative lesions should be
Although there are no widely available serologic tests for studied during the period of treatment and the following
leprosy other than in a research setting, various five years after achieving negativity.
immunological tests may be useful for monitoring patients
on chemotherapy as well as for confirming suspected cases HISTOPATHOLOGY OF RELAPSED
of relapse. LESIONS IN MB LEPROSY13
As lepromatous (LL) lesions resolve under treatment,
PGL-1 Antibodies
increasing number of macrophages become foamy,
Lepromatous patients show a significant rise in titre of Schwann cells show foamy change, there is reactive
PGL-1 IgM antibodies during the time of relapse. TT/BT proliferation of the perineurium, and increasing
cases who relapse as BL/LL types may be detected by fragmentation and granularity of the AFB in the granuloma.
measuring anti-PGL-1 and anti-35 kD antibodies.10 The granuloma gradually resolves, without any residual
The dipstick assay for detection of anti-PGL-1 fibrosis or scar formation and there is fibrous replacement
antibodies has been used as a simple tool for classification of the perineurium and hyalinization of the nerve
of patients and for identification of those patients who have parenchyma. Foam cell collections are known to persist
an increased risk of relapse.11 for long periods in tissues, many years after the skin smears
have become negative. A mild non-specific chronic
The ND-O-BSA ELISA inflammation characterized by small focal collections of
This method (ELISA using the natural disaccharide (ND) lymphocytes around skin adnexae can also persist in
of the phenolic glycolipid antigen of M. leprae linked to resolved LL lesions for several years.
bovine serum albumin as antigen) is another useful test In the early phase of relapse, small and large foci of
both for screening for early infection with M. leprae and for newly arrived spindle-shaped macrophages with pink
predicting a relapse, particularly in cured multibacillary granular cytoplasm are identified along with a few small
patients.12 clumps of persisting foamy macrophages. Solid staining
AFBs reappear in skin smears and biopsy specimens, in
Interleukins-based Assays patients who may or may not have become completely
The Th1 and Th2 type of interleukin profile may be a useful smear negative. Once the lesion is well established, the
method of identifying the type of relapsed leprosy. For foamy change becomes obscured by collections of spindle
example, when BL/LL patients relapse as TT/BT type, an shaped and immature macrophages. Skin adnexae are
upgradation of cell mediated immunity is expected, in the markedly atrophic and scanty, and dermal nerve bundles
form of a Th1 type of immune response, which consists of are few and show perineurial thickening and fibrosis.
CHAPTER
37
Macrophages, Schwann cells and endothelial cells are Rarely, PB cases will relapse as MB, and this is usually
packed with solid staining AFBs. due to misdiagnosis of spectrum of disease and the
Occasionally, there is infiltration by polymorphs, and it resultant inadequate treatment in the first place.
is also not uncommon to see LL patients relapsing with
upgrading reactions, in the form of borderline lepromatous Relapse Interval
(BL) or rarely, borderline tuberculoid (BT) lesions. Relapse interval is otherwise known as incubation period
Lesions of BL resolve much faster than polar LL cases of relapse.14 It is different with monotherapy and multidrug
and become bacteriologically negative much earlier. therapy.
Histopathologically, BL lesions leave behind a few focal
Dapsone monotherapy:14
collections of mononuclear cells around skin adnexae, and
foam cells are not usually seen. Relapses in BL leprosy Fifty-five to fifty-seven percent of relapses occurred within
manifest as LL, BL or rarely; as BT. • Three years in non-lepromatous
• Five years in borderline
HISTOPATHOLOGY OF RELAPSED • Six years in lepromatous
LESIONS IN PB LEPROSY13 Multidrug therapy: 14
• PB – same as with monotherapy
Lesions in BT and TT leprosy are the result of a
• MB – 9 years (median)
hypersensitive granulomatous response to the antigens
The implication of these figures is that paucibacillary
of M. leprae, and are not directly due to the presence of
patients should be under surveillance for at least 3 years
M. leprae. With treatment, there is reduction in the size of
and multibacillary patients for 9 years so that majority of
the granuloma without any fibrous replacement of the skin
the relapses can be detected.14
adnexae. Dermal collagen is destroyed during the
inflammatory process, leading to an atrophied and wrinkled
Predisposing Factors for Relapse14
appearance of healed skin lesions. Nerves undergo
perineurial and intraneural fibrosis. M. leprae get buried 1. Persisters
alive in these nerves and also in the arrector pili muscle Persisting organisms or “persisters” consist of permanently
cells, thereby serving as a focus for relapse. or partially dormant organisms that have the capacity to
The difficulty that arises in PB cases is the differentia- survive in the host despite adequate chemotherapy. They
tion of relapse from type1 reaction. Features that suggest have been identified in immunologically favourable sites
a reaction include oedema around the granuloma, dilated such as dermal nerves, smooth muscle, lymph nodes,
lymphatics and proliferating fibroblasts throughout the iris, bone marrow and liver. These organisms, which are
dermis. A true relapse can be detected histopathologically responsible for relapse, are present in about 10% of MB
only after recording complete histological resolution of the patients, and their proportion may be higher in cases with
lesion, which may take years. Relapse indicates that the higher BI.
bacilli have survived despite antileprosy therapy and have
multiplied and released antigens to produce fresh 2. Inadequate Therapy
granulomas. This manifests as appearance of solid staining This is usually the result of clinical miscategorization of
organisms inside fibrosed nerve bundles (where there were multibacillary leprosy with few skin lesions as
none earlier), and the reappearance of a granuloma at the paucibacillary cases, who receive 6 months of MDT instead
site of the original lesion. This granuloma usually begins of 12 months, initially respond to treatment, and eventually
as a small focus of lymphocytes and epithelioid cells, relapse.
which often starts in fibrosed nerve bundles or arrector pili
muscle cells. Once the granuloma becomes well 3. Irregular Therapy
established, it grows and involves large portions of the Irregularity in ingesting self-administered clofazimine and
dermis, becoming indistinguishable from the original lesion. dapsone either due to irregular supply of drugs or non-
Therefore, in PB patients, regular 6-monthly biopsies compliance on the part of the patient will effectively result
showing disappearance of the granuloma will confirm “cure”, in a scenario of rifampicin monotherapy. This will lead to
and reappearance of the granuloma will identify “relapse”. rifampicin resistance, and subsequent relapse.
CHAPTER
37
4. Monotherapy Relapse in PB Leprosy
The relapse rate is high among patients who have received 1. Skin lesions: Previously subsided skin lesions show
dapsone monotherapy, and did not later receive MDT. This signs of renewed activity, such as infiltration, erythema,
is also due to the development and multiplication of increase in extent, and appearance of satellite lesions.
resistant organisms. Often, there is an increase in the number of lesions as
well.
5. High Initial BI 2. Nerves: New nerves may become thickened and tender,
Patients who have a high BI initially, are at greater risk of accompanied by extension of area of sensory loss and
relapse after fixed duration MDT compared to patients who insidious onset of motor deficit. Patients may complain
are smear negative or have a low BI. of aches and pains along the peripheral nerves with or
without evidence of nerve damage. Relapse may occur
6. Number of Skin Lesions and Nerves only in nerves without skin involvement (neural
The number and extent of lesions including nerve lesions, relapse), and there may be a change in the spectrum
when multiple, i.e. more than five and covering three or of disease on relapsing.
more areas of the body correlate with higher relapse rate.
Mycobacterial antibodies have been found in TT leprosy Relapse in MB Leprosy
with a large number of lesions and in BT leprosy with more 1. Skin lesions: Relapse may present as localized areas
than ten lesions. Since this is evidence of a fairly large of infiltration over the forehead, lower back, dorsa of
number of organisms, these patients may not be truly hands and feet and the upper part of the buttocks.
paucibacillary, and treatment with two drugs for 6 months Soft, pink, and shiny papules and nodules may be found
might be considered inadequate for these patients. at these sites, with or without a background of
infiltration. Papules may enlarge to form plaques.
7. Lepromin Negativity Subcutaneous nodules may appear on the posterior
Borderline patients with a positive lepromin test have been arms and anterolateral thighs. They feel like peas in a
observed to have a lower relapse rate than those with a pod, and increase in size with time. Skin smears from
negative response. the overlying skin may be negative; hence, the scalpel
should be plunged deep into the core of the nodule
8. HIV Infection
while taking smears.
Although leprosy has now been reported presenting as an 2. Nerves: Nodular swellings may occur along the course
immune reconstitution disease among patients of cutaneous nerves and peripheral nerve trunks, in
commencing highly active antiretroviral treatment, there addition to fresh nerve thickening and/or tenderness,
is no evidence as yet to suggest an increased risk of with insidious loss of function.
relapse in patients with HIV co-infection. 3. Ocular lesions: Cases with pre-existing eye involvement
may relapse with iris pearls or rarely, lepromata.
9. Physiological Conditions, e.g. Pregnancy (discussed
4. Mucosal lesions: Papular or nodular lesions may be
later) .
seen on the hard palate, inner lips and glans penis.
Clinical Features14,15
DIFFERENTIAL DIAGNOSIS
Age: In MB cases, relapse is more common in the older
Differences between ENLs and Relapsed Fresh
age groups. PB leprosy with single skin lesions is more
common in younger age groups, and relapse is less
Papules and Nodules14
common in this group. Papules and nodules that occur as part of relapse in the
Sex: Relapses are more common in males, possibly MB spectrum should be differentiated from erythema
because of the higher prevalence of leprosy in males. nodosum leprosum (ENL) nodules. The most important
Relapses are seen in females in the setting of pregnancy point of difference is that ENL nodules are tender and
and lactation. These aspects are discussed in details in evanescent, unlike lepromatous nodules. Additional
the chapter on “Leprosy and pregnancy”. differences are listed in Table 37.1.
CHAPTER
37
Table 37.1: Differences between ENLs and relapsed fresh papules and nodules14
Feature ENL Relapsed papules and nodules
History of therapy Episodes during therapy in LL, LLs, After completion of therapy, during
and rarely BL surveillance in BB, BL, LLs, LL, and
rarely BT
Onset Sudden Insidious
Constitutional symptoms Present Absent
Physical signs Nodules are evanescent tender, warm, Non-tender, not warm, pink, do not
erythematous, blanchable on pressure, blanch, involve full thickness of skin
superficially located
Skin smears Fragmented AFB, polymorphs BI > 2+, long solid staining AFB, globi +
Course Change from red to bluish and dusky, Pink changes to skin coloured,
evanescent – subside within 48-72 hours consistency changes from soft to firm,
in months
Table 37.2: Difference between reversal reaction and relapse 14,15

Feature Reversal reaction Relapse
Time course Usually within 6 months of release from 1 year or more after release from
treatment; in recurrent reactions up to 2 years treatment
Type of disease BT, BB, BL All types
Skin lesions Increased erythema, swelling, tenderness on Increase in extent and number of
pressure, succulent consistency; upward or lesions, no tenderness, rubbery
downward change in the spectrum may occur; consistency; edema of hands and
edema of hands/ feet feet rare
Ulceration Seen in severe reactions Not seen
New lesions Few, same morphology Many
Nerves Acute painful neuritis; nerves exquisitely tender; New nerves involved; no
nerve abscess; sudden paralysis of muscles spontaneous pain; tenderness on
and increase in extent of sensory loss pressure; sensory and motor
deficits slow and creeping
Skin smears Continued decrease in BI. Granularity of bacilli AFB positivity may occur in skin
increases in reactions. smear negative patients.
Lepromin test Progressively positive Fernandez reaction in Corresponds to the type of
BL and BB upgrading to BB and BT respectively relapsed leprosy
Response to systemic steroid Complete subsidence of lesions in 2-4 weeks; No response or partial response
remain subsided with 2 months therapy
DIFFERENCES BETWEEN REVERSAL resistance may be primary, wherein lepra bacilli are
REACTION AND RELAPSE14,15 resistant to the concerned drug from the onset itself, or
It is often a diagnostic dilemma to differentiate true relapse secondary, wherein resistance develops as a result of
from a late reversal reaction in a PB case. Many studies mutant bacilli surviving in the setting of irregular therapy
on PB leprosy show falsely high relapse rates, possibly or monotherapy. Dapsone resistance is the most
because of the inclusion of cases which are probably common, owing to the earlier concept of dapsone
reactions and not really relapses. Some of the features monotherapy. Rifampicin resistance occurs in the setting
that will help in differentiating these two conditions are of irregular therapy. Clofazimine resistance is very
given in the Table 37.2. uncommon. Although mouse foot pad studies are
recommended for confirmation of drug resistance in
Relapse vs Resistance leprosy, these facilities are not available freely, forcing
Drug resistance is an emerging problem in leprosy clinicians to rely on clinical features alone. Drug resistance
worldwide, owing primarily to the chronicity of the disease may itself be a reason for relapse, and it is important to
and the long duration of treatment required. Drug differentiate the two, as outlined in Table 37.3.
CHAPTER
37
Table 37.3: Difference between drug is not high, there is a definite risk. When reinfection does
resistance leprosy and relapse occur, the incubation period is bizarre, and fresh skin and
Drug resistant leprosy Relapse nerve lesions do not correspond to the original lesions.
1. Due to primary or secondary Mainly due to persisters
drug resistance Diagnosis
2. Initial amelioration followed by halt Recurrence after release
The diagnostic criteria for relapse are:10, 14
or worsening from MDT
3. Appearance of new lesions Reappearance of lesions
over old lesions
Clinical Criteria
4. Patient downgrades Patient rarely downgrades 1. Increase in size and extent of existing lesion(s)
2. Appearance of new lesion(s)
Relapse vs Reactivation14, 16 3. Infiltration and erythema in lesions that had completely
Reactivation of lesions occurs due to treatment failure, subsided
i.e. premature termination of treatment or gross irregularity 4. Nerve involvement (thickening or tenderness)
in treatment either due to non-compliance or irregular supply
Bacteriological Criteria
of drugs. Reactivation occurs soon after subsidence of
the disease while relapses occur after complete and Positivity (in a smear negative patient) at any site in skin
sustained subsidence of the disease. smears for acid-fast bacilli at two examinations during the
period of surveillance is diagnostic of relapse. In patients
Relapse vs Reinfection14, 16 with a positive BI, if BI increases by 2+ over previous
smears at any two sites and continues to be so at two
Recurrence of disease in a cured case may be due to
examinations, it is diagnosed as relapse, provided the
reinfection. Reinfection is an extremely difficult condition
patient has ingested 75% of the drugs.
to prove, especially in an endemic area. It is a possibility
when the time interval after RFT and new lesions is beyond Therapeutic Criteria
sufficient period, of duration concordant with the incubation
This is useful when reversal reaction is suspected. The
period of the disease, on relapse. When cured leprosy
patient may be treated with prednisolone (reaction dose
patients continue to live in and around leprosy sanatoria
being around 1 mg/kg/day), after which a reversal reaction
or in hyper-endemic areas, they may develop the disease
should subside completely in 2 months. If symptoms do
again due to exogenous infection. Also, patients get cured
not only by the killing of germs by bactericidal drugs but
also by the added immunity the patients develop subse-
quent to the treatment. This is supported by the fact that
even an LL patient is able to actively dispose of the dead
bacilli. Hence, a treated lepromatous case is not truly
immuno-incompetent, and although the risk of reinfection
Fig. 37.2 Hypopigmented macular lesions in a patient of Borderline

leprosy who had completed her 1 year course of MB-MDT. After 4
Fig. 37.1: New lesions in a patient of LL leprosy 15 years after RFT. months of RFT she developed these lesions, for which she was put
This patient first seen in 1992 (initial BI 4.0), received 30 pulses of on oral steroids. After 3 months of steroid course the lesions did not
MB-MDT and released from treatment in July 1994, after attaining show any sign of resolution and persisted like before. Later on the
smear negativity. In April 2009 he reported with this type lesions, and patient was put on MBMDT. Such type cases pose a difficulty in
enlargement of multiple nerves. This time his BI was 3+, currently he is differentiation of late reversal reaction from relapse (Photo courtesy:
on MDT (Photo courtesy: Dr HK Kar) Dr HK Kar)
CHAPTER
37
not subside or only partially subside or lesions persist or Previous Therapy

increase under the cover of steroid, then relapse should 1. Patient previously treated with dapsone monotherapy
be suspected. – standard WHO MDT is sufficient
2. Patient previously treated with clofazimine monotherapy
Histopathological Criteria
– standard WHO MDT is sufficient (clofazimine
This includes the reappearance of granuloma in PB cases; resistance is extremely rare)
and increased macrophage infiltration with solid staining
bacilli and increasing BI in MB cases. (already discussed Drug-resistance
in section on histopathological aspects, earlier). Patients with known or suspected drug-resistance pose a
treatment problem only in the case of rifampicin-resistance,
Serological Criteria
which is rare (Table 37.4). MB patients who have received
In LL cases, the measurement of PGL-1 IgM antibodies is rifampicin as part of MDT, are not at any significant risk of
a good indicator of relapse (as discussed earlier). rifampicin resistance, unless they were infected with fully
The first 3 criteria are sufficient to make a diagnosis of dapsone-resistant bacilli and either did not take their
relapse; criteria 4 and 5 are additional, and may be used clofazimine or were not given another effective drug.
wherever facilities are available. Dapsone-resistance occurs in the setting of prior dapsone
monotherapy, and such cases respond well to standard
Treatment17
WHO MDT. Clofazimine-resistance is extremely rare, if at
Relapsed cases of leprosy should be identified and put all it occurs, and these cases also respond to the other
back on chemotherapy as soon as possible to prevent two drugs in the standard WHO MDT.
further disability and transmission of infection. Factors that Although drug-resistance ideally is determined using
should be considered in choosing an appropriate regimen the mouse foot-pad or other techniques, relatively few
are: leprosy centres have such a facility available. Thus, the
1. Type of leprosy (PB or MB) decision on drug-resistance most often is based on clinical
2. Previous treatment history information alone.
3. Drug-resistance
Type of Leprosy FAILURE TO RESPOND TO THERAPY

PB cases usually relapse as PB and MB cases as MB. This group includes patients who do not respond as
However, PB cases occasionally relapse as MB, and such expected, in terms of clearance of skin lesions and bacilli,
cases should receive MB-MDT. after the therapy is discontinued or patients who actually
Table 37.4: Recommended treatment regimens

Resistance Scenario Treatment
1. Relapse with M. leprae sensitive to all Relapse after a course of MB-MDT Re-treatment with WHO MDT
standard drugs depending on the type of disease
(PB or MB-MDT)
2. Relapse with dapsone-resistant M. leprae Relapse after previous “cure” with Standard WHO MDT
dapsone monotherapy
3. Relapse with rifampicin-resistant or Primary or secondary dapsone-resistant Clofazimine 50 mg daily for 24 months
rifampicin- and dapsone-resistant M. leprae MB cases who received standard WHO plus 2 of the following drugs
MB-MDT but did not take their clofazimine for 6 months:ofloxacin 400 mg
(situation equivalent to rifampicin daily/ minocycline 100 mg daily/
monotherapy) clarithromycin 500 mg daily,
followed by: ofloxacin 400 mg daily
or minocycline 100 mg daily for the
remaining 18 months.
CHAPTER
37
2. Becx-Bleumink M. Relapses among leprosy patients treated with
Table 37.5: MDT regimens in the United States of America18
multidrug therapy: Experience in the leprosy control programme
Type of leprosy Dosage of drugs Dapsone 100 mg of the All Africa Leprosy and Rehabilitation and Training Centre
CLF may be daily after MDT for (ALERT) in Ethiopia; Practical difficulties with diagnosing relapses,
added operational procedures and criteria for diagnosing relapses. Int J
Paucibacillary (Dapsone 100 mg 3 yr (I, TT) 5 yr (BT) Lepr 1992; 60: 421-35.
(I, TT, BT) daily + Rifampin 3. Boerrigter G, Ponnighaus JM, Fine PEM et al. Four-year follow-
600 mg daily) for up results of a WHO-recommended multiple-drug regimen in
6 months paucibacillary leprosy patients in Malawi. Int J Lepr 1991; 59:
Multibacillary (Dapsone 100 mg 10 yr (BB) 255-61.
(BB, BL, LL) daily + rifampin 600 Lifelong (BL, LL) 4. Pandian TD, Sithambaram M, Bharathi R et al. A study of relapse
mg daily) for 3 years in nonlepromatous and intermediate groups of leprosy. Indian J
Lepr 1985; 57: 149-58.
5. Ali MK, Thorat DM, Subramanian M, et al. A study on trend of
relapse in leprosy and factors influencing relapse. Indian J Lepr
show disease progression during therapy. The former group 2005; 77: 105-15.
contains potential relapse cases, but great care must be 6. Shen J, Liu M, Zhang J, Su W, Ding G. Relapse in MB leprosy
taken to rule out reaction and/or slow clearance of lesions patients treated with 24 months of MDT in south-west China: A
and bacilli as a cause of poor response. short report. Lepr Rev 2006; 77: 219-24.
7. Gebre S, Saunderson P, Byass P. Relapses after fixed duration
The WHO defines a “satisfactory result from MDT” in multiple-drug therapy: The AMFES cohort. Lepr Rev 2000; 71:
a patient who complies with treatment as - one in which, 325-31.
after the start of therapy, bacilli begin to clear in MB cases 8. Katoch VM. Microbiological aspects of relapse in leprosy. Indian J
and lesions generally (though not necessarily) rapidly Lepr 1995; 67: 85-98.
9. Ebenezer GJ, Daniel S, Norman G et al. Are viable Mycobacterium
improve in both PB and MB cases. Clearance of lesions
leprae present in lepromatous patients after completion of 12
is related more to the patient’s immune response than to months’ and 24 months’ multi-drug therapy? Indian J Lepr 2004;
anti-leprosy treatment; all lesions and bacilli should 76: 199-206.
eventually clear even though clearance may be incomplete 10. Sengupta U. Immunological aspects of relapse in leprosy. Indian
at the time treatment is discontinued.17 J Lepr 1995; 67: 81-83.
11. Bührer-Sékula S, Cunha MG, Foss NT et al. Dipstick assay to
MDT regimens being used in the US are more robust
identify leprosy patients who have an increased risk of relapse.
than the ones being recommended in developing countries Trop Med Int Health 2001; 6: 317-23.
by the WHO (Table 37.5). Although studies show that 12. Wu Q, Yin Y, Zhang L, Chen X, Yu Y, Li Z, et al. A study on a
relapse rates are very low after WHO MDT, the fact possibility of predicting early relapse in leprosy using an ND-
remains that relapses do occur. There is a possibility that O-BSA based ELISA. Int J Lepr Other Mycobact Dis 2002;
70: 1-8.
more relapses in leprosy may occur if the WHO accepts 13. Job CK. Histopathological features of relapsed leprosy. Indian J
uniform MDT (U-MDT). Unfortunately, it is not practical to Lepr 1995; 67: 69-80.
introduce regimens like those in the U.S. on a large scale 14. Ramu G. Clinical features and diagnosis of relapses in leprosy.
in a resource poor setting like India. However, clinicians Indian J Lepr 1995; 67: 45-59.
15. Pfaltzgraff RE, Ramu G. Clinical leprosy. In: Hastings RC,
may use their judgment and tailor treatment regimens for
Opromolla DVA, editors. Leprosy. 2nd edn. Edinburgh: Churchill
individual patients wherever practicable. In selected cases, Livingstone; 1994. 237-87.
longer regimens similar to those used in the US may be 16. Desikan KV. Relapse, reactivation or reinfection. Indian J Lepr
useful. 1995; 67: 3-11.
17. Jacobson RR. Treatment of relapsed leprosy. Indian J Lepr 1995;
REFERENCES 67: 99-102.
18. Jacobson RR. Treatment of leprosy. In: Hastings RC, Opromolla
1. The Leprosy Unit, WHO. Risk of relapse in leprosy. Indian J DVA, editors. Leprosy. 2nd ed. Edinburgh: Churchill Livingstone;
Lepr 1995; 67:13-26. 1994. 317-49.
CHAPTER
38
38 Drug Resistance Studies, Viability

and Bacterial Persisters and Animal
Models in Leprosy
Umesh D Gupta, Vanaja P Shetty
In leprosy, the experimental models play a critical role MURINE MODELS

because artificial media are not yet available for the
(A) Immuno-competent Mice and Rats
cultivation of Mycobacterium leprae (M. leprae). They fall
under two main categories (1) animal model (in vivo) and Fenner demonstrated the multiplication of M. balnei and
(2) tissue culture model (in vitro). In this chapter, some M. ulcerans in the hind foot pad of mice, for which the
important animal and tissue culture models, their optimal temperature for growth was lower than 37°C.3
applications and contributions towards understanding the Shepard in the year 1960 demonstrated that following
disease are reviewed and discussed. inoculation of <10,000 bacilli/foot pad M. leprae multiply
to a limited extent in the hind foot pads of immunologically
ANIMAL MODELS intact mice (Fig. 38.1).4 There was very little change during
the first 4 to 5 months though later, round cells containing
From the historical point, around the year 1873, rabbits acid-fast bacilli (AFB) appear and gradually increase in
and guinea pigs were inoculated with M. leprae by various number and size at the local site. This significant finding
routes, particularly in the anterior chamber of the eye. The was subsequently reproduced using the same as well
most difficult task that took all attention in the initial stage as different strains of mice and rats with complete
was the successful transfer of leprosy to animals and the success.5-7 Mice are readily available laboratory animals
widely varying definitions of success. While most and are easy to maintain. Inbred lines provide genetically
researchers considered generalized infection to be the uniform individuals in large numbers. Studies have shown
proof of transmission, others opined that the development that, BALB/c, CBA and CFW mouse lines allow higher
of localized lesions was enough evidence.1 plateau levels of M. leprae than A/J and C57BL mouse.8
Over 30 animal species have been tried for the The proportion of bacilli attained per foot pad in rat is about
experimental transfer of leprosy over the years. the same as in mice, so the normal rats are not used as
Reproducible, characteristic, localized infections were much as mice for experimental leprosy.
obtained in rodents of several species.1 It became evident To monitor the course of infection, the method is to
that M. leprae multiply to a limited extent in count the AFB yield in the foot pad at appropriate intervals.
immunologically intact rodents, and to greater degree in For this purpose, the foot pad tissue are cut off, minced
immunologically disabled rodents and in the armadillo. The and homogenized in a known volume. If around 5,000 or
choice of the experimental species to be inoculated 10,000 M. leprae of good viability are used as inoculum, a
depends upon the purpose of the experiment.2 Following detectable number (approximately 5x104) of AFB yield is
are some of the important animal models and their land obtained in about 90-120 days. Logarithmic growth
mark applications in the field of leprosy. (generation time of about 12.5 days) carries the bacterial
CHAPTER
38
Drug Resistance Studies, Viability and Bacterial Persisters and Animal Models in Leprosy 493
mouse, following inoculation of the foot pad, there is a
striking local growth of organisms with invasion of nerves
followed by late widespread dissemination to the liver and
spleen. This model is particularly useful in the evaluation
of drug regimens for the treatment of leprosy as it can
support the growth of large inocula to levels of 1010 per
foot pad. It has been shown as a good model for
chemotherapeutic studies12, mechanisms of reversal
reactions13 and for studying the nasal transmission of the
disease.14
Beige Mice
These mice lack natural killer cells and have been lately
introduced in leprosy studies. They have been found
suitable for chemotherapy studies (discussed later) and
Fig. 38.1: Formation of bleb following subcutaneous inoculation of
0.03 ml M. leprae suspension into the hind foot pad – in normal Swiss
have a potential in the study of the pathogenesis of
White (SW) mice leprosy.15
SCID Mice
population to approximate 106 at about 150-180 days. The Severe combined Immunodeficient (SCID) mice, with an
number of AFB then remains more or less constant for a enzymatic defect that results in a lack of functional T and
year or more, in most mouse lines.4,5 B lymphocytes, are proposed to be a good model for cell
transfer experiments.16 SCID mice can take up to 106 bacilli
(B) Immunosuppressed Mice and Rats in foot pads and the yield is up to 109 by 8 months. These
As mentioned earlier, the growth of M. leprae in normal mice are promising strain for studies of persisters,
mouse and rat footpads ceases at about 106, apparently discussed later.
because of a T cell immune response that M. leprae
Neonatally Thymectomized Lewis Rats (NTLR)
triggers. Several models of T cell deprived mice and rats
have therefore been used. All involve thymus deficiency. NTLR are found to be a useful model for the detection of
Thymectomy is performed on normal adults (4-8 weeks) small numbers of viable bacteria and hence, for the
to prevent future formation of T cells. The mice are then enumeration of persister organisms after MDT.17 Their
irradiated with 900-950 rads of Gamma irradiation (to kill maintenance is easier than that of nude mice.
existing circulating T cells) and transfused with syngeneic Though Shepard’s model4 ranks as a milestone in
bone marrow cells to prevent the otherwise lethal effects leprosy research, the immunocompetent and immuno-
of irradiation on the hematopoietic system. Syngeneic compromised animals; feature only polar tuberculoid
animals must be used for success of the bone marrow
transfusions. In thymectomized – irradiated mice (T/900R
mice) the minimal infectious dose is same as for normal
mice and the growth in logarithmic phase does not appear
to be any faster. Instead when the growth reaches 106; an
attenuated immune response occurs in which the growth,
although slow, continues and reaches 107 and 108 at the
end of the second year.9
Nude Mice
Mice with the nu mutation are hairless and have rudimentary
thymuses (Fig. 38.2). These athymic animals were first
introduced in leprosy research in 1976.10,11 In the nude Fig. 38.2: Hairless athymic nu/nu Nude mice
CHAPTER
38
disease and polar lepromatous leprosy respectively. The inoculated, either into the footpad or intravenously, with
transgenic and knock out (KO) mice have also been large number of M. leprae, and the organisms are permitted
employed to study the role of individual genes in the ability to multiply. After about one year, the animals are sampled,
of the host to mount an effective immune response to the to ensure multiplication to a good level (at least 107 per
pathogens and to develop models for the immunologically footpad). The animals are then divided among control and
unstable borderline areas of the spectrum. To this effect treated groups, drugs are administered for a short; or a
certain knock out mice are exploited to understand the longer period, animals are sacrificed both during and after
CMI of M. leprae and to study the role of microenvironment the period of drug administration; and M. leprae are
of leprosy and granulomas in pathogenesis.18 harvested from the hind footpads. Although chemo-
therapeutic regimens must eventually be tested in patients,
APPLICATIONS OF MURINE MODELS there are many important questions about regimens,
questions relating to dosage variables and duration for
Cultivation of M. leprae example, that could be answered much more conveniently
Mouse foot pad (MFP) technique for cultivation of M. leprae and quickly by studies in experimental animals, than by
has assumed a role of primary importance in leprosy clinical trial.2
research activities, since its description by Shepard.4 This
is the only technique by which one can determine directly, Drug Resistance and Susceptibility Studies
whether M. leprae are viable or not. When organisms have Along the same lines, drug susceptibility testing is done
multiplied in mice, the inoculum must have contained viable using immunologically intact mice. They are inoculated
M. leprae, however when organisms have failed to multiply, with 5x103 or 104 M. leprae into one or both hind foot pads
one may not conclude that there were no viable bacteria in and divided into several groups. One group is kept as
the specimen. untreated control and fed normal diet, the rest are divided
into drug treated groups and fed with diets containing
Testing of Activity of Drug Against M. leprae different concentrations of the drugs to be tested. Usually
The continuous technique is the first technique employed 6-12 months after inoculation mice are sacrificed and the
for demonstrating the activity of a drug against M. leprae AFB are harvested from footpad tissue. If no multiplication
in mice which involves continuous administration of a drug of M. leprae is observed in the control group, the test is
beginning from the day of inoculation.2,19 Multiplication of considered to have failed, possibly because the proportion
M. leprae in untreated control mice is followed by interval of viable bacilli in the inoculum was too low. If multiplication
harvests. When the evidence of multiplication is of M. leprae is observed only in the controls and not in any
unequivocal – i.e. the organisms have multiplied in the of the drug treated mice, the strain is considered
footpads of control mice from an inoculum of 10 3.7 susceptible to the drug tested. If multiplication of M. leprae
organisms to a level of at least 105.7 (500000) organisms/ is observed in some or all drug treated mice, the strain is
footpad, harvests of M. leprae are performed from the resistant, and the degree of resistance is reflected by the
footpads of both control and drug treated mice. An active highest concentration of drug in the diet that permits
drug is one that inhibits multiplication of the M. leprae. If multiplication of M. leprae. Drug susceptibility testing by
on two successive occasions, approximately one month the mouse footpad technique has been found to be quite
apart, the number of M. leprae harvested from treated mice reliable.23 However, the technique is very time consuming
does not fall within the range of the results of four and tedious. Currently the molecular biological methods
simultaneous harvests from control mice, the drug can be are being developed and preferred for the examination of
stated to have been active with a probability of 0.04 (p = drug resistance.24
0.04).20
Detection of ‘Persister’ M. Leprae
Experimental Chemotherapy Study
Bacterial persistence is a phenomenon defined as the
Studies of experimental chemotherapy have also been capability of microorganisms to survive in the host despite
carried out on M. leprae infected, neonatally thyme- adequate antimicrobial treatment. They are regarded as
ctomized rats.21,22 Animals at the age of weaning are physiologically dormant but drug sensitive forms.25
CHAPTER
38
Persisting M. leprae are detected using immune- were introduced into the nose, mouth, lungs, stomach and
deficient rodents. Studies have shown that immunologically abraded skin over flanks. Some animals were injected with
intact mice, inoculated in the hind foot pad with 5000-10000 M. leprae in their foot pads and some were caged with
M. leprae, are not useful for the detection of persisting nude mice with large ulcerating lepromatous nodules in
M. leprae, at least early in the therapy of the lepromatous their feet. It was found that only mice receiving intranasal
patient. The proportion of viable organisms (defined as instillation and subcutaneous inoculation of the foot pads
persisters) is so small that a large inoculum (≥ 105) would developed the disease.27 In another experiment, exposure
be required to detect them. So large an inoculum, might of abraded skin of the dorsum of the foot to M. leprae and
serve in itself as a vaccine, thereby immunizing the infected thorn pricks over dorsum of the foot resulted in
immunologically intact animal so that viable M. leprae localized lepromatous granuloma followed by generalized
contained in the inoculum are unable to multiply. On the disease.28
other hand, animals that are sufficiently immune-deficient
are not immunized by the large inocula required for the Testing of Immunoprophylactic Agents
demonstration of persisters, and permit multiplication of Due to limited multiplication in mouse, this is not a suitable
viable M. leprae, even when these represent only a minute model for studying the protection mechanism of human
proportion of the inoculum. Later in therapy, when the disease.29 This model has been used for identifying
overburden of dead M. leprae has decreased, and the mycobacteria viz. Bacillus Calmette-Guerin [BCG],30 heat
proportion of viable organisms is larger, it may certainly killed M. leprae,31 Indian Cancer Research Centre [ICRC]32
be possible to readily detect persisting M. leprae by and M. habana33 for their ability to inhibit growth of M. leprae
inoculation of intact mice. Even in this situation, however, in mouse foot pad. Though discordant observations about
the use of immune-deficient mice appears preferable. ICRC and M. habana34 have been reported, results provide
Briefly, at least 105 M. leprae, or as many as possible, background information for use of these agents as
are injected into each hind footpad of a group of immune- immunotherapeutic and immunoprophylatic agents against
deficient rodents, taking advantage of the fact that these leprosy.
animals are not so readily immunized by large inocula. Much of the vaccine development in leprosy is based
Organisms are harvested approximately one year later, on the response to skin tests with soluble and integral
by which time the multiplication should be evident, even if (Mitsuda) antigens of M. leprae derived from armadillos.2
the large number of organisms inoculated had only a very Though the relationship between skin response and
few viable M. leprae. Because the demonstration of protective immunity is yet to be established, the Mitsuda
persisting organisms is commonly attempted after some test correlates best with capacity of the host to handle
duration (at least one year) of treatment, by which time M. leprae. The Mitsuda test is inversely related to the
the BI has decreased, and only small numbers of M. leprae bacillary load. In armadillos it has been shown that there
can be recovered from the biopsy specimen, it may be is a definite correlation between lepromin negativity and
difficult to prepare a concentrated inoculum. To maximize the susceptibility of the animals to develop lepromatous
the number of organisms that can be inoculated, recovery disease.35
of the organisms from the biopsy specimen is carried out
with minimal dilution.2 Study of Leprosy Reactions
Immunomodulation and its effect on pathomechanism/s
Studies Addressing the Route
have been studied in mice by several workers.36-38 One of
of Infection and Transmission
the classical study being, depiction of leprosy reaction by
Studies have shown that temperature at the entry point immune reconstitution in immune-deficient mice infected
could influence the multiplication and further dissemination with M. leprae.36 The study demonstrated abrupt swelling
of M. leprae.26 In thymectomized and irradiated (T-900) of the foot-lesion in thymectomized + irradiated mice, by
mice, M. leprae multiplied and disseminated when injected reconstitution of the mice with syngenic lymphocytes.
into the cooler foot pads while they failed to multiply if Other workers have reported reversal of the pathologic
they were injected into the warmer flanks of the animals. process in M. leprae infected nude mice by immune
In experiments using nude mice, suspensions of M. leprae reconstitution.39-41 However, employing an in vitro assay,
CHAPTER
38
Adams and co-workers were unable to demonstrate the study revealed a clear absence of ‘C’ fiber (un-myelinated
killing of M. leprae in infected and reconstituted nu/nu fiber) potentials at third month and changes in α fiber
mice.42 potentials at sixth post-inoculation month, indicating that
The effect of specific depletion of T-helper cells by the functional changes may precede morphological
cyclosporine A, and total T-cells using anti Thy1.2 was changes.48
compared to the T-200 x 5R model, which depletes both In another experiment, two strains of mice namely
T and B cells leaving the hemopoietic stem cells alone.43 S/W and C57BL/6 were compared for the growth of
Nerve damage was assessed at regular intervals during M. leprae in their foot pads and the concomitant damage
the course of M. leprae growth within the mouse foot pad. to their sciatic nerves. The study findings show that while
Three interesting features highlighted from this study were: M. leprae growth was comparable in these two strains of
a. The significance of non-T-cell-mediated antimyco- mice, there were differences in the progression of nerve
bacterial mechanisms, damage. It was noted that the changes during early nerve
b. The metabolic interactions between M. leprae and its damage (i.e. seen at sixth and eight post-inoculation
host cell in the precipitation and/or initiation of nerve months) were comparable but unlike S/W mice, C57BL/6
damage; and mice failed to show significant progressive demyelinating
pathology. A difference was also seen in their macrophage
c. The dissociation between M. leprae growth in MFP and
functions assessed in vitro. On injections with viable
sciatic nerve damage.43
M. leprae (down-regulation of Fc receptor) while the
Study of Pathomechanisms of Leprosy peritoneal macrophages from S/W mice were affected, like
the lepromatous macrophages; the macrophages from
Another important and extensively studied application of C57BL/ 6 mice were not affected, like those of the normal
mouse model is towards understanding the patho- individuals.49,50
mechanisms of leprosy in general and leprosy neuropathy In another study, the specificity of M. leprae induced
in particular. Initial studies by Rees44; Weddell et al45 and nerve damage was investigated in the mouse model.51
Boddingius et al46 have shown that several aspects of Among the multitude of pathogenic and non pathogenic
leprosy could be depicted in the mouse model. mycobacteria tested, M. leprae alone produced the typical
Sequential morphological and electrophysiological changes in the sciatic nerves of mice.
changes were recorded in the sciatic nerves of Swiss white Using protein tracer horse raddish peroxidase and
(S/W) mice, injected in the foot pad with freshly harvested electron immunocytochemical technique, the association
human-derived M. leprae. With the advent of electron between nerve damage and the disturbances, if any, in
microscopy, ultra-structural changes were documented in the blood-nerve and perineurial barriers, was also
the sciatic nerves as early as four months following foot investigated in mice. Interestingly, in mice the blood-nerve
pad inoculation. A slow, progressive nerve damage, that and perineurial barriers were found intact despite advanced
was followed for up to two years; has documented structural changes in the neural compartment.46
involvement of > 50-60% of nerve fibers in the M. leprae In yet another study, nerve damage resembling that
infected mice; as against 10-12% seen in age-matched caused by M. leprae in man was depicted by the injection
uninfected mice. However, there was conspicuous absence of cobalt irradiated M. leprae directly into the tibial nerve
of integral bacilli and granulomatous reaction in the involved of guinea pigs. Significant nerve damage occurred at ~3
nerves in the infected mice. A gradual reduction in the weeks after the injection of M. leprae. Motor and sensory
average conduction velocity in the sciatic nerves of these functional loss peaked at 5 weeks after injection and there
mice corroborated well with the morphological changes.47 was a significant decrease of peptide immuno-reactive
In another study, S/W mice similarly inoculated with nerves in all skin compartments. The nerve damage in
M. leprae in the hind foot pad, both sciatic nerves were this model was self limiting; and the functional recovery
excised at intervals of two weeks from the first month had occurred by 13 weeks.52
onwards up to the eighth month and in vitro conduction In another study, freshly harvested viable M. leprae
velocity of the excised nerves was carried out in a specially were microinjected into the sciatic nerves of both non-
designed chamber. A portion of the nerve was also taken immuno-suppressed (non-TR) and immuno-suppressed
for electron microscopy for morphological correlation. This (TR) mice and were studied at different time points to
CHAPTER
38
assess the fate of M. leprae and the resultant nerve Rhesus Monkeys
damage.53
Wolf et al have shown disseminated multibacillary diseases
The same group also tried systemic immobilization of
in 27% of Rhesus monkeys inoculated with M. leprae.66
macrophages using silica before the microinjection of bacilli
There was a good correlation between the lepromin
into the nerve.54 Macrophage granuloma similar to the one
negativity and susceptibility to leprosy in these animals.67,68
seen in human BL lesions was obtained in the nerves.
Delayed but severe and long-lasting lesions were obtained Cynomolgus Monkeys
in normal mice using a higher dose i.e. 30 x 106 M. leprae
indicating that the cellular dynamics and the intensity of Walsh et al have shown susceptibility of this species to
reaction could be altered by varying M. leprae dose. In disseminated leprosy.69
these studies, despite the large number of M. leprae that
Armadillo
were present in the macrophages like cells in the
endoneurial compartment, no bacilli could be traced to the Armadillos are the second most extensively studied animal
Schwann cells and the lesions remained highly localized.55 model in leprosy. They belong to the family Edentata and
Along the same line, a piece of freshly obtained nerve Dasypus novemcinctus is the species used most
from a lepromatous patient was xenografted on the sciatic commonly. Nine-banded armadillos (Fig. 38.3) were found
nerve of an immuno-suppressed (using anti Thy 1.2) to be naturally highly susceptible to M. leprae infection.70
mouse. Despite a good axon innervation into the grafted The progressive, lepromatous-leprosy like infection in
human nerve, no bacilli were seen in the host Schwann the nine-banded armadillo, which evolved in a proportion
cells even six months after grafting, again indicating a of animals inoculated with M. leprae has provided for the
high degree of resistance by mouse Schwann cells towards first time a substantial laboratory source of M. leprae. This
M. leprae infection in situ.56 This was unlike the in vitro encouraged the Immunology of Leprosy (IMMLEP)
findings where M. leprae readily entered both mouse and Scientific Working Group of the UNDP/ World Bank/ WHO
human derived Schwann cells.57,58 Special programme for research and training in tropical
A recent study in mice showed alterations in the diseases to undertake development of a specific vaccine
neurofilament cytoskeleton (NF) in the sciatic nerve for leprosy. Substantial progress has been made in
compartment, following inoculation in the hind footpad with standardizing the procedure for obtaining maximal infection
both live and heat inactivated M. leprae. 59 The in the armadillo and maximal yield of purified organisms,
hypophosporylation of NF observed in this study free from armadillo tissue by methods least likely to damage
corroborates with the earlier observation in human leprous M. leprae.2
nerves.60 M. leprae are extracted from the liver, spleen, lymph
nodes and non-ulcerated skin nodules of heavily infected
NON-HUMAN PRIMATE MODELS OF armadillos, yielding a total per animal of 250-300 grams of
LEPROSY infected tissue containing 109-1010 AFB per g tissue.
Chimpanzee
The first successful experimental infection of a non-human
primate with M. leprae was by Gunders in 1958.61 Leininger
et al in 1980 reported naturally acquired leprosy in a
chimpanzee. The histopathologic changes in this animal
were typical of borderline lepromatous disease with
bacterial invasion and destruction of nerves.62
Mangabey Monkeys
Naturally acquired leprosy was described in a sooty
Mangabey monkey.63,64 Extensive immunological studies
on the Mangabey monkey have shown similar changes to
those seen in human lepromatous leprosy.65 Fig. 38.3: Nine-banded Armadillo (Dasypus novemcinctus)
CHAPTER
38
In one of the studies in armadillos, full length dissection Further, several steps in the catabolic pathways and
was done of the major peripheral nerves in the extremities oxidation of carbon through TCA cycle have been
of six M. leprae inoculated animals, three of which had suggested as targets for developing viability methods.
developed characteristic disseminated infection.71 All of Based on other biochemical pathways (viz. uptake of DOPA,
the animals with disseminated infection had extensive acetate, palmitic acid, oxidation of palmitic acid as measured
involvement of the peripheral nerves, increasing in intensity, by Buddy / BACTEC, etc.) a number of viability assays for
as the nerve was followed distally. No M. leprae were found drug screening have also been developed.76 Another
in the nerves of the animals without disseminated infection. important development was the measurement of biomass
The degree of infection was greater in epineural tissue of M. leprae using ATP bioluminescence.77
than in the intraneural compartment (i.e. Schwann cells) Most of the morphological features of leprosy are
at all levels. The infection of nerves by M. leprae was attributed to the high lipid content of its cell wall. These
associated with focal interstitial, mononuclear cell include phenolic glycolipid (PGL-1), phthiocerol
infiltration of involved nerves. dimycocerosate (PDIM) and mycolic acids. These lipids
It has been envisaged that (1) armadillos offer a model can be demonstrated by TLC, HPLC and GLC – mass
for the study of neural involvement in leprosy, since the spectrometry and can be quiet sensitive to detect M. leprae
pattern of neural distribution in susceptible armadillos is specific lipids from clinical specimens.78 Antigens of
comparable to the pattern of nerve involvement in man, M. leprae have been extensively analyzed by a variety of
(2) early localization of M. leprae may be to the epineural methods. Many such specific and quasi specific (35 kD)
tissues, including lymphatic and vascular structures and antigens have been used for developing sero assays for
extra-cellular matrix, (3) Schwann cell involvement may the detection of M. leprae infection.77,79
be a late event, and (4) mechanisms involving the
endothelium of epineural and perineural tissues may be NERVE TISSUE CULTURE MODEL
important in the selective localization of M. leprae to
peripheral nerves. The armadillo genome has been Of the various types of nervous tissue preparations
sequenced recently and this is likely to further revolutionize available, sensory ganglion provides the most useful
the study of leprosy neuritis in this model.72 cytological model. Observations of transport within axons
Signs of naturally occurring leprosy in armadillos and neurons, the process of myelinogenesis and patterns
captured in Louisiana have shown that 5-10% of armadillos of myelin, glia or neuronal response to various stimuli have
had naturally acquired leprosy.73 A major limitation of this been recorded. More recently, immunohistochemical
model is the lack of breeding by armadillos in captivity. studies have transformed our view of the complexity of
both CNS and PNS. The specificity of antibodies combined
OTHER ANIMALS with the visual resolution obtained by microscopic
examination of neural cell cultures has allowed an analysis
Slender Loris, hedge hogs and hibernating ground squirrels of the component parts of the nervous system at a cellular
are some of the other animals where attempts to transmit level. It has also provided a means of detecting molecular
leprosy were made.1 heterogeneity in both morphologically similar and different
types of cells.80
DETERMINATION OF VIABILITY OF
Organotypic cultures of dorsal root ganglia and
M. leprae (IN VITRO METHODS)
dissociated Schwann cell cultures have been used in
In vitro techniques to determine the viability of M. leprae addressing some of the basic questions related to leprosy
based on metabolism, biochemical processes and neuropathy. It has been shown that M. leprae readily
morphological factors have been developed.74 It was entered the dissociated Schwann cells.57,58 This is in
observed that infection of the macrophages with live contrast to in vivo findings where mouse Schwann cells
M. leprae produced alterations on the surface as well as were found be resistant to M. leprae infection.55
metabolism of macrophages, which in turn has been used In studies using primary rat Schwann cell cultures and
for developing various viability assays.74 Nucleic acid Schwann cell/ neuron co-cultures, it has been demonstrated
synthesis was used as an indicator of viability of M. leprae that M. leprae adhere to the Schwann cell surface and
within different macrophages.75 they are slowly ingested. Mechanism/s of binding of
CHAPTER
38
M. leprae to the Schwann cell as the primary event, has inferred that this opposing effect of infection on NGF
been elucidated in several studies.81-83 Antibodies directed production and p75 expression by Schwann cells and
against polysaccharide and lipid components of M. leprae neurofibroblasts may result in suboptimal amounts of NGF
inhibited adhesion to Schwann cells, while those directed reaching neurons of the affected leprous nerves and result
against both surface and cytoplasmic protein epitopes did in alterations in different mechanisms of nerve repair in
not show any such effect, indicating that the adherence of SW and C57BL/6 mice.
M. leprae to Schwann cells is mediated by more than one
of its cell surface molecules.81 CONCLUSION
Studies have demonstrated that M. leprae specifically Experimental models have contributed immensely to our
bind to alpha-dystroglycan in the presence of the G-domain understanding of the disease- leprosy. However, it should
of the alpha-2 chain of laminin-2. Using alpha-2 laminins be noted that, though there are similarities that allow
as a probe, a major protein in the M. leprae cell wall fraction extrapolations, the spectral manifestations and the invasion
viz. ML-LBP21 has been identified that binds to alpha-2 of Schwann cells by M. leprae, the two most important
laminins on the surface of Schwann cells.84,85 Phenolic characteristic features of human leprosy are not depicted
glycolipid-1 (PGL-1) of M. leprae has also been in rodents. Armadillo and primate models have shown the
demonstrated to bind specifically to laminin-2 in the basal potential but more work is needed to see, whether they
lamina of Schwann cell axon units.86 However, recent fulfil these requirements besides availability and husbandry
additional information clearly suggests that this mechanism issues.
of binding is not unique to M. leprae. Other mycobacterial
species, including M. tuberculosis, M. cheilonae, and ACKNOWLEDGMENT
M. smegmatis have also been shown to express an alpha-
We gratefully acknowledge the help of Ms Anju Wakade
2-laminin binding capacity and these species readily
(FMR) and Fatema Khambati (FMR) in organizing the
interacted with human Schwannoma cell line ( ST88-14) in
references for this manuscript.
vitro.87
Using ST88-14 cell line, it was demonstrated that REFERENCES
several protein kinases were essential for ingestion, but
1. Johnstone PA. The search for animal models of leprosy. Int J
that, c-AMP–dependent kinases were not involved. Further,
Lepr 1987;55:535-47.
viable M. leprae interfere with the normal endocytic 2. World Health Organization. Laboratory techniques for leprosy.
maturation in Schwann cell is also indicated.88-90 WHO/CDS/LEP/86.4, 1987.
Using rat Schwann cell axon co-culture system, 3. Fenner F. The pathogenic behaviour of Mycobacterium ulcerans
and Mycobacterium balnei in the mouse and developing chick
Rambukkana and co-workers have reported rapid embryo. Am Rev Tuberc 1956;73:650-73.
demyelination following adherence of M. leprae to Schwann 4. Shepard CC. The experimental disease that follows the infections
cells in the absence of immune cells.91 Studies have also of human leprosy bacilli into the foot pads of mice. J Exp Med
shown that survival of M. leprae is greater at 33°C than at 1960;112:445-54.
5. Welch TM, Gelber RH, Murray LP et al. Viability of Mycobacterium
37°C.92 leprae after multiplication in mice. Infect Immun 1980;30:325-28.
Using the culture system, nerve growth factor (NGF) 6. Pattyn SR. Comparative behaviour of a strain of M. leprae in 5
production and expression of p75 by Schwann cells and different mouse strains and in thymectomized mice. Zentralbl
Bakteriol 1965;197:256-8.
neurofibroblasts; in response to M. leprae infection and
7. Levy L. Studies of the mouse foot pad technique for cultivation
macrophage secretory products, was compared in two of Mycobacterium leprae. Doubling time during logarithmic
strains of mice namely Swiss white and C57BL/6, as they multiplication. Lepr Rev 1976;47:103-6.
have been shown to differ in their response to M. leprae 8. Shepard CC, Habas JA. Relation of infection to tissue temperature
in mice infected with Mycobacterium marinum and
infection.93 On infection with M. leprae NGF levels Mycobacterium leprae. J Bacteriol 1967;93:790-6.
measured using semi quantitative ELISA, remained 9. Rees RJ. Enhanced susceptibility of thymectomized and
unaltered in Schwann cells from both the strains, while irradiated mice to infection with Mycobacterium leprae. Nature
fibroblasts from C57BL/6 strain showed an increase in NGF 1966;211:657-88.
10. Colston MJ, Hilson GRF. Growth of Mycobacterium leprae and
production. Expression of p75 by Schwann cells was M. marinum in congenitally athymic (nude) mice. Nature 1976;262:
decreased after infection in both strains of mice. It was 399-401.
CHAPTER
38
11. Kohsaka K, Mori T, Ito T. Lepromatoid lesion developed in nude 31. Shepard CC, Walker LL, van Landingham R. Heat stability of
mouse inoculated with Mycobacterium leprae—animal Mycobacterium leprae immunogenicity. Infect Immun 1978;
transmission of leprosy. Lepr Rev 1976;45:177-87. 22:87-93.
12. McDermott-Lancaster RD, Ito T, Kohsaka K, et al. Multiplication 32. Bhide MB, Pradhan KS, Bapat CV. A vaccine from ICRC bacilli
of Mycobacterium leprae in the nude mouse, and some against M. leprae infection in mouse foot-pad. Lepr Rev 1978;
applications of nude mice to experimental leprosy. Int J Lepr 50(3):334-44.
1987;55:889-95. 33. Sreevatsa, Desikan KV. Evaluation of the efficacy of candidate
13. Banerjee DK, McDermott-Lancaster RD. Effect of simultaneous vaccines against M. leprae infection in mice. Indian J Lepr 1988;
administration of interferon-gamma and chemotherapy against 60(2):252-59.
Mycobacterium leprae in experimental infection in nude mice.
34. Singh NB, Srivastava, Gupta HP, et al. Immunological potential
Int J Lepr 1990;58:690-6.
of a cultivable mycobacterial strain M. habana against leprosy
14. McDermott-Lancaster RD, McDougall AC. Mode of transmission bacillus in mouse foot pad. Indian J Lepr 1985;57(2):278-81.
and histology of M. leprae infection in nude mice. Int J Exp
35. Job CK, Sanchez RM, Hunt R, Hastings RC. Prevalence and
Pathol 1990;71:689-700.
significance of positive Mitsuda reaction in the nine-banded
15. Gangadharam PR, Dhople AM. Utility of beige mouse in leprosy
armadillo (Dasypus novemcinctus). Int J Lepr 1987;55:685-98.
research. Indian J Lepr 1992;64:475-81.
36. Rees RJW, Weddell AGM. Experimental models for studying
16. Azouaou N, Gelber RH, Abel K, et al. Reconstitution of
leprosy. Ann N Y Acad Sci 1968;154:214-36.
Mycobacterium leprae immunity in severe combined
immunodeficient mice using a T-cell line. Int J Lepr 1993; 61:398- 37. Gaugas JM. Enhancing effect of antilymphocytic globulin on
405. human leprosy infection in thymectomized mice. Nature 1968;
17. Gelber RH. The neonatally thymectomized Lewis rats as a tool 220:1246-8.
for chemotherapy research. Int J Lepr 1993;61:388-95. 38. Fieldsteel AH, McIntosh AH. Effect of neonatal thymectomy and
18. Krahenbuhl J, Adams LB. Exploitation of gene knockout mice antithymocytic serum on susceptibility of rats to Mycobacterium
models to study the pathogenesis of leprosy. Lepr Rev 2000; leprae infection. Proc Soc Exp Biol Med 1971;138:408-13.
71:S170-5. 39. Chehl SK, Shannon EJ, Job CK, et al. Reversal reactions in
19. Shepard CC, Chang YT. Effect of several anti-leprosy drugs on Mycobacterium leprae infected nude mice. Int J Lepr 1983;51:
multiplication of human leprosy bacillus in foot pads of mice. 649.
Proc Soc Exp Biol Med 1964;109:636-8. 40. Chehl SK, Shannon EJ, Krahenbuhl JL et al. Adoptive transfer of
20. Shepard CC. Statistical analysis of results obtained by two cell-mediated immunity in M. leprae-infected nude mice with M.
methods for testing drug activity against Mycobacterium leprae. leprae-immunized allogeneic leukocytes depleted of Thy-1.2-
Int J Lepr 1982;50:96-101. bearing cells and Lyt-2.2-bearing cells. Int J Lepr 1985;53:720-
21. Fieldsteel AH, Levy L. Dapsone chemotherapy of Mycobacterium 21.
leprae infection of the neonatally thymectomized Lewis rat. Am 41. Kohsaka K, Miyata Y, Mori T, et al. Reversal reaction by thymus
J Trop Med Hyg 1976;25:854-9. transplantation in experimental leprosy of the nude mouse. Int J
22. Fieldsteel AH, Levy L. Combined rifampin and dapsone Lepr 1984;52:608.
chemotherapy of Mycobacterium leprae infection of the neonatally 42. Adams LB, Gillis TP, Hwang DH, et al. Effects of essential fatty
thymectomized Lewis rat. Int J Lepr 1980;48:267-76. acid deficiency on prostaglandin E2 production and cell-mediated
23. Ji Baohong. Drug resistance in leprosy- a review. Lepr Rev immunity in a mouse model of leprosy. Infect Immun 1997;65:
1985; 56:265-78. 1152-7.
24. Katoch VM. Molecular techniques for leprosy: present
43. Shetty VP, Birdi TJ, Mistry NF, et al. Effect of T-cell depletion on
applications and future perspectives. Indian J Lepr 1999;71:45-
bacterial multiplication and pattern of nerve damage in M. leprae-
59.
infected mice. Indian J Lepr 1995;67:363-74.
25. McDermott W. Microbial persistence. Yale J Biol Med 1957;30:
44. Rees RJW. The impact of experimental human leprosy in the
257-91.
mouse on leprosy research. Int J Lepr 1971; 39:201-15.
26. Ebenezer GJ, Arumugam S, Job CK. Infection by M. leprae is
governed by the temperature at the entry point: a preliminary 45. Weddell AG, Palmer E, Rees RJ. The fate of Mycobacterium
note. Int J Lepr 1999;67:162-4. leprae in CBA mice. J Pathol 1971;104:77-92.
27. Chehl SK, Job CK, Hastings RC. Transmission of leprosy in 46. Boddingius J, Rees RJW, Weddell AGM. Defects in the blood
nude mice. Am J Trop Med Hyg 1985;34:1161-6. nerve barrier in mice with leprosy neuropathy. Nature 1972;
28. Job CK, Chehl SK, Hastings RC. Transmission of leprosy in 237:190-1.
nude mice through thorn pricks. Int J Lepr 1994;62:395-8. 47. Shetty VP, Vidyasagar PB, Antia NH. Study of evolution of nerve
29. Sengupta U. The utility of animal models for selection of a damage in leprosy. Part III—Sciatic nerve lesions in mice
candidate vaccine for leprosy. Indian J Lepr 1991;63:153-8. inoculated with M. leprae with nerve conduction velocity
30. Shepard CC, van Landingham R, Walker LL. Immunity to correlates. Lepr Rev 1980;52:26-47.
Mycobacterium leprae infections in mice stimulated by M. leprae, 48. Vidyasagar PB, Damle PS, Antia NH. A study of the sciatic
BCG and graft-versus-host reactions. Infect Immun 1976; nerve compound action potential in vitro in normal and M. leprae
14:919-28. infected mice. Lepr Rev 1981;53:537-55.
CHAPTER
38
49. Birdi TJ, Antia NH. The macrophage in leprosy: A review on the 67. Baskin GB, Gormus BJ, Martin LN, et al. The lepromin test in
current status. Int J Lepr 1989;57:511-25. rhesus monkeys. Int J Lepr 1986;54:427-36.
50. Birdi TJ, Shetty VP, Antia NH. Differences in M. leprae induced 68. Baskin GB, Gormus BJ, Martin LN, et al. Experimental leprosy
nerve damage in Swiss white and C57BL/6 mice. Int J Lepr in a rhesus monkey: necropsy findings. Int J Lepr 1987;
1995;63:573-4. 55(1):109-15.
51. Kamala AN, Antia NH, Shetty VP. Study of the involvement of 69. Walsh GP, dela Cruz EC, Abalos RM, et al. Leprosy studies in
the sciatic nerve following inoculation with M. leprae and other Philippine cynomolgus monkey (Macaca fasicularis): preliminary
mycobacteria in the mouse foot-pad. Int J Lepr 1984;52:506-14. report. Int J Lepr 1990;58:193.
52. de Blaquière GE, Santamaria L, Curtis J, et al .A morphological 70. Kirchheimer WF, Storrs EE. Attempts to establish the armadillo
and functional assessment of Mycobacterium leprae-induced (Dasypus novemcinctus Linn.) as a model for the study of
nerve damage in a guinea-pig model of leprous neuritis. leprosy. Report of lepromatoid leprosy in an experimentally
Neuropathol Appl Neurobiol 1994;20:261-71. infected armadillo. Int J Lepr 1971;39:693-702.
53. Shetty VP, Matharu PS, Antia NH. Sciatic nerve of normal and 71. Scollard DM, Lathrop GW, Truman RW . Infection of distal
T200x5R Swiss white mice fails to support multiplication of peripheral nerves by M. leprae in infected armadillos; an
intraneurally injected M. leprae. Int J Lepr 1999;67:446-52. experimental model of nerve involvement in leprosy. Int J Lepr
54. Muller HW, Minwagan P. Non-resident macrophages in peripheral 1996;64:146-51.
nerve of rat: effect of silica on migration, myelin phagocytosis 72. Scollard DM. The biology of nerve injury in leprosy. Lepr Rev
and apolipoprotein expression during Wallerian Degeneration. J 2008;79:242-53.
Neurosci Res 1987;81:222-30. 73. Binford CH, Meyers WM, Walsh GP, et al. Naturally acquired
55. Shetty VP. Animal model to study the mechanism of nerve leprosy-like disease in the nine-banded armadillo (Dasypus
damage in leprosy – A preliminary report. Int J Lepr 1992;61:70- novemcinctus): histopathologic and microbiologic studies of
75. tissues. J Reticuloendothel Soc 1977;22:377-88.
74. Mahadevan PR, Jagannathan R, Bhagaria A et al. Host-pathogen
56. Shetty VP, George V. Xenograft studies in leprous neuropathy.
interaction—new in vitro drug test systems against
Int J Lepr 1986;54:133-5.
Mycobacterium leprae-possibilities and limitations. Lepr Rev
57. Samuel NM, Crawford CL, Crange JM. Ultrastructure of human
1986;57:182-200.
foetal Schwann cells in tissue culture infected with M. leprae.
75. Wheeler PR. Biosynthesis and scavenging of pyrimidines by
Lepr Rev 1988;59:17-24.
pathogenic mycobacteria. J Gen Microbiol 1990;136:189-201.
58. Mukherjee R, Antia NH. Intracellular multiplication of leprosy
76. Wheeler PR. Enzymes and other biochemically active
derived mycobacteria in Schwann cells of dorsal root ganglion
components of mycobacteria. Lepr Rev 1986;57:21-32.
cultures. J Clin Microbiol 1985;21:808-14.
77. Katoch VM, Sharma VD. Recent advances in the microbiology
59. Save MP, Shetty VP and Shetty KT. Hypophosphorylation of of leprosy. Indian J Lepr 2000;72:363-79.
NF-H and NF–M subunits of neurofilaments and the associated
78. Datta AK, Katoch VM, Katoch K, et al .Appearance of a methoxy
decrease in KSPXX kinase activity in the sciatic nerves of Swiss
mycolate-like component by the acid methanolysis of
white mice inoculated in the foot pad with Mycobacterium leprae.
Mycobacterium leprae. Int J Lepr 1987;55:680-4.
Lepr Rev 2009 (in press).
79. Bharadwaj VP, Katoch K. An overview of the current status of
60. Save MP, Shetty VP, Shetty KT, et al. Alterations in neurofilament serological techniques in the epidemiology of leprosy. Trop Med
protein(s) in human leprous nerves: morphology, Parasitol 1990;41:359-60.
immunohistochemistry and Western immunoblot correlative
80. Protocols for neural cell culture. Series: Springer Protocols
study. Neuropathol Appl Neurobiol 2004;30:635-50.
Handbooks, Doering, Laurie C (Ed.), 4th ed., 2009.
61. Gunders AE. Progressive experimental infection with 81. Choudhury A, Mistry NF, Antia NH. Blocking of Mycobacterium
Mycobacterium leprae in a chimpanzee; a preliminary report. J leprae adherence to dissociated Schwann cells by anti-
Trop Med Hyg 1958;61:228-30. mycobacterial antibodies. Scand J Immunol 1989;30:505-9.
62. Leininger JR, Donham KJ, Meyers WM. Leprosy in a 82. Rambukkana A, Salzer JL, Yurchenco PD, et al. Neural targeting
chimpanzee. Post-mortem lesions. Int J Lepr 1980;48:414-21. of M. leprae mediated by the G domain of the laminin alpha-2
63. Meyers WM, Walsh GP, Brown HL, et al. Naturally acquired chain. Cell 1997;88:811-21.
leprosy in a Mangabey monkey (Cercocebus sp). Int J Lepr 83. Rambukkana A. How does M. leprae target the peripheral
1980;48:495-6. nervous system? Trends Microbiol 2000;8:23-28.
64. Meyers WM, Gormus BJ, Walsh GP, et al. Naturally acquired 84. Suneetha LM, Vardhini D, Suneetha S. et al. Biochemical aspects
and experimental leprosy in nonhuman primates. Am J Trop of Mycobacterium leprae binding proteins: a review of their role
Med Hyg 1991;44:24-7. in pathogenesis. Int J Lepr 2001;69:341-8.
65. Ohkawa S, Martin LN, Gormus BJ. Lepromin-induced 85. Shimoji Y, Ng V, Matsumura K, et al. A 21 kDA surface protein of
lymphoproliferative response of experimental leprosy monkeys: M. leprae binds peripheral nerve laminin-2 and mediates Schwann
regulatory role of monocyte and lymphocyte subsets. J Immunol cell invasion. Proc Nat Acad Sci 1999;96:9857-62.
1987;138:3943-8. 86. Ng V, Zanazzi G, Timpt R, et al. Role of the cell wall phenolic
66. Wolf RH, Gormus BJ, Martin LN, et al. Experimental leprosy in glycolipid-1 in the peripheral nerve predilection of Mycobacterium
three species of monkeys. Science 1985;227:529-31. leprae. Cell 2000;103:511-29.
CHAPTER
38
87. Marques MA, Antonio VL, Sarno EN, et al. Binding of alpha2- on selective host kinases and pathogen modulated endocytic
laminins by pathogenic and non-pathogenic mycobacteria and pathways. FEMS Microbiol Lett 2004;238:429-37.
adherence to Schwann cells. J Med Microbiol 2001;50:23-28. 91. Rambukkana A, Zanazzi G, Tapinos N, Salzer JL. Contact-
88. Soares de Lima C, Zulianello L, Marques MA, et al. Mapping the dependent demyelination by Mycobacterium leprae in the
laminin-binding and adhesive domain of the cell surface- absence of immune cells. Science 2002;296:927-31.
associated HLp/LBP protein from M. leprae. Microbes Infect 92. Hagge DA, Oby Robinson S, Scollard D, et al. A new model for
2005;7:1097-1109. studying the effects of Mycobacterium leprae on Schwann cell
89. Tapinos N. Ohnishi M, Rambukkana A. ErbB2 receptor tyrosine and neuron interactions. J Infect Dis 2002;186:1283-96.
kinase signalling mediates early demyelination induced by leprosy 93. Singh N, Birdi TJ, Antia NH. Differential in vitro modulation of
bacilli. Nat Med 2006; 12; 961-966. Schwann cell proliferation by Mycobacterium leprae and
90. Alves L, de Mendonca Lima L, da Silva Maeda E, et al. macrophages in the murine strains, Swiss white and C57Bl/6. J
Mycobacterium leprae infection of human Schwann cells depends Peripher Nerv Syst 1998;3:207-16.
39 Ocular Leprosy
Swapan K Samanta, Manav Deep Singh
There is no disease which so frequently gives rise to

