Thesiss University of Amsterdam, Ref.-With Summary in Dutch

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Clinical aspects of nerve damage in leprosy

Theuvenet, W.J.

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Citation for published version (APA): Theuvenet, W. J. (2002). Clinical aspects of nerve damage in leprosy.

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MWgMMfl lHANNE SS THEUVENET Clinicall Aspects of Nerve Damage in Leprosy Notess from Anandaban Leprosy Hospital, Nepal

Klinischee Aspecten van Zenuwbeschadiging door Lepra Notitiess vanuit Anandaban Leprosy Hospital, Nepal

Willemm Johannes Theuvenet

Clinicall Aspects of Nerve Damage in Leprosy Notess from Anandaban Leprosy Hospital, Nepal

Klinischee Aspecten van Zenuwbeschadiging door Lepra Notitiess vanuit Anandaban Leprosy Hospital, Nepal

ACADEMISCHH PROEFSCHRIFT

terr verkrijging van de graad van doctor aann de Universiteit van Amsterdam opp gezag van de Rector Magnificus prof.mr.. P.F. van der Heijden tenn overstaan van een door het college voor promoties ingesteldee commissie, in het openbaar tee verdedigen in de Aula der Universiteit opp donderdag 21 november 2002, te 10.00 uur

door r Willemm Johannes Theuvenet geborenn te 's-Gravenhage. Promotiecommissie: :

Promotores:: prof.dr. W.R. Faber prof.dr.. M. Vermeulen

Overigee leden: prof.dr. C.M.A.M. van der Horst prof.dr.. F.G.I. Jennekens prof.dr.. A.S. Muller prof.dr.. CS. Smith prof.dr.. M. de Visser dr.. J.H. Richard us

Faculteit: : Geneeskunde e

Theuvenet,, Willem Johannes

Clinicall Aspects of Nerve Damage in Leprosy; notess from Anandaban Leprosy Hospital, Nepal.

Thesiss University of Amsterdam, ref.-with summary in Dutch

Printer:: University of Amsterdam Graphic Productions, The Netherlands; p. 180. ISBNN 90-9016224-0

©© 2002 WJ.Theuvenet, Apeldoorn, The Netherlands. All rights reserved. No part of this publicationn may be reproduced or transmitted in any form or by any means, electronic or mechanical,, including photocopy, recording, or any information storage and retrieval system,, without permission in writing from the copyright owner.

Cover:: Painting of the Kathmandu valley and Anandaban Hospital by Sanu Kaje. Privatee Collection. Forr Sikiliya, Ganga, Suraj Kala and Raj Kumar, mayy their grandchildren see a world freee of leprosy. 6 6 TABLEE OF CONTENTS

TABLEE OF CONTENTS

Chapterr 1 Introduction:

1.. Nepal 1.1.. History 13 1.2.. Topography and Geography 15 1.3.. Climate 16 1.4.. Population 17 1.5.. Economic Situation 18 1.6.. Health Situation 19

2.. Leprosy in Nepal 2.1.. History 20 2.2.. The Social Consequences of Leprosy 21 2.3.. Leprosy in the World 24 2.4.. Leprosy Control Programme in Nepal 26

3.. Clinical Aspects of Leprosy 3.1.. Introduction 29 3.2.. Microbiology 29 3.3.. Immunology 30 3.4.. Classification 35 3.5.. Diagnosis 37 3.6.. Treatment of Leprosy 38 3.7.. Reactions 39 3.8.. Treatment of Reactions and Peripherall Nerve Function Loss 43 3.9.. Prevention of Impairment and Subsequent Disability (POID) andd Rehabilitation 44 3.10.. (Reconstructive) Surgery in Leprosy 47 3.11.. Eye Problems in Leprosy 52

4.. Scope of this Thesis 53

Chapterr 2 Mass Survey of Lalitpur District 55

Chapterr 3 Neuritis of the Lateral Femoral Cutaneous Nerve in Leprosy 69

Chapterr 4 Change of Sensation in Leprosy after Nerve Decompression byy Selective Meshing of the Epineurium 77

7 7 TABLEE OF CONTENTS

Chapterr 5 Cytological Needle Aspiration of the Nerve for the Diagnosis off Pure Neural Leprosy 93

Chapterr 6 The Paper Grip Test for Screening on Intrinsic Muscle Paralysis

inn the Foot of Leprosy Patients 101

Chapterr 7 Risk Factors for Type-1 Reactions in Borderline Leprosy Patients 119

Chapterr 8 Contributions of Type-1 Reactions to Sensory and Motor Functionn loss in Borderline Leprosy Patients and the Efficacy off Treatment with Prednisone 129 Chapterr 9 Psychiatric Morbidity in People Affected by Leprosy in Nepal

Assessedd with the WHO Self-Reporting Questionnaire (SRQ-20) 143

Summaryy 159

Samenvattingg 165

Referencess 172

Acknowledgementss 184

Curriculumm vitae 184 FOREWORD D

FOREWORD D

Itt is impossible to write anything about leprosy in Nepal without putting the illness into the contextt that was created for it over thousands of years. To be involved in any attempt to eradicatee leprosy means, therefore, that you have to start looking beyond the bacillus responsible,, namely Mycobacterium leprae, to the historic, cultural, social, economic and geo- graphicc features of Nepal itself.

Too be diagnosed with leprosy in a country like Nepal means that one is struck by "the curse off God". This feeling often persists regardless of the level of education. The religious laws aree much the same as those applied by European Christians in the Mediaeval period. l This includess excluding patients from participating in religious activities, and thus contributing too the forced isolation from the rest of society. Religion and life here are entwined in the mostt intimate way.

Inn a country that is already ranked amongst the poorest of this planet, having leprosy often meanss the loss of economic security. This is aggravated when deformities take their toll - still thee case in about one-third of all patients. Families often break up and planned marriages aree cancelled. Female patients face great social and economic difficulties. Often they are left withh the responsibility for the children, and this in a society where females more than males needd the protection of the family. Althoughh leprosy treatment is provided free of charge to all patients, the infrastructure of thee leprosy control programme is such that many patients have to travel by foot for many dayss and over considerable distances to collect their medicines or to receive treatment. In manyy regions the roads and passes are blocked by snow fall for many winter months, while duringg the monsoon season the rivers have high levels of water. This often prevents patients fromm attending clinics. Most of the patients are on the lowest steps of the economic ladder, thereforee the cost of a bus ticket to collect their anti-leprosy drugs or to replace damaged footwearr can be far out of their price range.

Effortss to reduce the existing stigma, to provide health education and to stimulate self-care aree made harder by the high illiteracy rate.

Addedd to this the many complications of immunological and micro-biological features of thee disease and you may get the impression that being involved in the treatment of leprosy patientss in Nepal is a disheartening enterprise. However, the opposite is true.

Thiss thesis may hopefully reflect some of the enthusiasm felt when one realises that there aree ways to lighten the burden of this disease. It is indescribable to reflect on how much we cann learn from the patients when we join their struggle against the disease.

9 9 FOREWORD D

Anandabann Hospital enjoys an excellent co-operation with several staff at the Ministry of Healthh and especially with the staff of the Leprosy Control Programme of His Majesty's Governmentt of Nepal. Ultimately, it will be through their dedication and efforts that leprosyy will be eradicated in Nepal.

Reference: : 1.. Toth-Ubbens M. Verlorenn beelden van miserabele bedelaars. Dee Tijdstroom b.v. Lochem, Netherlands. 1987.

10 0 Chapterr 1

Introduction n

11 1 CHAPTERR 1

12 2 INTRODUCTION N

Ï.NEPAL L

1.11 HISTORY

Thee history of Nepal dates back to ancient time. Legend has it that Manjusri Bodhisattwa fromm China came on a Pilgrimage to worship Swayambhu. When he reached the top of Nagarkott he saw flames constantly emanating from Swayambhu in the midst of the lake "Nagarad."" Eager to reach the Divine Lotus he drained the lake by cutting the lowest part off the mountain thus creating the Kathmandu valley. The founder of Buddhism, Shakyamunii Gautama Buddha, was born in 560 BC in Rupandehi (Lumbini).

Thee period of 350 to 630 AD, known as the Lichavi period, is considered in many ways to bee the Golden Age in the history of Nepal. Until the 12th century the majority of hill tribes off Tibeto-Burman origin lived in small autonomous chiefdoms. Trade with Tibet exposed themm to Tibetan traditions of animism and later to Tibetan Buddhism. In the early 13th centuryy the Islamic Mogul invaded North West India. The high caste Hindu Rajput nobil- ityy fled to the North and East into the contemporary Far West region of Nepal, bringing withh them their fourfold Hindu caste system with the attendant Brahmans (the highest caste off the priests and teachers), the Kshatriyas (the second highest rulers and warrior's caste of whichh the present caste name of Chetri is derived), the Vaisya (merchants and traders) and thee Sudra (farmers, artisans and labourers). The fifth class of untouchables are the outcastes andd the socially polluted like those who are diagnosed with leprosy. The Brahmans have the strictestt rules with regard to purity and leprosy beggars will need to remove their leather pro- tectivee footwear before being allowed to approach the house for receiving alms.

Afterr the 14th century Nepal remained fragmented into a group of small prosperous king- domss for centuries. The present kingdom was created about 200 years ago when the Gorkha Kingg Prithvi Narayan Shah annexed the Eastern and Western hill states. This expansion gave himm control over the major trade routes and the Terai with its sources of high revenue. The near-feudall rule of the Rana Prime Ministers dynasty isolated Nepal in the 19th century fromm the outside world and all their developments. The Ranas were actively opposed to pop- ularr education and engaged in a period of intensive Hinduisation. Theyy laid the foundation for what till today is called: "Nepal; the only Hindu Kingdom in thee world", introducing Hindu religious laws which prohibit leprosy patients from entering aa temple and exclude them from religious ceremonies, this in a country where religion is absorbedd in every aspect of life.

Att the time that the fight for Independence was gaining ground in India, discontent with the autocraticc regime of the Ranas spread in Nepal. As long as British rule in India existed there wass litde hope for sympathy from that side, but after India's Independence in 1947 all activ- itiess against the regime of the Ranas were carried out with backing from India. Under the

13 3 CHAPTERR 1

rulee of the Rana Prime Ministers the Kings of the Shah Dynasty had become nominal fig- ureheadss and virtual prisoners, but King Tribhuvan still enjoyed the sympathy of his people.

Inn November 1950, on the pretext of going on a hunting party, the King fled with almost hiss whole family to the Indian Embassy in Kathmandu and took political asylum there. The Nepalii Congress Party launched a country wide armed revolution and Birgunj and Biratnagarr fell into their hands. Finally,, the Rana Government had to sit at a table with the Nepali Congress in Delhi. With thee Delhi agreement of November 1950, King Tribhuvan was restored to the throne and underr his leadership a cabinet was formed consisting of five ministers from the Rana side andd five ministers from the Nepali Congress. Dissatisfied with Parliamentary Democracy as itt functioned in Nepal, his successor King Mahendra did away with it and replaced it by whatt he called Panchyat Democracy in 1962.

Afterr considerable political turmoil in spring 1990 this Panchyat system1 of "indirect government",, also described as "partyless democracy2'", was abandoned and Nepal shifted again towardss democracy with King Birendra Bir Bikram Shah as constitutional monarch. On Aprill 16th the King appointed members of the previously illegal Democratic Movement to formm a new interim government. General elections were held in May 1991 in which the Nepalii Congress gained the majority. Shortly after they formed a new Government with a significantt number of Communists in the opposition. In the 1999 elections of the three majorr parties the Nepalese Congress Party (social-democratic) got 36.3 % , the Communist Partyy of Nepal-Unified Marxist-Leninists (communist) got 23%, and the Rastriya Prahantra Partyy (national democratic party, conservative) got 10.2 % of the votes. Since 1994 the dis- satisfiedd Maoist faction of the communist party went underground and since then their guerrillass have launched numerous attacks against military barracks and police stations throughoutt the country. Onn June 1st 2001 the Crown Prince Dipendra assassinated almost all members of the Royal familyy and the brother of the King, Prince Gyendra was crowned as the new King. Since thenn the Maoist guerrillas have greatly stepped up their attacks in an attempt to end the monarchy.. This has brought tourism, the major source of national income, almost to a completee standstill. Thee future will show whether Nepal will succeed in maintaining a stable democratic system whilee trying to uplift its fragile economy. Nepal, in spite of its Shangri-La image, is poorer thann Bangladesh with an average income of $214 per year, a population of about 22.6 millionn inhabitants, and a population growth of 2.6 %.

References: : 1.. Shrestha DB and Kansakar CB. Thee history of modern Nepal, Kathmandu, Amar Press; 1974. 2.. Thapa NB. Shortt history of Nepal. Kathmandu, Ratna Pustak Bhandar; 1981.

14 4 INTRODUCTION N

1.22 TOPOGRAPHY AND GEOGRAPHY.

Nepall is a landlocked country. It borders Tibet (China) in the North where the Himalayas formform a natural barrier. The other three sides are bordered by India. It is located on a longi- tudee 80°-88°.5' east and latitude 26°.30'-30° north. The total land area is 147,181 sq.km stretchingg over 800 km from east to west and between 150 and 250 km from north to south. Aboutt 71% of Nepal is hilly and mountainous. The highest mountain peaks in the world aree located in the northern area. Withh these geographical conditions it is no surprise that many leprosy patients find it diffi- cultt to remain ulcer free once they have lost the sensation and the muscle balance in their feet. Becausee three mountain ranges (from north to south: the Himalayan range, the Mahabarath Lekhh and the Churia range) run in the direction of the longitudinal axis of the country, there aree three typical regions in Nepal:

1.. The Terai; a strip of the Indo-Gangetic plain with an elevation of 150-300 meters con- tainingg the most fertile land in the country with rich deposits of alluvial soil and a belt of forest.. It represents roughly 20% of the country. 2.. The Trans-Himalayas or the "Hills." This is the most heavily populated part of the countryy and accounts for 43% of the country's land, this includes the valleys of Kathmandu, Pokharaa and Surkhet.

15 5 CHAPTERR 1

3.. The Inner-Himalayas or the Himalayan Highlands, range from 3000 to over 8000 meters,, lying on the northern border. There are three major river systems having their ori- ginn here: the Karnali River, the Narayani River and the Saptakoshi, draining respectively the western,, the central and the eastern part of the country. Each of these has a catchment area off about 12,500 square miles. With almost equal intermediate distances of about 180 miles thee three rivers continue their courses through the Terai plain to the northern part of India.

1.33 CLIMATE.

Thee climate is determined by its topography and by the monsoons. The Terai is subtropi- cal,, the hill region temperate and the inner-Himalayas have an alpine climate. Rainfall is abundant.. In general, in amount it decreases from east to west. The short monsoon (2 lh to 33 months) falls during the summer (June to September) and combined with melting snow causess excessive river levels. The dry season (September to June) coincides with the winter seasonn when there is almost no glacier water. The result is great changes in river levels over thee year. This is further influenced by the ongoing deforestation. As an example the Sapta Koshii River has a top level of 450,000 cusec and a minimum level of only 9000 cusec, a decreasee of 98%.] Aboutt one-third of all leprosy patients live in the hills and mountains where the roads and passess are frequently blocked by snowfall during winter. The remaining two-third live in the Teraii where high water levels during the monsoon can block their way to the nearest anti- leprosyy drug distribution centre. Apart from the present difficulties (mainly infrastructural andd financial) that the leprosy control programme of His Majesty's Government is facing, thee geographical and climatological situation of Nepal may be held responsible for the high defaulterr plus irregularity rate (48%) and disability rate (30% of all new cases)1'2 of the leprosyy patients in Nepal. Nepall is endowed with an enormous hydroelectric potential of some 83.00 MW, in theory. Lesss than 200 MW has been tapped to date, and Nepal remains a country with inordinately loww consumption of electricity. Anticipated rural electrification benefits have not yet mate- rialisedd and electrification has yet to generate significant fuel-wood savings3-.

References: : 1.. Report Leprosy Control Section, HMGG Nepal; 1988-1989. 2.. Annual report INF/HMG Westernn & Midwestern Regions of Nepal; 1989-1990. 3.. World Bank Nepall Policies for Improving Growth and Alleviating Poverty. Worldd Bank report No. 7418-NEP; 1988.

16 6 INTRODUCTION N

1.44 POPULATION.

Inn 2000 Nepal's total population was 22.6 million with an annual growth rate of 2.6 % betweenn 1995-2000. The average annual growth rate for the Terai is 4.1%, for the Terai urbann areas 8-12% and for the Hills and Mountains 1.5%. The proportion of the overall urbann population is rapidly increasing, amounting to 7.9% in 1998. In 1995 42% of the populationn was below 15 years. Thee current national literacy rate is 40%. But woman, many caste, ethnic and regional groupss and the poor have a much lower literacy rate. In 1995 two-thirds of the 6-10-year oldd children not enrolled in schools were girls.

Farmm income is the major source of household earnings accounting for 61% of total house- holdd income in 1996. Only about 17% of the total land area of the country is comprised of agriculturall land. The average size of landholding is only 0.24 ha, with, on average, more thann four land parcels per holding. Forty-five percent of the population lives below the absolutee poverty line.

Nepall has also provided shelter to migrants from both the north and south. Nowadays,, the Nepalese population is broadly classified into three major ethnic groups in termss of their origin: Indo-Nepalese, Tibeto-Nepalese and indigenous Nepalis. Up to 60 differentt ethnic groups, self-defined by clan names, are identified in middle Nepal (Frank, 1974)) while 25 languages are recorded in the 1981 Government census. Nepali, a language off Sanskrit origin, is actively promoted as the 'lingua franca' for the whole of Nepal and is thee only language taught in schools. This policy meets resistance from a number of minorityy ethnic groups like the Newars who fear that their cultural heritage will be lost. Inn the last two centuries Nepal has become increasingly a Hindu Kingdom with at the moment,, according to official figures, about 90% of the population subscribing to this religion.. This is at the cost of the Buddhists who now officially constitute only 5% of the population. . Nepall is, nevertheless, unique in the fact that religions have peacefully existed side by side overr the past centuries and to a unique degree are amalgamated now. Nepal has been describedd as the contact zone of "Indian Hinduism" and "Tibetan Buddhism". There are smalll minorities of Muslims and Christians. Naturall immunological resistance to leprosy varies amongst the different races 12 and in Nepall Indo-Aryan and Mongolian influences can be studied side by side, which is an almost uniquee situation. In the Hindu Caste system those affected by leprosy are regarded as "jutho",, meaning unclean, which positions them at the very bottom of the social ladder.

References: : I.. Bryceson A and Pfaltzgraff RE. Leprosy. . Churchilll Livingstone; 1979.

17 7 CHAPTERR 1

2.. Thangaraj RH. AA Manual of Leprosy. PRINTAID,, Delhi; 1983.

1.55 ECONOMIC SITUATION.

Feww countries began developing as late and with such meagre resources as Nepal.1' The averagee per capita income in the year 2000 was $214, while the GDP growth rate was on an averagee of 5.2% per year during 1991-1996, this with an annual rate of inflation of approximatelyy 10%. Approximately 45% of the population live below the poverty line. Thee unemployment rate is high at 14% (1997 figure). Thee natural resource base has been undermined by human and livestock pressures resulting mostt critically in extensive degradation of the country's forest and pasture land. A major constraintt to agricultural growth has been ineffective land irrigation, a problem already recognisedd in one of the first FAO reports on irrigation in Nepal, published in 1953.2 82%% of Nepal's agricultural production consists of food grains (rice, maize, wheat and mil- let). . Inn 1997 63% of the rural working day and 44.7% of the urban working day were spent in underemployment.. In view of the expanding labour force and the limitations for greater employmentt in agriculture, it is expected that this situation is likely to be aggravated in the future. . Forr over 90% of the population, agriculture is the primary source of sustenance, income and employment.. Two-thirds of the population are poor.3 Leprosyy patients who lose sensation of the extremities (about 33%) are in general incapable off remaining free from ulcers if they continue to farm their land; this results in increased disability.. Social isolation and disability may be the main reasons why leprosy patients contributee about 30% of the cash and non-cash household income while for non-leprosy patientss this is nearly 70%.4 Theree is considerable aid assistance from foreign programmes. Donors have financed about halff of Nepal's development efforts in the past. Whilee enrolments to schools have risen more than fivefold between 1965 and 1986, two- thirdss of Nepal's population still remains illiterate. This has major implications on the potentiall pace of development and on the success of health and population programmes.

References: : 1.. World Bank. Nepall Policies for improving Growth and Alleviating Poverty. Worldd Bank report No. 7418-NEP; 1988. 2.. Theuvenet S. Reportt to the Government of Nepal on irrigation. FAOO report No. 162; 1953. 3.. World Bank. Nepall Agricultural Sector Review. Worldd Bank report No. 7693-NEP; 1989.

18 8 INTRODUCTION N

4.. Cardinaili RJ.et al. Att the feet of Lord Vishnu: An ethnographic study of Leprosy in Nepal. Publ.Germann Leprosy Relief Ass. and The Netherlands Leprosy Relief Ass; 1982.

1.66 HEALTH SITUATION.

Approximatelyy 5.3% of GDP is spent on health. Three-quarters of this expenditure, however,, is made by households. The infant mortality rate in 1996 was 83.7/1000 for females andd 101.9/1000 for male live births. The child mortality rate was 56.5/1000 for females and 45.5/10000 for males, while in the same year the life expectancy for males was 57 years and forr females was 56 years. The maternal mortality ratio, 539/100,000, is one of the highest inn the world. As only 61% of the population has access to safe drinking water, the incidence off waterborne diseases continues to remain at unacceptable levels. Diseases such as diar- rhoea,, dysentery, worm-infestations, typhoid and jaundice are the major causes of high mor- talityy and morbidity, particularly among infants. The percentage of children underweight is 48%.. Prevalence of anaemia in pre-school children is 78% (1998). The incidence of tuber- culosiss is approximately 3.5 per 100 persons. Nearly three out of five households report that theyy do not have adequate access to health facilities and services.1

References: : 1.. UNDP. Countryy Report on Nepal; 1998.

19 9 CHAPTERR 1

2.. LEPROSY IN NEPAL

2.11 HISTORY.

Leprosyy could be the oldest disease known to man. In China1 the oldest reports of leprosy aree found in the ancient medical text, the Nei Ching ("Canon of Internal Medicine"). Traditionn ascribes its authorship to Huang Ti (2698-2598 BC), the legendary third emperor. Itss actual authorship is dated in the transition period of the Eastern Chou (771-255) and earlyy Chin (221-207) dynasties.

Inn India2 Sushruta is considered to be the father of Indian surgery. He is believed to have livedd at least two centuries before the birth of Buddha (563 BC). In his writings leprosy is referredd to as "Vat-Rathka" or "Vat-Shonita" and categorised among the diseases of the nerv- ouss system. It is also referred to as "Kushta" and as such is grouped under the diseases of the skin. .

Inn Nepal leprosy is known as "Khustro". Its local written history starts in AD 1857 in which yearr King Surendra Bir Bikram Shah Deva issues an order that all leprosy patients are to be isolatedd at a leprosarium near Khokana, with the provision of shelter, food and clothes. Khokanaa is a small village at the side of the Bagmati River. It is likely that in this period peo- plee affected by leprosy who were ostracised by family, neighbours and society had already settledd there. Khokana may have been chosen because the leprosy patients could beg for foodd from the worshippers of the Kathmandu valley on their way to visit Dakshin Kali, one off the most venerated deities in Nepal.

Att the start of the year 2000 there were in Nepal 13,572 registered cases of leprosy with a prevalencee of 5.7 per 10 000. In the year 1999, 18,693 new cases were detected with a detectionn rate of 78.7 per 100 000 inhabitants. On 1/7/1999 a total of 60,995 patients were mentionedd as released from treatment after Multi Drug Therapy (Rifampicin, Clofazamine and Dapsone). . Inn the 1970s the Integrated Community Health Programme was initiated in several districts withh the intention of moving towards full integration of the Leprosy Control Programme.

References: : 1.. Skinsnes OK., Chang PHC. Understandingg of Leprosy in ancient China, Intt J Lepr 1985; 53(2):289-307. 2.. Dharmendra. Notess on Leprosy Thee Ministry of health, 1960 Governmentt of India.

20 0 INTRODUCTION N

2.22 THE SOCIAL CONSEQUENCES OF LEPROSY.

Inn societies where leprosy is found, or has been known, the disease promotes different degreess of fear and abhorrence1'9 which can have grave consequences for those recognised as havingg leprosy. Differencess in the behavioural patterns of patients and community members are determined byy the differences in the social (thus cultural) perceptions of leprosy of each community.10 Identifyingg these differences is important in the selection of priorities, preventive strategies andd the interpretation of epidemiological data.

Womenn face the greatest burden as the diagnosis is often a reason to cancel an arranged marriage.. Leprosy has caused married women to be abandoned, often left with children to care for. . Furthermoree a woman can only normally function in Nepali culture within the boundaries off family life. The very protection she requires, she often loses when diagnosed with leprosy. Marriagee in Nepal is traditionally arranged by the parents; almost always in rural areas and stilll most common in the urban areas. AA survey in 1982 among leprosy patients11 showed that the overwhelming majority had takenn a partner of their own choice. Generally this was either another leprosy patient or someonee lower in caste hierarchy. This would indicate that their parents did not take the normall active part in the marriage process of their Leprosy children; either from lack of interest,, social shame, or the inability to find suitable partners. Thee traditional Hindu Wedding cannot be performed except in arranged marriages. The culminatingg point of the ceremony is the "Kanyadan" or gift of a virgin, in which cleanli- nesss in every sense is an important feature. Femalee leprosy patients complained that suffering from leprosy made the local priest refuse too perform these rituals at their weddings. Wee noticed at Anandaban Hospital that the majority of the referred young, female patients appearedd to have lost contact with their social background. A number of them were dis- couragedd by family members from returning to their paternal families, knowing that this wouldd present difficulties for their parents when arranging a suitable marriage for the remainingg brothers and sisters. These girls often married other more disabled leprosy patientss whom they had met at Anandaban, regardless of differences in original caste hierarchy. . Inn the above-mentioned ethnographic survey10 among the population of non-leprosy people,, it was revealed that 87% of the boys and 40% of the girls attended school. However of thee children of leprosy patients only 42% of the boys and 9% of the girls attended school. Sixtyy two per cent of leprosy patients who had children of school age who were not actively orr regularly attending school, admitted that the community had pressured them against sendingg their children to school. The remaining 38% stated that for economic reasons they weree unable to send their children to school.

21 1 CHAPTERR 1

Inn Bulu and Koluwa Districts the prime reason for not allowing the leprosy patients or their childrenn to attend public schools was that the children of leprosy patients would undoubtedlyy (!) become unable to function normally with the advancing disease, and therefore the needd to give them an education was denied. Thiss attitude reflected the assumption that once a person develops leprosy, he or she will becomee disabled and that children of leprosy patients would, of necessity, get leprosy.11 In Nepall the leprosy patient is regarded as "jutho," unclean, and will therefore be treated as an "untouchable",, which automatically implies a severe degradation in caste position. Att the beginning of the New Millennium opinion seems to be improving. However, the abovee cited study suggests that leprosy is still widely assumed to be highly infectious, hered- itaryy and incurable and that it is grossly deforming. Itt is still believed that leprosy is a divine retribution for sins or misdemeanours committed inn the past, or for offending the snake god which dwells at a corner of each field. It is also believedd that the disease can be caused by a curse, a spell or inhaling the smoke of the funeral pyree of another leprosy patient. Ass a result it is no surprise that very few Nepali health workers seek employment in the Leprosyy Control Programme as an optimal way of making a career. Those who have made thee step voluntarily, however, perform their work with exemplary care and dedication.

Inn Nepal rituals surrounding birth, life and death are all crucial to spiritual life. It is imper- ativee that an individual be disposed of in the manner prescribed by the regulations of one's castee or ethnic group. Leprosyy patients, like those who died unnamed or who committed suicide, cannot be cre- matedd but are buried or pushed over the cliff to provide carrion for other animals or birds. And,, as mentioned, it is believed that you can get leprosy from inhaling the smoke from the pyree of someone who has concealed the disease.

Thee stigma attached to leprosy often discourages patients from taking care of their hands andd feet in public. Those with loss of sensation or with muscle dysbalance are faithfully taughtt in every health education session that they should walk limited distances, inspect theirr feet regularly and do the exercises to prevent contracture of joints and muscles. Often healthh workers do not recognise that most patients try to conceal their affected limbs (unless thee patient has made begging his/her profession), and that walking along the paths it is not possiblee to inspect the feet in private. Thee same real life limitations apply to the advice of health educators to soak affected extremities,, scrape callous skin with a stone, and oil the skin while it is still wet. Onee mechanism for coping with the severe stigma associated with leprosy can be denial. Thiss was found in more than half of the "non-compliant" patients examined for a study of compliancee of leprosy patients in Pakistan.12 Inn this context it has to be remarked that the majority of the hospital inpatients, labelled as compliant,, often owe their hospitalisation to the fact that they have been markedly non- compliantt in the past.

22 2 INTRODUCTION N

Inn dealing with non-compliance in the early phase of disease and treatment, it has to be realisedd that this behaviour is often based on the fact that the patient is still making efforts too be part of a stigmatising society. Thee success of a Leprosy Control Programme and especially its disability prevention and communityy based rehabilitation components may be largely dependent on its ability to reducee stigma, to recognise mechanisms leading to early non-compliance and to deal with thesee problems in the most constructive way.

References: : 1.. Skinsnes OK. Leprosyy in Society I. Leprosy has appeared on the face. Leprr Rev 1964;35:21-35. 2.. Skinsnes OK. Leprosyy in Society II. The pattern of concept and reaction to Leprosy in oriental antiquity. Leprr Rev 1964;35:105-122. 3.. Skinsnes OK. Leprosyy in Society III. The relationship of the social to the medical pathology of Leprosy. Leprr Rev 1964;35:175-181. 4.. Shiloh A. AA case study of disease and culture in action: Leprosy among the Hausa in Northern Nigeria. Humm Org 1985;24:140-147. 5.. PedleyJC. Thee stigma of Leprosy in four countries. Leprr Rev 1972;43:94-95. 6.. Browne SG. Leprosy. . Actt Clin Geigy.Basle; 1965. 7.. Bijleveld I. Leprosyy in the Three Wangas, Kenya, stigma and stigma management. Proc.Roy.Trop.Inst.. Amsterdam; 1978. 8.. Waxier NE. Learningg to be a leper: a case study in the social construction of illness. Sociall contexts of Health, Illness and Patient Care. Mishlerr EG.editor. Cambridge University Press; 1981. 9.. Duncan ME. Leprosyy and procreation, a historical review of social and clinical aspects. Leprr Rev 1985;56:153-162. 10.. Fassin D. Influencee of Social Perceptions of Leprosy and Leprosy Patients on Public Health Programmes. IntJLeprl990;58(l):lll-ll4. . 11.. Cardinalli JR. et al. Att the feet of Lord Vishnu: An ethnographic graphic study of Leprosy in Nepal. Publ.. German Leprosy Relief Ass. and The Netherlands Leprosy Relief Ass. 1982. 12.. Mull JD. et al. Culturee and Compliance among Leprosy patients in Pakistan. Socc Sc Med 1989;29(7):799-811.

23 3 CHAPTERR 1

2.33 LEPROSY IN THE WORLD.

Leprosyy continues to be a serious public health problem in developing countries, particu- larlyy because: a.. The populations at risk of contracting the disease are very large. b.. More than one third of all leprosy patients face the threat of permanent and progressive physicall and social disability. c.. In most endemic areas the incidence rate is not coming down (yet).

Inn the year 2000, according to WHO figures, 1.5 billion people in South-East Asia and 0.8 billionn people in the Americas live in areas where leprosy is a public health problem, i.e. wheree the prevalence is over 1 case per 10,000 persons, and therefore individuals are runningg a significant risk of contracting the disease. Thee prevalence rates in South-East Asia and the Americas are respectively 3.8 and 1.1 per 10,000. .

Tablee 1. Global Leprosy situation by WHO Regions 2000.

WHO O Casess on treatment Numberr of new cases Curedd with MDT. REGION N (ratee per 10.000) (ratee per 1.000.000)

Africa a 64.4900 (1,0) 55.6355 (8,6) 645.576 6 Americas s 90.447(1,1) ) 45.5999 (5,7) 256.670 0 Southh East Asia 574.9244 (3,8) 621.620(41,3) ) 9.507.660 0 Westernn Pacific 13.7711 (0,1) 9.5011 (0,6) 273.161 1 Europe e 8466 (-) 1722 (-) 3.683 3 Total l 753.2633 (1,25) 738.2844 (12,3) 10.759.213 3

Lastt Available Update: 14 December 2000 http://www.who.int/lep/det.htm

24 4 INTRODUCTION N

Tablee 2. Leprosy trend in 32 endemic countries combined 1985-1999(1>

Endd of year Registered d Prevalence e Newlyy detected Detectionn r Cases s perr 10.000 Casess during year 100.000 0

1985 5 4003742 2 21.1 1 550224 4 29.0 0 1986 6 4047385 5 20.9 9 573790 0 29.7 7 1987 7 3968347 7 20.1 1 595145 5 30.2 2 1988 8 3729982 2 18.5 5 553597 7 27.5 5 1989 9 3500723 3 17.0 0 550743 3 26.8 8 1990 0 2916407 7 13.9 9 571792 2 27.3 3 1991 1 2361032 2 1.0 0 613016 6 28.7 7 1992 2 1820302 2 8.3 3 667133 3 30.6 6 1993 3 1485785 5 6.7 7 615830 0 27.7 7 1994 4 1171711 1 5.2 2 553768 8 24.4 4 1995 5 924064 4 4.0 0 552416 6 23.8 8 1996 6 838718 8 3.5 5 614822 2 26.0 0 1997 7 767893 3 3.0 0 676319 9 26.3 3 1998 8 787468 8 3.1 1 786312 2 30.7 7

1999(2) ) 720371 1 2.8 8 716673 3 27.8 8 TOTAL L 9.191.580 0

1)) Bangladesh, Benin, Brazil, Burkina Faso, Cambodia, Chad, Colombia, Congo, Democraticc Republic of Congo, Cote dTvoire, Egypt, Ethiopia, Guinea, India, Indonesia,, Madagascar, Mali, Mexico, Mozambique, Myanmar, Nepal, Niger, Nigeria, Pakistan,, Philippines, Senegal, Sudan, Thailand, Venezuela, Viet Nam, Yemen, Zambia.

2)) Latest available information for Brazil, Colombia, Democratic Republic of Congo,, Cote d'lvoire, Ethiopia and Zambia

Lastt Available Update: 14 December 2000 http://www.who.int/lep/det.htm

Att present, for WHO's operational purposes, only (!) those who need or are under chemotherapyy are considered as cases of leprosy. The leprosy patient, who is faced with the threatt of social isolation, nerve impairment and disability, may hold a completely different view.. As much as a leprosy patient can be invalidated by an ulcer, the quality of a Leprosy Controll Programme can be invalidated by officers who are mainly interested in MDT sta- tisticss and who neglect the primary concerns of those affected by leprosy. We,, therefore, need more knowledge of the mechanisms causing physical, social, economic andd spiritual disability in leprosy and more effective ways of preventing and controlling this.

25 5 CHAPTERR 1

Insufficientt figures are available on physical disability rates, while the present WHO disabilityy grading system1 which combines grade 3 and 2 of the previous WHO system2 , only makess it much more difficult to assess accurately the development of nerve impairment and disabilityy after starting chemotherapy. Thee ILEP reports do not include data on the social, economic and spiritual consequences of thee disease.

Evenn after having long killed the last Mycobacterium leprae, we will have to face "ex-leprosy (?)) cases" who are disabled and dehabilitated, and who will need continuous care for decen- niaa to come. Many highly specialised leprosy control programmes are already looking into possibilitiess of diversifying their activities, but one should be careful that this should never bee at the cost of existing care for the disabled leprosy patients.

Thee present WHO disability-grading system as recommended in 1988:

Handss and Feet: Gradee 0: No anaesthesia, no visible deformity or damage. Gradee 1: Anaesthesia present but no visible deformity or damage. Gradee 2: Visible deformity or damage present.

Eyes: : Gradee 0: No eye problems due to leprosy, no evidence of visual loss. Gradee 1: Eye problems due to leprosy present but vision not severely affected as a result of thesee (vision 6/60 or better; can count fingers at six metres). Gradee 2: Severe visual impairment (vision worse than 6/60; inability to count fingers at six metres). .

References: : 1.. World Health Organisation. WHOO Expert Committee on Leprosy, sixth report, TRS 768; 1988. 2.. World Health Organisation. WHOO Expert Committee on Leprosy, second report, TRS 189;I960.

2.44 LEPROSY CONTROL PROGRAMME IN NEPAL.

Thee Leprosy Control Programme of His Majesty's Government of Nepal was launched in 19655 and the National Leprosy Control Project established in the whole country in 1972.

Thee multi-drug therapy was introduced in 1982 and complete MDT coverage of registered casess was reached in the year 1995/1996, in all 75 districts. Since the introduction of MDT theree has been a gradual decrease in the prevalence of the disease. The child 'new case detectionn rate' and the disability rate among new cases have, however, largely remained the same.

26 6 INTRODUCTION N

AA revised MDT treatment for MB (Multibacillary) cases (12 month instead of 24 month doses),, and for single lesion PB (Paucibacillary) cases (single dose therapy) was started in Januaryy 1998. In July 1999, according to the WHO figures of Nepal, in a population of aboutt 22 million inhabitants the prevalence was 19525, the new case detection 18569, the neww case child rate 5.8%, the new case WHO grade 2 disability rate 8.7%, the new case MB proportionn 56.1%. 60995 patients were recorded as cured with MDT.

