Leprosy Review Volume 87 Number 2 June 2016 by Lepra

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Editor’s Choice – June 2016 P. Saunderson

Editorial 146

An important perspective on the recent history of leprosy - and its implications for the current Global Strategy P.E.M. Fine

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The challenge of Multimorbidity in the context of leprosy C.R. Butlin

Original Papers 158

Need for, and acceptability of, rapid diagnostic tests that can facilitate the diagnosis of leprosy M.S. Duthie, F.M. Orcullo, A. Maghanoy and M.F. Balagon

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Outcome of 6 months MBMDT in MB patients in Bangladesh- preliminary results C.R. Butlin, D. Pahan, A.K.J. Maug, S. Withington, P. Nicholls, K. Alam and M.D.A.H. Salim

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Spatial and temporal trends in new case detection of leprosy in India V. Joshua

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Is the WHO disability grading system for leprosy related to the level of functional activity and social participation? V.T.C. De Souza, W.M. Da Silva Júnior, A.M.R. De Jesus, D.T. De Oliveira, H.A. Raptis, P.H.L. De Freitas and S. Schneiberg

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Nerve conduction study in leprosy: a hearty need or a customary practice? S. Marahatta, S. Bhattarai, B.H. Paudel and D. Thakur

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Experiences with Thalidomide for Erythema Nodosum Leprosum– a retrospective study J. Darlong, P. Govindharaj, D.E. Charles, A. Menzies and S. Mani

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The use of steroids and thalidomide in the management of Erythema Nodosum Leprosum; 17 years at the Hospital for Tropical Diseases, London L.E.B. Nabarro, D. Aggarwal, M. Armstrong and D.N.J. Lockwood

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Is nullity for Glutathione S-transferase genes GSTT1 and GSTM1 protective against leprosy? C.R. Graça, R.M. Cordeiro-Soubhia, S.M. Tonelli-Nardi, E. Belini Junior, C.R. Bonini-Domingos, C.R. Gauch, E.M.D.S. Da Rocha, V.D. Paschoal, J.A. Kouyoumdjian and A.R. De Souza Baptista

Leprosy Review Volume 87 Number 2 June 2016

CONTENTS

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Volume 87 Number 2 June 2016

Case Reports 239

Autonomic neuropathy impairing quality of life after completion of MDT: Are we managing enough? V. Anand, S. Pradhan and P. Kumar

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Pseudoathetosis and ataxia – a rare presentation of multibacillary leprosy in a non-endemic area J. Köstenbauer and H. Kempton

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Uncommon clinical presentations of leprosy: apropos of three cases R. Jindal and N. Shirazi

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Leukemia cutis in a patient of relapsed leprosy- Coincidence or predisposition? S. Reddy, A.R. Shashikiran, R. Basavaraj and M. Shamanur

Short Report 260

Disability aid compliance in people affected by leprosy in urban and rural Maharashtra, India – a need for comprehensive study M.D. Baker, V.V. Pai, N. Ajayan and C. Dhamale

Letter to the Editor 264

Prevalence of leprosy-related disability in Bangladesh C.R. Butlin, K. Kundu, D. Hossain, S. Singh and T.S. Warrender

Obituary 267

Robert Jacobson, M.D., Ph.D.

News and Notes 269

19th International Leprosy Congress: Welcome Note M. Virmond, W. Cairns Smith and G. Zhang

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Editor’s Choice – June 2016 P. Saunderson

Editorial 146

An important perspective on the recent history of leprosy - and its implications for the current Global Strategy P.E.M. Fine

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The challenge of Multimorbidity in the context of leprosy C.R. Butlin

Original Papers 158

Need for, and acceptability of, rapid diagnostic tests that can facilitate the diagnosis of leprosy M.S. Duthie, F.M. Orcullo, A. Maghanoy and M.F. Balagon

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Outcome of 6 months MBMDT in MB patients in Bangladesh- preliminary results C.R. Butlin, D. Pahan, A.K.J. Maug, S. Withington, P. Nicholls, K. Alam and M.D.A.H. Salim

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Spatial and temporal trends in new case detection of leprosy in India V. Joshua

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Nerve conduction study in leprosy: a hearty need or a customary practice? S. Marahatta, S. Bhattarai, B.H. Paudel and D. Thakur

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Experiences with Thalidomide for Erythema Nodosum Leprosum– a retrospective study J. Darlong, P. Govindharaj, D.E. Charles, A. Menzies and S. Mani