disorders of the eye, as leprosy does.
— GA Hansen (1873)
INTRODUCTION
The eyes were frequently affected in leprosy in pre-MDT
(multidrug therapy) era with most eye complications
occurring in advanced lepromatous cases (Figs 39.1 and
39.2). Probably no other systemic disease has such a
high proportion of involvement of the eyes as leprosy has.
It not only affects all the coats of the eyeball but affects
ocular adnexa as well.
Fig. 39.2: Blind population affected with leprosy
Among these, the involvement of uveal tissue has been
an important cause of blindness in the past. Uveitis in
leprosy is potentially blinding because even in the absence
of ocular treatment, it has a symptom free course. This
gets transformed into manifest visual loss because by the
time pain or ocular congestion develops, the complications
are irreversible. In the early stages, which are amenable
to treatment, the signs may be missed unless the eyes
are examined very carefully. The affection of the uveal
tissue was recognized for centuries but the relatively low
incidence of this ocular manifestation of leprosy reported
in earlier studies. This might have been because the
observation of the eyes was limited to gross examination.
Following the invention of slit-lamp in 1920s there was
also enlistment of the early diagnosis. The early diagnosis
of uveitis resulted in early treatment of active disease, thus
preventing the complications and in turn reducing blindness.
Advent of Sulphone therapy in 1950s revolutionized
the outlook for ocular lesions. Most of the developments
of early diagnosis and management of ocular leprosy took
Fig. 39.1: A blind leprosy sufferer place in the post World War II period. The leprosy situation
CHAPTER
39
has undergone a sea change over the last twenty years or Epidemiology of ocular leprosy is confusing as many
so. There has been a phenomenal reduction in prevalence studies show methodological flaws and wide variation in
though incidence continues to defy a declining trend. The the methods, planning, setting up and reporting of ocular
occurrence of serious and progressive forms of leprosy leprosy surveys. From existing surveys it is estimated
has greatly diminished, so also the occurrence of that between 2.5 and 5 lakh leprosy or ex-leprosy patients
deformities due to this disease. It has been reflected in could be blind (vision less than 6/60).6 Definition of
the occurrence of the ocular complications as well. This “blindness” may also vary in different studies. Studies vary
progress has been mainly due to two important factors, in inclusion of lesions: Some include only potentially sight
viz. (a) the introduction of MDT for the treatment of the threatening lesions due to leprosy, others include all typical
disease in 1980’s and subsequent free supply of MDT ocular lesions but without ocular morbidity (such as
drugs to all patients in the world through WHO and madarosis) and yet others include general lesions (like
(b) intensification of antileprosy activities following the 1991 age-related cataract) not directly related to leprosy. A bias
towards elderly institutionalized patients or patients
declaration of the goal of WHO to decrease the level of
clustered in leprosy settlements is common. Examinations
leprosy in the world by 90%. The target was fixed to
are done with the help of torch light or slit-lamp and by
eliminate leprosy as a public health problem, i.e. reducing
different levels of personnel, from basic leprosy field staff
the prevalence to less than 1 case per 10,000 by 2000
to qualified ophthalmologists. Only a few studies give a
which was revised to the year 2005. India achieved this
clear picture of the status of eye problems among new
target in December 2005.
patients at the time of starting MDT.
As a blind man could use his limbs to find out his
The recent trend is to compare data on morbidity and
livelihood, the disabled leprosy patient could meet his
blindness in leprosy to the same data in the general
minimal daily routine if the eyes were intact. Leprosy gave population to give a better insight into the burden of disease
the sufferer a double handicap—the visual impairment in relation with leprosy. However, even recent studies
ending in blindness and deformities of the extremities confined to leprosy settlements or in leprosy-based
resulting in additional disabilities. Poor vision did not permit hospitals show a high prevalence of blindness and ocular
care of affected body parts (which are specially required morbidity. Cataract is the most common cause of blindness
for areas of reduced sensation) and deformed extremities in both types of studies.5 As observed in the longitudinal
did not permit proper eye care. This was superadded with study of ocular leprosy (LOSOL) in Ethiopia, India and
social stigma, old age (as leprosy is not a killing disease) Philippines, at the time of diagnosis approximately 11%
and poor availability of eye care services. Today, there is of people with multibacillary (MB) leprosy had
hardly any addition of the blind in the family of newly lagophthalmos, uveitis or trichiasis related to their disease
diagnosed “PAL” (patients affected with leprosy). and 2.8% were blind.7
Nowadays, most eye problems in leprosy patients are due
to normal aging process or other phenomena as observed Blindness and Severe Visual Impairment (SVI)
in otherwise healthy individuals.1 in Leprosy (Visual Acuity < 0.1)
EPIDEMIOLOGY Estimate in 2003#

• Number of blind 200,000 – 300,000 (< 0.1), including
Ocular leprosy is a lifelong accompaniment for the person
RFT
affected with leprosy. The prevalence of ocular leprosy
• Incidence of blindness due to leprosy 0.5-1%.
and its complications are influenced by the type and
• Incidence of blindness due to other causes 1-2%.
duration of disease and the treatment received for the
• Women > Men
disease in general and eyes in particular.2-4 In control
# Ocular manifestations of Leprosy. In: The Epidemiology of
programs, after implementation of MDT, potentially sight
Eye Disease. 2nd Edition. Johnson GJ, Minassian DC, Weale
threatening (PST) lesions have been reported in 15-20% RA, West SK (Eds), Hodder Arnold (Pub.), London 2003; 309-
and blindness in 1-3%. This is about double the level of 317.
blindness in general population of endemic countries.5
CHAPTER
39
Ocular Leprosy 505
Wani reported ocular lesions in 69% patients with 9 moderate visual impairment in 20.7%.10 They also found
unilateral and 19 bilaterally blind cases among 100 cases that longer duration of disease, treatment at more advanced
of leprosy referred to the eye department of a Medical stage and the older age were independently associated
College in Srinagar (J&K).8 Gupta et al from Nepal reported with blindness. There were different patterns of leprosy
ocular involvement in 66.3% of RFT patients and only related ocular morbidity, blindness and disease type even
14.3% in patients with active disease.9 The incidence of in different areas of the same region. Daniel et al found
blindness was 24 and 2.9% respectively. Thompson et al that during a 2 years course of MDT, approximately 20%
in a study of 1137 subjects in three centers in Eastern patients of multibacillary (MB) leprosy could be expected
India reported blindness in 2.9% (WHO criteria) and to develop ocular complications and out of these, 11%
Manifestations of Eye Involvement in Leprosy
Extraocular
Eyebrows: Madarosis
Tear glands: Chronic dacryoadenitis causing keratoconjunctivitis sicca
Nasal deformities: Nasolacrymal duct block
Neural involvement: Facial 7th nerve
Lagophthalmos with or without exposure keratitis
Ectropion of lower lid, entropion of upper lid, trichiasis
Trigeminal 5th nerve
Corneal anesthesia
Ocular
(A) Infiltration by M. leprae
(B) Immune damage (reactions)
Conjunctiva: Inflammation and edema with dilated blood vessels
Pterygium
Cornea: Thickening and beading of corneal nerves
Superficial punctate keratitis
Interstitial keratitis
Corneal anesthesia (due to V nerve involvement)
Corneal ulcers
Episclera/Sclera:
Episcleral nodules
Episcleritis
Scleritis- staphyloma
Iris and ciliary body:
Iris pearls
Iridocyclitis
Synechiae
Trabeculitis and secondary glaucoma
Phthisis bulbi
Lens: Cataract
Age-related (senile)
Complicated
Steroid induced
Posterior segment
Focal retinal lesions
CHAPTER
39
could be potentially sight threatening.11 In the follow-up of reduced quantum of irreversible blindness as well as of
the same cohort of patients after 2 years of MDT, follow- other deformities.13-15 Ocular involvement that is not a
up results at 5 years were available for 278 MB cases. It threat to sight like madarosis normally does not require
was found that 5.6% of these patients could be expected any management in addition to the treatment of leprosy.
to develop new ocular complications every year and this however, cosmetic surgery may be undertaken. The
could often (3.9%) be potentially vision threatening.12 management of PST lesions is very important to avoid
blindness. Therefore, the recent modules of management
EFFECTS OF LEPROSY ON EYES AND of the sight threatening components of ocular leprosy have
OCULAR ADNEXA been described in the following lines along with details of
ocular lesions.
Leprosy preferentially affects anterior segment of eye
because of the affinity of M. leprae for cooler temperature
EXTRAOCULAR LESIONS
and the presence of rich network of non-myelinated nerve
fibers in this region. Thus, the disease mainly affects Diseases of the Eyebrows
cornea, sclera, iris, ciliary body and lens sparing the Madarosis
posterior segment, i.e. vitreous, choroid and retina.
Madarosis, i.e. falling of the eye lashes (specially the outer
Additionally, it may also involve all ocular adnexal
two-third) is one of the diagnostic signs of lepromatous
structures. These lesions may be the result of infiltration
leprosy. In the advanced disease there may be total loss
of periorbital structures, nerve involvement or invasion of
of eye lashes and eyebrows (Fig. 39.3). It is a part of the
eyeball by M. leprae and also as part of leprosy reactions.
lepromatous skin lesions where the hair bulbs are lost due
Conjunctival effects include inflammation with edema
and dilated vessels as well as pterygium formation. In to the disease process. In earlier days this diagnostic sign
was specially mentioned as a part of the stigma so as to
cornea it may cause thickening and beading of corneal
identify a leprosy sufferer.
nerves, superficial punctate keratitis, interstitial keratitis
and lepromatous pannus. Episcleral involvement can Management
present as episcleral nodules, episcleritis and scleritis or
Cosmetic dermatological surgery can be done for the
even staphyloma formation. Iris and ciliary body
sufferer with skin graft over the eyebrow with skin from a
involvement may result in iris pearls, iridocyclitis, synechiae
formation, trabeculitis leading to secondary glaucoma or
phthisis bulbi. Lens can become cataractous and
occasional posterior segment lesions in the form of focal
retinal lesions have been reported. Involvement of 5th and
7th cranial nerves can lead to corneal anesthesia and
lagophthalmos (causing exposure) respectively. Together
or independently they may result in infection of cornea
causing corneal ulceration, perforation and panophthalmitis
or healing with scarring. Both can lead to blindness. 7th
(facial) nerve palsy may also lead to lower lid ectropion,
upper lid entropion and poor lacrimal drainage in addition
to lagophthalmos. Adnexal lesions include: Superciliary
madarosis; loss of eye lashes; eyelid nodules and placoid
lesions; acute or chronic dacryoadenitis and nasolacrimal
duct block due to nasal deformities.
There has been a considerable reduction in the
incidence of risk factors for ocular involvement in leprosy
due to proper and effective treatment of the primary
disease. This ultimately offers a positive outcome with Fig. 39.3: Bilateral madarosis and superciliary madarosis
CHAPTER
39
Ocular Leprosy 507
hairy region. But at the same time regular trimming of the
growing hair on that region should follow at regular intervals
to maintain normal look.
Diseases of Eyelids
1. Lagophthalmos (with or without exposure keratitis)
2. Ectropion
3. Entropion
4. Trichiasis
Lagophthalmos
Eyelids are affected in both PB and MB leposy. The
commonest complication is lagophthalmos where the
patient cannot close the eyes properly, leaving a lid gap
(Figs 39.4 to 39.6) which puts the eye at the risk of constant Fig. 39.5: Lagophthalmos (right eye)
exposure and external injury. The condition is further
aggravated by anesthesia of cornea caused by 5th nerve
involvement. This may give rise to exposure keratitis
(Fig. 39.7) with secondary infection resulting in corneal
ulcer and eventual loss of vision. Sometimes, it may be
so fulminating that it may involve inner tissues of the eye
causing panophthalmitis and eventual loss of eye.
Extrusion of lens from a perforated corneal ulcer has also
been seen (Fig. 39.26).
Medical Management
Medical treatment for lagophthalmos is neither satisfactory,
nor cost effective, nor permanent, furthermore, it requires
constant monitoring. If left untreated, there is every chance
of developing further fulminating corneal complications.
Therefore, the role of medical management is usually
Fig. 39.6: Lagophthalmos (left eye) with protective glasses
limited to the first six months of its onset. If significant

lagophthalmos (lid gap more than 5 mm) persists after
that, surgery is often required.
A few of the ongoing measures to tackle the situation include:
1. Prompt intervention with systemic steroids (Predni-
solone: 40-60 mg daily in a single dose after breakfast
for 4-6 weeks) in the early phase or on development of
Figs 39.4A and B: Lagophthalmos of left eye with severe dryness, facial patches without lagophthalmos.
with eyes closed (A) and eyes open (B). Also note the facial nerve
palsy of left side, resulting in absence of wrinkles on left side of forehead
2. Artificial tear substitutes (Carboxy methyl cellulose
while trying to open the eyes forcefully (B) solution as eye drops).
CHAPTER
39
3. Physiotherapy with “Think Blink” concept (active and

passive exercise to close the eye).
4. Muscle stimulation (Electrostimulation).
Surgical Management
Surgical intervention is indicated in the treatment of
lagophthalmos if the problem persists for more than six
months (although spontaneous recovery has been reported
even after one year).16
Types of Surgery17
Static procedures: A large number of procedures have been
described like tarsorrhaphies (medial, temporal or lateral),
palpabroplasties and canthopexies, lid magnets, gold
implants, slings, springs, lid loading and ear cartilage grafts.
However, only two procedures remain popular for their
Fig. 39.8: Lateral tarsorraphy done in both eyes
simplicity and reasonable amount of efficacy in preventing
corneal blindness. These are lateral tarsorrhaphy and tarsal
strip (Kuhnt-Szymanowski) procedure. Tarsorrhaphies are
very simple but cause restriction of field of vision and
provide poor cosmetic appearance. Therefore, they are
more useful as temporary treatment (Fig. 39.8).
Dynamic procedures: These include Gillie’s and Johnson’s
temporalis muscle transfer (TMT) procedures. At the
current situation the Johnson’s temporalis muscle transfer
is considered to be the surgery of choice in Indian
subcontinent (Figs 39.9 to 39.11). Well done, it can give
excellent cosmetic results. Patient can blink, although no
spontaneous blink habit develops. The limitations of the
procedure include the need of a well trained oculoplastic
surgeon, well motivated patient, need for long admissions,
Fig. 39.9: TMT operation: Incisions
Fig. 39.10: TMT operation: Tunnelling of the strips and anchorage

Fig. 39.7: Lagophthalmos and exposure keratitis (right eye) to medial canthal ligaments and tarsal plates
CHAPTER
39
Ocular Leprosy 509
Fig. 39.12: Ectropion lower lids of both eyes
Fig. 39.11: Successful TMT operation done in right eye
intensive physiotherapy and preferably good corneal

sensitivity. Some patients may have a residual gap of
more than 5 mm after surgery. These are the candidates
for resurgery as they are still prone to corneal complications.
Ectropion, Entropion and Trichiasis

Ectropion (outrolling of the lid margin) and entropion
(inrolling of the lid margin), especially of lower lid are seen
amongst old sufferers where the tarsal plate and most of
the fibers of orbicularis oculi are thinned out due to leprosy
(Figs 39.12 to 39.14). Many a time entropion may be
associated with trichiasis (misdirected eye lashes towards
the cornea) which leads to persistent rubbing over the
cornea further leading to potential complications like
keratitis and corneal ulceration (Fig. 39.15). Fig. 39.13: Ectropion in left eye with keratitis. Note the loss of labial
fold on left side due to 7th nerve palsy
Management: Trichiasis is temporarily managed by
epilation or electrolysis of the disturbing lashes. Shortening
the fibers of orbicularis oculi (Whillis operation) is the surgery
of choice for entropion and trichiasis which in many cases
was found to be unsuccessful due to the atrophied muscle
fibers. However, sometimes the entropion is caused by
associated trachoma. In these cases there is thickening
of tarsal plate and the procedure of tarsal plate fracture
with rotation may give better results.
The surgical coverage rate for eyelid surgery has been
reported at 30% in Eastern India.18 In Africa, lagophthalmos
has a better surgical coverage of 40.4% as compared to
entropion and trichiasis which have 24.7% coverage. Lack
of awareness about the treatment available was the most
common reason for not seeking surgery.19,20 But most of Fig. 39.14: Ectropion (left eye)
CHAPTER
39
Fig. 39.15: Entropion of both upper eyelids.

Blind right eye with pterygium
these leprosy sufferers remain untreated for lagophthalmos Fig. 39.16: Episcleritis (right eye)
due to lack of proper eye health care delivery system and
patients’ lack of awareness and apathy towards surgery.
OCULAR LESIONS
Diseases of Conjunctiva and Sclera
• Conjunctivitis
• Scleritis
• Episcleritis
Conjunctival inflammation and edema usually have no
long term implications. However, pterygium can cause
astigmatic refractive errors in early stage. Delay in
treatment may result in involvement of central part of cornea
causing severe visual disturbance (Fig. 39.15).
Management: Although astigmatism may be corrected A
with spectacles, definitive treatment is surgical excision.
High recurrence rate (almost 50%) has been discouraging
the surgeons from doing this surgery but the introduction
of antimetabolites (like Mitomycin C) and use of
conjunctival autografts has improved the results.
Episcleritis (Figs 39.16 to 39.18) is usually an
inoccuous condition and responds well to treatment with
steroid eye drops. Mostly, it has no long-term implications.
Occasionally, deeper layers may be involved resulting in
scleritis. This is a painful condition and may require oral
indomethacin or systemic steroids in addition to local
steroids and cycloplegics. Even when well treated, it may
rarely result in scleral thinning. This may result in the
formation of ciliary staphyloma especially if it is associated B
with raised intraocular pressure. Figs 39.17A and B: Episcleritis (left eye)
CHAPTER
39
Ocular Leprosy 511
Fig. 39.18: Episcleritis (right eye) Fig. 39.19: Avascular punctate keratitis visualized as area of
haziness of the cornea
Diseases of Cornea
1. Corneal pearls
2. Superficial punctate keratitis
3. Corneal ulcers
4. Corneal perforation
5. Corneal opacity
6. Pannus formation
Direct bacterial invasion of the cornea leads to punctate
avascular keratitis, corneoscleral roll and corneal nerve
beading. Avascular punctate keratitis usually occurs in
the upper temporal quadrant of the cornea and represents
the true infection of the eye by the M. leprae (Fig. 39.19).
It resembles chalk dust with white punctate subepithelial
opacities that may stain with fluorescein in the early stages.
Later, the lesions become confluent and advance into other
quadrants and also into the deeper layers (interstitial Fig. 39.20: Scleral leproma progressing to cornea
keratitis) of the cornea with pannus formation. Usually,
there is no visual loss associated with avascular punctate
keratitis. Interstitial keratitis and pannus seriously affect
the prognosis.
True corneal leproma is very rare. Less uncommon is
a lesion called corneoscleral roll. It is a leproma that arises
at the limbus or on the sclera and progresses across the
cornea (Fig. 39.20). There is no associated visual loss
unless visual axis is involved. Corneal nerve beadings are
enlarged edematous nerves that can be visualized with
slit-lamp examination. Sometimes, the nerves appear with
focal swelling resembling beads on a string (Fig. 39.21).
When facial nerve is involved, orbicularis oculi muscle
gets paralysed. As a result, the palpebral aperture cannot
be closed fully (lagophthalmos) leaving central part of
conjunctiva and inferior part of cornea exposed (Fig. 39.5). Fig. 39.21: Beaded corneal nerve
CHAPTER
39
This also results in lower lid margin not remaining snuggily

attached to the eyeball, resulting in poor capillary action
which is essential for proper tear drainage. All this leads
to excessive tear loss/evaporation, resulting in dryness of
exposed area. Nutrition and protection provided by tears
is lost resulting in keratinization of conjunctiva (Fig. 39.4A)
and slow melting of cornea, i.e. exposure keratitis
(Fig. 39.7). The loss of protection may lead to bacterial
invasion resulting in corneal ulceration (Figs 39.22 and
39.23). If the ulcer is treated, it heals leaving a corneal
opacity (Fig. 39.24) which can cause variable visual loss
depending on location and extent of opacity. In the absence
of proper treatment, the corneal ulcer may perforate
(Fig. 39.25) or the infection may travel to inside the eye Fig. 39.24: Corneal opacity (right eye) with perforated corneal ulcer
causing panophthalmitis. This almost invariably leads to (left eye) and bilateral facial palsy
blindness or may even end in phthisis bulbi. These events
Fig. 39.25: Perforated corneal ulcer with extrusion of lens
Fig. 39.22: Corneal ulcer (stained with fluorescein) progress rapidly if there is associated loss of sensation
due to trigeminal nerve involvement.
Management
The treatment involves management of lagophthalmos in
addition to frequent instillation of local artificial tears and
passive closure of palpebral aperture. If corneal ulcer has
developed, frequent use of broad spectrum antibiotic eye
drops, along with atropine are prescribed. Systemic
antibiotics and anti-inflammatory drugs may be required in
selected cases. Supportive treatment with vitamins and
high protein diet may hasten the healing. Temporary
tarsorrhaphy is frequently required to support healing as
definitive surgery for lagophthalmitis is not feasible during
the presence of acute infection.
Constant supervision with measures for proper closure
Fig. 39.23: Exposure keratitis leading to fulminating ulcer with of the cornea by effective lid surgery for lagophthalmos,
lagophthalmia (left eye) entropion and trichiasis has markedly minimized the corneal
CHAPTER
39
Ocular Leprosy 513
diseases in leprosy. Availability of artificial tears to keep drugs or oral steroids may be indicated in severe cases or
the cornea moist and transparent has come as a boon for in case of doubtful compliance. Oral steroids may also be
PAL. These drops should be used throughout life to given as part of the treatment of reaction. YAG laser
maintain health of the cornea. New generation of antibiotics iridotomy is indicated to relieve iris bombe, especially if it
for the treatment of bacterial or fungal corneal ulcers in is associated with raised intraocular pressure (IOP). Pan
hypoaesthetic cornea offer good healing. uveitis (inflammation of posterior segment in addition to
Keratoplasty (corneal transplantation) is the treatment iridocyclitis) (Fig. 39.27) may need intensification of
for corneal opacities after healing of the ulcer. This can be treatment including high dose systemic steroids which may
done very successfully amongst PAL. Although it has been be given orally or as intravenous methyl prednisolone (if
tried in different parts of India from 1975, the ultimate optical macula is threatened). During quite phase, Argon laser
results were good but the results are better if undertaken may be used to increase the size of pupil by photo-
after proper case selection. coreplasty.21
Diseases of Uveal Tract

1. Chronic iridocyclitis
2. Acute iridocyclitis (red eye)
3. Pan-uveitis
4. Iris pearls
Iridocyclitis
(Principles of management)
Symptom/signs
Red eye, watering, constricted pupil, photophobia, pain
and diminished vision.
Early recognition of insidious iritis (in lepromatous
leprosy) is by slit-lamp examination.
Acute red eye
Give topical antibiotics, if no improvement in 48 hours,
Fig. 39.26: Acute iridocyclitis (left eye)
refer to eye care services.
Iridocyclitis is usually a part of lepra reactions in LL

leprosy. Although chronic lingering uveitis may not have
symptoms but slit-lamp examination may show keratic
precipitates (KPs). Aqueous flare and cells in anterior
chamber of eye (AC) may be absent but they constitute
essential signs in acute uveitis which has ciliary congestion
as well (Fig. 39.26). Untreated, it can lead to synechiae
formation causing occlusio papillae and secondary
glaucoma. Complicated cataract caused by uveitis is
usually located in the central posterior subcapsular region.
Thus, a minimal cataract associated with small pupil may
cause significant visual disability.
Management
Anterior uveitis is usually treated by local steroid and
atropine eye drops. Subconjunctival injections of these Fig. 39.27: Pan uveitis (both eyes)
CHAPTER
39
Trabeculitis is a poorly recognized entity which may be aqueous humor physiology due to early ciliary body
a part of chronic uveitis but is usually missed, pending involvement. It also results from chronic/recurrent acute
gonioscopy by an expert. It may cause damage to uveitis and steroid therapy for reversal reactions. Usually,
trabecular meshwork and result in secondary glaucoma it is not possible to differentiate between age-related and
even in the absence of peripheral anterior synechiae (PAS). leprosy related cataract (Figs 39.28 and 39.29) because
Early recognition of insiduous iritis in LL can be both cause a gradual painless visual loss. Possible history
detected only by slit-lamp examination. In case of an acute of previous pain and redness suggestive of uveitis and
red eye, the field worker should start topical antibiotics. In the history of steroid therapy for reversal reactions or local
case there is no improvement within 48 hours the case ocular pathology may help to reach the diagnosis.
should be referred to eye care services for slit-lamp Treatment is surgical but small pupil and intraocular
examination and proper treatment. inflammation with associated complications could make
Today following the advent of MDT, iris involvement
has become rare amongst new cases and in case it
happens, the severity is usually of minor degree and often
associated with episcleritis. During ENL reaction, it is
mostly a painless cold iritis. The sequelae of scleritis and
iritis have become very rare. Small pupil is common and
difficulty may arise during cataract surgery. Acute uveitis
is well managed by initial treatment with local as well
systemic steroids along with mydriatics and these may
be continued with NSAIDs in cases of lingering low grade
uveitis.22
Diseases of Lens
Cataract
Salient Features
• Risk of cataract is increased three times especially in Fig. 39.28: Bilateral mature cataract
MB patients.
• Most common cause is age-related.
• Also results from
– Chronic / recurrent acute uveitis (5-10%)
– Steroid therapy for reversal reactions.
• Usually not possible to differentiate between age-related
and leprosy related cataract.
• Gradual painless visual loss.
• Possible previous history of pain and redness from
uveitis.
• History of steroid therapy for reversal reactions or local
ocular pathology.
• Treatment is surgical but intraocular inflammation with
complications could make surgery more challenging
with guarded prognosis.
• Good outcome is possible even after chronic uveitis
but ocular hypotony and iris atrophy are challenges.
Risk of cataract is increased three times especially in
MB patients. Although the most common cause is age-
related, it may set in early because of compromised Fig. 39.29: Aphakia (right eye), mature cataract (left eye)
CHAPTER
39
Ocular Leprosy 515
surgery more challenging with guarded prognosis. Good
outcome is usually possible even after chronic uveitis.23,24
The field of cataract surgery has undergone a revolution
due to the introduction of microsurgical procedures during
the past quarter of a century. So the benefit of improved
cataract surgical procedures have been extended to the
“PAL” as well. This has lead to a dramatic change in their
quality of life (imagine the condition of a leprosy sufferer
with deformed nose and ears wearing a pair of heavy
aphakic glasses following cataract surgery by conventional
intracapsular cataract extraction method! (Figs 39.30 to
39.32).25,26
During the later part of twentieth century, there was a
great dilemma among the eye surgeons about the rationality
of putting IOL amongst “PAL” where the eye is already in
a burning condition with cold uveitis.27 Nowadays the
standard microsurgical procedure adopted for the “PAL” is Fig. 39.30: Bilateral aphakia with heavy spectacles
Fig. 39.31: File picture of aphakic leprosy sufferers with heavy spectacles (1988)
CHAPTER
39
Fig. 39.32: A group of pseudoaphakic leprosy sufferers with IOL (2009)
phacoemulsification. Other methods include simple complication but they were well controlled by local steroids.
extracapsular cataract extraction (ECCE) with sclero- Exposure keratitis, ulcers on the palmer aspect of the hand
corneal stitches and manual small incision cataract surgery and insensitive cornea were the common source of infection
(SICS). However, implantation of IOL is recommended in in the operated eye. PCO was the major complication
all procedures under most circumstances including amongst PAL. LASER capsulotomy can help to regain
complicated cataracts with rigid small pupil, capsulo- better vision but it was not available at the centers where
zonular complications, iris atrophy and hard nucleus. The the study group used to perform surgery.28-30 The same
postoperative visual outcome is usually satisfactory. The situation has been observed in Nigeria.31
complications are limited and can be easily controlled. On the other hand in a study in Western India on
The immediate success of surgery is between 90 and 95% 40 cases with the postoperative complications following
(Figs 39.33A and B). SICS with IOL showed that 90% patients had visual acuity
In one longitudinal study on 200 cases (ECCE with (VA) > 6/12 and only 5% patients had PCO and iris
IOL with stitches) in Eastern India the following compli- atrophy.24 In South India, a study on 500 postoperative
cations were noted in the postoperative period during the cataract cases reported that 86% had VA 6/6-6/18.
five year follow-up: Posterior capsular opacity (PCO) 30%, Postoperative complications like vitreous haze (4%), iritis
endophthalmitis 2%, retinal detachment 1%, optic atrophy (8%) and phthisis bulbi (8%) were noted.32 In Brazil the
or pallor of the optic disk 2% and other complications 1%. visual outcome and complications following cataract
Corrected visual status at the end of the fifth year was as surgery by phacoemulsification and IOL implantation in a
follows: (i) > 6/18 (30%), (ii) > 6/60-6/18 (40%), (iii) 6/60- leprosy group were reported as follows: VA > 20/40-83.9%,
CF (25%), (iv) only hand movements (HM) (2%), and (v) VA 20/60 to 20/100-9.7% and VA ≤ 20/200-6.5%. A fare
no perception of light (PL) (3%).28 Frequent attacks of number of complications were observed, e.g. IOL
uveitis in the postoperative period were the major dislocation (3.2%), synechiae (12.9%), IOL decentration
CHAPTER
39
Ocular Leprosy 517
of visual acuity (VA) at least at intake and at release from
treatment should be checked. In “care after cure” patients
older than 50 years, VA should be assessed annually.
Potentially Sight Threatening