Inn the Joint HMG/WHO/NGO's Report of an Independent Evaluation of the National Leprosyy Control Programme in Nepal in January 1996 l one of the recommendations was that,, in addition to the goal of elimination of leprosy through MDT, due attention should bee given to the prevention of impairment and disability, including the early diagnosis and properr treatment of reactions and neuritis. Inn the report the MDT completion rates for PB cases varied in the districts between 33 to 90%,, while for MB cases the range was 44 to 68%. It was concluded that treatment default ratess were very high. Recent figures of relapse rates are not available.

Inn the Eastern District Region and the Far West District Region (15 districts) the Leprosy Controll Programme is implemented with assistance from the NLR (de Nederlandse Leprastichtingg or the Netherlands Leprosy Relief Association). Inn Solukhumbu district the leprosy work is supported by the Himalayan Trust (Sir Edmund Hillary)) hospitals at Kunde and Phaphlu. In Okhaldunga, Palpa and Gorkha districts the leprosyy work is supported by the UMN (United Mission to Nepal) hospitals. Between 40- 50%% of all new cases seen at the regional clinic at Biratnagar come from India and most want too be treated in Nepal.

Inn the Central District Region, Anandaban Hospital, supported by TLMI (The Leprosy Missionn International), services 19 districts. It functions as a 120 bedded leprosy referral hospitall for the Central and Eastern Regions, and the Government of Nepal plans to appointt it as the National Leprosy Centre. It has a training centre and a M, leprae Research Centre.. It also runs an outpatient clinic for non-leprosy patients and a community health programmee for the district. Assistancee in Dhanusha and surrounding districts is given by the Nepal Leprosy Trust.

Inn the West and Midwestern District Regions, the INF (International Nepal Fellowship) assistss the Leprosy Control Programme in 31 districts by providing referral facilities at Green Pasturess Hospital, Pokhara. The INF also runs a training and rehabilitation programme. Patientss are referred by INF referral centres at Jumla, Surkhet, Ghorahi, and Baglung as well ass from two UMN hospitals at Tansen and Amp Pipal.

Thee National Leprosy Control Programme, The Leprosy Mission, The International Nepal Fellowshipp and the Dutch Leprosy Relief Association all co-operate excellently in the fields off training, technical assistance and research.

27 7 CHAPTERR 1

Nowadayss most programmes put more emphasis on disability prevention, disability control andd rehabilitation. These issues are traditionally regarded as being of secondary importance too the introduction of MDT.

Inn Nepal the average patient has little awareness of micro-organisms and therefore being put onn MDT and the consequent killing of M. leprae in the body has little appeal if it does not solvee the more practical problems like the fear of physical, social and economic disability.

Inn the future, with health education, disability prevention and rehabilitation, a large rehabilitationn programme may be of secondary importance in a Leprosy Eradication Programme (LEP).. These issues should be an integrated part of every LEP and should be addressed at thee time of diagnosis. In the first six months of treatment a patient faces the greatest risk of developingg reactions. There is also an increased risk of nerve damage at this time and con- sequentlyy non-compliance and defaulting from treatment.

Disabilityy prevention and control requires the involvement of all health workers.

References: : 1.. Joint HMG/WHO/NGOs Report of an Independent Evaluation. Thee National Leprosy Control Programme, Nepal. WHOO Project: ICP LEP 001, SEA/LEP/140; 1996.

28 8 INTRODUCTION N

3.. CLINICAL ASPECTS OF LEPROSY

3.11 INTRODUCTION

Itt is beyond the aim of this chapter to provide a complete up-date of all clinical aspects of leprosy.. Basic information is presented in order to make the following chapters accessible for thosee with little experience in the treatment of leprosy, while relevant new data are added wheree necessary. Leprosyy is a chronic infectious disease of man caused by the bacterium M. leprae. It is essen- tiallyy a disease of the skin and peripheral nerves but also affects other tissues. Too a great extent it can also be considered to be an immunological disease as the suscepti- bilityy to the disease, most symptoms and important complications are due to immune reactionss to the bacilli.

3.22 MICROBIOLOGY.

Inn vivo M. leprae is an obligate intracellular parasite residing and multiplying mainly in macrophagess and Schwann cells. It seems likely that the latter are not antigen presenting cells,, at least in the early stage of infection, and that bacilli lying within them are not rec- ognizedd by the host lymphocytes. One can get Schwann cells to present antigen in vitro: whatt is not known is whether this happens in vivo. M.M. leprae has an almost1 exclusive habitat in man, and is readily found inside cells in which otherr mycobacteria are rarely seen; it has very low virulence and it is non-toxic, so that damagee done to the host results solely from the host's inflammatory response.2 Thee frequency of subsequent development of clinical disease is dependent on various factors att present still largely unknown, but the majority of the infected cases develop a sub-clinicall infection and will never develop any signs of the disease. When, though, a susceptible hostt is infected, the type of leprosy which will develop, will be determined by the way in whichh the immune cells respond to the infectious challenge. The first testing place is likely too be inside the peripheral nerves, for leprosy bacilli have a predilection for neural tissue and theree the target is the Schwann cell, which they most likely reach via endoneurial blood vessels.3 3

Thee incubation period can vary from a few weeks to 30 years but in general falls between twoo and five years.4

References: : 1.. Valverde CR., Canficld D. et al. Spontaneouss leprosy in a wild-caught cynomolgus macaque. Intt J Lepr & Mycobact Dis 1998;2:140-8.

29 9 CHAPTERR 1

2.. Lucas SB. Mycobacteriaa and the tissues of man. Thee biology of the Mycobacteria Vol.3. Academicc Press 1998. p. 107. ISBN 0 12 582303 7. 3.. CreelA., Smith WC. Leprosyy transmission and mucosal immunity: towards eradication? LeprRev.l998;69(2):ll 12-21. 4.. Hastings, RC. Leprosy,, second edition. Churchilll Livingstone , ISBN 0-443-04405-8, 1994. p.39.

3.33 IMMUNOLOGY.

Lepromatouss leprosy patients show evidence of a specific failure of the cell-mediated immunee response to M. leprae. The cause of this is still unknown but in 1986 suppressor T-cellss were recognised in the blood of leprosy patients that are triggered by a group of M.M. leprae antigens (group I antigens) and act specifically to suppress responses to these antigens.. l Thee immunological responsiveness of circulating T lymphocytes to M. leprae as measured in vitroo by the lymphocyte transformation test (LTT) shows a strong correlation between the meann test values and the position of the disease in the spectrum.2 The response is the strongestt in TT leprosy and declines towards the LL pole where it virtually becomes negative.. A parallel responsiveness is found with the lymphocyte stimulation test (LST) in borderlinee patients where the strongest response is found in BT patients and the weakest in BL patients.3 3

Thee research into the immunological and serological aspects of leprosy are increasingly gain- ingg importance as they may help to answer the following clinical questions:

1.. Is it possible to identify parameters that correlate with an increased risk of developing reversall reactions and subsequent nerve damage? Leprosyy would hardly be a clinical problem would it not be for the nerve damage that it causess as a part of a reaction or as a "silent" neuritis. Especially the reversal or Type-1 reactionss are feared for the quick and sometimes dramatic onset of nerve involvement. Thee use of the anti-phenolic glycolipid-l (PGL-1) as an independent prognostic marker off reaction remains a matter of controversy, but at the Mycobacterium Research Laboratoryy of Anandaban Hospital, Paul Roche was the first to demonstrate that of all thee borderline patients with positivity to the IgM anti PGL-1 antibodies test and the leprominn test as well, 78% developed a reversal reaction at a later stage. Though this com- binedd positivity is found in only a minority of the borderline patients, it is of the great- estt clinical importance that a high-risk group has been identified and prophylactic meas- uress to control nerve damage can be considered.4 It would therefore be of interest to see whetherr the same correlation can be found with nerve function loss over the time of treatmentt as there are indications that PGL-1 plays a role in the induction of tumour

30 0 INTRODUCTION N

necrosiss factor during the natural infection.5 Perhaps the ML dipstick test6, a simple fieldfield essay to detect IgM anti PGL-1 antibodies, can be used for assessing this under field conditions.. Also patients with high levels of IL-lp appear to be more susceptible to the developmentt of reactions after the initiation of treatment.7

Theree is a great need to further develop these tools as corticostereoid treatment at the timee of a diagnosed type 1 reaction/silent neuritis only results in an "improvement" in a minorityy of cases while considerable numbers of patients suffer from further nerve functionn loss while on prednisone.8,9 One can only guess at the percentage of patients in whichh this "improvement" also leads up to restoration of "protective sensation" and "functionall muscle strength ".

2.. Is it possible to modulate the deficient cellular immune response to M. leprae ? Inn the WHO Immunology of Leprosy (IMMLEP) programme several investigations 10'n aree going on to assess the influence of either injected killed M. leprae alone or in combinationn with live BCG or of components of mycobacteria upon the immune system.. Various mechanisms have been proposed to account for the specific cellular immune deficiencyy in leprosy. Onee of these is based upon the lack of specific T cell cytokines. Though,, in general, the hypo-responsiveness of most lepromatous leprosy patients to M.M. leprae appears to be mediated by an absence of antigen reactive cells12 , it appears that thee addition of interleukin-2 to mononuclear cell preparations from lepromatous leprosy patientss sometimes restores the ability to respond to M. leprae in lymphocyte stimula- tionn tests.13 Interleukin-22 is of paramount importance for the proliferation of T cells in vitro and vivoo after specific antigen stimulation. Nogueira et al.14 found that peripheral blood lymphocytess of lepromatous patients failed to produce gamma-interferon upon exposure too M. leprae and detected that this deficiency was restored by the addition of purified humann interleukin-2 to the lymphocyte cultures in vitro. Further studies show differencess in the degree of proliferative responses and gamma-interferon production in lepromatouss leprosy lymphocytes after addition of interleukin-2, suggesting heterogeneity inn the (still poorly understood) causes of immune deficiency in this category of patients.

Inn 1989 in a collaborative study15 with the Ministry of Health of His Majesty's Govern- mentt of Nepal, the Rockefeller University (New York), the Dartmouth Medical School (Neww Hampshire) and the Gillis W. Long Hansen's Disease Center (Louisiana), we injectedd at Anandaban human recombinant interleukin-2 intradermally in lepromatous leprosyy patients. Thee majority of the patients showed a significant upgrading of their disease according too clinical, histopathalogical and bacteriological parameters. Withinn two months, skin slit smears showed a 0.5 log or greater reduction in 12/14 patientss with a mean of 0.65 log units. Historical controls in this Nepalese population

31 1 CHAPTERR 1

showedd a 0.5 log unit reduction following multidrug therapy in a period of 12 months. Itt can therefore be concluded that the administration of interleukin-2 upgrades the immunee response to M. leprae

3.. Is it possible to find tools sensitive enough for the early detection of leprosy? Antibodyy molecules do not bind to the whole of an infectious agent. Because of their specificityy in recognition, each antibody molecule tends to bind to only one of the many antigenn molecules on the microorganism's surface. Each antibody then again binds to a restrictedd part of the antigen molecule, called an epitope. Antibodies are specific for the epitopess rather than the whole antigen molecule and different antibodies to an antigen oftenn bind to epitopes that overlap on the antigen surface. Antibodies against the cap- sularr phenolic glycolipid (PG-1) are highly specific to the M. leprae. The serum levels of thesee antibodies to these M. leprae specific capsular epitopes correlate well with the type off the disease within the spectrum. As the levels of IgM leprae anti-PG-1 antibodies cor- relatee well with the bacterial load of M, leprae, it is no surprise that these levels are higher inn untreated than in treated patients. In a majority of new MB patients, who were ini- tiallyy highly IgM anti-PG-1 seropositive, there is a 50% decrease of this antibody level inn the first 12 months of MDT.16 Becausee of the low sero-positivity rate among paucibacillary patients, this antibody assay iss not very specific in detecting PB leprosy though it could be helpful in assessing the indi- cationn for MB instead of PB-MDT for PB patients with an extensive form of the disease. Inn untreated paucibacillary leprosy patients in Nepal 20% have IgM anti-PGL-1 antibodies177 while this was 29% in untreated primary neuritic patients18 and 89% inn multibacillary patients.19 Itt was noted that the seropositivity rate and the antibody level against a common mycobacteriall carbohydrate antigen such as lipoarabinomannan (LAM), PG-1 and to thee 35kD peptide specific to M. leprae tend to rise with increasing extent of the disease whenn measured by the number of skin patches, by the number of nerves involved and withh a position closer to the lepromatous pole of the spectrum On the other hand half off the TT/BT patients are seronegative so that seronegativity cannot exclude leprosy as aa cause of peripheral neuropathy.

AA more recent development is the use of the polymerase chain reaction (PCR) for the (oftenn several million fold) multiplication and so the much easier demonstration of the presencee of very small quantities of A/, leprae specific DNA fragments in the body.20 The over-alll detection rates of M. leprae in biopsy samples of leprosy patients are lower with standardd PCR than when histopathology examination is used.2123 A more specific tech- niquee is the reverse transcriptase polymerase chain reaction (RT-PCR) in which the start- ingg template is not DNA but a specific RNA fragment, which with the use of reverse transcriptasee is translated in copy DNA (cDNA), which, in turn and with the help of DNAA polymerase, can be made ready for multiplication like in the standard PCR. When aa RT-PCR assay is used, targeting the 16S rRNA fragment ofM.leprae, 53 % of acid fast

32 2 INTRODUCTION N

bacilluss negative biopsy specimens are RT-PCR positive.24 Althoughh it is encouraging to observe that some serology tests and the reverse transcrip- tionn (RT)-PCR assay may demonstrate M. leprae in a proportion of the paucibacillary patients,, tools that are sensitive and specific enough to detect early leprosy are still lacking.

4.. Is it feasible and necessary to develop and to implement a vaccine against leprosy? Inn the year 2000 according to WHO figures 1.5 billion people in South-East Asia and 0.88 billion people in the Americas live in areas where leprosy is a public health problem, i.e.. where the prevalence is over 1 case per 10 000 persons and therefore individuals are runningg a significant risk of contracting the disease. The prevalence rates in South-East Asiaa and the Americas are respectively 3.8 and 1.1. per 10,000.25

Thee ratio for risk of contracting the disease for contacts of lepromatous cases against contactss of non-lepromatous cases and non-contacts have been described for the Philippines266 to be 8:2:1 and for South India27 to be 9.5:3.7:1. Theoretically,, vaccination of especially the contacts could greatly assist in eradicating the disease.. But the slow multiplication time of M. leprae will create the need of a long follow-upp period of a large vaccinated population being at risk for assessing its protection ratee against a similar non-vaccinated population. Multiplee vaccine trials are being conducted in several countries2830 but at present, the priorityy of vaccine strategies for leprosy has diminished, since the costs of development andd implementation far outweigh the costs of controlling ("eliminating") the disease withh MDT.

References: : 1.. Stanford JL. Immunotherapyy for mycobacterial disease, in:: The biology of the Mycobacteria Vol. 3. Academicc Press; 1998.p 565. ISBN 0 12 582303 7. 2.. Myrvang G et al. Immunee responsiveness to Mycobacterium leprae and other mycobacterial antigens throughout the clinical andd histopathological spectrum of leprosy. Clinn Exp Immunol 1973;14: 541-553. 3.. Bjune G et al.. Lymphocytee transformation test in leprosy; correlation of the response with inflammation of the lesions. Clinn Exp Immunol 1976;25: 85-94. 4.. Roche PW, Theuvenet WJ and Britton WJ. Riskk factors for type 1 reaction in borderline leprosy patients. Lancett 1991;38: 654. 5.. Charlab R, Sarno EN et al. Effectt of unique Mycobacterium leprae phenolic glycolipid-1 (PGL-1) on tumour necrosis factor production byy human mononuclear cells. Leprr Rev 2001;72:63-9. 6.. Buhrer SS, Smits HL et al. AA simple dipstick assay for the detection of antibodies to phenolic glycolipid - 1 of Mycobacterium leprae. Amm J Trap Med Hyg 1998;58:133-136.

33 3 CHAPTERR 1

7.. Moubasher AEA, Kamel NA et al. Cytokiness in leprosy, II. Effect of treatment on serum cytokines in leprosy. IntJDermm 1998;37:741-46. 8.. Britton WJ. Thee management of leprosy referral reactions, LeprRevv 1998;225-34. 9.. Roche PW, Theuvenet WJ et al. Contributionss of Type-1 Reactions to Sensory and Motor function Loss in Borderline Leprosy Patients and thee Efficacy of Treatment with Prednisone. IntJLeprr 1998;66:340-47. 10.. GupteMD. Vaccinee trials in leprosy—Venezuela, Malawi and India. Intt J Lepr & Mycobact Dis 1999;67(4 Suppl):32-7. 11.. Bertolli J, Pangi C et al. AA case-control study of the effectiveness of BCG vaccine for preventing leprosy in Yangon, Myanmar. Intt J Epidem 1997;26(4):888-96. 12.. Mullins JR.Roche P., Adams E, Jones P, Chen S, Theuvenet WJ., and Basten A. Limitingg dilution analysis in leprosy. Immunologyy &Cell Biology 1992;70: 277-290. 13.. Haregewoin A.Godal T, et al. T-celll conditioned media reverse T -cell unresponsiveness in lepromatous leprosy. Naturee 1983;303: 342. 14.. Nogueira N, Kaplan G, Levy E. 1983. Defectivee gamma-interferon production in leprosy. JJ Exp Med 1983:218:158:216. 15.. Kaplan G, Britton WJ, Hancock G, Theuvenet WJ, Smith KA. Job CK., Roche P.W. Thee systemic influence of recombinant IL-2 on the manifestations of lepromatous leprosy. JJ Exp Med 1991;173: 993-1006. 16.. Roche PW, Failbus S, Ludwig H, Bhanya TK, Britton WJ and Theuvenet WJ. Serologicall responses to the specific glycolipid of Mycobacterium leprae in Nepali leprosy patients. JJ Inst Med.(Kathmandu) 1998;11:197-204. 17.. Roche PW, Britton WJ, Failbus S, Ludwig H, Theuvenet W Jand Adiga RB. Heterogeneityy of serological responses in paucibacillary leprosy: differential responses to protein and carbohydratee antigens and correlation with clinical parameters. Intt J Lepr 1990;58:319-327. 18.. Roche PW, Britton WJ, Failbus S Theuvenet WJ, Lavender M., and Adiga RB. Serologicall responses in primary neuritic leprosy. Transs Royal SocTrop Med.& Hygiene 1991;85: 299-302. 19.. Roche P, Britton WJ, Failbus S, Williams D, Pradhan HM, and Theuvenet WJ. Operationall value of serological measurements in multibacillary leprosy patients: Clinicall and mycobacteriological correlates of antibody responses. Intt J Lepr 1990;54(3): 480-490. 20.. Job CK., Jayakumar J et al. Rolee of polymerase chain reaction in the diagnosis of early leprosy. IntJJ Lepr 1997;65(4): 461-4. 21.. Kampirapap K, Singtham S.et al. DNAA amplification for detection of leprosy and assessment of efficacy of leprosy. IntJJ Lepr 1998;66(1): 16-21. 22.. Scollard DM., Gillis TP et al. Polymerasee chain reaction assay for the detection and identification of Mycobacterium leprae in the United States. . Amm J Clin Path 1998;109(5): 642-646.

34 4 INTRODUCTION N

23.. De Wit MYL, Faber WR et al. Applicationn of a polymerase chain reaction for the detection of Mycobacterium leprae in skin tissues, JJ Clin Microbiol 1991;29: 906-10. 24.. Kurubachew M, Wondimu A et al. Reversee transcription-PCR detection of Mycobacterium leprae in clinical specimens. JJ Clin Microb 1998;36(5): 1352-6. 25.. WHO Weekly Epidemiological Records 2001, www.who.int/lep/12.htm m 26.. Doull JA,Guinto RS, Rodriguez JN and Bancroft H. Thee incidence of leprosy in Cordova and Talisay, Cebu, Philippines. IntJLeprr 1992; 10:107. 27.. Noordeen SK, Neelan PN. Extendedd studies on chemoprofylaxis against leprosy. Indd J Med Research 1978;67: 515. 28.. GupteMD. Vaccinee trials in leprosy-Venezuela, Malawi and India Intt J Lepr & Mycobact Dis 1999;67(4 Suppl):32-7. 29.. Bertolli J, Pangi C et al. AA case-control study of the effectiveness of BCG vaccine for preventing leprosy in Yangon, Myanmar. Intt J Epidemiology 1997;26(4): 888-96. 30.. Chaudhury S, Hajra SK et al. Immunotherapyy of lepromin-negative borderline leprosy patients with low-dose Convit vaccine as an adjunctt to multi-drug therapy, a six-year follow-up in Calcutta. Intt J Lepr & Mycobact Dis 1997;65(l):56-62.

3.44 CLASSIFICATION.

Thee clinical picture of leprosy depends on the leprosy specific immunological response of thee host. The differences in manifestation of the clinical, histological, immunological and bacteriologicall aspects form the basis of the classification. Thee immunopathological spectrum described for leprosy by Ridley and Jopling1 in 1966 arrangedd the immunological phenomena (skin tests and lymphocyte transformation tests), thee clinical picture, the histological appearances and the bacillary density in a consistent mannerr so that patients could be placed along a continuous spectrum. On this basis they cann then be compared, treatments decided upon, and complications predicted. The five- pointt classification based upon this spectrum is:

TTT = Tuberculoid leprosy. BTT = Borderline Tuberculoid leprosy. BBB = Borderline (Borderline) leprosy. BLL = Borderline Lepromatous leprosy. LLL = Lepromatous leprosy.

Thee more the disease has a position closer to the centre of the spectrum, the more unstable itt will be. The most unstable position is BB leprosy where with treatment an upgrading of

35 5 CHAPTERR 1

thee cellular immune response and therefore a shift in position towards the tuberculoid pole iss common, while in the absence of treatment an opposite shift towards the lepromatous polee can often be observed.

Twoo additional classifications of leprosy are recognised outside the framework of the Ridley- Joplingg spectrum. In Indeterminate (I) leprosy clinically and histologically the disease has nott yet fully established itself. At this stage there is no doubt about the diagnosis of the skin lesionn but its position in the spectrum is still unclassifiable. In the 1982 WHO2 system it iss considered paucibacillary. Alsoo Primary Neuritic or Pure Neural (PN) leprosy is an early form of leprosy but here it is totallyy confined to a manifestation in the nerve(s). Early PN leprosy without definite signs posess a great diagnostic challenge to the clinician.3 Onn clinical grounds the number of nerves affected in pure neural cases is helpful. Only one nervee is usually affected in tuberculoid cases while in the borderline group several nerves are likelyy to be affected.

However,, for the field worker the Ridley-Jopling classification with all its modifications is tooo complicated and therefore the 7th WHO Expert Committee4 on Leprosy meeting of Junee 1997 proposed the following Clinical classification for Control Programmes:

a.. Paucibacillary single-lesion leprosy (one skin lesion).

b.. Paucibacillary leprosy (2-5 skin lesions).

c.. Multibacillary leprosy (smear positive patients as well as patients with more than 5 skin lesions). .

Att Anandaban, in addition to counting the number of skin lesions, we also include the numberr of nerves involved (defined as enlarged, palpable, with function-loss) as serology seems too suggest that this is a better indicator of the extent of disease than the number of skin patches.. We treat PN leprosy when more than 2 nerves are involved as MB leprosy. The rea- sonn is that the PGL-1 seropositivity in paucibacillary patients and in PN patients with only 1-22 nerves involved is about the same; 20% and 25% respectively, but is much higher when eitherr more skin lesions and/or more nerves 5-6 are involved.

References: : 1.. Ridley DS. and Jopling WH. Classificationn ofleprosy according to immunity. IntJLeprr 1996;34:255-273. 2.. World Health Organization. Chemotherapyy for leprosy control programmes Technicall report series No.675.1982.

36 6 INTRODUCTION N

3.. Ganapti R and Revankar CR. Clinicall aspects of Leprosy. Thee biology of the Mycobacteria Vol.3. Academicc Press, 1989. p.327. ISBN 0 12 582303 7. 4.. World Health Organization. Thee Report of die 7th WHO expert Committee on leprosy, WHOO Technical Report Series No. 874,1998. 5.. Roche PW, Britton WJ, Failbus SS, Ludwig H, Theuvenet WJ and Adiga RB. Heterogeneityy of serological responses in paucibacillary leprosy; differential responses to protein and carbohydratee antigens and correlation with clinical parameters. Intt J Lepr & Mycobact Dis 1990;58:319-27. 6.. Roche PW, Britton WJ, Failbus SS, Williams D, Pradhan MH, and Theuvenet WJ. Operationall value of serological measurements in multibacillary leprosy patients: Clinicall and bacteriological correlates of antibody responses. Intt J Lepr & Mycobact Dis 1990 ;58: 480-90.

3.55 DIAGNOSIS.

Thee diagnosis can in general be made by proper clinical examination and, if available, be supportedd by slit skin smears.1'2 For the diagnosis of leprosy four cardinal signs can be present: : a.. Anaesthesia. Thiss can be of individual skin lesions or in the area supplied by a large peripheral nerve. b.. Thickened nerves. Thiss at the sites of predilection or as cutaneous branches supplying affected skin. c.. Skin lesions. Thesee can show a change in colour, sensation, and can be infiltrated (inflamed), raised, andd show diminished perspiration and hair growth. d.. Acid fast bacilli in slit skin smears.

Twoo out of the first three signs or the fourth sign should be present for the diagnosis to be made. . Sometimess only nerve involvement in the absence of skin lesions can be found.3 If in such aa case the nerve is enlarged, a cytological aspiration of nerve fluid can assist in making the diagnosis.4 4 Slitt skin smear taking, staining (the Slit and Scrape Method of Wade, 1935) and reading are oftenn of insufficient quality in many field programmes.5

37 7 CHAPTERR 1

References: : 1.. Wade HW. AA description of leprosy. LeprRevv 1935;6:54-60. 2.. Ridley D. Therapeuticc trials in leprosy using serial biopsies. LeprRevv 1985,29: 45-52. 3.. Theuvenet WJ et al. Neuritiss of the lateral femoral cutaneous nerve (meralgia paraesthetica) in leprosy. Intt J Lepr 1993;61:592-6. 4.. Theuvenet WJ et aJ. Cytologicall needle aspiration of the nerve for the diagnosis of pure neural leprosy. Intt J Lepr 19993:61:597-99. 5.. World Health Organization. WHOO Expert Committee on Leprosy. WHOO Technical Report Series no 768.1988.

3.66 TREATMENT OF LEPROSY.

Dapsonee (Diaminodiphenyl sulphone) for the treatment of leprosy was first1 used in 1941 byy Guy Faget. This drug has appeared to be very effective, be it that it is only bacteriosta- tic.. When either used in low dosages or in a patient who is not fully compliant, sulfone resistantt M. leprae readily develops. Forr this reason in 1977 the WHO's Fifth Expert Committee on Leprosy called for the replacementt of monotherapy with combination drug therapy in the form of Dapsone com- binedd with Rifampicin or Clofazamine. In this combination Rifampicin is a very potent bac- tericidall drug.

Thee present recommendations of the 7th WHO Expert Committee on Leprosy of June 199722 are:

Forr Single Skin Lesion Paucibacillary Leprosy: A single supervised dose of: 1.. Rifampicin 600 mg. 2.. Ofloxacin 400 mg. 3.. Minocycline 100 mg.

Forr Paucibacillary cases: during 6 months: 1.. Dapsone 100 mg daily, unsupervised. 2.. Rifampicin 600 mg once monthly, supervised.

Forr Multibacillary cases: during 12 months: 1.. Dapsone 100 mg daily, unsupervised. 2.. Clofazamine 300 mg once monthly, supervised and 50 mg daily, unsupervised. 3.. Rifampicin 600 mg once monthly, supervised.

38 8 INTRODUCTION N

MBB patients who do not accept clofazimine can be treated with a monthly administration off a combination consisting of 600 mg rifampicin, 400 mg ofloxacin and 100 mg of minocyclinee for 24 months. For adult MB patients who cannot take rifampicin, the Committeee recommended the daily administration of 50 mg of clofazimine, together with 4000 mg of ofloxacin and 100 mg of minocycline for 6 months; followed by daily adminis- trationn of 50 mg clofazimine, together with 100 mg of minocycline or 400 mg of ofloxacin forr at least 18 months.

References: : 1.. Faget GH, Johansen FA, Ross H. Sulfanilamidee in the treatment of leprosy. Publicc Health Reports 57:1892. 1942. 2.. World Health Organisation. 7thh WHO Expert Committee on Leprosy Technicall Report Series No. 874.1998. www.who.int/lep/exp/exp.htm m

3.77 REACTIONS.

Inn leprosy the term reaction is used to describe acute inflammatory episodes superimposed onn the usually relatively uneventful course of leprosy. a.. The type 1 or reversal reaction (RR) iss caused by delayed cell-mediated hypersensitivity reactions with a shift of the patient's posi- tionn in the spectrum.1 They occur in patients with borderline leprosy. Iff there is an increase in immunity, the shift is towards the tuberculoid pole and is called upgradingg or reversal reaction. Skin lesions become swollen and raised, macules become plaquess or they develop raised edges. In lighter skinned individuals the lesions can become quitee red. Usually the lesions become more erythematous, sometimes purple, or in white skin,, coppery brown. Occasionally they are oedematous and pale. The edges become more distinctt than before so that the lesions stand out sharply from the surrounding normal skin. Thee lesions are often tender or even painful. New lesions may appear. Usually they resem- blee the pre-existing ones, but sometimes they are very numerous and small and clinically confusing. . Whenn there is a reduction in immunity with a shift towards the lepromatous pole, one speakss of a downgrading reaction. Almost no downgrading reactions are seen in treated patients.. The new lesions in an episode of downgrading may be more lepromatous in appearancee than the previous ones, and if the reaction is severe the skin lesions may desqua- matee or even ulcerate. As the reaction starts to subside, the skin becomes dry and scaly and ultimatelyy flattens, leaving a wrinkled hypo-pigmented surface. Untreated, type 1 reactions tendd to last for months or years, and may relapse.

39 9 CHAPTERR 1

Neuritiss with nerve function loss can be acute and dramatic in type 1 reactions2 and seems too be more common in men with BT leprosy, while women commonly get more extensive skinn changes. Thee neuritis presents classically with tender enlargement of nerves at the sites of predilection.. Sometimes the nerves are grossly enlarged. Loss of function may be marked with sud- denn paralysis of the muscles of the hand or foot, wrist drop, foot drop or lagopthalmus or evenn hemi-facial paralysis. Anaesthesiaa develops rapidly in the distribution of the affected nerve. Nerve pain may cause greatt suffering and may even mimic ischialgia when the lateral femoral cutaneous nerve is involved.3 3 b.. Type 2 or erythema nodosum leprosum (ENL) reaction are also known as lepromatouss lepra reactions and erythema nodosum leprosum (ENL). They are associated with pocketss of polymorphonuclear leucocytes and degenerate acid-fast bacilli in the skin (ENL), nervess (neuritis), lymph nodes, joints, eyes (iridocyclitis) and testis (orchitis) etc. Typee 2 reactions occur in patients with multi-bacillary leprosy. Often there is generalized illness,, sometimes with a fatal outcome. c.. Lucio phenomenon. occurss almost exclusively in patients of Mexican origin. It is characterised by marked small pinkk lesions, vasculitis and thrombosis of the superficial and deep vessels resulting in haem- orrhagee and necrosis of the skin, usually on one of the limbs.

AA component causing tissue damage during type 1 reaction may be CD4+ M. leprae respon- sivee T cells with a polarised Type 1 -like phenotype.4 There is also evidence5 of a T helper-1 responsee with presence of interferon-gamma and absence of interleukin-4 (IL-4) mRNA in thee peripheral blood mononuclear cells of 85% and 64% of type 1 and 2 reaction patients respectively,, and in all reaction sites, whereas a T helper-0 was seen in some and a T-helper- 2-likee response was absent. IFN-gamma was detected6 in 84% of the patients with ENL and inn 100% of the patients with a reversal reaction. Yet, the pathogenesis of reactions is still to bee clearly elucidated. Recent immunologic studies have shown that heat-shock-protein 70 (HSPP 70) is formed by M. leprae and also by Schwann cells under stressful conditions and thatt there is significant homology between the two HSP's. Therefore, T-cells of the host, primedd against HSP-70 of M. leprae origin can cause an auto-immune reaction against Schwannn cells. It is possible that this mechanism may be one of the important causes for extensivee damage to peripheral nerves in borderline leprosy.7 Skinn changes, nerve function loss and nerve pain are often the first symptoms for which the patientt seeks medical help.

40 0 INTRODUCTION N

Thee detection of (early) nerve function loss is very dependent on the techniques used:

1.. Electrophysiology. Motorr Nerve Conduction Velocity (Motor NCV) studies in leprosy patients as conducted byy Naafs8,9 showed that tender nerves conduct more slowly than non-tender nerves, while thee latter are slower again than the normal nerves of healthy individuals, and that affected tenderr and non-tender nerves both improved with steroid treatment. Inn general, facilities to study Motor NCV are not available at the sites where most patients aree seen.

2.. Voluntary muscle testing (VMT) to test muscle strength10 cann be performed under field conditions but will only reveal pathology when already at least 300 % of the nerve fibres are affected.

3.. The Paper Grip test forr early detection of intrinsic muscle weakness in the foot.11 Leprosyy feet with a normal sensibility showed an abnormal paper grip test in 24.8 % of the patients. .

4.. Sensory testing by using the Semmes-Weinstein monofilaments forr measuring light touch sensation can be extremely useful in assessing mild nerve involve- ment12-133 in a clinical setting. Att Anandaban we compared the bending forces of the same calibres of filaments coming fromm different sets of different age, but of the same manufacturer. We found a great varia- tionn in bending force and consequently a reduced reliability. Therefore, it deserves recom- mendationn to use the same set of filaments for the follow-up of one and the same patient andd to verify the calibration regularly. Thee introduction of the monofilaments for sensory testing in order to identify damaged nervess at an earlier stage of disease almost doubled the number of patients put on corticos- teroidss at Anandaban Hospital.

Inn spite of the fact that we now have more sophisticated equipment available to measure also otherr modalities of sensation like temperature sensation and vibration, we are still looking forr reliable and simple tools that can be used under field conditions. Inn a study of 28 leprosy patients Jennekens & Jennekens14 found changes of position sense andd decrease of some tendon reflexes in a minority of these cases. Though it is concluded thatt an extensive neurological examination is probably not required for the diagnosis, it pro- videss more accurate information on the extent of damage to the peripheral nerve system.

41 1 CHAPTERR 1

References: : 1.. Hastings RC. Leprosy. . Churchilll Livingstone, second edition. 1994.ISBN 0-443-04405-8. 2.. Naafs B. Reactionss in leprosy. in:: The biology of the Mycobacteria Vol.3. Academicc Press 1989. p 359. ISBN 0-125-82303-7. 3.. Theuvenet WJ, Finlay K et al. Neuritiss of the lateral femoral cutaneous nerve in leprosy. Intt J Lepr 19993;6l(4):592-96. 4.. Verhagen CE, Wierenga EA et al. Reversall reaction in borderline leprosy is associated with a polarized shift to type 1 -like Mycobacterium lepraee T cell reactivity in lesional skin: A follow-up study. Immunologyy 1997; 159: 4474-83. 5.. Sreenivasan P, Misra RS et al. Lepromatouss leprosy patients showT-helper 1 -like cytokine profile with differential expression of interleukin-100 during type 1 and 2 reactions. Immunologyy 1998;95(4):529-36. 6.. Moraes MO, Sarno EN et al. Cytokinee mRNA expression in leprosy: a possible role for interferon-gamma and interleukin-12 in reactions (RRR and ENL). ScandJJ Immunol 1999;50(5): 541-9. 7.. Choudhuri K. Thee immunology of leprosy. Unravelling an enigma. IntJJ Lepr 1995;63:430-7. 8.. Naafs B, Pearson JMH and Baar AJM. AA follow-up study of nerve lesions in leprosy during and after reaction using motor nerve conduction velocity. . IntJJ Lepr 1976;44:188. 9.. Naafs B. Thee prevention of permanent nerve damage in leprosy. Thesis.. University of Amsterdam. 1980. 10.. Cocchiarella L and Anderson GBJ. Guidess to the evaluation of permanent impairment, fifth ed. Americann Medical Association , 2000, ISBN 1-57947-085-8 11.. de Win MML, Theuvenet WJ et al. Intrinsicc muscle paralysis in the foot of leprosy patients: The paper grip test for screening on intrinsic muscle weakness. . IntJJ Lepr 2002; 70(1): 16-24. 12.. van Brakel WH, Khawas IB et al. Intra-- and Inter-tester Reliability of Sensibility Testing in Leprosy. IntJJ Lepr 1996; 64(3): 287-298. 13.. van Brakel WH., Kets CM et al. Functionall sensibility of the hand in leprosy patients. Leprr Rev 1997; 68:25-37. 14.. Jennekens FGI and Jennekens-Schinkel A. Neurologicall examination of patients suffering from leprosy: Is it worthwhile? Leprr Rev 1992;63:269-276.

42 2 INTRODUCTION N

3.88 TREATMENT OF REACTIONS AND PERIPHERAL NERVE FUNCTION LOSS. .

Medicall treatment:

NSAID's s Inn mild reactions with only discomfort or mild p&in NSAID s in general suffice. In our experience,, when acetylsalylic acid (Aspirin) is taken in combination with a high dosage (200- 3000 mg daily) of Clofazamine, as sometimes required to control reaction, the risk of peptic irritationn is strongly increased and additional precautions are advisable.