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Leprosy Review Volume 87 Number 2 June 2016

CONTENTS

TRIM: 169 X 242 MM

Leprosy Review

Volume 87 Number 2 June 2016

Case Reports 239

Autonomic neuropathy impairing quality of life after completion of MDT: Are we managing enough? V. Anand, S. Pradhan and P. Kumar

243

Pseudoathetosis and ataxia – a rare presentation of multibacillary leprosy in a non-endemic area J. Köstenbauer and H. Kempton

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Uncommon clinical presentations of leprosy: apropos of three cases R. Jindal and N. Shirazi

252

Leukemia cutis in a patient of relapsed leprosy- Coincidence or predisposition? S. Reddy, A.R. Shashikiran, R. Basavaraj and M. Shamanur

Short Report 260

Disability aid compliance in people affected by leprosy in urban and rural Maharashtra, India – a need for comprehensive study M.D. Baker, V.V. Pai, N. Ajayan and C. Dhamale

Letter to the Editor 264

Prevalence of leprosy-related disability in Bangladesh C.R. Butlin, K. Kundu, D. Hossain, S. Singh and T.S. Warrender

Obituary 267

Robert Jacobson, M.D., Ph.D.

News and Notes 269

19th International Leprosy Congress: Welcome Note M. Virmond, W. Cairns Smith and G. Zhang

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Lepr Rev (2016) 87, 145

Editor’s Choice – June 2016 The Global Leprosy Programme of the World Health Organization has just released a new, five-year Global Strategy, subtitled ‘Accelerating towards a leprosy-free world.’ Professor Paul Fine, a member of our Editorial Board, has written an interesting Editorial, which starts with a review of the published speeches of Dr Yo Yuasa, one of the initiators of the concept of leprosy elimination, and then moves on to some helpful commentary on the new Strategy. A second Editorial, also by an Editorial Board member, Dr Ruth Butlin, reminds us that leprosy remains a complex clinical condition that requires good clinical skills to manage effectively; an increasing problem, especially in elderly patients is the likelihood that they suffer from a number of other unrelated conditions, which adds further complexity. The case reports published in this issue further illustrate the complexities of leprosy and the way it can mimic many other conditions. So-called Uniform MDT (U-MDT: 6 months standardised treatment for all cases of leprosy) remains controversial, but the way forward can only be illuminated by well-conducted clinical trials, and we publish preliminary results from a trial in Bangladesh. It is to be hoped that this group will be able to continue the follow-up of this cohort for several more years. Measuring the burden of disability is notoriously difficult, but in a small survey in Bangladesh, Butlin et al. show in their Letter to the Editor that it is likely to be higher than previously estimated. This is a challenge to collect better data, and perhaps present it more tellingly through maps. Another challenging preliminary finding in the Short Report by Baker et al, is that disability aids, including MCR sandals, are only utilised successful by about 60% of the people to whom they are given. Two papers look at the use of thalidomide in ENL reactions, demonstrating a steroid-sparing effect. Both are retrospective studies and we look forward to publishing prospective studies on ENL in future, as the ENLIST consortium gains momentum. Paul Saunderson

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An important perspective on the recent history of leprosy - and its implications for the current Global Strategy PAUL E.M. FINE* *London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK Accepted for publication 4 May 2016

The Sasakawa Memorial Health Foundation (SMHF) has just published a fascinating book: “A Life Fighting Leprosy: a collection of the speeches and writings of Dr Yo Yuasa”, which will be of interest to many readers of Leprosy Review, and beyond.1 Few, if any, individuals have played so many important roles in the field of leprosy over the past several decades as has Dr Yuasa: from clinical medical officer in leprosy hospitals in Hong Kong and Nepal, to Secretary and then President of the International Leprosy Association, to Medical and then Executive Director of the Sasakawa Foundation, which has been one of the largest and most influential supporters of leprosy work around the world over the past 40 years. The book consists of 22 speeches and essays by Dr Yuasa, delivered or written over 30 years, 1982 – 2012. Few of them have been published before, and all are elegantly written. They cover the important period from the initiation of MDT as recommended by the WHO Study Group in 1981, to the elimination declaration by the World Health Assembly (WHA) in 1991, to the struggles to maintain the ILA and the International Leprosy Journal in the early 2000s, and include reflections on the successive strategies developed and promoted through ILEP, the ILA and WHO through 2012. They reveal their author to be both a pragmatist and a philosopher. The book contains many references to major figures in the leprosy world of recent decades, providing glimpses of personal interactions and events behind the scenes at important points in the history of leprosy policy. There are fascinating historical anecdotes – such as how what became known as the first International Leprosy Congress in Berlin was organised in 1897 because of concerns over 34 leprosy cases among Russian immigrants to Prussia. And we learn of a bargain between Riochi Sasakawa, founder of the SMHF, and Halfdan Mahler, Director General of WHO, in 1974/5, when WHO accepted $500,000 for leprosy work only on the condition that an equivalent amount from the SMHF went to rescue a funding shortfall of the Smallpox Eradication Programme. Correspondence to: Paul Fine, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK (e-mail: Paul.Fine@lshtm.ac.uk)