(PST) Lesions
The lesions arising out of the disease process which (if
remain unattended) may lead to blindness, are termed
“Potentially Sight Threatening” (PST) lesions. Originally,
the term was described by Dr Lamba of New Delhi in early
seventh decade (the pre-MDT era) which included the
following ocular morbidities: Corneal hypoesthesia,
lagophthalmos with or without corneal exposure leading to
keratitis, complicated cataract and recurrent uveitis. Dry
A eye syndrome is the new addition to the list. These morbid
conditions are the ones that put the eye at high-risk.
Association of old age, facial patches, deformities and
disabilities in limbs have been reported as risk factors for
ocular lesions in new as well as in RFT patients.33 Luxmi
Singh studying 1500 patients, living in different settings,
found that ocular lesions were aggravated by relapse,
leprosy reactions, chronic ulceration on the extremities,
chronic osteomyelitis and delay in initiation of treatment.34
PST lesions were noted equally in paucibacillary (PB) and
multibacillary (MB) cases, however, the nature of lesions
was different. Keratitis and its sequelae were significantly
more common in PB patients (p < 0.01). Iridocyclitis and
its sequelae were more common in MB cases (p < 0.005).
All PST lesions were found to increase with the duration
B of the disease.16,34,35
Figs 39.33A and B: Bilateral pseudoaphakia
with intraocular lens (IOL) implant
Risk groups for PST
1. Elderly (> 50 years).
(3.2%), debris on IOL surface (3.2%), sphincter tear
2. Long history of leprosy and disability.
(19.4%), capsular opacification (9.7%) and persistent ocular
3. Initial treatment by dapsone monotherapy.
inflammation (3.2%).23
4. MB > PB.
5. Women > Men.
PREVENTION OF BLINDNESS
IN LEPROSY
Corneal Hypoesthesia
Ocular leprosy is one of the serious community eye health
concerns of the Indian subcontinent. In this era of “RFT” Corneal hypoesthesia may be accompanied by entropion
around 10 million people affected with leprosy (PAL) are and trichiasis which may lead to fulminating corneal
living within the society whether independently, with their ulceration. Corneal involvement occurs in both types of
families or in old age homes. About 30% of them carry leprosy (PB and MB). Corneal disease following leprosy is
some ocular morbidity as an aftermath of leprosy which common in Africa and the Indian subcontinent where PB
requires constant monitoring, supervision and treatment. disease predominates. In a rare case, corneal leproma
In order to improve eye care in leprosy, routine assessment was an initial feature of lepromatous leprosy.36
CHAPTER
39
Lagophthalmos with or without VISION 2020

Corneal Exposure
Sponsored by WHO, VISION 2020 is the ongoing Global
Next to cataract, lagophthalmos is the major ocular compli- initiative for prevention of blindness all over the world. At
cations in leprosy. Although more common amongst PB the country level in India, this is being taken care of by the
cases, it is found in both types of disease. In Eastern “National Program for Control of Blindness” (NPCB).
India 80% of the leprosy sufferers are PB patients and However, ocular leprosy has not been considered a priority
20% are of MB variety.37 Lagophthalmos leads to exposure area in any of them. The need of the hour is to integrate
which invites infection causing infective keratitis and its anti leprosy activities into general health care activities
sequelae especially if it is associated with corneal and to integrate eye care of these patients into NPCB and
hypoesthesia. VISION 2020 initiative, by strong political and organizational
(professional) commitment. Cataract is a priority component
Cataract in all programs. A policy should be developed to provide
Cataract is the most common cause of blindness amongst high quality cataract surgery to these patients (Figs 39.34A
the “PAL”. Cataract in leprosy may be age-related, steroid and B). Leprosy care takers should develop coordination
induced or complicated, i.e. secondary to keratitis or uveitis.
About 20% of the total cataract cases have been reported
to be complicated in nature. These are the ones that are
difficult to treat. Cataract may be associated with
lagophthalmos as well.38
Uveitis and its Sequelae

Leprosy related iridocyclitis is common in East Asia and
South America where MB disease predominates.22,39
Nowadays very few cases of iridocyclitis are found in Indian
subcontinent amongst the newly diagnosed cases and also
the severity of disease is less. However, it continues with
keratic precipitates, flare, cells and pupillary shape
abnormalities in MB patients. Cumulative incidence of any
uveitis has been reported to be about 5% at the end of
A
MDT which increases to 13% 2 years after RFT.5 Advanced
cases of uveitis are complicated by blocked pupil
(occlusiopupillae), complicated cataract, corneal
degenerations, iris atrophy and absolute glaucoma.
Dry Eye Syndrome

Loss of conjunctival and other tear secreting glands like
meibomian glands can give rise to disturbance in
maintaining precorneal tear film. The resultant dry eye
hampers in the process of keeping proper corneal
transparency and nutrition. All the three layers of tear film
namely mucin, aqueous and lipid layer may be affected.
Reduced levels of IgA, lysozyme and lactoferrin have been
reported.40 The lepromatous type (74.2%) of Hansen’s
disease was the most prevalent and dry eye (66.7%) was
B
more frequent in this clinical form of the disease.40,41
Figs 39.34A and B: How can they carry on with proper ocular hygiene
Chronic dacryoadenitis can lead to severe dry eye in the
with all these deformities? Leprosy patients with severe visual disability
form of keratoconjunctivitis sicca (KCS). and hand deformities.
CHAPTER
39
Ocular Leprosy 519
with local district blindness control societies (DBCS) and presence of epiphora. Visual acuity and intraocular pressure
local NGOs working for blindness. It is common for should be recorded.
ophthalmologists and paramedical ophthalmic assistants
(PMOAs) working in general hospitals to have lack of Examination of Eyes
knowledge about ocular leprosy. This is due to poor 1. Any complication – dryness, redness, foreign body
exposure during training or earlier part of their career. Thus, sensation, diminution of vision.
it is not unusual for them to make errors in diagnosis when 2. Ask patient to close eyes – gently/with effort.
they are treating patients of leprosy (PAL) or the treated 3. Examine cornea and conjunctiva.
leprosy cases. The time is now mature to integrate the 4. Check pupils–size, symmetry, color, reaction to light.
community leprology and community ophthalmology. 5. Tenderness over eyelids.
Similar recommendations have been made earlier by 6. Epiphora.
International Federation of Antileprosy Associations (ILEP) 7. Visual activity and intraocular pressure.
in their 2001 meeting42 and by African Leprosy Congress 8. Do refraction.
in 2005.43
The prevention of ocular leprosy and its complications
can be achieved by the following plan: Secondary Level Eye Care
1. Early detection and treatment of leprosy. This is to be undertaken at the intermediate level through
2. Eye care at primary /district/ regional centers under the eye departments of subdivisional and district hospitals
VISION 2020 plan. under government control and base eye hospitals run by
NGOs. These should provide specialized OPD and simple
Primary Level Eye Care surgical facilities.
Every patient suffering from leprosy should have a routine
examination of the eye and this should be repeated at Tertiary Level Eye Care
frequent intervals. The interval period recommended is six This is delivered from the medical colleges and the centers
monthly in the absence of any symptoms or active ocular of excellence, i.e. regional institutes of ophthalmology.
disease (for both PAL and RFT up to 5 years). Promotion India has a great concept of eye camps and high volume
and protection of eye health by trained health workers surgeries. Although this has been practiced mainly for
through recognition and early referral of visual disability, cataract surgeries, similar system can be developed for
common simple eye diseases and refractive errors, lagophthalmos surgeries with a plastic/oculoplastic surgeon
lagophthalmos, painful red eye and sudden loss of vision. as a member of the team. Tertiary level government or
The simple protocol for the field workers may be to nongovernment institutes should coordinate with secondary
assess visual acuity [either visual impairment (VA< 6/18) level health care providers to organize such camps.
or blindness (VA < 6/60 ) depending upon the setting] and This chapter on “Ocular Leprosy” can be best concluded
lagophthalmos. These should be the primary indicators with the words of Dr Desikan, “today the hesitations of
for monitoring disability (grade 2).6 However, since 1997, doctors to treat leprosy patients have gone, more so with
WHO system for reporting eye disability includes not only the ophthalmologists, because they do not have to handle
visual loss (either visual impairment or blindness depending a patient much. Handling a leprosy patient is no personal
upon the setting) but also lagophthalmos, iritis and corneal risk which the doctors should understand and tell others.
opacity in grade 2 disability. Let us all unite to drive away the ignorance in medical
Examination of eyes by medical officer should include personnel, doctors, nurses, technicians, ward attendants
examination of cornea and conjunctiva to look for any and others and stand united to treat leprosy as a disease.”
complication of leprosy like dryness, redness, foreign body (Keynote address during the poster exhibition and round-
sensation, diminution of vision. He should ask the patient table discussion on “progress towards-the integration of
to close eyes gently/with effort in order to look for any management of ocular problems of “people affected with
lagophthalmos. Pupils should be examined for any alteration leprosy” with general eye health care delivery system in
in symmetry and reaction to light. Examination should also Indian subcontinent at Sarojini Devi Eye Hospital,
include assessment of any tenderness over eyelids and Hyderabad, 30th January, 2007).
CHAPTER
39
REFERENCES 20. Mpyet C, Hogeweg M. Lid surgery in patients affected with

leprosy in North-Eastern Nigeria are their needs being met?
1. Samanta SK, Das S. Recent advances in Ocular Leprosy. Indian Trop Doct 2006; 36:11-13.
J Lepr 2007; 79:135-50. 21. Lamba PA, Srinivasa R, Rohatagi J. Surgical management of
2. Samanta SK, Sarkar K, Chatterjee PR et al. A current profile of ocular leprosy. Indian J Ophthalmol 1987; 35(3):153-57.
the pattern of ocular leprosy in RFT (released from treatment) 22. Citirik M, Batman C, Aslan O et al. Lepromatous iridocyclitis.
era in Eastern India. Abstract: First Asian Leprosy Congress, Ocul Immunol Inflamm 2005; 13: 95-99.
Agra, India, 2000. 23. Maakaroun MJ, Castro AVD, Dias RN. Phacoemulsification
3. Samanta SK, Roy IS, Dey AK et al. Ocular lesions amongst the cataract surgery and IOLimplantation: A case control study in
MB leprosy sufferers up to twenty-five years of age group with leprosy patients. Proceedings of the First International
the duration of the disease under five years. Abstract: 16th Symposium on Ocular Leprosy, Kolkata, India 2005; 150-53.
International Leprosy Congress, Salvador, Brazil, 2002. 24. Sharma G. Surgical outcome of small Incision Cataract Surgery
4. Samanta SK, Bhowmick N, Patra D. Ocular leprosy in children: in Leprosy patients, a reprospective study. Proceedings of the
Indian J Lepr 2004; 76: 256. First International Symposium on Ocular Leprosy, Kolkata, India,
5. Hogeweg, M. Proceedings of the First International Symposium 2005; 136-40.
on Ocular Leprosy, Kolkata, India, 2005; 76-82. 25. Samanta SK. Surgical management of cataract. Symposium on
6. Courtright P, Lewallen S. Ocular manifestations of leprosy. In: prevention of blindness in leprosy patients in Africa. African
The Epidemiology of Eye Disease. 2nd edn. Johnson GJ, Leprosy Congress, Johannesburg, South Africa, 2005.
Minassian DC, Weale R, West SH (Ed.). Chapman and Hall 26. Samanta SK, Sarkar K, Chatterjee PR et al. A twenty-five years
Medical, London. 2002. retrograde audit of cataract surgery in leprosy sufferers in
7. Courtright P, Daniel E, Rao S et al. Eye disease in multibacillary Eastern India. Abstract: First Asian Leprosy Congress, Agra,
leprosy patients at the time of their leprosy diagnosis: Findings India 2000.
from the Longitudinal Study of Ocular Leprosy (LOSOL) in India, 27. Samanta SK, Samanta A, Kundu M. A follow-up study of cataract
the Philippines and Ethiopia. Lepr Rev 2002; 73: 225-38. surgery with IOLimplantation amongst the leprosy sufferers in
8. Wani JS, Rashid S, Sherwani M et al. Ocular Manifestations of Eastern India. Clin Exp Ophthalmol, 2002; 30: Supplement A-
Leprosy—A clinical study. JK Practioner 2005; 12:14-17.
262.
9. Gupta HR, Shakya S, Shah M et al. Leprosy blindness in Nepal.
28. Samanta SK, Roy IS, Dey AK et al. The follow-up study of the
Nepal Med College J 2006; 8:140-42.
outcome of intraocular lens implantation as a part of the
10. Thompson KJ, Allardice GM, Babu GR et al. Patterns of ocular
cataract surgery amongst the leprosy sufferers in Eastern India.
morbidity and blindness in leprosy—A three center study in
Abstract: 16th International Leprosy Congress, Salvador, Brazil,
Eastern India. Lepr Rev 2006; 77:130-40.
2002.
11. Daniel E, Ffytche TJ, Sundar Rao PSS et al. Incidence of ocular
29. Samanta SK. Chattopadhya BP, Bhowmick N. The five years
morbidity among multibacillary leprosy patients during a 2 year
follow-up study of cataract surgery with IOL amongst people
course of Multi Drug Therapy. Br J Ophthalmol 2006; 90: 568-
affected by MB leprosy in Eastern India. Abstract: 63rd. Annual
73.
Conference of All India Ophthalmological Society, Bhubaneswar,
12. Daniel E, Ffytche TJ, Kempen JH et al. Incidence of ocular
Orissa, India, 2005.
complications in patients with multibacillary leprosy after
30. Samanta SK. A five years longitudinal study of the outcome of
completion of a 2 year course of Multi Drug Therapy: Br J
ECCE with IOL by can opener technique for cataract operation
Ophthalmol 2006; 90:949-54.
in leprosy. Proceedings of the First International Symposium on
13. John AS, Kumar DV, Rao PS. Patients’ perceptions of
Ocular Leprosy. Kolkata, India 2005; 147-49.
reconstructive surgery in leprosy. Lepr Rev 2005; 76: 48-54.
31. Mpyet C. Cataract as a cause of blindness in leprosy.
14. Samanta SK, Chattopadhyay BP, Nag P et al. Major ophthalmic
Proceedings of the First International Symposium on Ocular
surgical problems prevalent amongst leprosy sufferers in
Leprosy, Kolkata, India, 2005; 113-14.
Eastern India. Indian J Lepr 2005; 77: 345.
32. Goud S. Surgical Experience in Ocular Leprosy. Proceedings
15. Samanta SK, Das D, Das S et al. Magnitude of the major surgical
of the First International Symposium on Ocular Leprosy, Kolkata,
blinding problems prevalent amongst leprosy sufferers in Eastern
India. Abstract of the 21st. Congress of the Asia Pacific Academy India, 2005; 141-46.
of Ophthalmology, 2006, Singapore. 33. Samanta SK, Roy IS, Marandi A. High risk eyes in leprosy. In:
16. Rajan MA. The eye in Leprosy 1980 to 2005 – A study of 30,121 Indian Ophthalmology Today. Pasricha JK (Ed). All India
patients. Proceedings of the First International Symposium on Ophthalmological Society, New Delhi 1993; 574-75.
Ocular Leprosy, Kolkata, India, 2005; 86-89. 34. Singh L, Garg P, Singh P et al. Potentially sight threatening
17. Joshua J. Surgical management of lagophthalmos in leprosy. lesions in leprosy and their relation to type and duration of disease.
Proceedings of the First International Symposium on Ocular Proceedings of the First International Symposium on Ocular
Leprosy, Kolkata, India, 2005; 125-35. Leprosy, Kolkata, India , 2005; 115-18.
18. Samanta SK, Roy IS, Dey AK et al. Lagophthalmos in leprosy— 35. Maity P, Samanta SK. The pattern of ocular leprosy amongst
A current status report from Eastern India. Abstract: 16th the indoor patients of a leprosy hospital in Eastern India. Indian
International Leprosy Congress, Salvador, Brazil, 2002. J Lepr 2004; 76: 257-58.
19. Mpyet C, Solomon AW. Prevalence and causes of blindness 36. Yuen HK, Liu DT, Lam DS. Corneal leproma as an initial
and low vision in leprosy villages of North Eastern Nigeria. Br J feature of lepromatous leprosy. Arch Ophthalmol 2006;
Ophthalmol 2005; 89: 417-19. 124:1661-62.
CHAPTER
39
Ocular Leprosy 521
37. Cakiner-Egilmez T. Hansen’s disease and the eye. Insight 2006; 41. Frazao KC, Picolo NB, Hanouche RZ et al. Prevalence of dry
31:18-21. eye in Hansen’s disease patients from a colony hospital in
38. Samanta SK, Bhowmick N, Patra D et al. Management of Goiania, Brazil. Arq Bras Oftalmol 2005; 68: 457-61.
complicated cataract cases in leprosy. Indian J Lepr 2004; 76: 42. Courtright P, Tamplin M. Guidelines for the management of eye
54. care in leprosy: Recommendations from ILEP-supported
39. Roy IS, Samanta SK. Uveitis in leprosy patients and the role of meeting. IAPB News 2002; 8-9
intra ocular surgery. Proceedings of the XIIth International 43. Guidelines for the management of eye care in leprosy:
Leprosy Congress, New Delhi, 1984 670-72. Recommendations from African Leprosy Congress,
40. Sen DK. Abnormality in the quantity and quality of the tear fluid in Johannesburg, South Africa. 31st January – 3rd February 2005.
patients with leprosy. Proceedings of the First International Proceedings of the First International Symposium on Ocular
Symposium on Ocular Leprosy, Kolkata, India 2005; 107-08. Leprosy, Kolkata, India 2005; 198-202.
Section
8 Rehabilitation and
Social Issues
40
Rehabilitation
D Kamaraj
INTRODUCTION health care as close as possible to where people live and

work, and constitutes the first element of a continuing
“Rehabilitation includes all measures aimed at reducing
health care process.”
the impact of disability for an individual, enabling him or
her to achieve independence, social integration, a better Primary health care focuses on3:
quality of life and self-actualization.” • Maximum use of local resources, including traditional
(United Nations)1 healers and trained community health workers.
The strategies for rehabilitation involves multi-sectoral/ • Participation of the individual and the community.
multidisciplinary approach, involving medical, social welfare • Affordable and accessible care.
and education sectors and good referral services by • Integration of prevention, promotion, treatment, and
rehabilitation departments, reconstructive surgery units, and rehabilitation.
community based rehabilitation (CBR) programs, etc. • Coordination between the health care sector and other
aspects of society, such as social welfare, housing
REHABILITATION AS A COMPONENT OF and education.
PRIMARY HEALTH CARE
By the end of 1978, the WHO and UNICEF conference on
REHABILITATION PROVISION
“Primary Health Care” was held in Alma-Ata with Rehabilitation usually includes the following types of
participation of health officials and many nongovernmental services4:
organizations from all countries in the world. This • Early detection, diagnosis and intervention;
Conference had a major influence on the standing of • Medical care and treatment;
rehabilitation. The final Declaration included these • Social, psychological and other types of counseling
statements2: and assistance;
“Primary health care is essential health care based on • Training in selfcare activities, including mobility,
practical, scientifically sound and socially acceptable communication and daily living skills, with special
methods and technology made universally accessible to provisions as needed, e g. for the hearing impaired,
individuals and families in the community through their full the visually impaired and the mentally retarded;
participation and at a cost that the community and country • Provision of technical and mobility aids and other
can afford to maintain at every stage of their development devices;
in the spirit of self-reliance and self-determination. • Specialized education services;
It forms an integral part both of the country’s health • Vocational rehabilitation services (including vocational
system, of which it is the central function and main focus, guidance), vocational training, placement in open or
and of the overall social and economic development of sheltered employment;
the community. • Follow-up.
It is the first level of contact of individuals, the family Examples of rehabilitation interventions are given in
and community with the National Health System bringing Table 40.15
CHAPTER
40
526 Rehabilitation and Social Issues
Table 40.1: Examples of rehabilitation interventions
Problem Rehabilitation interventions

Anatomical
Deformity of the hand Reconstructive surgery (RCS) and Physiotherapy
Foot drop Ankle-foot orthosis, RCS
Amputation Prosthesis
Psychological
Depression Counseling
Functional
Limitation to fine hand movements Occupational therapy
Mobility limitations Crutches or wheel chairs (Tricycles)
Social participation
Stigma in the family Counseling
Exclusion from community functions Education and advocacy
Children with disability Promoting inclusive education
Economic
Loss of employment/ Unemployment Vocational training and Placement / Reservation of seats for disabled
for higher education; and employment in private and public sector
Poverty Micro-credit for selfemployment
INSTITUTION BASED REHABILITATION functioning are able to enhance their abilities, and are hence
(IBR) 6 better able to live independently and participate in their
societies.
In 1995, O’Toole suggested that institution-based
In many low-income and middle-income countries, only
rehabilitation was helping no more than 2% of those in
5-15% of people who require assistive devices and
need. There is however an increasing shift away from
technologies have access to them.
delivering health services managed from institutional care
The Convention on the Rights of Persons with
facilities to primary health services, centred on the needs
Disabilities (Articles, 20 and 26), the World Health
of the local community and delivered in the community.7
Assembly resolution WHA58.23 and the United Nations
Most of the estimated 650 million people living with
Standard Rules on the Equalization of Opportunities for
disabilities around the world lack access to appropriate
Persons with Disabilities, all highlight the importance of
medical care and rehabilitation services, especially those
assistive devices.
living in low- and middle-income countries. As a consequence,
people with disabilities experience greater challenges in
attaining and maintaining maximum independence and
health.
Rehabilitation encompasses a wide range of activities
including rehabilitative medical care, physical,
psychological, speech, and occupational therapy and
support services. People with disabilities should have
access to both general medical care and appropriate
rehabilitation services.
ASSISTIVE DEVICES/TECHNOLOGIES
Assistive devices and technologies; such as wheelchairs,
prostheses, mobility aids, hearing aids, visual aids, and
specialized computer software and hardware increase
mobility, hearing, vision and communication capacities.
With the aid of these technologies, people with a loss in Fig. 40.1
CHAPTER
40
Rehabilitation 527
CAPACITY BUILDING therefore a multisectoral strategy with some key principles
to enable people with disabilities to participate in the whole
At present most schools of public health, medical schools
range of human activities.
and other institutions involved in training health
CBR as a system consisting of several components
professionals around the world do not include disability
which can be illustrated as a house with three pillars
and rehabilitation in their curricula. Nor are disability issues
(Fig. 40.3).10
included in the curricula of other technical or professional
The first pillar represents the members of the local
schools, such as those training architects, urban planners,
community with an understanding of disability issues and
and engineers.
with positive attitudes towards disabled persons. The
The Convention on the Rights of Persons with
second pillar represents a selected group of local volunteers
Disabilities in Articles 20, 25 and 26 requires Member
and others who have specific knowledge and skills in CBR
States to develop initial and continuing training for
and also have positive attitudes. The third pillar represents
professionals and staff to improve access to mobility
individuals and organizations outside the local community
devices, health care, habilitation and rehabilitation services.
who have knowledge and skills in CBR, resources for CBR,
along with positive attitudes. The base represents the
community development philosophy which believes in the
capability of the community. The roof represents the
achievement of CBR when the community takes the
responsibility of implementing its own program. It must be
emphasized that when a CBR framework is proposed, it
must consider the different contributions from all these
participants, and facilitate easy understanding of the
concepts so that all those who are involved in the program
can work together efficiently.10
Fig. 40.2
COMMUNITY BASED REHABILITATION8

Community Based Rehabilitation (CBR) is recognized as
best practice in addressing the needs of people with
disabilities, including those affected by leprosy. The
definition recognized by the ILO, UNESCO and WHO
describes CBR as follows:
“CBR is a strategy within general community
development for the rehabilitation, equalization of
opportunities and social inclusion of all people with
disabilities. CBR is implemented through the combined Fig. 40.3: Components of community based rehabilitation visualized
efforts of people with disabilities themselves, their families, as a house standing on three pillars, with each having an important
contribution in the attainment of objectives of CBR.
organizations and communities, and the relevant
governmental and nongovernmental health, education,
CBR AND POVERTY REDUCTION 9
vocational, social and other services.”
The basic needs of all people, including people with Poverty is the root cause of many disabilities and disability
disability (and also the people affected by leprosy), are further increases poverty. About 400 million people with
the same – food, health, education, shelter, and so on. disabilities live in low income countries, often amidst
CBR facilitates access to basic needs, and at the same poverty, isolation and despair. Poverty further limits access
time promotes equal opportunities and equal rights. It is to the basic health services, including rehabilitation and
CHAPTER
40
accessing education. Community Based Rehabilitation is However, in recent years there has been a change in
a strategy for socioeconomic development. It is essentially attitude towards leprosy. The stigma associated with the
about human rights. disease has lessened. People affected by leprosy now
often remain within their families and communities. As a
POTENTIAL OF THE COMMUNITY10 result, involving the family and community members is
now seen as a key strategy to empower people affected
It is important to recognize communities and individuals by leprosy, encouraging them to play an active role in their
and their family members within the community as the rehabilitation.
primary resource available for rehabilitation. Communities One of the aims of CBR is to ensure that people with
understand the problems that arise. They have access to disabilities get the same rights and opportunities as all
resources and can provide long-term support. Developing other community members. This includes rights such as,
community support and participation in the rehabilitation equal access to health care, education, skills training,
process is essential for effective rehabilitation. Even the employment, family life, social mobility and political
poorest community has resources that can facilitate empowerment. A successful CBR aims at meeting the
inclusion and participation. To achieve this, community needs of people affected by leprosy and promoting their
and CBR workers need a good understanding of the quality of life. Therefore, CBR is highly relevant to the
community and its potential. The various levels of rehabilitation of people affected by leprosy.
interaction between community and CBR workers are Moreover, just as leprosy control activities have been
depicted in Figure 40.4. integrated into general health services, the rehabilitation
of people affected by leprosy should be integrated into
general CBR programs. In leprosy-endemic areas where
only a leprosy-related program is available, these programs
are encouraged to introduce CBR strategies and to open
up their services to people with other disabilities.
CHANGING SCENARIO OF LEPROSY

REHABILITATION
Even though the strategies in leprosy rehabilitation have
been modified to suit the present situation for sometime
now, it is still unclear as to who needs rehabilitation and
which services are best suited for different groups of
patients. In an analysis of studies on leprosy, Srinivasan
Fig. 40.4: The picture depicts the three spheres of influence on an reported that 21 to 45% of all persons affected by the
individual (people with disability) and the appropriate rehabilitation disease deteriorated economically.
interventions targeting all the three areas.
A high proportion of this group had deformities. Yet,
not all persons with deformities deteriorated economically.
LEPROSY AND CBR10 Conversely, some persons without deformities also
deteriorated economically. The dilemma is to identify ‘who
Historically, people with leprosy-related disability have been amongst leprosy affected persons need community level
ostracized from their communities and have rarely rehabilitation to address the economic and other
accessed integrated disability services, which includes psychosocial impact of the illness’. Are they persons with
all disabilities provided by the Government and NGOs in deformities? Or are they leprosy affected persons with
general. They preferred the services offered by dedicated some other parameters that are not yet identified?
leprosy NGOs in the vertical approach. This institution- (Fig. 40.5)10
centric approach and the stigma surrounding leprosy meant Likewise, it is yet unclear what kind of rehabilitation is
that communities had little involvement in the rehabilitation most acceptable to leprosy affected people. For example,
process of people affected by leprosy. only a very small number of people with deformities are
CHAPTER
40
Rehabilitation 529
contributors to the CBR program, from policymaking to
implementation and evaluation, for the simple reason that
they know what their needs are.
Case Study
(Participation)
“Shiv Kranti Apang Bachat Gat” is the first self-help
group (SHG) for the disabled in a village in Amravati
district of Maharashtra. The group comprises of
6 members belonging to different age group and
disability category. Among them 4 males of age group
50-60 yrs., 1 female, and a girl (7 yrs old studying in a
normal School) are among the group members. They
have opened their bank account in Amravati District
Fig. 40.5: Steps in identifying people in need of rehabilitation services. Central Cooperative Bank, Amravati.
The group members are actively working as unpaid
finally fit and willing for reconstruction surgeries. Similarly, volunteers in their village. They go in group conducting
a substantial number of economically deteriorated leprosy survey of the disabled in Kurha village. Their main motive
affected people show no interest in seeking available of doing this survey is to:
rehabilitation schemes. Traditionally, health care institutions 1. Provide information about the government schemes
used a ‘top-down’ approach in service delivery and to the individual as per their age group and
governance. In some cases, the systems became so capabilities.
autocratic that ‘needs’ of clients were ignored and they 2. To provide information about the importance and
never became empowered to choose their goals. In benefits of Self-help Group and thereof motivating
contrast, ‘community based organisations’ do not have them to form SHG on behalf of the project.
highly differentiated structures or systems of 3. Their future plan is to start a ration shop in their
communication that are imposed on clients. They use a village; from the loan which they will be getting from
‘bottom-up’ approach that allows client participation in the bank.
strategy development. The major difference between A Self-help group, which was formed for the socio-
institutions and community-based organizations is that economic rehabilitation of the group members, is now
institutions discouraged people from accessing services
helping the other disabled in the community voluntarily.
if they disagreed with the institutional goals. In community-
A good example of positive role model of the people
based organizations any such differences are settled
with disabilities; as active contributors of their own and
through a change in program plan to make it more client-
working for the cause of the society at large.
centred.
BASIC PRINCIPLES OF CBR10 Empowerment

The principles outlined below are overlapping, Local people and especifically people with disabilities and
complementary and interdependent. their families, ultimately may make the program decisions
and control the resources. This requires people with
Participation disability taking leadership roles within programs. It means
CBR focuses on abilities, not disabilities. It depends on ensuring that the CBR workers, service providers and
the participation and support of people with disability, family facilitators include people with disabilities; and that all are
members and local communities. It also means the adequately trained and supported. Results are seen in
involvement of people with disabilities as active restored dignity and self-confidence.
CHAPTER
40
Case Study Case Study

(Empowerment) (Awareness and Advocacy)
The community participation in Prem Nagar leprosy Bhusan Mahato, is a 60-year-old man living at Simonpur
colony in Janjgir-Champa district of Chhattisgarh has village, a leprosy colony in Purulia district of West Bengal.
been very successful. People in the community have Due to leprosy and the associated stigma he lost his
helped in conducting the general survey and the leprosy job. This put his family in a very difficult situation. They
survey. Prevention of disability (POD) training of had to struggle even to get their daily bread. One day,
leprosy-affected volunteers of the colony was one of following a community awareness meeting, Bhusan was
the highlights in the project, and then using them as so enthusiastic about all that he had heard that he
supervisors and trainers in the selfcare groups was decided to apply for a disability certificate and later
very effective. Successful outcome of the five days approach the government for the benefits. But he was
training workshop had encouraged these thirteen soon turned away and was not able to get a disability
volunteers to share the knowledge and skill of selfcare
certificate. He approached the staff of the project team
to others, and increased their own confidence as well.
instead. The team advised him that first he has to apply
So far 51 selfcare groups have been organized in the
to the Medical Board for the Disability Certificate. He
colony. In the beginning the project staff faced difficulty
was soon able to get a Leprosy Cured Certificate and
getting the people to practice selfcare at home, but
then after nearly eight months was issued a disability
after organizing the self-care groups, there were
certificate. With this, he was able to apply for the
amazing results. The members reprimanded each other
if they had not cared for themselves properly, and government benefits. Today, he receives a monthly
shared any trouble they were having in their families pension with which he is able to support his family.
or community. The result has so far been significant. It There was screening camp of the Indian Red Cross
has led to improvement in prevention of disability, Society in his area and he was gifted a tricycle, which
increasing numbers of people using protective footwear, today helps him to be mobile. Having received the right
reduction in the recurrence of ulcers and reduction in help at the right-time, Bhusan has come a long way
hospital admittance. and is living a life of contentment.
Raising Awareness Self-advocacy

CBR addresses attitudes and behavior within the CBR consistently involves people with disabilities in all
community, developing understanding and support for issues related to their well-being. Self advocacy is a
people with disabilities and ensuring sustainable benefits. collective notion, not an individualistic one. It means self-
It also promotes the need for and benefit of inclusion of determination. It means mobilizing, organizing, representing,
disability in all developmental initiatives. and creating space for interactions and demands.
Experience has shown that impairment is only one Advocacy means promoting or speaking out for a cause.
limiting factor in the life of a person with disability. Since people with disabilities have the best understanding
Attitudinal, institutional and other barriers have a strong of their situation and needs, it is important that they take
influence on the level of disability experienced, and limit a lead in advocacy. If they do not do this their situation
the opportunities of people with disabilities. While the first and needs will not be effectively expressed. The act of
step for many people with disabilities is a fundamental expression itself is empowering and can motivate action.
change in their mindset—from passive receiver to active Rehabilitation workers become involved in advocacy on
contributor—removal of the barriers that deny them full behalf of people with disabilities. This involves speaking
participation in their communities is a key step in the out against injustice and working for equality of rights.
rehabilitation process. Community-oriented interventions Communities and governments are encouraged to accept
are needed that increase knowledge, change attitudes, and take up their responsibilities towards people with
mobilize resources, and encourage participation in disabilities. Where disabilities result in loss of rights or
rehabilitation activities. social exclusion, advocacy draws attention to these
CHAPTER
40
Rehabilitation 531
injustices and seeks to correct them. Involving more may provide resources or services such as loans,
people, speaking with a united voice, and working in vocational/skills training, marketing opportunities or other
alliance with other interest groups all contribute to services or expertise.
successful advocacy. Activities commonly associated with
advocacy include large-scale education programs or Sustainability
lobbying for changes in society to address injustice. CBR activities must be sustainable beyond the immediate
Advocacy begins when individuals or groups contact the life of the program itself. They must be able to continue
relevant authority and raise a specific issue, such as the beyond the initial interventions, and be independent of the
need to enrol a disabled child in a local school, to access initiating agency. The benefits of the program must be long-
credit, to access housing benefit, etc. lasting.
Partnerships Case Study

CBR depends on effective partnerships with community- (Gender – Women SHG)
based organizations, government organizations and other
The Laxmi Mahila Self Help Group (SHG) is based at
organized groups.
Nangchui, Kota District of Bilaspur, Chhatisgarh. Initially,
Being aware of the services available in the community
people were unaware of the concept of such a group.
to people with disabilities is important information for the
There were several visits by CBR workers and repeated
rehabilitation process. Networking among potential partner
sessions with the women to explain, how the self help
organizations provides the opportunity to share information
groups function. After a certain level of rapport was
on local services, reduce duplication, and open new ways
established, the women were willing to give it a try. In
to respond to rehabilitation needs. It ensures that
March 2006, eleven members got together to form the
rehabilitation programs and their clients gain access to
group. There were two leprosy affected women, two with
the services they need. Organizations may represent the
physical disability and 7 others who were living below
community or groups within the community. They may
the poverty line. The group meets regularly and each
represent the interests of people with disabilities. They
member contributes 20 rupees and therefore a collection
of Rs. 220 in a month is gathered from the group. The
Case Study local government, i.e. the Panchayat, gave them the
(Partnerships and Sustainability) responsibility of a mid-day meals project. Later they
A good example for partnerships and sustainability is went on to get involved in a fisheries project. Today
seen in the Mega Mela for the disabled, organized at these SHG activities stand as very successful income
Ramachandra Puram, Andhra Pradesh in 2005. The generating programs. The self-help group made a profit
highlight is, that most of the resources for the mela of about Rs. 8500 in mid day-meal program and from
were drawn from the local community itself, with fisheries got a profit of Rs.6690. In the month of July
encouraging support from the following organizations. 2007, the self help group women purchased 15 kg fish
1. Organising Camp Krushi Orthopaedic Society, seed worth Rs. 3000 and the members are carrying out
Vizag and the community interlending and raising Rs 21000.
project The Laxmi Self Help Group has helped improve the
2. Food Sri Chaitanya Rice Mills standard of living of these eleven women and has also
3. Venue (Mandapam) Lions club (at a subsidized given them a sense of pride and purpose, which has
rate) changed their outlook on life. It has also had a wider
4. Technical support Krushi Orthopaedic society, impact in the village. Seeing the good work of the Self
AVFTD, Help Group, the Gramin Bank is ready to give financial
Bhagwan Mahavir Seva help according to government scheme.
Samiti (Rajasthan) They have also started making plates out of palm
5. Mobility aids Bhagwan Mahavir Seva leaves and are trying to get a good market for it. Having
Samiti (Rajasthan) enjoyed the many benefits, the women are enthusiastic
6. Miscellaneous New Hope Loving Mission to take-up new challenges and move forward.
CHAPTER
40
SECTORS AND ROLES FOR THE cooperation, support and involvement are essential if CBR
DEVELOPMENT AND IMPLEMENTATION is to cover the total population and be sustainable. They
OF COMMUNITY-BASED should implement and coordinate the development of the
REHABILITATION 12 entire program structure, including the development of the
referral system, as well as should also provide resources
The initiative to start CBR programs and to facilitate their
for non-governmental organizations (NGOs) and community
development may come from any one of the following
groups. However, the effectiveness of CBR and the long- activities. Finally, they should ensure that discriminatory
term development and sustainability of any CBR initiative legislation is changed and that the rights of people with
will require the coordination, involvement and collaboration disabilities are guaranteed and protected. The governments
of all seven groups. The seven groups and their suggested (local, regional and national) must ensure reservation of
roles are as follows: seats for disabled people, for higher education and
employment.
People with Disabilities
People with disabilities can and should contribute to all
Nongovernmental Organizations (NGOs),
levels of CBR programs in every position within a program.
Local, Regional, National and International
They know what the effects of local conditions are on Organizations
themselves. They are likely to have a good understanding NGOs, including organizations of people with disabilities,
of those effects on their peers with disabilities. They also are often able to provide resources and skills to facilitate
know what impairment really means in the context of their the development of new programs, especially in areas
family, community and nation. This knowledge enables where none exist. They can develop new approaches to
them to be very effective members of a CBR team. People CBR and provide training programs for government
with disabilities have an important role in community employees, CBR workers, people with disabilities, families,
education. As community educators, they serve as living and community members. NGOs are effective in facilitating
examples of people with disabilities that can make a the development of community members as CBR program
significant contribution, provided that they are given the leaders. They are often best able to provide long-term care
opportunity and the right type of assistance. facilities for those people with extensive disabilities whose
families cannot or will not look after them.
Families of People with Disabilities
Families have the primary responsibility for caring for all Medical Professionals, Allied Health Science
of their members. They are the first line of support and Professionals, Educators, Social Scientists
assistance for people with disabilities at the local level. and Other Professionals
As such, families must be included in CBR program
activities as the family members are the people who most Professionals are often in a position where they can, as
often initiate CBR programs and are, or prove to be, the trainers and educators, facilitate the development of new
most effective contributors at all levels. programs by making their knowledge and skills accessible
to community members and CBR program workers. They
Communities can also ensure that they support community efforts by
Community members should be involved in CBR programs making themselves available and accessible on a referral
at all levels because they already know the local basis. When they are in government service, they can
environmental conditions, the local economy, the local advocate and promote the development of CBR programs
political situation and how to work with them. Community as an effective way to provide local-level services quickly.
involvement usually requires the agreement and approval,
both formal and informal, of the community leaders. The Private Sector (Business and Industry)
The private sector has a social obligation to return some
Governments (Local, Regional, National) of the benefits of its operations to the communities that
Governments have the most important role in the support it. In the past, this support has largely taken the
development and sustainability of CBR programs. Their form of charity. Charity occurs when donors “give” whatever
CHAPTER
40
Rehabilitation 533
they feel, is needed or appropriate to people with • Encouraging people with disabilities to join mainstream
disabilities. This approach to assisting people with self-help groups;
disabilities is no longer appropriate and needs to be • Skills training and income-generating activities.
changed. Supporting CBR program activities eliminates As can be seen by the interventions listed above,
the need for charity. By supporting CBR programs, the income generation is just one of the many types of
private sector receives credit for its social involvement intervention. Clients and PHC staff may identify other forms
while being guaranteed that its support is put to effective of intervention that are appropriate to the specific needs
and efficient use. of the client. Some or all interventions may be arranged
through referral to services provided by other organizations.
ARRANGEMENTS FOR THE DELIVERY
Choosing an Intervention
OF CBR SERVICES10
The choice of intervention is central to the client’s individual
Arrangements for the delivery of primary-level CBR rehabilitation plan. The intervention should match the
services vary according to the local situation. Depending needs, skills, expectations and resources of the client and
on which organizations exist, CBR services may be other family and community members involved. The
delivered through some or all of the following: Community- objective is to identify an appropriate activity to meet an
based organizations; Organizations of people affected by agreed priority need, whether physical, psychological,
leprosy or other disabilities; Voluntary, nongovernmental social or economic. The result may be an intervention with
organizations; Government services. the community, the family or the client. In choosing an
intervention it is important that clients recognize the risks
Intervention and costs as well as the opportunities and benefits.
Interventions are activities agreed between CBR workers
and clients that seek to address an agreed need or problem Promoting Community Awareness
related to individuals or communities. They take many and Participation
different forms, such as: Experience has shown that impairment is only one limiting
• Supplying information to clients or communities about factor in the life of a person with disability. Attitudinal,
resources and opportunities available in and around institutional and other barriers also have a strong influence
them; on the level of disability experienced, and limit the
• Counseling or social work to address psychological or opportunities of people with disabilities. While the first step
social problems; for many people with disabilities is a fundamental change
• Formation and development of self-help groups or in their mindset—from passive receiver to active
advocacy groups; contributor—removal of the barriers that deny them full
• Educational activities to enhance social harmony or to participation in their communities is a key step in the
promote an inclusive society; rehabilitation process. Community-oriented interventions
• Advocacy to promote equal opportunities and equal are needed that increase knowledge, change attitudes,
rights in the society; mobilize resources, and encourage participation in
• Negotiating access to local government services, rehabilitation activities.
schools, pensions or benefits;
• Promoting the participation of people with disabilities Advocacy
in community development activities; Activities commonly associated with advocacy include
• Small projects that provide income without the risk of large-scale education programs or lobbying for changes in
aggravating disabilities; society to address injustice. Advocacy begins when
• Developing home-based care programs—preferably individuals or groups contact the relevant authority and
selfcare; raise a specific issue, such as the need to enrol a disabled
• Providing assistive devices to overcome physical child in a local school, to access credit, to access housing
disabilities; benefit, etc.
CHAPTER
40
a developmental process. If CBR is externally

initiated, communities can remain passive and do not
develop capacity to manage their own affairs.
2. “Community participation” is the central and essential
tenet in the social model. However, communities are
often quite heterogeneous, with wide differences in
socioeconomic, educational, religious and ethnic
status. This diversity can cause friction, because
some groups have different needs and priorities
compared to others. Similarly, needs and priorities of
people with disabilities are not always at the forefront
when competing issues occur simultaneously.
3. People in some developing countries also expect
benefits from their governments as doles, and as a
result show a reluctance to take charge of their affairs.
Decentralization and “bottom-up” strategies become
difficult to implement in these circumstances.
4. The emphasis in CBR today is on integrating disability
into the development processes, making the program
(Source: The advocacy cycle, Practical action in advocacy, Tearfund) cost-effective, promotes better social integration and
ensures access to people with disabilities as much
as others in the community. Besides, community
Networking with Community and Other participation is greater when the majority rather than
Organizations only a minority shares its benefits. At the same time,
Being aware of the services available in the community to unplanned integration of disability into development
the people with disabilities; is important information for can ignore ‘real rehabilitation’ needs of people with
the rehabilitation process. Networking among potential disabilities and segregate them further. During the last
partner organizations provides the opportunity to share few years, integration of disability into community
information on local services, reduce duplication, and open development programs has shown some tangible
new ways to respond to rehabilitation needs. It ensures benefits and some problems. Poor organizational
that rehabilitation programs and their clients gain access capacity to integrate two functionally different streams
to the services they need. Organizations may represent of interventions and lack of familiarity with
the community or the groups within the community. They rehabilitation on the part of community development
may represent the interests of people with disabilities. They organizations, have acted as major barriers for
may provide resources or services such as loans, integration.
vocational/skills training, marketing opportunities or other 5. Lack of mobility, education and other skills also
services or expertise. prevent disabled people from being a part of the
broader development process.
6. Integration of rehabilitation into development programs
CBR CHALLENGES12
needs a high degree of co-ordination and collaboration
1. CBR has become a community development process. between different sectors such as health, education,
The debate whether it should be initiated by outsiders employment and others. Barriers in this process have
or started by the community, has been of interest. to be removed before such collaboration can succeed
Votaries of the former view advocate starting delivery and make the social model of CBR effective.
of services without waiting for the community to 7. CBR was promoted to gain wider coverage at
participate. The alternate view is that concerned affordable costs. In order to reduce costs, many
groups themselves should initiate CBR because it is interventions were shifted to families of disabled
CHAPTER
40
Rehabilitation 535
Table 40.2: Sample referral form
EDUCATION Interventions Select Where to Refer? Select

Is she/he could not pursue ICDS (Balwadi) Anganwadi Worker
education (or) dropped-out due Primary education Women Self-help groups (select
to leprosy/disability related Secondary education groups)
reasons? Higher education Primary school (SSA)
YES - NEXT COLUMN → Counseling Secondary school
NO - NEXT STAGE Week-end /Evening Tuition Higher secondary school /Inter-
(LIVELIHOOD) Bridge courses college
↓ Special school Child-focus NGOs (incl. ILEP)
Distance education Philanthropists
Faith-based organizations (FBO)
Self-help Groups (SHG)
District Disability Rehabilitation
Centre (DDRC)
Govt. / Private universities
LIVELIHOOD Job counseling Vocational training centre VTC

Is she/he (with leprosy Nonformal vocational training like, (Govt)
disability) skillfully and/or Tailoring, Weaving, Carpentry, Bag / Vocational training centre (Private)
gainfully employed? Candle-making… Vocational training centre (NGOs
NO - NEXT COLUMN → Formal Training like Motor incl. ILEP)
YES - NEXT STAGE mechanic, Refrigeration, Radio and Employment Exchange
(AIDS and APPLIANCES) Television, Computers … (common/special)
↓ Employment:Wage employment Private sector
(Salaried) Banks
Self-employment and any other SER4 NGOs (incl. ILEP)
like Grants/Loans/Subsidies Philanthropists (Lions/Rotary club,
etc.)
SHGs
FBOs
AIDS and APPLIANCES MCR /Suitable footwear DDRC