Corticosteroids s Inn severe nerve pain or when there is nerve function loss, corticosteroids like Prednisone and Prednisolonee are the most commonly used preparations. Various regimens with, for example,, 40 mg/day for the first 3 weeks, after which the dosage can be tapered off, are often used alsoo in the field. Unfortunately the influence of Prednisone 40 mg/day on the recovery of nervee function seems rather limited.1 Inn this article an overall improvement was found in 37% of the patients only, while 40% remainedd the same and 23% even worsened during prednisone treatment. Ongoingg trials of high ("pulse therapy") and low dose fixed duration prednisone treatment mayy produce better results. Whilee many encouraging publications on the outcome of prednisone therapy speak of "improvement"" or "recovery rates" of nerves2, one has to interpret these data with caution ass only results showing sufficient recovery of protective sensation and functional muscle activityy may have clinical relevance. Trialss are going on to assess the effect of prophylactic corticosteroids on the incidence of reactionss in newly diagnosed multibacillary leprosy patients.3 Preliminary results suggest thatt prophylactic corticosteroids decrease the number of reversal reactions during the first sixx months of MDT, but that, when compared with the effect of a placebo, there is no significantt difference in loss of nerve function when assessed after one year of treatment.

Thalidomide e Thiss drug is known to suppress ENL and often is the last option for treating a persistent and severee type 2 reaction. Teratogenicityy ("the Softenon effect") is its most serious side effect and for this reason the usee is still prohibited in many countries. Other serious side effects are thrombocytopenia, eosinophiliaa and peripheral neuropathies.

Clofaziminee (Lamprene) Thee drug is reported to be mildly bactericidal towards M. leprae, but it is also effective in thee management of leprosy reactions, apparently because of its anti-inflammatory capacity.

43 3 CHAPTERR 1

Physiotherapy: : Nervee function loss or severe nerve pain can further be treated with partial immobilisation andd by padding joints. Controlled and supervised partial exercises of the joints are needed too preserve the gliding function of the nerve.

Surgery: : Whenn corticosteroids fail to relieve severe nerve pain and to restore nerve function, nerve decompressionn with selective meshing of the epineurium to preserve the well-developed vas- cularr plexus in the epineurium, is indicated.4

Forr an excellent discussion on the care of the neuropathic limbs I like to refer to the practi- call manual written by Grace Warren.5

References: : 1.. Roche WP, Theuvenet WJ et al. Contributionn of type 1 Reactions to Sensory and Motor Function Loss in Borderline Leprosy Patients and thee efficacy of treatment with prednisone. IntJLeprr 1998;66(3):340-7. 2.. Jiang J, Watson JM et al. AA field trial of detection and treatment of nerve function impairment in leprosy-report from national POD pilott project. Leprr Rev 1998;69(4):367-75. 3-- Croft RR Nicholls P et al. Effectt of prophylactic corticosteroids on the incidence of reactions in newly diagnosed multibacillary leprosy patients. . Intt J Lepr & Mycobact Dis 1999;67(1): 75-7. 4.. Theuvenet WJ, Roche PW et al. Nervee decompression by selective meshing of the epineurium. submittedd for publication. 2002. 5.. Warren G and Nade S. Thee care of the neuropathic limbs, a practical manual. Parthenonn Publishing U.K. 1999. ISBN 1-85070-048-6

3.99 PREVENTION OF IMPAIRMENT AND SUBSEQUENT DISABILITY (POID) ANDD REHABILITATION.

Accordingg to the WHO Expert Committee on Leprosy, Fifth Report of 1977: l

"...Inn an efficiently conducted programme no new cases with irreversible disabili- tiess should be detected, and further deterioration can and should always be prevented". .

Itt is clear from the chapter on "Leprosy in Nepal" that in 2002 this is neither the current situationn in Nepal, where in the past ten years the percentage of patients with disabilities

44 4 INTRODUCTION N

amongstt newly detected cases has lingered around 10, nor elsewhere in the world. At nationall level, hardly any leprosy control programme has a clear strategy for POID and rehabilitationn yet.

1.. The prevention of impairment and disability Besidess early case detection, POID research priorities include studies of methods a.. to strengthen health education, b.. to prevent social, economic and mental malfunctioning, c.. to promote patient compliance, d.. to improve the early detection of autonomic, sensory and motor neuropathy; too find alternative drugs or regimens for treating neuropathies, and e.. studies of the use of various POID monitoring systems.

Concentrationn on medical care of people affected with leprosy (MDT, surgery, etc), though vastlyy beneficial, has for a long time led to a neglect of POID, this resulting in a poor qual- ityy of life of many affected by leprosy.

2.. Rehabilitation Onn the other hand it is encouraging to note that (finally) by the year 2000 POID and the Sociall and Economic Rehabilitation (SER) of people affected by leprosy has become a major priorityy and Leprosy Review devoted a special issue to this topic in December of the same year.2 Moree than 10 million persons affected by leprosy have been cured with MDT in the last decadee but studies done by IDEA, DAHW and ALES suggest that up to 35% of leprosy- affectedd persons may need socio-economic rehabilitation and that barely! 5% of the disabled personss have access to any rehabilitation services at this moment. In these studies there is no mentionn at all of the disabling influence of having leprosy on the mental status of those affected.. Immediately after diagnosis grief appears to be the first and most general reaction experiencedd by leprosy patients,3 while mental stress can further increase when self, social andd community acceptance become a problem and visible signs of leprosy set in. According too van Parijs4 one-third of leprosy patients suffer desertion by marriage partners, while more womenn than men suffer from isolation, rejection and decreased family support.5-6 Itt is no surprise that also in Nepal persons affected by leprosy try to hide their disease, out off fear for negative family and community behaviour. Theyy stop going to the clinic (non-compliance) which seems to be one of the defence mech- anismss to conceal their disease and thus to maintain their social integrity. The major prob- lemm in Nepal has to deal with this high non-compliance rate which remained stable over the pastt 5 years at more than 40%, and which directly affects the outcomes of MDT, POID and rehabilitationn programmes Ass a result a need was felt to conduct a specialized study of the psychosocial effects of leprosyy in Nepal This study was titled "Psychiatric morbidity in people affected by leprosy in Nepall assessed with the WHO Self-Reporting Questionnaire (SRQ)". The results are presentedd in Chapter 9.

45 5 CHAPTERR 1

Rehabilitationn is a unique task and the approach may not be duplicated between places or evenn from one person to another, and therefore in the report on the WHO AIFO Joint workshop77 emphasis was placed on the need to adopt a multi-sectorial, holistic approach to addresss the issues of physical, psychological and socio-economic rehabilitation for the affectedd individuals as well their communities. Att the ILA Conference in Beijing in 1998 it was stated that the approach to SER should be basedd on three principles:

a.. Recognition of the broad impact of leprosy on the individual; in other words, its physical,, psychological, social and economic effects. b.. Responsiveness to the concerns of the individuals affected by leprosy. This requires ann approach that restores dignity and self-respect; in other words participation and empowerment. . c.. Sensitivity to the concerns of the families and communities affected by leprosy as memberss of the family and the community have an important role to play in rehabilitation. .

Justt as with the prevention of impairment and deformity, the assessment of the needs and skillss of patients affected by leprosy should be done at the earliest possible opportunity after diagnosis. .

References: : 1.. World Health Organization . WHOO Expert Committee on leprosy. WHOO Technical Report Series, Fifth Report, No. 607.1997. 2.. Smith WCS. Speciall Issue on Socio-Economic Rehabilitation, Leprr Rev 2000;71:420-1. 3.. Scott J. Thee psychosocial needs of leprosy patients. Leprr Rev 2000;71:486-91. 4.. Van Parijs LG. Healthh education in leprosy work. A manual for health workers, 2ndd edn.Stanley L.Hunt. Northamptonshire.1988. 5.. Zodpey SP, Tiwari RR et al. Genderr differentials in the social and family life of leprosy patients. Leprr Rev 2000;71: 505-10. 6.. Floyd-Richard M and Gurung S. Stigmaa reduction through group counselling of persons affected by leprosy - a pilot study. Leprr Rev 2000;71: 499-504. 7.. Report on WHO AIFO Joint Workshop. Leprr Rev 2000;71:524-5.

46 6 INTRODUCTION N

3.100 (RECONSTRUCTIVE) SURGERY IN LEPROSY.

Thee first responsibility of a reconstructive surgeon involved in leprosy is to prevent impair- mentt and deformity. It is, therefore, that only at this stage of the introduction, a summary iss given of some of the main procedures used in reconstructive surgery in leprosy.

Thesee reconstructive procedures can be divided into:

A.. Operations for the restoration of dynamic function:

1.. In the face for the compensation of facial nerve paralysis: lagophthalmuss correction by e.g. medial canthopexy mediall and/or lateral suspension plasty faciall sling procedure temporaliss muscle transfer (Thee tarsoraphy procedure is simple but gives aa terrible cosmetic result). faciall paralysis temporalis muscle many tail procedure masseterr sling procedure

2.. In the hand for the compensation of ulnar/median/radial nerve paralysis: claww hand correction by e.g. palmaris longus transfer* Zancolli-Lassoo procedure EF4TT (= extensor to flexor many tail) procedure* * FDS-IIII (= sublimus) transfer* opponenss plasty by e.g. FDS-IV transfer# extensorr indicis proprius transfer# wristt drop correction by e.g. pronator teres and flexor carpi radialis transfer r

47 7 CHAPTERR 1

Lagopthalmuss right eye

pre-operative;; eyes light closure pre-operative;; eyes open

post-operative;; eyes light closure after right post-operative;; eyes open temporaliss muscle transfer

48 8 INTRODUCTION N

Ulnarr and Median Claw Hands

pre-operative;; fingers in "intrinsic position" pre-operative;; fingers in extension

post-operative;; sublimus IV transfer right hand, post-operative;; fingers in extension fingersfingers in "intrinsic position"

49 9 CHAPTERR 1

Rightt footdrop

pre-operative;; right footdrop pre-operative;; loss of dorsoflexion at time of heel-strike e

peroperative;; transfer tibialis posterior tendon

post-operative;; corrected footdrop post-operative;; corrected dorsoflexion at time of heel-strike e

50 0 INTRODUCTION N

extensorr aponeurosis dorsall interosseous muscle e

** In claw-hand correction the proper selection of the site of insettion of the slips into the extensor apparatus of thee digits gives a tool to further balance the fingers when there is a difference in the degree of clawing at PIP jointt level. Insertion either distally (a) or proximally (b) at the conjoined tendon will influence the strength of thee mechanical arm of the transferred tendon over the MCP joint and thus create a variable degree of MCP flexion.. Insertion of the transferred slip either laterally (conjoined tendon) or dorsally (c, central slip) will cause a variablee degree of PIP and DIP extension .

## In die absence of FPB function the transfer should cross the dorsum of the thumb distally from the MCP joint inn order to add MCP flexion.

3.. In the foot a.. for the compensation of peroneal nerve paralysis: completee foot drop correction by e.g. TPT, circumferential or interosseous route. . laterall foot drop correction by e.g. Peroneus Longus transfer. b.. for the compensation of n.n. plantares paralysis: claww toe correction by e.g. FDP to extensor transfer. thiss merely corrects the position and not as much function at MTP and PIP jointt level.

4.. Nerve decompressions. Att Anandaban Leprosy Hospital we developed a new technique named nerve decompressionn by selective meshing of the epineurium, described in chapter 5, pagee 88.

B.. Operations for the restoration of joint position: Inn general these are the arthrodesis operations for finger, toe, wrist and ankle joint position. .

51 1 CHAPTERR 1

C.. Operations for cosmetic correction: Forr instance reconstructions of the eyebrows, the collapsed nose and the atrophied firstfirst web-space of the hand, correction of ear lobe hypertrophy and the face-lift for faciall wrinkling after reaction etc. Althoughh the septic surgery procedures are in a stricter sense more salvage operations and nott as much reconstructive procedures, they form a major part of the routine surgical inter- ventionss and are therefore included here.

D.. Septic surgery: Foott ulcers are by far the most frequent indication for admission in a hospital. Inn general it is not difficult to get an ulcer healed but the real challenge lies in the understandingg of why it has occurred and how to prevent recurrence. Forr this it is essential that one has a thorough knowledge of the normal functional anatomyy and of the disturbances caused by specific nerve function loss as caused by thee Mycobacterium leprae.

Inn the last 15 years these techniques have been the subject of team-training courses in POID andd reconstructive surgery in Asia, Africa and South-America on behalf of The Leprosy Missionn International and the Netherlands Leprosy Relief Association.

3.111 OCULAR PATHOLOGY IN LEPROSY

Itt is estimated1 that there are a total number of 350,000-400,000 blind leprosy patients, by WHOO standards blindness is visual acuity (VA) of <3/60. Inn control programmes, after implementation of MDT, potentially sight threatening lesions aree reported in 15 to 20 percent; blindness in 1-3 percent. This is about double the level of blindnesss in the general population in developing countries. It is reported2 that blind leprosyy patients have a 4.8-fold excess risk of dying compared to nonblind leprosy patients of thee same age. Eyee complications are caused by the same mechanisms that cause complications in general inn leprosy;

a.. Type 1 reactions: lagopthalmus and corneal anaesthesia. b.. Type 2 reactions: acute iritis and scleritis c.. Infiltration and secondary atrophy: a series of extra and intra-ocular lesions.

Itt speaks for itself that just as with leprosy neuritis in general, also eye complications need too be diagnosed and treated in an early stage. Age-related cataract is the most important causee of blindness in leprosy nowadays and it is rightfully stressed by Hogeweg3 that leprosy patientss with loss of sensation in hands and feet should receive early cataract surgery as

52 2 INTRODUCTION N

severee visual impairment or blindness may hamper or preclude self-care and is, therefore, moree disabling in leprosy patients than in the general population. Facial patches over the faciall nerve almost seem to announce a lagopthalmus4 Andd when conservative treatment fails and a 5-6 mm lid gap in mild closure remains, lid surgeryy is indicated by an experienced surgeon (see page 47). Inn order to improve eye care in leprosy, routine assessment of VA should be included in the protocoll for the screening of the early signs of nerve function loss, this especially during the timee that a patient is prone to develop type 1 and 2 reactions but also during the care after curee . Leprosyy programmes should establish cooperation with the local eye care services for refer- rall of patients.

References; ; 1.. Courtright R and Lewalijen S, Ocularr manifestations of leprosy In:: The Epidemiology of Eye Disease, Johnson,, Minassian & Weale 1998, ISBN 0 412 643103 2.. Courtright P, Kim S et al, Excesss mortality associated with blindness in leprosy patients in Korea, Lepr.. Rev. 1997, 68: 326-30. 3.. Hogeweg M, Ocularr leprosy, Intt J Lepr 2001,69; 2suppl; S30-35. 4.. Hogeweg M, Kiran K et al. Thee significance of facial patches and type 1 reactions for the development of facial nerve damage in leprosy; aa retrospective study among 1226 paucibacillary leprosy patients. Lepr.. Rev. 1991,62; 143-9.

4.. SCOPE OF THIS THESIS.

Withoutt nerve damage there would be neither physical impairment nor disability in those affectedd by leprosy and leprosy would not be very different to many of the other contagious diseasess of the skin that can be successfully treated nowadays. It is for this reason that in leprosyy we need to focus on the clinical aspects of nerve damage. Fromm Anandaban hospital between 1985 and 1990 an intense (house-to-house) survey of Lalitpurr district was conducted in order to improve on early case finding and the early diagnosiss of neuritis (Chapter 2). An unknown manifestation of neuritis in leprosy, the neuritis off the lateral femoral cutaneous nerve (meralgia paraesthetica), was detected (Chapter 3). In orderr to facilitate the diagnosis of pure neural leprosy, we developed the cytological needle aspirationn of the nerve (Chapter 4). Foott ulcers are the most frequent reason for admission in leprosy hospitals and in spite of pro- tectivee footwear they tend to have too high a recurrence rate. In order to improve on the early detectionn of intrinsic muscle function loss in the foot, a simple test was developed that may

53 3 CHAPTERR 1

assistt in taking timely preventive measures to protect the foot (Chapter 5). A nerve decompressionn study using a new technique of selective meshing of the epineurium was conducted too improve nerve function loss when steroids had failed (Chapter 6). Reversal (type-1) reactionss are the main contributor to nerve damage and besides the need to identify risk factors forr type-1 reactions (Chapter 7), there is a need to understand more of the immuno-patho- logicall mechanisms involved and the efficacy of prednisone in leprosy neuritis (Chapter 8). Alll the previous chapters deal with issues seen from the medical perspective, but the people affectedd by leprosy have hardly any notion of germs, the struggle to implement MDT, reactionss etc. Their main concerns lie at a totally different level where they fear isolation, rejection,, disability and the social and economic consequences of these for themselves and their families.. In order to bring the patient's perspective in line with the medical perspective, we assessedd the mental stress factors that a patient affected by leprosy is facing in daily life (Chapterr 9).

54 4 Chapterr 2

Masss Survey of Leprosy in Lalitpurr District, Nepal

From:: Mass Survey of Leprosy in Lalitpur District, Nepal WJJ Theuvenet, D Soares, JP Baral, AH Theuvenet-Schutte, JP Palla, K Jesudasan, JJ Nakami, RB Bista, P Jayakumar, and PK Failbus Int.J.Lepr.. 1994, 62(2), 256-262

55 5 CHAPTERR 2

56 6 MASSS SURVEY OF LALITPUR DISTRICT, NEPAL

SUMMARY Y

Ann intense mass survey of leprosy in Lalitpur District, Nepal, was carried out during the periodd 1986 to 1990. This was the first such large-scale survey in Nepal; 85% of the total populationn was examined. The 5-year case detection rate was 13 per 10,000; the 5-year child detectionn rate was 4 per 10,000. By the end of the survey the prevalence rate was 6.8 per 10,000;; at the end of 1992 this had dropped to 2.2 per 10,000. In 1989, after a 3-year interval,, a re-survey was done in three village development committees (VDCs) and 4 new cases weree detected, bringing the 3-year case detection rate to 3.3 per 10,000; 36% of the old cases,, 20% of the new adult cases, and 3% of the new child cases were classified as multibacillary.. Overall, 62.7% of the patients had no disability, 18.8% had disability grade 1, and 12.7%% had disability grade 2, while for 5.8% the data were incomplete. By the end of the surveyy 91% of the patients needing medical treatment were on multidrug therapy (MDT). Att present this has increased to 100%. The regularity rate was 86%; at the end of 1992 this hadd increased to 96%. The cost for detecting one new patient was US$ 298. Because of the highh cost, it is recommended that intense mass surveys not be performed when the esti- matedd prevalence rate is less than 10 per 10,000 inhabitants. From the data collected con- clusionss were drawn and recommendations were formulated for developing new strategies forr the National Leprosy Control Programme of the Government of Nepal.

INTRODUCTION N

Inn 1990 approximately 1.32 billion people1 live in areas in developing countries where leprosyy is an important problem, i.e., where the prevalence is over 10 cases per 10,000 persons andd where an individual may thus be considered at significant risk of contracting the disease.. More than one third of all leprosy patients face the threat of permanent and progres- sivee physical and social disability. One of the difficulties in properly assessing and monitor- ingg the leprosy problem is that enumeration of cases in many developing countries is incom- pletee or irregular. AA country that in particular is struggling with this problem is Nepal, with in 1990 a populationn of about 19 million and a prevalence rate of 13.6 leprosy patients per 10,000 inhab- itantss (Notes of the WHO Inter-Country Meeting of Leprosy Programme Managers, Kathmandu,, December 1990). In addition to these patients, numerous leprosy patients fromm northern India are crossing the border for free leprosy treatment. For this reason and ass agreed between the Government of Nepal and Anandaban Leprosy Hospital, an intensive masss survey was carried out in the Lalitpur District of Nepal from the Spring of 1986 until thee Autumn of 1990 in order to:

57 7 CHAPTERR 2

a)) collect reliable epidemiological data on leprosy in this area; b)) provide a baseline of relevant data for monitoring the efficacy of the leprosy control programmee in this area; and c)) assess the indication and feasibility of this type of survey against the leprosy problem inn this district.

Thiss was the first and only survey of leprosy on such a scale in Nepal, and was considered byy the Government of Nepal to be of paramount importance for developing future strate- giess for the National Leprosy Control Programme.

Fig.. 1. Nepal: located at the northern edge of the Indian subcontinent

Nepall is located between longitude 80o-88°.5' east and latitude 26°.30'-30° north. About 71%% of the country is hilly and mountainous. The total population in 1990 is around 19 millionn inhabitants with an average annual growth rate of 2.7%, an estimated crude death ratee in 1981 of 13.5 per 1000 and an infant mortality rate in 1987-1988 of 108 per 1000 livee births.2 Thee per capita gross domestic product (GDP) of US$190 (1990-1991) places it among the veryy poorest countries in the world.

58 8 MASSS SURVEY OF LALITPUR DISTRICT, NEPAL

Fig.. 2. Lalitpur District with Anandaban Hospital shown in the centre of Lele panchayat.

Lalitpurr District, one of the 75 districts of Nepal, is located in the Central Region of Nepal immediatelyy south of Kathmandu, the country's capital. From north to south the district is dividedd into the flat area of the Kathmandu valley with the city of Patan as the district's administrativee centre. In the centre is a semi-hilly region forming the most southern exten- sionss of the Kathmandu valley (Anandaban Leprosy Hospital is located in this area). In the southh there are hills reaching a maximum height of 2831 metres which form the boundary withh the Terai, the strip of Indo-Gangetic plain forming the southern part of Nepal border- ingg India.

59 9 CHAPTERR 2

Inn Lalitpur one can identify about 11 different ethno-linguistic groups of Burmese- Mongoliann and Indo-Aryan origin. The main languages spoken are Nepali, Newar and Tamang.. Until the political changes in 1990, each district in Nepal was divided administra- tivelyy into panchayats (hereafter renamed as Village Development Committees) which, in turn,, were subdivided into wards, and these into villages. The area of Lalitpur District cov- erss 413 sq. km. and has 41 Village Development Committees (VDCs). Each VDC has a healthh post, and each village is visited by a village health worker. Sincee 1956 Anandaban Leprosy Hospital has been one of the two leprosy referral hospitals inn the country, and receives patients from all over the country as well as from India, Tibet andd Bhutan. As per agreement with the Government of Nepal, all medical assistance to leprosyy patients is provided free of charge. Anandaban Hospital has 120 beds of which 10 beds aree reserved for non-leprosy patients. The main reasons for admission are treatment of leprosyy complications that cannot be dealt with at the peripheral level. Oncee a week the hospital runs a leprosy outpatient clinic at Patan Hospital (a general hospitall at the northern edge of the district), twice a week a combined leprosy and non-leprosy outpatientt clinic at Anandaban itself and, since 1991, once bimonthly leprosy clinics at Ghotikhell and Bhattedanda. Attached to the hospital are a training centre and the Myco- bacteriumm Research Laboratory. The leprosy eradication programme of Anandaban Hospital andd the mass survey of Lalitpur District are supervised by and operated in close cooperation withh the Leprosy Control Programme of the Government of Nepal.

METHODS S

Thee survey itself was performed by nine male paramedical workers, one of whom was also ann experienced physiotherapy technician, another who was also trained as a health educator, andd a third as a smear technician. Among them were native Nepali, Newar and Tamang speakers.. In the survey of the area close to Anandaban Hospital, a female paramedical workerr and a female medical aide were added to the team. In the urban areas females were farr more reluctant to be examined by a male paramedical worker, so for the survey of the urbann area of Patan eight females were trained and used as paramedical assistants, each workingg side by side with an experienced male paramedical worker. The field work was supervisedd by a medical officer trained in epidemiology. Thee different areas were surveyed depending on weather conditions; in the monsoon, when travellingg on foot was often difficult, the areas accessible by road (mainly the northern and centrall parts of the district) were visited; in the dry season, the southern parts of the district weree surveyed. This was mainly done on foot using porters and tents, and the team was fre- quentlyy away from the hospital for several weeks. Preceding the survey of a specific area, per- missionn was sought from the VDC leader who, in turn, would mediate in getting the cooperationn of the ward leaders. After this was established, health education was given in the formm of slide shows, films and open-air talks on leprosy at community centres. Thereafter thee survey was conducted in a house-to-house manner, at which all household members

60 0 MASSS SURVEY OF LALITPUR DISTRICT, NEPAL

weree listed and the family structure recorded. The household members present were examinedd for signs of leprosy by at least two paramedical workers or, in the urban area of Patan, byy one experienced paramedical worker and a female paramedical assistant. All suspected andd diagnosed cases were seen by a medical officer for confirmation of the diagnosis.

Newlyy found cases were further examined at the leprosy clinic at Patan Hospital or Anandabann Hospital, at which complete body charting would be done. Nerves prone to be affectedd would be examined and their qualities with regard to sensation and muscle strength assessedd and recorded by the physiotherapy department. Skin smears of three standardized sitess and one active skin patch were taken, blood was sampled for serological examination, aa lepromin test was performed and, again, health education would be given. After the final decisionn on the classification of the disease, medical treatment would be started. Those listed ass suspect cases were revisited at a later stage or instructed to come for re-examination to the leprosyy clinic at either Patan Hospital or Anandaban Hospital.

RESULTS S

Populationn examined. The survey provided, at the same time, an accurate census of the populationn which at the end of the survey appeared to be 210,358. Those up to 15 years of agee were counted as children (Table 1).

Tablee 1. Population examined.

Enumerated d Examined d Percentage e Adults s Childeren n Adults s Childeren n examined d

Males s 67.726 6 50.470 0 74% % Females s 66.802 2 58.038 8 87% % Males s 38.720 0 36.248 8 94% % Females s 37.110 0 36.055 5 94% % Subtotal l 134.428 8 75.830 0 108.533 3 71.303 3 Total l 210.358 8 179.811 1 85% %

61 1 CHAPTERR 2

Casee detection rate. In the group of 179,811 inhabitants of Lalitpur District who were examinedd for leprosy, 458 old cases and 234 new cases were found (Table 2).

Tablee 2. Case detection rate.

Oldd New Males % Females % A.. Old patients released from 458 287 63 Ï7Ï 37 treatmentt or still on treatment B.. New patients found by house- 162 97 60 65 40 to-housee survey C.. New patients who voluntarily 72 38 53 34 47 reportedd or were referred by a healthh post Totall 458 234" 422 6Ï 270 39

Tablee 3. Classification of leprosy patients.

TT T BT T BB B BLL LL PN N IND D Total l

Oldd cases** Malee and female 69 9 106 6 9 9 577 47 22 2 0 0 310 0

Neww cases*** Adults s Maless 14 46 2 11 3 19 2 97 Femaless 11 32 1 14 3 8 2 21 Totall 25 78 3 25 6 27 4 168

Childeren n Males s 5 5 9 9 1 1 1 1 16 6 Females s 6 6 6 6 1 1 1 1 15 5 Total l 11 1 15 5 2 2 2 2 31 1

Classification:: TT = tuberculoid, BT = borderline tuberculoid, BB = midborderline, BL = borderline leprornatous, LLL = leprornatous, PN = pure neural, IND = indeterminate leprosy. Oldd cases were 310 known out of 458. Outt of the 234 new patients, 21 patients registered elsewhere and 12 are unwilling to be registered. Of the 168 registeredd new adult patients, 97 were males and 21 were females. There were 31 new child cases (16 boys and 15 girls). .

62 2 MASSS SURVEY OF LALITPUR DISTRICT, NEPAL

Thee sex ratio male-to-female was in group A 1.66/1, in group B 1.36/1, and in group CC 1.12/1. Out of the 234 new patients 49 were not registered as taking treatment at Anandabann Hospital by the end of the survey: a) 12 new patients were still unwilling to commencee treatment (in spite of repeated visits to motivate them for treatment); b) 8 patientss were free of signs and symptoms of leprosy by the time they reported at the clinic andd were listed as subsided; c) 21 patients were taking treatment at another centre; d) 3 cases hadd moved out of the district; e) 2 patients died before starting treatment; and f) 1 patient couldd not be traced back. The number of new patients was therefore set at 232. New patientss found in 179,811 people examined gave a 5-year case detection rate of 13 per 10,0000 inhabitants examined (2.6 per 10,000 per year).

Childd detection rate. In the period 1978-1980 and in the year 1985, a total of 144 schools weree surveyed; 33,058 children were examined and a total of 29 new child cases were found. Inn the 1986-1990 mass survey group of 71,303 children examined, 31 new child cases were found,, and the 5-year child detection rate was, therefore, 4 per 10,000 (0.8 per 10,000 per year). .

Prevalencee rate. In 1990 the measured prevalence rate (patients needing anti-leprosy treatment/populationn examined) was 6.8 per 10,000. By the end of 1992 this had dropped to 3.11 per 10,000.

Incidencee rate. Three VDCs (Lele, Champi and Badiikhel) with a total population of 14,4622 were re-surveyed in 1989 after an interval of 3 years; 11,964 people were examined (82.7%% of the population) and 4 new patients were found in Lele VDC (3 females and 1 male).. Only the male was skin-smear positive (0. 1 +), and was classified as borderline lepromatous.. The 3 females were all smear negative and were classified as 2 borderline tuber- culoidd and 1 midborderline. The 3-year incidence rate for these three VDCs was, therefore, 3.33 per 10,000 (1. 1 per 10,000 per year).

Classification.. The classification of the patients registered during the survey is presented in Tablee 3. Approximately 36% of all old cases, 20% of all new adult patients, and 3% of all neww child cases were classified as multibacillary; 20% of all new patients were skin-smear positive,, and all of this group of patients was taking multidrug therapy regularly.

Disability.. The disability grading* of hands and feet among new cases was:

Gradee 0 Grade 1 Grade 2 Unknown 62,7%% 18,8 % 12,7 % 5,8 %

*Presentt WHO disability grading system as recommended in 1980 for hands and feet: Gradee 0 = no anaesthesia, no visible deformity or damage; Grade 1 = anaesthesia present but noo visible deformity or damage; Grade 2 = visible deformity or damage present.

63 3 CHAPTERR 2

Inn the total population of leprosy patients of the Lalitpur District the disability ratio for pau- cibacillaryy (PB) patients versus multibacillary (MB) patients was:

Gradee 0 Grade 1 PB/MBB \A 1:1:6

Therapy.. Of all the patients not yet released from treatment, 82% took multidrug therapy (MDT)) as recommended by the World Health Organization (WHO) in 1982 by the end off the survey. Of the remaining proportion, 16% were on dapsone monotherapy and 2% tookk other medical treatment. By the end of 1992 full MDT coverage had been reached. By 311 December 1992, 644 patients were released from MDT and 56 were still on treatment.

Regularityy rate. As per the WHO definition, more than 86% of the patients on MDT took regularr treatment by the end of the survey. For those patients taking dapsone monotherapy, 43%% were regular. By the end of 1992 full MDT coverage was achieved and 96% of all of ourr patients were taking regular treatment.

Costt of the survey. The total cost of the intensive mass survey over its 5-year period amountedd to Nepali rupees 2,205,667 (about US$ 71,150 at the exchange rate of January 1991);; 70% of this amount was spent on salaries. The approximate cost for detecting one neww patient was Nepali rupees 9551.42 (about US$ 298).

Leprosyy in Lalitpur in 1999 and 2000. Inn 1999 54 cases were registered (48 MB cases, 6 PB cases) with a prevalence rate of 1.72 perr 10,000. Twenty-five new cases were detected (17 MB cases and 8 PB cases) with a new casee detection rate of 0.80 per 10,000. At the end of 2000 there were only 21 active cases withh a prevalence of 0.55 per 10,000 while 7 new cases were diagnosed with a new case detectionn rate of 0.23 per 10,000.

DISCUSSIONN AND CONCLUSIONS

Thee percentage of examined people of Lalitpur District of 85% was sufficient, according to WHOO standards, to draw reliable conclusions for an epidemiological assessment of the area. Thee lower percentage of adult males examined possibly was due to the fact that many of the maless have accepted employment away from home. The difference in the sex ratio between thee already registered, the newly found cases, and the voluntarily reporting patients perhaps cann be explained by the fact that female leprosy patients, in general, are more reluctant to seekk medical help. We assume that our intense health education in the district has helped in decreasingg the ratio in the last two categories.

64 4 MASSS SURVEY OF LALITPUR DISTRICT, NEPAL

Thee 1986-1990 child detection rate for Lalitpur was 4 per 10,000 over the 5 years or 0.8 perr 10,000 per year. One should consider, though, that in the earlier school surveys almost halff of the children of Lalitpur District already had been examined, which may have influ- encedd the proportion of new child cases found in the mass survey. The child rate of newly detectedd cases in Nepal was officially 5.57% in 1988-1989. The value of school surveys in loww leprosy-endemic areas may be merely in providing a chance to give health education.

Thee measured prevalence rate in 1990 of 6.8 per 10,000 inhabitants means that by the end off the survey one could speak of leprosy being endemic in the Lalitpur District. Thanks to fulll MDT coverage and a regularity rate of 96%, the number of patients still needing treatmentt had decreased greatly by the end of 1992, resulting in a prevalence rate at that point off 3.1 per 10,000. Only a few VDCs have been resurveyed as yet and, therefore, reliable data onn the incidence rate are pending.

Off all newly detected cases the MB rate was 20%; for the whole of Nepal this was 45% for thee years 1988-1989. Fourteen percent of all our new patients were classified as having pure neurall leprosy; for the whole of Nepal this was 7%. The difference may be explained by the factt that we developed a new technique for diagnosing this form of leprosy. The method was calledd "cytological needle aspiration of nerve fluid for the diagnosis of pure neural leprosy" andd enabled us to simply screen the nerve for acid-fast bacilli.3

Overalll 62.7% of the patients had no disability, 18.8% had disability grade 1 and 12.7% hadd disability grade 2; while for 5.8% the data were incomplete. In the Western Region of Nepall a disability grade 2 was found in about 16% of all new cases. For the whole of Nepal (Notess of the WHO Inter-Country Meeting of Leprosy Programme Managers, Kathmandu, Decemberr 1990), grade 1 was 18% and grade 2 was 12% in 1988-1989. At the end of the survey,, 86% of all registered Lalitpur patients took MDT regularly; by the end of 1992 this hadd increased to 96%. For the whole of Nepal, 52% of the patients took MDT in 19902. Thee differences with regard to the MB rate, disability grades, and the proportion of patients onn MDT between the Lalitpur District data and the data for the rest of Nepal can be explainedd by the fact that the mass survey in Lalitpur made early case detection and control feasible.. Loss of sensation in the extremities is often the first symptom motivating patients too seek medical help. Intensee health education, also employing "cured" patients and early case finding, is needed too diagnose new cases before nerve damage has occurred. Thee difference in the regularity rate between patients taking MDT and monotherapy was explainedd by the fact that the monotherapy group mainly consists of patients living in the relativelyy inaccessible southern part of the district from where they have to walk for several dayss to collect their medicines. For this reason, two bimonthly clinics were opened in the villagess of Bhattedanda and Ghotikhel in 1991.

65 5 CHAPTERR 2

Onee has to be cautious in extrapolating Lalitpur data to the situation in other hill districts inn Nepal. Anandaban Hospital, being one of the two leprosy referral hospitals in the country,, is located in the heart of Lalitpur District and has been providing assistance to leprosy patientss of this district for more than 30 years.

Thee costs of Nepali rupees 9951.42 (US$ 298) for the detection of each new leprosy case in Lalitpurr District stands in sharp contrast with the amount of Nepali rupees, 44.00 per person,, that the Nepali Government had available for health care in 1992.

Planss are prepared to re-survey the 10 VDCs with the highest prevalence within 2 years of thee last survey in order to monitor the 2-year incidence, multibacillary rate, child rate and deformityy rate. These will be used as key parameters to assess the success of the leprosy controll programme in the district.

Alll contacts of already diagnosed cases will be kept under surveillance. Health education will bee continued and combined with radio spots on leprosy. Patient self-care will be further stimulatedd while the facilities for rehabilitation are reinforced. Irregular patients and default- erss will continue to be followed up.

Basedd upon our experiences gained in this survey, we came to the following recommendations: :

Infrastructure.. Adequate training of health post staff and village health workers and the handingg out of drugs through the health posts may improve compliance and the earlier detectionn of nerve damage. Clinical facilities providing possibilities for example the treatmentt of immune reactions, foot problems, reconstructive surgery, eye care, and a rehabilitationn programme should be available in the region since this will stimulate patients to com- plyy with medical treatment.

Medical.. Disability prevention and control should receive the same priority and timing as thee implementation of MDT. The old WHO disability grading (grade 0 to 3) offers more realisticc parameters than the present one (grade 0 to 2) in assessing the outcome of the disabilityy prevention and control programme and, to some degree, by this the success of patient self-care. .

Finance.. An intensive mass survey as conducted in Lalitpur District serves well as a scientificc study, but the cost per newly detected patient renders it far too expensive for an area withh such a low prevalence rate. More than 30% of the new cases were referred or self-reporting.. For this reason in hilly regions like Lalitpur with a prevalence of <10 per 10,0000 only flash surveys combined with intense health education should be done. For all thesee activities it is of great benefit to employ staff who are familiar with or originate from aa population similar to the one to be surveyed.