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For many readers, the most interesting portions of the book will be those which describe the background to and evolution of the global leprosy elimination initiative and its sequelae, with which Dr Yuasa was intimately involved for the latter 20 years of his career. This is touched upon in several of the essays and speeches, and documents changes in the author’s own views concerning the nuances of the declaration’s wording and associated policy implications. Given the continued interest in this topic in the leprosy community, and the proliferation of elimination targets for many diseases in recent years, these reflections are an important contribution to public health in general, reaching well beyond the leprosy field itself. Dr Yuasa describes how the word ‘elimination’ was adopted from a policy promoted by the US CDC for the ‘elimination of tuberculosis in the United States’, in which elimination was defined as reducing the ‘case rate of tuberculosis to less than one per million population by the year 2010.’ The adoption took place in the course of discussions between Yuasa and Dr J W Lee (subsequent Director General of WHO) and Dr R Jacobson (of Carville) in the Western Pacific Regional Office (WPRO) in Manilla in 1989. In considering options for leprosy control in the region, Yuasa, Lee and Jacobson decided to call the policy ‘Elimination of leprosy as a major public health problem by the year 2000’. There is an interesting comment (p 263) that Dr Lee was ‘reprimanded’ for this decision by Dr Noordeen, in Geneva, for not consulting beforehand with the WHO leprosy Unit! We also learn how Noordeen then adopted the elimination target idea from WPRO, and proposed it to the World Health Assembly in 1991, but with an important change – the removal of the word ‘major’ - so that the target was phrased as ‘elimination of leprosy as a public health problem by the year 2000’, defined in a footnote thus: “Elimination of leprosy as a public health problem is defined as the reduction of prevalence to a level below one case per 10 000 population.” Yuasa comments with perfect irony that this was done in Geneva with no consultation with WPRO (p 263)! This little anecdote provides a unique insight into the genesis of the WHA declaration, and may lead us to reflect on the nature and extent of consultation appropriate for declarations put to international bodies, which can in turn be so influential in directing national and global policies and actions. Equally if not more important than the issue of process is the precise wording change between the WPRO and WHA declarations – from “elimination as a major public health problem” to “elimination as a public health problem”. Yuasa is sensitive to this semantic issue, and refers to it explicitly in an essay published in 2011 (p 222). This may have been particularly problematic because of the leprosy context, insofar as it appeared to place the WHO at odds with the responsibility of leprosy workers on the ground. Leprosy is an infectious disease, reflecting past transmission of an infectious agent from some source, and the possibility of further transmission to others in the community. These are public health concerns, by definition. Beyond that, leprosy is unusual in terms of the stigma and fear it raises in most societies, which often brings a variety of complex issues for communities with leprosy cases. Dealing with these issues is part of the responsibility of leprosy workers at every level, worldwide, and one can easily argue that every single leprosy case raises public health issues, and is thus of public health importance. In this vein one may agree with the 1989 WPRO resolution’s wording, and with Dr Yuasa, that a small number of leprosy cases may not constitute a major public health problem, given that there may well be other problems of greater magnitude, be they HIV or polio or measles vaccine coverage : : : but to imply that they raise no problem at all is less appropriate.