Does she/he (with leprosy/ Splints ILEP NGOs (leprosy)
disability) have the necessary Goggles Other NGOs
mobility aids and support Self-care kit Philanthropists
devices? Crutches
NO - NEXT COLUMN → Tricycle
YES - NEXT STAGE
(SOCIAL and EMPOWERMENT)
↓
SOCIAL and EMPOWERMENT Counseling DDRC

a. Does she/he enjoy being with Awareness on basic fundamental Dept. of Human Rights
family, friends, neighbours? rights of human-being + Rights of Like-minded NGOs
b. Is she/he aware basic people with disabilities Philanthropists
fundamental rights/disability Advocacy SHG
rights Capacity-building FBOs
c. Can she/he get relevant
information necessary for day-
to-day life easily?
d. Can she/he go/use public
places easily?
e. Does she/he have a positive
identity in the society?
f. Can she contribute to the fullest
potential in the society?
g. Is she/he part of a people’s
group like SHG?
CHAPTER
40
persons and community. Although CBR appears to entire Indian nationals on payment of minimal fee. Provision
be cheaper, in reality much of the costs are transferred of financial assistance for disabled persons is also
to the consumers. If the consumers’ costs are also available.
included in computing the expenditure, it may turn For information on the various schemes from the Central
out to be much higher than what is generally assumed. Government of India, a useful guide called Information
Many families in developing countries do not have and Guidance Booklet for Persons with Disabilities
the means to support their disabled members. In an Jan 2004 was released and is available from Rehabilitation
environment of increasing difficulty to access Council of India (RCI) Office, 23-A, Shivaji Marg, New Delhi
resources, these families are more likely to choose 110015 and also can be downloaded from http://
their ‘normal’ members to support than their disabled www.rehabcouncil.nic.in/programs/info_guide.htm
relatives.
8. About 30% of people with disabilities in CBR have NATIONAL PROGRAM FOR
severe and multiple disabilities. Sometimes, severely REHABILITATION OF PERSONS
disabled persons get neglected while CBR focuses WITH DISABILITIES 13—A BLEND
on issues such as “community participation” and equal OF CBR AND IBR
“rights”. When they are neglected, programs tend to The two broad approaches to rehabilitation are community
gloss over their shortcomings as a “limitation of CBR”. based rehabilitation (CBR) and institutional based
9. Women with disabilities are another group whose rehabilitation (IBR). Several schools on the subject tend
needs are not adequately addressed. They face unique to look at these as two distinct, mutually exclusive
disadvantages simultaneously, such as difficulties in alternatives and generally argue in favor of one or the other.
performing traditional gender roles, participating in However, the two approaches are complementary to each
community life, and accessing rehabilitation services other and the policy option is not one of CBR vs IBR, but
provided by male service providers. one of focus, prioritization and a judicious mix of both in
10. The problems of community volunteers illustrate how any comprehensive package of rehabilitation for persons
difficult it is to translate a theme like “community with disabilities. An important step by the government in
participation” into practice. Volunteers are difficult to the direction of an appropriate blend of the two approaches
find, their turnover is high, large resources are required on a large scale, is the implementation of a comprehensive
to train them continuously, they lack motivation and scheme—National Program for Rehabilitation of Persons
do not perform if incentives or small salaries are not with Disabilities (NPRPD). The scheme is a state sector
paid. However, there are programs that have scheme with a four tier delivery system at Gram Panchayat
successfully used volunteers, though they are the (GP), Block, District and the State levels. The scheme
exceptions. envisages a CBR approach at GP / Block levels to be
dovetailed with an institution based approach at District /
State levels. The Union Government provides financial
REHABILITATION SERVICES FOR
resources, guidelines on implementation of the scheme
DISABLED PERSONS INSTITUTIONS and monitors its implementation by the States. The scheme
UNDER THE MINISTRY OF SOCIAL aims to create a strong network of rural-based rehabilitation
JUSTICE AND EMPOWERMENT services.
Physical, occupational, social rehabilitation and financial
assistance for purchase of Aids and Appliances are provided CONCLUSION
under Ministry of Social Justice and Empowerment, Govt. 1. In all rehabilitation efforts, emphasis should be placed
of India, with the basic objective to bring the target groups on the abilities of the individual, whose integrity and
(disadvantaged and marginalized section of the society viz. dignity must be respected. The normal development
scheduled caste, minorities, backward classes, persons and maturation process of disabled children should be
with disability, aged persons, street children and victims of given the maximum attention. The capacities of disabled
drug abuse, etc.) into the main stream of development by adults to perform work and other activities should be
making them self-reliant. Services are available for the evaluated, recognised and utilized.
CHAPTER
40
Rehabilitation 537
2. Important resources for rehabilitation exist in the working with and through the community to create positive
families of disabled persons and in their communities. attitudes towards people with disabilities, to provide
In helping disabled persons, every effort should be assistance to people with disabilities and to make the
made to keep their families together, to enable them to necessary changes to the environment and service delivery
live in their own communities and to support family systems. The resources, skills and initiatives to start and
and community groups who are working with this sustain CBR programs require the cooperation and
objective. In planning rehabilitation and supportive collaboration of seven relevant sectors: People with
programs, it is essential to take into account the disabilities; Families of people with disabilities;
customs and structures of the family and community Communities; Governments (local, regional, national,
and to promote their abilities to respond to the needs international); NGOs, local, regional, national and
of the disabled individual. international organizations, and organizations of people
3. Rehabilitation programs should make it possible for with disabilities; Medical professionals, allied health science
disabled persons to take part in designing and professionals, educators, social scientists and other
organizing the services that they and their families professionals; The private sector (business and industry).
consider necessary. When people such as the severely
mentally disabled may not be able to represent REFERENCES
themselves adequately in decisions affecting their lives,
1. From Global Strategy to National Action: Workshop for Health
family members or legally designated agents should Service Managers in Charge of Leprosy Control Programs,
take part in planning and decision-making. Session 6, Rehabilitation, Topic: Rehabilitation, definitions and
4. Efforts should be increased to develop rehabilitation policy environment http://www.ilep.org.uk/fileadmin/uploads/
services integrated in other services and make them Documents/WHO_Publications/wkshpguidepartrevised.pdf
2. Helander E. The origin of community based rehabilitation. APDRJ
more readily available. These should not rely on
2007; 18(2): 3-32
imported costly equipment, raw material and technology. 3. Bury T. Primary Health Care and community based Rehabilitation:
In recent years, a multisectoral (or multi-disciplinary) Implications for Physical Therapy. APDRJ 2005; 16(20): 29-61
concept of CBR has evolved. That concept emphasizes 4. UNO. Objectives, Background and Concepts, World Program
of Action concerning Disabled Persons. Available at http://
www.un.org/disabilities/default.asp?id=23
Highlights of CBR 5. WHO. Global strategy fir further reducing the leprosy burden &
sustaining leprosy control activities (2006-2010): Operational
1. CBR is a low cost strategy which can address the Guidelines. WHO SEARO New Delhi.p.38
rights of all disabled children and adults in their own 6. http://www.aifo.it/english/resources/online/apdrj/frimeet202/
homes and communities. It may cost about Rs.1,000 national.doc
7. O Toole B. Community based rehabilitation program. Prospects
per disabled person per year.
1995; 25(2):311-19
2. It can fit well within current community health or 8. WHO’s Key activities, Disability and Rehabilitation team (DAR),
development project structures, ideally with a Medical care and Rehabilitation www.who.int/disabilities/care/
manager for 6 CBRWs covering approx 12,000 en/index.html
population. 9. Towards the 21st Century: Challenges for Community Based
Rehabilitation in Asia and the Pacific Region - Asia Pacific Disability
3. It will assist in preventing disease and illness that
Rehabilitation Journal Vol.9, No.1, 1998
cause disability. 10. WHO/ILEP Technical guide on community-based rehabilitation
4. CBR helps to reduce unemployment and poverty and leprosy—Meeting the rehabilitation needs of people affected
in the families of disabled children and adults. It is a by leprosy and promoting quality of life
11. 2nd Meeting Report on the development of guidelines for
way to include disability in mainstream development
Community Based Rehabilitation (CBR), 25th and 27th July 2005,
objectives, addressing the Millennium Development Geneva, Switzerland)
Goals. 12. Thomas M, Thomas MJ. Challenges in Leprosy Rehabilitation.
5. Finally, it is a strategic way of improving the lives APDRJ 2004; 15(1): 45-49
of disabled people and the whole community, 13. Meeting Report on the development of guidelines for Community
Based Rehabilitation (CBR) programs (1st and 2nd November
making it more responsible, caring and inclusive.
2004, Geneva, Switzerland)
CHAPTER
41
41 Community-based Comprehensive
Leprosy Work
R Ganapati, VV Pai
INTRODUCTION considered and conceived in such a manner that it had its

firm roots at the community level. Once dapsone
Can leprosy work be managed totally at the community
(considered to be a miracle drug) became available,
level, and relying on the institutions only to the extent;
everything seemed to change. The main reason for the
when it is absolutely essential?
optimism was the realization of the proven effectiveness
Can the utopian concept of community-based
of this inexpensive drug and more importantly the ease of
rehabilitation, which aims at integrating all patients with
its oral administration at the mass level. The survey,
handicaps due to any disease including leprosy, be ever
education and treatment (SET) strategy was so designed
realized at the community level?
that the trained paramedical workers were engaged, each
Unfortunately, this ideal is not believed to be feasible
worker combing a population of 20,000 to 40,000 and
by many well meaning leprosy workers and managers,
administering dapsone at the clinics, exclusively
whose sincerity, commitment and concern for leprosy
functioning for leprosy patients who were detected by
patients cannot be questioned. They may be correct in
house-to-house survey.
their personal assessment of the situations because their
This simple technique to create awareness about
style of management has been conventional, owing to the
leprosy through health education; was actively practiced
lingering misconceptions engendered over centuries, which
at the community level. This strategy worked reasonably
perhaps, influence their approach to the problem.
well as far as the distribution of dapsone was concerned,
We can confidently say that even in the current
raising an expectation that leprosy work could be a totally
scenario, achieving the objective stated above is possible
community-based program, which could be integrated with
to a great extent, if one is determined and makes persistent
other disease control activities later at some stage.
efforts to overcome the hurdles in the realization of the
However, this ideal of comprehensive survey, education
goal.
and treatment work at the rural and urban community level
For any community problem to be solved, effective
has never been achieved, except perhaps in some
linkages (between the personnel active in the field; and
experimental areas.
the community members) should be planned for
establishing rapport with the patients living in that
community. How can this be achieved with reference to INTEGRATED SET-UP
leprosy? Before one thinks about reaching the ideal, it is The current situation to achieve the ideal in leprosy control
important first, to examine the ground realities of the field and rehabilitation, in fact is more favorable than it was at
situation relating to leprosy. any time in the past, as leprosy has been integrated into
general health system, and the disease has been declared
SET STRATEGY eliminated from the country on 31st December 2005 by
Whatever the situation prevailing in the chaulmoogra era, the Government of India. The “disease burden” in the
leprosy work in India was always (and expectedly) community is claimed to have come down. There is no
CHAPTER
41
Community-based Comprehensive Leprosy Work 539
doubt that the transmission of leprosy has come down comprehensive manner in all the rural communities. The
considerably in most endemic countries as judged by scheme covers urban areas under National Urban Health
prevalence rate (PR), though new case detection rate Mission (NUHM) employing “Urban Social Health Activists”
(NCDR) in many countries, particularly India and Brazil, (USHA).
continues to cause concern. This implies that the disease ASHA, who is a female volunteer belonging to the same
is still plaguing the community, asking for a solution through village, selected by the community; could be utilized for
initiatives arising from within the community. early detection of suspected cases of leprosy, and referral
What causes even more anxiety (than the almost stable of such cases to the nearest health center for confirmation
NCDR) is the abnormal load of patients with deformities in and completion of treatment. Rogi Kalyan Samitis at PHC,
the postelimination era. Fairly reliable statistics are available CHC and district level are autonomous registered bodies
on new cases identified in 2007 with grade2 deformities, constituted at each level to facilitate in the management
i.e. 10,612 globally (3477 in India), as per WHO. However, of hospitals and delivery of quality care to the patients.
no accurate figures are known about the total pool of such Rogi Kalyan Samiti is authorized to procure drugs at local
patients living in the community, as well as those settled level in emergency, out of funds available with the Samiti.
in leprosy colonies due to social ostracism. Numbers given Similarly, medical rehabilitation of persons affected with
as 2 to 3 million in the world and 1-1.5 million in India may leprosy may be supported by Samiti. District health
well be underestimates. Whatever the veracity of these mission, which is chaired by president of “Zila Parishad”
figures, the problem of disability care and rehabilitation may be helpful; and should be utilized for advocacy of the
faced by the government and NGOs is of insurmountable program.
magnitude indeed. The initial reports of the performance of ASHAs in rural
It is in this context one has to address the task of areas of some states are found to be satisfactory. This
comprehensive leprosy work and plan community-based class of grass root level workers can be trained sufficiently
strategy. Almost all the facets of leprosy management can in leprosy so as to act as a bridge between health care
indeed be practiced at the grass root level, laying strong providers and the people at the community level, so that
emphasis on integrating leprosy with nonleprosy sector/s,
leprosy work can be made a community enterprise in the
which are already showing concern for community
true sense of terms.
problems including health delivery.
The basic principle of the “vertical” SET program was
COMPREHENSIVE LEPROSY CARE
to employ workers who were actively visiting households
for survey and education. In fact, it was this program which Besides medical treatment, several other clinical problems
paved the way for involving multipurpose workers in an peculiar to leprosy demand attention. Hence a holistic
integrated set-up. As the population per worker is much approach is required for providing comprehensive leprosy
less in integrated setup, as compared to that in vertical care to enable us to manage all aspects of leprosy.
system, the situation is rendered more conducive to reach
out to the society more effectively. While it is debatable Objectives of Comprehensive Leprosy Care
whether integration is successful, a new health delivery 1. Treatment with MDT
strategy has come into vogue which apparently aims to
2. Management of reactions and neuritis
establish rapport with the community even more intimately.
3. Prevention of disability
4. Reconstructive Surgery
National Rural/Urban Health Mission
5. Care of the disabled
Under the National Rural Health Mission (NRHM) a new 6. Vocational rehabilitation
category of health workers called “Accredited Social Health 7. Overcoming stigma and discrimination
Activists” (ASHA) are being recruited. About 6 lakhs of All aspects of above except surgery can be attempted
ASHAs are already engaged in the country today. When at the domiciliary level. It is needless to stress upon the
this scheme is successfully implemented, theoretically, it significant role of a referral center equipped with trained
should be possible to achieve the utopian concept of manpower and equipment which is easily accessible to
establishing/ building leprosy related work in a the patient. Expertise of a higher caliber than what is
CHAPTER
41
available at the PHC in an integrated setup; is crucial for immediate treatment with a complete course of
offering select specialty services to the patients whose prednisolone, as well as other supportive drugs. Any delay
complaints cannot be managed in the community and at in the treatment of reaction may lead to further damage to
PHC level. the affected nerves, resulting in disability/ deformity.
Unfortunately, this is the weakest link in the current In case of early reversible disabilities, the workers/
setup. So many patients are forced to seek health care at volunteers are trained to provide simple tools like
the tertiary level as the services in the communities where prefabricated splints to patients with early disability and
they live; are either nonexistent or are so poor that the regularly monitor them. The volunteers can also provide
patients lose faith in the system. People feel that leprosy health education to patients with insensitive limbs to prevent
is a special disease to be managed in isolation in some injury, burns, wounds, and ulcers. Physiotherapy exercises
specialized institutions, tertiary care in hospitals, medical can also be taught to prevent worsening and deterioration
colleges, etc. Leprosy institutions are generally satisfactory of deformities, at the community level.
in the country today, but many patients would find it difficult
(if not impossible) to avail of their services. Disability Care
It is therefore clear that to provide services in a
Care of the disabled (Grade-2) is a necessary pre-requisite
comprehensive, integrated, cost effective and sustainable
manner, it is necessary to plan this service provider scheme for reaching the ultimate goal of community-based
as a part of the community development. rehabilitation (CBR). Delayed or inadequate management
of reactions and neuritis leads to disabilities of the hands,
Medical Treatment feet, eyes, etc. Trophic ulcers are a chronic problem
requiring regular care. Field workers are trained in detecting
Treatment for leprosy with MDT is now available at the
and providing home-based material support like dressing
primary health centers. Field workers are trained to monitor
of ulcers, microcellular rubber (MCR) footwear, splints and
compliance and the early detection of reactions. The clinical
other aids and appliances required for providing care for
management of reactions is possible at the PHC level
the disability. Tailor made ulcer care kit can be provided at
bringing it closer to the patient. It is expected that under
the patients doorstep for daily care of ulcers and wounds.
the NRHM scheme the services would be brought even
MCR footwear in novel (and fancy!) commercial designs
nearer to the patient, virtually at the door step.
would not only help in preventing ulcers/injuries to the foot;
Prevention of Disability but also in reducing the stigma associated with traditional
MCR footwear.
There is strong evidence to show that the stigma and For patients with irreversible deformities, surgical
apathy of the community to accept leprosy patients arises interventions may be the only option. Reconstructive
from the concept that disabled patients are infectious. The surgery is the only component of disability care needing
status and self-confidence of leprosy patients is also
highly specialized setup. The field workers can be trained
affected, especially if they have deformities. According to
to act as a link between the patient and referral centers at
Kopparty et al, proportion of families facing social problems
district level and tertiary level institutions.
having patients with deformities, was ten times higher
(57.3%) than those having patients without deformities
Vocational Rehabilitation
(5.7%).1
Persons suffering from leprosy are prone to disabilities Rehabilitation of the disabled is a very important and the
due to neural involvement. The community workers/ most difficult aspect of CBR. The disabled person needs
volunteers in addition to existing ASHA, can be recruited to be mainstreamed back into the society and this is the
and trained in early identification of neuritis and reactions. only way the stigma and discrimination can be addressed.
Once the indication of steroid administration is decided; Though mainstreaming is a tough and challenging task,
the maintenance of medication in a domiciliary manner vocational rehabilitation helps persons suffering from
can be ensured by the field workers/volunteers. Reaction disability due to leprosy; to stand on their own feet by
in person with leprosy is an emergency which can occur learning various skills. Providing equipment and articles
during treatment or post-treatment period and requires for income generation helps in achieving social and
CHAPTER
41
financial well-being and also heightens the self-esteem of goal by making sincere efforts. It is also imperative to
the patient. understand what really CBR means in its true sense.
Stigma and Discrimination WHAT IS CBR?

As deformity due to leprosy is the root cause of stigma,
If one wants to achieve the goal of community participation
offering domiciliary disability care reduces stigma
in rehabilitation with reference to any disease, one has to
considerably. Wherever disability care is practiced at the
understand the definition and guidelines of CBR offered
door step of patients, the families and the neighborhood
by authentic international bodies.
tend to accept the patients better. Gigantic rehabilitation
problem is faced by patients and their families still-living WHO (1960)4 defined rehabilitation as follows:
in leprosy colonies; because being an inmate of such “By rehabilitation is meant the physical and mental
colony is a big stigma in itself. Practice of rehabilitation in restoration as far as possible, of all treated patients to
the community is the most difficult component of leprosy normal activity, so that they may be able to resume their
management, because of the stigma and paucity of place in the home, society and industry. To achieve this,
available/ appropriate disability care. treatment of the physical disability is obviously necessary,
Field experiments by Bombay Leprosy Project (2008)2 but it must be accompanied by the education of the patient,
over more than three decades indicate that with dedication, his/her family and the public, so that not only can he/she
all aspects of leprosy management can be successfully take his normal place, but society should also be willing to
practiced in urban slums and rural areas. The efforts to accept him/her and assist in complete rehabilitation.”
address all these issues will pave the way to achieve the The above definition itself implies that any attempt at
goal of CBR, by no means an easy task (see Epilogue). rehabilitation of the handicapped should indeed be
community based. The actual concept of CBR, however,
IS THE CONCEPT OF CBR A REALITY aims one step higher in stating that, besides accepting
OR A MYTH? the handicapped patients, the community should itself take
In the current scenario, there are difficulties in offering the responsibilities of supporting /assisting him.
even this relatively easier and simpler aspect of the The term CBR is defined as “Community-based
leprosy services mentioned above, to the patients in the rehabilitation for and with people with disabilities” in a Joint
community with confidence. In some rural areas adjoining position paper by the International Labor Organization; the
Mumbai, prevalence rate of visible deformities due to United Nations Educational Scientific and Cultural
leprosy (Grade 2) alone, is of the order of 27 per 10,000 Organization (UNESCO); and the WHO (1994)5, as follows:
population.3 Offering services to such large number of “Community-based Rehabilitation is a strategy within
patients at their door step by any category of field workers community development for the rehabilitation, equalization
defies any easy solution, considering the logistic of opportunities and social integration of all people with
difficulties, and the paucity of manpower and resources disabilities. CBR is implemented through the combined
required for their delivery. As disability care is not the urgent efforts of disabled people themselves; their families and
felt need of many patients, it is unreasonable to expect the communities, and appropriate health education,
them to attend any referral centers which as such, are not vocational and social services.”
able to function up to an acceptable minimum of expertise. According to WHO (1995) CBR activities at the
It is in this backdrop that one has to study the feasibility community level rarely begin spontaneously. Rather, they
of implementing CBR. The principles of CBR demand that are stimulated by contact from the Ministry in charge of
such package of services should reach all the handicapped Rehabilitation or by a nongovernmental organization (NGO).
patients; including those suffering from leprosy, without If a ministry is in charge, it is the responsibility of the
any discrimination and that the community itself should Ministry of Health to provide disability prevention and
take these responsibilities by harnessing resources for medical rehabilitation services.
the support of the handicapped. This indeed is truly a tall “If the Ministry of Health (MOH) is responsible for the
order to achieve! Though we may not reach the ideal, it is CBR program, the community health worker may be asked
definitely possible to make some progress towards this to play an active role in disability prevention and
CHAPTER
41
rehabilitation. If another ministry is in charge and another India may pave the way for achieving the goal of CBR, in
volunteer, such as the community development worker is due course of time. The Ministry of Health and Family
the community contact for rehabilitation, the community Welfare (MOHFW) and the Ministry of Social Justice &
health worker should also support the rehabilitation program Empowerment, GOI are expanding rehabilitation services
by promoting disability prevention and the social integration to the persons with disabilities. For example, MOHFW is
of disabled people.” under the process of establishing physical medicine and
The WHO manual “Training in the Community for people rehabilitation departments in medical colleges and regional
with Disabilities” published in 1989 contains information hospitals. Additional support is being provided to
about the role of the community worker in a CBR program; institutions carrying out polio-related disability corrective
as well as information about what families can do to help surgeries.
someone with disability.
If the above principle is to be adopted, one can visualize LEPROSY AS A COMPONENT OF CBR
the following levels of patient care through which the
There can be no two opinions that ideally it is desirable to
services have to flow before the responsibilities are handed
make leprosy as an integral component of CBR, though
to the community, as shown in Figure 41.1.
there are only stray reports in the literature of this concept
being implemented successfully. A literature review on CBR
by Finkenflugal et al revealed that “despite this broad and
vast body of experiences, research on CBR is still rare
and the evidence base of the concept is fragmented and
incoherent”. Field studies incorporating leprosy as an
integral part of CBR are virtually non-existent.7
Comprehensive leprosy work alone will not be
meaningful unless all the components of leprosy
management (including rehabilitation) are integrated with
other diseases and practiced as a part of the community
development. Operational research in rural and urban areas
Fig. 41.1: Routes of devolution of health services is called for, before one can understand the difficulties
to community level one may have to overcome in implementing this
challenging task.
CBR may be initiated through outside intervention It is hoped that a day will come when the concept of,
however ultimately, the community will have to be not only the totally field based comprehensive work related
persuaded that it is worthwhile and in line with their interest to leprosy, but even CBR in the true sense of term, would
to become involved in CBR activities.6 be a reality.
For any CBR program with special reference to leprosy
to succeed, staff at the peripheral level should develop
EPILOGUE
good links with the referral units they are most likely to
use regularly. Staff at peripheral centers should know the
……..…..And miles to go before I sleep,
specialist clinics and other professionals to whom they
And miles to go before I sleep
may refer the patients, such as ophthalmology for significant
—Robert Frost
eye problem; dermatology for diagnosis of difficult skin
conditions; laboratory for skin smears and histopathology, It is clear from the foregoing account that reaching the
physiotherapy for assessment and management of ideal of
disability, podiatry for feet and footwear, occupational 1. Totally community-based leprosy work in a compre-
therapy for rehabilitation and adaptations, reconstructive hensive manner
surgery and plastic surgery, social workers for assessment 2. Integration of leprosy work with other diseases as a
and further referral to a CBR program. part of community development, including disability
The recently implemented Disability Prevention and care and rehabilitation, is too farfetched to think of at
Medical Rehabilitation (DPMR) program of the Govt. of this stage.
CHAPTER
41
serve, if properly trained and supervised. In a massive
field operation, more than 1,250 disabled leprosy patients
(with Grade 2 deformities) were identified in an adopted
rural population of nearly 4.8 lakhs, covering 11 primary
health centers (PHCs) in 3 “taluks” of Thane district, in the
suburban areas of Mumbai (Fig. 41.2). In some of the PHC
areas, the prevalence rate of visible deformities is about
25-27 per 10,000.
Services at the door-step using simple inexpensive
aids and appliances are already being offered by 8 rural
volunteers. They work in close coordination with the PHC
staff. The overall supervision is done by trained and
Fig. 41.2: Group of rural volunteers working in 11 PHC areas in experienced staff visiting from BLP. This cost effective
coordination with Govt. staff
model we believe, is worth replicating in other geographic
areas with comparable situations.
If any other agencies specializing in other conditions
causing handicaps become available in the same villages,
Fig. 41.3: Gutter splints being provided by a volunteer who is

himself cured of leprosy
Fig. 41.4: A patient being provided MCR footwear
However, one can progress towards the above goal
step-by-step and making sincere efforts.
In this context, it may be worthwhile referring to the
work of Bombay Leprosy Project (BLP) in offering disability
care to persons affected by leprosy, in rural Maharashtra
as a preliminary step towards implementing CBR; and at a
later stage, in larger areas and for disabilities due to causes
other than leprosy as well. All the field work in the adopted
villages is managed by volunteers including some persons
who were affected by leprosy in the past and are living in
the same community as of the disabled patients whom
they serve. With this work engagement, these volunteer
youths are also rehabilitated.
It is interesting to know how effectively these Fig. 41.5: A volunteer who is a cured of leprosy advising
volunteers, derived from the same rural community can a patient on how to use an ulcer dressing kit
CHAPTER
41
we may be able to collaborate and implement CBR for

them also. Unfortunately services to the physically
challenged due to causes other than leprosy are presently
not planned in a community based manner.
This is the area where planners of leprosy program
have scored over others concerned in community health.
ACKNOWLEDGMENTS
The technical assistance provided by Dr Raghuram Rao
(Ex-Assistant Director); and the secretarial and field
assistance provided by Mr Rahul G Gupta, of Bombay
Leprosy Project in preparation of this document is gratefully
acknowledged.
Fig. 41.6: Home-self care being practiced by a patient REFERENCES

with plantar ulcer
1. Kopparty SNM, Kurup AM, Sivaram M. Problems and coping
strategies of amilies having patients with and without deformities,
Indian J Lepr 2005; 67: 133-15.
2. Bombay Leprosy Project, Annual Report, 2008
3. Ganapati R, Pai VV, Tripathi AP. Can Primary Health Centres
Offer Care to the Leprosy Disabled After Integration With General
Health Services? A Study in Rural India. Leprosy Review,
2008;79: 340-41.
4. WHO, Technical Report Series No 221, 1960.
5. WHO, Technical Report Series No 847, 1994.
6. Momm W, Konig A. From community-based rehabilitation to
community-integration programs, Experiences and reflections
on a new concept of service provision for disabled people,
International Labour Office, Geneva, 1989.
7. Finkenflugal H, Wolffers I, Huijsman R. The evidence base for
community based rehabilitation: a literature review. Int J Rehabil
Fig. 41.7: A patient being provided MCR footwear Res 2005; 28:187-201.
42 Health Education, Promotion
and Counseling
Manimozhi Natarajan
Over the years, a paradigm shift has occurred in terms of HEALTH EDUCATION
public health strategies to provide treatment for leprosy.
Health education in leprosy encompasses all the activities
This has resulted in a move away from the vertical
which are aimed to:
approach of National Leprosy Eradication Programs, to
• Understand persons affected by leprosy in order to
the provision of integrated, sustained quality leprosy
achieve early reporting and timely completion of
services at all health centers.
treatment
The two main targets for the success of integrated • Ensure that people affected by leprosy learn taking
programs are: Early case detection with no disabilities and care of their own disabilities and deformities along with
Completion of treatment without disabilities. In order to the support of the health system
achieve these objectives, it is indispensable to ensure • Initiate and sustain the participation of the community
that a robust Communication Program can address the at various levels through community based
needs of the local community. rehabilitation.
Due to the complex socio-cultural perceptions of the
HEALTH PROMOTION signs and symptoms of leprosy, “Communication” is now
regarded as one of the essential elements of any leprosy
Health promotion consists of comprehensive social and
control program. Over the years, various approaches have
political process. It aims to:
been adopted in order to set up appropriate communication
• Strengthen the skills and capabilities of individuals
initiatives. Some of the approaches include health
• Change social, environmental and economic conditions education, IEC, behavior communication campaigns (BCC),
to alleviate their impact on public and individual health and health education as a part of health promotion. All of
It is a process which enables people to increase control them serve to achieve a better health of the target
over determinants of health thereby improving the general population.
health conditions of a population.
Leprosy program is no different from any other national ACTIVITY PLANNING V/S STRATEGIC
program and requires three main components:1 PLANNING
1. Competence
In general, any program needs planning, and so does the
2. Comprehensive health system to respond to the needs health education programs, mainly focusing interventions
of population not only towards results; but also against the causes of
3. Community participation the problems. Activity planning forms the basis for strategic
Information, education and communication (IEC) is an planning. It allows planners to break down the complex
important strategy of health promotion especially for issues into smaller tasks while shifting from activity based
diseases like leprosy. to result oriented approaches with numerous uncertain
CHAPTER
42
Fig. 42.1
causes. Therefore, strategic planning is particularly useful suspected, motivate them for acceptance and
when the issues to be tackled are not clear. adherence to treatment and self-care practices for
Leprosy is an unpredictable disease with intense prevention/management of disabilities and deformities?’.
psychosocial implications. As a result, activity planning is Effective communication at the patient as well as the
particularly recommended for leprosy programs. According community level will play an important role to tackle all
to this methodology, situational strengths, weakness, the above issues. Therefore, the role of communication
opportunities and challenges (threats) should be analyzed component in leprosy program should never be
while preparing a plan of action. One should bear in mind underestimated.
that from the community/patient’s perspective, leprosy Information about various diseases and health problems/
could be quite different from what the medical staff regard and instructions related are indiscrimately displayed in most
as the actual health problem. of the Health centers with no idea or plan. Well prepared
Some basic issues to be considered could be: and useful information materials often get muffled due to
• ‘What do we need to know about persons affected by various other unsuitable displays (Fig. 42.2).
leprosy, the attitudes and beliefs towards this disease
and the persons affected?’ These differ from person to
INFORMATION, EDUCATION AND
person, and region to region, with some commonalities
COMMUNICATION
(like stigma and discrimination). It is essential therefore
that information be gathered and analyzed. Information, education and communication (IEC) is an
• ‘What could be done in relation to communication to inter-related triad of planned activities which combine
promote acceptance of persons affected due to leprosy informational, educational and communication processes.
by the community, how can we make them realize and They aim to bring about objective behavioural, attitudinal,
follow advise/suggestions to take care of their disease, and participatory changes within a target population, based
encourage self-reporting when early problems are on a study of their needs and perceptions.
CHAPTER
42
Health Education, Promotion and Counseling 547
Fig. 42.2: Display of health education material at health centres could be organized with a proper plan
IEC process should be clear, concise, and avoid the medical interventions remain indispensable for the
confusion that generally arises in dynamic situations related treatment of leprosy as a disease.
to health and disease (Fig. 42.3). The objective is to foster
change in health perceptions and behavior, taking into Information
account the idiosyncratic challenges of the time and place. (Collected facts and data, about a specific issue)
An effective IEC program requires the support of an
Leprosy programs collect information focusing on
effective health system. In fact, it can only address
relevant target groups, their influence in the community,
communication-related problems, while the practical
and program expectations. Once the data on target groups
are available, information (talking points or messages)
needs to be tailored for different target groups depending
on the program expectations.
The Table 42.1 below presents some points that are
critical for a successful IEC strategy. Methodologies
to address these points need to be individualized
and group-specific:
Table 42.1: Points required for situational analysis and

planning for strategies
• Collection of data from and with community/client

• Review of literature
• Collection of information from other sources
• Survey and exploration to:
– determine needs
– influences on health
Fig. 42.3: IEC triad—information, education and communication a • Collection of data to explore opportunities for
crucial cycle intervention
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42
Education 5. Support communities to develop actions on health

issues
Education consists of systematic processes bringing out
6. Improve competence of the health staff, manage,
the ability to learn and apply knowledge.
supervise, and support sustained health activities
These processes are:
7. Alert the decision makers to consider implementation
• Selection of target groups and modifications
• Classifying them to various levels 8. Network and develop Public Private Partnerships.
• Formulating methods and approaches Typically, a communication process is made up of a
• Designing of schedules and syllabuses/curriculum Purpose (objective), and specific Procedures (directions
• Teaching, training and learning activities by qualified and activities that need to be undertaken).
competent staff.
IEC IMPLEMENTATION APPROACHES
Communication (TABLE 42.2)
The use of verbal and nonverbal means of communication The three basic IEC method such as Mass (for a large
is to express concepts; and to convey meaning between group-community), Group (health providers, influencers,
participants while interacting. It is difficult not to family members, and peer groups) and Individual (clients,
communicate. In its simplest form, communication involves patients as inter-personal communications) still hold well
exchanges of information between people. in planning IEC strategies.
All three components of health promotion, i.e., Health Some target groups
Education, Service Improvement and Advocacy—involve 1. Health Service Sector: Doctors, nurses, auxiliary staff,
communication in some form or the other. The main mid-wives, dressers, compounders, pharmacists.
objectives of health promotion activities are to: 2. Public Health Sector: Supervisors, Health Inspectors
1. Interact with communities (stake holders) to promote (male /female), Anganwadi workers, ASHA (Accredited
health empowerment, developing their skills and taking Social Health Activists), and others.
into account their beliefs 3. Community Level: Panchayat-Raj Institutional
2. Stimulate community participation members, leaders of all categories, traditional healers,
3. Provide information about existing initiatives and spiritual leaders, women groups, youth groups, village
opportunities administrators, non-governmental organizations.
4. Raise awareness and motivate the community to 4. Other Sectors: Those willing to participate could be
mobilization and participation mobilized.
Table 42.2: Integrated Approaches/ Methods of IEC

1. Collecting Information At the community level—Collect information about the specific health problem. Use various data
collection methods (ask who, when, where, and how)
2. Interpretation of information • Discuss the problem with those concerned and outline focus areas
• Select a priority problem and make an ordered list of other problems
3. Action Plan • Define what change is expected in the specific situation
• Analyze influencing factors that might encourage or discourage the intended changes
• Discuss intended changes with all stake holders
4. Implementation Activities • Lead group discussion on main topic
• Develop audio-visual (and other) material, if needed
• Use innovative methods/techniques as appropriate
• Decide the ‘who, where, when and how’ activities should be implemented
• Develop indicators to assess the impact of the intervention
5. Supervision Monitoring Assess the impact of the activities carried out as a basis for ongoing planning of future steps
and Evaluation
(Source: TALC)
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42
Fig. 42.4: Leprosy by definition is diagnosed by one of its cardinal signs: sensory loss. Yet, it is important to explain to patients that although
sensitivity might be reduced, sensibility is not lost!
Physical weakness might be detected as one of the signs of leprosy. Yet, it is important to help the patient understand the immense potential of
his/her personal strength!
Leprosy is a mycobacterial disease which affects the skin and nerves. It is important to help individuals and communities to understand that
there is no reason for worry and fear, since leprosy is curable with multidrug therapy. This disease no more represents a psychological burden
and a threat for the affected individuals and their communities.
Advocacy CRUCIAL DECISIONS

Advocacy refers to persuading others to support an issue There are 4 crucial stages of which decision patients may
of concern to an individual, group or community. With undertake from the early onset of signs/symptoms of
relevance to IEC activities, advocacy consists of activities leprosy till the disease has taken full course (Fig. 42.5).
directed at the general public, but mostly at policy-makers, During this process, there could be desirable or undesirable
as they influence laws and policies concerning the decisions to be made, and relating to issues such as:
allocation of resources, priorities for expenditure, direction 1. What to do when suspicious signs/symptoms are found
of services and enforcement of laws. Advocacy is vital by oneself or others
and necessary part of IEC activities. It is essential for a 2. What to do if these signs/symptoms are diagnosed as
program to have an impact. Its component of intervention leprosy and treatment is started
will usually consist of a balanced mix of short-term and 3. How to follow continuous treatment daily, and how to
long-term activities. tolerate and manage complications, disabilities/
deformities
Behavior Communication Campaigns (BCC) 4. How to accept treatment termination while problems
These are series of strategically planned activities, targeted still persist. When to attend clinics for follow-up if
and delivered through multiple channels to a large audience needed, several other personal/family decisions.
and designed to achieve a specific cognitive or behavioral While decision making is in progress, there are ‘positive’
goal in a predefined period of time. and ‘negative’ forces at play, which might push an individual
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42
or community, back and forth from a desirable to an Dealing with beliefs

undesirable pathway.
• Collect and compile list of existing beliefs about leprosy, and assess
Positive forces like self-motivation and attitude, beliefs, their effects on decision making.
spouse/family/friends’ support, committed health workers • Make sure that beliefs are respected and not ridiculed (since this
etc. will lead the person to progress on a desirable pathway. could result in emotional situations and resentment feelings). Stiff
Negative forces like beliefs, superstitions, wrong resistance to the proposed treatment could lead to inappropriate
messages, denial could counter the push towards the traditional medicine approaches
desired pathway. Information about these forces could be • Provide simple facts to support medical world beliefs
collected from the patients during interviews and history • Discuss about beliefs and their consequences, and allow time for
taking. All efforts should be made to enhance positive change
forces and reduce or eliminate negative ones. • Find out the guardians of belief system, contact them and explain
the medical facts while respecting their thoughts and beliefs
Good communication skills are essential for this
purpose. It is essential to:
• Look at leprosy through the eyes of persons affected
External Influence
by leprosy and their community
• Identify and analyze the reactions of patients, family Even when decision making resides with just one individual,
members, friends and others to leprosy it is always influenced by external factors, such as threats,
• Analyze the reasons why individuals/communities fear, personal experience, advice, suggestions, the local
accept or reject participation in leprosy related activities. environment, financial considerations, etc. More
specifically, a person affected by leprosy is often influenced
Negative Forces by family members, friends, health workers, local elderly
Beliefs person, and others. Their influence can sometimes be
crucial in terms of decision making. Time and money have
Beliefs are the age-old sanctions which help persons
also been identified as important factors for the acceptance
affected by leprosy to give meaning to events and make
or rejection of leprosy programs and services.
them more predictable and less threatening. Beliefs about
Factors influencing desirable course of actions –
health events are generally associated with beliefs about
handling them. They can be useful, harmful or balanced. Positive forces which could be beliefs, attitudes etc. need
They are usually shared and passed on from generation to to be sustained and strengthened.
generation. Some beliefs disappear over time, and some Denial
become stronger in terms of their sentimental and emotional
undertones. When beliefs have a component of spiritual In situations of acute stress, individuals and communities
faith, they become more sensitive and difficult to address. sometimes react by pretending that the threatening situation
is nonexistent (denial). This reaction is due to helplessness
Attitudes, Norms and Values in the face of a threat that is felt as too overwhelming to
Attitudes are approaches based on personal feelings and be faced. The unconscious hope is probably that the
expressions towards persons, situations, events, diseases, resolution of the stressful condition will occur
self, and the surrounding world. Attitudes influence spontaneously. In many cases denial leads to irrational
decisions in positive or negative ways, thus leading to choices, resulting in the worsening of the situation.
initiate an action of some sort, or none at all. Handling denial requires in the first place an
Values are a commonly accepted code of conduct understanding of the whole process of “denial”. In the case
which is expressed to act or not in a certain way. For of leprosy, for example, an individual could react in two
example, a leprosy affected person is expected to behave ways, one by not accepting, withdrawing or denying the
in a certain way: like not to marry or share things with facts, or by coping with the situation by realizing, accepting,
others. seeking support, adjusting and proceeding. It is essential
These sanctions are powerful enough to influence the to handle the situation using methods to promote the choice
individual and the community to behave in a way that is of a “coping process”. The individual is assisted to find out
not justifiable in terms of medical evidence, and even less reasonable solutions enabling him/her to make a positive
in terms of human rights. decisions.
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42
Interpersonal communication (Counseling sessions, one to one):2
Counseling
Counseling is an interventional communication procedure aiming to stimulate the awareness and analysis of
various available options. It is mostly used in health related activities to address psycho-social issues.
Qualities of a good counselor: Should be compassionate, non-judgmental, keeping note of the verbal and non-
verbal communication.
Counselor should try and ensure that the clients have their rights to :
• Information: To learn about the benefits and availability of the services.
• Access: To obtain services regardless of gender, creed, color, marital status or location.
• Choice: To understand and be able to apply all pertinent information to be able to make an informed choice, ask
questions freely, and be answered in an honest, clear and comprehensive manner.
• Safety: A safe and effective service.
• Privacy: To have a private environment during counselling or services.
• Confidentiality: To be assured that any personal information will remain confidential.
• Dignity: To be Treated with courtesy, consideration and attentiveness.
• Comfort: To feel comfortable when receiving services.
• Continuity: To receive services and supplies for as long as needed.
• Opinion: To express views on the services offered.
• Summary and confirmation: End the session with clarity and confirmation that the information contents have
been understood.
The Role of the Counselor

The counselor’s role is to provide accurate and complete information to help the user make her/ his own decision
about which services (s)he will use. The role of the counselor is not to offer advice or decide on the service to be
used.
Effective counseling requires understanding one’s own values and not unduly influencing the users by imposing,
promoting or displaying them, particularly in cases where the provider’s and the user’s values are different.
Considerations of environment during communication

Space – for consideration while communicating:
Intimate Zone = ≤ 45 cm
Personal Zone = 45 cm – 1.2 m
Social Zone = 1.2 m – 3.5 m
Public Zone = >3.5 m
During interpersonal communications (counseling sessions), it would be advisable to limit to personal zone /social
zone if family members are included.
Communications as instructions v/s Communication for realization

Focus communication skills on Cause and Effect
Source: TALC IEC

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42
Fig. 42.5: Patterns of 4 crucial stages of decisions by persons affected by leprosy

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42
• Anger and hostile reactions: It should be kept in
mind that patients are hostile and expressing anger
not towards the health personnel, but towards the
situation. Health staff should not take this
behavior personally. Provide time and allow the
patient to get settled before resuming your work
with him/her.
4. Allow patients to express their thoughts freely at this
stage. Encourage them to speak out, and show your
appreciation for the fact that they are showing their
feelings. This is the best way to gain information on
their concerns and draw a plan on how to help.
5. Provide support to normalize fear and denial by finding
out the patient’s main concerns. Provide examples on
how the patient and family could overcome such
pressues. Emphasise that it is normal to feel worried,
Fig. 42.6
and that such thoughts normally occur. Tell patients
that they can come back to you again if they have
Disclosing Diagnosis to the Patient more queries.
Disclosure is often an object of major debate. On one hand, 6. Discuss the negative effects of denial and the positive
it is the person’s “Right” to know about a problem. A effects of addressing the situation from the onset.
competent health worker should be capable of breaking
the news in a sensible and appropriate way. Motivation
The terminology at disclosure must be carefully Motivation could be regarded as a person’s attitude and
selected. Phrases like “Do not worry” should be avoided, feelings towards a task ahead. Motivation will not
as they automatically trigger a psychological reaction of necessarily be observable in a direct way. Often it can
uncertainity as to what will happen. Encouragement and only be interpreted by observing the way in which patients
emotional, empathetic support will suffice to control the behave and explain their own actions.
problem much better than requests not to worry. At this Motivation is a kind of energy which is very vital and
stage, some key strategies should be followed: dynamic in nature. It is somehow a drive to fulfill basic
1. Remember and agree to the fact that leprosy is fearful needs. Such basic needs could be:
for others (community, world) and that those around a. Physiological – such as hunger, thirst, survival, safety
the patient may show unexpected reactions when and sex
informed of the disease (denial or coping mechanisms) b. Social – such as self-esteem, body image, status of
all kinds, self-image, relationships, religious/spiritual/
2. Pause, by providing some time as soon as diagnosis
non-religious attachments, philosophy, etc.
is disclosed. Keeping observing the patient without
c. Hierarchical – need to occupy a specific place in the
making attempts to hurriedly explain the disease, its
community
effects and management. All these talking shall be done
d. Priority and precedence – where one needs to take
at a later stage.
precedence over another.
3. Provide psychological reassurance and gain the It becomes important for the health worker to identify
person’s confidence. Try to instil the feeling that the needs which could generate positive energy leading to a
patient is in safe hands and provide a sense of security. motivational attitude (Fig. 42.7).
Once the diagnosis is disclosed, a variety of emotional
responses could be encountered, ranging from complete
COMMUNICATION SKILLS4
silence to desperate cry. This emotional reactional
episodes are to be expected, and are generally self It is a fact that health professionals often lack training in
limiting. Provision of time is important at this stage. communication skills. The importance of training and
Patients may show: practice in communication skills cannot be underestimated.
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42
Fig. 42.7: A model poster with motivational message
In leprosy programs it is extremely important to that they should pay attention to what is said while closely
communicate with the patients and help them face their focusing their vision – observing. There is a strong
problems, the disease, its manifestations, as well as to correlation between verbal and non-verbal interaction.
identify complications at their onset. There are three Wrong interpretation and misunderstandings, could
important components in communication. These can be impact negatively at the end of a counseling session. It is
described as an inter-related triad – Listening, observing therefore important to obsserve a patient and try to grasp
and talking(LOT), when interacting at the inter-personal the person’s non-verbal expressions. These should be
levels. analyzed as a whole with verbal communication contents.
Observation skills play a key role.
Listening “ What all is heard, and what all is seen may not be
Developing the art of listening requires patience, interest, true, until thoroughly analyzed.” Thorough analysis must
time and commitment. It is a process of paying attention be done by utilizing efficient listening and observing skills.
to collect as much information as possible in order to
provide appropriate services. In general, listening entails
Talking
hearing all the messages conveyed, keeping silence while This activity usually takes most of the health worker’s
carefully keeping eye contact, askings questions (closed, communication time. Although many of the messages sent
open and a mixture of both) for clarification, acknowledging out by the health workers are routine technical aspects,
that attention is been paid (e.g. by summarising what the there comes a point when the patient must finally be
patient just said), pausing for a while, helping the person informed of his/her condition.
to recollect and reorganize to speak, reflecting feelings Two aspects of talking can be emphasised:
expressed by the person, initiating gestures like shaking 1. The matter—which is the actual content of the talk
one’s head with sigh/words like hmmm! Ha ha! Is it so, 2. The relationship—that is established between the
and so on. Time constraints/limitations at OPD could be a communicators (health staff and patient)
hinderance to a listening process. Effective talking will be promoted by:
1. Making the participants feel free and comfortable, giving
Observing them enough time to spend to carry out the intended
During the communication process we share ideas, actions (e.g. taking consent, formal or informal
messages and thoughts with other person. We also expect depending upon the situation),
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42
2. Making an attempt to check whether the main point of
concern is understood
3. Keeping questions simple and not challenging the
patient’s statements
4. Allowing the person to talk, asking for permission if
there is a need to interfere, and keeping intermissions
to as few as possible
5. Instructions vs. realization – the talk should depend
upon the situation. It should not be the same all the
time. It should not be a list of instructions, such as: “do
this, do that, never do this”.
Talking consists of a series of messages. Messages
are the main core constituents of communication. Effective
communication rests on 4 main cardinal components
(CARE): (i) Content, (ii) Appeal, (iii) Relationship, and
(iv) Emotions. These components make messages more
meaningful, as they show the communicator’s concern and
commitment.
Formulation of messages: While composing messages
as talking points, the health worker should keep in mind
the following: Fig. 42.8
• Whom the message is to be addressed to
• How it should be delivered and perceived – prevent an overload of suspect cases at the health
• The main idea to be conveyed to the patient must be centers
clearly expressed. – guarantee the provision of better attention
• Utilize all information gathered about the prevailing
POSTERS beliefs, notions and other related issues for the new
Posters should have a catching caption, with an appropriate area
picture, and with suggested line of action (Fig. 42.8). This • Develop health and motivational information on medical
needs to be pasted in appropriate site for visibility and facts and health service facilities
usefulness. • Pre-test them under field conditions and modify as
Talking points in posters need to be adapted to local necessary prior to use (assess impact after
settings, cultural perceptions and other changes that may implementation through indirect indicators, such as
have occurred since the poster was designed. Some number of people with suspected skin lesions reporting
examples can be found in Figures 42.9 and 42.10: voluntarily after IEC intervention, and analysis along
with other program/epidemiological indicators).
Communication is indispensable to help persons
PROGRAM FOCUS IN RELATION TO
affected by leprosy to accept diagnosis, adhere to
LEPROSY
treatment plan and report immediately in case of
The main objective is to make community aware of the complications. There are series of activities to be
disease, of its problems, and of the way in which the undertaken by all health facility staff to ensure the provision
community can participate, so as to foster early case of patient-friendly health services:
reporting. • Create conditions (IEC) for patients to understand the
Action which could be initiated in a new community: importance of self-care
• Select the area and conveniently sub-divide it into • Support patients’ active participation in the program.
sectors. This will: This will help them to adhere to positive health practices
– allow to carry out IEC activities on rotation basis/ • Organize interpersonal communication activities and
phases group discussions with peer groups if necessary
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42
Fig. 42.9 Fig. 42.10
Fig. 42.11
• Teach about self-care practices, prevention of KEY ISSUES IN COMMUNICATION FOR

disabilities (POD) and management of deformities. LEPROSY PROGRAMS
These represent a real challenge for IEC Programs. All
Understanding
IEC methods need to be adopted to achieve satisfactory
results in self-care and POD. Health services also need to Health workers must be aware that working with patients
be strengthened in providing referral system in the affected by leprosy could have negative implications for
management of disabilities/deformities. the lives of their patients if messages are not understood.
CHAPTER
42
Fig. 42.12
The role of effective and positive communication should to realize that the new habit is valuable and to learn
never be underestimated. the practice. Until then, patients need support and
motivation.
Perceiving
Family Based Support to Self-care Practices
Health workers should be trained to develop an instinct to
ask, look and feel in terms of the community in which they It is important to plan and run group IEC/ training programs
work. POD activities require practice in asking oneself for concerned family members. Their support can make a
whether a patient is at risk of developing disability/ huge difference in the cure of leprosy and prevention of
deformity, whether early damage can be readily identified, disabilities.
whether the patient will be able to ask/seek immediate
care in the existing rehabilitation services, if necessary. Self-care
Self-care practices are often a life-long task for a person
Interfering with Patient’s Habits
affected by leprosy. Individuals and families should be
It is usually difficult for a person to adopt a new habit to helped to come to grip with the reality and be consistent in
prevent/manage disabilities. It might take some time their self-care tasks.
CHAPTER
42
Promoting Self-help REFERENCES