66 6 MASSS SURVEY OF LALITPUR DISTRICT, NEPAL

RESUMEN N

Dee 1986 a 1990 se Uevó a cabo un extenso estudio masivo para la büsqueda de casos de lepra enn el Distritio Lalitpur de Nepal. Se logró examinar al 85% de la población total. La tasa de detecciónn de casos en ese periodo de 5 aflos fue de 13 por 10,000, la tasa de detección de casoss infantiles fue de 4 por 10,000. Al final del estudio la tasa de prevalencia fue de 6.8 por 10,0000 y a finales de 1992, ésta habia caido a 2.2 por 10,000. En 1991, después de un inter- valoo de 3 afios, se reestudiaron 3 aldeas, detectandose 4 nuevos casos, llevando la tasa de detecciónn a 3.3 por 10,000. Treinta y seis porciento de ios casos antiguos, 20% de los nuevos casoss adultos, y 3% de los nuevos casos infantiles, se clasificaron como multibacilares. Ell 62.7% de los pacientes no tuvieron multilaciones, el 18.8% tuvieron invalides de grado I, yy 12.7% tuvieron invalides de grado 2; para el 5.8% de los pacientes estos datos fueron incompletos.. Hacia el final del estudio, el 91 % de los pacientes que necesitaban tratamiento, estabann bajo tratamiento con poliquimioterapia (PQT). Actualmente el tratamiento con PQTT cubre al 100 de los casos. La frecuencia de regularidad, que al finalizar el estudio era dell 86%, a finales de 1992 fue del 96%. El costo de detección de un nuevo paciente fue de US$298.. Debido a este elevado costo se recomienda que los estudios masivos de detección dee casos solo se efectuen cuando la tasa de prevalence estimada sea mayor de 10 por 10,000 habitantes.. De los datos colectados se han sacado conclusiones y se han formulado recomen- dacioness para el desarrollo de nuevas estrategias para el Programa Nacional de Control de la Lepraa del gobierno de Nepal.

RÉSUMÉ É

Unee enquête intensive de masse pour la lèpre a été réalisée dans Le District de Lalitpur, au Nepal,, pour la période de 1986 a 1990. C'était la première enquête a une telle échelle au Nepal;; 85% de la population totale fut examinee. Le taux de detection pour les cinq années étaitt de 13 pour 10,000; ce même taux était de 4 pour 10,000 chez les enfants. A la fin de 1'enquête,, le taux de prevalence était de 6.8 pour 10,000; fin 1992, celui-ci était descendu a 2.22 pour 10,000. En 1989, après un intervalle de trois ans, une nouvelle enquête fut réaliséee dans trois comités de développement villageois (CDV), et 4 nouveaux cas furent détectés,, donnant un taux de detection sur trois ans de 3.3 pour 10,000; 36% des cas anciens,, 20% des nouveaux cas adultes, et 3% des nouveaux cas enfants étaient classes commee multibacillaires. Globalment,, 62.7% des patients n'avaient pas d'incapacités, 18.8% avaient une incapacité dee grade 1, et 12.7% une incapacité de grade 2; les données étaient incompletes pour 5.8% dess cas. A la fin de 1'enquête, 91% des cas nécessitant un traitement médical étaient sous polyy chimiothérapie. (PCT).. Ceci a présentement augmenté al00%. Le taux de régularité était de 86%; a la fin dee 1992, il avait augmenté a 96%. Le coüt pour détecter un patient était de 298 US$. A causee du coüt élevé, il est recommandé que les enquêtes intensives de masse ne soient pas

67 7 CHAPTERR 2

réaliséess quand la prevalence estimée est inférieure a 10 par 10,000 habitants. A partir des donnéess récoltées, on a tiré des conclusions et on a formule des recommandations pour développerr de nouvelles strategies pour Le Programme National de Lutte contre la Lèpre du Gouvernementt du Nepal.

Acknowledgment.. Thanks to the great efforts made by all Anandaban field staff, often underr very difficult conditions, this survey was successfully completed.

References: : t.. World Health Organisation Expert Committee on Leprosy. Sixthh report. Geneva, Tech. Rep. Ser. 768. 1988. 2.. World Health Organization. Healthh Care in South-East Asia. New Delhi: Worldd Health Organization 1989. S.E. Asia Ser. 14. 1989. 3.. Theuvenet WJ, Miyazaki N, Roche P and Shrestha I. Cytologicall needle aspiration of the nerve for the diagnosis of pure neural leprosy. Intt J Lepr 1993;61:597-599.

68 8 ^^JLJLÖLIMJJ Ib'Ve'JL ^J

Neuritiss of the Lateral Femoral Cutaneouss Nerve in Leprosy

From:: Neuritis of the Lateral Femoral Cutaneous Nerve in Leprosy Wimm J. Theuvenet, Kathleen Finlay, Paul W. Roche, Desmond Soares, andd John M. G. Kauer Int.J.Lepr.. 1993, 61(2), 592-596

69 9 CHAPTERR 3

70 0 NEURITISS OF THE LATERAL FEMORAL CUTANEOUS NERVE IN LEPROSY

SUMMARY Y

Neuritiss of the lateral femoral cutaneous nerve (meralgia paresthetica) is observed more fre- quentlyy in leprosy than in non-leprosy patients, and its symptoms can easily be confused withh those suggesting, e.g., ischialgia. A diagnostic block with a local anaesthetic solution cann confirm the diagnosis. Analgesics, anti-inflammatory drugs, bed rest and, in severe cases, therapeuticc blocks were successfully applied in the treatment of the neuritis, and no surgicall intervention was needed. Three leprosy patients with severe meralgia paresthetica are presented. .

INTRODUCTION N

Leprosyy is frequently complicated by localized neuritis of the peripherall parts of the ulnar, median, common peroneal, posteriorr tibial, facial and radial nerves, causing loss of sensationn and/or motor function. Thickening of cutaneous nervess can frequently be found, mostly in the tuberculoid formm of leprosy2. Neuritis of the lateral femoral cutaneous nervee (LFCN) was first described by Hager4 in 1885 and againn by both Bernhardt1 and Roth7 in 1895. Roth gave it thee name meralgia paresthetica. It is now generally accepted thatt meralgia paresthetica is a neuritis of the LFCN which is duee to low-grade, continuous trauma at the site where the nervee leaves the pelvis.8 In this paper we discuss the rela- tionshipp between leprosy and the occurrence of meralgia paresthetica,, an observation that we have not found in the literature.. Three leprosy patients (the basis for this study) are presentedd as case reports.

Fig.. 1. The lateral femoral cutaneous nerve (LFCN).

MATERIALSS AND METHODS

Wee compared a group of 205 leprosy patients seen at the clinic at Patan Hospital with a matchedd (age, sex, body weight, and height) control group of 50 non-leprosy patients seen att the general outpatient clinic of Anandaban Hospital.

71 1 CHAPTERR 3

Inn both groups the individuals were examined for:

a)) enlargement of the LFCNs; b)) past and present complaints of a tingling, painful sensationn over the lateral and antero-lateral aspect of the thigh,, and c)) sensation over the area when measured with a Semmes-Weinsteinn nylon monofilament with a bending forcee of 5 g. Examinations were done with the patient in aa supine position by an experienced physiotherapist and aa physio-assistant.

Fig.. 2. (<—)) = Lateral femoral cutaneous nerve.

Thee significance of the differences in enlargement, as well as the history and present complaints,, were tested with the chi-squared test.

RESULTS S

Off the 205 leprosy patients, 90 (44%) had loss of sensation as measured with a 5 g nylon monofilamentt only on the anterolateral side of the thigh; in 37 patients loss of sensation was alsoo found elsewhere in the thigh. None of the control group had loss of sensation in this areaa when measured in the same way.

Inn the period prior to this survey we saw six severe cases of meralgia paresthetica in leprosy patientss at Anandaban Leprosy Referral Hospital in Nepal. Of these, three are presented as casee reports.

72 2 NEURITISS OF THE LATERAL FEMORAL CUTANEOUS NERVE IN LEPROSY

Casee 1. Mr. B.B.S. (45 years of age) presented at our outpatient clinic and was diagnosed as havingg borderline lepromatous leprosy. His skin smear was: BI = 4, MI = 0, the lepromin testt was negative. Treatmentt was started with multi-drug therapy for multibacillary patients (M.MDT) accordingg to the regimen recommended by the World Health Organization (WHO) in 1981. . Threee weeks later he returned to our clinic one week earlier than planned with complaints off pain in multiple nerves in his left thigh and in his swollen facial patches. These symptoms weree diagnosed as originating from a type 1 or reversal reaction. Treatment with prednisone 200 mg b.i.d. was started. Onee week later he complained again of severe pain at the anterolateral side of his left thigh. Inn the same area no sensation was detected when touched with a nylon monofilament bend- ingg at 5 g pressure. On his left side just mediocaudal to his anterosuperior iliac spine he had aa greatly enlarged LFCN (Fig. 2). At this site there was a positive Tinel's sign for the above- mentionedd pain. There was no sign of infection in the left leg. A cytological needle aspirationn of the nerve showed multiple acid-fast bacilli (AFB). The diagnosis was made of meralgiaa paresthetica in the left thigh as part of the type 1 reaction. This diagnosis was further supportedd by immediate and complete relief of the pain after blocking the LFCN with 10 cccc bupivacaïne 1.5% solution with epinephrine to which was added 8 mg dexamethasone acetate.. This block was repeated twice after which the LFCN only remained tender on palpation. .

Casee 2. In consultation we saw Mr. B.B. (52 years of age) who had been on the M.MDT-WHOO regimen for 14 months because of BT-BB type of leprosy. He complained off severe pain in both of his thighs for 6 months. This was earlier labelled as ischialgia due too a herniated intervertebral disc. At examination we saw that the patient could walk only whilee bending forward. Both of his LFCNs were grossly enlarged. On palpation a tingling sensationn at the anterolateral aspects of both thighs was experienced. There were no other signss of nerves in reaction. His skin smear BI = 2+, MI = 8%. A cytological needle aspirationn of the affected nerves showed multiple AFB in both nerves. Bilateral diagnostic blocks eachh with 10 cc lidocaïne 0.5% to which was added 8 mg dexamethasone acetate supported thee diagnosis of meralgia paresthetica due to leprosy neuritis. Subsequent to administration off the LFCN blocks the patient could walk in an erect position since there was complete relieff from the pain. A local physician later repeated the blocks twice and reported that the patientt had responded well and had remained free of pain thereafter.

Casee 3. Mrs. P. L. (40 years of age from the Lhasa region in Tibet) presented at our Patan clinicc with severe osteomyelitis of the left calcaneus with fracture of the corpus. The diagnosiss of BL leprosy was made and the M.MDT-WHO regimen was started. Her BI = 3 +, MII = 0, the lepromin test was negative. During the subsequent hospital admission the osteomyelitiss was successfully treated by septic surgery.

73 3 CHAPTERR 3

Duringg a readmission for a finger infection one year later, the patient developed excruciat- ingg pain in her left lower extremity with moderate enlargement of the LFCN which was very tenderr on palpation. There were no signs of a leprosy reaction and no recurrence of infec- tionn of the left foot. Cytological needle aspiration of the LFCN showed AFB in clusters. Thee diagnosis of meralgia paresthetica was supported by immediate and complete relief of thee pain after blocking the LFCN with 10 cc bupivaca'ine 1.5% solution with epinephrine too which was added 8 mg dexamethasone acetate. We prescribed bed rest and another two blockss with bupivaca'ine without dexamethasone were given over the next month. There has beenn no recurrence of her complaints.

DISCUSSION N

Wee found a significant difference in the occurrence of involvement of the lateral femoral cutaneouss nerve (LFCN) in leprosy patients compared to the control group. There was a higherr proportion of nerve enlargement, history of complaints (p < 0.00 1) and of present complaintss (p < 0.05J in the patient group compared to the controls. Isolated loss of sensationn at the antero-lateral side of the thigh was found in 44% of the leprosy patients but in nonee of the controls. The proportion might have been even higher if lighter filaments had beenn used in testing for sensation. Sometimes the complaints can be severe, as illustrated in ourr case reports.

Causativee factors. The constituent fibres of the LFCN are derived from varying combina- tionss of the first-to-third lumbar nerves. The nerve emerges from the lateral side of the psoas musclee and passes under the lateral end of the inguinal ligament at the site of its attachment too the anterosuperior iliac spine and becomes cutaneous in the lateral thigh (Fig. 1). Here thee nerve is wedged in the angle between the bone, the ligament, and the sartorius muscle. Hereafterr it enters the thigh beneath the fascia lata and provides sensation to the lateral and anterolaterall aspect of the thigh. Itt is generally accepted that meralgia paresthetica is due to low-grade continuous trauma at thee site where the nerve leaves the pelvis. In leprosy, localized swelling of the LFCN may contributee to the mechanical trauma. In this area the nerve runs at a cool superficial site, whichh in leprosy seems to predispose to leprosy neuritis 2. Inn the non-leprosy literature several anatomical arrangements have been described3 at the sitee where the nerve enters the thigh which increase the risk of damage when, for any reason,, the nerve is stretched.

Diagnosis.. In neuritis of the LFCN the patient may complain of a tingling, dull aching, burningg sensation or numbness over the lateral and anterolateral aspect of the thigh. The painn can be aggravated when the limb is extended at the hip and when the patient stands or walkss for any length of time. In order to flex the hip and relieve stretch on the nerve, the patientt may limp or walk while bending forward. The pain is sometimes severe and inca-

74 4 NEURITISS OF THE LATERAL FEMORAL CUTANEOUS NERVE IN LEPROSY

pacitating.. At physical examination one may find:

a)) Localized tenderness and swelling of the LFCN; onn palpation the nerve may be tender just below and medial to the anterosuperior iliac spine;; in varying degrees the LFCN can be swollen. b)) Loss of sensation; theree may be loss of sensation in the skin area supplied by the LFCN in varying degrees although,, of course, other mechanisms also can be responsible for this, especially in leprosy. . c)) Nerve conduction studies; thee finding of slowing or absence of LFCN conduction may be helpful, especially when aa difference between the LFCN conduction of the affected and contralateral side can be found.. But these studies are difficult, often not conclusive9, and in general not available inn developing countries. d)) Diagnostic block withh local anaesthetic solution; under field conditions a simple diagnostic block as describedd by Moore6 can support the diagnosis.

Inn leprosy the complaints are often, but not always, associated with a reactional state.

Therapy.. In a case with severe pain suspected to be due to neuritis of the LFCN, we inject togetherr with our diagnostic block a single dose of 40 mg methylprednisolone (Depo- Medrol®).. If the diagnosis is confirmed by a total disappearance of the complaints, we pre- scribee bed rest, oral analgesic and anti-inflammatory drugs, depending on the severity of the complaintss and the extent of leprosy neuritis elsewhere in the body. In a case of very severe, localizedd neuritis we repeat the blocks with only a local anaesthetic solution on alternating days. . Whenn meralgia paresthetica forms a part of a severe leprosy reaction, oral corticosteroids are alsoo given; we give oral prednisone in a basic adult dose of 60 mg daily for 2 weeks after whichh the daily dose is tapered, depending on the clinical situation. Althoughh various surgical interventions have been described5,10 in severe, disabling meralgia paresthetica,, surgery has not been necessary in our patients suffering from meralgia pares- theticaa since, so far, all of them have reacted favourably to the therapy we have described.

RESUMEN N

Laa neuritis del nervio cutaneo femoral lateral (meralgia parestésica) se observa con mas frecuenciaa en los pacientes con lepra que en los pacientes sin lepra, y sus sintomas pueden confundirsee facilmente, por ejemplo, con aquellos de la isquialgia. EI diagnóstico puede confirmarsee por un diagnóstico de bloqueo con una solución de un anestésico local. Loss analgésicos, las drogas antiinflamatorias, el reposo en cama y en los casos severos los

75 5 CHAPTERR 3

bloqueoss terapéuticos, fueron exitosamente aplicados en el tratamiento de la neuritis sin necesidadd de recurrir a la intervención quirürgica. Se presentan los casos de tres pacientes conn meralgia parestésica severa.

RÉSUMÉ É

Unee névrite du nerf fémoro-cutané lateral (méralgie paresthésique) est observée plus fréquemmentt chez des malades de la lèpre que chez des non lépreux, et ses symptómes peuventt aisément être confondus avec eux suggérant par exemple, 1'ischialgie. Le diagnostic peutt être confïrmé par un blocage diagnostique avec une solution anesthésique locale. Des analgésiques,, des medicaments anti-inflammatoires, du repos au lit et, dans les cas sévères, dess blocages thérapeutiques ont été utilises avec succes dans le traitement de la névrite, et aucunee intervention chirurgicale n'était nécessaire. Trois patients présentant une sévère méralgiee paresthésique sont présentés.

References: : 1.. Bernhardt M. Ueberr isolirt im Gebiete des N. Cutaneous Femoris Externus vorkommende Paresthesian. Neuroll Zentbl 1895;l4: 242-243. 2.. Brand PW and Fritschi EP. Rehabilitationn in leprosy. In: Leprosy. Hastings, R. C, ed. Edinburgh:: Churchill Livingstone, 1985, p. 209. 3.. Chusid JG. Spinall nerves, in: Correlative Neuroanatomy and Functional Neurology. Neww Delhi: Lange. 1976, p. 124. 4.. Hager W. Neuralgiaa Femoris. Dtt Med Wschr 1885;11:218-219. 5.. Keegan JJ and Hoyoke EA. Meralgiaa paresthetica, an anatomical and surgical study. JJ Neurosurg 1964;19:341-345. 6.. Moore DC. Blockk of the lateral femoral cutaneous nerve. In:: Regional Block; 4th edn. Springfield, II: Charles Thomas. 1978, p.294-99- 7.. Roth WK. Meralgiaa paresthetica. Medd Oboz Mosk 1895;43:678-9. 8.. Sunderland S. Laterall femoral cutaneous nerve, meralgia paresthetica. In:: Nerves and Nerve Injuries , 2nd edn. New York: Churchill Livingstone, 1978, p. 1007-8. 9.. Taylor RG and Lieberman JS. Electrodiagnosiss in lower extremity nerve compression. In:: Nerve Compression Syndromes, Szabo,R.M.ed.Thorofare, NJ: Slack, Inc., 1989. 10.. TengP. Meralgiaa paresthetica. Bull.Loss Angelos Neurol.Soc. 37: 75-83. 1972.

76 6 Chapterr 4

Changee of Sensation in Leprosy by Selectivee Meshing of the Epineurium

From:: Change of Sensation in Leprosy by Selective Meshing of the Epineurium WJ.. Theuvenet, Kathleen Finlay, and P.W. Roche Submittedd for publication

77 7 CHAPTERR 4

78 8 CHANGEE OF SENSATION IN LEPROSY BY SELECTIVE MESHING OF THE EPINEURIUM

SUMMARY Y

Att present the administration of prednisone remains the first choice of treatment for early losss of protective sensation in leprosy. However, in cases where sensation is not restored by corticosteroidd therapy, a definite improvement of sensation can still be obtained by a new microsurgicall approach known as "selective meshing of the epineurium (SME)". This improvementt is the best (a moderate and definite improvement in 70 % of the nerves) when thee operation is performed within six months after loss of sensation, is still definite in 43 % off the nerves when operated within five years and in 32 % of the nerves when operated withinn 10 years after loss of sensation. The results of 195 nerves operated on in 95 patients aree presented. Thee outcome of nerve decompressions by selective meshing of the epineurium may even be betterr when performed earlier after the initial loss of sensation. Theree is a need to reconsider prednisone regimens and the timing and indications for nerve decompressionn by a selective meshing of the epineurium.

INTRODUCTION N

Inn leprosy neuritis the involved nerve may be affected in two ways1. First, all the fascicles in aa nerve may be destroyed by the acute granulomatous reaction and this damage is irreversible.. The second possibility is that the endoneurial fluid pressure increases causing oedemaa and consequently obstruction of the venous outflow through the epineurium. This mayy be to such an extent that it leads to microvascular insufficiency (ischaemia) and conse- quentlyy loss of nerve function. When the cause of the oedema is eliminated at an early stage thesee effects are rapidly reversible, but when the oedema is long lasting the nerve tissue can bee invaded by connective tissue cells and organized to a fibrous scar. This may explain why severee nerve pain and loss of nerve function in leprosy often fails to respond to corticosteroid therapyy only2'3 although varied success rates of steroid therapy have been reported, and why thee lack of improvement seems to correlate well with the severity and the duration of the neuritis. . Inn cases where the response to conventional steroid therapy is not up to the level of functionall recovery, surgical intervention can be contemplated, albeit that surgical decompressionn of the affected nerve has not always enjoyed a favourable press as illustrated by Graham Greenn in his novel "A burned out case", 1961 (p. 12): Shee had made her moutii with a mauve lipstick, which went badly with the black skin, and herr right breast was exposed, for she had been feeding her baby on the dispensary steps. HerHer arm was scarred far half its length where the doctor had made an incision to release the ulnarulnar nerve, which had been strangled by its sheath. Now the girl was able with an effort to movemove her fingers a further degree. The doctor wrote on her card, for the sisters attention; "Paraffinn wax " and turned to the next patient.

79 9 CHAPTERR 4

Inn the past nerve decompression to prevent the fascicles from being strangulated by the scle- rosedd epineurium was looked upon as a deliberate infliction of injury because the epineuriumm as well as the matrix in which nerve fascicles are embedded, were divided. Inn ENL neuritis sometimes the epineurium was stripped off the compressed fascicles4. Thiss technique is likely to damage the interconnected intrinsic microvascular systems in the epineurium,, perineurium and endoneurium, a system upon which impulse transmission andd axonal transport are dependent. Inn 1993 when faced with a patient who's neuritis did not respond to prednisone treatment, Anandabann Hospital performed a nerve decompression using a new microsurgical approach, whichh would better respect the epineural blood vessels. Since then good results have been obtainedd from this procedure,, later named "nerve decompression by selective meshing of the epineuriumm (SME)".

MATERIALSS AND METHODS

Numbers: : Thee SME was performed on 105 patients with a total of 208 affected nerves (91 ulnar nerves,, 68 median nerves and 49 tibial nerves). When more than one nerve per patient neededd decompression this was in general done in the same session. AA control study was done on a matched group (for type of leprosy, age and duration of loss off sensation) of 100 non-operated patients.

Selectionn of patients for surgery: Onlyy included were those who had at least 3 points (see assessment) loss of sensation per nervee in the hand and/or foot and who had received no corticosteroids in the past two months.. All of these nerves previously failed to improve with a standardised course of pred- nisonee of 40 mg/day for three weeks, after which the dosage was reduced by 5 mg per week. Becausee of time constraints at the always-crowded outpatients department we focussed on losss of sensation and therefore intrinsic muscle weakness was not included in the selection criteria. .

Assessmentt of sensation: Ideallyy we would have liked to use the Semmes Weinstein filaments for sensory testing. Earlierr we had tested the different sets obtained from the same supplier (Hansens Disease Centre,, Carville, U.S.A. that were used by our physio-assistants. Because of too wide a vari- ationn in the forces needed for bending the same calibres of filaments of the different sets, the Semmess Weinstein monofilaments were not used in this study. AA sort-like finding was earlier described in literature5,6.

Thee inter-observer reliability was much better when sensory testing was done with the ball penn test. For this only pressure was applied for making a minimal, just visible indentation.

80 0 CHANGEE OF SENSATION IN LEPROSY BY SELECTIVE MESHING OF THE EPINEURIUM

Twoo experienced physio-assistants independently did this in two consecutive sessions, at the followingg intervals:

1.. Within one week preoperatively. 2.. At one week, two weeks, three weeks, one month, three months, six months, one year andd two years postoperatively.

Sensationn was measured three times at two sets of three standardised points in the hand each coveringg the median and ulnar nerve territories, and at three standardised points in the foot coveringg the area supplied by the posterior tibial nerve. These points were agreed upon at thee Neuritis Workshop in Karigiri, South India (fig. 1).

Fig.. 1. The standardised points for testing the ulnar, median and posterior tibial nerves.

Scoringg of die sensation per nerve was as follows: Normall sensation: 2 points Whenn there was a correct response at least once within 2 cm of the test point. Partiall sensation: 1 point Whenn there was no correct response within 2 cm, but at least twice a response within 44 cm of the test point. Noo sensation: 0 points Whenn there was no correct response within 2 cm, or maximally one single response withinn 4 cm of the test point. Ass every nerve was tested at 3 points, the maximum score for each nerve was 6 points.

81 1 CHAPTERR 4

Recordingg of the change of sensation: Thee result of the decompression by selective meshing of the epineurium (SME) was marked ass follows: Definitee result: 3 to 6 points improvement. Moderatee result: 2 points improvement. Noo result: further decreased sensation or 0 or 1 point improvement.

Surgicall procedure: Thee operation was performed by the senior author under regional anaesthesia, with a tourni- quett inflated at a pressure of 250 mm respectively 350 mm/Hg for the arm respectively the leg,, with the help of magnifying glasses (4.5 times) and a number 15 surgical blade.

Fig.. 2. The epineurial blood vessels and the incisions for the selective meshing of the epineuriumm (SME).

82 2 CHANGEE OF SENSATION IN LEPROSY BY SELECTIVE MESHING OF THE EPINEURIUM

Fig.. 3. The incision for the decompression of the Ulnar Nerve

Overr the ulnar nerve at the elbow an S-skin incision is made from about 8 cm proximal of thee medial epicondyl, over the cubital tunnel, and over the first 5 cm of the flexor carpi ulnariss muscle. Proximallyy external neurolysis is done by carefully freeing the ulnar nerve from under the mediall intermuscular septum and the fibres of the arcade of Struthers. Hereafter the aponeu- roticc roof of the cubital tunnel is incised while preserving the ulnar collateral artery and leav- ingg the soft tissue attachment in the depth of the groove intact in order to prevent later lux- ationn of the nerve. After this the fibrous arcade over the flexor ulnaris muscle is incised. Whilee flexing the elbow, the free gliding capacity of the nerve in the groove is checked. Subsequentlyy internal decompression of the enlarged nerve is done by selective meshing of thee epineurium while carefully sparing its vascular plexus and the extrinsic blood vessels. Decompressionn is done at the superficial, medial and lateral site of the affected nerve leav- ingg the bottom of the groove undisturbed. For this with a number 15 surgical blade partially overlappingg incisions of about 2 mm lengths are made in the epineurium, between the epineurall blood vessels (fig. 2) which remain clearly visible as the extremities are only briefly elevatedd before inflating the tourniquet. This expansion of the constricted epineurium par- allelss the resulting expansion after meshing a skin graft and is done until a proper refill of thee epineural vessels is observed. Onlyy in those cases where there is a tendency for ventral luxation of the nerve over the epicondyl,, a double, winged medial epicondyl based fascial flap is used to reconstruct the roof off the cubital tunnel this of cause without again constricting its blood supply. Noo indication was ever found for performing a medial epicondylectomy and the ventral transpositionn of the nerve. The procedure is finalised by closure in layers.

83 3 CHAPTERR 4

Fig.. 4. The incision for the decompression of the Median Nerve

Thee median nerve is approached through a S-curved, 3 to 4 cm longitudinal incision just proximall of the carpal tunnel, as much as possible paralleling the ulnar side of the palmaris longuss tendon. In this way there is the least chance of damaging the palmar cutaneous branchh of the median nerve. The antebrachial fascia is incised over the full length of the enlargedd nerve and the transverse carpal ligament is divided at the ulnar side in case the nervee is also affected inside the tunnel. In the latter situation the limited open approach is usedd which saves the structures superficial to the roof of the carpal tunnel. The selective meshingg of the epineurium and closure are done as described above.

Fig.. 5. The incision for the decompression of the Tibial Nerve

84 4 CHANGEE OF SENSATION IN LEPROSY BY SELECTIVE MESHING OF THE EPINEURIUM

Thee tarsal tunnel is approached through a curved incision which starts about 8 -10 cm proximall to the tip of the medial malleolus, then reaches the malleolus about 3 cm posterior of itss tip and after this bends to ventral to the point of bifurcation of the medial and lateral plantarr nerves. After opening the deep fascial layer proximally, the tibial nerve and vessels aree identified and the tarsal tunnel is opened. Dissection is continued as far as the bifurca- tionn of the lateral planter and the medial plantar nerves and the branching off of the medial calcaneall branches. At the level of the bifurcation a vascular plexus often surrounds the tib- iall nerve. Over the length of the enlarged nerve the selective meshing of the epineorium and closuree are done as described above with special attention not to damage the network of the extrinsicc blood supply. Thee whole procedure will take about 20 minutes per nerve after which a compression band- agee is applied. The joints are elevated for one week. Limited joint exercises are started by the physiotherapyy department the day after the operation in order to prevent adhesion forma- tionn and thus to preserve the gliding function of the nerves.

Parameters: : Thee following parameters were recorded: 1.. Preoperative time of loss of sensation. 2.. Postoperative time before change of sensation was noticed. 3.. Classification. 4.. Presence of M.leprae in the fascicle biopsies. 5.. Presence of M.lepra in the skin-smears. 6.. Lepromin test. 7.. IgM anti-phenolic-glycolipid-1 (PGL-1) titre in serum.

Thee information on preoperative time of loss of sensation was retrieved from the patient's record.. The fascicle biopsies were prepared with fresh FMA fixative and after this they were stainedd by the modified Job & Chacko method with the reduced use of ethyl alcohol. Skin smearss were stained in the standard way using carbol-fuchsin and 1 % hydrochloric acid in 700 % ethanol. For the lepromin test lepromin A (3x106 bacilli in 100 pi; supplied by the Immunologyy of Leprosy Programme of the World Health Organisation) was injected intra- dermallyy on the volar aspect of the forearm, and the degree of induration at 3-4 weeks was measured.. Induration of greater than or equal to 3mm was considered positive. IgMM anti-phenolic-glycolipid-1 (PGL-1) antibodies were measured at Anandaban's Myco- bacteriumm Research Laboratory by enzyme linked immunosorbant assay (ELISA), withh disaccharide bovine serum albumin at a concentration of 250 ng/ml as the glucocon- jugatee and serum diluted 1:300. Samples with absorbency greater than 0.199 (mean absorbencyy plus 3 SD of serum from 91 healthy Nepali control subjects) were considered positive. .

Statistics: : Thee differences in proportions of change in sensation were tested by the chi-squaired test.

85 5 CHAPTERR 4

RESULTS S

Anandabann Hospital provides clinical treatment to leprosy patients who sometimes come fromm as far away as Tibet. Ten operated patients were lost for the follow up. Ultimately data couldd be collected from 95 patients (64 males and 32 females, with ages ranging from 16 to 544 years) in whom a total of 195 nerves were operated on. Thee average follow up time was 25.9 months (24.0-28.7 months). Off the control group 4 patients were lost for the follow up.

Tablee 1: Durationn of preoperative loss of sensation and the postoperative change of sensation when dividedd in no result (NR), moderate result (MR) and definite result (DR):

Lesss than 6 66 months-1 11 to 5 55 to 10 Moree than 10 months s year r years s years s years s

NR R 30% % 27% % 47% % 54% % 50% % (n=89) ) MR R 4% % 13% % 10% % 14% % 23% % (n=27) ) DR R 66% % 60% % 43% % 32% % 27% % n=79) ) n== number of nerves that were operated on.

Tablee 2: Outt of 117 fascicle biopsies the relation between M.leprae in the decompressed nerve and thee postoperative change of sensation when divided in no result (NR), moderate result (MR) andd definite result (DR):

M.lepraee in the decompressed nerve nott present present t NR R 32% % 511 % (n=522 ) MR R 19% % 13% % (n=18) ) DR R 9% % 35% % (n=47) ) n== number of nerves that were operated on.

86 6 CHANGEE OF SENSATION IN LEPROSY BY SELECTIVE MESHING OF THE EPINEURIUM

Tablee 3: Relationn between M.leprae in the skin-smears and the postoperative change of sensation whenn divided in no result (NR), moderate result (MR) and definite result (DR):

MJepraee in the skin smears Present t Nott present NR R 22% % 53% % (n=89) ) MR R 11% % 15% % (n=27) ) DR R 67% % 32% % (n=79) ) n== number of nerves that were operated on.

Tablee 4: Relationn between the lepromin test and the postoperative change of sensation when divided inn no result (NR), moderate result (MR) and definite result (DR):

Leprominn test positive e negative e NR R 55% % 39% % (699 nerves) MR R 18% % 14% % (233 nerves) DR R 27% % 47% % (488 nerves) n== number of nerves that were operated on.

Tablee 5: Relationn between the PGL-1 antibodies in the serum and the postoperative change of sensationn when divided in no result (NR), moderate result (MR) and definite result (DR):

PGL-11 antibodies positive e negative e NR R 29% % 53% % (811 nerves) MR R 15% % 13% % (266 nerves) DR R 56% % 34% % (788 nerves) n== number of nerves that were operated on.

87 7 CHAPTERR 4

Tablee 6: Relationn between classification, duration of the preoperative loss of sensation, and the postoperativee change of sensation when divided in no result (NR), moderate result (MR) and definitee result (DR):

Classificationn of Leprosy

Losss of sensation < 1 year Losss of sensation > 1 year Paucibacillary y Multibacillay y Paucibacillary y Multibacillary y NR R 311 % 22% % 52% % 50% % (566 nerves) MR R 10% % 0% % 16% % 27% % (199 nerves) DR R 59% % 78% % 32% % 23% % (488 nerves) n== number of nerves that were operated on.

Att the end of the follow-up there was a further decrease in sensation in seven patients in whomm 12 nerves had been operated on. Six of them had multibacillary leprosy and five sus- tainedd one or more recorded episodes of type 2 reaction after the time of nerve decompression.. In the control group there was a decrease of sensation in 43 patients (97 nerves), while inn 7 patients (15 nerves) improvement was found. Thee degree of improvement after selective meshing of the epineurium is significantly higher whenn the nerve decompression is performed within 6 months after loss of sensation than whenn done after 5 years (p<0.01). Although,, the significance could not be proven, improvement seems better when M.leprae aree demonstrated in nerves, in skin smears, when there is anti-PGL-1 positivity, lepromin negativityy (all signs of multibacillary leprosy) and in the early phase of multibacillary leprosy.. In 35 patients M.leprae was found in one or more nerves while the skin smears were negative.. On the other hand in seven patients no M.leprae was found in the nerve(s), while thee skin smear was positive. In a total of 18 patients the serum anti-PGL-1 titre was positivee while the skin smear was negative. Of these anti-PGL-I positivity was found in two patientss who had been smear negative for more than 5 years, suggesting a possible relapse. Inn 13 patients the anti-PGL-1 was negative while the skin smear was positive.

DISCUSSION N

Inn those patients in whom no improvement of sensory nerve function loss was observed after corticosteroidd therapy, a moderate and definite improvement (2-6 points per nerve) could bee obtained in about 70 % of the nerves when surgical decompression was done by selective meshingg of the epineurium.

88 8 CHANGEE OF SENSATION IN LEPROSY BY SELECTIVE MESHING OF THE EPINEURIUM

Thiss compares favourably with the control group in which such an improvement was found inn only 7% of the affected nerves. This difference is significant (p<0.05) and it may signify thatt after unsuccessful corticosteroid therapy the chances of spontaneous improvement of sensationn are very slim. There is an inexplicably wide variation in the reported efficacy of onlyy prednisone therapy for nerve function loss. In a study conducted in our hospital2, an over-alll improvement was found in 37% of the nerves. Inn leprosy when nerve decompressions by the selective meshing of the epineurium are done att an early stage of loss of sensation, the recovery is significantly better than when done at a laterr stage. This corresponds with previous reports on non-leprosy nerve decompressions, e.g.. the carpal tunnel release7 and when done for nerve function loss in leprosy8"14. Our findingsfindings suggest that nerve decompressions performed in patients with multibacillary leprosyy who had a loss of sensation of less than 1 year duration and in whom SME was performed,, had better recovery of sensory loss. Thiss can be explained by the fact that in early multibacillary leprosy the neuritis in general iss less severe and advanced than in paucibacillary leprosy and the oedema formation is thereforee easier to reverse. In longstanding multibacillary leprosy the low-grade inflammation in thee nerve persists for years leading to progressive scar formation. At that advanced stage it tendss to respond less well to decompression than in paucibacillary leprosy, where the neuritiss in general is confined to the earlier phase of the disease except in cases of type 1 reaction, relapse,, or downgrading of the disease. Inn a number of treated patients who had become skin smear negative, acid-fast bacilli were foundd in the nerve biopsy together with serum anti-PGL-1 positivity. Thiss demonstrates that nerves may be the last tissue to be cleared from bacilli and that until thiss process is completed, cell wall antigens will be released that can evoke an immune response. . Thee reliability of Semmes Weinstein monofilaments for the assessment of sensation in leprosyy can be enhanced when for each patient a same observer will use the same one set. At thee time of the study this was not feasible in our busy hospital and the reliability of the monofilaments,, in contrast to a well-performed ball pen test, failed to meet our standards. Thiss situation is rather similar to e.g. the one observed in most of the other countries where leprosyy is endemic.

CONCLUSIONS S

Att present the administration of prednisone remains the first choice of treatment for early losss of sensation in leprosy. But when this fails a definite improvement of sensation can still bee obtained by selective meshing of the epineurium. This improvement is the best (a moderatee and definite improvement in 70% of the nerves) when the operation is performed withinn six months after loss of sensation, is still definite in 43% of the nerves when oper- atedd within five years and in 32% of the nerves when operated within ten years after loss of sensation. .

89 9 CHAPTERR 4

Evenn after failed corticosteroid therapy the results of our nerve decompressions by selective meshingg of the epineurium were significantly better than our results of corticosteroid therapyy only, and may even be better when performed complementary to corticosteroid treatmentt and much earlier after the initial loss of sensation. Thereforee there is a need to reconsider prednisone regimens and the timing and indications forr nerve decompression by a selective meshing of the epineurium.

Illustrations: : 1.. The standardised points for testing the ulnar, median and posterior tibial nerves. 2.. The epineurial blood vessels and the incisions for the selective meshingg of the epineurium (SME). 3.. The incision for the decompression of the ulnar nerve. 4.. The incision for the decompression of the median nerve. 5.. The incision for the decompression of the tibial nerve.