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It is interesting that Dr Yuasa discussed the wording of the WHO resolution on so many occasions, reflecting, and in response to, the widespread concern with this issue throughout the leprosy community. Though he described the 1991 elimination declaration as a “brilliant marketing manoeuvre” which encouraged the mobilisation of resources and energy for leprosy during the 1990s (p 170), several chapters document his growing concern that the elimination word became less appropriate after the initial phase of the programme – in particular that it logically implies the need for eradication (reduction to zero), a target which he came to appreciate was as not feasible in practice. He explicitly comments on the importance of the animal reservoir in some areas of the world, which makes eradication effectively impossible (p 141). As a result of his reflections on the semantics of elimination, and his own deep concerns over the important social implications of leprosy, even as a symbol of human intolerance, Dr Yuasa came to favour a goal for leprosy control described at the time of the 1998 Beijing Congress as ‘a world without leprosy’ and later as ‘a world without leprosy-related problems, both medical and social.’ (p 242). It is interesting that a version of the shorter, former, phrase (which was ultimately rejected by Yuasa as implying eradication and thus effectively impossible – p 264), is included as subtitle for WHO’s recently released “Global Leprosy Strategy 2016 – 2020: Accelerating towards a leprosy-free world”.2 The tension between aspiration versus marketing versus politics versus feasibility of public health ambitions and slogans is palpable throughout this book. All this makes for fascinating reading, and is important history, documenting the experiences, opinions and reflections of one of the most influential figures in the leprosy world of recent times. We are grateful to Dr Yuasa for his many contributions, and to the Sasakawa Foundation - not only for their generous support of so much leprosy work – but for their decision to publish this revealing memoir.

II The Yuasa memoir provides a thought-provoking background against which to contemplate the current Global Strategy.2 The WHO document refers to the successive quinquennial plans and notes that “They have been moving from targets on ‘elimination’ in terms of prevalence of the disease to targets that emphasise a decrease in the number of new cases with Grade 2 Disability (G2D) to promote early detection and reduction in transmission.” (p 2) Specifically it outlines a vision of a “leprosy free world” (apologies to Dr Yuasa!), a goal “to further reduce the global and local leprosy burden” and three main targets: “Zero G2D among paediatric leprosy patients”; “Reduction of new leprosy cases with G2D to less than one case per million population”: and “Zero countries with legislation allowing discrimination on the basis of leprosy”. An ambitious series of activities is proposed, including the collection of 23 performance indicators, ranging from new case detection statistics, to the proportion of contacts screened, to the availability of data to assess the level of stigma, to the number and proportion of drug resistance cases. There is emphasis on six guiding principles: strengthening government commitment, sustaining expertise, providing quality services focusing on women and children, enhancing participation of persons affected by leprosy in leprosy services, protection of human rights, and encouraging research. There are three pillars: to strengthen government ownership, to stop leprosy and its complications, and to stop discrimination and promote inclusion. Finally there are Implementation plans, set out in four categories,

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relating to: regional and country implementation, monitoring of targets and indicators globally and at country level, advocacy, and changes to WHO technical advisory bodies. It is a very large agenda, and while all involved in leprosy may agree with most of the proposals, some will wonder if the programme can succeed on so many fronts. Some prioritization will be necessary. One may ask, for example, to what extent targets need to be achievable, as well as – or as opposed to – being aspirational. This is a major issue in public health (indeed in all aspects of development) today as targets proliferate, with goals to “eradicate” this, “eliminate” that, “interrupt” this, “stop” this, “end” that : : : . We have just completed the last quinquennial plan (2011 – 2015), which proposed a target of “reducing the rate of new cases with Grade-2 Disability per 100,000 population by at least 35% by the end of 2015 compared to the baseline at the end of 2010”.3 Unfortunately, not only was this target not met, but the detection rate of G2D hardly changed at all.2,4 Should one ask why the target was missed? Should one ask how the target came to be set in the first place? If it was an error, or a miscalculation, should such mistakes be avoided in the future? Does it matter? What are targets for? In considering targets, it is interesting to reflect that Dr Yuasa became concerned that some of the targets which had been proposed were not achievable, once the armadillo reservoir of M. leprae had been recognised. This fact is not mentioned at all in the Global Strategy, despite its elegant confirmation through genetic sequencing of bacilli from human and armadillo sources in recent years,5 and the recognition that this reservoir is now increasing in geographic extent in at least one country, the USA, along with associated human cases.6 The reservoir species is found throughout most of Latin America – but there is as yet no solid evidence of its role in human leprosy south of the Rio Grande River. This is now an important research question. The latest numerical targets (Zero G2D among paediatric leprosy patients, and Reduction of new leprosy cases with G2D to less than one case per million population) might in theory be achievable, even if M. leprae infection is to persist, if it could be ensured that incidence of infection in humans is low and cases are recognised early, and managed properly. Assurance of these conditions in practice will not be easy, however, given the difficulty of diagnosing early leprosy and the state of many leprosy control services, which have been wound down as a result of WHO’s declaration that leprosy was no longer a public health problem and the misinterpretation by some that leprosy had in effect been eradicated.4,7,8 We may recall Dr Yuasa’s concern over words and their implications. Several authors have argued for the introduction of more systematic contact tracing and chemoprophylaxis, which would probably reduce new infections and incidence, and this is referred to in the new Strategy document, with the proviso that practicability in the field still needs to be shown.2,4 If this can be organised and funded, so much the better, as it might accelerate leprosy’s decline to some degree. However, the relative contributions of improved living standards, widespread BCG vaccination of infants (not mentioned in the Strategy) and case detection and treatment, let alone chemoprophylaxis of contacts, to declines in leprosy incidence, are likely to differ between populations, and have nowhere been rigorously defined. It has been noted that new case detection numbers at the global level have remained relatively constant in recent years.4 In fact, they have varied considerably within and between countries, but the global total has declined every year but one (it increased from 226,626 to 232,857 between 2011 and 2012).9 One might argue, however, that the problem is not that the numbers of new cases appear to be declining slowly in recent years, as a slow decline is at