Patients and their families should be able to: (1) listen to 1. Health education in Leprosy work, A manual for Health workers:
explanations about self-care techniques, (2) see the Van Parjis LG. Pub. Leprosy Mission International. London, 1986.
techniques being carried out, and (3) practice them (role 2. TALC (Teaching Aids at Low Cost) publications.
play exercises) – Leprosy programs should propose self- 3. Education for health: A manual on health education in primary
care training in these three phases. health care. WHO publication.
Not all problems are communication problems, but 4. Doctor – Patient: Interaction and Communication. Division of
practice leads to perfection, and effective communication Mental health, WHO – Geneva.1993.
can be learnt. 5. A Guide to Health Education in Leprosy: Neville PJ. TALMILEP
teaching and learning Materials. ILEP.1993.
ACKNOWLEDGMENTS 6. Communication for Health and Behaviour Change: A Developing
Country Perspective. Graeff JA, Elder JP and Booth EM. Jossey-
Sincere thanks to beloved persons affected by leprosy, AIFO, Bass Pub. San Francisco, 1993;205.
ILEP, IAL, Dr Luc, Mrs. Chiara Carcianiga, Dr V Pannikar, 7. Windahl S, Signitzer B, Olson JT. Using Communication theory.
Prof Bhusan Kumar, Prof H K Kar, Dr PL Joshi, Mr Jose, SAGE publications, New Delhi, 2008.
my parents, family and friends for their contributions and 8. Riva Miller and Robert Bor. AIDS: A guide to clinical counselling.
help. Science Press Pub. London, 1988.
43
Psychosocial Aspects
PK Gopal
INTRODUCTION Social stigma in leprosy is widely prevalent not only in

India; but also in many other countries. The social
The term psychosocial refers to “one in psychological
acceptance of leprosy affected persons still remains a
development in and interaction with a social
critical intervention for integration of such people in the
environment. The individual is not necessarily fully
society. Young leprosy affected children have difficulty in
aware of this relationship with his or her environment.”
getting admission into schools. Employers do not like to
This term was first used by a psychologist Erik Erikson in
employ leprosy affected persons. The leprosy affected
his description on stages of social development. Contrasted persons also have difficulties in accessing public services
with social psychology, which attempts to explain social like transport, accommodation in hotels, etc. Marriage in
patterns of behavior in a general sense, the term a family where a leprosy affected person lives, is a problem.
“psychosocial” can be used to describe the unique internal Still (in some parlours, though it deserves to be condemned)
processes that occur within the individual.1 the undignified word “leper” is used to address the leprosy
Psychosocial problems occur more frequently in affected persons. In spite of best efforts by the government
patients who suffer from chronic illnesses like leprosy. and voluntary agencies, the social acceptance is still a
Any chronic illness takes a long time to get cured, and by reality faced by most of the leprosy affected persons. This
that time the psychosocial problems get set in the patient’s is so because such acceptance depends on the mind-set
life. The social stigma in leprosy makes the patient’s of the community they live in; or are trying to integrate with.
condition worse in their psychosocial development and It may be difficult to ascertain the level of stigmatization
behavior. Psychosocial support for leprosy patients through by focussing only on the people with leprosy affliction. It is
counseling, etc. was not the usual practice among the also necessary to know the level of stigma of many other
treatment facilities in India till recently. diseases prevailing in the community; in which the leprosy
affected persons are also living. When a person is diagnosed
STIGMA with leprosy, his normal psychological condition is affected.
The negative reaction of his family, friends and community
“Stigma is a social process or a related personal aggravates his declining morale and the overall psychological
experience characterized by exclusion, rejection, blame, state. In many patients, suicidal thoughts came after the
or devaluation that results from experience or reasonable diagnosis of leprosy. Many patients have committed suicide
anticipation of an adverse social judgement about a person in the hospitals and at homes as they had undergone extreme
or a group”. In health-related stigma, this judgement is psychosocial stress and depression. The social environment
based on an enduring feature of distortion of identity; around the patient is responsible to a large extent for damage
conferred by a health problem or health-related condition. to the patient’s psyche. The patient needs psychological
It results into unjustifiable different treatment given to support and counseling; as soon as the diagnosis of leprosy
different people or groups by the society.”2 is made.
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43
The psychosocial and economic problems of leprosy normal person desires to be useful to his family, social
patients often continue, even after they are released from group and the society in general. Each individual in the
treatment and declared cured from the disease. In many society has a role to play as father, mother, son, daughter,
cases the cure alone does not restore the normal employer, and employee and so on. The society expects
psychosocial and economic conditions. Proper intervention the individual to take up the responsibilities and perform
by rehabilitation professionals (from all fields, especially them for self, and to help others in the fruitful coexistence
from the socioeconomic area) at the right time, is required of the family and community.
to deal with such situations. Leprosy as a disease interferes to disrupt the process
of socialization in certain proportion of persons affected
Social and Economic Rehabilitation with the disease. For some, the disruption is for a shorter
The overall objective of providing treatment to a patient is period and for others, the disruption may be life long. To
to enable him to return back to his family and community make the leprosy affected persons return to their original
after cure; and attain the same social and economic status social and economic status; or to bring them back to their
which he was enjoying previously. Enabling a patient to own role in their society and establish them in order to
achieve this status through socioeconomic rehabilitation lead a normal life, is termed as social and economic
measures cannot be neglected while implementing the reintegration.
leprosy eradication program.
At a time, when there is a great success in the treat- Self Settled Leprosy Colonies
ment of the disease, it is also necessary to achieve Leprosy is a unique disease, which had rendered those
socioeconomic integration of the persons affected by affected, as a vulnerable target for discrimination around
leprosy in the society which would give a greater meaning the world, regardless of the country, religion, or culture. It
for cure of the disease, in real sense. was the first disease which brought a division among the
Since deformity is the main cause for social stigma in people; segregating and isolating the persons with leprosy,
leprosy, it is most likely that majority of the cases having from homes, villages and the society.
deformities are also subjected to psychosocial problems The persons affected by leprosy till recently, had been
and thus, there are social and economic dislocations in segregated compulsorily by law in some countries like USA,
their life up to varying degrees. Therefore, measures should Japan, and Korea and removed from their families and
be introduced to identify the socially and economically community, to live a segregated life in isolation in leprosaria.
displaced persons; and rehabilitation facilities be provided They were denied normal living. They were unable to marry
to them to resolve their psychosocial sufferings. and prevented from having children. Their human rights
In no other disease, the affected persons were made were also curbed. Those who violated the restrictions were
to leave their families and community, and forced to spend severely punished, jailed, tortured, buried alive or even
lives of seclusion and destitution, far from the realms of burnt.
social niche. This really used to happen with the segregated In India, though there was no law to segregate them,
and isolated persons affected by leprosy. As a result, they the family and community abandoned the affected persons
started to live away from the community and these places (or made to so, out of severe social pressure) and forced
have been called as leprosy colonies, leprosy villages, them out of their families. These persons, with no
etc. where they lived as unfortunate, forsaken and outcasts opportunity whatsoever, to earn for themselves, had to
human beings, ostracized by the society. resort to begging for their living. They used to join together
as a group and started to live away from the community.
Social and Economic Integration They married among themselves and had children. These
The term “Social” has a very broad meaning. The dictionary places were called as leprosy colonies.
meaning for social is “living in company”, “One who is not With the support of The Nippon Foundation, the social
practicing solitary life”, etc. The social process or organisation IDEA India (IDEA stands for Integration,
socialization is a life-long happening and living phenomenon. Dignity and Economic Advancement) conducted a survey
It begins with the family and is continued through school, to know about the ground realities of leprosy colonies in
contacts with relatives, friends, co-workers, etc. Every India. According to the observations there are about 700
CHAPTER
43
Psychosocial Aspects 561
such self settled leprosy colonies all over India and people charity based. In this system, the inmates developed a
are living a marginalized life. The disease played havoc in total dependency upon the institutions. They were not
totally destroying the social fabric of families of the persons exposed to the society and its daily life situations. The
affected by leprosy. inmates of such institutions were happy to stay in the
institution even when cured, than to go out and face the
REHABILITATION society.
With the advancements in medicine, surgery and
What is Rehabilitation? treatment procedures, such institution based rehabilitation
“Rehabilitation aims to provide regalement of physical has become outdated.
function, re-adaptation in the existing physical condition
to the life situations; and reintegration with the family and COMMUNITY BASED REHABILITATION
community, resuming his/her normal social and economic In community based rehabilitation (CBR), the leprosy cured
living.” person is helped to return to his own environment to live
WHO experts committee on leprosy defined with his family and the community. Both his family and
rehabilitation as: community are involved in the rehabilitation process. He
“The physical and mental restoration, as far as is helped to do a suitable, productive occupation to
possible, of all treated patients to normal activity, so contribute to the economy of his family and thus live as a
that they may be able to resume their place in the home, useful and self-supporting member of the community.
society and the industry.” Education, vocational training and employment are the main
Rehabilitation in the field of leprosy requires much tasks which fall within the principles of community based
greater efforts than the rehabilitation of persons disabled rehabilitation.
from any other cause, because of the simple reason that In India, rehabilitation in the field of leprosy has been
the question of social acceptance does not arise in non- provided in some places by few non government
leprosy disabled persons. In case of an orthopedically organizations (NGOs). Majority of the leprosy affected
handicapped, blind or a deaf person, his stay with the family persons however, have not received the benefits of
is considered essential / obligatory; but it is prejudiced in rehabilitation to the desirable extent. The experiences gained
case of leprosy patients. This is chiefly due to the stigma by some of the organizations in the field of rehabilitation
attached to the disease. Therefore, one of the essential have shown clearly, that the leprosy cured persons could
requirements in the socioeconomic rehabilitation is to create be successfully rehabilitated in the community and thereby
a suitable environment in the community; for social their psychosocial and economic problems could be solved
acceptance of leprosy cured persons through effective to a large extent.
Health Education measures.
SOCIAL AND ECONOMIC
INSTITUTION BASED REINTEGRATION THROUGH
REHABILITATION (IBR) REHABILITATION
In olden days, leprosy affected persons were segregated Social and economic reintegration of persons affected by
from the normal population and thereby leprosy villages leprosy could be achieved through rehabilitation measures
and leprosy colonies sprang up. When institutions (created which would bring normalization in their lives.
with efforts from missions, and financial support from Rehabilitation means a return to a state of complete
government and public charity) started to take care of these or near normalcy. This definition encompasses the need
patients, some of the patients were given permanent shelter for social and psychological assimilation as a necessary
in such institutions. The inmates of such asylums were component and complement to economic independence.
engaged in different occupations like agriculture, animal Scientific knowledge of leprosy regarding causation, cure
husbandry, mat and cloth weaving, etc. mainly to meet and deformities has disproved the traditional beliefs. This
the requirements of the institution. Some others inmates scientific information needs to be conveyed to the mass
were assigned the role as barber, washer man, cobbler, public, which is very important to bring about a change in
sweeper etc. The approach was sympathy as well as the attitude of people towards persons affected by leprosy.
CHAPTER
43
Normalization is a holistic goal. It cannot be achieved them in priority based on their needs, capacity, available
by addressing only the physical problems of persons resources, etc.
affected by Hansen’s disease. It is necessary also to help The persons in need of rehabilitation also differ
them solve their disease related psychological, spiritual, considerably in many other ways. The person may be a
social and economic problems. male or female, young or old, educated or uneducated,
rich or poor, etc. These wide variations among leprosy
The Ultimate Objectives of Socioeconomic affected persons also emphasize the need of selection of
Rehabilitation could be Summarized as follows needy persons among the persons treated.
The socioeconomic rehabilitation is a major task
1. Socially, the goal is to help persons affected by the
involving different kinds of programmes suitable for each
disease to remain within their home communities,
category of persons and the problems of each individual
participating with the same rights and duties in the
are unique. Each person needs to be assessed and helped
groups they would normally have participated, if they
accordingly. It is necessary to broadly categorize the
had never contracted the disease.
leprosy affected persons to find out who would need, what
2. The goal is to avoid all types of segregation which
type of assistance, and also those who are not suitable
place persons affected by the disease in specialized
for rehabilitation. Those not requiring any kind of help could
leprosy institutions or bar them from availing general
also be found and marked in this study selection process.
services provided by community institutions like
Based on the field experience in socioeconomic
schools, churches, housing, recreation facilities,
rehabilitation in India, a methodology was developed. This
hospitals, rehabilitation centers, homes for the elderly
methodology is already in use in some other Projects in
persons and disabled, etc.
India. It has also been applied (either in totality or with
3. Economically, the goal is that persons affected by
little modifications) by most of the rehabilitation Project
Hansen’s disease continue to lead an economic life as Managers in many other countries.
similar to the one they would have led, had they never
contracted the disease. This means that they have
CATEGORIZATION OF THE LEPROSY
equal access to jobs and to vocational training
AFFECTED PERSONS
opportunities for development of their skills. Access
to economic assistance should be based not only on (All leprosy affected persons in the area need to be studied)
the criteria of Hansen’s disease but on more general 1. Persons who do not have any deformity; and do not
factors such as age, disability level, financial need and have any social and/or economic problem and are
availability of alternative sources of support. leading a normal life.
2. Persons who have deformities but do not have any
IDENTIFYING THE TARGET GROUPS FOR social and/or economic problem and are leading a
SOCIOECONOMIC REHABILITATION normal life.
3. Persons who do not have any deformity but have social
In the field of leprosy, some data are available on physical and/or economic problems; just because they have/
disability, but the data on social and economic disability had leprosy.
of leprosy affected persons are not generally available. 4. Persons with deformities, whose social and economic
It is quite obvious that not all leprosy affected persons lives are under threat of dislocation.
need rehabilitation. In a sample study conducted by the 5. Persons with deformities whose social and economic
author in India in 1988 among 53,000 leprosy affected positions have been dislocated already. Their normal
persons nation wide, it was found that about 34% of them life conditions are very much affected (Dehabilitated).
had the need of some kind of social and/or economic 6. Persons who are aged and have reached a state of
rehabilitation assistance.4 The number of leprosy affected destitution because of severe deformities and long
persons treated by MDT so far is very high in endemic sufferings, due to which they have dislocation of their
countries. Therefore, it is necessary to make a selection socioeconomic life conditions.
of the leprosy affected persons who would need As summarized in Table 43.1, the persons with first
rehabilitation. After selection, it is also necessary to list and second category of socioeconomic condition do not
CHAPTER
43
Psychosocial Aspects 563
Table 43.1: Categorization of leprosy affected persons in need of rehabilitation

S.No. Deformity Socioeconomic Life condition Rehabilitation
problems measures needed
1 Nil Nil Normal Nil
2 Yes Nil Normal Nil
3 Nil Yes Affected (due to stigma) Psychological support,
Counseling
4 Yes Threatened Threatened Investigation and suitable
rehabilitation
5 Yes Dislocated Seriously affected Investigation and suitable
rehabilitation
6 Yes Totally Dislocated Seclusion and destitution No rehabilitation, only
(Severely incapacitated) food, shelter and
general life support
need any kind of rehabilitation. The persons who fall in the • It beckons the group seeing the situation through
third category need counseling and psychological support. different eyes and realising the possibilities for change.
Persons in the fourth and fifth categories are a very • The essence of empowerment is; that the people
vulnerable group and deserve serious attention. They need affected by leprosy and their families take responsibility
to be investigated either to prevent dehabilitation or to be for their development within the context of general
provided socioeconomic rehabilitation.3 community development.
The people in the sixth category are old and/or much Ownership results from participation and involvement
disabled and are not suitable for rehabilitation because of in decision-making. Responsibility and ownership are part
their old age and severe deformities. They must have of the empowering process. Empowerment is sustainable
special care which might be in the form of food, help in when based on understanding and skill. The understanding
daily activities, shopping assistance, medical care and and skill can be applied again and again to solve further
financial support. They have no money, no homes, no jobs problems, and in turn this will generate a cycle of energy
and no family to take care of them. Some of such persons and creativity.
may need institutional care. • Empowered people participate in family and community
The identification of eligible persons needing the life; in learning, playing, working, in household activities,
community based rehabilitation in an area is a major step relationships, decision-making, and in political and
in planning for suitable measures. It is also possible to cultural activities.
identify the various target groups for socioeconomic • Change has to start with the people themselves. This
rehabilitation by this method. means that the first step for many people affected with
leprosy is a fundamental change in their own mindset,
i.e. from a passive receiver to an active contributor.
EMPOWERMENT
The process starts from the time when they are given
The psychosocial problems of leprosy affected persons counseling to get relieved from their psychosocial
could be relieved through engaging them in the process of problems.
achieving empowerment. Empowerment enables a person • Once people with similar problems meet in socio
to make his own decisions about his life. It is not something economic empowerment workshops, they can realise
which can be given to a person, on the other hand, a person that their individual problems are common to the group;
must work to get himself empowered. and that there are common solutions for many of them.
• Empowerment is strengthened by groups of individuals Being together helps to minimize isolation and to
working together, realizing they have the potential to increase the will to sharing and mutual support.
bring about a change in their situation. For any group to become empowered and to act
• The goal of empowerment is the inclusion and effectively, they need to:
assimilation of leprosy affected persons in the family, • Identify the common threads between the problems of
the community; and the mainstream development the individuals.
programs. • Recognize their strength in togetherness.
CHAPTER
43
• Gather information to increase their understanding and REFERENCES

knowledge. 1 Wikipedia, Free Encyclopaedia. “Psychosocial” available
• Empowerment is very much essential to fight against at http://en.wikipedia.org/wiki/Psychosocial. last accessed 10th
stigma and discrimination; and to be free from psycho- July 2009.
social problems, which would automatically improve 2. Tom Frist. In: DON’T TREAT ME LIKE I HAVE LEPROSY.
the quality of life and help to lead an integrated, dignified Publisher ILEP, 234, Blyth Road, London. 1996.
life. 3. Upadhyay VS. “The Concept of Dehabilitation and Rehabilitation”
Paper presented at WHO Seminar on Preventive aspects of
• To enable the persons to achieve empowerment, they
Dehabilitation Community Based approach, Gandhi Memorial
need support and opportunities from the Governments, Leprosy Foundation (GMLF), Wardha, 1990.
NGOs and the community at large. The NGOs can 4. Gopal PK. Methods to identify the leprosy patients needing
play a major role in this process. rehabilitation. Indian J Lepr 1997; 69:438.
44
Human Rights and Leprosy
VV Dongre
IN THE FOOTSTEPS OF TIME...

Leprosy is an ancient disease, confined to man. Man is a
social animal, so, there are social dimensions to this
disease.
i. Prince Devashi (brother of Prince Shantanu) with
leprosy could not become a crowned king in 5000
BC. (Mahabharata).1
Supreme Court’s verdict in Sept 2008 declared that a
leprosy patient cannot contest an election. (Violation
of article 21 of HR declaration).2
ii. Supreme Court’s verdict in 1974 AD allowed divorce
on the ground of leprosy.3
iii. International Hostel denied admission to leprosy
patients in New Delhi as recently as in Nov.2006 AD.
(News in Deccan Herald November 11, 2006).4
iv. A person who has no leprosy but is doomed because as tuberculosis and leprosy are not genetic diseases.
he lives in a leprosy colony in East Delhi with his (News in The Hindu dated, 9th January, 2009)
parents, who have leprosy. He has been refused a In 1970, a member of the parliament (MP) tried to table
driving licence more than once and he stopped trying a bill for the compulsory sterilization of leprosy patients.
after being told, Dr RV Wardekar, Director, GMLF, Wardha, fought tooth and
“Lepers should beg, not drive cars” (News in Hindustan nail against this damaging bill and saw to it that the bill
Times dated, 27th February, 2009) was never tabled on the floor of the parliament.
(NB—The motor vehicle Act 1989 does not debar a The document is available in the archives of GMLF,
leprosy patient from getting a driving licence). Wardha.
v. Unfortunately, even persons who are concerned with (The news that appears in the print media creates a
human rights commission at times make very wrong deep impression on the minds of the people. It is believed
statements. that the news is published after due confirmation of the
Chennai: Chairman of the Andhra Pradesh Human facts. Needless to say that media have accountability for
Rights Commission has called for legislation to whatever they publish.)
prosecute parents with diseases such as tuberculosis,
HIV, leprosy and dyslexia should they, knowing that SOCIAL ASPECTS
they have the disease, have children. The local Societal attitudes, legal prescriptions and cultural
doctors protested against this baseless statement, perceptions are blended together to make social aspects.
CHAPTER
44
Disease MEDICAL IMPLICATIONS

The disease itself is mildly infectious and not hereditary, Stigma impacts negatively on early diagnosis and treatment
but, actually in the society it is believed to be infectious leading to increase in the transmission of the disease and
and hereditary and hence, the social stigma attached to it, prevalence of deformity.
affects the children of the leprosy patients – both in the
social sphere and in the cultural life. ASPECTS OF DISCRIMINATION: HUMAN
Early detection and regular, adequate Multi Drug RIGHTS VIOLATIONS8 (HR)
Treatment (MDT) cures leprosy without deformities.
• Community discrimination – (Violation of article 2&7
Ninety-eight percent people have immunity against
of HR declaration)
leprosy. Only 2% are susceptible to leprosy in the
• Religious – entry into temple forbidden, right of worship
community. Only 8 to 10% of untreated leprosy patients
is denied (Violation of article 27 of HR declaration)
are infectious, they spread the disease in the society and
• Social – visits to families of leprosy patients are avoided
the family mostly by droplet infection during coughing and
(Violation of article 27 of HR declaration)
sneezing or direct skin to skin contact under ideal
• Self inflicted –visits to relatives and visits for social
conditions. They can be made non-infectious by multi drug
and cultural events are avoided by leprosy patients
treatment within a short period of time. One dose of
themselves. ( Violation of article 27 of HR declaration)
rifamycin kills 99.99% germs of leprosy that are in the
• Educational – school admission at times is denied to
process of multiplication in the body of the patient under
children of leprosy patients (violation of article 26 of
treatment.
HR declaration)
• Economic – jobs are not easily available to leprosy
Misconceptions in the Community
patients and their children (Violation of article 23 of HR
It is considered to be due to the sins committed in the declaration)
previous incarnation and due to curse of God/Goddess. It • Health related – admissions in general hospitals to
is believed to be incurable. Assisted suicides were leprosy patients for treatment of other ailments are
suggested to leprosy patients and many did happen. many a times denied (Violation of article 2&7 of HR
Manusmriti 5 condones suicide by an incurable leprosy declaration)
patient with advanced disease. Relatives and friends were All the above subjects involved human rights issues.
expected to be dutiful to help a leprosy patient to end his Articles 38 and 41 of Indian Constitution provide the relevant
life by drowning or burying himself alive or burn himself to ethos to the subject.
death.6 The problem is not what the disease is, but what
the people believe it to be!7 It is also a subject concerning Consequences of Social Stigma
the ‘human rights’!
On the intra-familial relation:
The patient is not able to share meals with the family
Social Stigma and Its Effects
members. He is forced to live apart.
The disease itself has variegated forms and is on the decline He is supposed to use separate articles, vessels and
due to multiple factors such as multi drug treatment (MDT), clothes of daily use. He is not allowed to touch family
prevention of deformity program, early case detection due members. He cannot contribute to family decisions.
to public education and the ultimate integration of leprosy For him marriage is not permissible and if already
services with general health care system which helped to married, he is not permitted to have physical relationship
reduce the stigma. Unfortunately, some patients hide the with the spouse. The female patient is not allowed to bear
disease because of the fear of dissociation by the family a child or if already a mother, she is not allowed to fondle
and the community – which delays the treatment and leads her child or breast feed her child. Finally the leprosy patient
to deformities. Deformity is equated mostly with infectivity is “abandoned” by the family and divorce is asked for, on
and hence the fear and associated social stigma. the basis of the disease.
CHAPTER
44
Human Rights and Leprosy 567
Legitimacy for Social Ostracism alliance with a leprosy patient, provided the disease is
revealed to the spouse before marriage.
The dictums of religious books and traditional social codes
• Indian Divorce act of 1869,12
or attitudes are more severe than any law. Societal attitudes
Clause 10 (iv) has for a period of not less than two
are set in laws. The attitudes have roots in the religious
years immediately preceding the presentation of the
books thus religion and law give the legitimacy for such a
petition, been suffering from a virulent and incurable
behavior.
form of leprosy.
The need for change was recognized and recommen-
• Hindu Marriage Act of 1955,13
dations were proposed in the International Leprosy
Section 13 (iv) has been suffering from a virulent and
Congress in 1963 at Rio-de-Janeiro. Swaminathan
incurable form of leprosy.
Committee of Government of India in 19829 and Gavai
• Hindu Special Marriage Act of 1954,14
Committee of Government of Maharashtra in 198210 also
Section 27 (g) has been suffering from leprosy, the
recommended to repeal outdated, outmoded acts pertaining
disease not having been contracted from the petitioner.
to leprosy patients, inflicting social injustice on them.
• Muslim Marriage Act of 1939,15
For social assimilation of leprosy patients, the retrograde
Section 2 (vi) that the husband has been insane for a
legislation needs changes in the light of modern concepts
period of two years or is suffering from leprosy or a
of leprosy. All derogatory acts adversely affecting the
virulent venereal disease.
fundamental rights of a leprosy patient as a citizen should
• Indian Christian Marriage Act of 1872. 16
be repealed, where needed, without any delay, as
Section 10 (iv) virulent and incurable form of leprosy
connivance of the provisions in the acts and laws amounts
for a period of not less than two years.
to their acceptance.11
The objectionable terms used in the laws are
The outdated, outmoded Indian lepers act of 1898 was
‘‘Virulent and incurable forms of leprosy’’
repealed in October, 1984 in the state of Maharashtra and
There is nothing like virulent form of leprosy and
thereafter, in the Union territories and other states of India.
every form of leprosy is curable with Multi Drug
This act considered leprosy patients as criminals for no
Treatment (MDT).
crime of theirs. It did not protect the society at large from
the infection of the disease. It did not help in any way for Matrimonial laws need changes as
the control of the disease. On the contrary it perpetuated • Leprosy is neither hereditary nor congenital
the social stigma. The patients used to hide the disease • All the types of leprosy are curable with MDT
in the early stages for the fear of getting committed under • All the patients are not necessarily infectious
the said act. • Infectious patients can be made non- infectious by MDT
Leprosy patients were not allowed to inherit ancestral within a short period of time
property till 1956. The ancient literature like Koutiliya
Arthashashtra did support this tradition. The Hindu PARSI MARRIAGE ACT OF 1936 (NO
Succession Act of 1956 rectified this error and leprosy DIVORCE GRANTED ON THE GROUND
patients now are allowed to inherit ancestral property. OF LEPROSY)17
However, on account of selfish motives, it is not so easy The grounds of divorce, dissolution and decree of nullity
for a leprosy patient to get the due share of the ancestral of marriage do not include leprosy.
property. (NB – Dr RV Wardekar, Director, GMLF, Wardha, who is
the father of Survey, Education and Treatment (SET) pattern
Laws on Matrimonial Alliance and Divorce of leprosy control, had a different view which was expressed
The present matrimonial acts are negative and punitive in in his letter dated, September 4, 1953 to Dr. P. Sen of
their approach towards leprosy patients which are needed School of Tropical Medicine, Calcutta, WB. He has cited
to be revisited. two case studies of two young, married female patients.
Manusmriti did not allow matrimonial alliance with In those days, bigamy was allowed. The husbands of both
leprosy patients in the 3rd chapter of the book. However, the female patients, after abandoning their wives who had
in the 8th Chapter of the book, Manu allows matrimonial leprosy, got married again; but did not give divorce to their
CHAPTER
44
first spouses having leprosy. The unfortunate females, areas of Christian and Muslim cemeteries in spite of a
victims of leprosy, could not get married again as their circular by Executive Health Officer – Municipal Corporation
previous husbands did not give them divorce. He expected of Greater Mumbai -198321 which orders all the crematoria
that the law for divorce should be so flexible that the cases to accept the dead bodies of leprosy patients for disposal.
which were mentioned should get justice). Such a situation may be prevalent in other states of
(Copy of the original letter is available in the archives India, too.
of Gandhi Memorial Leprosy Foundation, Wardha,
Maharashtra State). EMPLOYMENT RULES…
Stigma in the Community New recruits having leprosy find it difficult to

get employment. The State and the Central government
Most of the victims are “abandoned” to their fate outside rules22,23 for leprosy patients to get reinstated in the jobs
the court of law. The “supreme committees” of different are not uniform.
castes give verdict for divorce which is true till today (Article
16 violated of HR declaration) Life Insurance and Leprosy Patients
Stigma in the Leprosy Hospitals Smear positive leprosy patients are not insured. Leprosy
per se is not a cause of death and does not shorten the
These hospitals were situated on the outskirts of the city/ life of a patient.24 (Violation of article 22 of HR declaration)
village. There were physical barriers which existed between Letters asking about any change that has taken place
the patients and the staff members. Leprosy phobia was in the above mentioned condition, are not replied by the
the cause for the same. Positive change is seen in this concerned officer of LIC.
respect nowadays. Paradoxically, “Janashree Bima Yojna” includes leprosy
patients with physical deformity / deformities.
Stigma in Leprosy Settlements/Leprosy
Colonies Transports and Leprosy Patients
There used to be separate rows of huts for skin slit smear Maharashtra State Road Transport Corporation rules
positive and negative patients. The children used to get (1980) do not allow leprosy patients with recognisable
isolated in orphanages inside the settlements. deformity to travel with others. Usually the deformed
As these patients are outcasts from the society they patients are non-infectious.25 (Violation of article 13 of HR
loose their self esteem. declaration)
Letters asking about any change that has taken place
Stigma: Admissions/Treatment in in the above mentioned condition are not replied by the
General Hospital concerned officer of MSRTC.
In the general hospitals, “No touch technique” is used most Paradoxically, concession is given to leprosy patients
of the times by hospital staff members. in the ticket fares when his or her disease is not in
Circulars by Coroner of Mumbai,18 Commissioner of recognizable form. (Early infectious patients cannot be
Municipal Corporation of Greater Mumbai , Executive recognized, so easily by anyone). However, nowadays,
Health Officer – Municipal Corporation of Greater Mumbai19 so many patients with leprosy come to hospital in public
were sent to General Hospitals from time to time for transport, many of them with obvious deformities and facies
admissions of needy leprosy patients for treatment for other typical of leprosy, but no body objects or throws them out.
ailments besides leprosy. Though slowly, the stigma has reduced considerably not
Leprosy is a notifiable disease according to Bombay only among the family members; but also in the community
Municipal Corporation Act,20 under “Control of Communi- following effective IEC programme through NLEP. In
cable Diseases” which is incorrect as leprosy cannot be villages also our experience of last 10 years shows that
compared with diseases like cholera and typhoid. the active leprosy cases (on treatment); and those treated
Disposal of unclaimed dead bodies of leprosy patients previously, live in the families, in the village itself, as a
is done in separate crematorium of Hindus and in separate part of the society.
CHAPTER
44
Similar laws may be prevalent in other states of India, Winds of Change
too.
Gloomy picture of leprosy is becoming rosy but we have
Indian Railways Act, 1989 under Section 56
to offer roses without thorns to leprosy sufferers.
empowers a railway servant on duty to ask a passenger
There are several welfare schemes under the state
with infectious disease to vacate the compartment before governments and the central government of India for the
reaching the destination. Leprosy is included in the category
handicap persons including leprosy. Unfortunately, they
of infectious diseases. This is again unscientific as leprosy
do not percolate to the needy patients. NGOs working for
is not a disease like tuberculosis, influenza.
the welfare of handicaps should make an endeavour to
Leprosy patients do get concession in the ticket fares
extend such welfare schemes to the needy patients.
(e.g. 75% concession on rail travel), if they are holding a The walls are crumbling, clappers of leprosy patients
certificate from a medical officer as non-infectious patients.
are replaced by clapping with them by the people.
Repealment of acts pertaining to leprosy, in proper direction
Rehabilitation
would change quality of life of leprosy patients. Early
It is difficult to get market for articles made by leprosy detection and regular, complete MDT have answered all
patients due to leprosy phobia. Local Governmental questions raised in the legal context about incurability;
organizations too do not purchase articles from infectivity and deformity.
rehabilitation centres of leprosy patients despite the At a recent meeting of the human rights commission
Maharashtra Government Resolution, 1961, to that in Geneva (January, 2009), representatives of the countries
effect.26 having leprosy problem, were allowed to project their views,
The Persons with Disability act of 199527 includes experiences and suggestions before the commission; and
only cured leprosy patients with 40% deformities. Out of the ambassadors of the concerned countries were asked
the 3% reserved jobs of physically handicapped persons, to take note of the same.
only 1% jobs are reserved for persons with physical
deformities (besides vision impaired and hearing impaired) VOICE OF AWAKENING
including leprosy patients.
Government of India has appointed a Committee During the International Leprosy Congress at Hyderabad,
for suitable amendments and the acceptance thereof India in 2008, it was revealed that the discriminatory acts,
is awaited. laws are currently in force only in Nepal and India. Nowhere
Rehabilitation Council of India Act, 1992 needs in the World, are such laws existing at present. They were
repealment in the clauses pertaining to definition of repealed or amended suitably in the light of modern
Handicapped persons as the definition of Handicapped concepts of leprosy. (Proceedings of the pre-congress
persons does not include leprosy affected. workshop on “stigma and leprosy” held at the International
Leprosy Congress, Hyderabad, January 2008).
Juvenile Justice and Care and Protection Act 2000, The leprosy patients in Japan, who were incarcerated
Section 48 in leprosy homes, have been compensated financially as
This Act classifies leprosy as a disease that is per the verdict of the court of law of Japan.
communicable and inherently risky. This representation Human Right Commission of the world has appointed
spreads wrong and adverse message about leprosy. a sub-commission to look into the matter. The sub-
commission has visited India and had discussions with
Prevention of Begging Act 1959 (Maharashtra) the concerned authorities.
After two years of tenure in the receiving homes, beggars The International Leprosy Union, based at Pune, India
who do not have leprosy are released from the receiving did approach the Human Right Commission of India and
homes; whereas the beggars having leprosy are not has submitted a memorandum on the said subject.
released. This again is not justifiable. International Leprosy Union, SASAKAWA Memorial
Similar laws may be prevalent in other states of India, Health Foundation and The Law Society of Pune have
too. published their reports on the said subject during 2007.
CHAPTER
44
Leprosy patients all over the world have formed an • What is meant by cure from leprosy?
association of theirs. In India, we have its chapter • What is the magnitude of re-infection and relapse?
consisting of representation from nearly 700 self-settled • Has the conjugal leprosy rate come down after the
leprosy colonies. A recent positive development—the advent of MDT?
association of Leprosy patients of India (IDEA- India) along • Is there any test for detecting susceptibility?
with some NGOs have made an appeal to the speaker of • How much inoculum is needed to get infection?
Rajya Sabha (The Upper house of parliament) in the form • What is/are the mode/s of transmission of the disease?
of a petition,28 as a result, the petition committee of Rajya • What is the period of viability of the M.leprae outside
Sabha (headed by Shri Venkaiyya Naidu) visited some the human body?
states for on the spot enquiry about the leprosy situation • What is the incubation period of leprosy?
over there. The report has been submitted by the petition • Can a cured leprosy patient donate blood?
committee to the speaker of Rajya Sabha for further action. Provisions in laws may be affecting human rights
The Petition committee has referred certain queries to the of leprosy patients but the exact number of legally
respective departments for clarifications, e.g. department handicapped leprosy patients is not available as hardly
of revenue, ministry of finance. any leprosy patient knocks the doors of court of law
Strategies to Address the Social Aspects for justice. Therefore, the unjustifiable provisions in
the laws are like rabid animal that is sleeping. On
• Integration of leprosy services with general health care
awakening, it will take bite of an innocent person. Hence,
system will increase early detection and good
the utter requirement of replacement / repealment of
compliance of the treatment and help in reducing
such outdated, outmoded provisions, serving no good
stigma.
purpose.
• Successful Community Based Rehabilitation (CBR) of
Social justice cannot be achieved by following the
leprosy sufferers will help to reduce social stigma
letters of law but only by proactive actions.
attached to the disease
Administrative and policy changes need to ensure the
• Behaviour Change Communication (BCC) for legislators,
medicos, administrators and people at large will human rights of the patients. There should not be step
hopefully help to change their attitude for good. Mass - motherly attitude towards leprosy problem by the
media and celebrities in the society have major role to authorities concerned. Ensure proper places for
play in this regard. Awareness and awakening about treatment centers / care after cure, adequate / prompt
the disease will have to be undertaken by all the health supply of multi drugs to needy patients. Ascertain the
functionaries. Advocacy role will have to be played by real situation and act on the basis of the local baseline
leprosy workers, General Health Care staff members data of the disease.
and the school teachers as well as scientists working A synergistic joint action between the stakeholders
in the field of leprosy. namely, the patients, the providers, the people along
• Empowerment of leprosy patients will increase their with a positive “political will” will go a long way to
self esteem remove the social stigma that is attached to leprosy
• Counseling for medical and social problems of leprosy for centuries together. Then and then only leprosy will
sufferers will go a long way to improve the quality of be considered as a disease like any other disease and
their life. violation of Human Rights of the leprosy patient will
If we want Repealment of outdated acts / laws, few come to an end.
points need to be clarified by the scientists working in
the field of leprosy without any credibility gap, to REFERENCES
remove doubts, confusion, misconceptions about
1. Mahabharata - Maharshi Vyas.
leprosy from the minds of the people at large including 2. The Hindu, Tamil Nadu, 24th Sept 2008 (News paper).
medical fraternity and the law makers. 3. Karipurath P. Should Leprosy be a ground for divorce? Leprosy
• Is susceptibility genetically determined? in India 1976;48(3):304-08.
• How much period is required for an infectious leprosy 4. Deccan Herald, 11/11/2006, News paper.
patients to become non-infectious after starting MDT? 5. Manusmruti, Dharmasindhu (Kashinath Shastri, Pg 636).
CHAPTER
44
6. Ramu G., 1990, Indian Leprologists Look Back, Publication of 20. Bombay Municipal Corporation Act, 1888, Clause 419.
RRE Society of Acworth Leprosy Hospital, Wadala, Mumbai - 21. Circular EHO MCGM, Public Health Dept. - Dead Body - No.HO/
400 031. 56708/R-I of 25/5/1984.
7. R K Mutatkar GMLF Wardha, (Book - Society and Leprosy). 22. Employment Rules Govt. of Maharashtra, Urban Development
8. UNO’s the Universal Declaration of Human Rights, Dec. 10, Public Health & Housing Department, Resolution No. LEP/2571/
1948 (A/HRC/8/L.18) 77663-D, 14th Nov 1972.
International covenant on economic, social and cultural rights 23. Employment Rules Govt of India, No.A-17020/1/74-MG, 5/4/
1966 [GA res. 2200A (XX1)] 1974.
Convention on the rights of persons with disabilities, UN 24. LIC Act 1956, 9 Nov 1987, Press Release.
department of economic and social affairs 2007. 25. Maharashtra State Road Transport Corporation, Traffic Circular
The Elimination of discrimination against persons affected by No.11 of 1980, 21/4/1980, No.ST/TD/CNS/208/5/79/2928.
leprosy and their family members, 18.06.2008. Indian Railway Act, 1989 Section 56
9. Swaminathan Committee Report: Govt. of India, 1982. 26. GR Govt. of Maharashtra - purchase of bandage cloth & bed-
10. Gavai Committee Report: Govt. of Maharashtra, 1982. sheets, Industries & labour resolution no.STO-1059-21957-IND
11. M S Mehendale, Poona District Leprosy Committee, Pune (Book III, Sachivalaya, Bombay 32, 11/4/1961 (Para 3).
- Health Education and Social Aspects in Leprosy work). 27. Persons with Disability Act 1995, Govt. of India Section 2 (i)
12. Indian Divorce Act, 1869 Section 10 (iv) and (iii)
13. Hindu Marriage Act, 1955, Section - 13 (iv). Prevention of Begging Act, 1959 (Maharashtra), The
14. Hindu Special Marriage Act, 1954, Section - 27 (g). Rehabilitation Council of India Act, 1992 Section 2 (c),
15. Muslim Marriage Act 1939, Section - 2 (vi). The Juvenile Justice and Care and Protection of Children Act,
16. Indian Christian Marriage Act, 1872, Section - 10 (iv). 2000 Section 48
17. Parsi Marriage Act, 1936. 28. Petition to Rajya Sabha by ex MP, Mr. Ram Naik et al, Mumbai,
18. Coroner of Bombay, 24/12/1960, No.2/1960 Circular. which was admitted by the Hon. Chairman Rajya Sabha on 3rd
19. Municipal Corporation of Greater Bombay - Municipal April, 2008. The petition was reported to the council on 16th
Commissioner, HO/41153/R-I of 15/3/84. April, 2008, thereafter, it was referred to the committee on petitions
Director Health Services, Maharashtra, DHS/CELL/Lep/Medical for examination and report.
Care/1990 (2/1/1990). Report of Law & Leprosy 2006-07, by Indian Leprosy Union,
Surgeon General, Public Health, MISC-23185-G of 1969 (10- SASAKAWA Memorial Health Foundation and Indian Law Society,
15/7/69). Submitted to Human Right Commission of India
CHAPTER
45
45 Role of NGOs in National Leprosy

Eradication Program
Thomas Abraham, Pankaj Sharma, R Ganapati, Atul Shah
INTRODUCTION pockets with high prevalence. The incidence of the disease

presently is either stationery or declining very slowly. The
Involvement of Non-Governmental Organizations (NGOs) major problems that still need attention are the hidden
in the National Leprosy Eradication Program (NLEP) is of cases, prevention and management of disabilities,
vital importance; these had and still have an active role in rehabilitation, sustaining quality leprosy control activities
health promotion in the community. Many patients even including supervision and monitoring of programs at the
seek treatment through them. Though the Government of district and subdistrict level. The main role of NGOs is to
India tackles the major burden of leprosy work, about support the NLEP to tackle these issues. Though the
20-25% of the workload is handled by the NGOs. The leprosy services are now provided through the general
significant role played by the NGOs in different leprosy health care system, the Government of India has
related activities is very well acknowledged by the National established the District Nucleus (DN) for proper
Program. The technical support rendered has facilitated operationalization of NLEP by effective program planning,
the elimination of the disease and its integration with the implementation of guidelines, record maintenance at district
General Health Services. However, there still exist certain level, financial management and periodic program review.
MAJOR NGOs WORKING IN PARTNERSHIP WITH NLEP

International Federation of Antileprosy Associations (ILEP)
Sr No Organization Full Name Country
1. AIFO Associazione Italiana Amici di Raoul Follereau Italy

2. ALES Aide aux Lépreux Emmaüs-Suisse Switzerland
3. ALM American Leprosy Missions USA
4. DAHW Deutsche Lepra- und Tuberkulosehilfe Germany
5. DFB Damien Foundation Belgium Belgium
6. FL Fondation Luxembourgeoise Raoul Follereau Luxembourg
7. FRF Association Française Raoul Follereau France
8. LEPRA British Leprosy Relief Association United Kingdom
9. NLR Netherlands Leprosy Relief Association Netherlands
10. OM Comité International de l’Ordre de Malte Switzerland
11. SF Fontilles Lucha contra la Lepra Spain
12. SJ Sasakawa Memorial Health Foundation Japan
13. SLC Le Secours aux Lépreux Canada
14. TLMI The Leprosy Mission International United Kingdom
CHAPTER
45
Role of NGOs in National Leprosy Eradication Program 573
ILEP is an international federation of 14 autonomous
non-governmental anti-leprosy organizations with a powerful
financial partnership, raising funds from public and
institutional sources. Membership of ILEP enhances the
capacity of these member associations to work towards
the common goal of a “World without leprosy” (Table 45.1
and Fig. 45.1).
Their annual contribution to antileprosy work amounts
to about Euro 61 million globally, during the year 2007–
2008. Members of ILEP work in partnership with the
governments; international and local partners, supporting
the development and sustenance of quality leprosy
Fig. 45.1: Distribution of ILEP members’ field support by region
services.
ILEP globally supports the leprosy field activities, ILEP member organizations in India support National
including case finding, multidrug treatment (MDT), training, Leprosy Eradication Program (NLEP) through three main
hospital care for complicated cases, research and socio- types of projects: (a) Own, (b) NGO-run, and (c) through
economic rehabilitation. In India, ILEP contribution to District Technical Support Teams (DTST).
leprosy services is around Rs 60 crores annually. Own projects are generally hospitals which are operated
directly by the concerned ILEP member organization and
ILEP Partners Working for Leprosy in India they provide a broad spectrum of services including
1. Foundation Raoul Follereau (FRF) management of leprosy and its complications,
2. Aide aux Lepreux Emmeus-Suisse (ALES) reconstructive surgery, socioeconomic rehabilitation. NGO-
3. Amici di Raoul Follereau (AIFO) run projects are generally managed by a local NGO with
4. American Leprosy Mission (ALM) total or partial support from ILEP member organisation.
5. Deutsche Lepra-und Tuberkulosehilfe (DAHW) The third type of project, DTST, involves provision of
6. Damien Foundation Belgium (DFB) technical support to the district staff at all levels through
7. Fontilles – India (Fontilles) an experienced senior level team consisting of a Medical
8. British Leprosy Relief Association ( LEPRA) Officer and a supervisor with a vehicle for mobility.
9. The Leprosy Mission International (TLMI) There are totally 18 own-run, 122 supported and 174
10. Netherlands Leprosy Relief (NLR) DTST projects belonging to the ten member organizations
Table 45.1: ILEP Members’ support to leprosy work (in Euro) during 2007- 2008
Sr No Organization Support to field projects Support to research* Indirect field support** Total support
1. TLMI 14078331 196887 7232 14282450
2. DAHW 12471338 104656 47500 12623494
3. NLR 8087390 719396 290932 9097718
4. DFB 6429595 300246 0 6729841
5. FRF 4004544 396200 157435 4558179
6. LEPRA 3296240 162373 1636 3460249
7. ALM 1804736 627661 873 2433270
8. ALES 2056750 39057 0 2095807
9. AIFO 2044334 6532 5400 2056266
10. SJ 584023 246952 311266 1142241
11. FL 840000 0 0 840000
12. SF 719922 29203 8000 757125
13. SLC 703012 16418 11016 730446
14. OM 331782 0 0 331782
Total 57451997 2845581 841290 61138868
*including other scientific activities such as congresses and journals.