References: : 1.. JobCX, Nervee in reversal reaction. Indiann J.Lepr. 1996, 68(1) : 43-7. 2.. Roche P.W., Theuvenet W.J. et al., Contributionn of type 1 reactions to sensory and motor function loss in borderline leprosy patients and the efficacyy of treatment with prednisone. Int.J.Lepr.. 1998,66(3): 340-346. 3.. Lewis S, Reproducibilityy of sensory testing and voluntary muscle testing in evaluating the treatment of acute neuritis inn leprosy patients. Lepr.Rev.. 1983,54, 23-30. 4.. Srinivasan H. Disability,, deformity and rehabilitation, In:: Leprosy by Hastings, R.C. Churchilll Livingstone, 1994, ISBN 0-443-04406-8. 5.. McGill M, Molyneaux L and Yue D.K. Usee of the Semmes-Weinstein 5.07/10 Gram monofilament: the Long and the Short of it. Diabeticc Med. 1998; 15:615-17. 6.. Yong R, Karas T.J., Smith K.D. and Petrof O. Thee durability of the Semmes-Weinstein 5.07 Monofilament. J.Foott & Ankle Surg. 2000, 39(1): 34-8. 7.. Sunderland S, Nervess and nerve injuries, p.723, Churchilll Livingstone 2nd ed. 1978, ISBN 0 443 01653 4. 8.. Antia N.H. and Pandya N.J. Surgeryy of the peripheral nerves in leprosy. Lepr.Indiaa , 1974,(46): 140-7. 9.. Pandya N.J. Surgicall decompression of nerves in leprosy. Int.J.Lepr.,, 1978, (46): 47-55.

90 0 CHANGEE OF SENSATION IN LEPROSY BY SELECTIVE MESHING OF THE EPINEURIUM

10.. PaiandeD.D. Preventivee nerve surgery in leprosy. Lepr.India,, 1980, 52(2): 276-298. 11.. Malaviya G.N. and Ramu G. Rolee of surgical decompression in ulnar neuritis in leprosy. Lepr.India,, 1982, 54(2): 287-302. 12.. Brandsma J.W., Nugteren W.A.H. et al., Functionall changes of the ulnar nerve in leprosy following neurolysis. Lepr.Rev.,1983,, 54: 31-8. 13-- Srinivasan H. Surgicall decompression of the ulnar nerve. Indiann J.Lepr.,1984, 56(3) : 520-31. 14.. Nores J.M., Redondo A. et al., Traitementt chirurgical des névrites lépreuses. Laa Presse Médicale, 1988, 17no. 34: 1756-1759.

91 1 CHAPTERR 4

92 2 Chapterr 5

Cytologicall Needle Aspiration off the Nerve for the Diagnosis off Pure Neural Leprosy

From:: Cytological Needle Aspiration of the Nerve for the Diagnosis of Puree Neural Leprosy Wimm J. Theuvenet, Nobuko Miyazaki, Paul W.Roche, and Ishwar Shrestha, Int.J.Lepr.. 1993, 61, 597-99.

93 3 CHAPTERR 5

94 4 CYTOLOGICALL NEEDLE ASPIRATION OF THE NERVE FOR THE DIAGNOSIS

SUMMARY Y

Puree neural (also called primary neuritic) leprosy manifests itself by involvement of only the nervee in the absence of skin lesions. Therefore, it sometimes can pose a diagnostic problem. Cytologicall needle aspiration of an affected nerve can be a valuable tool under such circumstances.. The method as developed at Anandaban Leprosy Hospital, Nepal, is described andd two cases are presented.

INTRODUCTION N

Duee to the scarcity of the cardinal signs of leprosy, pure neural leprosy can be difficult to diagnose.. This is because there are no anaesthetic skin lesions, only in some cases is there nervee enlargement and, in general, no acid-fast bacilli (AFB) can be demonstrated in the skinn or nasal mucosa. The neuritis may express itself in sensory and/or motor function loss resemblingg other peripheral nerve diseases, such as M. Charcot-Marie-Tooth, etc.

Thee skill and facilities for additional examinations, such as histopathology of nerve biopsies, immunologicall assessments, etc., are usually not available where needed for the diagnosis of mostt leprosy cases, i.e., in the field. Cytological needle aspiration of an affected nerve can bee a valuable tool under such circumstances. The method developed at Anandaban Leprosy Hospital,, Nepal, is described here and two cases are presented.

MATERIALSS AND METHODS

Inn the past 6 months we have performed cytological needle aspirations of enlarged nerves in 111 patients suspected of having pure neural leprosy. Before aspiration the patient was thor- oughlyy screened for changes in motor function and light touch sensation with Semmes-Weinsteinn nylon monofilaments (GWL Hansen's Disease Center, Carville, Louisiana,, U.S.A), and this was repeated both the day and the week after the procedure. The cytologicall needle aspiration was performed as follows:

Wee prepared the skin with alcohol and put a nerve block with 5 ml lidocaine 0.5% proximall to the site of the intended cytological needle aspiration. A new disposable needle (18 G) andd syringe was filled with 0. 5 ml physiological saline to be used as a carrier. The nerve to bee aspirated was fixed between the thumb and index fingers of one hand while with the otherr hand the needle was inserted into the nerve as parallel to its fascicles as possible. After positioningg the tip of the needle, the body of the syringe was steadied between the thumb andd index finger while with the ring and little finger the plunger was pulled outwardly, thus creatingg a negative pressure inside the syringe and needle (Figure 1). While maintaining the negativee pressure and with the other hand fixing the nerve, the needle was moved to and fro

95 5 CHAPTERR 5

insidee the nerve three times over a distance of about 2 cm. In this way cells from inside the nervee were aspirated into the needle. Then the plunger was carefully and slowly released. An abruptt release would briefly create a positive pressure inside the syringe with the consequent losss of aspirated material. The needle was withdrawn, then it was disconnected, the plunger wass pulled back, and the needle was remounted. With the tip of the needle above a glass slide,, the plunger was pressed, and thus the aspirated fluid inside the needle together with thee saline was discharged onto the slide. The material was stained by the Ziehl-Neelsen methodd for AFB at the Mycobacterium Research Laboratory of our hospital.

RESULTS S

Multiplee AFB were found in the aspirated nerve fluid of 7 out of the 11 examined patients. Twoo of the seven patients are presented here as case reports.

Casee 1. Mr. K. B. A. (Hosp. no. 10362, 26 years of age) was seen on 2 January 1991, referredd by another hospital with the possible diagnosis of leprosy because of a 2-month old ulcerr of the left foot and foot drop on the same side of 1-year duration. There was a history off a cut injury on the medio-dorsal side of the left foot 1 year before. He had been treated withh 3 months of multidrug therapy (rifampin 600 mg once monthly, clofazimine 300 mg oncee monthly, clofazimine 50 mg once daily and dapsone 100 mg once daily).

Fig.. 1. Cytological needle aspiration of the left lateral popliteal (common peroneal) nerve.

Onn physical examination no skin patches were seen. On the left foot total anaesthesia was foundd on the plantar side with complete loss of dorsiflexion (0 on the VMT scale) and almostt complete loss of eversion (1 on the VMT scale) of the ankle joint, this of 1-year durationn according to the patient. At the mediodorsal side of the foot a scar was visible 3 cm in lengthh over the tendons of the anterior tibial muscle and the long extensor of the big toe.

96 6 CYTOLOGICALL NEEDLE ASPIRATION OF THE NERVE FOR THE DIAGNOSIS

Theree was minor enlargement of the left common peroneal (lateral popliteal) and sural nervess with doubtful enlargement of the left ulnar and posterior tibial nerves. Onn the suspicion of pure neural leprosy, a cytological needle aspiration was done which revealedd AFB 1 +. This added one of the cardinal signs of leprosy and confirmed the diagnosis.. With conservative treatment the foot ulcer healed well, and the patient was discharged withh a PVC footdrop inlay splint.4 He is scheduled for surgical treatment of the footdrop withinn 1 year.

Casee 2. Mr. D. B. T. (Hosp. no. 10384, 40 years of age) presented at our clinic because of aa tingling sensation in his left hand and foot of 2 months' duration. No diagnosis had been made,, and he had taken no medical treatment. Onn physical examination a tender, elastic, round, subcutaneous swelling about 8-10 mm in diameterr was found at the mid-dorsal aspect of his left lower arm. There were no skin patchess and no abnormalities were found with regard to sensation (when measured with 5-g nylonn monofilaments) or muscle strength (on the 0 to 5 VMT scale). Slit-skin smears for AFBB at five routine sites were negative, his lepromin skin test was negative, and antipheno- licc glycolipid-1 antibodies were negative. Sincee pure neural leprosy was suspected, we performed a cytological needle aspiration of the swellingg on the left lower arm which revealed a bacterial index (BI) of 3 +. This confirmed thee diagnosis, and multidrug therapy was started with rifampin 600 mg once monthly, clofaziminee 300 mg once monthly, clofazimine 50 mg once daily, and dapsone 100 mg once daily. . Becausee of a persistent local tenderness we explored the tumour and took a biopsy of what appearedd to be a tumour of the posterior branch of the antebrachial cutaneous nerve. AA histopathological examination (S. Lucas) showed: "a multibacillary leproma (undoubted leprosy)) of the borderline leprosy type with a BI of 4.5+. It could very well be a leprosy colonizationn of an old traumatic neuroma."

DISCUSSION N

Theree seem to be variations in the epidemiology of pure neural leprosy. In Nepal about 7% off all our patients present with this form of leprosy, but in other areas this amounted to one sixthh of all patients.3 Puree neural leprosy in general will fall from typical tuberculoid to borderline lepromatous leprosyy in the Ridley-Jopling classification. A few cases of the lepromatous form of pure neurall leprosy have been reported.2 Appropriate typing of pure neural leprosy requires addi- tionall study of the immunological, bacteriological and histopathological features.1 Presently availablee immunological tests have their limitations as diagnostic tools, while for bacteriologicall and histopathological tests one needs a nerve biopsy specimen. Skinn biopsies from anesthetic areas may fail to show histological changes suggestive of leprosy.. When the symptoms of nerve involvement are scarce and where laboratory facilities for

97 7 CHAPTERR 5

thee above-mentioned examinations are not available, the diagnosis of pure neural leprosy cann offer a challenge to the clinician. Inn an attempt to acquire a tool less invasive than a nerve biopsy and still suitable under field conditions,, we performed a number of cytological needle aspirations of nerves of patients suspectedd of having pure neural leprosy. In 7 of the 11 patients in whom cytological aspirationn of the affected nerve was done multiple AFB were found, thus strongly supporting the diagnosiss of pure neural leprosy. Inn none of the patients who underwent cytological aspiration of the nerve was a subsequent iatrogenicc loss of motor function or sensation found the next day or 1 week after. Besides minorr discomfort on palpation of the nerve at the aspirated site in three patients on the first postoperativee day, no local changes could be detected. Since most field programmes have limitedd facilities yet, in general, are capable of doing Ziehl-Neelsen staining, a cytological aspirationn of the nerve can be a valuable tool in supporting the diagnosis of pure neural leprosy. . Inn advance research programmes aspirated nerve fluid could provide valuable information onn the pathoimmunology and serology of, for example, reversal reaction mechanisms inside thee nerve. Inn 1991 at Anandaban Hospital the multidrug therapy for smear-positive patients was con- tinuedd for at least 2 years and only discontinued when the slit-skin smear had become negative. . Accordingg to the latest recommendations of the World Health Organization, we now recommendd repeating the cytological aspiration of the nerve for AFB at the same site after com- pletingg 12 doses of multidrug therapy in order to determine if additional treatment is neededd for pure neural leprosy cases.

RESUMEN N

Laa lepra neural pura (también Ilamada lepra neui'ritica primaria) se manifiesta por la sola afecciónn de nervios sin la presencia de lesiones en piel, ésto a menudo causa problemas en el diagnósticoo de la enfermedad. Bajo tales circumstancias, la aspiración citológica de un nervio afectadoo puede ser de gran utilidad en el diagnóstico. En este trabajo se describe el método desarrolladoo en el Hospital Anandaban de Nepal, en relación dos casos de lepra neuritica primaria. .

RÉSUMÉ É

Laa lèpre purement néviritique (également appelée névritique primaire) se manifeste par Ie seull envahissement de nerfs en 1'absence de lésions cutanées. Cela peut done parfois poser unn problème pour Ie diagnostic. Une aspiration cytologique par aiguille d'un nerf affecteé peutt être un instrument valide dans de telles circonstances. La methode est décrite telle

98 8 CYTOLOGICALL NEEDLE ASPIRATION OF THE NERVE FOR THE DIAGNOSIS

qu'ellee a été développée a I'Hópital pour la Lèpre d'Anadaban au Nepal, et deux cas sont présentés. .

Acknowledgment.. We are indebted to Mr. Ross Morgan, graphic designer at our hospital, forfor helping us with the preparation of the illustration. We are grateful for the assistance of Dr.. Sebastian Lucas, Pathologist, Middlesex Hospital, London, U.K.

References: : 1.. Dharmendra. Classificationn of leprosy. In:: Leprosy. Hastings, R. C, ed. Edinburgh:: Churchill Livingstone, 1985. 2.. Jacob M and Mathai R. Diagnosticc efficacy of cutaneous nerve biopsy in primary neuritic leprosy. IntJLeprr 1988;56:56-60. 3.. Noordeen SK. Epidemiologyy of polyneuritic type of leprosy. Leprr India 1972;44:90-96. 4.. Theuvenet WJ, Ruchal SP, Soares DJ and Roche PW. Advantages,, indications and the manufacturing of melted PVC water pipe splints. Leprr Rev 1994;65:385-95.

99 9 CHAPTERR 5

100 0 Chapterr 6

Thee Paper Grip Test for Screening on Intrinsicc Muscle Paralysis in the Foot off Leprosy Patients

From:: The Paper Grip Test for Screening on Intrinsic Muscle Paralysis inn the Foot of Leprosy Patients Maartjee MX. de Win, Wim J. Theuvenet, Paul W. Roche, Rob A. de Bie andd Henk van Mameren Intt J Lepr, 2002; 70(1) : 16-24.

101 1 CHAPTERR 6

102 2 THEE PAPER GRIP TEST

INTRODUCTION N

Foott problems are one of the most common causes of 'dehabilitation' and morbidity in leprosy.. Mostly, there is a combination of sensory, motor and autonomic nerve affection result- ingg in progressive loss of protective sensation, weakness and muscle atrophy.12 Approxi- matelyy 10% to 15% of leprosy patients have impairments and disabilities involving their feet,, especially plantar ulceration, drop-feet, claw feet and tarsal disorganisation.23 Recurrentt ulceration in spite of protective footwear is the most frequent indication for admissionn in leprosy hospitals.

Althoughh a lot of attention is paid to anaesthesia of the foot sole as a cause of foot problems inn leprosy and other neuropathies of the foot, less attention is paid to paralysis of the intrinsicc muscles. However, it is thought that anaesthetic feet without intrinsic muscle paralysis aree not prone to ulceration.24 As paralysis of the intrinsic muscles of the hand leads to claw hands,, paralysis of the plantar intrinsic musculature of the foot leads to claw toes.12 Intrinsic muscless contribute to the architecture of the longitudinal and transverse arches of the foot, whichh aid in the distribution of mechanical stresses especially during walking.3'19,20 Paralysiss will lead to abnormal foot structure and increased peak-loads. Clawing of the toes duee to intrinsic muscle paralysis also causes a shift in distal direction of the plantar fat pad beloww the metatarsophalangeal (MTP) joint, exposing the thinner part of the skin to pressure.77 Therefore, additional intrinsic muscle paralysis increases the risk of ulceration in anaestheticc feet by a factor of 10 to 12.23 The combination of anaesthesia and paralysis is foundd in 85% of all ulcers; the majority is located in the forefoot, especially in the MTP jointt region.8-23 Infectious conditions, like osteomyelitis, septic arthritis and septic ten- dosynovitiss are most common complicating factors causing further deformation.14

Inn the early stage of intrinsic muscle paralysis, education, self-care and special footwear can helpp prevent further deformities.4'15,21'22 Moreover, claw toe deformity and its consequences mayy be prevented and corrected by tendon transfer surgery, employing the long flexor of eachh digit. This procedure is only possible in flexible claw toe deformities and is preferable too procedures used for fixed claw toe deformities (arthrodesis with or without shortening of thee toe) because it provides a partial restoration of function.13 Thus, just as with the early detectionn of sensibility loss, die early detection of intrinsic muscle paralysis has important implicationss for the prevention of impairment and deformity. In spite of this, there is no reliablee manual test that can be used as a screening test for intrinsic muscle strength in leprosyy patients, unlike the routine tests that are done for the examination of the extrinsic muscless or the sensibility of the foot.

Thee lack of a reliable screening test gave rise to the development of the Paper Grip Test (PGT)) by W. J. Theuvenet and P.W. Roche, from The Anandaban Leprosy Hospital, The Leprosyy Mission, Nepal in 1990. This PGT can be used as a screening test for plantar intrinsicc foot muscle paralysis. The PGT resembles the Froment test for detection of intrinsic

103 3 CHAPTERR 6

handd muscle paralysis, where the patient has to hold a piece of paper between the pulp of thee thumb and that of the index finger while the examiner tries to pull it away.25 This test becomess positive when the adductor pollicis, the first dorsal and the second palmar interos- seii muscles are paralysed, because the patient in an effort to hold on to the sheet, will flex thee distal phalanx of the thumb before losing grip of the paper. In the PGT for the hallux, thee patient will try to hold a piece of paper pressed between the pulp of the big toe and the floor,floor, while the examiner tries to pull it away. If the flexor hallucis brevis is paralysed, the patientt will flex the distal phalanx of the hallux before losing grip of the paper.

Thee purpose of this study was to investigate the reliability of the PGT as a screening test for intrinsicc muscles weakness of the foot. We investigated the outcome of the PGT in leprosy patientss compared to non-leprosy controls. Also, the correlations between the outcome of thee PGT's and different factors such as foot sole sensibility, gender, age and type of leprosy weree objectives of this study.

MATERIALSS AND METHODS

Thee Paper Grip Test Twoo variants of the PGT were conducted, PGT1 to detect intrinsic muscle weakness of the greatt toe and PGT2 to detect weakness of the combined intrinsic muscles of the lesser toes (second,, third, fourth and fifth toe).

Thee Paper Grip Test of the great toe (PGT1). A paperr slip is put under the great toe just distal to thee MTP joint. While the examiner tries to pull thee paper away, the patient offers maximal resistance.. The hand of the examiner rests on the patient'ss knee assuring the heel is kept on the floor.

Duringg the test the person (footwear and socks removed)) sits up straight with hips, knees and ankless in 90° of flexion. The examiner supervises thatt patients stay in the same position and keep theirr heels on the floor during the test. Patients havee to look at their feet, because leprosy patients withh anaesthetic feet will not feel the paper, caus- ingg difficulty in holding the paper. Thee examiner puts a slip of strong rough paper underr the phalanges of respectively the great toe (forr the PGT1) or the four lesser toes (for the PGT2),, just distal to the MTP joints (see photo-

104 4 THEE PAPER GRIP TEST

graph).. The examiner tries to pull the paper away with gradually increasing power in a hori- zontall direction, while the person offers resistance. Solid rough paper (2x10 cm, 100g/m2 type)) that did not easily tear, and a smooth underground of concrete was used in all examinations. .

Thee PGT was carried out up to three times when the patient was not able to grip the paper. Thee PGT was considered positive (abnormal), when it was possible to pull die strip away easilyy all three times. The test was considered negative (normal) when the patient was able too grip the paper at least one out of three times testing.

Patientss and controls Inn 1998, during a period of four months, leprosy patients (new patients and patients who camee for follow-up) and non-leprosy subjects from the Purulia Leprosy Home and Hospital (Thee Leprosy Mission, Purulia, West Bengal, India) were examined for their intrinsic musclee function. Patients with paralysis of the long flexors and extensors of the toes, infective ulceration,, rigid claw toes or other gross deformities were excluded. Patients widi small non- infectivee ulcerations were not excluded. The non-leprosy subjects were volunteers without foott deformities, selected from the same background (family members of the patients and personss matched for social standing) in order to prevent bias due to different types of feet andd footwear.

5177 leprosy patients and 170 non-leprosy controls met the inclusion criteria. Information aboutt age (<20, 20-39, 40-59 and >59) and type of leprosy (TT= tuberculoid leprosy, BT= borderlinee tuberculoid leprosy, BB= borderline leprosy, BL= borderline lepromatous leprosy, LL=lepromatouss leprosy, PN= pure neuropathic leprosy) was obtained of each person. The proportionn of males was 67.4% in the leprosy group and 66.5% in the control group. A majorityy of males corresponds with the general gender-distribution of leprosy.11 The mean agee was 30.3 years in a range from 4 up to 81 years old. Of those 517 leprosy patients, 496 mett the criteria for both feet and 21 patients for only one foot, so a total amount of 1013 leprosyy feet were included in die study. The results of these 21 patients were only regarded inn the analysis of the relation between outcome of the PGT and foot sole sensibility. The otherr analysis required both feet to be included (n=496).

Extrinsicc muscle testing Functionn of the tibialis anterior, the extensor digitorum longus, the extensor hallucis longus, thee flexor digitorum longus, and die flexor hallucis longus were tested by means of isomet- ricc contraction against resistance in unloaded feet.6 For testing of the tibialis anterior, extensorr digitorum longus and the extensor hallucis longus, the patient had to move feet and toes dorsally,, while the examiner offered resistance to extension of the toe and fixed die ankle in 90°° of flexion. For testing the flexor digitorum longus and flexor hallucis longus the patient movedd his toes plantarwards, while the examiner offered resistance to the distal phalanges andd fixed the proximal phalanges in a flexed position to relax the intrinsic muscles.

105 5 CHAPTERR 6

Sensibilityy testing Sensibilityy of the foot sole was tested by means of a 10 gram Semmes-Weinstein monofilament.55 This has been described to be a reproducible method for detecting loss of protective sensationn of the sole of the foot.17 After adequate explanation and demonstration, sensibilityy was tested at three regions: the first metatarsal head (medial plantar nerve), the fifth metatarsall head (lateral plantar nerve), and the heel pad (tibial nerve). The examiner gave a stimuluss up to three times at each region. Sensibility was regarded normal when a patient waswas able to indicate all three regions of pressure stimulus with closed eyes at least one out of threee times tested. A foot was regarded partially anaesthetic when the patient was able at leastt once to indicate the pressure stimulus at either one or two regions, and as totally anaestheticc when the patient was not able to indicate the pressure at any of the three regions.

Examiners s Too diminish information bias, two examiners performed examination. The first examiner determinedd whether patients and controls met the inclusion criteria. This examiner also determinedd the function of the plantar intrinsic muscles of the foot by means of the PGT1 andd 2. The second examiner, a physiotechnician of the hospital staff, performed sensibility testingg of the sole of the foot as part of a three monthly routine check up for leprosy patients. AA third examiner was involved to measure the inter-observer variability of the PGT.

Validityy and reliability of the Paper Grip Test Inn seven leprosy patients with loss of protective sensation of the forefoot but normal PGT 1 andd seven non-leprosy subjects with normal PGT 1 an experiment was done to test the validityy of the PGT in determining plantar intrinsic muscle paralysis of the foot. In all 14 persons thee tibial nerve of one foot was artificially blocked by injecting 5cc bupivacaine 1% inside thee tarsal tunnel. After that the PGTl testing was repeated. Inn three healthy persons we tested the activation of the plantar intrinsic muscles and long muscless of foot and toes, while performing the PGTl by means of surface electromyography. . Inter-- and intra-observer reliability was determined on the basis of the results of the exami- nationss of 20 leprosy patients (n=40 feet) independently by the first and third examiner, alternatelyy just after each other. Intra-observer variability was determined by examining 43 leprosyy patients (n=86 feet) twice by the same examiner on two separate occasions with an intervall of about three months.

Dataa analysis Thee bivariate Pearson correlation-analysis was used to detect linear relations between out- comess of the PGT's and leprosy, foot sole sensibility, gender, age and type of leprosy. Throughh this analysis it is possible to present the relation between two variables, correcting itt for other variables by means of the partial correlation coefficient (pec). A p-value <0.05 waswas regarded as significant.'

106 6 THEE PAPER GRIP TEST

Agreementt in inter- and intra-observer examinations was analysed separately for PGT1 and 22 through the non-weighted Cohen's kappa coefficient (/-value) for two categories (PGT positivee either negative).2

RESULTS S

PGTT in leprosy patients and controls, specificity of the PGT

% % 100--

90--

80 0 280 0 70-- 318 8 60-- 140 0 80-- 1M M

40--

30--

20-- 10-- H H 0^ ^ H H bprnsyy non-feprosy leprosy non-leprosy PGT11 PQT2 BB both feel abnormal I one toot abnormal D both feet normal

Fig.. 1. positive PGT1 of the great toes and PGT2 of the lesser toes in leprosy patients and non-leprosyy controls. Numbers in the columns present absolute amounts of persons.

Figuree 1 shows that 35.9% of the leprosy patients (n=496) had a positive PGT1 and 49.6% aa positive PGT2 of one or both great toes. In comparison, in the control group (n=170), 7.1%% had a positive PGT1 and 17.6% a positive PGT2 of one or both great toes. Corrected forr gender and age, significantly more leprosy patients than non-leprosy controls had a positivee test (pcc=0.29 and p<0.01 for both PGT1 and PGT2). Positive tests in the control groupp can be regarded as false positive tests, so from these results specificity can be calculated.. Sixteen (2x4 + 8) false positive results in 340 tested feet give a specificity of 95.3% for PGT1,, and 47 (2x17 +13) false positive results in 340 tested feet give a specificity of 86.2% forr PGT2.

Influencee of sensory loss, gender, age and leprosy type on the outcome of the PGT Too examine the relation between a positive PGT and loss of foot sole sensibility all feet of leprosy-affectedd people were regarded separately. These were divided into three groups accordingg to the degree of sensibility loss of the foot sole.

107 7 CHAPTERR 6

100--

90 90 30 0 80 0 7 7 „ „

70" " 456 6 60-- 50-- 1 1 40-- 30 0 IH I H 20--

10--

j j total total normall partial sensibilityy anaesthesi1a anaesthQs11e e 1 PGTlan dd FQT 22 abnorrrBt PGTlorP G G722 abnormal DPGT Tland P PGT 22 normal

Fig.. 2. positive PGT1 of the great toes and PGT2 of the lesser toes in the feet (n=1013) of leprosyy patients with different levels of foot sole anaesthesia; normal sensibility (n=606),, partial anaesthesia (n=211), total anaesthesia (n=196). Numbers in the columnss present absolute amounts of feet

Figuree 2 shows that 71.3% of the total anaesthetic feet had a positive PGT of both great and lesserr toes (positive PGT1 and PGT2). In the group of partial anaesthetic feet 33.2% had a positivee PGT1 and PGT2, while 25.6% showed either PGT1 or PGT2 positive. Leprosy feett with a normal sensibility showed a positive PGT1 and/or PGT2 in 24.8%. The relation betweenn degree of sensibility loss and a positive PGT proves to be significantly correlated afterr correction for gender, age and type of leprosy (pcc= 0.49, p<0.01).

108 8 THEE PAPER GRIP TEST

100 0

90 0

80 0

70--

60 0

50 0

40 0

30 0

20 0

10--

0-- mate e female female male e temate temate nan-teproey y PGT1 of one or both great toes abnormal OO PGT1 of both greal toes normal

Fig.. 3. intrinsic muscle weakness of the great toes in males and females in both leprosy patientss (N=496) and non-leprosy controls (N=170). Numbers in the columns presentt absolute amount of persons.

Thee presentation of a positive PGT test among males and females in both leprosy and non- leprosyy groups is shown in figure 3. Female leprosy patients turned out to have a higher prevalencee of a positive PGT of one or both great toes (46.0%) than male leprosy patients (31.0%).. After correction for age and type of leprosy this relation proved to be significant (pcc== 0.21, p<0.01). In the non-leprosy group these values were 14.0% for females and 3.5%% for males (pcc= 0.24, p<0.01).

109 9 CHAPTERR 6

<200 20-39 40-S8 >59 <200 20-39 40S9 ! tep-osy tep-osy ncn-leprosy y II one or both gnat lose abnormal DD both graal toee normal

Fig.. 4. positive PGT1 of the great toes in different age groups in leprosy patients and non- leprosyy controls. Numbers in the columns present absolute amounts of persons.

Figuree 4 shows that the prevalence of a positive PGT increases with older age. PGT1 was positivee in 49.5% of leprosy patients in the age group 40 - 59, against 21.0% positive tests inn the age group up to 19. After correction for gender and type of leprosy the relation betweenn a positive PGT1 and age proves to be significant for both leprosy group (pcc= 0.22, p<0.01)) and control group (pcc=0.19, p=0.01).

110 0 THEE PAPER GRIP TEST

BTT BB BL LL PN differentt types of tnpwy II one or berth great bee abnormal O boihgreei toee normal

Fig.. 5. positive PGT1 of the great toes in different types of leprosy. Numbers in the columnss present absolute amounts of persons.

Thee distribution of a positive PGT among different types of leprosy is shown in figure 5. Thee percentages of patients with positive PGT1 of one or both feet varies significantly per typee of leprosy after correction for gender and age (pcc=0.l6, p<0.01). The highest per- centagess of a positive PGT were found among patients with PN, BB and LL type of leprosy. AA positive PGT1 in TT type of leprosy (14.3%) is two times higher than in non-leprosy patientss (7.1%, fig-1)-

Validityy and reliability of the Paper Grip Test Inn both leprosy patients and non-leprosy subjects the PGT1 changed from negative (normal)) to positive (abnormal) in all 14 feet tested, after blocking the tibial nerve inside the tarsall tunnel with 5cc bupivacai'ne 1%. The long flexors of the foot and toes remained unaf- fected. . Electromyographyy in three healthy persons confirmed that the plantar intrinsic muscles weree used in testing with the PGT. However, also long flexors of foot and toes showed elec- tromyographicc activity. Thee

Ill l CHAPTERR 6

DISCUSSION N

Validity,, specificity and reliability of the PGT Thee results of the experiment, before and after the block of the tibial nerve at the level of thee tarsal tunnel (unaffecting the long flexors and extensors of foot and toes), show that the PGTll is capable to selectively demonstrate intrinsic foot muscle weakness. The EMG exper- imentt shows that also extrinsic muscles were activated during the PGT but by assuring normall strength of the long flexors in all our subjects there was no difference between our sub- jectss regarding extrinsic muscle function. Thee specificity of 95.3% for PGTl found in this study can be considered as high compared too that of other manual muscle strength tests.16 There is a lower specificity of PGT2 (86.2%)) than PGTl. To prevent many false positive results the PGTl is probably a better screeningg method to detect intrinsic muscle weakness than the PGT2. However, the two testss do not provide identical information, so another possibility, explaining the higher per- centagess of positive PGT2 than PGTl in the leprosy group, is that the lateral plantar nerve iss more often affected by leprosy than the medial plantar nerve. Thee inter-observer agreement can be regarded as good for PGTl and moderate/good for the PGT2.. This is comparable to the intertester reliability of otherr manual muscle strength testingg used in leprosy9, but the number of patients was small. The intra-observer reliability is moderatee for both PGTl and PGT2.2 When the moderate K value really reflects the intra- reliabilityy of the PGT, this is a relative weakness of the PGT. However, the moderate reproducibilityy may also be caused by actual changes in muscle function during the long interval betweenn the first and second measurement (about three months). Especially in the begin- ningg phase of multidrug therapy nerve reactions that cause changes in muscle function may occur. . Thee correlation that we found between both age and type of leprosy and positive PGT's is similarr to the correlation between several disabilities, based on peripheral nerves affection, andd age and type of leprosy described in other studies.10-18

Thee use of the PGT as a screening test for intrinsic muscle paralysis of the foot Thee PGT can be a valuable addition to the physical examination of leprosy outpatients. It iss a simple, cheap and non-invasive test that does not require additional equipment. These propertiess make the test especially suitable for screening on the function of plantar intrinsic foott muscles in leprosy patients in hospitals and during fieldwork in developing countries. Fromm our results we conclude that screening of leprosy patients with PGT's additional to sensibilityy testing is very important. Firstly, because we found that the intrinsic muscles of thee great toe are affected in more than one-third of the leprosy patients without gross deformities.. Secondly, because many partially anaesthetic feet appeared to have intrinsic muscle weakness.. Thirdly, in this study intrinsic muscle weakness of both great and lesser toes is foundd in more than 70% of the total anaesthetic feet, making them especially vulnerable to ulceration.. On the other hand, 15% of the patients with total anaesthetic feet has strong intrinsicc muscles making them less vulnerable to ulceration.24 The care of these patients in

112 2 THEE PAPER GRIP TEST thee long-term could be limited to regular control of the skin of the foot and the use of pro- tectivee footwear. Late development of plantar paralysis long after cure of the disease is quite rare.. Fourthly, because the PGT may give early warning of nerve function impairment in patientss with intact foot sole sensibility measured by a 10 grams monofilament method.

Clinicall consequences of a positive PGT- prevention of foot deformity Whenn impaired intrinsic muscle function of the foot is detected by means of the PGT screeningg method, this has important clinical consequences. An early sign of loss of intrinsicc muscle function deserves the same treatment as for instance signs of ulnar nerve neuritis.. Apart from the attempt to treat the neuritis e.g. with corticosteroids, other measures to preventt deformity of the foot are necessary. When a patient has a positive PGT, a Harris mat printt can be used, if available, to detect changes in the weight bearing areas8 as an indica- tionn to adapt the footwear. Special protection of especially the metatarsal area can be created byy e.g. the provision of a rigid sole, which will prevent stress to the metatarsal pads during thee push-off phase of walking. In a flat terrain also a rocker mechanism can be considered. Thee insole should provide support to the longitudinal arch by an arch-support, to the trans- versee arch and the metatarsal heads by a metatarsal button, and add stability to the heel by aa heel cup. Signs of collapse of the longitudinal arch can be detected by measuring a decreasingg projection height of the medial malleolus of the weight bearing foot. In an early stage of claww toes, when the toes are still mobile, a tendon transfer is possible to prevent further claw- ingg of the toes.13

Limitationss of the PGT and recommendations for improvement Thee lack of another reliable, non-invasive clinical test that measures intrinsic muscle strengthh with which the PGT could be compared, is a limitation of this research. Because wee could not compare the PGT to another test, it was not possible to assess the sensitivity off the PGT. The only reliable gold standard would be needle electromyography, which we didd not use in this study. Surface electromyography showed not only electromyographic activityy in the intrinsic muscles but also in the long muscles of the toes. But, by assuring normall strength of the long flexors in all our subjects, a positive PGT caused by weak extrinsicc muscles is excluded. Thee first examiner performed the inclusion of patients and PGTs so the outcome of the PGTss was potentially vulnerable to information bias due to knowledge of variables as leprosy/non-leprosyy and type of leprosy. During examination of the foot this examiner also becamee aware of ulcerations of the foot. This bias was limited by emphasising to all subjects too give as much pressure to the paper slice as they could. Falsee positive PGT s may be caused by generally small muscle power and/or persons' mis- understandingg of the test procedure. This may also explain the higher percentages of positivee PGT's in older people and females in both leprosy and control groups. Moreover, femaless were less inclined to give firm resistance with their feet in reaction to the pulling of thee paper.

113 3 CHAPTERR 6

AA relatively high proportion of feet of leprosy-affected persons with no loss of plantar sensibilityy was found to have positive PGTs (PGTl 10.7%, PGT2 23.1%). Partially this could bee explained by false positive results of the PGTs, but in the control group the proportions off positive PGTs are significantly lower. This could probably be explained by the relatively loww sensitivity of the 10 grams monofilament sensibility test for mild sensibility loss of the footsole.. More sensitive sensibility testing, with a 2 grams monofilament for example, shouldd be performed in these patients. Also, sensibility was regarded as normal when a patientt was able to indicate all three regions of pressure stimulus with closed eyes at least one outt of three times. This will not eliminate some errors due to guessing so this could have leadd to underestimation of sensibility loss in the leprosy group. Thee exclusion of patients with foot deformities gives an underestimation of the percentage off leprosy patients with intrinsic muscle weakness. It is likely that the majority of them has paralysisparalysis of intrinsic foot muscles. Thee influence of the use of different types of paper slips and different types of underground iss not investigated in our study. When the paper slip used is too thin, the tearing point of thee paper will become critical to identifying the threshold for a negative test. Therefore we recommendd standardisation of the paper quality and paper size. We would advise the size andd type that is used for business cards ( at least 100 g/m2), as this paper will not easily tear andd is widely available. Also the direction and rate of force, the area the force is applied to thee paper and testing surface could probably influence the outcome of the PGT We recommendd standardisation of these as a further objective of study. Itt would also be interesting to correlate the PGT results with additional variables such as presencee of ulcer/scar at certain sites and site of anaesthesia to increase the validity of the PGT. .

SUMMARY Y

Plantarr intrinsic foot muscles provide structure to the foot during walking and thus regulate mechanicall foot sole stresses. When paralysed, for instance in leprosy patients with neu- ropathyy of the distal part of the tibial nerve, there is a high prevalence of plantar ulceration andd deformities, especially when muscle weakness goes together with loss of foot sole sensibility.. These patients should get immediate care involving education, special footwear and reconstructivee surgery before further foot impairment and deformity become manifest. Thus far,, in leprosy patients little attention is paid to screening of plantar intrinsic muscles activity.. This can be done with a new simple and non-invasive method, the Paper Grip Test (PGT).(PGT). There are two variants for detecting intrinsic muscle weakness of the foot, PGTl for thee great toe and PGT2 for the combined lesser toes. Inn this study, 517 leprosy patients and 170 healthy volunteers were investigated with the PGT.. Sensibility of the foot sole was tested by means of a 10 grams monofilament. Specificityy of the PGTl is found to be about 95.3%, which is good for physical diagnostic tests.. PGT2 is less specific than PGTl. Individual muscle power and understanding of the

114 4 THEE PAPER GRIP TEST

patientt seems to influence the outcome of the test to a certain extent. Sensitivity can only bee calculated when the diagnosis is confirmed by electromyography. Especiallyy patients with anaesthetic feet, females, older patients and patients with PN, BB orr LL types of leprosy appeared to have a higher prevalence of intrinsic foot muscle weakness.. All results were analysed by means of the bivariate Pearson correlation-analysis and provedd to be statistically significant (p<0.05). It is concluded that the PGTl, more than the PGT2,, is a useful screening test on the function of plantar intrinsic foot muscles in leprosy patientss in hospitals and during fieldwork in developing countries.