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least a decline, and a rapid decline is unlikely for a condition with a long incubation period, let alone no test for infection and generally poor control services. The larger problem is that many of the published numbers are of questionable validity.10 Surveillance is an essential aspect of public health, and this poses a major problem in the leprosy field. It is therefore commendable that the new strategy does mention a commitment for “strengthening surveillance and health information systems for programme monitoring” and states that “A pool of monitors shall be trained.” This is crucial, as the programme ultimately turns to the numbers reported in order to monitor progress. However, nineteen (40% of) African nations are recorded as ‘NR’ (no report) in the most recent summary.9 Europe does not report at all. Some Latin American countries report zero new or prevalent cases after reporting more than a hundred a very few years ago. And the India data (specifically the 66% decline in numbers of cases detected, from 474,286 to 161,457 between 2000 and 2005) have repeatedly been questioned : : : , all leading to the claim that millions of cases may have failed to be reported in recent years.11 At the end of the day, the numbers are what matters, and if they are not robust, and not credible, the entire programme suffers. Programmes with serious surveillance typically include a condition that the comparison of numbers to targets must be based upon high quality surveillance - and they set out hard criteria for such quality (the polio programme is the most prominent example of this today).12,13 We encourage that this aspect of the leprosy strategy, to improve and monitor surveillance in all endemic countries, receives high priority and critical attention, in the years to come.

References 1 2 3 4 5 6 7 8 9 10 11 12 13

Yuasa Y. A life fighting leprosy: A collection of the speeches and writing of Dr Yo Yuasa, Tokyo: Sasakawa Memorial Health Foundation, 2015. WHO. Global Leprosy Strategy 2016 – 2020 – Accelerating towards a leprosy free world, http://www.searo. who.int/entity/global_leprosy_programme/documents/global_leprosy_strategy_2020/en/. WHO. Enhanced global strategy for further reducing the disease burden due to leprosy (Plan period 2011 – 2015). WHO Regional Office for Southeast Asia, 2009. Tiwari A, Richardus JH. Investment case concepts in leprosy elimination. Lepr Rev, 2016; 87: 2–22. Truman RW, Singh P, Sharma R et al. Probable zoonotic leprosy in the Southern United States. N Eng J Med, 2011; 364: 1626–1633. Villada G, Zarei M, Romagosa R, Forgione P, Fabbrocini G, Romanelli P. Autochthonous borderline tuberculoid leprosy in a man from Florida. Lepr Rev, 2016; 87: 101–103. Lockwood DN, Shetty V, Penna GO. Hazards of setting targets to eliminate disease: lessons from the leprosy elimination campaign. BMJ, 2014; 348: g1136. Fine PEM. Leprosy: what is being eliminated? Bull WHO, 2007; 85: 1–2. WHO. Global leprosy update, 2014: need for early case detection. Wkly Epidemiol Rec, 2015; 90: 461 –474. Declercq E. Leprosy figures: no time for self-complacency. Lepr Rev, 2012; 83: 3 –5. Smith WC, vanBrakel WV, Gillis T, Saunderson P, Richardus JH. The missing millions: a threat to the elimination of leprosy. PLoS Negl Trop Dis, 2015; 9: e0003658. http://www.polioeradication.org/Aboutus/Strategy/Surveillance.aspx http://www.who.int/immunization/monitoring_surveillance/burden/vpd/surveillance_type/active/ poliomyelitis_standards/en/