**including support to training, consultancies and patients’ associations.
CHAPTER
45
of ILEP operating in India. The contribution of ILEP to 5. Support operational research covering specific as-
leprosy control in India has been conspicuous, considerable pects of common concern related to provision of
and consequential. It has enabled the government to quality services / sustaining leprosy control activi-
establish and maintain integrated leprosy services in ties / DPMR, etc.
endemic states mainly through the DTSTs. In all the 12 6. Assist in developing training curricula especially
endemic states, thanks to the committed involvement of DPMR for various categories of personnel. They
the government staff facilitated by DTSTs, a reasonably also print and supply the learning material of DPMR
well functioning mechanism of detecting, diagnosing and for different categories of general health care staff.
treating the leprosy affected has been installed. In addition 7. Involved in organizing State Leprosy Officers’
ILEP has produced learning material in 12 different review meetings.
languages for various categories of government workers; 8. The NLEP website was developed by ILEP-India
trained the district nucleus teams and other staff in 590 for ready reference.
districts in the country. One of the strong features of ILEP
9. Supports central leprosy division in organizing need
in India has been the healthy, reciprocally beneficial
based, specific goal oriented workshops involving
partnership with major players in leprosy field; which has
various stakeholders on specific issues of NLEP.
resulted in remarkable progress in leprosy control and has
10. ILEP supported hospitals; function as referral hos-
become a model worthy of emulation.
pitals to treat complications of leprosy as a part of
Involvement of ILEP in the NLEP (2007-2012) referral mechanism of general health care system.
These hospitals are providing disability care for lep-
The present support to NLEP is planned in line with the
rosy affected persons in an integrated approach
new WHO Global Strategy and its operational guidelines,
depending on availability of the funds, expertise
to sustain good quality leprosy services in the integrated
and other resources. Forty-one ILEP supported lep-
scenario.
rosy hospitals will function as tertiary level care
1. The ILEP has significant role in providing National
centers for DPMR activities.
Disability Prevention and Medical Rehabilitation
(DPMR) Consultant to Central Leprosy Division who 11. The ILEP supports the NGO projects which are
functioning in accordance with GOI guidelines.
assists NLEP in planning, monitoring and evaluat-
ing DPMR activities in the country. 12. ILEP assists in establishing reconstructive surger-
2. Provides state level NLEP coordinators for perform- ies at medical college hospitals by building the ca-
ing following functions pacity of the surgeons in reconstructive surgery
• Capacity building of District Nucleus (DN) through the visits of their core surgical teams.
teams. 13. Continuing medical education (CME) for Medical
• Advise and guide State Leprosy Office in as- Colleges:
sessing training needs and defining strategy. • Over the years, many goals have been achieved
• Assist in capacity building of state leprosy of- in NLEP including elimination of leprosy, inte-
fice on managerial, analytical and supervisory gration of the vertical program with the general
skills. health services; and introduction of DPMR. To
• Advise and guide the state leprosy office in es- improve the students’ knowledge on leprosy with
tablishing referral system. the changing scenario, ILEP has decided to sup-
• Analyze the data and advise the state leprosy port holding the seminars and CME programs
society on implementation of the program. on Leprosy in Medical Colleges.
• Participate in the surveillance system. 14. Support to improve monitoring and supervision
• Arrange for independent evaluation. (including disease surveillance system):
3. ILEP also provides technical inputs for the inde- • The functional and structural integration has hap-
pendent evaluations of NLEP including DPMR. pened in all the states after successful elimina-
4. State and regional level workshops are supported tion of the disease. In this scenario it is neces-
by ILEP to develop skills in supervision and moni- sary to improve monitoring and supervision of
toring. leprosy services. The ILEP plays a major role in
CHAPTER
45
facilitating this task by helping the district 3. To undertake advocacy program “To give leprosy a
nucleus through state coordinators. human face”, the mission statement of ILU.
15. Community-based Rehabilitation (CBR): Ongoing activities:
• ILEP agencies continue to participate in CBR 1. Field research on social aspects of leprosy.
activities to enable people affected with leprosy 2. Advocacy and networking of NGOs working in leprosy.
to gain a sustainable and improved quality of 3. Human rights for leprosy affected persons.
life. CBR is a multidisciplinary approach, imple- 4. Publication of books, periodicals and educational
mented through the combined efforts of individu- materials.
als with disabilities themselves, their families, 5. Community awareness program.
disabled people’s organizations, communities, 6. Sponsorship of children under shadow of leprosy for
governmental and nongovernmental, health edu- higher studies.
cation, vocational, social and other service 7. Organization of seminar/workshops at National and
organizations. International level.
Involving the family and community members in the The ILU was granted official status by WHO in 1998
process of rehabilitation is a key strategy to empower and Dr SD Gokhale, Chairman ILU, was appointed as a
people affected by leprosy, encouraging them to play an member of the Technical Advisory Expert Group of WHO
active role in their rehabilitation and to further reduce in Geneva. Dr SK Noordeen took over as the President of
stigma. The central strategy of community-based ILU in 1998 from Dr MF Lechat. ILU has close collaboration
rehabilitation is to facilitate community action; to ensure and coordination with the Government of India (GOI), WHO,
that people with disabilities have the same rights and Sasakawa Memorial Health Foundation (SMHF), The
opportunities as all other community members. This applies Nippon Foundation, etc. and has been contributing to bring
equally to people affected by leprosy. To improve about remarkable changes in the social acceptance of
rehabilitation coverage for people affected by leprosy, the leprosy affected in the community.
CBR approach to facilitate integrative and participative
rehabilitation with limited and locally available resources; Gandhi Memorial Leprosy Foundation (GMLF)
to as many people as possible is found as an effective
The Gandhi Memorial Leprosy Foundation was established
tool. It is estimated that approximately 85% of rehabilitation
in the year 1951 with its National Headquarter at Wardha
needs of people with disabilities can be met within the
to commemorate the thoughts and ideals of Mahatma
community.
Gandhi, on leprosy and leprosy work in India.
The Sevagram, Wardha was the first unit to be
International Leprosy Union (ILU), Pune
established in 1951 which covered 27 villages in Wardha
The International Leprosy Union, Pune was established in district. With special emphasis on health education GMLF
the year 1986 by voluntary organizations and leprosy started its leprosy control units for the first time in the
workers from over 20 developing and developed countries; country in different regions. These units were located at
that recognized the need for linkage and networking among Chilakalpalli (Andhra Pradesh) set up in 1953; T’Narasipura
like minded groups and individuals; actively pursuing the (Mysore district), Karnataka (in 1955) and Balaram Pur
cause of eliminating leprosy and mainstreaming the leprosy (West Bengal) in 1977. Ultimately, the units were handed
affected in society. It has since worked as a catalytic over to the State Governments.
agency with the unique objective not only to serve as the Soon after its inception, at Sevagram unit, the GMLF
voice of NGOs active in developing countries but more launched the pilot project to control leprosy in the country
importantly to give leprosy a human face. with the new and the only drug ‘Dapsone’ available in those
The main objectives of ILU may be summarized as days. Thus, the survey, education and treatment (SET)
follows: pattern of leprosy work was evolved which was adapted
1. To establish links between National and International by GOI in 1955, by incorporating in the 5-year plan and
Voluntary Organization working in the field of leprosy. that is how the National Leprosy Control Program came
2. To collect and disseminate information from various into effect. Gradually, GMLF also developed the
sources. methodologies of Urban Leprosy Control Program,
CHAPTER
45
Community Awareness Program and establishment of

referral hospitals for leprosy. The concept of socioeconomic
rehabilitation for leprosy affected persons was also
developed by GMLF and all these methodologies were
incorporated by Government of India in the national
program.
Today, after integration, GMLF has suitably changed
its strategy to collaborate its leprosy activities with the
government policies and diversified its activities
incorporating tuberculosis control, eye care, program for
women development, imparting training in general health
care, etc.
It is noteworthy that GMLF evolved the first leprosy Fig. 45.2: Distribution of medicines by mobile treatment unit of
training curricula for medical doctors, nurses and HKNS (DSB)
paramedical workers. The first training center was
established by GMLF at Wardha in 1952 for the above Late Shri DC Aggarwal (a social activist and philanthropist),
cadres which created a team of trained leprosy workers the main activities have been in distribution of MDT and
throughout the country. providing rehabilitative services to leprosy patients (Fig.
45.2). The branch raises funds from sale of leprosy seals
Hind Kushth Nivaran Sangh (HKNS- and from other voluntary donors (Fig. 45.3). There are
Previously: Indian Leprosy Association) arrangements of daily dressings of wounds and ulcers of
patients, appointment of dressers in the leprosy colonies,
The Hind Kushth Nivaran Sangh (HKNS) is the premier supply of dressing materials; cotton, bandages, antiseptic
voluntary organization working for the eradication of leprosy. solutions and creams, etc. There is also a regular supply
In the British rule in 1925, the British Empire Leprosy Relief of medicines for ulcers and others common ailments.
Association (BELRA) was established with a view to Distribution of tricycles to patients with deformities,
provide medical and social support to the leprosy sufferers. financial help to patients for social purposes like education
The branch of BELRA in India was called as Indian Council of children, marriages of daughters, etc. are other notable
(ICBELRA) which soon after its formation was in position activities of the branch.
to functional independently from its parent body on account HKNS publishes a research journal in India “Indian
of generous financial and other support gathered in India. Journal of Leprosy”, which is the official organ of Indian
After independence it was renamed as Hind Kushth Nivaran leprosy Association. Previously known as “Leprosy in
Sangh (Indian Leprosy Association) and was registered in India”, it was started by Dr Ernest Muir in July 1929 and it
1950 under Societies Registration Act, XXI of 1860. The
Hon’ble President of India is the President of the Sangh.
The Sangh has a Governing Body of 41 members with its
headquarters at Delhi. HKNS has at present its 18
branches in States/UTs headed by Hon’ble Governors of
respective states.
Objectives:
1. Promote and coordinate voluntary work in leprosy in
order to eradicate leprosy.
2. Promote and support advocacy in leprosy.
3. Promote and undertake IEC activities
4. Promote and support rehabilitation activities.
5. Promote and support dissemination of scientific
research through publication.
Fig. 45.3: Members of Delhi State Branch of HKNS with Smt. Indira
Delhi State Branch of HKNS has been active in the Gandhi on the occasion of leprosy seal campaigns. (Photo courtesy:
field since its inception in 1961 (Fig. 45.2). Founded by HKNS (DSB)
CHAPTER
45
retained this name till 1983. From January 1984 it was
renamed as Indian Journal of leprosy by Dr Dharmendra,
its editor.
Missionaries of Charity, Gandhiji

Prem Nivas, Titagarh
For those not loved, I give love, For those discarded,
I give shelter and care. –Mother Teresa
Gandhiji Prem Nivas Leprosy Center (mobile clinic) at

Titagarh, 24-Parganas (West Bengal) was started by
Mother Teresa in 1958. Later in 1960, the Titagarh Baba Amte (1914–2008)
Municipality leased a piece of land to establish the

two kilometres away. Those days, leprosy was associated
permanent center for leprosy services which included
with intense social stigma and patients were disowned by
regular treatment and management of leprosy complication.
society. It was then believed that the leprosy patients were
The railway authorities donated a long stretch of land on
sinners, paying for the sins they had committed. There
the eastern side of railway track, between Titagarh Kharda
was also a widespread fear that leprosy was contagious
station where the Brothers have been offering distinguished
and could be spread by touch. Baba Amte strove to dispel
services in the areas of counselling and rehabilitation.
these myths and once, even to the extent; that he allowed
Other facilities for leprosy affected:
bacilli from a leprosy patient to be injected into him while
1. The outdoor clinic
participating as a volunteer in an experiment.
2. 200 bedded inpatient care center
Later, Baba Amte also founded the Somnath and
3. Surgical care (operation theater)
Ashokvan ashrams for treatment and rehabilitation of
4. Artificial limb center leprosy patients. The community development project at
5. Footwear center
Anandwan in Maharashtra is recognized and respected
6. Rehabilitation programs around the world and has done much to dispel the prejudice
– Handloom center against leprosy victims (Figs 45.4 to 45.6). The whole
– Carpentry section geosocial environmental milieu at. Anandwan is of
– Tailoring unit community living with farming, fruits, food and crops
cultivation, cottage industries making household products,
Anandwan
handicrafts, woven clothes, carpets, and decorative items.
Anandwan was the first of the three ashrams started by
Baba Amte to treat and rehabilitate leprosy victims from
the disadvantaged sections of society. After taking a leprosy
orientation course at the Calcutta School of Tropical
Medicine, Baba Amte began his fight against leprosy. He
set up about 11 leprosy clinics running weekly around Warora,
in Chandrapur district (Maharashtra). Taking his work to
the next level, he started the “Anandwan” (Forest of Joy)
ashram in a remote jungle at Warora, in Chandrapur district
of Maharashtra, about 100 km from Nagpur, to help
rehabilitate patients. Anandwan was registered in 1951 and
received a state land grant of 250 acres (1.0 km²) (Fig.
45.4).
The land was barren rocky, covered with scrubs and Fig. 45.4: The campus of Anandwan in present times
infested with scorpions and snakes. The nearest well was (Photo courtesy: ©mss.niya.org)
CHAPTER
45
institution in the production of vaccine in India) and a great

philanthropist.
During his young age Dr Jal Mehta was extremely
influenced by the plight of the leprosy suffers in his area.
He established Bandorawalla leprosy hospital which he
named in fond memories of his father-in-law. The hospital
is located on a big piece of land (over 100 acres) at Yeolewadi
(Kondhwa) on the outskirts of Pune. There are 350 beds in
the hospital which is fully equipped with all the facilities
for diagnosis and treatment of leprosy, reconstructive
surgical care, physiotherapy, and rehabilitation units. There
are well formed sections on artificial limbs, manufacturing
Fig. 45.5: Colony houses at Anandwan for leprosy affected special foot wears and splints for leprosy patients. After
residents (Photo © mss.niya.org) death of Dr Jal Mehta, due to paucity of funds, the hospital
was handed over to State Government in 2001.
Besides leprosy relief work, Baba Amte also made Dr Jal Mehta’s work in leprosy-medical, social relief,
forays into other issues of social and public causes related research and rehabilitation, during his tenure of more than
to environment, human rights for which he was accorded 40 years of voluntary and honorary service, brought the
a series of international awards which include Damien- Dr Bandorawalla Leprosy Hospital and its associated
Dutton Award, USA (1983), Magsaysay Award, Philippines rehabilitation and allied projects to national and international
(1985), UN Human Rights Award (1988), GD Birla fame. By his rehabilitation work he has raised these leprosy
International Award (1988). The National Awards include patients (from the weakest of the weaker section of society)
Padma Shri (1971), Padma Vibhushan (1986), Welfare of to the men and women; who can stand on their own feet,
Disabled Award (1988), and Jamna Lal Bajaj Award (1979). earn well, and this has increased their self-esteem to that
of any other human being.
A big example of successful economic rehabilitation
of leprosy patients has been presented by the rehabilitation
units run by a cooperative body formed by leprosy cured
patients, called as “Minoo Mehta Apangoddhar Sahakari
Audyogik Utpadak Maryadit Sanstha (MMASAUS)” (Fig.
45.7). This Sanstha (organization) was set-up in 1983 by
55 leprosy cured patients (LCPs), and is now has 110
members. Based at Yeolewadi in Kondhwa, the group is
scaling greater heights with every passing day. The Sanstha
was set up under the guidance of Dr Jal Mehta, who helped
rehabilitate the LCPs after using innovating techniques of
surgeries for correcting their deformities at the Bandorawala
Leprosy Hospital.
Fig. 45.6: Agriculture farmland crops at Anandwan
(Photo © mss.niya.org)
In the rehabilitation units 110 leprosy-cured patients
work in two shifts and earn between Rs 4,500 and
Rs 5,500 per month. The machines have been designed in
Pune District Leprosy Committee (PDLC) a manner for easy operation by persons with deformities.
No form of rehabilitation is complete without economic The organization has been manufacturing motor engine
rehabilitation –Jal Mehta parts like chassis cross box and clutch-plates for heavy
vehicles and mounting bracket and assembly lever for light
Pune District Leprosy Committee (PDLC) was founded in vehicles of Tata Motors in Pune. It is pleasing to note that
1957 by Late Dr Jal Mehta. He was an industrialist, the the common popular vehicles of today Indica, Sumo or
Vice-Chairman of Serum Institute of India (the premium Safari; all are likely to have some vital engine components
CHAPTER
45
Fig. 45.7: Cured leprosy patients in role of mechanical workers at the MMASAUS rehabilitation units at Pune. The machine designs are
such that even persons with deformities can operate. (Photo courtesy: Apoorva Gupte)
manufactured by a group of leprosy-cured patients (LCP). single dose ROM treatment for single lesions as well as
The other clients of the organization include Forbes 2 to 5 PB lesions.
Marshall, Lucas TVS, Poonawala Group, besides Tata Motors. The fact that relapses in MB leprosy in FDT occurs
mostly beyond 5 years was established through
Bombay Leprosy Project—A Model NGO surveillance by volunteers in a cost effective manner. The
Bombay Leprosy Project (BLP), an innovative concept in first RO-28 relapse was reported in 1998 and later
leprosy management was conceived on11th September documented relapses after ROM.
1976 and has been in operation for over 3 decades with More recently preliminary results of clinical trials of
the basic objectives of operational research in parts of moxifloxacin based regimens have been published for the
Bombay and adjoining rural areas. Pioneering field oriented first time in the literature.
concepts in chemotherapy, disability care, rehabilitation,
Disability Care
IEC and medical education have been the subjects of study
and documentation. These innovations have become more After years of field investigations in Andhra Pradesh,
relevant in the current scenario of declining endemicity in inexpensive araldite grip aids (1982) prefabricated splints
the background of dwindling funds from donor agencies. (1985), ulcer dressing kits, etc. were widely practiced (1985)
by community volunteers.
Key Areas of Project Activities A low cost disability program was started in Mumbai
Chemotherapy slums (1994) and later in rural Maharashtra (1998) in which
BLP was the first to introduce multiple drugs even before through massive campaigns; a high load (25-27 per 10,000
WHO MDT was implemented by NLEP in early 80s. In population) of leprosy-disabled (Grade 2) was unearthed
1988, BLP reported that the initial intensive 21 days of in some PHC areas of Thane district. The operations
rifampicin therapy (IAL) had no added advantage over the revealed 1,250 disabled leprosy patients (grade 2) living in
WHO recommended monthly pulse therapy. Documentation an adopted rural population of 4,76,970 covering 11 PHCs.
of experiments with fixed duration treatment (FDT) for 24 Recently, at the request of DLO Thane BLP has been
and 12 months have helped to save cost and manpower. offering POD training to ASHAs under National Rural Health
In 1986, BLP for the first time published data on BI decline Mission (NRHM) scheme. A highly cost-effective model
in drop out patients. This finding helped reduction of using village youth for door step services has been
treatment duration to 12 months. established with a view to implement community based
Research trials with rifampicin and ofloxacin for 28 days rehabilitation (CBR) at a later stage (Fig. 45.9).
(RO-28) showed that the rate of fall in BI is parallel to Tertiary level care is also a part of this activity. BLP
WHO MDT; BLP published for the first time efficacy of has broken ground in involving orthopedic and plastic
CHAPTER
45
surgeons of general hospitals and private nursing homes of allopathic and non-allopathic (Homeopathic etc.) Medical
to perform reconstructive surgery. Colleges, as well as postgraduate (PG) students of
Dermatology Departments, officially posted to BLP sites
Rehabilitation for fixed periods as a part of their academic curriculum
In collaboration with general rehabilitation organizations (Fig. 45.11). They not only learn the subject but also provide
working in Dharavi and other slums, an integrated vocational assistance in academic and research work. As it is
rehabilitation training program was started in 1993, as a expensive to employ full time doctors, this strategy has
major step in abolishing stigma. The first attempt in CBR proved to be cost effective. Expert guidance has been
was made in Bharat Nagar slum in 1998. Community provided to more than 25 PGs to write their dissertations.
volunteers screened 74,000 slum dwellers and identified The successful efforts of BLP have been:
173 disabled people, including those due to leprosy.
1. Organizing National Conferences in medical college
Services were provided in collaboration with existing
campuses (e.g. IAL Biennial Conference, two National
rehabilitation agencies (Fig. 45.8). The experiment was Conferences of NGOs at the request of the government
repeated in a part of Dharavi, the biggest slum in Asia of India, WHO / NLEP meetings, etc.
with 600,000 population. Out of 93,000 persons screened;
2. Arranging guest lectures by visiting leprosy experts.
487 were found disabled. Appliances and mobility aids were
3. Donating leprosy books, training materials and
provided with the help of AIIPMR.
pamphlets to libraries.
In year 2000, computer training was offered to leprosy–
4. Organizing exhibitions of leprosy books and journals.
disabled along with other physically challenged persons in
the slum centers in an integrated manner. Many of these 5. Promoting PG students to present reviews and updates
trained persons and other handicapped patients are in innumerable seminars.
assisting BLP in academic work (Fig. 45.10). 6. Deputing interns and PGs to leprosy research
institutions.
IEC Activities 7. Providing skin smear facility and POD services in
In 1977, health education was used as a tool to identify private clinics.
leprosy patients, especially BI +ve cases in Bharat Nagar. 8. Offering special drugs like thalidomide to dermato-
Nearly 54% of total cases; and 82% of BI +ve cases were logists and including them as partners in research
spotted and identified by IEC technique. Later on, BLP publications.
received an Award for documenting this investigation. The
immensely popular Ganpati festival was used to spread Other Highlights and Achievements
leprosy awareness in Dharavi, followed by a massive As a cost effective method, BLP right from its inception
campaign in which 200 medical students of city colleges has been engaging volunteers to assist trained PMWs in
screened about 20,000 slum dwellers and detected 200 case detection, supervised treatment and POD work, a
new leprosy cases. procedure which long afterwards received approval by the
The innovative campaign of BLP using local trains and government and other funding agencies. First such
Bombay Electric Supply and Transport (BEST) buses as volunteer was a Muslim girl in Bharat Nagar, who not only
a medium of public education for the first time was later assisted surveys in 1976 but motivated her parents to run
followed by other NGOs. a BLP leprosy clinic in her own house in the slum.
Thorough surveys of slums, schools, factories,
Involving Medical Fraternity and hospitals, leprosy colonies have led to the documentation
Promoting Medical Education
of the quantum of infection and disability burden in the
Association with Medical Colleges and medical metropolis. Paramedical personnel were encouraged to be
professionals by creative techniques has been a regular partners in academic work, write research papers and
feature of BLP. A novel method of continuing medical present them at conferences. More than 80 papers have
education (CME) by displaying updates on leprosy scenario been co-authored by 20 such staff members, out of the
in 8 medical colleges through “Wall Journal” was total of over 300 publications from the BLP in all. Student
instrumental in creating interest among the students and volunteers were made to shed their stigma and were
the faculty in the often sidelined subject of leprosy. A engaged to offer supervised MDT in 9 leprosy colonies in
breakthrough achievement in this area was to get interns 1982.
CHAPTER
45
Fig. 45.8: A community volunteer using mobile phone in Dharavi Fig. 45.10: A physically challenged person using the computer
provides assistance in office work of BLP research activities
Fig. 45.9: A volunteer in rural area who is himself a cured leprosy Fig. 45.11: Interns from medical colleges examine patients at BLP
patient, offers door step rehabilitative services Referral Center
BLP has also exploited information technology methods shown that by following low cost techniques in field
in leprosy management. To cite one technique, mobile applications about 67% of the financial burden on donor
phones were used as early as 1998 by field workers to agencies was relieved. BLP model of integration may be
establish contact with the expertise available at the main replicable in other metropolitan situations in India.
centers; and improve care at the periphery. In 2000, BLP
hosted an academically oriented website which has not Acknowledgments
only motivated many students abroad to volunteer; but I am indebted to the Management of BLP for encouraging
also has helped in fund raising. me to undertake all these activities and the staff for the
assistance. GLTRA provided financial support for the basic
Conclusion routine control program and the infrastructure. This was
We believe that NGOs functioning under severe resource helpful to raise funds from several other sources for various
constraints may continue to assist NLEP, provided they areas of research.
adopt creative strategies and effect savings. A cost Various field activities of Bombay Leprosy Project (Figs
analysis of BLP working system during 1976 to 1995 has 45.8 to 45.11).
CHAPTER
45
Novartis Comprehensive Leprosy Care and taught the measures of splint application and
Association (NCLCA) carrying out exercises at home.
3. Prefabricated standardized splints have proved to be
Novartis is at the forefront in the global fight against leprosy highly effective in the prevention and correction of claw-
and its consequences, as a part of its corporate social hand, a common deformity in leprosy (Fig. 45.12). The
responsibility. In addition to the role of Novartis in splints are made of durable and easily available
collaborating with the WHO in arrangement of supply of materials such as PVC, rexene and rubber bands.
MDT free of cost worldwide, it established the CLCP has pioneered the reach of prefabricated splints
Comprehensive Leprosy Care Project (CLCP) in India in through government health care staff in the public health
1989. program. Grip-Aids with Modulan® epoxy resin have
The objectives of the project were to enhance access been innovated by the Novartis Foundation for patients
to MDT, provide services for prevention, correction and with advanced deformities of the hands who have
care of disabilities; with rehabilitation, as a comprehensive difficulty in holding and using articles of daily use. The
package to the leprosy-affected. The CLCP activities are Instant Grip-Aid Kit developed by CLCP is a
carried out in active collaboration with government health tremendous boon in such instances (Fig. 43.13). The
care personnel and other NGOs, to extend the coverage use of Instant Grip-Aid in other disabilities like burns
of disability prevention and medical rehabilitation (DPMR) and amputation helps patients to adjust to their
services. It provides the physical aid materials, technical handicap remarkably. They increase the patients’ quality
support, reconstructive surgery and rehabilitation articles of life and their self-esteem, because they enable them
for income generation activities, free of costs to patients to perform many everyday tasks without the help of
besides training the participating health care providers. others.
4. The most effective way of dealing with ulcers is by
Key Modalities in Leprosy Care and Rehabilitation “empowering patients” to take care of their own limbs.
1. For health education about importance of care of CLCP conducts self-care empowerment camps to teach
anesthetic hands and feet in prevention of secondary groups of patients the ‘how’s and ‘why’s of self-care. It
deformities through injuries or burns, NCLCA has has developed a special Self-care Kit (Fig. 45.14),
designed an educational pamphlet, which has been containing sterile gauze pieces, scissors, sticking
adopted in many languages. It has also developed a plaster, foot scraper, bandages, antiseptic cream and
booklet, which deals with typical questions asked by
patients, their families and the public.
2. For physiotherapy NCLCA advocates a simple package
of domiciliary physiotherapy in the form of “one exercise
for each major deformity”, which can easily be done at
home by the patient. NCLCA uses the approach of
“Group therapy” where many cases are brought together
Fig. 45.12: Prefabricated finger-loop splint for correction clawhand Fig. 45.13: Instant Grip-Aid
CHAPTER
45
medical college hospitals; involving the general
physiotherapists in postoperative care; and arranging
for the admission of patients along with the stay of one
relative (including food). The Government of India has
since named the approach-“the Gujarat model”. Since
the inception of the project, thousands of cases have
been benefited not only in Gujarat; but also in Goa and
Sri Lanka.
8. CLCP provides an appropriate “Economic Rehabilitation”
aid, e.g. sewing machines, handcarts, kits for bicycle
repair, carpentry, masonry work, agricultural tools etc.
The economic rehabilitation program has had a dramatic
impact on the disabled individuals and has transformed
the lives of hundreds of people (Fig. 45.15).
Achievements in objectives and components of NLEP:
Fig. 45.14: Self- care Kit
1. At Borsad Taluka in Gujarat, in 1989, CLCP was started
as an activity of leprosy control with improving access
a simple moisturizing cream, which is distributed free to disability care services, which was later adopted as
at the self-care camps (Fig. 45.14). Patients are also the target for leprosy “elimination” when WHO
instructed to use the proper footwear. Follow-up clinics announced its new approach with definition of
held after two months have clearly indicated good elimination (less than one case per 10,000 population)
compliance with the self-care instructions and nearly and this was achieved it within six years.
60% reporting healing. The ‘self-care kit’ now forms a 2. At Goa too from 1993 to 1999, CLCP helped to bring
part of the POD guidelines endorsed by the Government the prevalence rate from 10 to about 3 per 10,000
of India. Besides, many other organizations have also population thus, paving the way for eventual elimination.
adopted its principles and are making their own kits Incidentally, Goa was one of the first states where
with similar materials. Novartis Foundation also provided blister combo-pack
5. CLCP has designed MCR footwear using commercially (BCP) of MDT for nearly 3 years. Involvement of
available patterns in order to overcome the reluctance dermatologists of Goa Medical College was a pioneering
of patients to use the typical leprosy footwear, which step for eventual integration of leprosy services.
labels them as leprosy sufferers. CLCP provides the 3. By supporting early new case detection by special
footwear free of cost in its areas. surveys, improving access to MDT and training the
6. One of the key achievements of CLCP is in the medical and health staff in “reaction management”, the
improved management of foot drop. CLCP has project has contributed to primary prevention of
prefabricated the Foot Drop Splint (FDS) and trained disabilities significantly. CLCP has also helped to
health care staff to provide it at the earliest sign of decrease the secondary deformities in the disabled
weakness in the leg to prevent the complications. The cases, nearly 20,000 cases have been benefited by
foot drop splint can be easily attached to the MCR the project over the years directly; and many more have
footwear or patients own footwear with a buckle on the benefited indirectly by training of health care staff.
dorsal strap. Recently, prefabricated FDS made of Dr. Atul Shah received ALIMCO award for designing
thermoplastic material is given in cases where long- the splints, “Instant Grip-Aid Kit” researched by Ms Neela
term use is indicated as it fits in the footwear making Shah has reached those in need even at Africa and the
the walking comfortable. “Self-care Kit” has become an integral part of ulcer care
7. CLCP has been instrumental in the adoption of the practice. Training the interested surgeons in reconstructive
“Camp and Workshop Approach for Reconstructive surgery with camp and workshop approach and transfer of
Surgery” at Gujarat. This involves training of the local technology has increased the acceptability of the leprosy-
surgeons; deputing the field staff to inform, take the disabled into the integrated set-up for surgical correction
patients’ consent and transport them to district or and medical rehabilitation.
CHAPTER
45
Fig. 45.15: Rehabilitation clinic in progress at CLCP
The offering of articles of income generation for rehabilitation activities. We have been able to give
economic rehabilitation has transformed the lives of those description of worked carried by only a few of them.
who were the poorest of the poor, dejected due to disease
or it’s after effect, and lacked moral support. Their ability CONCLUSION
to earn and support themselves, along with the use of the
NGOs have an important role of NGOs to strengthen the
articles by their family members, has brought about
National Leprosy Eradication Program through activities
increased income, better social acceptance and their
that include District Nucleus (DN), Disability Prevention
integration and above all, the heightened self-esteem.
and Medical Rehabilitation (DPMR) and Community-based
Over the years, the key modalities practiced in the
Rehabilitation (CBR). They also help in sustaining a good
field area by CLCP have been gradually accepted by the
quality leprosy services through the existing Integrated
government and other nongovernment organisations.
Health Care System in line with the WHO Global Strategy
NCLCA has also undertaken assignments at Mexico,
Guidelines (2006-2010).
Myanmar, Tanzania and Sri Lanka. Embarking on its
journey of restoring health and hope to leprosy patients.
There have been many awards to the credits of NCLCA REFERENCES
and its personnel, most coveted ones and notable are the 1. Memorandum of Understanding between Government of India
Golden Peacock Award by the Institute of Directors of India and ILEP Members active in India (24.10.2007 – 31st March
for the Innovative Products and Services; and the Reader’s 2012).
Digest Gold Award for Corporate Social Responsibility to 2. International Federation of Antileprosy Association (ILEP) –
working together for a world without Leprosy, ILEP Strategy
Novartis.
2005-2010.
3. ILEP India update, Vol.I, No.1 Jan. 2007. ILEP Annual Report
LOCAL VOLUNTARY ORGANIZATIONS 2005-2006, The situation of Leprosy activities supported by
ILEP Member Associations in 2005.
More than 250 local voluntary organizations are doing
4. Role of International Agencies in Leprosy Control – Studies on
leprosy services in India, mainly on disability care and Leprosy by Bombay Leprosy Project, 1967-1986.
46
Case Studies
Pankaj Sharma, Hemanta K Kar
About 2-3 years later, Vitthal met Laxmi (a young

CASE STUDY NO. 1 woman around 17-18 years age) at Kukudpalli hospital in
Andhra Pradesh. Laxmi was also a leprosy patient who
Vitthal is a 60-year-old male, leprosy affected person (LAP) used to come to the same hospital for treatment. She was
with deformities, living in a leprosy colony in Patel Nagar also forsaken by her parents and left to herself (like Vitthal,
area in Delhi. He hails from village Madnoor (District mainly for the reason leprosy). During their acquaintance
Nizamabad, Andhra Pradesh) of South India. He got at hospital, both got friendly and started helping each other
married at the age of 25 years age (around 1974), to Gango in managing their common illness. In view of the apathy
Bai, his maternal cousin. In his native area consanguineous seen by both, at their homes, they started living together,
marriages are common in the Hindu community as well. the bond they share even today (Fig. 46.1).
Few months after his marriage, he noticed a light colored For past around 25 years both are staying together
patch over arm where he could not sense properly about (though their marriage could never be solemnized) as a
touch. In 5-6 months times more similar patches developed family. They have two children, the elder is daughter,
in other body parts. Venkatamma now around 28 years age, married to a farmer
He was seen in the government hospital in Dichhpalli and staying in Andhra Pradesh with 3 children. The younger
district in AP. That was the pre-MDT era of dapsone one is a son Raju, now around 24 years, working a
monotherapy, with high leprosy prevalence rates (around shattering labourer in house construction business in
18-25 per one thousand population) and dapsone was the
usual drug regimen for leprosy. Also probably, isolation
treatment in leprasorium was also prevalent, as seems
from patient’s statement that he stayed admitted in the
hospital for 2 years. He remembers taking some red colored
capsule once in a while, after which the urine color used to
turn red for a day or two. In that period he also remembers
several episodes of fever and painful nodular lesions
developing (and clearing) over face and limbs.
While Vitthal was in hospital for leprosy treatment, his
spouce Gango Bai never came to see him at hospital.
Although she stayed at Vitthal’s home, the marriage was
somehow never consummated and no issues were
produced out of the wedlock. By the time Vitthal came
home after treatment, wife had deserted the home. She
did not reach even her parents home, instead found Fig. 46.1: Vitthal and his mate Laxmi (the two on extreme right)
with Father of the Church and missionary workers.
someone else as life companion.
CHAPTER
46
Andhra Pradesh, he is married and has a son. Both children Pavanamma around 50 years of age, his daughter and
of Vitthal and Laxmi, (Venkatamma and Raju) are healthy son-in-law, and 2 grand children also live next door.
(and without any leprosy stigma attached to their parents), We go back into past when Mohan was a young man
so are the grandchildren. They have settled with their of about 25 years (around 1979-80) living in Chingelput
families in the mainstream of society (Fig. 46.2). district of Tamil Nadu. The leprosy prevalence rates were
Three years ago, the right leg of Vitthal had to be very high in some states in those times, around 15-20 per
amputated below knee, for reasons of recurrent infections one thousand population, Tamil Nadu being one of them.
and subsequent gangrene, at government hospital in east Like many other people in the area, Mohan also contracted
Delhi. He now wears an artificial limb, where he gets problem leprosy for which he went to Chingelput leprosy hospital
of stump ulcer off and on (Fig. 46.3). (Central Leprosy Training and Research Institute- CLTRI)
Vitthal and Laxmi stay in a small colonial house for treatment. That was a time when it was not easy for a
provided by a missionary welfare agency. They get a family to keep at home a member afflicted with leprosy
monthly pension (about Rs 800 each) from the department (out of peer pressure from society, due to very deep
of Social welfare, Delhi government. The medical team stigma). Many leprosy affected patients (LAP) used to
from Delhi state branch of Hind Kushth Nivaran Sangh stay in leprosaria for treatment, so Mohan was also sent
(HKNS), an NGO active in the field of leprosy since 1963, there.
visits the colony every 6 weeks and provides medication During treatment period at Chingelput hospital Mohan
for common ailments. The arrangements are there for daily met Pavanamma, who was also admitted in the leprosy
dressing of patients’ ulcers, the regular supply of dressing home. After completion of their treatment of three years
bandages, cotton, antibiotic ointments is provided by HKNS during 1980-83, both came under wedlock by simple
(Delhi State Branch). exchange of garlands in the temple near the hospital
So leprosy the disease, which made Vithhal and Laxmi residential complex. According to Mohan and Pavanamma,
face apathy from home, also in a way brought them they used to come across many other patients (like them)
together. Their children and grand children remained free tying the nuptial knot in the same temple, with the
from leprosy and leprosy stigma, now well settled in the blessings of the hospital staff. They were blessed with
mainstream community. two children during their stay in leprosarium, the elder one
Jayanti (now 27 years age) and the younger Kumar, who
CASE STUDY NO. 2 died of fever at 10 years of age. However, he did not
contract leprosy by then (Figs 46.4 and 46.5).
Mr P Mohan (simply called Mohan) is a 55-year-old male, In the Mohan’s native place there was no other leprosy
treated leprosy patient living in a leprosy resettlement case in his family. Pavanamma had a younger sister
colony of Shalimar Bagh in Delhi. He lives with his wife (Yelamma), who also a leprosy patient, she received
Fig. 46.2: Vitthal and Laxmi in the past and now (2009)
CHAPTER
46
Case Studies 587
his maternal unlce’s home in a village name Bawani (in
Erode district of Tamilnadu). He got his treatment from
government hospital at Bawani, subsequently because of
recurrent severe episodes of ENLs, he was referred to
CLTRI, Chingelput, where he continued his treatment. After
completion of his treatment, he came over to Delhi, along
with another old leprosy affected person (called Baba) who
used to stay at Chingelput hospital. Baba used to treat
Amavas like his son, when Baba moved to Delhi, he took
Amavas along (Fig. 46.10). After coming to Delhi they
found a shelter in the same leprosy colony where Mohan
and Pavanamma had put up.
Jayanti was healthy (free from leprosy) and after her
Fig. 46.3: The amputated right leg of Vitthal with stump ulcer, marriage to Amavas, she gave birth to 2 children,
which troubles him off and on Shivkamini (now 11 years and studies in class VII) and
Raja now 10 years age and a student of class VI, both the
children are healthy (Fig. 46.6). The colony of leprosy
people at Shalimar Bagh has around 20 adults who had
leprosy and some of them now live with their deformities.
Around 10 of their children stay in Delhi and are day
scholars in “Nirmal Chhaya” a boarding school for children
of leprosy patients, run by Department of Social Welfare,
Delhi Government and located adjacent to Tihar Central
prison campus.
Due to recurrent episodes of ENLs and neuritis at
CLTRI, Chingelput, Amavas developed claw hands
(Fig. 46.9). After he came to Delhi, he underwent
reconstructive surgery done at leprosy mission hospital
(Tahir Pur) in trans-Yamuna area of Delhi.
It was observed that both Mohan and Pavanamma,
Fig. 46.4: Mohan and Pavanamma, with children Jayanti
and Kumar (in 1992) had extensive body pigmentation after their treatment which
is clearly evident in the photographs (Fig. 46.8).
treatment from the same hospital. While on treatment at
CLTRI she found a match in a hospital inmate (a leprosy
patient) and married him, in the same temple at hospital
area. Now she has two children (both healthy) and settled
at Panipat district of Haryana.
It was not easy for Mohan and Pavanamma to go back
to their native places, even after completion of their
treatment, such was the stigma attached to leprosy at
that time. Like many other leprosy patients, both moved
to Delhi in 1989 and settled in a camp like slum colony on
a piece of government land. After about 10 years of their
shifting to Delhi, they found a suitable match for their
daughter Jayanti and married her off to Amavas.
Amavas also had a similar trail of story behind him, he
got leprosy patches when he was barely 11-12 years old. Fig. 46.5: P Mohan and Pavanamma, with their daughter
Both his parents had already died and he was staying at Jayanti (in 2009)
CHAPTER
46
choose a healthy match for her. But their children (the

third generation) are going to school and would probably
settle in their life with some respectable means of earning
livelihood. It can be hoped they would not be carrying the
burden of leprosy stigma, so it may also be hoped that,
the society of the future would also be free of it. The leprosy
stigma is also expected to wane out after the elimination
of the disease is achieved.
CASE STUDY NO. 3

Narayan Choudhary is a 65-year-old leprosy affected
person (LAP) presently living in a government set up
leprosy colony of Delhi. At the first look, seeing his
deformities we can make some idea/guess the problems
Fig. 46.6: Jayanti with husband Amavas, and children
Shivakamini and Raja and difficulties he must have been facing in his daily life,
right from the morning till bedtime. But what a long tale of
physical and mental agonies he has faced in his life, one
just can not imagine. The narration of his illness and apathy
from the society surpasses all the tales of LAPs which
have been heard by the authors themselves and for that
matter (we believe) by all those doctors and health
personnel who might have spent even 20-30 years of their
career dealing with the leprosy patients.
Childhood and Disease Detection

Narayan (a Hindu by religion) was born on 5th October
1944 in a family in Bidar district of Karnataka, which lies
on the border area of three states—Maharashtra, Karnataka
and Andhra Pradesh. His father was a landlord who had a
Fig. 46.7: An old picture of a community ceremonial gathering showing large chunk of land under cultivation; he was also a fatherly
Mohan (sitting on left in red sweater), Pavanamma (standing back in figure for the whole village and the other surrounding
pink sari) and Amavas (on right in brown Adidas T-shirt) villages. He used to support the people of the whole village
with food from his grain store in the times of natural
It is a fact that Mohan, Pavanamma and Amavas, all calamities like floods and famines. When he was 9 years
suffered a lot in their lives because of leprosy, but the old (1953); a light colored patch was noticed by parents
consolation is that their next generation is free from leprosy, over his buttock region. At that time they did not have any
and largely from the leprosy stigma. The elders hardly idea about the nature of the disease, but with the passage
have anything to do other than the most usual occupation of time it became clear that the disease he suffered from
for them, i.e. begging. They start off from homes in the was none other than leprosy. Slowly, pressure started
morning, go to their respective spots on the roads and mounting from the villagers to isolate Narayan away from
come back by noon. Some of them again go to the begging the home, and the village (Fig. 46.11).
spots in the evening also.
It may also be seen that Jayanti, who was healthy and Public Pressure for Isolation
free from leprosy, was not actually free from leprosy stigma. Amid serious pressure from society to leave, Narayan
She married a leprosy patient with deformity (both claw continued to stay at home on account of show of family’s
hands), probably her parents did not have much option to financial stability and muscle power. He was also well aware
CHAPTER
46
Case Studies 589
Fig. 46.8: Clawhand deformities of Mohan (left) and Pavanamma (right)
injections the patch looked indistinct. In the meantime,

his mother passed away when Narayan was just 12 years
of age.
Survival by Rough and Tough Means

As the time passed by, the threat to his very existence on
account of his disease was real, in spite of the treatment
he took for his disease available at that time. In the process
of putting stiff resistance to the society, slowly and steadily,
he chose path outside the preview of the law. He got named
in 14-15 cases of robbery, looting, arsoning but it was not
easy for the police to book him. His modus operandi was
like Robin Hood, he used to rob the riches and distribute
Fig. 46.9: Clawhand deformity of Amavas. Note the scar marks of

reconstructive surgery over wrist areas, he underwent, which partially
improved function of hands
of the fate of leprosy sufferers in his area at that time.