ACKNOWLEDGEMENTS S

Thee authors want to thank The Leprosy Mission International and The Leprosy Mission Purulia.. Especially Dr. Kiran Sarkar, reconstructive surgeon, for supervision during the project,, and the physio-technicians of the Purulia hospital staff for their help in sensibility testingg and translation. We also want to thank Prof. Dr. F.G.I. Jennekens for his valuable remarkss on the manuscript. Fundingg for this project has been provided by Universiteitsfonds Limburg / SWOL and the medicall faculty of Maastricht University.

References: : 1.. Altman DG. Correlation. . In:: Practical Statistics for Medical Research. London:: Chapman and Hall; 1991. p. 278-291. 2.. Altman DG. Inter-raterr agreement. In:: Practical Statistics for Medical Research. London:: Chapman and Hall; 1991.p. 403-409. 3.. Basmajian JV and Stecko G. Thee role of muscles in arch support of the foot: An electromyographic study. JJ Bone Joint Surg 1963;45(A):1184-1190. 4.. Bauman JH, Girling JP and Brand PW. Plantarr pressures and trophic ulceration. JJ Bone Joint Surg 1963;45(B):652-658. 5.. Birke JA and Sims DS. Plantarr sensory threshold in the Hansen's disease ulcerative foot. Readd at the Proceedings of the International Conference on Biomechanics and Clinical Kinesiology of Hand andd Foot; Madras, India; 1985. 6.. Boumans MTA and van Ooy A. Hett onderzoek van de voet. In:: Lege artis: het onderzoek van de onderste extremiteiten. Utrecht:: Wetenschappelijke uitgeverij Bunge; 1995. p. 47-68. 7.. Brand PW. Thee insensitive foot (including leprosy). In:: Jahss MH, Disorders of the Foot. Philadelphia:: W.B. Saunders Company; 1982. p. 1266-1286.

115 5 CHAPTERR 6

8.. Brand PW. Insensitivee feet; a practical handbook in leprosy. London:: The Leprosy Mission; 1989. 9.. Brandsma JW, van Brakel WH., Anderson AM, Kortendijk AJ, Gurung KS, and Sunwar SK. Intertesterr reliability of maual muscle strength testing in leprosy patients. Leprr Rev 1998;69:257-66. 10.. Browne SG. Somee less common neurological findings in leprosy. Intt J Lepr 1965;33 :267-272. 11.. de Vries JL and Perry BH. Leprosyy case detection rates by age, sex and polar type under leprosy control conditions. Amm J Epidemiol 1985;121:403-413. 12.. Enna CD. Peripherall Denervation of the Foot. Neww York: Allan R. Liss; 1988. 13.. Fritschi EP. Surgicall Reconstruction and Rehabilitation in Leprosy. Neww Delhi: The Leprosy Mission; 1984. 144 Harris JR and Brand PW. Patternss of disintegration of tarsus in the anaesthetic foot. JJ Bone Joint Surg 1966 ;48 (B) :4-16. 15.. Harris JR and Browne SG. Thee management of dry skin in leprosy patients. Lancett 1966;1:1011-1013. 16.. KimSH.HaKI, Han, KY. Bicepss load test: a clinical test for superior labrum anterior and posterior lesions in shoulders with recurrent anteriorr dislocations. Amm J Sports Med 1999;27:300-3. 177 Kumar S, Fernando DJS, Veves A, et al. Semmes-Weinsteinn monofilaments: a simple, effective and inexpensive screening device for identifying diabeticc patients at risk of foot ulceration. Diabetess Research and Clinical Practice 1991;13:63-68. 188 Kuswah SS, Govila AK, and Kuswah J. Ann epidemiological study of disabilities among leprosy patients attending leprosy clinic in Gwalior. Leprr India 1981;53:240-247. 199 Mann RA. Biomechanicss of the foot. In:: Jahss, Disorders of the Foot. Philadelphia:: W.B. Saunders Company; 1982. p. 37-67. 20.. Mann R and Inman VT. Phasicc activity of intrinsic muscles of the foot. JJ Bone Joint Surg 1964;46(A):469-481. 211 Neville PJ. AA guide to health education in leprosy. Würzburg:: German Leprosy Relief Association; 1980. 22.. Neville P J. AA foorwear manual for leprosy control programs, No I & II. Würzburg:: German Leprosy Relief Association; 1980. 23.. Srinivasan H. Disability,, deformity and rehabilitation. In:: Hastings, Leprosy. Edinburgh:: Churchill Livingstone; 1994. p. 411-447-

116 6 THEE PAPER GRIP TEST

244 Srinivasan H. Trophicc ulcers in leprosy II. Intrinsic muscles of the foot and trophic ulcers. Leprr India 1964;36:110-118. 25-- Tubiana R, Thomine JM, and Mackin E. In:: Examination of the hand and wrist. London:: Martin Dunitz Ltd; 1996. p. 326-327.

117 7 CHAPTERR 6

118 8 Chapterr 7

Riskk Factors for Type-1 Reactions in Borderlinee Leprosy Patients From:: Risk Factors for Type-1 Reactions in Borderline Leprosy Patients Paull W. Roche, Wim J. Theuvenet, and Warwick J. Britton Thee Lancet, 1991, 338 : 654-57

119 9 CHAPTERR 7

120 0 RISKK FACTORS FOR TYPE-1 REACTIONS IN BORDERLINE LEPROSY PATIENTS

SUMMARY Y

Type-11 or reversal reactions are the major cause of nerve damage and disability in leprosy. We wishedd to determine whether there were any clinical or laboratory markers that identified patientss with an increased risk of type-1 reaction. 42 (31%) of 136 Nepalese borderline leprosyy patients (97 male, 39 female; age range 7-73 years) had a type-1 reaction during the first 22 years of multidrug therapy. Before therapy, 41 (98%) of the 42 patients were seropositive forr antibodies to one of three mycobacterial antigens. Seropositivity for IgM antiphenolic- glycolipid-11 (PGL-1) antibodies, but not IgG anti-lipoarabinomannan or anti-M. leprae 355 kDa protein antibodies, was significantly associated with subsequent manifestation of a type-11 reaction (p<0.001). The concentration of IgM anti-PGL-1 antibodies in serum was significantlyy higher in patients in whom a type-1 reaction developed. The risk attributable too anti-PGl-A seropositivity was independent of leprosy class, skin smear positivity, and the presencee of other anti-M leprae antibodies (adjusted odds ratio = 8-7, p<0.001). In the 87 patientss who had a lepromin test, anti-PGL-1 seropositivity and lepromin reactivity were significantt independent risk factors for subsequent reaction. 78% of patients with positive leprominn reactivity and IgM anti-PGL-1 antibodies had type-1 reactions. Patients with these riskk factors should be carefully monitored during antimicrobial therapy to permit early ini- tiationn of anti-inflammatory treatment thus minimising permanent nerve damage and result- antt disability.

INTRODUCTION N

Leprosyy remains a significant cause of morbidity in countries where it is endemic.1 Thee development of effective multi-drug therapy (MDT)2 is a major advance in treatment andd raises the possibility of long-term control of the disease. However, nerve damage can occurr despite adequate antimicrobial therapy, largely because of the complication known as type-11 or reversal reactions.3 These are episodes of increased inflammatory activity in nerves,, skin lesions, or both, and the resulting nerve damage is responsible for muscle imbal- ancee and anaesthesia leading to increased deformity. Type-1 reactions occur in patients with borderlinee leprosy rather than in those with immunologically stable polar tuberculoid or polarr lepromatous leprosy. During the first 6-12 months of therapy with dapsone alone, 50%% of borderline leprosy patients have type-1 reactions.4 In a field study of MDT, 25% of Ethiopiann borderline leprosy patients developed a reversal reaction.5 In addition, nerve damagee can occur without overt neuritis despite adequate MDT, probably because of low-gradee inflammation within the perineural sheath.1-6

Type-11 reactions have been associated with an increase in the cellular immune response to mycobacteriall antigens7, but the reasons for fluctuations in immune responsiveness and the factorss predisposing to reactions are not well understood. We have monitored 136 newly diagnosedd borderline leprosy patients who were commencing MDT to determine whether

121 1 CHAPTERR 7

anyy clinical or laboratory markers found at the time of diagnosis identified patients at increasedd risk of developing type-1 reactions.

PATIENTSS AND METHODS

Patients s Thee study population comprised 136 self-referred borderline leprosy patients presenting to Anandabann Leprosy Hospital. The patients had not been treated previously or had active diseasee after defaulting from prior monotherapy for more than 1 year. Leprosy was diagnosedd on clinical and bacteriological grounds8 and confirmed by histopathology in a minorityy of cases. The duration and extent of disease were estimated at the time of initial examination.. Extent of disease was assessed by the number of involved nerves (defined as unequiv- ocall enlargement or loss of function) and affected skin patches and body areas.9 Patients weree followed-up for an average of 21 months (range 7-35 months), including visits followingg release from treatment. Patients were seen at monthly intervals during the first 6-12 monthss and thereafter at a maximum interval of 2 months. 121 patients received multibacillaryy MDT and 15 paucibacillary MDT.l Bloodd for serological testing was taken before starting MDT. Type-11 reaction was defined as an acute neuritis that presented with the tender enlargement off a peripheral nerve trunk associated with partial or complete loss of motor or sensory function.. This was accompanied in most patients by swelling and erythema in skin patches. Cell-mediatedd immunity was assessed by lepromin reactivity in 87 patients. Lepromin A (33 x 106 bacilli in 100 pi; supplied by the Immunology of Leprosy [IMMLEP] programme off the World Health Organisation) was injected intradermally on the volar aspect of the forearmm and the degree of induration at 3-4 weeks was measured. Induration of greater than orr equal to 3 mm was considered positive. The mean bacteriological index was calculated fromm slit skin smears taken from four sites including, one clinical lesion.

Immunologicall assays IgMM anti-phenolic-glycolipid-1 (PGL-1) antibodies were measured by enzyme linked immunosorbantt assay (ELISA), with disaccharide bovine serum albumin (provided by the IMMLEPP programme) at a concentration of 250 ng/ml as the glucoconjugate and serum dilutedd 1 in 300.910 Samples with an absorbance greater than 0. 199 (mean absorbance plus 33 SD of serum from 91 healthy Nepali control subjects) were considered positive. Known positivee and negative control sera were included in each assay. Variation between assays was lesss than 10%. IgGG anti-lipoarabinomannan (LAM) antibodies11 were measured by ELISA, with Myco- bacteriumbacterium tuberculosis LAM (provided by Dr P. J. Brennan) at a concentration of lu/ml as thee antigen and serum diluted 1 in 1000.9 Samples with an absorbance greater than 0.419 (meann absorbance plus 3 SD of serum from 100 healthy controls) were considered positive.

122 2 RISKK FACTORS FOR TYPE-1 REACTIONS IN BORDERLINE LEPROSY PATIENTS

Tablee 1. Number of patients with a type-1 reaction and number positive or negative for antibodiess or skin smear out of 136 Borderline Leprosy Patients.

OR(95%CI) ) No.. with type-1 reaction) No.. with type-1 reaction/ Unadjusted d Adjustedd by Totall no. positive (%) Totall no. negative (%) multivariant t analysis s Anti-PGL-11 antibody 38/833 (46) 4/533 (7,5) 10,3** (2,3-26,7) 8,7** (2,5-30,5) Anti-LAMM antibody 27/700 (39) 15/66(23) ) 2,11 (1,0-4,4) 1,00 (0,4-2,5) Antii 35 kDa antibody 30/800 (38) 12/566 (21) 2,22 (1,0-4,6) 0,99 (0,3-2,5) Skinn smear 30/700 (43) 12/666 (18) 3,4*** (1,5-7,1) 1,77 (0,5-5,6)

** p < 0,001 *** p < 0,05

Tablee 2. Number of patients with a type-1 reaction and number positive or negative for antibodies,, skin smear, or lepromin reactivity out of 87 Borderline Leprosy Patients tested forr Lepromin Reactivity

ORR ( 95 % CI) No.. with type-1 reaction/No .. with type-1 reaction/ Unajj listed Adjustedd by Totall no. positive (%) Totall no. negative (%) multivariantt analysis

Anti-PGL-ll antibody 29/511 (51) 3/366 (8) 10,4** (2,9-34,0) 28,3*** (5,0-162) Anti-LAMM antibody 19/466 (41) 10/411 (24) 2,22 (0,8-5,3) 0,77 (0,2-2,7) Antii 35 kDa antibody 18/455 (40) 11/42(26) ) 1,99 (0,7-4,5) 1,11 (0,3-4,0) Skinn smear 17/388 (45) 12/499 (24) 2,55 (1,0-6,0) 2,88 (0,6-12,0) Lepromin n 17/466 (37) 12/41(29) ) 1,44 (0,6-3,4) 11,2**** (2,3-53,6)

** p < 0,005 *** p < 0,01 **** p < 0,0005

Antibodiess to the M leprae-specific 35 kDa protein were detected by a monoclonal antibody (ML04)) inhibition ELISA12. Serum samples were considered positive if they caused 50% inhibitionn of binding of ML04 to M leprae sonicate at a titre greater than 10. 566 control sera were all negative.

Statisticall methods Thee significance of differences in rates of seropositivity was tested with the chi-square sta- tisticc and Yates correction. Chi-square contingency tables were used to calculate the odds ratioss (ORs) and 95% CI's for unadjusted differences in the prevalence of type-1 reactions. Adjustedd ORs and 95% CI's were calculated by multivariant analysis to assess the significancee of individual factors. Tests for colinearity between factors were done by multiple

123 3 CHAPTERR 7

regressionn analysis. Differences in the range of antibody levels were assessed by the Mann-Whitneyy test.

RESULTS S

Theree were 97 male and 39 female patients, with an age range from 7 to 73 years. 42 patientss (31 %) had type-1 reactions during the study period. Reactions occurred from the timee of presentation to 19 months after the start of therapy, and developed in 37 patients (88%)) within the first 6 months of therapy. Type-1 reactions were significantly more com- monn in patients classified as mid-borderline (BB) and borderline lepromatous (BL) leprosy comparedd with those classified as borderline tuberculoid (BT) leprosy (6 of 13 [46%],0-05< pp < 0.1, and 24 of 62 [39% ]> p < 0.05. vs 12 of 61 [20%]). Leprosy classification was not ann independent risk factor for the type-1 reaction when paucibacillary BT patients were comparedd with multibacillary BB and BL patients (12 of 61 [20%] with a type-1 reaction vss 30 of 75 [40%]; OR=0.4 [95% CI=0.2-0.8], adjusted OR= 1.2 [95 % CI = 0.4-3.8]).

Alll but one of the patients who had a type- 1 reaction were initially seropositive for one of thee three antibodies tested. Type-1 reactions developed in a significantly greater proportion off anti-PGL-1-antibody-positive patients than seronegative patients (p<0.001). When indi- viduall risk factors were assessed by multivariant analysis, anti-PGL-1 antibodies were asso- ciatedd with a significant increase in the risk of a type-1 reaction (adjusted OR = 8-7, p < 0.001)) (table 1). There was no significant association between risk of a type-1 reaction and positivityy for anti-LAM or anti-35 kDa antibodies (table 1), or between risk of a type- 1 reactionn and a patient's age or sex (data not shown). Patients with a positive skin smear had ann apparent increased risk of reaction but this was not independent of PGL-1 seropositivity orr leprosy class (adjusted OR = 1.7) (table 1). The relation between skin smear positivity andd anti-PGL-1 seropositivity has been reported previously13 Analysis of the different patientt categories revealed that PGL-1 seropositivity was an independent risk factor in BT patientss (OR= 10-0, 95% CI = 8.4-11-6, p < 0.005) and BB/BL patients (OR = 7-6, 95% CII = 0-8-67-9, 0.05 < p < 0. 1).

Off the 87 patients skin tested with lepromin, 46 were positive and 41 negative. 17 (37%) lepromin-positivee and 12 (29%) lepromin-negative patients had a type-1 reaction. Multi- variantt analysis of individual risk factors in patients tested for lepromin showed that PGL-1 seropositivityy (OR=28.3, p<0.0005) and to a lesser extent lepromin reactivity (OR=11.2, p<0.005)) were independently associated with increased risk of type-1 reactions (table 2). Thee effect of lepromin positivity was only apparent in the multivariant analysis. It was not duee to a difference in the rates of type-1 reaction in the lepromin-tested group (33%) and thee whole cohort (31%). Patients with anti-PGL-1 seropositivity and positive lepromin reactivityy had a high rate of type-1 reactions. 78% of patients with both risk factors devel- opedd type-I reactions (table 3).

124 4 RISKK FACTORS FORTYPE-1 REACTIONS IN BORDERLINE LEPROSY PATIENTS

Thee mean absorbance of serum samples tested for anti-PGLl antibody was significantly higherr (p < 0.01) in patients who subsequently manifested type-1 reactions (A492 = 0.758) thann those who did not (A492 = 0.457) (figure top next page). This effect was most appar- entt in BT patients (A492 = 0.674 in patients with subsequent reactions and 0.185 in those withoutt reactions; p<0.01). The mean absorbance of serum samples tested for anti-LAM antibodyy was also significantly higher in patients who developed type-1 reactions than in thosee who did not (A492 = 0.866 vs 0.564; p<0.01), and there was a simular, though non- significant,, trend for anti-35 kDa antibodies (mean litres causing 50 % inhibition= 33 vs 13).. The three patient subgroups were not significantly different in the mean absorbance of 500 % inhibition titre of serum samples tested for anti-LAM and anti-35kDa antibodies.

Meann initial antibody levels in borderline leprosy patients whoo did or did not develop a type-1 reaction.

Barss represent mean (SE) absorbance at 492 nm (anti:PGL-1 and anti-LAM)) or mean titre causing 50% inhibition (anti-35 kDa) in patientss who did (0) or did not (S) have a type-1 reaction. *p<< 0 01 compared with patients who did not have a type-1 reaction.

Tablee 3. Relationship between Lepromin Reactivity, Seropositivity to PGL-1, and the Incidencee of Type-1 reactions in 87 Borderline Leprosy patients tested for Lepromin Reactivity. .

Leprominn positive ( N = 46) Leprominn negative ( N = 41) Anti-PGL-11 positive Anti-PGL-1 1 Anti-PGL-1 1 Anti-PGL-1 1 (( N - 18) negativee ( N =28) positivee ( N 33) negativee ( N = 8) No.. (%) of patients with aa type-1 reaction 14** (78) 33 (28) 122 (36) 0 0

** p<0.01 compared with proportion of lepromin-positive anti-PGL-1 negative andd lepromin-negative anti-PGL-1- negative patients with a type-1 reaction.

125 5 CHAPTERR 7

DISCUSSION N

Inn our patients multivariant analysis of the clinical, bacteriological and serological parame- terss of new borderline leprosy patients showed that the presence of anti-PGL-1 antibodies andd lepromin positivity were significant risk factors for manifestation of type-1 reactions. Thee presence of other anti-leprosy antibodies and skin smear positivity were not useful pre- dictorss of reaction, nor were leprosy class, age, and sex. The risk attributable to PGL-1 seropositivityy was greater among BT patients than BB/BL patients. Concentrations of anti-PGL-11 antibody (as indicated by absorbance) were significantly higher in those patients withh subsequent type-1 reaction. Iff type-1 reactions are caused by delayed-type hypersensitivity reactions directed against per- sistingg mycobacterial antigens3, why are they associated with anti-PGL-1 antibodies? In patientss with multibacillary and paucibacillary leprosy there is a strongg correlation between seropositivityy and bacterial load13 and the clinical extent of the disease.9 In particular, increasingg neural involvement is associated with and-M leprae antibodies in patients with BT111 and primary neuritic14 leprosy. Although anti-Af. leprae antibodies may not be involvedd directly in the pathogenesis of type-1 reactions, antibodies may be a marker of significantt antigen load in nerves, which predisposes to type-1 reaction in the presence of an activee T-cell response to M leprae. Lepromin positivity is evidence of M. leprae-specific cel- lularr reactivity, and patients who were both lepromin positive and IgM anti-PGL-1 seropos- itivee had a greatly increased risk of type-1 reaction.

Leprosyy patients mount a humoral response to a range of protein and carbohydrate antigens.15-166 The 35 kDa protein and PGL-1 are recognised by M leprae-specific antibodies whilee LAM is recognised by a crossreactive anti mycobacterial response. PGL-1 is a major secretoryy product of M. leprae 17 and there is a strong correlation between the viability of M.lepraeM.leprae u and PGL-1 production.18-19 PGL-1 is readily detectable in the sera of untreated multibacillaryy patients 20 and it elicits a dominant IgM antibody response in contrast with thee IgG response to LAM and 35 kDa protein antigens. Concentrations of PGL-1 fall rap- idlyy with antimicrobial therapy 20 as do concentrations of IgM antiPGL-1 antibodies, but att a slower rate.21 While PGL-1 is not itself a T-celll antigen22 other antigens released from degradedd bacilli may_be the target of cellular immune responses during the type-1 reaction. Itt is significant that most reactions occur while antigen release is at its greatest during the firstfirst 6 months of therapy. Althoughh the factors that initiate type-1 reactions in individual patients are uncertain, the combinationn of PGL-1 seropositivity and lepromin positivity identifies a group at increased risk.. Such patients should be carefully monitored during the first 6 months of therapy to detectt clinical signs of type-1 reaction. This may lead to early treatment of reactional episodess with a resultant reduction in nerve damage and disability. The frequency of type-1 reactionss in borderline leprosy patients appears sufficiently high to warrant a clinical trial to determinee whether prophylactic therapy with and-inflammatory drugs can prevent the developmentt of overt or silent neuritis during antimicrobial treatment.

126 6 RISKK FACTORS FORTYPE-1 REACTIONS IN BORDERLINE LEPROSY PATIENTS

ACKNOWLEDGEMENT T

Wee thank the staff of Anandaban Leprosy Hospital for their cooperation, Dr.RJ.W. Rees for thee provision of Mycobacterium leprae sonicate through the IMMLEP component of the WHO/UNDP/Wbrldd Bank Tropical Diseases Research Programme, Dr. J.Ivanyi for pro- vidingg ML04 conjugate, and Dr.P.J.Brennan for providing LAM (prepared under NIH con- tractt Al-52582). The Mycobacterial Research Laboratory is fully supported by The Leprosy Missionn International. We also thank Ms. Jenny Peat of the Department of Medicine, Sydneyy University, for assistance with statistical analysis.

References: : 1.. Anon. Expertt Committee on Leprosy, 6th report. Geneva:: World Health Organisation, Technical Report Series no 768; 1988. 2.. Anon. Chemotherapyy of leprosy for control programmes. Geneva:: World Health Organisation, Technical Report Series no 675; 1982. 3.. JobCK. Nervee damage in leprosy. Intt J Lepr & Mycobact Dis 1989;57:532-39. 4.. Pfaltzgraff RE and Bryceson A. Clinicall leprosy. In:: Hastings RC, ed. Leprosy. Edinburgh:: Churchill Livingstone; 1985. p.166. 5.. Becks-Bleumink M. Operationall aspects of multidrug therapy. Intt J Lepr & Mycobact Dis 1989;57:540-51. 6.. Srinivasan H, Rao KS, and Shanimugan N. Steroidd therapy in recent "quiet nerve paralysis" in leprosy: Reportt of a study of twenty-five patients. Leprr India 1982;56:412-19. 7.. Barnetson RStC, Bjune G, Pearson J.M.H., and Kronvall G. Antigenn heterogeneity in patients with reactions in borderline leprosy. Brr MedJ 1985;iv:435-37. 8.. Ridley DS, and Jopling WH. Classificationn of leprosy according to immunity: a five-group system, Intt J Lepr & Mycobact Dis 1966;34:255-73. 9.. Roche PW, Britton WJ, Failbus SS, Ludwig H, Theuvenet WJ, and Adiga RB. Heterogeneityy of serological responses in paucibacillary leprosy - differential responses to protein and carbohydratee antigens and correlation with clinical parameters. Intt J Lepr & Mycobact Dis 1990;58:319-27. 10.. Brett SJ, Payne SN, Gigg J, Burgess P and Gigg R. Usee of synthetic glyconjugates containing the M leprae specific and immunodominant epitopee of phenolic glycolipid-I in the serology of leprosy. Clinn Exp Immunol 1986;64:476-83. 11.. Levis WR, Meeker HC, Schuller-Levis GB, Sersen E, Brennan PJ, and Fried P. Mycobacteriall carbohydrate antigens for serological testing of patients with leprosy. JJ Infect Dis 1987 ;56:763-69.

127 7 CHAPTERR 7

12.. Sinha S, Sengupta U, Ramu G, and Ivanyi J. Serologicall survey of leprosy and control subjects by a monoclonal antibody based immunoassay. . Intt J Lepr & Mycobact Dis 1985;53:33-38. 13.. Roche PW, Briton WJ, Failbus SS, Williams D, Pradban MH, and Theuvenet WJ. Operationall value of serological measurements in multibacillary leprosy patients: clinicall and bacteriological correlates of antibody responses. Intt J Lepr & Mycobact Dis 1990;58:480-90. 14.. Roche PW, Britton WJ, Failbus SS, et al. Serologicall responses in primary neuritic leprosy. Transs R Soc Trop Med Hyg 1991;85: 299-302. 15.. Editorial. Serological tests for leprosy. Lancett 1986;i:533-35. 16.. Gaylord H, and Brennan PJ. Leprosyy and the leprosy bacillus; recent developments in characterisation of antigens and the immunology of thee disease. Annuu Rev Microbiol 1987;41:645-75. 17.. Hunter SW, and Brennan PJ. AA novel phenolic glycolipid from Mycobacterium leprae possibly involved in immunogenicity and pathogenicity. . JJ Bacteriol 1981;147:728-35. 18.. Franzblau SG, Harris EB, and Hastings RC. Axenicc incorporation of [U"l4C] palmitic acid into the phenolic glycolipid-I of Mycobacterium leprae. FEMSS Microbiol Lett 1987;48:407-11. 19-- Mistry Y, Antia NH and Mukherjee R. Correlationn of bacterial viability with uptake of [l4C] acetate into phenolic glycolipid of MycobacteriumMycobacterium leprae, within Schwanoma cells. JJ Bioscience 1989;l4 :37-45. 20.. Roche PW, Britton WJ, Neupane KD. Thee response to chemotherapy of serum Mycobacterium leprae specific antigen in multibacillaryy leprosy patients. Amm J Trop Med Hyg 1991;44:702-08. 21.. Chanteau S, Cartel JL, Celerier P, Plichart R, Desforges S, and Roux J, PGL-11 antigen and antibody detection in leprosy patients: evolution under chemotherapy. Intt J Lepr & Mycobact Dis 1989;57:735-43. 22.. Brett SJ, Lowe C, Payne SN, Draper P. Phenolicc glycolipid 1 of Mycobacterium leprae causes non-specific inflammation but has no effect on cell-mediatedd responses in mice. Infectt Immun 1984;46:802-08.

128 8 Chapterr 8

Contributionn of Type-1 Reaction to Sensoryy and Motor Function Loss in Borderlinee Leprosy Patients and the Efficacyy of Treatment with Prednisone

From:: Contribution of Type-1 Reaction to Sensory and Motor Function Loss in Borderlinee Leprosy Patients and the Efficacy of Treatment with Prednisone Paull W. Roche, Wim J. Theuvenet, Joseph W. Le Master, and C. Ruth Butlin Int.. J. Lepr 1998, 66: 340-47

129 9 CHAPTERR 8

130 0 CONTRIBUTIONN OF TYPE 1 REACTIONS TO SENSORY AND MOTOR FUNCTION LOSS

SUMMARY Y

Thee prevention and treatment of reactions and nerve damage has recently been highlighted ass the top research priority in leprosy.1 Much of the nerve damage in leprosy is thought to takee place during reactions.4 There have, however, been very few, large, long-term assess- mentss of the impact of type 1 reactions (TlR) neither on nerve function nor on the effec- tivenesss of current prednisone treatments for TlR in terms of nerve function recovery.

Thee aim of this paper was to quantify the changes in sensory and motor functions in a cohortt of new borderline leprosy patients with and without episodes of TlR in order to assesss the contribution that these episodes make to nerve function impairment and the efficacyy of a semi-standardized prednisone treatment regimen.

MATERIALSS AND METHODS

Patients s Thiss retrospective study consisted of 360 borderline leprosy (BT, BB, BL) patients diagnosed onn clinical and bacteriological grounds according to the Ridley-Jopling classification9, who presentedd at Anandaban Leprosy Hospital between 1989 and 1996. These patients had had noo previous antileprosy treatment, were regular patients at Anandaban Hospital, and had hadd sensory and voluntary muscle testing performed at diagnosis and on a second occasion att least 6 months later. Typee 1 reactions were diagnosed as neural when there was marked tenderness, weakness, paralysiss or anaesthesia of less than 3 months' duration. In practice, patients with nerve functionn loss but having no nerve pain or tenderness or other signs of reaction were not included.. Cutaneous reactions were characterized by inflamed plaques, erythematous lesions withh raised edges (with or without scaling), ulceration, oedema in hands or feet, an inflamed faciall patch, or the appearance of new lesions during multiple drug therapy (MDT). Patients withh erythema nodosum leprosum (ENL) nodules were not included.

Sensoryy and voluntary muscle testing Sensoryy testing (ST) was performed at 14 points on the palms of each hand and the sole of eachh foot by the ball-point pen test.12 The sensation of the cornea was tested with sterile cot- tonn wool. For this study, definite sensation was scored as 1 and doubtful or insensitive as 0. Totall scores for the hands and feet of 28 and for the eyes of 2 were recorded and combined inn a cumulative sensation score with a maximum of 58. Voluntaryy muscle testing (VMT) was performed at the same time as sensory testing by standardd methods.3 This VMT gave a score of 15 for each hand based on little finger abduction,, thumb abduction and wrist extension. A score of 10 for each foot was based on foot dorsiflexionn and eversion. The strength of eye closure gave a maximum score of 5 for each eye.. Scores were combined to give a cumulative VMT score with a maximum of 60.

131 1 CHAPTERR 8

STT and VMT scores at presentation and at the most recent testing (at least 6 months after initiall testing) were compared using a grading previously described.' * Scores on the second testingg more than 1 point higher than those at diagnosis were regarded as improvement; thosee patients with a score less than 1 point lower than their initial score were regarded as worsening. . Disabilityy classification was performed on all patients at their initial consultation using the Worldd Health Organization (WHO) 1977 disability index (DI)13 and in 278 patients on a secondd occasion at least 6 months later.

Statistics s Thee significance of changes in ST, VMT and DI in individual patients was tested by the pairedd Wilcoxon Z test. Differences in proportions were compared by means of the chi-squaredd test. Differences in the ST and VMT scores between patient groups were tested byy the Mann-Whitney U test.

RESULTS S

Off the 360 patients enrolled in this study, 63 were excluded from further analysis. These 63 includedd 24 patients with T1R who had no details of anti-inflammatory treatment and 39 patientss with sensory or motor function loss of less than 6 months' duration, without symptomss of TlR, who were being treated with prednisone.

Thee final group consisted of 297 patients, 205 of whom were male and 92 were female with agess ranging from 7 to 78 years; 143 were classified as borderline tuberculoid (BT), 27 as truee borderline (BB) and 127 as borderline lepromatous (BL).

Off the 297 patients 157 (53%) experienced a T1R reaction during the follow-up period (averagee follow up 30.7 months; range 6 to 74 months). Patients who experienced a T1R reactionn were followed for a longer period (33.4 months) than those patients without T1R (27.66 months, p <0.05). The T1R reaction was cutaneous in 68 cases, neural in 37 and mixedd (both cutaneous and neural) in 52 cases. There were no significant differences in the prevalencee of TlR between male (107/205, 52%) and female (50/92, 54%) patients or betweenn younger (<40 years) or older (>40 years) patients (93/176, 53% versus 64/121, 53%).. There was a significantly lower proportion of TlR among BT patients (51/143, 36%)) than either BB [17/27 (63%), p <0.051] or BL [89/127 (70%), p <0.001] patients.

Thee majority of patients (111, 71%) had a single episode of TlR; 29 patients (18%) had twoo episodes, 11 (7%) had three episodes, 5 (3%) had four episodes and 1 patient had five episodes.. These were distinct episodes following at various times after completion of treatmentt for TlR. There was no significantly greater recurrence of TlR in patients with neural orr mixed TlR (25/89), compared with patients with cutaneous TlR (21/68).

132 2 CONTRIBUTIONN OF TYPE 1 REACTIONS TO SENSORY AND MOTOR FUNCTION LOSS

Thee length of untreated TlR was recorded in 67 cases. While 73% of all TlR cases were treatedd within 2 months of the symptoms appearing, 12/27 (44%) of the patients with neurall TlR compared with 6/30 (20%, p = NS) patients with cutaneous TlR had symptoms forr 3 months or longer before reporting for and receiving anti-inflammatory treatment.

Tenn patients had relapsing TlR during which symptoms increased while under treatment andd the dose and duration of treatment had to be increased (mean treatment length 21.3 weeks);; five patients had cutaneous TlR and five had neural or mixed TlR (p = NS).

Treatment t Alll TlR patients were treated with prednisone and 86% of them were treated with a maxi- mumm dose of 40 mg daily, reduced in steps over a period of 4 to 74 weeks (average 15.8 weeks).. Generally, two schedules were followed: a) in the earlier part of the study, patients receivedd 40 mg reduced by 5 mg weekly over a period of 8 weeks, and b) later most patients receivedd 40 mg for 2 weeks followed by 30, 20, 15, 10 and 5 mg for a total of 12 weeks. However,, the length of treatment varied with individual patients. Ten patients were treated withh a maximum 60-80 mg daily and 12 were treated with a 20-30 mg maximum for an averagee of 12 weeks. Patients with skin TlR symptoms were treated for an average of 17.5 weeks;; those with mixed cutaneous and neural TlR for an average of 16.5 weeks. Patients withh neural TlR were treated for significantly shorter periods (average 11.5 weeks, p <0.01). Thee mean maximum dose for patients with neural TlR (41.62 mg) was not significantly higherr than that given to patients with skin TlR (40.15 mg).

133 3 CHAPTERR 8

Tablee 1. Changes in cumulative sensory test score for four limbs and both eyes in various studyy groups.

Studyy Group Improved d Worsened d Unchanged d Mediann score (Range) Significancee of differences betweenn pre- and post-

No.. (%) No.. (%) No.. (%) Pre-TreatmentP Post-Treatmen t t treatmentt scores Totall (N - 297) 1099 (37%) 688 (23%) 1200 (40%) 488 (0-58) 499 (0-58) 0.0006 6 T1R(N== 157) 655 (41%) 399 (25%) 533 (34%) 488 (1-58) 488 (0-58) 0.015 5 Noo T1R (N = 140) 44 (31%) 299 (21%) 677 (48%) 48.55 (0-58) 500 (0-58) 0.023 3

Episodes s Singlee (N = 111) 466 (41%) 255 (23%) 400 (36%) 477 (0-58) 488 (0-58) 0.024 4 b b Multiplee (N = 46) 199 (41%) 144 (30%) 133 (29%) 511 (2-58) 50.55 (0-58) NS

Skinn (N = 68) 322 (47%) 111 (16%) 255 (37%) 477 (2-58) 533 (2-58) 0.003 3 c Nervee (N = 37) 122 (32%) 166 (43%)d 99 (25%) 433 (2-58) 444 (0-58) NS S Bothh (N = 52) 211 (40%) 122 (23%) 199 (37%) 511 (1-58) 499 (2-58) NS S

Agee (yrs) <400 (N = 176) 666 (38%) 333 (19%) 777 (43%) 522 (2-58) 544 (2-58) 0.001 1 e >400 (N = 121) 433 (35%) 355 (30%) 433 (35%) 422 (0-58) 444 (0-58) NS S

Admissionn for 477 (47%) 222 (22%) 300 (30%) 477 (1-58) 499 (0-58) 0.009 9 T1R(N== 99) Noo admission for 188 (31%) 177 (29%) 233 (40%) 488 (2-58) 47.55 (0-58) NS S T1R(NN = 58)

aa Differences between paired measurement from inidvidual patients in each group tested by Wilcoxon Z test. bb NS = Not statistically significant cc Significantly lower post-treatment ST score in patients with nerve T1R compared to patients with skinTIR dd Significantly higher proportion of nerve TlR had worsening ST scores relative to patients with skin TlR (p < 0.01) ee Significantly lower pre-treatment and post-treatment ST scores in patients aged > 40 (p < 0.001)

Off the 157 patients with TlR, 99 were admitted to our hospital for treatment for periods off between 1 and 30 weeks (average stay 7 weeks); the remainder were treated as outpatients.

Sensoryy and motor function Thee changes in ST and VMT scores in patients in various clinical groups are shown in Tabless 1 and 2. No significant differences were found between BT, BB or BL patients. The differencess between left and right hands, feet or eyes were found to be not significant (data nott shown).

Off the 297 patients, less than half (117, 39%J improved in either ST or VMT scores; 51 patientss (\7%) improved in both ST and VMT scores, while 15 (5%) improved in VMT scoress only, and 51 (17%) improved in ST scores only. Sensory and VMT changes in indi- viduall patients were significantly correlated (p <0.001).