Lepr Rev (2016) 87, 151– 157

EDITORIAL

The challenge of Multimorbidity in the context of leprosy C. RUTH BUTLIN* * DBLM Hospital, Nilphamari, Bangladesh Accepted for publication 4 April 2016 Introduction Multi-morbidity (generally defined as the presence of two or more chronic health conditions simultaneously),1 – 2 is increasingly recognised in the medical literature as a problem both for care providers and for sufferers. However, while there are many discussions about it, there are few studies on which to base recommendations. The residual morbidity arising from leprosy is one serious long term condition which requires on-going care and attention from both the sufferer and the concerned clinician, but as life progresses people affected by leprosy are also at risk of incurring any of numerous other chronic conditions which in turn need care and attention. In fact they may be at higher risk than same-age members of the community for some conditions, because of the well-known association between illness/disability and socio-economic status. In many countries guidelines for management of chronic conditions are proliferating, but each addresses one particular condition and they rarely address the issue of adapting guidelines to individuals cases where multiple pathology complicates the clinician’s decision making. This is also true of some international guidelines.3 At the same time health services (at least for secondary care) are organised on a disease-specific basis, and except in a few countries (where general practice is recognised as a specialty in its own right) post-graduate training of doctors is largely confined to the narrow boundaries of their chosen specialty with the result that consultants feel uncomfortable handling diseases outside their area of expertise. This growing problem is affecting leprosy as much as any other field, although in many places more for the leprosy staff trying to manage other conditions with which they are unfamiliar, than for other specialists trying to manage leprosy in their own clinics. Despite World Health Organisation (WHO) encouragement and the acceptance of ‘integration of leprosy into basic health care services’ (with leprosy-related treatment being offered by the same staff at the same place and time as treatment for other medical conditions) as policy in most endemic countries, such full integration is not yet achieved everywhere and ‘reverse integration4 - often pioneered by leprosy organisations - is the next best solution. Correspondence to: Ruth Butlin, 42 Old Drive, Polegate, East Sussex, BN 26 5ES, UK (e-mail: drbutlin@yahoo. com) 0305-7518/16/064053+07 $1.00

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For some combinations of conditions polypharmacy is the biggest challenge, but leprosyaffected people spend only a small proportion of their ‘disease career’ taking regular medication (6 – 12 months of Multi Drug Therapy, then maybe a few courses of prednisolone over the first 2 – 5 years after diagnosis), and a much higher proportion of time struggling with self-care for residual morbidity such as nerve function impairment. The ‘burden of self-care’ can become very high if an individual also has other chronic conditions necessitating daily attention, for example diabetic peripheral vascular disease or lymphatic filariasis (as well as leprosy). Some combinations of conditions present the patient with risks of complications which are overlapping (risk may be multiplied rather than additive). USING GUIDELINES

When medical practitioners attempt to apply several individual guidelines to one patient with multiple conditions, they meet a situation in which every individual recommendation made by a guideline may be rational and evidence based, but the sum of all recommendations in the individual is not.2 The need to adapt guidelines when a person has more than one condition has been discussed5: to help clinicians’ decision-making, it is suggested, guidelines should include a mention of which treatments are least likely to benefit/most likely to harm. There is also a need to improve the evidence base from which guidelines are created by undertaking trials which include as subjects those with at least the most common combinations of conditions, and older people, then examining outcomes in subsets of subjects. The same points were made by Roland6 who also mentions a need for published guidelines for a few specific combination of conditions. As it will never be feasible to have evidence for every possible combination of conditions, at least diseasespecific guidelines could be delivered in a format that is more useful for managing people with Multi-Morbidity5 and methods developed to facilitate integration and prioritisation of different clinical pathways.7 Nonetheless, professionals will use personal judgement in the face of uncertainty6 and the appropriateness of their decisions varies with their individual clinical acumen. Some attempts have been made to obtain evidence on management of dual morbidity. The combination of physical and metal conditions is particularly challenging:8 Ackroyd looked at either diabetes or heart disease, with depression.9 Apart from when it is coincidental comorbidity, depression may result from other long term illness or disability as well as impair one’s ability to manage other conditions.2 This was recognised by NICE when it published a clinical guideline on depression with other long term conditions.10 The value of well-prepared guidelines lies partly in the authors having properly assessed the evidence base, to identify interventions which are not of proven effectiveness even though their usefulness might have seemed self-evident. This prevents burdening patients with unnecessary workload. Sun and Xin studied self-care training sessions for Chronic Obstructive Pulmonary Disease, Irritable Bowel Syndrome and diabetes and concludes that “not all feasible interventions are effective and not all effective interventions are feasible”.11 NEED FOR AWARENESS AMONGST HEALTH WORKERS