They had to either leave the village voluntarily or face
elimination. He narrated to the author, that at least 15-20
people with leprosy were burnt alive in the fields by villagers,
during the time of his stay in the village. There was a
collusion and secret understanding among the natives that
no information about such killings used to reach the police
authorities. While Narayan was at home, he kept on getting
some form of treatment for his patch, which comprised
Fig. 46.10: The eternal bond of valued relationship. The man who
some desi oral medicine and an oily injection (obviously
brought Amavas to Delhi (the Baba), in front, (second from right, in
he was referring to Chaulmoogra oil) which was injected at blue shirt and pink scarf) and Amavas on extreme left. After Baba’s
the periphery of the patch. After about 2 years of weekly death, his last rites were performed by Amavas
CHAPTER
46
Fig. 46.11: Narayan and his wife Pushpa in 2009 (left). The old pictures of the two on the right (around 1975) when Narayan did not
have deformities and Pushpa was pregnant with the eldest daughter (Ganga) and her patch on dorsum of left hand had resolved by
then, after treatment with dapsone and Rifampicin
the money to poor villagers. No one used to say anything Choice of Profession
against him to the police authorities, but ultimately the
Although he did not have any visible deformities due to
hands of the law reached him and he was imprisoned for 3
leprosy at that time but he could identify the people with
years in Bellary jail of Karnataka.
leprosy. He had developed a notion that only someone
suffering from leprosy would listen to his plight in the city
Shift Away from the Native Land
and would give him right advice. In front of the temple in
By the time he came out of prison he was 23 years old, Chandni Chowk, he met Bandhu Sen, a LAP who came
his father also expired during his imprisonment. He had from Moradabad and had settled on the pavement. His
virtually no family to go to, his land was also taken over daily job (like so many other LAPs) was begging and he
by relatives. Then, on the advice of some leprosy sufferer advised Narayan also to adopt this profession. The idea
whom he met at his native place, he moved to Delhi in of begging did not find favour with Narayan and he preferred
around 1968. He reached Delhi station, all alone in the to work as a labourer. He joined as unskilled labourer with
city, had no money to feed. He stayed on the platform a contractor who was building Lajpat Rai market; the
only, started doing the job of a coolie. He was happy to construction of which was inaugurated very recently, just
earn some quick money but this boon was also short lived. across the road in front of the temple. He spent many
He was stopped by a policeman on duty there, on account years as a labourer in this construction work with the same
of working as a coolie without a badge (unregistered construction contractor at different sites at Gandhi Nagar
worker); in the process he got into altercation with the in trans Yamuna area and later at the new interstate bus
policeman who was stopping him. The matter worsened terminus (ISBT) building near Kashmiri Gate. At ISBT work
as Narayan did not know Hindi and the policeman did not site, he came in contact Marathi Baba, a LAP who worked
understand the language spoken by Narayan. Then a senior as a priest and lived in Anandgram leprosy colony
police officer (by chance a South Indian) came on the (Fig. 46.17). He used to move around different leprosy
scene who understood both the languages. He pacified colonies all over Delhi for his social role as a mediator for
Narayan and made him understand that provision of marriage proposals among LAPs. In the same context he
carrying the badge by coolies is a must, it was meant to proposed the name of Pushpa to Narayan for marriage.
prevent theft of baggage by unauthorized persons on the
platform. So it was not possible for Narayan any longer to Marriage
stay on the railway station, he moved to a temple site in Pushpa was a young girl of 16-17 years age (in 1973)
Chandni Chowk, situated opposite Red Fort. living with her father at Anandgram, the first leprosy colony
CHAPTER
46
Case Studies 591
developed by missionary organization headed by Mother
Teresa. Pushpa’s father was a leprosy patient with severe
deformities of hands and feet. She herself had a leprosy
patch over dorsum of left hand for which she was taking
treatment from the nearby municipal corporation of Delhi
(MCD) dispensary at Tahir Pur. She remembers her doctor
(Dr Chawla) in the dispensary who had a kind heart and
was very popular among leprosy patients coming to the
dispensary. The usual treatment at that time was a green
colored tablet (from Ciba company, as mentioned by
Pushpa), she had to go to the dispensary daily for
consumption of the drug in the clinic itself, this treatment
by taken by her for about 6 months. Years later, she also
took Dapsone for about 4 months from Thangraj Leprosy Fig. 46.12: Narayan with Pushpa and other family members in the
Hospital, nearby, in the year 1982. wife’s native place in Andhra Pradesh, when he was taken over there
for treatment of his severe infection in arm
The Social Mobilization of LAPs

In year 1974 Pushpa and Narayan came under wedlock
and moved to a small place in Ghaziabad where Narayan
opened a tea stall. In 6 months period they came to a
place near Tahir Pur (close to the leprosy colony they
reside now) and started a tea stall. Most of his customers
were the LAPs and very few other persons (mainly those
ignorant about leprosy) used to come to their teashop.
While interacting with leprosy patients Narayan developed
an idea to form a registered society of leprosy patients, so
that they would get a piece of land to form a settlement
colony with monetary help from Delhi government. He had
a hard time persuading the LAPs to pay for the registration
charges. He personally went to Wardha (Maharashtra),
considered in those times the Mecca for LAPs, raised and Fig. 46.13: Narayan and Pushpa at their son’s wedding
maintained with the blessings of Mahatma Gandhi and (according to Christian rites)
Acharya Vinoba Bhave, to get the information regarding

society registration. He even kept Pushpa’s sarees and a level of being non-functional. All his daughters completed
jewellery as security to raise money for registration fee. their studies up to 10th class. The son (Parsram) could
Ultimately the society was registered and the present day not study beyond 3rd class due to some infection persisting
Kasturba Kushth colony came into existence at Tahir Pur, in the ears which made him deaf. He could not be helped
their home till date. for ear function much even by the reconstructive surgery.
Later he learnt the job of motor mechanic. All the children
Family and the Children were healthy, and in course of time all the daughters got
In the meantime, Pushpa gave birth to 5 children (four married into the families who had no family member with
daughters and a son), the last two children being twins leprosy. The son Parsram also got married to a girl without
(Figs. 46.15 and 46.16). Narayan ran the teashop till 1994, any disease in her family. Now son and daughter-in-law
wherein Pushpa also used to sit at for many hours to help take care of Narayan, who has severe deformities. Narayan
him, besides looking after household work. Ultimately also owns an auto three wheeler which he lends on rent
resorption of Narayan’s hands and feet had progressed to and has some earning daily.
CHAPTER
46
Embracing Christianity months and his arm was saved from the suggested
amputation. Moved by this severely emotional event of
Pushpa was from a Christian family but Narayan remained
life, Narayan embraced Christianity (Fig. 46.18). Of the
as Hindu till long. Once he had severe infection of arm
five children of Narayan, eldest daughter Ganga is married
(probably cellulites) he visited many doctors and even
into a Charistian family (Fig. 46.13), next 3 daughters are
hospital, who all advised for amputation. He prayed before
married in Hindu families and the son’s wife is a Christian
all Hindu Gods but his problem did not wane. Then Pushpa
(Fig. 46.14).
took him to her native place Baptala, in Vijaywara district
of Andhra Pradesh to a missionary leprosy hospital Message
(Fig. 46.12). He received treatment at that hospital for many
Narayan knew he had leprosy and the only job adopted by
virtually all LAPs was begging, but he resisted this option.
Rather he chose to work as a labourer, till his hands and
feet remained functional. Later on when deformities and
associated disabilities occurred, he changed over to lesser
physically demanding work of running a teashop. He
continued to take care of the tea shop till his hands and
feet remained partly functional. He used his leadership
quality to organise LAPs to form a society, travelled long
distance all the way to Wardha for a public cause, married
all his children into respectable families and remained
independent throughout his life, never resorted to begging.
When society rejects someone, the new relations are
made with those with similar destiny who provide some
solace, irrespective of caste, religion and community. The
present thrust on information, education and communi-
cation (IEC); and prevention and early detection of deformity
and disability; and treatment their of and rehabilitation, in
the newer strategy of NLEP would go a long way in
Fig. 46.14: Performed all the worldly duties of a father;
with eldest daughter Ganga at her marriage preventing the similar situation, as happened with Narayan.
Fig. 46.15: Pushpa with two children (left) and in an old picture of time before marriage (Right). She had a leprosy patch (paucibacillary)
then and was taking dapsone, the only chemotherapy available at that time (around 1972).
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Case Studies 593
CASE STUDY NO. 4

Note: The family discussed in this case study was
extremely apprehensive of the social repercussions and
adverse reaction from the society, especially fearfully
concerned about their children who have now reached to
socially reputable places in their careers. At their request,
the names of characters have been changed, the names
of places have been kept non-revealing, and no
photographs are presented.
Maharaj is a 60 years old (born 1949) LAP living with
his wife in a colony of old leprosy patients in Delhi. He
studied up to 10th standard in a leprosy mission school in Fig. 46.17: Marathi Baba (the priest, and a leprosy sufferer himself)
Maharashtra. He was born in the family of a factory worker, who made a match of Narayan and Pushpa, also solemnized the
long time after his parents’ marriage, as a result in jubilation; marriage of their son (performed again with Hindu rites)
at the insistence of family members and friends, he was

named Maharaj. After the early death of his mother Maharaj
was brought up in the home of his maternal grandparents,
since the age of 6-7 years, where, he was joined in a local
government school.
Disease Detection
At the age of around 9 years (when Maharaj was in his 3rd
class) there came a health team from a government
hospital for school health check up of students. On
examination Maharaj was found to have some patches
over arms, which were totally asymptomatic. The disease
of Maharaj was described as “Maharog” by the health team
leader and the school Principal was informed and advised
Fig. 46.18: Religion lies where heart finds solace and peace. The
to remove the child from the school immediately, lest it small “Church” inside Narayan’s house.
would be dangerous to others. In compliance with the usual

practice in those days, the very next day Maharaj was
sent back home where more problems were in store for
him.
Social Implications of Disease

The fact of disease was no more a secret among villagers.
The grandfather of Maharaj was advised by village Pradhan,
to shift the habitat of the child to outskirts of the village for
the best interest of the whole village, where there were
some other people too with “Maharog” out shifted. In a
difficult situation arising out of illness of Maharaj, the
grandfather informed his father, who was living with his
Fig. 46.16: Going without celebration? No way. Narayan celebrating
“Bara din” (X-mas) with son Parsram (sitting by him), and daughter second wife, and working in a factory in Madhya Pradesh.
Ganga (on chair). On hearing about the news of Maharaj’s illness, his father
CHAPTER
46
came and took him along. Maharaj started living with his were in circulation. He had joined the school run by leprosy
stepmother. He used to be kept indoors completely for mission (located within the hospital campus) where he
fear of his illness getting revealed in open. By this time studied up to 10th class. This boarding school also admitted
Maharaj had developed sensory loss over hands and feet the children affected by leprosy from nearby villages and
and other body areas, the patches were also increasing in cities, whose parents were healthy but could not keep them
number and size. He was allotted a separate small room at homes, out of social peer pressure. After treatment,
in which he was made to sleep on floor. During sleep, he once the children were declared cured, the children were
used to suffer rat bites, the fact coming to notice only on either taken back home by the parents, or they used to
waking up in the morning by finding the blood stains over spend years in the hospital complex, doing social service
his clothes and on the piece of jute bed sheet on which he or working as labourers in the mission farm lands, where
used to sleep. crops and vegetables were cultivated meant for
But in course of time, Maharaj’s illness was revealed consumption in the mission complex only. Some of them
to public. Soon the ladies in nearby households started were engaged for other duties like washing and ironing
advising the stepmother, to get rid of Maharaj anyhow, or clothes, as a dresser in the dispensary doing the dressings
else it could be dangerous to her own self. At home, of patients, as the cook in the campus kitchen or for other
Maharaj’s father was also not oblivious to the fact, that such jobs in the campus. Unfortunately in the case of
his wife was adverse to keep Maharaj at home. From his Maharaj, his father never visited him, once after he got
side he always used to take personal care of Maharaj and admitted in the hospital.
make him sit for food, right with him. One day the child
Maharaj noticed some hard grains in his rice, because of No Family, Alone in the World
which he was not able to eat. He told about this to his When Maharaj completed the study in 10th class at the
father sitting by his side, who also tasted food in Maharaj’s age of about 17-18 years (around 1967), he came in contact
plate. It turned out to be powdered glass in the food, with some other LAP visitors at hospital who told him that
following which the father became very distressed and situations for LAPs were somehow better in Punjab. At
helpless, worrying about what to do with the child. that stage, he took a leap into outside world and reached
Leprosy Treatment in a city of Punjab where many colonies of LAPs were
established with the financial contributions from many rich
Under these gloomy circumstances in the course of donors. Maharaj also landed up in one of them and he
discussion on “how to take care of the child” his father spent over 20 years in the same city, the main regular
came across a fellow labourer working in the same factory, profession for LAPs was begging. After initial hiccup for
who knew about a leprosy mission hospital in Maharashtra. roadside begging he also got engaged in this profession.
Immediately the 10 year old Maharaj was taken by his
father to that hospital. At the hospital some blood tests Marriage
and skin smear examination were carried out which were Maharaj got married in 1979 at 30 year age with Harsha
all “negative” (as described by the hospital staff). He was from West Bengal. The movement of LAPs used to be all
admitted to the hospital only for the management of ulcers. over the country (but strictly within confines of the
At that time Chaulmoogra oil was the only medication community) for social purposes like marriages, etc. The
available for the treatment of leprosy. He used to get LAPs were well-informed about the eligible bachelors in
15-16 injections every week, over different patches. Some the similar communities in other cities. In the process to
time after the injections, the skin at the injection site turned find a match for himself, Maharaj reached West Bengal
black. through some contact. Harsha was a young girl of 14-15
years getting treatment for leprosy from a local leprosy
Schooling mission hospital. She was born in a very poor family, both
He stayed in the hospital for 6-7 years, during which he her father and mother used to work as labourers. She had
remembered one important national event, i.e. the release developed patches over the body at the age of 2-3 years
of “Naya Paisa” the new coin of one paisa by the but the matter remained unattended for long since the
Government of India in 1957, before that the English coins parents were not aware of the nature of illness. The only
CHAPTER
46
Case Studies 595
treatment administered to the child was “Jhaar Phoonk” begging completely. In a long persevered thought about
by the local “Ojha” in the village. Years later when Harsha the role the leprosy mission played in their lives, and in
was around 14 years, she was suspected having leprosy the lives of their children, both Maharaj and Harsha (like
by a leprosy patient; who happened to be a friend of her far many other LAPs) feel extremely indebted and pay a
father. He took her to the same leprosy mission hospital thankful tribute to the mission.
where he himself was getting treatment, and the disease In the extremely hard times for LAPs, 50-60 years ago,
was confirmed and the treatment was started. The treatment the mission arranged for leprosy hospitals, leprosy homes
for leprosy at that time (1979) was once a month Rifampicin within the hospital campus or in nearby areas, schools for
capsule and daily Dapsone. She started staying in the children of LAPs providing them free education and even
leprosy colony with her LAP uncle. Hardly a month passed hostel facilities. A fully organized chain was formed across
and she was introduced to Maharaj who had gone there in the country. Besides, the children were well supported for
search of a bride. higher education as well, into mainstream institutions. For
After marriage with Maharaj she moved to Punjab where
example Harsha got care from mission institutions in West
the same treatment was continued at the local leprosy
Bengal, Punjab, Delhi and their children got educational
mission hospital which she took for 18 months. During the
support from the mission in UP. So in a way it is evident
treatment in Punjab she had ulnar neuritis and developed
how the mission was instrumental in providing care and
clawing of both hands. Unfortunately this happened due to
support to those, forsaken even by their family and the
fear psychosis among patients, of using steroids for its
society.
presumed side effects; even though it was prescribed for
neuritis by their doctor.
The Religion
The Children Both Maharaj and Harsha were Hindus and they are till
Both Maharaj and Harsha stayed in Punjab for nearly 10 date. The children, in a matter of upbringing in the mission
years. Begging was their main profession and both had institutions, are now baptized Christians. Both are settled
their own begging points (spot locations) in the city. They in the mainstream of society and provide financial support
were blessed with 2 children, elder one a boy and a girl. to their parents. The parents still stay in their small quarter
Concerned about the future of the children, and to keep in the leprosy colony, away from their children lest the
them away from the leprosy stigma, they were sent to the leprosy stigma affect their children’s personal or
missionary school in a hilly area of Uttar Pradesh. The professional lives.
school used to provide free education and boarding to the
Message
children of LAPs. After completion of schooling the children
were fully supported for higher education in the outside The earlier times portray a very gloomy picture of lives of
(mainstream) institutions. So both children of Maharaj and LAPs. The job options were virtually nil (other than
Harsha completed their education up to graduation and begging), partly on account of physical deformities due to
post-graduate level, now both are settled in their respective leprosy, but more due to the attached stigma. Now the
professions. time seems to be changing, most of the new leprosy
patients live with the families. The leprosy colonies in the
The Mission Factor cities now harbour old LAPs mostly burnt out cases with
During the study period of their children away from home, severe deformities. The children remain generally
Maharaj and Harsha moved to Delhi in 1989 and settled in healthy and leading a happy prosperous life. Expectedly,
a leprosy colony. They got registered in the leprosy society in a matter of 20-30 years or less, as the older generations
and started getting the financial grant of Rs.800 per month of LAPs will be eliminated from the scene, the leprosy
from the Department of Social Welfare (Government of stigma will also wane out slowly. By that time the new
Delhi). In Delhi, though Harsha went for begging for 2-3 case detection is also expected to come down to meagre
years but Maharaj did not do so. With the financial help levels, and we can expect to see a leprosy free society, in
coming in from government, ultimately both stopped real terms.
CHAPTER
46
was a signal conveyed to the family that Kartik also could

CASE STUDY NO. 5 not stay in the village any longer.
This story describes the long run of life documentary seen Shifted to Madhya Pradesh (MP) in Search
by the lead character Kartik (Fig. 46.19). He is a 59-year- of Treatment
old male (born 1950) hailing from a village in Sambalpur
After leaving the village, Kartik reached a place called
district of Orissa, from a farming family who owned some
“Chapa” in MP where he consulted in a private clinic. That
land in the village. The whitish patches were noted over
clinic was known to be a “specialized” clinic in the area,
his body at the age of 12 years, which remained
for leprosy treatment. No investigations were performed
undiagnosed until they were spotted by a small pox
on Kartik and he was admitted for treatment. He received
vaccination team during their visit to the village. The
injection Penicillin, some particular soap for bath, in
diagnosis of leprosy for Kartik soon came to the knowledge
between he was also administered injection “Calcium
of villagers, and like we have seen in the previous case
Sandoz” as recalled by Kartik. He stayed in that clinic for
studies originating in other parts of the country, i.e.
about 6 months and paid a sum of Rs 22,000/- (rupees
Maharashtra, Andhra Pradesh, Tamil Nadu and Karnataka,
twenty two thousand was a big sum in those days around
the same thing happened in this far eastern state of Orissa
1963, raised by the family from the sale of landed property
too, the pressure started building up for extradition of Kartik
in the village).
from the village.
Indirect Pressure for Extradition “Private Leprosy Hospitals” Minting Money,

Well Organized Racket
For the reason of robust position of Kartik’s family in the
Kartik used to go to a river for bath few kilometres away
village, it was not easy for the villagers to send him out of
from the domiciliary clinic he was staying in. One day he
the village straightaway, instead they adopted a curvilinear
came across some LAPs bathing at the riverside who were
course. It was known to some of the people that another
leprosy affected person (LAP), was also living in village staying in a leprosy mission hospital, in the same city.
They were well aware of the reality of the kind of leprosy
clandestinely, with his illness under cover. In the heated
clinics, Kartik was getting treatment from. There were many
environ arising out of Kartik’s illness, the message also
such residential clinics run by unscrupulous people guising
spread around about that LAP living in the village in hiding.
as “leprosy doctors” who (taking advantage of necessity
Soon a “Panchayat” meeting was called, wherein it was
of people to get their kin LAPs some habitat) used to charge
decided to send that person out of village. Indirectly, it
exorbitant fee in lieu of the so called leprosy treatment.
There were specially recruited agents of such hospitals
whose job was to pull the new leprosy patients to the clinic,
as soon as they entered the city. The agents used to place
themselves at transit points like railway station, bus stands,
and their main effort was to get the patients by any means
to the clinic, they were working for, before the patient or
his accompanying person get any hint or information about
the mission hospital in the city, where treatment for leprosy
was free.
The “hospital” where Kartik got admitted comprised
about 7-8 rooms accommodating 20-25 patients. At the
meeting at riverside with people staying at mission hospital,
they explained to Kartik that, if he really wanted to get
treatment for his disease, he should either go to a mission
hospital or to the government hospital at Jabalpur. Or else,
these private hospitals are going to extract even the last
Fig. 46.19: Kartik as seen in 2009 penny from him and his family. He came back to the hospital
CHAPTER
46
Case Studies 597
and discussed the matter with a fellow patient and soon not recollect what transpired between Dr Gupta and the
both of them decided to run away to Jabalpur government hotel owner, but the very next day Kartik lost his job.
hospital, also called in the surrounding areas as the medical He went to the residence of Dr Gupta in protest, under
college. the impression that he was responsible for making him
They took a train for Jabalpur but at Katni railway station lose his job by revealing his illness. But Dr Gupta pacified
they were caught up by police. In those days there were him that it was not at all the matter, and the choice of
instructions for police to arrest the leprosy patients from keeping or not keeping a worker rests with the hotel owner.
public places like bus stands, railway stations etc and get He also advised Kartik to go to the new missionary leprosy
them admitted to the nearest government hospital for hospital at Sambalpur for further treatment, which would
treatment. Initially, both of them got panicky where police also be nearer to his native village, and convenient for
would be taking them to, but they were relieved to know him.
that police was taking them to the place, they themselves
wanted to go to, i.e. Jabalpur Medical College. Treatment and Long Stays at Various
Missionary Hospitals
Treatment at Jabalpur Medical College
(1962-63) The usual treatment for leprosy at mission hospital at
Sambalpur included Chaulmoogra oil orally (given with
Both of them were admitted to the hospital, first of all they “Batasha”; a sweet preparation). Chaulmoogra oil was also
were investigated. Slit-skin smear and biopsy were given as intra-lesional injections. It may be noted, no
performed. By that time Kartik had developed earlobes
dapsone was available. Tablet APC (a very popular
infiltration, and partial nasal deformity. A biweekly injection
combination of acetyl salicylic acid, phenecetin and
used to be given to patients. Chaulmoogra oil was given
caffeine, as a pain reliever tablet around 1960s to 1980s,
for massage and another ointment for application over hands
especially in government hospital supplies) was the usual
and feet, which used to give a sensation of warmth. Kartik
treatment for pain due to neuritis or reactions. Kartik stayed
even now remembers the name of his doctor who was
in that hospital for 3 years, subsequently he moved to the
treating him at Jabalpur Medical College, Dr Devendra
leprosy mission hospital at Naini, near Allahabad (UP).
Gupta. Kartik stayed in the hospital for 4-5 months and
The treatment at Naini hospital comprised dapsone (called
then went back to his native village. There again, a
popularly by staff and patients as DDS) and it was available
“Panchayat” was called and he was allowed to stay in the
in three strengths, i.e. 25, 50 and 100 mg. Besides these,
village, but with some conditions. He was neither allowed
injection calcium gluconate was also given.
to take bath in the village pond; nor was allowed to avail
the services of the village barber for shaving and haircut, At hospital most of the admitted patients were engaged
nor he could ask the village washer man to wash his in community services in the hospital complex. Kartik
clothes. worked as cook in the hospital kitchen at the salary of
After staying in the village for some time, he was sent Rs.3 per month. Subsequently he moved to mission
to his maternal uncle who used to live at a place called hospital at Taran in Punjab, with some fellow LAPs, where
Ropia (near Sambalpur, Orissa) where he stayed for nearly he stayed for 2 years and worked as labourer. He also
one and a half year. At that place he started getting travelled a lot with LAP friends to Bhav Nagar (Gujarat),
reactional episodes but there was no treatment for it in the Soroh (district Etah in UP), then to Shahjehan Pur (near
village. He again went to Jabalpur and got admitted in the Lucknow). In the last mentioned city he, for the first time,
medical college and same treatment was resumed. resorted to begging. He joined the group of LAPs engaged
After some time he started working as a helper in a in begging, the gang was called among its members as
hotel nearby where he was happy to earn some money. the “Company”. He started moving with the company from
One day, his treating doctor at the hospital Dr Devendra city to city, Nazibabad (UP), Moga (Punjab) and other cities,
Gupta came to that hotel to have some snacks. He was with the common job everywhere, begging. During his stay
happy to see Kartik working there and earning a livelihood in Punjab, Kartik got the company of Vimla, a leprosy
for himself. Dr Gupta was a frequent guest at the hotel patient in the local colony, subsequently both started living
and the hotel owner was also friendly with him. Kartik can together (Fig. 46.20).
CHAPTER
46
CASE STUDY NO. 6

Akbar Ali (born 1965) affectionately called Raju by all,
basically hails from Dibrugarh district of Assam, where
his father was a motor mechanic. He was the only child of
his parents. After an early death of his father (Raju was
barely 5 years of age then) his mother moved with him to
Delhi in 1969 for making a livelihood. His mother started
working as an “Aaya” (governess) in a school and also
stitching clothes at home. Raju was admitted in a mission
school with hostel facility, where he continued his education
till 8th class.
Disease Detection, Treatment as Hospital

Inmate, in the Role of Patient and Server
Fig. 46.20: Kartik with Vimla, whom he met in the leprosy When Raju was 10 years old few indistinct patches started
colony in Punjab
appearing on his body but since there was no significant
problem, they were ignored. About 5 years later, when
Raju was in 8th class (15 years of age), he was sent to a
Move to Delhi (and NO to Begging) charitable nursing home for check up and his illness was
At the time of riots following assassination of PM Indira diagnosed as leprosy. Raju’s illness was not disclosed to
Gandhi (November 1984), he was in Punjab. After that he Raju or his mother, though it was revealed to the hostel in-
and Vimla moved to Delhi and landed up in the leprosy charge. The hostel administration was not in favour of
colony he is residing in even to this day. In Delhi they got keeping Raju in the school hostel and he was referred to
registered in the society of leprosy affected people in the Mother Teresa Mission Hospital (Figs 46.25 and 46.26) in
colony set up by Delhi Government (Fig. 46.22). Both Nand Nagri (trans-Yamuna area), Delhi, for treatment. He
started getting a monthly pension of Rs.800 p.m., got admitted for treatment in the hospital where besides
subsequently Kartik firmly made up his mind and stopped his treatment, he also started learning the methods of
begging altogether, he never begged in Delhi.
Here in the colony, he got engaged in social work,
mobilized donations from various donors and got a temple
constructed in the colony campus (Fig. 46.21). He helped
many other leprosy affected persons in getting their
pensions approved, helped in their papers and
documentations, taking them to courts for affidavits, etc.
He also helped in school admissions of many children of
the colony.
In the meantime, Kartik and Vimla were blessed with a
daughter. They sent her to local school where she grew up
with good academic records. Now their daughter is a
student of nursing at the Christian Nursing School at
Jagadhari (Haryana). She never suffered from leprosy and
looking forward to settle in her life with a career as a nurse,
Fig. 46.21: The temple in the leprosy colony campus in Delhi,
free also from the leprosy stigma. for which Kartik made considerable efforts in raising funds.
CHAPTER
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Case Studies 599
A Social Server by Heart and a Philanthropist
Rosy was also educated till 10th class and after settling in
the colony both (Raju and Rosy) started giving tuitions at
home to poor children of the colony free of charge for many
years, and later at very nominal charges, the kind of social
service which they do even to this day (Figs 46.23 and
46.24 and 46.30). Raju works as a daily wages employee
in Municipal Corporation of Delhi. He has a great passion
of helping others and spends his free time in such
activities. Be it admission of child in school, or arranging
for donors for some poor girl’s marriage in the community,
he is always ready and ahead. The first author of this
chapter also visits various leprosy colonies for social
service at the weekends, as a Medical Officer of the mobile
Fig. 46.22: The donors at the colony are the usual sites. clinic team, run by Delhi State branch of Hind Kushth
Distribution of food grains, cooked food, clothes is regular Nivaran Sangh. The follow up of patients is looked after
very well by Raju, from arranging for medication if a patient
dressing the leprosy patients. Soon he started working as is not able to go to the market, taking the patients for
a dressing helper in the hospital. He continued his further investigations and reporting the author about any urgent
studies side by side from open school in which he development in the course of illness of any patient.
continued till 10th class. During his tenure as a dresser in
the hospital he was sent to Mission Leprosy Hospital and Leprosy Treatment Regime at
Training Centre at Chittaranjan (West Bengal) for a 6-month Mother Teresa Hospital
training course in physiotherapy. On his return he was Although in 1970-71 when Raju got the treatment for his
positioned in the hospital in dual role as senior dresser disease, Dapsone, Rifampicin and Lamprene had become
and the physiotherapist. He worked in the hospital for 5 available, but the usual practice was administration of
years, honorary- without taking any wages. dapsone monotherapy to all patients, and other two drugs
only in cases when patches became red (in reaction). Other
Marriage and Children treatment for leprosy in practice was injection Calcium
During his stay in job at the hospital he came in contact gluconate of which 10 ml used to be given I/V, the purpose
with 17 years old Rosy, who was not a leprosy patient but
a worker as a cook in the hospital kitchen (Fig. 46.27).
Hailing from a poor family from Tata Nagar (now in
Jharkhand) she was left in the Hospital service by her
parents. After some time both got married and Rosy (a
Christian before) became Rosy Begum after marriage. After
marriage, to meet the expenses of the family, both of them
left the Mother Teresa hospital and settled in a leprosy
colony at Tahir Pur, set up by Delhi Government. Raju
started working as a building supervisor and was also
engaged in social service, helping people in their various
matters.
Raju and Rosy got blessed with 3 children, all of them
were sent to school. The eldest daughter is now a nursing
student in GTB Hospital School of Nursing, Delhi. The Fig. 46.23: Akbar Ali (Raju) with Rosy at the small class room in their
second child has been sent to Mission school at Dehradun house in the leprosy colony where children of leprosy affected persons
and the youngest son is studying in 6th class (Fig. 46.28). from neighbourhood are taught tuitions at very nominal charges
CHAPTER
46
Message
Raju lost his father at a very young age and had to move
to Delhi with mother. He was the only child of his parents,
both of whom were free from leprosy. His illness was
limited, he got prompt treatment (whatever was available
those days) and he never developed any deformity.
But the fact worth noting is that after spending so much
time in the leprosy hospital, dealing with all sorts of leprosy
patients, and subsequently after leaving the hospital and
spending so many years living in the leprosy colony, he
Fig. 46.24: A foreign visitor at the small

school of Raju and Rosy
Fig. 46.26: Mother Teresa with a child during her visit to the hospital
named after her, where both Raju and Rosy worked together
Fig. 46.25: Sisters of Mother Teresa leprosy hospital where Raju

and Rosy worked and came under wedlock
being (as told to the patients) “to induce sweating” in the

dry patches. For nerve pain, injection Neurobion, tablet B
complex, and Tablet APC were the usual treatments. For
deformities of hands and feet, hot wax bath and finger
massage were the routine.
Mother Teresa Hospital, an Institutional

Leprosy Care Home
As has been stated in previous case studies about the
institutional nature of patient care at most of the mission
hospitals providing treatment to leprosy patients, this
hospital was also no exception. Most of the inmates were
employed in the campus itself, in various occupations of
farming, growing vegetables, ward boys, dressers (like
Fig. 46.27: Rosy (before marriage) with a Sister nun at Mother
Raju), Security guards and so on. Teresa Hospital while she worked there as a cook
CHAPTER
46
Case Studies 601
Fig. 46.28: Akbar Ali (Raju) at the naming

ceremony of his son
Fig. 46.30: Children performing at a function at the small school run

by Raju and Rosy on charitable basis for the children of leprosy
affected persons in the colony.
big city like Delhi, when he developed the disease. Had he

been in some remote rural areas (as like many other
patients described in previous case studies), the thing could
have been different.
So it would not be inappropriate to say that leprosy
debilitates the patient’s body, but the stigma debilitates
the mind and the patient’s psyche as a whole, greatly
shaking the patient’s confidence and self-esteem. He is
Fig. 46.29: Raju performing at a community
driven so much to the brink that he is left with no option
function in the leprosy colony except begging to earn a livelihood, the usual escape route
to survival followed by most of the leprosy patients.
never developed any complex in his psyche of being a The persons with serving inclination and philanthropic
leprosy patient. Today most of the old leprosy patients thinking are difficult to come across in today’s materialistic
with deformities are in the psyche of “takers” who begged world. Both Raju and Rosy have set an example worth
all their lives. The reason could be that Akbar Ali did not emulation not only for leprosy patients; but also the healthy
have to face the discrimination on account of being in a members of the society.
Section
9 Future Prospects
47
Leprosy Scenario Beyond 2010
PSS Sundar Rao
INTRODUCTION Cases were recorded through surveys by the leprosy

workers in the year 1983-84.
“When you are shooting at the stars, make sure your
In Figure 47.1 the bar chart gives some idea of the
feet are firmly on the ground”
case load in the country from 1961 to 1984. It is worth
Before we venture into the future, it will be good to recalling that prevalence of leprosy shows a highly uneven
recount all our accomplishments in the past and take stock distribution geographically, with rates varying from zero to
of the situation at present, especially since dynamic over 60 per 1000 population even within the same district
changes have been taking place in the leprosy scenario in or tehsil.
India. These changes were partly due to changing The steady increase in the case load up to 1981 may
leadership, but largely influenced by the quantum leaps in not necessarily indicate significantly more leprosy, but
our understanding of leprosy control in the MDT era, which better survey procedures and inputs into carrying out more
culminated in the processes of integrating leprosy into the complete screening and recording of leprosy cases. In
general health services. particular, the highest number seen in 1981 reflects the
special efforts taken to identify all cases of leprosy that
THE PAST could be put on MDT.
With such efforts aimed at new case detection and
In 1953, the Government of India launched the National initiation of anti-leprosy therapy, the prevalence and
Leprosy Control Program (NLCP) as an integral part of its incidence rates declined. During early seventies, the
first Five-Year Plan.1 DDS or Dapsone was the antileprosy spectre of dapsone resistance raised its head, when urgent
drug of choice, and the NLCP used this drug as its sheet research on efficacy and tolerability of MDT started. Field
anchor, recruiting one paramedical worker per 20,000
population, who carried out general household case-
detection surveys once every 3-5 years. In addition, annual
contact surveys, school surveys and special
epidemiological surveys were also conducted. The voluntary
case reporting was encouraged at innumerable field
stations all over the country. One nonmedical supervisor
per 4-5 paramedical workers; and one leprosy medical
officer were appointed at every “taluk” (Block) level.
Monitoring was done by estimation of prevalence rates
of leprosy based on decennial population census till 1981.
Mostly it remained as an understatement due to recording
of only cases with advanced leprosy, low self-reporting
mainly due to stigma; and errors in coverage of population. Fig. 47.1: Prevalence of leprosy from 1961 to 1984
CHAPTER
47
606 Future Prospects
trials on MDT began in late seventies and by 1984, most When the case load became manageable, the vertical
states in the country started initiating MDT. The dramatic component for leprosy control was removed and case
effects of MDT were visible, and in 1991 the WHO issued detection was conducted through General Health Care
a clarion call to eliminate leprosy as a public health problem System since 2002-2003. Independent evaluations were
by 2000. Except for 12 countries including India, globally also carried out during 2000, 2002 and 2005. Leprosy
this “Elimination” was reached by that date. Because of Elimination Monitoring (LEM) was conducted in 2002, 2003
the heavy disease burden and extensive geographic areas and 2004. The sample survey-cum-assessment unit
involved, some in very difficult to access terrains, India (SSAU) made a monthly visit report on LEM type study
could achieve elimination (leprosy prevalence of less than for state consumption. Further, two Block Leprosy
1 per 10,000 population) only in December 2005, along Awareness Campaigns (BLAC) were also undertaken in
with few more countries. 2004 and 2005 with case detection component.
The impact of all these strong measures can be seen
THE PRESENT in the form of declining trends in the Annual New Case
Detection Rates (ANCDR) and Prevalence Rates (PR)
The major feature of the present era has been the active
during the period from 1985 onwards. The figures from 1991
case detection campaigns to enable MDT to be
to 2009 have been displayed in Figure 47.2.2
administered to all patients as early as possible. MDT
The annual new case detection rates were remarkably
coverage of all districts was done in a phased manner and
steady up to 1997, and showed a significant increase in
since there was shortage of infrastructure, only 201 districts 1999 and subsequent decline. Between a period of 4 years
could be covered till 1994. Contractual staff was provided (from 2001 to 2005), the new case detection rates have
to the remaining districts and all districts were covered by halved from 5.5 to 2.3.
1996. Case detection was recorded and reported by a large The new case detection rate is only a proxy indicator
number of voluntary organizations till 2004. During the Fifth for the true incidence of a chronic disease and is influenced
Five Year plan, Case detection was also made through by many operational factors such as delay in reporting or
urban leprosy centers. Five modified leprosy elimination registration, socioeconomic factors, gender biases and also
campaigns were visualized and implemented from 1997 low priority for voluntary registration of children or those
to 2005. A Special Action Plan for Elimination of Leprosy with minor signs and symptoms of leprosy.3 Thus, the WHO
(SAPEL) was undertaken during in 1997-2000. Leprosy and Government of India have placed great importance in
elimination campaign (LEC) was also pushed through in calculating indicators such as multibacillary rates,
urban localities during 1997-2000. proportion of children and of those with grade II deformity
Fig. 47.2: Trends of leprosy prevalence (PR) and Annual New Case Detection (ANCDR)
CHAPTER
47
Leprosy Scenario Beyond 2010 607
among the new cases detected each year. An account of observe the impact of various operational factors like MLEC
these statistics from 1985 to 2008 is presented in Figure activities, retrenchment of paramedical workers, active
47.3. case detection, etc. on NCDR. From the Figure 47.4 it
While the proportion of multibacillary cases shows may be noted that there was a first peak of prevalence
significant increase from 1997 onwards, Grade II rate (6.4) in 1993 and the second peak (8.9) in 1999. The
deformities have also declined markedly during the same fall in the prevalence started in 2003 (by as much as 25%)
period. The proportion of child cases has been showing and followed a steady decline thereafter. There were other
fluctuations but overall, indicates some decline. The changes also like increase in MB case percentage from
emphasis on voluntary reporting and the cessation of 25 to 40% and a significant fall in the child proportion and
vertical surveys, especially school surveys, might be deformity rates among the new detected cases, during
responsible for these trends and the true picture may be the same period (Fig. 47.3) without any significant changes
quite different. Dependence solely on voluntary in the epidemiological factors.
registrations at general health facilities will thus miss most The picture clearly demonstrates the value of special
of the early cases, in which MDT would be most effective efforts in flushing out all new cases. Health-seeking habits
to prevent irreversible disabilities. Further, late registration of the public will only change slowly and it would be
of multibacillary cases implies a continued transmission disastrous to depend solely on the voluntary reporting of
of infection till they are put on treatment. Thus, it would be newly detected cases, and the valuable opportunity would
expedient for the Government to supplement the voluntary be missed to fully utilise the power of MDT in early cases.5
reporting with selected sample surveys and modified The prevalence rates in India from 1981 to 2008 in
leprosy elimination campaigns (MLEC) and other similar various states have been shown in Figure 47.5 where it
activities. can be seen the situation of leprosy before the introduction
The trends in new case detection rates are further of MDT, and the impact it had on the scenario in a span of
depicted in Figure 47.4, with the base year as 1991 and a about 25 years. The prevalence rate came down from 56
prevalence of 5.9/10000. An attempt has been made to to less than 1.
Fig. 47.3: Percent MB, children and grade-II deformities among new case detections
CHAPTER
47
Fig. 47.4: New case detection rates (NCDR) during period 1991 to 2008. Two peaks can be seen in the years 1993 and 1999
The picture of leprosy in the country as on March 2009, There are some disturbing signs of slackness in the
the state-wise prevalence rates are presented in Figure administrative actions such as non-availability of blister-
47.6. It seems inevitable that very soon, all states and packs of MDT, insufficiently trained primary health care
almost all districts will reach the magic elimination target staff, lack of motivated medical and paramedical staff,
of less than one per 10000 population. and the continued prevalence of leprosy stigma in many
parts of the country. If these issues are not tackled firmly
THE FUTURE and urgently, there could be a set-back to India’s target of
gradually but finally eradicating leprosy.
As of the beginning of 2009, leprosy control programs in Managers of national programs cannot afford to be
many endemic countries including India, are sustaining complacent. A bigger challenge lies ahead for these
their activities successfully; as a result of these efforts programs, especially for those operating in areas of low
the number of new cases detected globally continued to endemicity, to sustain political commitment and maintain
decline during 2008.4 services, especially at peripheral levels, for leprosy control
The picture presented so far seems quite rosy for India activities. At present, although leprosy services are
to move rapidly into the eradication phase. No doubt that rendered as part of the general health services, the
the political commitment and administrative support for bureaucratic system in the health services prevailing in
this to happen will be crucial, as also the increasing various states does not have a focused and coordinated
awareness of the general public to self-report and take full approach to leprosy control at the primary health center
advantage of the facilities of integration and free supply of level or even at district and state levels. This leads to
MDT. different and often multiple lines of control, duplication of
CHAPTER
47
Fig. 47.5: Declining leprosy prevalence in India
reports and statistics, and a general disinterest in special international, which have acted in unison and supported
programs such as leprosy. Unless, the integration is fully all initiatives taken for the national leprosy eradication
understood and implemented in toto, the message of program.5
leprosy eradication will not be conveyed forcefully to all Maintaining expertise in leprosy among health care
health care staff, as well as to the public. workers is challenging, especially in countries where the
Another important aspect of leprosy control has been disease has become relatively rare. The role of WHO and
the strong partnerships between governmental and NGOs in the training of health professionals has been highly
nongovernmental organizations, both national and significant, especially in the process of integration. Such
CHAPTER
47
Fig. 47.6: Prevalence of Leprosy in India (as of March 2009). Total population 1199.50 million, Recorded Leprosy Patients – 0.86 Lakh
and Prevalence rate (PR) 0.72 per 10,000 population
training will have to take into account the newer The following seven parameters which have varied and
developments in the management and treatment of leprosy defied clear-cut answers are given below:
and its complications. 1. Percentage of infected individuals who do not develop
Two important factors would be crucial in our efforts to the disease.
eradicate leprosy: One, to increase awareness for patients 2. Duration of the incubation period.
to self-report for early detection and prompt treatment with 3. Percentage of new cases who develop contagious
MDT to prevent deformities and disabilities. Secondly, the disease.
efforts to identify geographically hidden pockets which still 4. Self-healing rate for non-contagious self-healing
have a relatively high prevalence and incidence of leprosy, disease.
and take suitable control measures.1 5. Trends in detection delay.
Leprosy epidemiology is fraught with uncertainty. In a 6. Duration of dapsone monotherapy.
simulation study, the future trends of new case detections 7. Relapse rate after dapsone.
were presented in a dramatic manner, using sensitivity The scenario analysis demonstrates that the present
analyzes.6 leprosy elimination strategy will reduce transmission
CHAPTER
47
although, the decline may be slow. Early case detection is attitude and behavioral changes using the best
the key factor in the success of the strategy. communication strategies, increasing motivation for self-
There are a number of questions that need to be reporting; especially at early stages of disease or its
answered properly for implementing a successful complications, changing health –seeking habits of people
eradication program. These are: to facilitate prompt and correct treatment, reducing stigma
1. How to measure the difference between the recorded levels, preventing/reducing defaulters to treatment,
new cases and actual incident cases? changing the image of leprosy from a deforming incurable
2. How to come out with a realistic estimate of new cases disease to the one which is treatable, not contagious and
over the entire country? with deformities which are preventable subjected to early
3. How to identify cases of recent origin? institution of treatment, etc. It will be necessary to develop
4. How to distinguish the changes in trends due to
community-based and participant-driven strategies in
epidemiological and operational factors?
tackling this most important aspect of any health
5. Should performance in eradication be monitored at the
intervention, particularly in dealing with a stigmatised
state and national levels?
disease like leprosy.
6. Have social perceptions, especially the negative ones,
In the light of the above factors, one could project three
changed?
scenarios of leprosy in the country for the future:
7. How to enhance accessibility and acceptability of
leprosy treatment?
Most Pessimistic Picture
8. Are drug resistances and relapses promptly notified
and managed? Due to lack of political commitment and budgetary support,
Thus, the important factors for successful eradication administrative slackness and lack of trained manpower to
of leprosy (or at least its major consequences) can be tackle complications and consequences of leprosy, leading
grouped under three categories : to loss of confidence of the general public in governmental
efforts, the incidence and prevalence of leprosy will
A. Leprosy Services gradually increase, and leprosy will once again be a major
Must have sustained trained manpower, availability of MDT communicable disease.
and anti-reactional drugs, facilitation through existing health
network, good and successful referral system, alertness Most Optimistic Picture
in detecting any drug-resistances or relapses, maintaining Given the political support and administrative efficiency
leprosy expertise in selected institutions, continuous in organizing integrated leprosy services, success in
surveillance for hidden cases, and periodic use of rapid reducing stigma with massive public support, as well as
appraisal systems.
general socioeconomic improvements, coming all together
will promote successfully India’s target to eradicate leprosy
B. Leprosy Research
from the country in the next two to three decades, may be
Availability of second line drugs and contingency measures even earlier.
to prevent transmission of leprosy, continued research in
management of reactions and neuritis, and continued
Most Realistic Picture
research into extra-human reservoirs. The invention of
prophylactics and even vaccines can be an added boost The future will lie somewhere in between the most
for leprosy eradication. The need for research into safe pessimistic and the most optimistic scenarios, with more
immunotherapy and newer techniques for reconstructive and more states having a better control of leprosy
surgeries to prevent plantar ulcer recurrences cannot be eradication programs, while a few states such as Bihar,
under-stated. UP, some north-eastern states, Orissa and West Bengal
continuing to have highly bacillated new cases reporting
C. Leprosy Awareness for treatment. These states will need maximum national
This should not confine only to describing the signs and and state support not to fall back into the previous hyper-
symptoms of leprosy. The future needs are in terms of endemic status.
CHAPTER
47
CONCLUSION 2. Vijayakumaran P, Prasad B, Krishnamurthy P. Trends in Detection

of New Cases. Indian J Lepr 2006; 78: 103-14.
India has shown great resilience in overcoming great 3. Sundar Rao PSS. Current epidemiology of leprosy in India.
Editorial. Lepr Rev 2006; 77: 292-94.
obstacles in the past and one can only hope, that it will be
4. WHO. Global leprosy situation, beginning of 2009. Weekly
successful in eradicating the ancient scourge of leprosy Epidemiological Record, 2009; 84: 333-40.
through its medical and social breakthroughs. 5. World Health Organization (2006). Global strategy for further
reducing leprosy burden and sustaining leprosy control activities
(2006-2010): operational guidelines. WHO, Geneva, WHO/SEA/
REFERENCES GLP 2006;2:28.
6. Meima A, Smith WCS, van Oortmarssen GJ, et al. The future
1. Interviews with two key leaders in Leprosy: Prof. PL Joshi, Prof. incidence of leprosy: a scenario analysis. Bull World Health Organ
Maria Leide. Lepr Rev 2008; 79:130-33 2004; 82:374-80 and Appendix A-E.
Index
A Attitudes, norms and values 550 other experimental animals 81

Autoimmune type of damage 242 armadillo 81
Accompanied MDT (A-MDT) 68 363
Axonotmesis 213 nonhuman primates 81
Accredited social health activist (ASHA) 42
Azathioprine 390,396,404 Bacteriological criteria 145,489
Acedapsone 338,420
Aceto acetylated M. leprae 414 Bacteriology 171
B Basic considerations of nerves 211
Acquired hypomelanosis 199
Acquired immunity 63, 70 Bacillary load 317 Basic principles of CBR10 529
Activity of leprosy 316 Bacillemia in leprosy 293 Basic reproduction rate (BRR) 27
Activity planning v/s strategic planning 545 Bacterial growth and cell division 79 Basic scientific considerations and
Acute and chronic inflammatory demyelinating Bacterial index 178 pathology 45
polyradiculopathy 217 Bacteriological aspects 74 Beginnings of leprology 3
Acute idiopathic polyneuritis 217 biological properties of M. leprae 79 Behavior communication campaigns (BCC)
Acute trauma and chronic compression bacterial growth and cell division 79 549
(entrapment) neuropathies 214 generation time 80 Beige mice 493
Additional indicators for case detection 43,370 growth 79 Beliefs 550
Additional measures for neuritis/nerve minimum infective dose 80 Bell’s palsy 217
function impairment 389 strain differences 80 Bernhardt’s syndrome 216
temperature for optimum growth 80 Beta lactamase resistant antibiotics 345
Adverse effects of thalidomide 394
viability and stability 80 Betamethasone pulse therapy 396
Advice to patients 441
cellular morphology 75 Bhore committee 18
Advocacy 533,549
capsule 77 Biochemical aspects 87
Age 26,27,121
cell membrane 77 hematological, serological and
Agent factors 27
cell wall 76 biochemical changes in
Agranulomatous stage 102
cytoplasm 77 patients with leprosy 92
Ainhum 222
metabolism of M. leprae 78 biochemical changes in host 93
Alcohol iodine solution 182
pyridine extraction 78
Allergic granulomatosis 214 connective tissue catabolism 94
solid bacteria 77
Altered secretion of steroids 314 endocrine function 94
conclusion and future prospects 84
Alternate therapies 396 glucose tolerance 95
drug resistance 81
Analgesics 405 hematological profile in leprosy 92
molecular mechanism of drug
Anandwan 577 hepatic involvement 93
resistance 82
Anesthetic lower limb 473 experimental animal models for lipid profile 93
Anesthetic upper limb 472 M. leprae 81 minerals and trace elements 95
Animal models 492 mouse 81 oxidative stress and antioxidant
Animals 498 laboratory diagnosis of leprosy 82 status 95
Annual new case detection rate 26 assays using radiolabeled renal involvement and kidney
Ansamycins 345 substrate 83 function 94
Anticipating nerve function impairment 454 clinical spectrum of leprosy 75 serological profile in leprosy 92
Anticonvulsants 405 determination of bacillary ATP serum enzymes 95
Antigen serology 190 biomass 83 serum protein profile 93
Antigenically related mycobacteria 412 fluorescein diacetate-ethidium host—M. leprae interactions 90
Anti-inflammatory agents 403 bromide staining 83 interaction with dendritic cells 91
Anti-inflammatory therapy 402 immunological properties of interactions of macrophages with
Anti-leprosy treatment 387 M. leprae 75 M. leprae 91
Armadillo 81,497 Mycobacterium leprae 75 interactions with the Schwann cells
Assistive devices/technologies 526 pathogenesis of M. leprae 75 and mechanisms of nerve
Associated diseases 124 slit- skin smear 82 injury 90
614 IAL Textbook of Leprosy
Mycobacterium leprae and Case studies 585 deoxy fructo serotonin (DFS) 347
endothelial cells 92 childhood and disease detection 588 dihydrofolate reductase 346
Mycobacterium leprae, etiologic agent children 595 fusidic acid 346
of leprosy 87 disease detection 593,598 chemotherapeutic drugs for leprosy in
cellular morphology 87 embracing christianity 592 common use 336
chemical composition of cell wall of family and children 591 acedapsone 338
M. leprae 88 indirect pressure for extradition 596 dapsone 336
genome of M. leprae vis-à-vis that leprosy treatment 594 dapsone resistance 338
of M. tuberculosis 89 leprosy treatment regime at Mother dapsone syndrome 338
genotypic variations in M. leprae 89 Teresa Hospital 599 persisters 339
growth and metabolism 88 marriage and children 599 clofazimine 341
molecular identification of M. leprae mission factor 595 clofazimine resistance 342
89 Mother Teresa Hospital, an institutional dosage and clinical effects 339
leprosy care home 600 adverse effects 340
pregenomic study of a few
move to Delhi (and no to begging) 598 rifampicin resistance 341
enzymes of M. leprae 90
public pressure for isolation 588 drug-resistance and multidrug therapy
Biochemical changes in host 93
social implications of disease 593 347
Biological properties of M. leprae 79
social mobilization of laps 591 ethionamide and prothionamide 342
Biopsy procedure 181
social server by heart and a newer drugs for leprosy 343
Blindness and severe visual impairment
philanthropist 599
(SVI) in leprosy 504 fluoroquinolones 343
treatment and long stays at various
Bombay leprosy project 579 macrolides-clarithromycin 344
missionary hospitals 597
Bone marrow 300 minocycline 344
treatment at Jabalpur Medical
Bones, joints and muscles 294 thiacetazone 342
College(1962-63) 597
Borderline borderline (BB) 159,187 Child proportion 26
Cataract 514,518
Borderline lepromatous (BL) 107,159,187 Childhood and disease detection 588
CBR 527,541,534
Borderline leprosy 157 Chimpanzee 497
awareness 611
Borderline tuberculoid (BT) 107,158 Chromosomal regions 10p13 and 20p12 55
children 325
Buerger’s disease 222 Chronic hepatitis 221
component of CBR 542
HIV infection 305 Chronic neuropathic pain 405
C ICD-10 (version 2007)2 25 Clarithromycin 321
International Disease Classification 24 Classification 144
Capsule 77
nerve damage 244 concept of polar and subpolar forms 148
Carbol fuchsin 177 correlation among various
Cardiovascular system 300 pregnancy/lactation 478
reactions 66,109,244,269 classifications 149
Care of eyes 454 criteria 145
Case definition and clinical types 152 research 611
scenario beyond 2010 605 bacteriological criteria 145
classification of disease 154 histopathological features 145
treatment regime at Mother Teresa
current WHO classification 155 immunological factors 145
Hospital 599
paucibacillary leprosy 155 infective (open) and non-infective
vaccines and immunotherapy 410
clinical problems with cardinal signs 152 categorization 145
Cell mediated immunity 315
peripheral nerve trunk enlargement Indian classification 146
Cell membrane 77
153 Madrid classification 146
Cell wall 76
skin lesions with sensory Cellular morphology 75,87 new IAL classification 147
impairment 153 Central nervous system 300 Ridley-Jopling classification 147
slitskin smears 154 Cervical rib 217 WHO classification (1988) for leprosy
early lesions and presenting symptoms Changing scenario 174,528 control programs 148
155 Chaulmoogra/hydnocarpus oil therapy 10 WHO classification (1998) for leprosy
borderline borderline (BB) 159 Chemical composition of cell wall of control programs 149
borderline lepromatous (BL) 159 M. leprae 88 Claw-hand deformity 221
borderline leprosy 157 Chemoprophylaxis 418 Clinical and laboratory diagnosis 119
borderline tuberculoid (BT) 158 application of chemoprophylaxis 422 Clinical grading of nerve thickening,
diffuse lepromatous leprosy 161 dapsone chemoprophylaxis 419 tenderness and pain 260
indeterminate leprosy 155 dapsone chemoprophylaxis in Clofazimine 320,341,342,353,392,395,,404
infiltrated lepromatous leprosy 162 entire endemic population 420 Common peroneal (lateral popliteal) nerve
lepromatous leprosy (LL) 161 studies in contacts 419 215,249
nodular lepromatous leprosy 162 Chemotherapeutic drugs for leprosy in Communication 548,553
tuberculoid leprosy (TT) 156 common use 336 Community based rehabilitation 527,561
histoid leprosy 164 Chemotherapy: drugs used in leprosy Community-based comprehensive leprosy
lazarine leprosy 164 including newer drugs 335 work 538
lucio leprosy 164 adverse effects 342 CBR 541
nerve involvement 165 ansamycins 345 comprehensive leprosy care 539
pure neuritic leprosy 164 beta lactamase resistant antibiotics disability care 540
rare variants of leprosy 163 345 medical treatment 540
Index 615
objectives of comprehensive D oro-nasal defects 451
leprosy care 539 skin damage 451
Dapsone 320,336,353
prevention of disability 540 evaluation of patient and assessment of
chemoprophylaxis 419,420
stigma and discrimination 541 resistance 338 disability 455
vocational rehabilitation 540 factors affecting onset and progression
syndrome 338
epilogue 542 of disabilities 449
Decolorizing agent 177
integrated set-up 538 Deformities of face, hands and feet, and grading of disabilities and deformities 447
National Rural/Urban Health prevention of disabilities 454
their management 424
Mission 539 anticipating nerve function
clinical manifestations 424
leprosy as a component of CBR 542 episodes of reactions 424 impairment (NFI) 454
set strategy 538 care of eyes 454
deformities in leprosy 429
Comprehensive leprosy care 539 management of reactions 455
primary and secondary deformities
Congenital flexion of fingers 221 429 monitoring and self-reporting 455
Connective tissue catabolism 94 role of nerve trunk decompression
deformities of face 437
Continue multi-drug therapy 391 454
depressed nose collapsed nose 437
Corneal hypoesthesia 517 ectropion 438 role of steroids 454
Correlation among various classifications role of physiotherapy 456
lagophthalmos 438
149 electrical stimulation 463
loss of eyebrows 438
Corticosteroids 321,402 wrinkled face 437 exercises 457
heat therapy 462
Corticosteroids administration 388 deformities of feet 433
soaking in water and oil application
Corynebacterium diphtheriae 220 foot drop and claw toes 433
footwear 436 456
Counseling 545
splints and splinting 457
activity planning v/s strategic planning 545 plantar ulcers 434
techniques of physiotherapy as
communication skills 553 surgery for plantar ulcers 436
deformities of hands 429 applied to leprosy affected
listening 554
persons 456
observing 554 clawhand 429
prevention of progression of disabilities
attitudes, norms and values 550 grip-aids 431
reconstructive surgery 433 464
denial 550
management 464
disclosing diagnosis to patient 553 splints 431
types of deformities 447
external influence 550 disabilities and deformities in leprosy—
terminology 425 Demyelination 212
motivation 553 Dendritic cells 91
negative forces 550 economic rehabilitation 439
Denial 550
health education 545 health education to a person affected
with leprosy 441 Deoxy fructo serotonin (DFS) 347
health promotion 545 Depressed nose (collapsed nose) 437
IEC implementation approaches 548 advice to patients on completion of
Development and evolution of WHO MDT
advocacy 549 MDT 441
advice to patients who have and newer treatment regimens
behavior communication 353
campaigns (BCC) 549 deformities 441
chemotherapy of leprosy—further
information, education and advice to patients with loss of
sensation in hands and challenges 359
communication 546 drug safety with MDT 360
feet 441
posters 555 multibacillary leprosy 360
nerve involvement 426
program focus in relation to leprosy 555 paucibacillary leprosy 360
surgery on nerves 427
Course of leprosy in pregnancy 314 history of MDT in India and controversy
reconstructive surgery (RCS) in
Criteria system 275 over intensive treatment 355
DPMR—a Government of India
Crucial decisions 549 fixed duration treatment (FDT) for
(GOI) initiative 438
Cultivation of M. leprae 494 24 months 356
testing for nerve damage 427
Current WHO classification 155 fixed duration treatment for 12
motor testing 427
Cutaneous (medial, anterior and lateral) months 356
quick test to assess motor damage
nerves of thigh 252 rationale for shortening the duration
in hands 427
Cutaneous branch of ulnar nerve 252 of MDT to 12 months 357
sensory testing 427
Cutaneous examination 126 Deformity/disability prevention 447 newer chemotherapeutic agents in
Cutaneous nerves of forearm 251 leprosy 360
causation of deformities 450
Cutaneous plaques 170 post-treatment surveillance and
damage to other tissues 452
Cutaneous sarcoidosis 205 effects of anesthesia and analgesia relapses in leprosy 357
Cutaneous tuberculosis 208 reasons for shift from monotherapy to
453
Cyclosporine 390,404 MDT 354
effects of infiltration of tissues by M.
Cynomolgus monkeys 497 leprae 450 persisters 354
Cystic cavitations of spinal cord 221 rifampicin-based combined therapy
effects of motor paralysis 453
Cytokines/interleukins 414 for MB patients 354
gynecomastia and associated
Cytological diagnosis of leprosy 186 changes 451 sequence of significant events in
Cytoplasm 77 treatment of leprosy 354
nerve damage 450
clofazimine 353 Dupuytren’s contracture 221 Distribution of lesions 123