134 4 CONTRIBUTIONN OF TYPE 1 REACTIONS TO SENSORY AND MOTOR FUNCTION LOSS

Off patients with completely anaesthetic hands, 8/18 (44%) recovered some sensation; 16/59 (27%)) of patients with anaesthetic feet and 3/20 with corneal anaesthesia also recovered somee sensory function. Of the 7 patients with paralysed hands or feet or lagophthalmus, onlyy 1 patient with a paralysed hand and 1 patient with lagophthalmus recovered some musclee function; 4 patients with paralysed feet did not recover any muscle function.

Tablee 2. Changes in cumulative VMT scores for four limbs and both eyes in various study groups. .

Studyy Group Improved Worsened Unchanged Median score (Range) Significancee of differences betweenn pre- and post- No.. {%) No. (%) No. (%) Pre-Treatment Post-Treatment treatment scoresa Totall (N = 297) 777 (26%) 333 (11%) 1877 (63%) 588 (8-60) 599 (8-60) << 0.0005 T1R(N== 157) 566 (36%) 200 (13%) 811 (51%) 588 (18-60) 599 (26-60) << 0.0005 Noo TlR (N = 140) 211 (15%)b 133 (9%) 1066 (76%) 588 (8-60) 599 (8-60) 0.031 1

Episodes s Singlee (N= 111) 422 (38%) 122 (11%) 577 (51%) 588 (18-60) 599 (31-60) << 0.0005 Multiplee (N=46) 144 (30%) 88 (17%) 244 (53%) 588 (32-60) 599 (26-60) NSC C

Skinn {N = 68) 277 (40%) 33 (4%) 388 (56%) 588 (16-60) 600 (31-60) << 0.0005 Nervee (N = 37) 122 (32%) 77 (19%) 188 (49%) 577 (32-60) 588 (26-60) NS S Bothh (N = 52) 177 (33%) 100 (19%) 255 (48%) 588 (40-60) 599 (36-60) NS S

Agee (yrs) <400 (N = 176) 522 (30%) 166 (9%) 1088 (61%) 588 (18-60) 600 (20-60) << 0.0005 >400 (N = 121) 255 (21%) 177 (14%) 799 (65%) 588 (6-60) 599 (8-60) NS S

Admissionn for 399 (40%) 122 (12%) 488 (48%) 588 (32-60) 599 (26-60) 0.002 2 T1RR (N = 99) Noo admission for 177 (29%) 88 (14%) 333 (57%) 588 (18-60) 600 (31-60) NS S T1RR (N = 58) aa Differences between paired measurements from individual patients in each group tested by Wilcoxon Z test, bb Significantly fewer non-TIR improvements in VMT scores compared with reaction patients (p < 0.001) cc NS = Not statistically significant NN = number of patients

Sensoryy scores Thee sensory scores in hands and feet were significantly improved in the total group over the studyy period (Table 3 and data not shown). There was no improvement in corneal sensation (dataa not shown) but an over-all improvement in the cumulative sensory score (Table 1). Whenn patient subgroups were considered, sensation improved overall in patients with and withoutt T1R (Table 1). However, patients with multiple TlR episodes or with neural TlR (withh or without skin involvement) did not show any significant improvement. The improvementss seen were largely contributed to by improvements in hand ST scores; sensory scoress in feet and eyes did not reach significance for any subgroup (Table 3 and data not

135 5 CHAPTERR 8

shown).. The magnitude of the difference in post-treatment sensory scores between different subgroupss was further tested by the Mann Whitney U test. Differences reached statistical significancee between skin and neural TlR patients for hand and cumulative sensory scores (Tabless 1 and 3, p <0.05^. There were significantly fewer patients showing improvement in sensoryy scores in the neural TlR group compared with the skin TlR group (Table 1), and fewerr TlR patients improved their hand sensory scores compared with non-TIR patients (Tablee 3).

Voluntaryy muscle testing (VMT) Voluntaryy muscle test scores improved for the whole patient group for hands (Table 3) and inn the cumulative total (Table 2). VMT scores did not improve in feet and eyes (data not shown). .

Thee changes in VMT for patient subgroups were greatest in the non-TIR patients and in thosee TlR patients with single, cutaneous reactions. Patients with multiple or neural TlR didd not improve their VMT scores in hands, feet or eyes. The magnitude of the difference inn post-treatment VMT scores between different subgroups was further tested by the Mann-Whitneyy U test. There were significantly lower median VMT scores for hands in thosee with neural TlR compared with those with skin TlR (Table 3). However, the pre-treatmentt VMT scores were also significantly lower. The proportion of patients improv- ingg their VMT scores was lower in non-TIR patients compared with TlR patients in the cumulativee VMT score (Table 2); this reflected significantly fewer patients who improved in handd and foot VMT scores (Table 3 and data not shown).

Otherr factors influencing nerve function Vann Brakel suggested that men with nerve function loss improved their VMT scores significantlyy better than women.11

136 6 CONTRIBUTIONN OF TYPE 1 REACTIONS TO SENSORY AND MOTOR FUNCTION LOSS

Tablee 3. Changes in nerve function scores in hands in various study groups.

Studyy Group Improved d Worsened d Unchanged d Mediann score (Range) Significancee of differences betweenn pre- and post- No.. (%) No.. (%) No.. (%> Pre-Treatment t Post-Treatment t treatmentt scores Sensoryy Testing Totall (N = 297) 62 2 (21%) ) 311 (10%) 2044 (69%) 28 8 (0-28) ) 28 8 (0-28) ) << 0.002 T1RR (N = 157) 38 8 (24%) ) 199 (12%) 1000 (64%) 28 8 (0-28) ) 28 8 (0-28) ) << 0.009 Noo T1R (N = 140) 24 4 (17%) ) 122 (9%) 1044 (74%) 28 8 (0-28) ) 28 8 (0-28) ) 0.092 2

Episodes s Singlee (N= 111) 28 8 (25%) ) 133 (12%) 700 (63%) 28 8 (0-28) ) 28 8 (0-28) ) 0.020 0 Multiplee (N = 46) 10 0 (22%) ) 66 (13%) 300 (65%) 28 8 (0-28) ) 28 8 (0-28) ) NSb b

Skinn TlR (N = 68) 20 0 (29%) ) 44 (6%) 444 (65%) 28 8 (0-28) ) 28 8 (0-28) ) 0.001 1 Nervess TlR (N = 37) b b(14% ) ) 99 (24%) 233 (62%) 25 5 (0-28) ) 26 6 (0-28)c c NS S Mixedd T1R( N =52) 13 3(25% ) ) 66 (12%) 333 (63%) 28 8 (0-28) ) 28 8 (0-28) ) NS S Voluntaryy Muscle Testing Totall (N = 297) 57 7 (19%) ) 200 (7%) 2211 (74%) 29 9(0-30 ) ) 30 0 (5-30) ) << 0.0005 T1RR (N = 157) 41 1 (26%) ) 144 (9%) 1022 (65%) 29 9(0-30 ) ) 30 0 (5-30) ) << 0.0005 Noo T1R (N = 140) 16 6 (11%) ) 66 (4%) 1188 (85%) 300 (5-30) 30 0 (5-30) ) NS S

Singlee episodes (N = 111) 31 1 (28%) ) 99 (8%) 711 (64%) 299 (0-30) 30 0 (10-30) ) << 0.0005 Multiplee episodes (N = 46) 10 0 (22%) ) 55 (11%) 311 (67%) 29 9(5-30 ) ) 30 0 (5-30) ) NS S

Skinn T1R (N = 68) 18 8 (26%) ) 22 (3%) 488 (71%) 300 (0-30) 30 0 (12-30) ) << 0.0005 Nervess T1R (N = 37) 11 1 (30%) ) 55 (14%) 211 (56%) 28 8(5-30) d d 29 9 (5-30)d d NS S Mixedd T1R ( N =52) 12 2 (23%) ) 77 (13%) 333 (64%) 28.55 (10-30) 29.55 (10-30) 0.036 6 a.. Significantly fewer patients without T1R improved in hand ST compared with patients with TlR (p< 0,05) and significantly fewer non-TIR patients thann TlR patients showed improvement in hand VMT (p< 0.05). b.. NS = Not statistically significant c.. Significantly lower post-treatment ST scores in patients with nerve TlR compared to patients with skin TlR d.. Lower pre- and post-treatment VMT scores in patients with neural TlR compared with skin TlR (p< 0.05)

Ann analysis of all sensory and motor function scores by sex showed no significant difference betweenn men and women. However, a significant difference was shown between patients olderr than 40 years and those aged 40 years or younger. While the prevalence of TlR was thee same between the age groups, older patients failed to improve either their cumulative ST orr VMT scores. The median sensory scores were significantly lower, both at diagnosis and afterr treatment, in the older group (Table 1). Whenn the outcomes for those with reaction in the two age groups were compared, only youngerr patients showed improvements in cumulative ST and VMT scores (data not shown). . Wee also investigated the effect of admission to our hospital on the cumulative ST and VMT scoress of patients with TlR. While the two groups were similar in composition (that is, there weree no significant differences in the distribution of new cases between admitted and non- admittedd cases), the outcomes for non-admitted TlR cases were significantly poorer. Thus, STT and VMT scores for admitted patients were significantly improved, while the non- admittedd patients' ST and VMT scores were unchanged (Tables 1 and 2).

137 7 CHAPTERR 8

Thee effect of the length of steroid therapy on nerve function outcomes was also investigated. However,, since the mean length of therapy for neural TlR was significantly shorter than for cutaneouss TlR, a valid comparison between shorter and longer treatment times could not bee made.

Disabilityy grading Tablee 4 shows the changes in disability grading for patients with and without TlR over the studyy period. While 13/55 (23%) of the TlR patients without initial disability developed somee disability during the study period, only 7/48 (14.5%) non-reactional patients did so (pp = ns). However, equal proportions of TlR patients (T2/93, 13%j compared with non- reactionall patients (10/82, 12%) with disability at presentation improved their disability grading. .

Tablee 4. Changes in disability index in patient groups.

No.. (%) patients with Initiall Grade Patient Group No. post-treatment disabilitya grade

00 1 ...... 2 Noo TlR 48 8 41 1 (88 5%) 4 4 (8%) ) 33 (6%) TlR R 55 5 42 2 (76%) ) 9 9 (16%) ) 44 (7%) Noo TlR 34 4 4 4 (12%) ) 24 4(71% ) ) 66 (17%) TlR R 58 8 6 6 (10%) ) 47 7(81% ) ) 55 (9%) Noo TlR 48 8 0 0 (0%) ) 6 6 (12%) ) 422 (88%) TlR R 35 5 1 1 (3%) ) 5 5(14% ) ) 299 (83%) aa Significantly more TlR patients with a DI of 1 compared with non-TlR (p< 0.05) ; significantlyy more non-TlR with DI of 2 compared with TlR patients (p< 0.05).

DISCUSSION N

Thiss study has assessed the outcomes for patients with type 1 reactions (TlR) treated with a semi-standardizedd course of a maximum dosage of 40 mg prednisone compared with a non- reactionall historical control group. We have used a conservative measurement of sensory nervee function, namely, touch thresholds as determined by the ball-point pen test. This test doess not measure milder nerve impairment, and, together with a conservative categorization off change (i.e., a change of more than 1 in any measure), tends to emphasize the validity of thee outcomes seen. The internal consistency of measurements by trained physiotherapy technicianss is high11, allowing us to compare sensory and motor function tests conducted (oftenn by the same technicians) over an average follow-up period of 30 months. Significant improvementss in ST and VMT scores were evident, particularly in the hands. Improvements inn foot muscle strength, corneal sensation and lid closure strength were not significant.

138 8 CONTRIBUTIONN OF TYPE 1 REACTIONS TO SENSORY AND MOTOR FUNCTION LOSS

Thee improvements in the TlR patients' cumulative ST and VMT scores and sensory scores inn hands were greater than in non-reactional patients. However, these improvements were limitedd to TlR patients who had experienced a single reactional episode and whose reaction wass limited to the skin. Patients with multiple episodes of reaction and reactions involving nervess with or without skin symptoms did not improve significantly in either ST or VMT scores. . Patientss developing TlR reactions in nerves tend to present later after the start of MDT10 and,, in this study, to have had symptoms of TlR for longer than did those with cutaneous symptoms.. These patients were also treated for significantly shorter periods than were those patientss with cutaneous TlR, possibly because of a more rapid diminution in symptoms. However,, these results would seem to indicate that there is continuing nerve damage after thee disappearance of symptoms. Longer treatment and perhaps higher doses of steroids are indicatedd for the successful treatment of neural TlR.7 Patientss who were treated as inpatients during their reaction improved significantly more thann those treated as outpatients. Hospital inpatients benefited from additional health education,, splinting and bed rest during reactions, and these factors had an obvious impact on recoveryy of nerve function. An unpublished survey of the completion rates for outpatients takingg steroids at this hospital suggests that between 20%-30% of outpatients fail to collect theirr full course of steroids. Patients older than 40 years of age had no improved nerve functionn when compared with their younger counterparts. This is, in part, due to a lower initiall ST score in older patients; however, the recovery of nerve function was also insignificant. Amongg older patients with TlR, in contrast to younger patients, there was also no significantt improvement in nerve function. Itt is significant that there is a decline in sensation (21%) and muscle strength (13%) in non- reactionall patients. This indicates a chronic nerve function loss often called silent neuritis, whichh is important to diagnose and treat in order to further reduce nerve impairment due too leprosy. Vann Brakel11 has reported a prevalence of 7% for silent neuropathy with 71% of episodes occurringg in the first year of MDT; hence, some of the patients in this present study were undoubtedlyy affected. These patients have been shown to respond well to steroid treatment, withh recovery of nerve function.

Differencess in the definition of TlR limit the ability to compare our results with those of otherr workers. We have used consensus criteria developed for a current randomised control triall of fixed-duration low- versus high-dose prednisone treatment trial (Waters, personal communication).. This categorization of TlR as cutaneous, neural or mixed has revealed importantt differences in the epidemiology and risk factors associated with these different formss of TlR10, and now reveals that current treatment regimens are inadequate for those patientss with neural TlR.

Modernn long-course treatment of TlR arose from a study comparing two cohorts of patients inn Ethiopia.8 Small-scale studies5 gave support to the idea that nerve function could be

139 9 CHAPTERR 8

recoveredd with steroid treatment of TlR. A large study of the application to the field showedd a recovery of some function in 74% of reactional patients. However, these patients weree selected by a positive response to steroids, with poor responses being hospitalised and removedd from the study. Hence, the proportion of patients with nerve function improvementt was much greater than seen here.2 AA comparable retrospective study in India reported on nerve function in 44 TlR patients overr a 6-year period.6 A bigger improvement in sensory and motor function was found in patientss with cutaneous TlR (93%) than in patients with neural TlR (50%) after treatment withh 10-30 mg prednisone. No significant differences were notedd in the improvement in differentt nerves or in patients receiving higher steroid doses.

Ourr results would lend support to a recent review which recommended extended high-dose dosee prednisone treatment of longer than 3 months' duration.7 However, the suggested use off courses in BT patients of 3-6 months, in BB patients of 6-9 months, and in BL patients off 18-24 months would not seem to be justified by our data. There were no differences betweenn leprosy classes in response to the regimens in the present study, and no significant differencess in the prevalence of different kinds of TlR (cutaneous, neural or mixed) between differentt leprosy classes.10 Extendedd prednisone treatment should be on the basis of the extent of involvement of nervess in TlR since patients with TlR in nerves are not improving nerve function under thee current regimens.

Thee ongoing trial of high- and low-dose, fixed-duration prednisone treatment for TlR will providee information on the effect of dosages of prednisone on skin, nerve and mixed TlR. Betterr measurements of the effect of anti-inflammatory drugs on nerve function along with betterr anti-reaction drugs may be required, particularly for neural TlR.

SUMMARY Y

Thee changes in nerve function tests in 297 new leprosy patients over an average period of 300 months were measured. The impact of type 1 reactions (TlR) on sensory and voluntary musclee function was measured by standard tests. Sensory function was improved in patients withh single episodes of cutaneous TlR, but not improved in patients with neural TlR or withh multiple episodes of either kind of TlR. Patients over 40 years of age improved less thann younger patients, and patients admitted for treatment of TlR improved more than thosee treated as outpatients. These data point to a need to find better regimens for the treatmentt of nerve damage in TlR.

140 0 CONTRIBUTIONN OF TYPE 1 REACTIONS TO SENSORY AND MOTOR FUNCTION LOSS

RESUMEN N

See midieron los cambios en las pruebas de función nerviosa en 297 pacientes con lepra, durantee un periodo de 30 meses. El impacto de las reacciones tipo 1 (RT1) sobre las runcioness sensorial y de los musculos volutarios se midió utilizando pruebas estandar. La funciónn sensorial mejoró en los pacientes con episodios ünicos de RTl cutdneas pero no mejoróó en los pacientes con RTl neurales o con episodios multiples de RTl de cualquier tipo.. Los pacientes de mis de 40 afios de edad mejoraron menos bien que los pacientes mis jóveness y los pacientes admitidos para tratamiento de RTl mejoraron mis que los tratados comoo pacientes externos. Estos datos senalan la necesidad de encontrar mejores esquemas paraa el tratamiento del dano a nervios en las RTl.

RÉSUMÉ É

Less variations observées a partir des tests neurologiques fonctionnels de nerfs périphériques ontt été mesurées chez 297 nouveaux patients atteints de lèpre sur une période moyenne de 300 mois. L'importance des reactions de type 1 (RTl) sur la fonction sensorielle et musculaire volontairee a été évoluée en utilisant les résultats obtenus a partir de tests standards. La fonctionn sensorielle s'est améliorée chez les patients présentant des épisodes uniques de RTl cutanées.. Elle ne s'est pas améliorée chez les patients souffrant de RT I nerveuses ou d'épisodess multiples de chaque type de RTl. Les patients de plus de 40 ans ont présenté une ameliorationn moins nette que les patients plus jeunes, et les patients hospitalises pendant leurr traitement contre la RTl ont joui d'une amelioration plus importante que ceux qui ont étéé traites dans la maison. Ces données suggèrent qu'il y a un besoin pressant de trouver de meilleuress modalités pour Ie traitement des atteintes nerveuses associées aux RTl.

Acknowledgment.. This work was supported by The Leprosy Mission International. Thee authors would like to thank the staff and patients of Anandaban Hospital for their cooperationn in this study.

References: : 1.. Anon. Settingg priorities. Intt J Lepr & Mycobact Dis 1996;64 Suppl: S91-S92. 2.. Becks-Bleumink M and Berhe D. Occurrencee of reactions, their diagnosis and management in leprosy patients treated with multidrug therapy: experiencee in the leprosy control programme of ALERT in Ethiopia. Intt J Lepr 1992;60:173-184. 3.. Brandsma W. Nervee function assessment in leprosy patients. Leprr Rev 1981;52:161-170.

141 1 CHAPTERR 8

4.. Job CK. Nervee damage in leprosy. Inrr J Lepr 1989;57:532-539. 5.. Kiran KU, Stanley, JNA and Pearson JMH. Thee outpatient treatment of nerve damage in patients patients with borderline leprosy using a semi-standardisedd steroid regimen. Leprr Rev 1985;56:127-134. 6.. Lockwood DNL, Vinayakumar S, Stanley JNA, McAdam KPWJ and Colston MJ. Clinicall features and outcome of reversal (type 1) reactions in Hyderabad, India. Intt J Lepr 1993;61:8-15. 7.. Naafs B. Treatmentt of reactions and nerve damage. Intt J Lepr 1996;64 Suppl:S21-S28. 8.. Naafs B, Pearson JMH and Wheate HW 1979. Reversall reaction: the prevention of permanent nerve damage; comparison of short and long-term steroid treatment. . Intt J Lepr 1979;47:7-12. 9.. Ridley DS and Jopling WH. Classificationn of leprosy according to immunity; a five-group system. IntJJ Lepr 1996;34:255-273- 10.. Roche PW, Le Master JW and Butlin CR. Riskk factors for type 1 reactions in leprosy. Intt j Lepr 1997;65 :450-455. 11.. vanBrakelWH. Ph.D.. thesis, University of Utrecht; 1994. 12.. Watson JM. Essentiall action to minimise disability in leprosy patients. London:: The Leprosy Mission; 1986. 13.. WHO Expert Committee on Leprosy. Fifthh Report. Geneva: World Health Organization. Technicall report Series 607; 1977.

142 2 Chapterr 9

Psychiatricc Morbidity in People affectedd by Leprosy in Nepal assessedd with the WHO Self-Reporting Questionnairee (SRQ-20)

From:: Psychiatric Morbidity in People affected by Leprosy in Nepal Wimm J. Theuvenet, Paul W. Roche, Sanju Ruchal, Sakalanandaa Shrestha and C. Ruth Butlin Submittedd for publication

143 3 CHAPTERR 9

144 4 PSYCHIATRICC MORBIDITY IN PEOPLE AFFECTED BY LEPROSY IN NEPAL

SUMMARY Y

Inn 1999/2000 a cohort of 146 leprosy patients enrolled from 1996 on for MDT treatment att Anandaban Leprosy Hospital, Kathmandu was interviewed using a questionnaire, which includedd the WHO SRQ-20 questions. These measure 'non-psychotic' disorders and have beenn validated in Nepal. Thee findings show a high level of psychiatric morbidity among leprosy patients, with 46/1466 (31.5%) attaining a significant score. In a community survey in the same area the scoree was 10%. Itt seems therefore that being diagnosed with leprosy adds considerably to psychiatric morbidity.. Patients who were female, older than 40, had established disability, were illiterate or lackedd formal education were more likely to have higher scores. Patients' experience of rejectionn by their families was also associated with high scores. Patients' beliefs were important determinantss of morbidity as well. Patients with feelings of sadness, fear or loneliness had highh scores. Patients with negative views of the future, or who did not believe they would bee cured, were also more likely to have a high score. There were significant differences in the frequencyy of positive answers to the 20 questions between men and women. A simple logis- ticc regression model showed the strongest determinants of morbidity to be age and sex, with strongg negative associations with education, literacy and family acceptance. Thesee results were compared with those collected from an earlier cohort of patients in 1990/11 at Anandaban Leprosy Hospital and two other leprosy centres in Nepal using the samee questionnaire. The prevalence of high SRQ scores had increased significantly in the laterr cohort and, while some important differences were noted between the two groups, manyy of the major determinants of morbidity were the same. Thiss survey identifies some clinical, social and psychological determinants of psychiatric morbidityy and documents that after ten years of intensive health education about leprosy, patientss are still the victims of ostracism and resultant mental stress. Itt is well known that mental stress is a causative factor in defaultering and non-compliance inn leprosy elimination programmes. We plan to use this test as a first screening of undue mentall stress as this latter may thus affect the efficacy of our Prevention of Impairment and Deformityy (POID) and Rehabilitation programmes.

INTRODUCTION N

Betweenn 1989 and 1999 more than ten million people were cured of leprosy but there is still aa problem to solve as more than 700,000 new cases have been registered annually. Since 19988 there remain today an estimated two to three million people with significant disabilities.. The successful introduction of MDT has had a major impact on all aspects of leprosy workk and now in many leprosy control programmes the focus of attention is turning towardss better prevention of impairment and disabilities and towards rehabilitation. However,, the sheer complexity of the physical, psychological, social and economical impact

145 5 CHAPTERR 9

off leprosy makes the task difficult. Unless patients can identify with the aims of these pro- grammess and become participants, they will not be fully committed and non-compliance willl remain a breaking point.1 Inn 1983 Wartman2 stated that a possible predictor of non-compliance could be the patients' levell of mental stress, and the attitudes and beliefs of significant people in their environ- ment.. In this there will be different cultural perspectives and therefore an instrument that recognisedd this factor was required when wanting to assess mental stress factors in leprosy at Anandabann Hospital, Nepal. Wee sought to measure mental stress by means of the WHO SRQ-20 in leprosy patients.

METHODSS AND MATERIALS

Interviews s Thee WHO Self-Reporting Questionnaire for Adults3 was selected as this is designed to identifyy psychiatric morbidity across different cultures. It is a 24-item inventory that has beenn translated into a number of languages. The questionnaire has 20 questions designed to detectt non-psychotic disorders. Validation data are available from a number of countries. Theree is a considerable variation in the optimal cut-off point on the scale, which results from substantiall differences in the response rates. Nevertheless, by careful translation and admin- istrationn acceptable levels of sensitivity and specificity have been obtained for the clinical assessmentt of non-psychotic mental stress. Another reason for selecting this test was that it hadd already been used in Nepal by Wright4 in 1987 for screening psychiatric morbidity in aa village health post and a district hospital. In this study it was shown that Nepali individ- ualss with 11 or more of the 20 questions answered in the affirmative were likely to show symptomss of depression, this with a 91 % specificity and 7A % sensitivity. Hence the same cut-offf of >=11 positive answers was used in both the surveys. The translation was produced byy a team of Nepali leprosy health workers and checked for accuracy by trying the questions onn a group of leprosy hospital staff and on villagers during a field survey. The same Nepali translationn of this questionnaire was used in both surveys. The questionnaire (in English) iss shown in the Appendix . A number of questions were added with regard to the patients' perceptionn of their social framework and their illness.

Patientt populations Inn the 1990/1 cohort were 411 patients from three centres (Anandaban Leprosy Hospital, Greenn Pastures Leprosy hospital and a large out-patient clinic), who were attending as both out-- and in-patients. Thee 2000/1 cohort included 146 patients: 67 in-patients and 79 outpatients of Anandaban Leprosyy Hospital.

146 6 PSYCHIATRICC MORBIDITY IN PEOPLE AFFECTED BY LEPROSY IN NEPAL

RESULTS S

Responsess to the WHO SRQ questions:

1.1. The year 2000/1 cohort: Thee answers of the 146 leprosy patients of this cohort are shown in Table 1. In 31% a positivee score of greater than 11 of the 20 questions was found. In our study there were significantt differences in the proportions of responses to each question between male and femalee patients. Women were more likely than men to say they felt more frightened or nervous,, had trouble thinking, found it difficult to make decisions, felt unable to be useful and hadd thoughts of ending their lives. More women than men had positive answers to 11 or moree of the SRQ questions (24/49 versus 22/97, p<0.01). The most common questions answeredd affirmatively were also different between men and women (Table 1 and 2). Theree was a clear trend for increased psychiatric morbidity in older patients (Table 2), with prevalencee rising from 18% in patients under 20 years to more than 50% among patients agedd more than 60 (trend test p<0.05). Theree was also a clear trend for greater psychiatric morbidity among patients with increasingg amounts of disability, rising from 22% among patients free from disability to 43% amongg those with visible disability (WHO grade 2; trend test, p<0.05, Table 2).

Amongg the strongest "protective factors" against psychiatric morbidity were education and literacyy (Table 2). The patient's own outlook on their disease and their future was associated witJhh a high risk of psychiatric morbidity. This association persisted after adjustment by other factors,, suggesting a causal link as well as a logical association as a product of psychiatric morbidity. . Patientss with families who reportedly treated them well and with a belief in their own even- tuall cure were at significantly lower risk of developing psychiatric morbidity: this effect, however,, was removed after adjusted Odds ratios were calculated (Table 2). Otherr factors such as leprosy type, duration of symptoms or treatment, the number of admissions,, occupation, marital status, and social acceptance in the village did not have significantt influence on the risk of developing psychiatric morbidity.

2.2. Comparison with the 1990/1 cohort: Wee were interested to see what the effect of ten years of leprosy health education had been onn the patients' attitudes and their social acceptability. We had surveyed 411 Nepali leprosy patientss in 1990-1991 using the same questionnaire and compared the current results with thiss unpublished data. Itt was surprising that the prevalence of psychiatric morbidity had apparently risen in the 20000 cohort (31.5%) compared with the 1990/1 cohort (16.3%, p<0.05). Thee responses of the two cohorts to questions about social circumstance and attitudes (Table 3)) were compared and some significant differences were noted

147 7 CHAPTERR 9

Thee 1990/1 cohort had more disabled patients (82% versus 55%) with a longer duration of diseasee (52% versus 30%) and more patients treated for multibacilary leprosy (64% versus 48%).. Social circumstances seemed to have improved by 2000, with a higher proportion of patientss (83% versus 68%) telling their families about their disease and living with their ownn families (79% versus 67%): this implies less social rejection than the earlier patients experienced.. Nevertheless, there were more patients whose family avoided them (33% ver- suss 19%), and more patients in the latest cohort reported difficulties in going to the shops (24%% versus 15%) while less patients faced problems in going to a temple (14% versus 23%) thann in the earlier group. Perhaps as an over-all consequence more patients in the latter groupp (78% versus 60%) felt negatively (with sadness, fear or alienation) about their disease thann those in the earlier cohort. Patients'' beliefs about their disease showed some changes over ten years, with more patients inn 2000 giving "germs" as the cause of disease (32% versus 16%). However, more also believedd their disease was a consequence of sin (7% versus 2%), a belief held perhaps more oftenn by older patients. Importantly, despite evidence to the contrary, fewer patients in 2000 believedd they would be cured

148 8 PSYCHIATRICC MORBIDITY IN PEOPLE AFFECTED BY LEPROSY IN NEPAL

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Tablee 3. Differences in rates of responses in two cohorts to questions about social ostracism andd attitudes to leprosy.

Factor r 19900 rate (%) 20000 rate (%) Significance* *

Female e 132/4111 (32%) 49/1466 (33%) Age>40 0 203/4111 (49%) 62/1466 (42%) MBB leprosy 191/2988 (64%) 71/1466 (48%) p<0.001 1 Durationn of disease >5y 215/4111 (52%) 44/1466 (30%) p<0.001 1 Disabilityy grade >0 245/3000 (82%) 81/1466 (55%) p<0.001 1

Farmers s 173// 293 (59%) 53/1466 (36%) Noo Education 130/1977 (66%) 90/1444 (63%) Illiterate e 176/3033 (58%) 77/1466 (53%) Married d 249/3088 (81%) 113/145(78%) ) Livingg with own family 200/2977 (67%) 115/146(79%) ) p<0.05 5 Familyy knows patient has leprosy 205/3000 (68%) 118/143(83%) ) p<0.01 1 Patient'ss family looks negativelyy on leprosy 73/2866 (26%) 43/1466 (29%) Patient'ss family helps patient 240/2999 (80%) 115/144(80%) ) Patient'ss family avoids patient 56/3000 (19%) 49/1422 (33%) p<0.01 1 Problemss going to: Shops s 41/2755 (15%) 33/1399 (24%) p<0.05 5 Schools s 39/1988 (20%) 5/277 (18%) Another'ss house 55/2811 (19%) 34/1411 (24%) Doo business 40/245(16%) ) 14/544 (26%) Gett a job 51/2166 (24%) 20/822 (24%) Goo to temple 63/2655 (23%) 20/1377 (14%) p<0.05 5 Gett married 62/2033 (29%) 20/555 (36%) Feelss negatively about disease 185/3055 (60%) 114/146(78%) ) p<0.001 1 Viewss future negatively 118/305(39%) ) 61/1466 (42%) Causee of disease is: Cursee of God 14/4066 (3%) 5/1466 (3%) Sin n 8/4066 (2%) 10/1466 (7%) p<0.05 5 Badd times 31/4066 (8%) 17/146(11%) ) Germs s 65/4066 (16%) 47/1466 (32%) p<0.001 1 Blood d 50/4066 (12%) 25/1466 (17%) Don'tt know 193/4066 (47%) 32/1466 (22%) p<0.001 1 Other r 45/406(11%) ) 10/1466 (7%)

Familyy treats patient kindly 321/4033 (80%) 112/140(80%) ) Villagess treat kindly 296/4066 (73%) 112/1411 (79%) Patientt believes they will be cured 373/3999 (93%) 123/1411 (87%) p<0.05 5 Patientt believes deformity willl be prevented 374/3977 (93%) 139/1466 (95%)

*Significancee of differences between two study groups tested by Chi-square test.

151 1 CHAPTERR 9

Tablee 4. SRQ scores in different communities* in Nepal

Author*** (year) Community y No.. Studied Prevalencee of psychiatric c morbidity* * Wright44 (1990) Population n 1011 (aged 9% % around d 166 or over) Kathmandu u area a Lalitpurr health postt attendees 1466 (aged 23% % 166 or over) Patann hospital 1500 (aged 28% % out-patients s 166 or over) PoPP (1998) Patann urban 252 2 11% % healthh project: Community y survey y Adhikarii & Southh Lalitpur: 362 2 10% % Denison6 6 community y (1999) ) survey y Adhikari, , Westernn rural 414 4 13.1% % Huttunenn and Nepal: : Kiljunen7 7 community y (2000) ) survey y Theuvenett et al Leprosyy in- and 411 1 16.3% % (1990) ) out-patientss in 33 referral hospitals s Theuvenett et al Leprosy y 146 6 31.5% % (2000) ) patients s Hospital l 167 7 61.7% % visitors s

** All studies used the same SRQ and the same cut-off point *** References

152 2 PSYCHIATRICC MORBIDITY IN PEOPLE AFFECTED BY LEPROSY IN NEPAL

Medico-Sociall Questionnaire Anandabann Leprosy Hospital 1999 Namee of patient: Hospitall Number: Samplee 1 = In-patient 22 = Outpatient Agee (years) Sex:: 0 = male; 1 = female Typee of leprosy: 0 = TT; 1 = BT; 2 = BB 33 = BL, 4 = LL; 5 = PN; 6 = IND Durationn of disease (years) Durationn of treatment (years) Numberr of admissions Treatmentt 0 = Nil; 1 = Leprosy only 22 = Leprosy plus prednisone; 3 = Prednisone only Disabilityy (WHO) 0 = 0; 1 = 1; 2 = 2 Interviewer:: 1 = Madan; 2 = Sanju 1.. Occupation: 0 = Farmer; 1 = Office work 22 = Business; 3 = Other 2.. Education. Which is the highest class the patient has passed? Classs 1-10; code as 1-10; SLC = 11 Intermediatee 1st year =12; intermediate 2nc* year =13 etc. 3.. Can the patient read and write?: 0 = No; 1 = Yes 4.. Is the patient married? 0 = No; 1 = Yes 5.. If married, is the patient living with spousee in the house? 0 = No; 1 = Yes Iff not living with spouse is the reason: 0 = spouse died 11 = spouse left 6.. With whom does the patient live? 00 = own family; 1 = parent-in-law; 22 = alone; 3 = children; 4 = other 7.. How many children does the patient have? 8.. Does the patient's family know that thee patient has leprosy? 0 = No; 1 = Yes Howw is the patient s family looking on leprosy? 00 = neutral; just a disease; 1 = negatively Doess the patient's family help the patient? 0 = No; 1 = Yes Iss the patients family avoiding him/her? 0 = No; 1 = Yes

153 3 CHAPTERR 9

9.. Is the patient accepted by his/her villagers? 0 = No; 1 = Yes Iss there any problem for the patient to: a.. Go to the shops 0 = No; 1 = Yes b.. Go to school 0 = No; 1 = Yes c.. Go to another's house 0 = No; 1 = Yes d.. Do business 0 = No; 1 = Yes e.. Get a job 0 = No; 1 = Yes f.. Go to the temple 0 = No; 1 = Yes g.. Get married 0 = No; 1 = Yes 10.. How does the patient look upon his/her disease? Does he/she: 11 = Feel angry; 2 = Feel sad; 3 = Feel afraid 44 = Feel lonely; 0 = Have no special feeling 11.. How does the patient see his/her future? 11 = Good; 2 = Bad; 3 = Does not care; 4 = Does not know

WHOO Questionnaire 1.. Do you often have headaches? 0 = No; 1 = Yes 2.. Is your appetite poor? 0 = No; 1 = Yes 3.. Do you sleep badly? 0 = No; 1 = Yes 4.. Are you easily frightened? 0 = No; 1 = Yes 5.. Do your hands shake? 0 = No; 1 = Yes 6.. Do you feel nervous, tense or worried? 0 = No; 1 = Yes 7.. Is your digestion poor? 0 = No; 1 = Yes 8.. Do you have trouble thinking clearly? 0 = No; 1 = Yes 9.. Do you feel unhappy? 0 = No; 1 = Yes 0.. Do you cry more than usual? 0 = No; 1 = Yes 1.. Do you find it difficult to enjoy your daily activities? 0 = No; 1 = Yes 2.. Do you find it difficult to make decisions? 0 = No; 1 = Yes 3.. Is your daily work suffering? 0 = No; 1 = Yes 4.. Are you unable to play a useful part in life? 0 = No; 1 = Yes 5-- Have you lost interest in things? 0 = No; 1 = Yes 6.. Do you feel you are a worthless person? 0 = No; 1 = Yes 7.. Has the thought of ending your life been on your mind? 0 = No; 1 = Yes 8.. Do you feel tired all the time? 0 = No; 1 = Yes 9.. Do you have uncomfortable feelings in your stomach? 0 = No; 1 = Yes 20.. Are you easily tired? 0 = No; 1 = Yes 21.. What do you think is the cause of your disease? 11 = Spell of God; 2 = Sin; 3 = Bad times 44 = Germs; 5 = Blood; 6 = Don't know; 7 = Other 22.. Are the people of your family treating you differently sincee you have had leprosy? 11 = Less kind; 2 = Kinder; 3 = Same

154 4 PSYCHIATRICC MORBIDITY IN PEOPLE AFFECTED BY LEPROSY IN NEPAL

23.. Are your villagers treating you differently since you have had leprosy? 11 = Less kind; 2 = Kinder; 3 = Same | | 24.. Do you think you can be cured? 0 = No; 1 = Yes | | 25.. Do you think that further deformity cann be prevented? 0 = No; 1 = Yes j |

155 5 CHAPTERR 9

DISCUSSION N

Psychiatricc morbidity measured by the WHO SRQ test varied from 10.6% in Sudan, 10.8% inn Colombia, and 16.3% in the Philippines, 17.7% in India, 22.7% in Brazil and 29% in Kenya.. The wide variation in cut-off points used in different countries makes one hesitant too conclude that a positive score above this point justifies the conclusion of "psychiatric caseness"4-88 and in general the SRQ test is merely used as the first filter for wider screening off a patients mental stress.9

Inn 1990/1 amongst 411 leprosy in- and outpatients in the Central, Eastern and Western Regionn a positive score was found of 16.3%, while in the general population around Kathmanduu a score of 9% was found. Tenn years later, in 1999 and 2000 (Table 4), the WHO SRQ test scored a 10%6 psychiatric morbidityy in the community of South Lalitpur District in the Central Region and 13.1%7 inn the Western Rural Nepal community survey respectively while in 2000 and 2001 amongstt leprosy patients visiting Anandaban Hospital, Lalitpur District, a positive score of 31.5%% was found. Bothh in the 1990/1 as well the 2000/1 cohort the positive scores amongst leprosy patients waswas much higher than in the general population, this until late 2001 when we conducted a surveyy amongst 167 Anandaban Hospital visitors and a surprising positive score of 60% was foundd The strong increase in positive scores amongst the population of Lalitpur district betweenn 1999 (10%) and 2001 (60%) can perhaps be attributed to the sharp increased Maoistt guerrilla activity at the end of 2001.