dapsone 353 progressive muscular atrophy 221 Dose and duration of prednisolone 388
rifampicin 353 sclerodactyly 221 Downgrading reaction 269
WHO study group on chemotherapy of conditions producing neuropathic ulcers Droplet infection 29
leprosy 355 222 Drug resistance studies, viability and
multibacillary leprosy 355 Buerger’s disease 222 bacterial persisters 492
paucibacillary leprosy 355 Planter corns 222 animal models 492
short course chemotherapy in leprosy 361 Raynaud’s disease 222 applications of murine models 494
accompanied MDT 68 363 Tabes dorsalis 222 cultivation of M. leprae 494
moxifloxacin-based regimens 363 yaws 222 detection of ‘persister’ M. leprae 494
recommendations for research developmental disorders 221 drug resistance and susceptibility
trials 361 spina bifida 221 studies 494
severe dapsone toxicity 365 syringomyelia (cystic cavitations of experimental chemotherapy study
uniform MDT (U–MDT) 363 spinal cord) 221 494
Developmental disorders 221 diseases causing peripheral study of pathomechanisms of
Dexamethasone pulse therapy with
neuropathy 213 leprosy 496
azathioprine 396
hereditary (familial) neuropathies 218 testing of activity of drug against
Diabetes mellitus (DM) 213
Refsum’s syndrome 218 M. leprae 494
Differential diagnosis of dermatological
Sensoriautonomic neuropathy 219 testing of immunoprophylactic
conditions 197
hereditary amyloid polyneuropathy agents 495
acquired hypomelanosis 199
219 determination of viability of M. leprae (in
cutaneous sarcoidosis 205
cutaneous tuberculosis 208 hereditary sensorimotor vitro methods) 498
discoid lupus erythematosus 209 neuropathy (HSMN) 218 murine models 492
granuloma annulare 207 hereditary sensory neuropathy beige mice 493
leishmaniasis 207 (HSN) 219 immunosuppressed mice and rats
Lupus miliaris Disseminativa faciei 208 infections 220 493
malignancies 209 chronic hepatitis 221 nude mice 493
nevus achromicus/nevus anemicus 198 Corynebacterium diphtheriae 220 scid mice 493
pityriasis alba 197 differentiation of leprosy 220 nerve tissue culture model 498
pityriasis versicolor 200 HIV associated neuropathy 220 non-human primate models of leprosy
polymorphic light eruption 198 metabolic conditions 213 497
psoriasis 200 diabetes mellitus (DM) 213 armadillo 497
vitiligo 198 hypercholesterolemia 214 chimpanzee 497
Differential diagnosis of neurological and porphyrias 214 cynomolgus monkeys 497
other conditions 211 uremia 214 mangabey monkeys 497
acute and chronic inflammatory peripheral neuropathy 211 rhesus monkeys 497
demyelinating psychiatric disorders 221 other animals 498
polyradiculopathy 217 hysteria 221 Drug safety with MDT 360
differentiation of leprosy 218 symptoms of nerve damage 213 Drug therapy of leprosy during pregnancy 320
Guillain-Barre syndrome (acute axonotmesis 213 Drugs 220,414
idiopathic polyneuritis) 217 neurapraxia 213
acute trauma and chronic compression Drugs for type 2 reactions 392
neurotmesis 213
(entrapment) neuropathies 214 Drugs/treatment modalities tried in ENL 396
toxic/nutritional conditions 220
Bell’s palsy 217 Dry eye syndrome 518
drugs 220
cervical rib 217 Dupuytren’s contracture 221
heavy metals 220
common peroneal nerve 215 malignancies and radiation toxicity
differentiation of leprosy 217 E
220
facial nerve paralysis 216 Economic rehabilitation 439
vitamin B complex deficiency 220
median nerve 215 Ectropion 438,509
vasculitic conditions 214
meralgia paresthetica (syn. Efficacy of steroids 403
allergic granulomatosis 214
Bernhardt’s syndrome) 216 acute neuritis 403
polyarteritis nodosa 214
radial nerve 215 chronic and recurrent neuritis 403
Diffuse lepromatous leprosy 161
Ramsay-Hunt syndrome 217 Electrical stimulation 463
Dihydrofolate reductase 346
trigeminal nerve 215
Diminished complement 172 Embracing christianity 592
ulnar nerve 215
Disability care 540,579 Empowerment 529,563
basic considerations of nerves 211
Disability in leprosy and its grading 264 Endocrine function 94
demyelination 212
Disclosing diagnosis to patient 553 Endocrine glands 299
distal axonopathy 212
Discoid lupus erythematosus 209 Enhanced humoral immune response 172
Wallerian degeneration 212
conditions producing claw-hand Discovery and properties of bacillus 8 ENL 279
deformity 221 Disease complications (nerve involvement, Entropion 509
ainhum 222 neuritis and reactions) 225 Environmental factors 29
congenital flexion of fingers 221 Distal axonopathy 212 Eosin stain 182
Index 617
Epidemiology 24 Footwear 436 Hematoxylin-eosin (H&E) stain 182
agent factors 27 Formats for recording and reporting 373 Hepatic involvement 93
agent 27 Fully developed granulomas in leprosy 104 Hereditary (familial) neuropathies 218
epidemiological indicators for Fusidic acid 346 Hereditary amyloid polyneuropathy 219
monitoring 25 Hereditary sensorimotor neuropathy
age and sex specific prevalence G (HSMN) 218
and incidence rates 26 Gandhi Memorial Leprosy Foundation Hereditary sensory neuropathy (HSN) 219
annual new case detection rate 26 (GMLF) 575 High-risk group 419
criteria of leprosy elimination 25 Gastrointestinal tract 298 Hind Kushth Nivaran Sangh (HKNS-
deformity rate 27 Gender 27 previously: Indian Leprosy
lepromatous rate 26 Gene amplification (PCR) techniques 192 Association) 576
MB proportion 26 General immune responses 60 Histamine test 185
treatment completion rate 27 Generation time 80 Histoid lepromas 174
host factors 27 Genes and proteins of major histocompatibility Histoid leprosy 104,164,167
age 27 complex (MHC) 47 bacteriology 171
familial clustering 28 Genes involved in susceptibility to leprosy 52 changing scenario 174
gender 27 Genetic factors 28 diagnosis 173
genetic factors 28 Genetic susceptibility and immunogenetics 47 characteristic clinical features 173
immunity 28 genes and proteins of major history 173
migration 28 histocompatibility complex microscopic examination 173
leprosy and International Disease (MHC) 47 differential diagnosis 173
Classification 24 MHC Class-I genes and proteins 48 epidemiology 167
leprosy in ICD-10 (version 2007) 25 MHC Class-II genes and proteins 50 histopathology 171
social factors 29 nomenclature of HLA 50 tuberculoid contamination 172
transmission 29 HLA and leprosy 51 historical 167
in utero transmission 29 mica 52 immunoprofile 172
incubation period 30 other genes involved in susceptibility to diminished complement 172
inhalation (droplet infection) 29 leprosy 52 enhanced humoral immune
inoculation following trauma 30 Genome of M. leprae 89,191 response 172
mode of transmission 29 Genomic probes and gene amplification lowered cell-mediated immunity
portal of entry 29 assays for M. leprae 191 172
portal of exit 29 Genotypic variations in M. leprae 89 significance of histoid lepromas 174
source of infection 29 Geographical information system 372 treatment 173
Erythema nodosum leprosum (ENL) 111 Global scenario 32 ultrastructure 172
Ethionamide and prothionamide 342 progress with leprosy situation 32 Historical background 3
Experimental animal models for M. leprae 81 source 34 etiological debates 4
Experimental chemotherapy study 494 Glucose tolerance 95 reactions 5
Experimental evidence 319 Gomori-Grocott methenamine Silver stain 183 nerve involvement and neuro-
External influence 550 Gonadal involvement in leprosy 313 pathogenesis 6
Extra-neural neurolysis 406 Governments (local, regional, national) 532 discovery and properties of bacillus 8
Extraocular lesions 506 Grading 275 nerve abscess 10
Eyes 114,296 deformities 447 Indian Council of the British Empire
disabilities 447 Leprosy Relief Association
F (ICBELRA) 13
nerve tenderness 260
Facial nerve 216 nerve thickening 260 other ICBELRA initiatives 15
paralysis 216 neuropathic pain 260 Robert cochrane(1899-1985) 17
zygomatic branch 250 Granuloma annulare 207 Bhore committee 18
Familial clustering 28 Granulomatous stage 104 coda 21
Family and children 591 Great auricular nerve 250 History taking and clinical examination 121
Family based support to self-care practices Grip-aids 431 clinical examination 125
557 Growth and metabolism 88 cutaneous examination 126
Female reproductive system 299 Guillain-Barre syndrome 217 examination of external genitalia 140
First presentation of leprosy in pregnancy 316 Gynecomastia and associated changes 451 examination of individual skin lesion
Fixatives 181 126
Fixed duration treatment (FDT) 356 H examination of musculoskeletal
Fluorescein diacetate-ethidium bromide system 136
Hand deformities 430
staining 83 general physical examination 125
Harris hematoxylin 182
Fluorescent microscopy to detect M. leprae ichthyosis 131
Healed lesions 103 mucosal examination 131
183 Health education, promotion 545
Fluoroquinolones 343 ocular examination 131
Heat therapy 462
FNAC for cutaneous lesions of leprosy 186 palpation of peripheral nerves 133
Heavy metals 220 sweating 131
Foot drop and claw toes 433 Hematology and serology 301
testing sensations 129 Humoral immunity 315 Institution based rehabilitation (IBR) 526,561
trophic changes 130 Hypercholesterolemia 214 Interfascicular neurolysis 406
history taking 121 Hysteria 221 Interfering with patient’s habits 557
address 122 Interleukins-based assays 485
age 121 I International Federation of Antileprosy
associated diseases 124 Icbelra initiatives 15 Associations (ILEP) 572
distribution of lesions 123 Ichthyosis 131 International Leprosy Union (ILU), pune 575
duration 122 Identification and demographic data 121 Intraneural administration of drugs 405
family history 125 Identify severity of T2R 390 Intra-neural neurolysis or longitudinal
history of present illness 122 Immunity 28 epineurotomy 406
marital status 122 Immunoassays 191 Iris 309
mode of onset 123 Immunochemical staining 183 Irregular therapy 486
name 121 Immuno-competent mice and rats 492
occupation 122 J
Immunogenetics of leprosy 70
past history 124 Immunohistochemistry-based approaches Job-Chacko modification of Fite-Faraco
personal history 125 191 stain for M. leprae 183
precipitating factors 123 Immunologic tests for relapse 485 Juvenile justice and care and protection act
presenting complaints 122 Immunological aspects 60 2000, section 48 569
progression and evolution 123 general immune responses 60
sex 121 immunological features of leprosy 61 K
socioeconomic status 122 leprosy reactions 66 Kidneys 115,299
symptoms 123 immunopathology of dermal lesions 67
treatment taken for presenting nerve damage in leprosy: immune L
complaints 124 mechanisms 68
visceral involvement and immunogenetics of leprosy 70 Laboratory diagnosis 176
complications 123 bacterial index (BI) 178
acquired immunity 70
HIV 220 cytological diagnosis of leprosy 186
Immunological aspects of nerve damage 242
associated neuropathy 220 Immunological factors 145 fixatives 181
infection 487 fluorescent microscopy to detect
Immunological features of leprosy 61
leprous neuritis 408 M. leprae 183
Immunological properties of M. leprae 75
HIV progression and antiretroviral therapy 307 Immunological response 314 FNAC for cutaneous lesions of leprosy
HLA and leprosy 51 186
Immunological studies 272
Host factors 27 Gomori-Grocott methenamine Silver
Immunological unresponsiveness 64
Host—M. leprae interactions 90 Immunology 277 stain 183
Human rights and leprosy 565 hematoxylin-eosin (H&E) stain 182
Immunology and histology in leprosy-HIV
employment rules 568 preparation of solutions 182
coinfection 308
juvenile justice and care and Immunomodulator drugs 413 sodium thiosulfate solution 182
protection act 2000, section 48 histamine test 185
Immunopathology of dermal lesions 67
569 method of doing test 185
Immunopathomechanisms 272,277
life insurance and leprosy patients Immunosuppressed mice and rats 493 principle of histamine test 185
568 immunochemical staining to
Immunosuppressive drugs 389
prevention of begging act 1959 demonstrate mycobacterial
Immunotherapy 411
(Maharashtra) 569 Immunotherapy in chronic and recurrent antigens 183
rehabilitation 569 morphological index 178
ENL 396
transports and leprosy patients 568 nasal mucosal smears 180
In utero transmission 29
footsteps of time 565 In vivo techniques 484 method of collecting nasal blows 180
medical implications 566 method of taking nasal mucosal
Inadequate therapy 486
parsi marriage act of 1936 (no divorce smears 180
Incubation period 30
granted on ground of leprosy) Indeterminate leprosy 102,155 nerve biopsy 184
567 S-100 stain for Schwann cell 184
Indian classification 146
stigma in leprosy settlements/ skin biopsy 180
Indian Council of the British Empire Leprosy
leprosy colonies 568 Relief Association (ICBELRA) biopsy procedure 181
stigma in community 568 site of skin biopsy 181
13
stigma in leprosy hospitals 568 size of the biopsy 181
Infective (open) and non-infective
social aspects 565 categorization 145 slit-skin smear examination 176
disease 566 carbol fuchsin (to make 200 ml) 177
Infiltrated lepromatous leprosy 162
misconceptions in community 566 decolorizing agent 177
Information, education and communication
social stigma and its effects 566 546 equipment used 177
voice of awakening 569 examination of smear 178
Inhalation 29
strategies to address social indications for slit-skin smear
Innate immunity 61,70
aspects 570 Inoculation 30 examination 176
Human rights violations 566 method of staining 178
Insidious nerve damage 244
Index 619
method of taking slit-skin smears 177 risk factors 271 Levamisole 413
methylene blue (0.2%) (counter signs 274 Life insurance and leprosy patients 568
stain)(to make 200 ml) 178 symptoms 274 Lipid profile 93
preparation of dichromate solution 177 type 2 reactions 276 Lithium carbonate 183
preparation of reagents 177 clinical tests 283 Liver 114
role of slit-skin smear examination 176 diagnosis 283 Local voluntary organizations 584
sites for slit-skin smear 176 differential diagnosis 285 Loss of eyebrows 438
staining of slides: Ziehl-Neelsen ENL 279 Lower respiratory tract 298
method 177 histopathological features of skin Lowered cell-mediated immunity 172
technique of slit-skin smear 177 from ENL lesions 283 Lucio leprosy 112,164
sweat test 185 histopathology 278 Lucio phenomenon 270,285,397
method of performing test 185 immunology 277 Lupus miliaris disseminativa faciei 208
principle of sweat test 185 immunopathomechanisms 277 Lymph nodes 113,300
technique of FNAC 187 laboratory tests 284
equipment 187 lepromatous exacerbation 280 M
preparing aspirate 187 mode of onset 279 Macrolides-clarithromycin 344
Laboratory tests 276 nerve involvement 281 Macrophages with M. leprae 91
Lagophthalmos 438,507,518 nomenclature 278 Madarosis 506
Larynx 113 reaction severity assessment Madrid classification 146
Laws on matrimonial alliance and divorce 567 system (RSS) 282 Male reproductive system 298
Lazarine leprosy 164 risk factors 277 Management of leprosy reactions 386
Legislation 20 clofazimine 392
severity of type 2 reaction 282
Legitimacy for social ostracism 567 adverse effects of thalidomide 394
skin lesions 279
Leishmaniasis 207 indications 393
systemic manifestations 280
Lepromatous exacerbation 280 neuropathy 394
time of onset 278
Lepromatous leprosy (LL) 104,161,187 other side effects 395
type 2 reactions without ENL 282
Lepromatous rate 26 somnolence 395
unusual pattern of vesiculobullous
Lepromin negativity 487 teratogenicity 394
type 2 reactions 280
Lepromin reaction 276 thalidomide 392
types 269
Leprosy elimination 25 thromboembolism 395
downgrading reaction 269
Leprosy in children 325 lucio phenomenon 397
lucio phenomenon 270
classification 326 prevention/early diagnosis of reaction 386
type 1 reaction (T1R) 269
diagnosis 329 principles of management 386
epidemiology 325 type 2 reaction (T2R) or erythema
nodosum leprosum (ENL) 270 additional measures for neuritis/
spectrum of clinical presentation in nerve function impairment
children 326 upgrading or reversal reaction 269
Leprosy scenario beyond 2010 605 (NFI) 389
deformities 329 adverse effects 389
evolution 329 future 608
anti-leprosy treatment 387
transmission 326 leprosy awareness 611
azathioprine 390
treatment 330 leprosy research 611
cyclosporine A (CYA) 390
prevention 331 leprosy services 611
dose and duration of prednisolone
Leprosy reactions 269 most optimistic picture 611
388
epidemiology 270 most pessimistic picture 611
methotrexate 389
Lucio’s phenomenon 285 most realistic picture 611
mycophenolate mofetil 390
clinical manifestations 286 past 605
other immunosuppressive drugs 389
diagnosis 287 present 606
outcome of timely and adequate
histopathological features 286 Leprosy vaccines and immunotherapy 410 corticosteroids administration
salient features of Lucio’s immunoprophylaxis 410 388
phenomenon 287 immunotherapy 411 specific therapy 387
type 1 reactions 271 antigenically related mycobacteria standard dose schedule at referral
clinical terms 273 412 center 388
course 276 immunomodulator drugs 413 standard dose schedule for field
criteria system 275 levamisole 413 purpose (WHO, 1998) 388
diagnosis 275 other drugs 414 surgical decompression 390
differential diagnosis 276 zinc 414 treatment of late RR 389
grading 275 other immunomodulators 414 treatment of mild RR 387
histopathological examination 275 aceto acetylated M. leprae 414 treatment of reaction 387
histopathological features 272 cytokines/interleukins 414 treatment of severe RR and acute
immunological studies 272 de-lipified cell components of neuritis 387
immunopathomechanisms 272 M. leprae (DCC) 414 principles of management of 390
lepromin reaction 276 soluble protein component obtained continue multi-drug therapy 391
rare or uncharacteristic from cell wall of M. leprae 414 identify severity of T2R 390
presentations 274 transfer factor 414 treat precipitating factors 391
steroid replacement by thalidomide for MB proportion 26 Motor nerve conduction study 234
ENL patients already on Median nerve 215,249 Motor testing 427
steroids 395 Meralgia paresthetica 216 Mouse 81
alternate therapies for T2R 396 Metabolic changes 314 Moxifloxacin-based regimens 363
azathioprine 396 Metabolic conditions 213 Mucosal examination 131
betamethasone pulse therapy 396 Metabolism of M. leprae 78 Multibacillary leprosy 155,306,355,360
dexamethasone pulse therapy with Methods of nerve examination 248 Murine models 492
azathioprine 396 palpation of cutaneous nerves 250 Musculocutaneous nerve 252
immunotherapy in chronic and cutaneous (medial, anterior and Mycobacteria 74
recurrent enl 396 lateral) nerves of thigh 252 Mycobacterium leprae 75
management of other manifestations: cutaneous branch of ulnar nerve endothelial cells 92
neuritis, acute 397 252 etiologic agent of leprosy 87
newer drugs in ENL management 397 cutaneous nerves of forearm 251 neural predilection 231
other drugs/treatment modalities great auricular nerve 250 specific lipid antigen 190
tried in ENL 396
radial cutaneous nerve 251 Mycophenolate mofetil 390
treatment for severe T2R (for 1st attack
superficial peroneal nerve
of severe ENL) 395 N
(musculocutaneous nerve) 252
treatment of recurrent or chronic ENL 395
supraclavicular nerves 251 Nasal mucosal smears 180
treatment of T2R 391
supratrochlear, supraorbital and National leprosy eradication program 36
type 1 reaction 386
infraorbital nerves 250 National program for rehabilitation 536
type 2 reaction (T2R) 390
types of reaction 386 sural nerve 252 National rural/urban health mission 539
useful drugs for type 2 reactions 392 palpation of nerve trunks 249 National scenario, national leprosy
oral corticosteroids 392 common peroneal (lateral popliteal) eradication program (NLEP)
Management of neuritis and neuropathic nerve 249 and new paradigms 35
pain 400 facial nerve and its zygomatic historical aspects of leprosy 35
anti-inflammatory therapy 402 branch 250 milestones under NLEP 36
corticosteroids 402 median nerve 249 epidemiological situation 36
efficacy of steroids in acute neuritis posterior tibial nerve 250 new paradigms in NLEP 38
403 radial nerve 249 Accredited Social Health Activist
efficacy of steroids in chronic and ulnar nerve 249 (ASHA) 42
recurrent neuritis 403 Methotrexate 389 additional indicators for case
chronic neuropathic pain 405 Methylene blue 178 detection 43
anticonvulsants 405 MHC 48 burden of leprosy 39
extra-neural neurolysis 406 class-I genes and proteins 48 improving community awareness
interfascicular neurolysis 406 class-II genes and proteins 50 and involvement 41
intra-neural neurolysis or Mica 52 improving the quality of services 39
longitudinal epineurotomy 406 Microbiological aspects 484 indicators for monitoring and
medical treatment 405 Microscopic examination 173 evaluation 43
nerve abscess drainage 406 Mid borderline (BB) 107 indicators for patient management 43
nerve transposition by means of Migration 28 integration of leprosy services with
medial epicondylectomy 407 Minerals and trace elements 95 sustainability 40
opioids 406 Minimum infective dose 80 number of new case detected in a
surgery 406 Minocycline 321, 344
tricyclic antidepressants (TCA) 405 given area each year 43
Miscellaneous issues in leprosy 481 prevention and management of
diagnosis and monitoring 401 Misconceptions in community 566
general measures 407 impairments and disabilities 41
Mission factor 595 referral services and long-term
HIV and leprous neuritis 408 Missionaries of charity, Gandhiji Prem
management 402 care 40
Nivas, Titagarh 577 registered prevalence 43
newer approaches of treatment 408
Molecular assays 485 rehabilitation 42
other anti-inflammatory agents 403
Molecular identification 83 Rogi Kalyan Samities 42
analgesics 405
M. leprae 89 support of national rural health
azathioprine 404
polymerase chain reaction (PCR) 83 mission 42
clofazimine 404
Molecular mechanism of drug resistance 82 treatment completion/cure rate 43
cyclosporine 404
thalidomide 404 Molecular techniques 485 village health and sanitation
prevention 407 Monitor drug stock 372 committee 42
Mangabey monkeys 497 Monitoring and self-reporting 455 National scenario, national leprosy
Marital status 122 Monotherapy 487 eradication program (NLEP)
Marriage 590,594,599 Morphological index 178 and new paradigms 35
Massage and exercises 475 Mother Teresa Hospital 600 Neonatally thymectomized lewis rats
fingers 475 Motivation 553 (NTLR) 493
paralytic deformity 475 Motor function assessment 266 Networking 534
thumb 476 Motor impairment 264 Neurapraxia 213
Index 621
Neuritis and neuropathic pain 400 proforma to record clinical grading O
Neuritis: definition, clinical manifestations of nerve involvement in leprosy
Ocular examination 131
and proforma to nerve 266
Ocular leprosy 503
impairment 253 proforma to record disability,
effects of leprosy on eyes and ocular
methodology to record nerve deformities and ulcers 266
adnexa 506
involvement 259 Neuropathic pain 253,257
epidemiology 504
application of clinical grading 261 Neuropathic ulcers 222
blindness and severe visual
clinical grading of nerve thickening, Neuropathy 394
impairment (SVI) in leprosy 504
tenderness and pain 260 Neurotmesis 213
manifestations of eye involvement
criteria for motor impairment 264 Nevus achromicus 198
in leprosy 504
criteria for sensory impairment 262 Nevus anemicus 198
extraocular lesions 506
disability in leprosy and its grading New IAL classification 147
diseases of eyelids 507
264 New paradigms in NLEP 38
diseases of eyebrows 506
electrophysiological study by Newer chemotherapeutic agents in leprosy
ectropion, entropion and trichiasis 509
needle electromyography 360
lagophthalmos 507
(EMG)43 263 Nodular lepromatous leprosy 162
madarosis 506
examination of eyes for NFI 264 Nomenclature 50,278
medical management 507
examination of peripheral nerves Nongovernmental Organizations (NGOS)
surgical management 508
259 532
types of surgery 508
grading of nerve tenderness 260 Non-human primate models of leprosy 497
ocular lesions 510
grading of nerve thickening 260 Nonhuman primates 81
cataract 514
grading of neuropathic pain 260 Nonimmune mechanism of nerve damage 69
diseases of conjunctiva and sclera
laboratory tools to test for sensory Nose 113
510
impairment 263 Novartis comprehensive leprosy care
diseases of cornea 511
nerve conduction studies 263 association (NCLCA) 582
diseases of lens 514
sensory testing by monofilaments NSAIDs 321
diseases of uveal tract 513
261 Nude mice 493
management 512
sites for testing 262 Nursing care for leprosy patients 468
prevention of blindness in leprosy 517
starch iodine test 264 nursing intervention: care of eyes in
cataract 518
sweat test 264 leprosy 478
corneal hypoesthesia 517
testing for hot and cold sensibilities nursing: assessment of a leprosy
dry eye syndrome 518
263 patient 468
lagophthalmos with or without
tools for testing neuropathy in nursing: assessment during follow
corneal exposure 518
leprosy 261 up visits 471
potentially sight threatening (PST)
tools to assess autonomic NFI 264 post-assessment nursing
lesions 517
tools to assess motor NFI 263 intervention 469
uveitis and its sequelae 518
tools to assess sensory NFI 261 through examination 470
vision 2020 518
voluntary muscle testing (VMT) through interview 468
primary level eye care 519
263 nursing: assessment of activities of
secondary level eye care 519
neuritis in leprosy 253 daily living 471
tertiary level eye care 519
clinical presentations (types) of nursing: assessment of ‘risk’ status 471
Ocular lesions 510
neuritis in leprosy 256 nursing: intervention in leprosy
Opioids 406
mechanism of neuritis during deformity 475
Oral corticosteroids 392
deformity of lower limb 476
reactions 255 Oro-nasal defects 451
deformity of upper limb 475
mechanisms of neuritis across clinical Oropharynx, larynx and upper respiratory
massage and exercises for hands
spectrum of leprosy 254 tract 297
with paralytic deformity 475
neuritis associated with reactions 256 Oxidative stress and antioxidant status 95
massage and exercises for fingers
neuritis associated with disease 256
475 P
neuritis during reactions in leprosy
massage and exercises for thumb
255 Parsi Marriage act of 1936 567
476
neuropathic pain in leprosy 257 Pathological aspects 100
nursing intervention 475,476
pathological basis of neuritis in agranulomatous stage 102
use of splints for hand 476
leprosy 253 healed lesions 103
nursing: role in care of anesthetic limbs
silent neuritis/quiet nerve paralysis indeterminate leprosy 102
472
257 attributes influencing pathogenesis 101
anesthetic lower limb 473
proforma to record nerve function concept of spectrum 102
anesthetic upper limb 472
impairment (NFI) 265 classification or splitting of
nursing intervention 472
form for sensory testing of hands spectrum 102
role of nurse in care of women with
and feet 265 granulomatous stage 104
leprosy 478
motor function assessment of borderline lepromatous 107
leprosy and pregnancy/lactation 478
important nerves 266 borderline tuberculoid 107
status in society 478
proforma for recording NFI in eye status in family 478 fully developed granulomas in
266 role of nurse: care of indoor patients 479 leprosy 104
granuloma is often nonspecific 104 Post-treatment surveillance and relapses in Reaction severity assessment system
histoid leprosy 104 leprosy 357 (RSS) 282
lepromatous leprosy 104 Potential of community 528 Recombinant antigens of M. leprae 190
mid borderline (BB) 107 Potentially sight threatening (PST) lesions 517 Recommendations for research trials 361
tuberculoid leprosy 105 Prednisolone 395 Reconstructive surgery 433,438
histopathology 100 Pregenomic study of a few enzymes of Recording, reporting and monitoring of MDT
need for biopsy/histopathology 100 M. leprae 90 and post-treatment follow-up 368
role of immunohistochemistry 101 Pregnancy and leprous neuropathy 318 additional indicators for case
involvement of other organs 113 Pregnant/ lactating woman with leprosy detection 370
eyes 114 develops type 1/type 2 geographical information system 372
kidneys 115 reactions 322 indicators for monitoring nlep functions
larynx 113 Pregnant/lactating woman is diagnosed to 369
liver 114 have leprosy 322 indicators for patient management and
lymph nodes 113 Previous therapy 490 follow-up 370
nose 113 Primary and secondary deformities 429 number of relapses reported during
spleen 114 Primary level eye care 519 year 370
testes 114 Private sector (business and industry) 532 proportion of new cases correctly
leprosy reactions 109 Probes targeting DNA 191 diagnosed 370
erythema nodosum leprosum Program focus in relation to leprosy 555 proportion of patients who develop
(ENL) 111 Progress with leprosy situation 32 new or additional disability 370
lucio leprosy 112 Progression and evolution 123
reversal reaction (RR) 110 proportion of treatment defaulters
Progressive muscular atrophy (PMA) 221 370
nature of granuloma 102
Promoting community awareness and records used in clinics treating
regressing lesions 108
participation 533 leprosy 371
relapse 112
Promoting self-help 558 monitor drug stock 372
Pathomechanisms of nerve damage 237
Psoriasis 200 strengthening evidence-based
autoimmune type of damage 242
Psychiatric disorders 221 decision-making 369
entry of M. leprae and its spread into
Psychosocial aspects 559 from evidence to decision-making
nerves 239
categorization of leprosy affected 369
general features of nerve damage in
persons 562 from information to evidence 369
leprosy 237
community based rehabilitation 561 Referral services and long-term care 40
immunological aspects of nerve
empowerment 563 Refsum’s syndrome 218
damage 242
infection of Schwann cells by M. leprae identifying target groups for Regimens for special situations (WHO) 21
240 socioeconomic rehabilitation 562 363
insidious nerve damage 244 institution based rehabilitation (IBR) 561 Registered prevalence 43
leprosy reactions and nerve damage rehabilitation 561 Regressing lesions 108
244 social and economic reintegration Rehabilitation 525
role of inflammatory cytokines in nerve through rehabilitation 561 arrangements for delivery of CBR
damage 243 stigma 559 services 533
role of mycobacterial antigens in nerve self settled leprosy colonies 560 advocacy 533
damage 243 social and economic integration 560
intervention 533
type of degeneration seen in leprous social and economic rehabilitation
networking with community and
nerves 240 560
other organizations 534
Paucibacillary leprosy 155,186,355,360 ultimate objectives of socioeconomic
promoting community awareness
Peripheral nerve trunk enlargement 153 rehabilitation 562
and participation 533
Peripheral nerves 231 Public pressure for isolation 588
assistive devices/technologies 526
Peripheral neuropathy 211 Pune district leprosy committee (PDLC) 578
basic principles of CBR 529
Persisters 339,354,486 Pure neuritic leprosy 164
empowerment 529
PGL-1 antibodies 485 Pyridine extraction 78
participation 529
Physical measures 430
partnerships 531
Pityriasis alba 197 Q
capacity building 527
Pityriasis versicolor 200 Quick test to assess motor damage in CBR and poverty reduction9 527
Plantar ulcers 434 hands 427 CBR challenges 534
Planter corns 222 Quinolones 321
Polyarteritis nodosa 214 changing scenario of leprosy
Polymorphic light eruption 198 rehabilitation 528
R community based rehabilitation 527
Porphyrias 214
Portal of 29 Radial cutaneous nerve 251 institution based rehabilitation (IBR) 526
entry 29 Radial nerve 215,249 leprosy and CBR 528
exit 29 Raising awareness 530 potential of the community 528
Post-assessment nursing intervention 469 Ramsay-Hunt syndrome 217 rehabilitation as a component of primary
Posterior tibial nerve 250 Rare variants of leprosy 163 health care 525
Posters 555 Raynaud’s disease 222 rehabilitation provision 525
Index 623
sectors and roles for development 532 Ribosomal RNA and RRNA genes based genomic probes and gene
communities 532 probes 192 amplification assays for
families of people with disabilities Ridley-Jopling classification 147 M. leprae 191
532 Robert Cochrane(1899-1985) 17 Mycobacterium leprae specific lipid
governments (local, regional, Rogi Kalyan Samities 42 antigen 190
national) 532 Role of NGOs in national leprosy probes targeting DNA 191
people with disabilities 532 eradication program 572 real time PCR 192
private sector (business and local voluntary organizations 584 recombinant antigens of M. leprae
industry) 532 major ngos working in partnership with 190
Rehabilitation and social issues 523 NLEP 572 ribosomal RNA and RRNA genes
Relapse in leprosy 483 anandwan 577 based probes 192
differences between reversal reaction bombay leprosy project—a model Serological criteria 490
and relapse 488 NGO 579 Serological profile in leprosy 92
relapse vs resistance 488 disability care 579 Serum enzymes 95
diagnosis 489 Gandhi Memorial Leprosy Serum protein profile 93
clinical criteria 489 Foundation (GMLF) 575 Severe dapsone toxicity 365
bacteriological criteria 489 Hind Kushth Nivaran Sangh 576 Severity of type 2 reaction 282
therapeutic criteria 489 IEC activities 580 Sex 121
histopathological criteria 490 International Federation of Short course chemotherapy in leprosy 361
serological criteria 490 Antileprosy Associations (ILEP) Silent neuritis/quiet nerve paralysis
treatment 490 572 253,257
type of leprosy 490 International Leprosy Union (ILU), Size of biopsy 181
previous therapy 490 Pune 575 Slit- skin smear 82,154,176,330
drug-resistance 490 Involvement of ILEP in the NLEP Social and economic integration 560
relapse vs reactivation 489 (2007-2012) 574 Social and economic rehabilitation 560
relapse vs reinfection 489 key areas of project activities 579 Social aspects 565
differential diagnosis 487 key modalities in leprosy care and Social factors 29
differences between ENLS and rehabilitation 582 Social implications of disease 593
relapsed fresh papules and missionaries of charity, Gandhiji Social mobilization of laps 591
nodules 487 Prem Nivas, Titagarh 577 Social server by heart and a philanthropist
histopathology 485 Novartis Comprehensive Leprosy 599
histopathology of relapsed lesions in Care Association (NCLCA) Social stigma and its effects 566
MB leprosy 485 582 Socioeconomic status 122
histopathology of relapsed lesions in PB Pune District Leprosy Committee Sodium thiosulfate solution 182
leprosy 486 (PDLC) 578 Solid bacteria 77
high initial BI 487 rehabilitation 580 Soluble protein component obtained from
HIV infection 487 Rom single dose regimen 362 cell wall of M. leprae 414
inadequate therapy 486 Rom trial (intermittent therapy) 362 Somnolence 395
irregular therapy 486 Spectrum of clinical presentation in children
lepromin negativity 487 S 326
monotherapy 487 S-100 stain for Schwann cell 184 Spina bifida 221
predisposing factors for relapse 486 Scid mice 493 Spleen 114,300
relapse in MB leprosy 487 Sclerodactyly 221 Splints 431,457,476
relapse in PB leprosy 487 Second line drugs in pregnant woman with Standard dose schedule 388
relapse interval 486 leprosy 322 Starch iodine test 264
immunologic tests for relapse 485 Secondary level eye care 519 Steroid replacement 395
interleukins-based assays 485 Self settled leprosy colonies 560 Strain differences 80
molecular assays 485 Self-advocacy 530 Structure and electrophysiological studies
ND-O-BSA ELISA 485 Self-care 557 of peripheral nerve 227
microbiological aspects 484 Sensoriautonomic neuropathy 219 electrophysiological study of peripheral
in vitro techniques for assessing Sensory impairment 262 nerves in leprosy 232
viability 484 Sensory nerve conduction study 234 application of electrophysiological
in vivo techniques 484 Sensory testing 261,427 studies in leprosy 234
molecular techniques 485 Serological and molecular diagnosis 189 electrophysiological study by EMG
relapse rate 484 detection 192 232
several definitions have been proposed future perspective 193 motor nerve conduction study 234
for relapse in leprosy 483 serodiagnosis 189 principle of nerve conduction
Religion 595 35 KD antigen serology 190 studies 233
Renal involvement and kidney function 94 future scope for immunoassays 191 sensory nerve conduction study 234
Reproductive system 298 gene amplification (PCR) structure and function of peripheral
Reversal reaction (RR) 110 techniques 192 nerves 227
Rhesus monkeys 497 genome of M. leprae 191 damage to peripheral nerves 231
mycobacterium leprae and neural Leprosy and pregnancy 313 Teratogenicity 394
predilection 231 activity of leprosy 316 Tertiary level eye care 519
nerve endings 230 bacillary load 317 Testes 114, 298
nerve supply to skin 230 clarithromycin 321 Thalidomide 321,392,395,404
Schwann cells and myelination of clofazimine 320 Therapeutics (medical and surgical), prophy-
nerves 227 corticosteroids 321 laxis and monitoring 333
structure of a nerve 228 course of leprosy in pregnancy 314 Thiacetazone 342
structure of axon 227 alterations in immunological Thromboembolism 395
types of nerves 229 response 314 TNF-alpha gene 52
Subcutaneous nodules 168 altered secretion of steroids 314 Toll-like receptor 2 (TLR2) 53
Superficial peroneal nerve 252 cell mediated immunity 315 Toxic/nutritional conditions 220
Support of National Rural Health Mission 42 humoral immunity 315 Transfer factor 414
Supraclavicular nerves 251 metabolic changes 314 Transmission 29,30,326
Supratrochlear, supraorbital and infraorbital reasons for altered course of
Transplacental infection 319
nerves 250 leprosy in pregnancy 314
Transporters associated with peptide
Sural nerve 252 dapsone 320
loading (TAP) 52
Surgery 406 drug therapy of leprosy during
Transports and leprosy patients 568
nerves 427 pregnancy 320
Trichiasis 509
plantar ulcers 436 effect of leprosy on fetus 319
Tricyclic antidepressants (TCA) 405
Surgical decompression 390 experimental evidence 319
Trigeminal nerve 215
Surgical management 508 transplacental infection 319
Survival by rough and tough means 589 first presentation of leprosy in Trophic changes 130
Sustainability 531 pregnancy 316 Tuberculoid contamination 172
Sweat test 185,264 gonadal involvement in leprosy 313 Tuberculoid leprosy (TT) 105,156
Sweating 131 females 313 U
Syringomyelia 221 males 313
Systemic examination 141 impact on fetus 319 Ulnar nerve 215,249
Systemic involvement and special situations impact on infants, childhood and Uniform MDT (U–MDT) 363
in leprosy 291 adolescence 320 Untreated patients of LL/BL presenting with
Systemic manifestations 293 impact on lactation 320 ENL 391
bacillemia in leprosy 293 impact on placenta 320 Unusual pattern of vesiculobullous type 2
bones, joints and muscles 294 minocycline 321 reactions 280
cardiovascular system 300 NSAIDs 321 Uremia 214
central nervous system 300 practical management 322 Uveitis and its sequelae 518
endocrine glands 299 pregnant/lactating woman is
eyes 296 diagnosed to have leprosy 322 V
gastrointestinal tract 298 second line drugs in pregnant Vasculitic conditions 214
hematology and serology 301 woman with leprosy 322 Village Health and Sanitation Committee 42
kidneys 299 with leprosy develops type 1/type 2 Visceral involvement and complications 123
lower respiratory tract 298 reactions 322 Vision 2020 518
lymph nodes, bone marrow, spleen 300 woman with leprosy becomes Vitamin B complex deficiency 220
oropharynx, larynx and upper pregnant 322 Vitamin D receptor 53
respiratory tract 297 pregnancy and leprous neuropathy 318 Vitiligo 198
reproductive system 298 neuritis in RR 319
Vocational rehabilitation 540
female reproductive system 299 neuritis in type 2 reaction 319
Voice of awakening 569
male reproductive system: testes quinolones 321
Voluntary muscle testing (VMT) 263
298 reactions and pregnancy 317
Leprosy and HIV infection 305 types of reactions 317
W
complications, reactions, relapse and relapse of leprosy 317
outcomes 306 rifampicin 75 320 Wallerian degeneration 212
immunology and histology in leprosy- thalidomide 321 Winds of change 569
HIV coinfection 308 type 1 reactions 317 Woman with leprosy becomes pregnant 322
impact of leprosy on HIV progression type 2 reactions 318 Wrinkled face 437
and antiretroviral therapy 307
iris 309 T
Y
predominance of multibacillary (MB) or Tabes dorsalis 222
paucibacillary (PB) 306 Yaws 222
Talking 554
prevalence and diagnosis 305 Technique
response to treatment 307 Z
FNAC 187
antileprosy treatment 307 physiotherapy 456 Ziehl-Neelsen method 177
treatment of reactions 307 slit-skin smear 177 Zinc 414

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IAL TEXTBOOK OF

Mahatma Gandhi serving Pandit Parchure Shashtri (a renowned

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD

IAL Textbook of LEPROSY

© 2010, Jaypee Brothers Medical Publishers (P) Ltd.

First Edition: 2010

Typeset at JPBMP typesetting unit

Printed at Ajanta Offset

Hemanta Kumar Kar

Hemanta Kumar Kar

Hemanta Kumar Kar MD, MNAMS Mehervani Chaduvula MD

Krishnamurthy Venkatesan MSc, PhD Nirmala Deo MSc, PhD

Utpal Sengupta PhD, FNASc, FAMS Vikram Mahajan MD

Vijay K Pannikar Vivek V Pai MBBS, DVD, FCGP

Section 2: Basic Scientific Considerations and Pathology

Section 3: Clinical and Laboratory Diagnosis

16. Differential Diagnosis of Dermatological Conditions ......................................................................................197

Section 4: Disease Complications (Nerve Involvement,

Section 5: Systemic Involvement and Special Situations in Leprosy

Section 6: Therapeutics (Medical and Surgical),

Section 7: Miscellaneous Issues in Leprosy

Section 8: Rehabilitation and Social Issues

Section 9: Future Prospects

1 The Disease History

Fig. 1.7: Schematic of Gerlach-Dehio of neuropathogenesis. Ascent

Fig. 1.8: GA Hansen (Left); Hansen’s depictions of intracellular bacilli

Fig.1.11: Paul Unna (Left); Depiction of the “grenz”

Fig.1.10: Georg Sticker (Left) and his demonstration of bacilli in the

Rogers was one of the most prominent tropical medicine

OTHER ICBELRA INITIATIVES

graduate medical curriculum. He was thus a pioneer in

THE BHORE COMMITTEE

INTRODUCTION treatment the persons affected with leprosy can lead

Treatment Completion Rate Age

Migration Genetic Factors

Immunity Familial Clustering

ENVIRONMENTAL FACTORS Portal of Exit

Source of Infection In utero Transmission

The Number of New Case Detected in Registered Prevalence

INTRODUCTION 3. Low molecular weight proteases 2 and 7 (LMP2 and

The MHC class-I molecule is a heterodimer of a heavy

CONCLUSION the alleles of different genes (See Table 5.2) that an

Indira Nath, Mehervani Chaduvula

INTRODUCTION from leprosy patients was described in great detail by Indian

S. No Gene/Function of product Position/ Country Reference Conclusion

LEPROSY REACTIONS increased cellular immune responses may be beneficial,

IMMUNOGENETICS OF LEPROSY agonists whereas, S 248 variant enables normal functioning.

INTRODUCTION molecular biological studies, carried out in the present era.

Cell Wall phthiocerol dimycocerosates as well as phenolic glycolipids

in these organs favors disintegration. The transformation

However, some nonleprosy mycobacteria have been

Mouse Nonhuman Primates

Krishnamurthy Venkatesan, Nirmala Deo

INTRODUCTION MYCOBACTERIUM LEPRAE, THE

HEMATOLOGICAL, SEROLOGICAL AND Serological Profile in Leprosy

INTRODUCTION patients. These are subsequently stained with simple dyes

GRANULOMATOUS STAGE are round cells appearing non-aggressive, as if peace time

Fig. 9.5: LL leprosy. Lepromatous granuloma with bacilli (pink color)

Fig. 9.8: Histoid leprosy. Spindle shaped cells arranged in bundles

Some of the cases show areas with predominately

Macrophages kill the bacilli, process the antigens and

by concentric perineural cell proliferation presenting a cut-

The process of regression is well appreciated in macrophage

Fig. 9.18: Regressing epithelioid cell granuloma (H&E x 100)