Wee were interested to see what the effect of ten years of leprosy health education had been onn the patients' attitudes and their social acceptability. We were initially surprised to find thatt it had risen in the 2000 cohort to 31.5% (p<0.05). This is perhaps explained by the significantt changed proportion of illiterate patients (176/411, 43% versus 77/146, 53%). Whenn we further compared the responses of the two cohorts significant differences were noted.. The 1990/1 cohort had more disabled patients with a longer duration of disease and treatment.. Social circumstances seemed to have improved by 2000, with a higher proportionn of patients telling their families about their disease and living with their families; this impliess less social rejection than the earlier patients experienced. Nevertheless there were also moree patients whose families avoided them, and more patients in the latest cohort reported difficultiess in going to the shops and the temple than in the earlier group. Perhaps as a con- sequencee more patients in the latter group felt negatively (with sadness, fear or alienation) aboutt their disease than those in the earlier cohort. Patients' beliefs about their disease showedd some changes over ten years, with more patients in 2000 giving "germs" as the cause off the disease. However, more also believed that their disease was a consequence of sin, but theree was also greater optimism about cure among patients in 2000 than in 1990.

156 6 PSYCHIATRICC MORBIDITY IN PEOPLE AFFECTED BY LEPROSY IN NEPAL

Lesss women than men were interviewed in both the 1990/1 and in the 2000 cohorts (32% andd 33% respectively) This may be explained by the fact that in the cultural milieu of Nepal womenn do not enjoy the same geographical mobility as men. If this causes a selection, it may explainn why women presenting gave more positive answers to 11 or more of the SRQ ques- tionss than men, in both the 1990/1 cohort (35/132 versus 45/279, p<0.05) and 2000 cohortt (24/49 versus 22/97, p<0.01). This finding corresponds with earlier studies in Nepal (4),, Saudi Arabia (10) and Brazil (11) but is in contrast with a Nigerian (9) and Kenyan (12) studyy where no sex differences in positive score were found.

Inn our first 1990/1 study women complained significantly more than men about poor appetite,, poor digestion, headaches, the tendency to cry more often, to feel frightened, and thatt their hands shake, while in the 2000 follow-up this had shifted to complaints of feel- ingg frightened, nervous, having trouble thinking, finding it difficult to make decisions, feel- ingg unable to play a useful part and having thoughts of ending their lives. This suggests a shiftt from psychosomatic to mental problems for which we have found no explanation yet. Wee feel that the SRQ is a useful instrument to assess the causative factors and the degree of mentall stress in individual leprosy patients in Nepal. It deserves further study to demon- stratee whether with the knowledge gained by this test, the compliance rate, the feasibility of preventingg disability and impairment and the outcome of rehabilitation programmes can be enhanced d

References: : 1.. Guidelines for the social and economic rehabilitation of people affected by leprosy. ILEP;; 1999. ISBN 0-9475-4317-1. 2.. Wartman SA. et al., Patientt understanding and satisfaction as predictors of compliance. Medd Care 1983;21:886-891. 3.. Harding TW et al., Thee WHO Collaborative Study on Strategies for Extending Mental Health Care, II: The Development of Neww Research Methods. Am.. J Psych 1983;140(11):1474-1480. 4.. Wright C, Nepal MK and Bruce Jones WDA. Mentall Healdi Patients in Primary Health Care Services in Nepal; 1987. 5.. Pol K, Nakarmi B, Thapa B and Ackland S. Yallaa Urban Health Project: A Mental Health Study. Unitedd Mission to Nepal, Kathmandu; 1998. 6.. Adhilcari KP and Denison BDB. Mentall Health in Nepal: A Community Survey of a village in South Lalitpur, Central Nepal. Unitedd Mission to Nepal, Kathmandu; 1999. 7... Adhikari KP, Huttunen J. and Kiljunen R. Mentall Health in Nepal; A Community Survey of Anandaban Village inn Western Region of Nepal. Unitedd Mission to Nepal, Kadimandu; 2000. 8.. Kortmann F and Ten Horn S, Deficienciess of the Self-Reporting Questionnaire: The validity of a WHO psychiatric screening instrument. Deptt Social Psychiatry, State University of Groningen, The Netherlands; 1987.

157 7 CHAPTERR 9

9.. Ohaeri JU and Odejide J. Somatizationn symptoms among patients using primary health care facilities in a rural community in Nigeria, Amm J Psych 1994;15K5):728-31. 10.. Al-Subaie AS et al. Thee Arabic Self-Reporting Questionnaire (SRQ) as a Psychiatric Screening Instrument in Medical Patients. Annn Saudi Med 1998;18(4):308-10. 11.. Lima MS, Beria JU et al. Stressfull life events and minor psychiatric disorders: an estimate of the population attributable fraction in a Braziliann community-based study. IntJPsychMedd 1996;26(2):211-22. 12.. Dhadphale M, Ellison RH et al. Thee Frequency of Psychiatric Disorders among Patients Attending Semi-Urban and Rural General OutpatientOutpatient Clinics in Kenya. Brr J Psych 1983;142:379-83.

158 8 SUMMARY Y

159 9 SUMMARY Y

160 0 SUMMARY Y

SUMMARY Y

Leprosyy is a chronic infectious disease caused by die bacillus Mycobacterium leprae, a fact thatt is either unknown or of little interest to most of those affected by leprosy in Nepal and elsewheree in the world where this disease is still endemic. The World Health Organization considerss leprosy a public health problem as long as the prevalence is over 1 case per 10,000 persons.. For operational purposes only those who need or are under chemotherapy are con- sideredd "leprosy cases". With constant changes in the recommended (especially length of the)) MDT regimens and with a lack of 10 years defaulter rates, it seems very questionable whetherr the prevalence rate of leprosy is a reliable parameter for weighing it as a public healthh problem. A more realistic parameter is the new case detection rate, a figure that has nott come down in the last 15 years. Consideration can be given to viewing leprosy as a publicc health problem as long as the prevalence is more than 1/10,000 or when, after becoming lesss than 1/10,000, the new case detection has not come down in 3 of the 5 consecutive years.. In the year 2000, 738284 new patients were registered world-wide. They may be con- frontedd with the often-disabling consequences of leprosy neuritis, social isolation, mental stress,, economical downfall and, when skilled assistance is offered, the difficult road towards rehabilitation.. In order to understand the world of Nepali leprosy patients, an introduction intoo the country of Nepal and the clinical aspects of leprosy is given.

InIn the second chapter the intense mass survey of Lalitpur District, performed between 1986- 1990,, is discussed. Eighty-five percent of the 210,358 enumerated inhabitants were examinedd and 234 new cases were found. The new case detection rate was 2.6 per 10,000 per year andd the child detection rate 0.8 per 10,000 per year. In 1999 the new case detection rate hadd dropped to 0.8 per 10.000 per year. Amongst the newly detected cases of the survey the multibacillaryy rate was 20% and the disability grade 2 rate was 12%. In 1999 of the 25 new cases,, 17 had multibacillary leprosy. Mostt of these multibacillary patients had worked and lived outside Lalitpur district for manyy years. It was concluded that adequate training of health post staff and village health workerss can both improve compliance as well the earlier detection of nerve damage. Since thenn Anandaban Hospital has not only trained this staff of its own district but, at the request off the Ministry of Health, of all staff of this level in the Central Region of Nepal. Disability preventionn has received the same priority and timing as the full implementation of MDT. Itt is concluded that an intense mass survey as conducted in Lalitpur district serves well as a scientificc study, but that the costs per newly detected patient renders it far too expensive for suchh an area with a prevalence rate of less than 10 per 10,000 inhabitants.

InIn the third chapter we note that neuritis of the lateral femoral cutaneous nerve (meralgia paraesthetica)) is observed more frequendy in leprosy than in non-leprosy patients and the symptomss may mimic those of e.g. ischialgia. After confirmation of the diagnosis by a diagnosticc block with a local anaesthetic solution, therapeutic measures like analgesics, anti- inflammatoryy drugs, bed rest and, in severe cases, therapeutic blocks containing a corticos-

161 1 SUMMARY Y

teroid,, can be successfully applied and may suffice. In our leprosy patients with a meralgia paraesthetica,, surgical decompression of the affected lateral femoral cutaneous nerve was not needed. .

Inn the fourth chapter it is stated that at present the administration of prednisone remains thee first drug of choice for the treatment of nerve function loss in leprosy. However, in only aa minority of patients restoration of sensation and muscle function up to a functional level iss obtained. In those cases a definite improvement of sensation can still be obtained by our neww microsurgical approach named "selective meshing of the epineurium (SME)" in which decompressionn is realized by the making of small overlapping incisions in the epineurium (muchh like in meshing a skin graft) while the epineural blood vessels are carefully spared. Thee improvement is the best when performed as early as possible, and a moderate and a definitee improvement was found in 70% of the nerves operated when the procedure was per- formedd within 6 months after loss of sensation, while a definite improvement was still found inn 32% of the nerves when operated within 10 years after loss of sensation.

Inn the fifth chapter the observation is discussed that, due to the scarcity of the cardinal signs off leprosy, pure neural leprosy can be difficult to diagnose. Under such circumstances cytologicall needle aspiration of an effected nerve can be a safe and valuable tool to set the diagnosis.. The method as developed by us at Anandaban Leprosy Hospital is presented in this thesis. . Inn seven out of eleven patients in whom cytological aspiration of the affected nerve was done,, multiple acid-fast bacilli were found, thus strongly supporting the diagnosis of pure neurall leprosy.

Chapterr six describes a new method for the early detection of intrinsic muscle function loss inn the foot. Plantar intrinsic foot muscles provide structure to the foot during walking and thuss regulate foot sole stresses. In leprosy, unlike with the intrinsic muscle testing of the hand,, little attention is paid to the early and regular examination of plantar intrinsic musclee activity. In the prevention of impairment and deformity of the foot most attention goes too the loss of protective sensation. In our view it is therefore not amazing that in spite of the prescriptionn of protective footwear, there is too high a recurrence rate of foot ulcers and that thesee remain the main indication for admission in hospitals specialized in leprosy. Intrinsicc muscle function loss in the foot equals intrinsic muscle function loss in the hand inn causing soft tissue damage. In order to assess the intrinsic muscles of the foot we devel- opedd and tested a new, simple and non-invasive method called "the Paper Grip Test (PGT)". Ass a result of an intrinsic muscle function loss in the foot, as demonstrated by the PGT, oftenn a "Failing forefoot syndrome" (clawing of the toes, flattening of the transverse arch, unduee stress under the MTP-I and MTP-2 joints) can be observed and this may explain whyy most (recurrent) ulcers can be found in this area. Therapeutic advices to prevent ulcer- ationn are discussed of which the most important one is the protection of the forefoot duringg the push-off phase of walking.

162 2 SUMMARY Y

Chapterr seven starts with the observation that type-1 or reversal reactions are the major causee of nerve damage and disability in leprosy. The Anandaban Mycobacterium Research Laboratoryy detected that seropositivity for IgM antiphenolic-glycolipid-1 (PGLA) antibodies,, but not IgG anti-lipoarabinomannan or anti-Mycobacterium leprae 35 kDa protein antibodies,, was significantly associated with subsequent manifestation of a type-1 reaction (p<0.001).. The concentration of IgM anti-PGL-1 antibodies in serum was significantly higherr in patients in whom a type-1 reaction developed, and this risk was independent of leprosyy class, skin smear positivity, and the presence of other anti-Af leprae antibodies. It was concludedd that anti-PGL-1 positivity and lepromin reactivity are significant independent riskk factors for subsequent reaction and patients with these risk factors should be carefully monitoredd during the first two years after commencing anti-microbial treatment. This mon- itoringg may result in the earlier initiation of anti-inflammatory treatment and so the min- imisingg of impairment and disability.

Inn chapter eight it is discussed how the contribution of type-1 reactions to sensory and motorr function loss in 297 borderline leprosy patients was measured and the efficacy of treatmentt with prednisone assessed. Of the 297 borderline patients 157 (53%) experienced aa type-1 reaction during an average follow-up time of 30.7 months (range 6-74 months). Noo significant differences were found between BT, BB or BL patients, neither between left andd right hands, feet or eyes. A decline in sensation (21%) and muscle strength (13%) in non-reactionall patients indicated a silent neuritis of which 71 % of the episodes will occur inn the first year of MDT. Off the 157 patients with a type-1 reaction treated with prednisone, in 65 (41 %) patients theree was an improvement in the cumulative sensory test score, in 39 (25 %) patients there wass a worsening while in 53 (34%) patients the score remained unchanged. Inn this same group the cumulative VMT scores improved with prednisone in 56 (36%) patients,, worsened in 20 (13%) patients and remained unchanged in 81 (51%) patients. Thesee data point to a need to find better regimens for the treatment of nerve damage in type-11 reaction. Patients who were treated as inpatients during their reaction improved significantlyy more than those treated as outpatients. The difference may be largely explained byy the fact that about 20%-30% of the outpatients failed to collect their full course of steroids.. The reasons for the non-compliance with this form of treatment are unknown.

Therefore,, in chapter nine we try to identify factors that are causing non-compliance. Ass mentioned earlier the primary concern of those affected by leprosy lies not in the eradi- cationn of the M. leprae in the body, but merely in how to hide the visible symptoms and to preventt social, physical and economic disablement. The resulting mental stress relates directlyy to the process of non-compliance with treatment and defaultering. For the identifi- cationn of factors contributing to mental stress in leprosy patients the WHO Self-Reporting Questionnairee was used, and to this test we added a number of separate questions on socio- economicc factors. This test was already validated in Nepal and was designed to measure non- psychoticc psychiatric morbidity by scoring twenty questions. We feel with other authors that

163 3 SUMMARY Y

aa positive score may not necessarily imply "hard" psychiatric morbidity but rather that a patientt is experiencing undue mental stress which needs further assessment. In the general Nepalii population and when using this test, the prevalence of "psychiatric morbidity" is aroundd 10%. In 1990/1 in the first survey among 411 leprosy patients from the Eastern, Centrall and Western Regions of Nepal, "psychiatric morbidity" was found in 16.3%. This figuree rose significantly in the follow-up survey of 2000/1 to a prevalence of 31.5%. Women,, older patients, and those with a visible disability scored significantly higher than males,, younger patients, and those without disability. The patient's own outlook on their diseasee and their future was also associated with a high risk of psychiatric morbidity. This latterr association persisted after adjustment by other factors, suggesting a causal link as well ass a logical association as a product of psychiatric morbidity. Among the strongest "protec- tivee factors" was education and literacy. Patients with families whom they reported as treat- ingg them well and with a belief in their own eventual cure were at significantly lower risk of developingg psychiatric morbidity; this effect however was removed after adjusted Odds ratioss were calculated. Comparison of the two cohorts showed in 2000/1 suggested that sociall circumstances seemed to have improved with a higher proportion of patients telling theirr families about their disease and living with their own families; this implies less social rejectionn than the patients of the 1990/1 experienced. Nevertheless there were also more patientss who stated that their families avoided them and that they faced difficulties in going too the shops. In 2000/1 more patients gave "germs" as the cause of their disease. Importantly,, fewer patients in 2000 believed that they would be cured than in 1990. The knowledgee gained by these surveys is helpful in monitoring mental stress and thus in the timelyy offering of assistance. Ultimately, one can expect that this will be reflected in an enhancedd quality of leprosy care.

Forr those affected by leprosy the magnitude of their problems is mostly beyond the limited reachh of the surgeon's scalpel and their burden is not relieved by sterile statistics. In order to bee of any real assistance, we are all challenged to involve ourselves in the leprosy patients' personall world in its widest sense. A small part of this endeavour is reflected in this thesis.

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Lepraa is een chronische, infectieuze ziekte veroorzaakt door de bacil Mycobacterium leprae, eenn gegeven welk onbekend of van geen belang is voor hen die deze ziekte hebben opgelo- penn in Nepal, of waar dan ook in de wereld, waar lepra nog steeds endemisch is. De Wereld Gezondheidsorganisatiee (WHO) beschouwt lepra als een probleem voor de publieke gezondheidd zolang het voorkomen ("prevalence") meer dan 1 patiënt per 10.000 inwoners is.. Om "operationele" redenen worden alleen zij die een medicamenteuze behandeling nodig hebbenn of hiermee reeds behandeld worden, als patiënt gerekend. Door het telkens wijzigen (mett name van de duur) van de aanbevolen behandelschemas is het zeer discutabel of alleen dee "prevalence" een goede graadmeter is voor het wegen van bestaande lepraproblematiek. Eenn veel realistischer maat is het aantal nieuw gediagnosticeerde patiënten per jaar ("New casee detection rate"), een cijfer welk de laatste 15 jaar wereldwijd gerekend, niet gedaald is. Hett is aan te bevelen om lepra als een publiek gezondheidsprobleem te beschouwen zolang hett voorkomen meer is dan 1 patiënt per 10.000 inwoner, of wanneer het voorkomen min- derr dan 1 patiënt per 10.000 inwoners geworden is, het aantal nieuw gediagnosticeerde patiëntenn per 100.000 inwoners niet daalt in 3 van de 5 hierop volgende jaren. Inn 2000 werden over de hele wereld 738284 nieuwe patiënten geregistreerd. Zij zullen mogelijkk te maken krijgen met de vaak invaliderende gevolgen van lepra neuritis, sociale iso- latiee door het bestaande stigma, mentale stress, een verslechtering van hun economische situatiee en, wanneer kundige hulp geboden wordt, de vaak moeilijke weg van reïntegratie en herwonnenn onafhankelijkheid. Omm de lezer enigszins inzicht te geven in de wereld van de Nepalese lepra patiënt wordt in dee inleiding informatie verstrekt over Nepal en de klinische aspecten van de aandoening.

Inn het tweede hoofdstuk wordt het hoofdelijk bevolkingsonderzoek op lepra besproken welkee tussen 1986 en 1990 plaatsvond in het Lalitpur District. Vijfentachtig procent van de 210.3588 geregistreerde inwoners werd onderzocht waarbij 234 nieuwe lepra patiënten wer- denn gevonden. De verhouding van de nieuwe patiënten kwam hiermee op 26 per 100.000 inwonerss per jaar; voor alleen de kinderen tot 12 jaar kwam dit cijfer op 8 nieuwe kinderen mett lepra per 100.000 inwoners per jaar. Van alle nieuw gediagnosticeerde patiënten had 20%% de multibacillaire vorm van lepra en 12% een invaliditeit graad twee ("Disability grade 2")) In 1999 werden 25 nieuwe patiënten geregistreerd waardoor de "New case detection rate"" op 8 per 100.000 inwoners kwam. Van hen hadden 17 patiënten multibacillaire lepra. Dee meeste van deze multibacillaire patiënten hadden de laatste jaren buiten het Lalitpur dis- trictt gewerkt. In 2000 werden 7 nieuwe patiënten gevonden hetgeen de "New case detectionn rate' op 2.3 per 100.000 bewoners bracht. Als conclusie van dit onderzoek werd gesteld datt adequate training van de staf van de gezondheidsposten en van de gezondheidswerkers inn de dorpen ("Village Health Workers") een gunstige invloed kan hebben op de therapie- trouww van patiënten èn op de mogelijkheid om in een vroeg stadium zenuwbeschadiging op tee sporen. Sindsdien heeft het Anandaban ziekenhuis niet alleen deze staf van het eigen Lalitpurr district opgeleid, maar op het verzoek van het Nepalese ministerie voor Volks-

167 7 SAMENVATTING G

gezondheid,, ook de staf van dit niveau van de gehele "Central Region". Sinds dit bevol- kingsonderzoekk heeft de preventie van functieverlies door neuritis dezelfde urgentie gekre- genn als de beschikbaarheid van de geneesmiddelen combinatie ("multidrug therapy") voor dee bestrijding van M.leprae. Eveneens werd geconcludeerd dat een hoofdelijk bevolkingson- derzoekk zoals in het Lalitpur district werd uitgevoerd nuttig is als wetenschappelijke studie, maarr dat op deze manier uitgevoerd, de kosten voor het opsporen van nieuwe patiënten vele malenn te hoog ligt in dit gebied met een voorkomen van ongeveer 10 patiënten per 10.000 inwoners. .

Inn het derde hoofdstuk wordt beschreven dat neuritis van de nervus femoralis cutaneous lateraliss (meralgia paraesthetica) vaker voorkomt bij leprapatiënten dan bij de doorsnee bevolkingg en dat de symptomen op die van een ischialgie kunnen lijken. Nadat de diagnose bevestigdd is middels een diagnostisch blok met een lokaal anaestheticum, kan behandeling mett pijnstillers, ontstekingremmers, bedrust, en bij ernstige gevallen corticosteroid injecties bijj de uittreeplaats van de zenuw, met succes worden toegepast. Bij de door ons beschreven patiëntenn voldeed deze behandeling en was chirurgische decompressie niet nodig.

Inn het vierde hoofdstuk wordt benoemd dat behandeling van lepra neuritis met prednison dee eerste keus is maar dat deze slechts in een minderheid van de gevallen leidt tot duidelijk functionelee verbetering van spierkracht en sensibiliteit. De indicaties en de resultaten van eenn chirurgische zenuwdecompressie worden besproken. Bij die patiënten bij wie behandelingg van de neuritis met prednison niet succesvol is gebleken omdat zenuwherstel tot een functioneell niveau niet gerealiseerd is, kan verbetering bereikt worden middels een door ons ontwikkeldee nieuwe techniek voor decompressie van de zenuw. De decompressie vindt plaatss via een selectieve verruiming van het vernauwde epineurium ("selective meshing of thee epineurium, SME). Bij deze techniek worden net zoals bij het "meshen" van een huid- transplantaat,, kleine, elkaar deels overlappende incisies gemaakt in het epineurium, tussen dee epineurale bloedvaten door. De mate van het herstel van zenuwfunctie is omgekeerd evenredigg aan de verstreken tijd van uitval. Een zeer duidelijke of redelijk herstel van sensi- biliteitt (zie het artikel voor de definiëring van deze begrippen) kan verkregen worden in 70 procentt van de patiënten wanneer de sensibiliteitsuitval niet langer aanwezig is dan 6 maanden,, terwijl tot onze verassing een duidelijk herstel nog waargenomen werd bij 32 procent vann de patiënten wanneer zij geopereerd werden binnen 10 jaar na verlies van sensibiliteits- verlies. .

Inn het vijfde hoofdstuk wordt gesteld dat de diagnose van lepra, in die gevallen waarbij er alleenn sprake is van zenuwuitval, vaak moeilijk bevestigd kan worden. In Nepal is dit bij 77 procent van de patiënten het geval. Dan kan een cytologische punctie uit een aangedane zenuww een goede en veilige methode zijn om de diagnose te stellen. Bij zeven van de elf patiëntenn bij wie een cytologische punctie werd gedaan, werden zuurvaste staafvormige bacillenn gevonden. Deze methode welke in het Anadaban Ziekenhuis werd ontwikkeld, wordtt in dit artikel gepresenteerd.

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Hoofdstukk zes behandelt een nieuwe methode voor de vroeg-diagnostiek van intrinsieke spieruitvall in de voet bij leprapatiënten. Deze spieren onderhouden de structuren van de voett tijdens het lopen en spreiden hierbij de mechanische stress over de zool van de voet. Bij hett lichamelijk onderzoek van lepra patiënten wordt in tegenstelling tot bij het onderzoek vann de hand, weinig aandacht besteed aan een tijdig en regelmatig onderzoek van de func- tiee van de intrinsieke voetspieren. Bij het voorkomen van functieverlies en uiteindelijk daar- doorr deformatie, gaat de aandacht voornamelijk uit naar een eventueel verlies van protec- tievee sensibiliteit van de voetzool. Het is naar onze mening dan ook niet verwonderlijk dat ondankss het voorschrijven van beschermend schoeisel, een veel te groot percentage van de voetulceraa recidiveren en dat deze de belangrijkste opnameindicatie blijven vormen voor klinischee behandeling. Intrinsieke spieruitval in de voet is vergelijkbaar met die in de hand en kann dus mede verantwoordelijk gesteld worden voor een uiteindelijke weke delen beschadi- ging.. Ten einde de intrinsieke spieren van de voet te kunnen testen ontwikkelden we een nieuwe,, eenvoudige, en non-invasieve methode genoemd de "Paper Grip Test (PGT)". Een aangetoondee intrinsieke voetspieruitval resulteert vaak in wat we "Het syndroom van de falendee voorvoet", noemen. De symptomen bestaan uit een klauwen van de tenen, een doorzakkenn van het dwarsgewelf en later de lengtegewelven, en daardoor een overmatige piekbelastingg onder de metatarsophalangeale gewrichten I en II. Dit is waarschijnlijk de ver- klaringg voor het hoge aantal (recidiverende) voetulcera in dit gebied. De "Paper Grip Test" wordtt beschreven en therapeutische suggesties worden gedaan om ulcera te voorkomen. Het belangrijkstee advies bestaat uit een beschrijving van een schoenaanpassing om de voorvoet beterr te beschermen tijdens de afzet ("push-off") fase van het lopen.

Inn hoofdstuk zeven wordt gesteld dat met name type-1 of "reversal" zenuwreacties verant- woordelijkk zijn voor de zenuwbeschadiging en daardoor het functieverlies, bij lepra. Uit onderzoekk in het Mycobacterium Research Laboratorium van het Anandaban ziekenhuis bleekk dat met name er een duidelijk verband bestaat tussen de hoogte van een positieve serumspiegell van IgM antiphenol-glycolipide-1 (PGL-1) antilichamen en de kans op het optredenn van een type-1 reactie (p<0.001), dit onafhankelijk van de lepraclassificatie, een positievee "skin smear", en de aanwezigheid van andere ani\-M.leprae antilichamen. Deze relatiee werd ook niet gevonden voor IgG anti-Iipoarabinomannan of anti-Mycobacterium lepraee 35 kDa eiwit antilichamen. Een positieve anti-PGL-1 spiegel in combinatie met een positievee "lepromin test", bleek een belangrijke risicofactor voor het later ontwikkelen van eenn type-1 reactie en daarom wordt aanbevolen patiënten met deze risicofactor nauwgezet tee controleren gedurende de eerste twee jaren na het starten van de gecombineerde medi- camenteuzee behandeling (MDT). Het herkennen van deze risicogroep en het nauwlettend vervolgenn van hun zenuwfunctie zal hopelijk resulteren in een tijdige behandeling van een eventuelee neuritis en daardoor een voorkomen of minimaliseren van functieverlies en invaliditeit. .

Inn hoofdstuk acht wordt het verband geanalyseerd tussen de type-1 reactie en sensibel en motoirr zenuwfunctieverlies bij 297 "borderline" leprapatiënten, alsmede het effect van de

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ingesteldee behandeling van de neuritis met prednison.. Van deze 297 borderline patiënten ontwikkeldenn 157 patiënten (53%) een type-1 reactie gedurende een gemiddelde vervolgtijd vann 30.7 maanden (met een spreiding van 6-74 maanden) Geen significante verschillen wer- denn gevonden tussen BT, BB of BL type lepra patiënten, noch tussen links en rechts, tussen handen,, voeten of ogen. Een afname van sensibiliteit bij 21% en in spierkracht bij 13% van dee patiënten die geen type-1 reacties doormaakten duidt op een stille neuritis ("silent neuritis")) waarvan 71% van de episodes in het eerste jaar van MDT behandeling zich afspelen.

Vann de 157 patiënten die een type-1 reactie ontwikkelden en behandeld werden met prednison,, werd bij 65 patiënten (41%) een verbetering in de cumulatieve sensibiliteitsscore waargenomenn terwijl bij 39 patiënten (25%) er een verslechtering hiervan optrad en bij 53 patiëntenn (34%) deze score onveranderd bleef. Inn deze zelfde groep werd bij 56 patiënten (36%) een verbetering in de cumulatieve kracht- scoree gezien, terwijl bij 20 patiënten (13%) de score verslechterde en bij 81 patiënten (51%) dezee score onveranderd bleef. Deze uitkomsten indiceren een duidelijk noodzaak om meer effectievee behandelingsschemas te ontwikkelen voor de behandeling van neuritis geasso- cieerdd met type-1 reacties. De zenuwfunctie van patiënten die opgenomen werden voor klinischee behandeling verbeterden significant beter dan bij hen die poliklinisch behandeling ontvingen.. Het verschil werd grotendeels verklaard door de constatering dat 20 tot 30% van dee poliklinisch behandelde patiënten niet therapietrouw ("non-compliant") waren en de hunn voorgeschreven prednison niet kwamen ophalen. De reden hiervoor is helaas niet bekend. .

Inn hoofdstuk negen trachten we oorzaken voor het gebrek aan therapietrouw ("non-compliance")) daarom te inventariseren. Zoals reeds eerder gesteld bestaat de voornaamste zorg vann hen bij wie lepra gediagnosticeerd is niet uit hoe de M.leprae in het lichaam kwijtge- raaktt kunnen worden, maar eerder uit hoe het beste de zichtbare kenmerken van lepra gemaskeerdd kunnen worden, dit om sociale uitstoting te voorkomen. Hiernaast bestaat er eenn angst voor invaliditeit en een verslechtering van de economische positie. De psychische spanningenn die hierbij optreden hebben een directe invloed op de motivatie om adviezen voorr behandeling op te volgen en zijn vaak de oorzaak waarom een patiënt zich aan de behandelingg onttrekt. In een pogen om de belangrijkste factoren en kenmerken te kunnen identificerenn die bij deze mentale stress een rol spelen, werd bij een groep patiënten de WHO-Selff Reporting Questionnaire (WHO-SRQ) gebruikt, een door de patiënt in te vul- lenn 20-vragenlijst welke door de Wereld Gezondheidsorganisatie aanvankelijk ontwikkeld is omm niet-psychotische psychiatrische problematiek op te sporen, dit door ons aangevuld met eenn aparte serie vragen over socio-economische factoren. Deze WHO-SRQ test was al eer- derr in Nepal gevalideerd. Wijj zijn het met andere onderzoekers eens dat een positieve score niet zonder meer geïnter- preteerdd mag worden als een teken van duidelijke psychiatrische morbiditeit maar eerder gezienn moet worden als een uitslag welke op bovenmatige mentale stress duidt en daarom aanvullendd onderzoek verdient. Bij ongeveer 10% van de gemiddelde Nepalese bevolking

170 0 SAMENVATTING G

wordtt een positieve score bij gebruik van deze test gevonden. In 1990 en 1991 in ons eerste onderzoekk van 411 lepra patiënten in de Oostelijke, Centrale en Westelijke regio's van Nepal,, werd deze te hoge mentale stress bij 16.3 procent van de patiënten gemeten. Bij het vervolgonderzoekk in 2000 en 2001 was dit cijfer gestegen tot 31.5 procent, dit terwijl onder vergelijkbaree algemene populaties in 1999 en 2000 de scores respectievelijk 10 en 13.1% waren.. Aan het eind van 2001, na het vermoorden van het Nepalese koningshuis en de scherpee toename van Maoïstische guerrilla aanslagen, steeg dit percentage bij de bevolking zelfss tot ruim 60 procent. Hoe dan ook, er kan geconcludeerd worden dat de diagnose lepra eenn duidelijke toename van psychische stress veroorzaakt. Vrouwen, patiënten ouder dan 40 jaar,, en patiënten met een functiebeperking, hadden duidelijk vaker een positieve score dan mannen,, jongere patiënten en hen zonder functiebeperking. Wanneer de patiënt een nega- tievee kijk had op het verdere beloop van de ziekte en op de toekomst dan werd ook vaker eenn positieve score gevonden. Patiëntenn met een goede opleiding hadden duidelijk minder vaak een positieve score. Dit nett zoals patiënten die goed opgevangen werden door hun familie en die geloofden in een goedee afloop van hun ziekteproces, hoewel deze factor te niet werd gedaan na aanpassing vann de Odds ratio's. Eenn vergelijk van de twee onderzoeken van 1999/1 en van 2000/1 suggereert dat de sociale omstandighedenn in de tussenliggende tien jaren verbeterd zijn met een groter percentage patiëntenn die hun familie over hun ziek zijn durfden in te lichten en die nog steeds samen wonenn met hun eigen familie; dit duidt op minder sociale uitstoting dan in de 1990/1 pop- ulatiee werd gevonden. Hierr tegenover staat dat ook meer patiënten melding maken van een ontwijkend gedrag van hunn familie en moeilijkheden om een winkel binnen te gaan. In 2000/1 duidden meer patiëntenn een micro-organisme als de oorzaak van hun lepra maar ook minder patiënten geloofdenn in hun kans op genezing dan in 1990/1. De kennis die vergaard is bij deze beide onderzoekenn heeft ons belangrijke inzicht gegeven in de achtergronden van de psychische stresss die bij lepra vaker voorkomt, een kennis die voor een adequaat behandelen, onont- beerlijkk is. We verwachten dat dit zal resulteren in een verbetering van de leprazorg.

Dee verscheidenheid en de omvang van de problemen waar lepra patiënten mee geconfron- teerdd worden, liggen meestal ver buiten het bereik van het scalpel van de chirurg. De pro- blematiekk van de lepra patiënt wordt nauwelijks beïnvloedt door steriele statistieken. Een iederr die echt effectieve zorg wil verlenen wordt uitgedaagd zich te verdiepen in de wereld vann problemen waar de patiënt zich voor gesteld ziet. Een klein deel van deze uitdaging wordtt gereflecteerd in dit proefschrift.

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183 3 ACKNOWLEDGEMENTSS AND CURRICULUM VITAE

ACKNOWLEDGEMENTS S

Thiss thesis was prepared with the kind support of the Staff of Anandaban Leprosy Hospital, Nepal,, the Department of Neuromuscular Diseases (Emeritus Prof.Dr. F.G.I. Jennekens) of thee University of Utrecht, and the Departments of Dermatology (Prof.Dr. W.R. Faber) and Neurologyy (Prof.Dr. M. Vermeulen) of the University of Amsterdam, The Netherlands. Thee assistance of Dr. RW. Roche, Drs. A.H. Theuvenet-Schutte, the staff and patients of Anandabann Leprosy Hospital (Mr. P.K. Failbus), Mr. S.P. Ruchal, Mrs. Neruh Shrestha, Mrs.. K. Gavin-Finlay, Miss N. Miyazaki, the staff of the Nepali Leprosy Control Pro- grammee (Dr. J.P .Baral), Dr. H.M. Pradhan, the staff of Green Pastures Hospital, Pokhara, Thee Leprosy Mission International (Leprazending), the Netherlands Leprosy Relief Associationn (Leprastichting), Dr. A. Jennekens-Schinkel, Emeritus Prof.Dr. J.M.G Kauer, Drs.G.F.. Koeijers, Mrs Donna Bowers (editing), Annette Noordzijl (INFOLEP), Mrs J.M.M.. Linssen (photography) and Onno Theuvenet (computer support), is gratefully acknowledged. .

CURRICULUMM VITAE

Thee author of this thesis was born on December 20, 1950 at The Hague, the Netherlands. Afterr living in the Surinams for a number of years, he obtained the diploma HBS-B from thee Gemeentelijk Lyceum in Den Helder in 1970. After completing his military service he commencedd his medical training at the State University of Groningen, from which he grad- uatedd in May 1979. Between 1975 and 1979 he was student-assistant at the Department of Surgeryy of the University Hospital of Groningen. From 1979 untill 1983 he was trained in Surgeryy at the Deventer Ziekenhuizen, while from 1983 untill 1985 he specialized in Plastic andd Reconstructive Surgery at the University Hospital of Nijmegen. From 1986 untill 1992 hee served as initially the first Plastic and Reconstructive Surgeon in the Royal Kingdom of Nepal,, at the Anandaban Leprosy Hospital. He was appointed as Medical Superintendent off Anandaban Leprosy Hospital in 1987. Since 1993 the author has been working as a Plastic,, Reconstructive and Hand Surgeon at the regional hospitals of Apeldoorn, Deventer andd Zutphen, in the Netherlands. In 1996 he obtained the European Diploma in Hand Surgeryy (EFSSH) at Paris. From 1987 to the present day he has served as a Consultant in Plastic,, Reconstructive and Hand Surgery for The Leprosy Mission International (TLM) andd the Netherlands Leprosy Relief Association (NLR), participating in training pro- grammess in a number of countries in Asia, Africa and South America.

184 4 "Mother"Mother with multibacillary leprosy holding her baby"

Thee succes of every leprosy eradication programme largely depends on its possibilities too prevent impairment and deformity due to neuritis.

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