It is important for those generalists with overall responsibility for individual patients (rather than for specific diseases) to be aware of their difficult role in balancing ‘benefits and risks of multiple recommended treatments’5 since “individual recommendations may be

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harmful/burdensome”. Sinnott who interviewed General Practitioners as to how they cope, coined the word ‘Satisficing’ for what they do when conflicts arise. These clinicians “accept trade-offs between drugs, diseases and recommendations”, and their compromise is to half satisfy and to half suffice. It sounds almost like sacrificing one goal for another. As it was put in a Royal College of General Practitoners paper “we need to rediscover the essential skill of good judgement- not everything that could be done for a patient with just one problem should be done for patients with lots of problems”.1 Another aspect of the ‘good clinical judgement needed’ is the willingness to change management priorities over time in response to evolving conditions.7 Care of a patient with multi-morbidity is often shared between specialists, but needs to be coordinated (preferably by a generalist clinician who is able to offer long term continuity of care). Issues related to management of multi-morbidity are being researched by the “School for advancing generalist expertise” (SAGE).13 The wise generalist will attempt to understand the patient’s priorities, helping the less articulate to express their opinions6 as well as interpret management plans for them (bringing order into chaos for patients). When one negotiates with patients and carers regarding the goals of treatment, instead of simply using physicianset targets,14 one may find they rank social participation and functional status above clinical and health service chosen targets.15 This may be particularly true of older people. “Single disease guidelines rarely refer to people with limited life expectancy : : : ” Guthrie,5 but multiple morbidity may include at least one life-limiting condition, and anyway is more common in the elderly. Guidelines which recommend interventions likely to have delayed or long-term benefits (e.g. reduction in 10 year risk of a complication) are not appropriate to apply in people who – on account of another health condition, or simply their advanced age are unlikely to survive 10 years. Polypharmacy presents a real risk (in terms of pharmacological interactions) and practitioners need to focus on ‘medicine optimisation’ and the place for ‘deprescribing’ some long term medications,16 not least because handling complex drug regimens demands a lot from the patient: “the burden of the treatment” may be excessive,17 or even exceed the expected benefit. For many, having a ‘normal’ daily life and fulfilling perceived social obligations may take priority over control of symptoms or of risks.16 Multi-morbidity may be not the only problem (nor the major problem) in the lives of the patients concerned. Mere survival in a resource-poor situation may be occupying most of their attention,18,19 leaving health matters to a lower level of priority. There is an association with lower socioeconomic status: looking at prevalence and type of patients with multimorbidity, even in the relatively well-provided population of Scotland (1·75 million people in GP), Mercer20 found increasing prevalence with age and with deprivation compared with the more affluent. To supplement such cross-sectional data one needs longitudinal studies looking at the progression of the burden over a lifetime.

NEED FOR MONITORING HOW PEOPLE COPE

Empowerment has been described as a “goal in rehabilitation of disabled people which provides tools they need to attain independence and self-determination”.21 So called ‘selfcare’ is a major tool, but it is not a single entity and responsibility for self-care is not something which can be easily handed to a patient: “(the concept of) self -care involves a spectrum of activity: : : many patients already self-manage. : : : . for many others self-care is

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a distant aspiration : : : many have a more complex task : : : ”:15 Personalised care planning is at the centre of good management. If we do not know how to measure empowerment we will not know which methods are best for enhancing it. One systematic review by Bakker & van Brakel22 identified 17 questionnaires to assess empowerment in context of disability, but none had been developed/ validated in developing countries and there was variation in ‘construct of empowerment’. The most widely used and best validated/tested was the ‘empowerment scale’ (ES) of Rogers;23 most scales (including this one) although they had been developed primarily for mental illness seemed to be applicable other disabilities. Bakker pointed out the need for “cultural validation of any tool and to look at equivalence criteria”.

MODELS OF SELF-MANAGEMENT

Self-management which can be defined as “the care taken by individuals towards their own health and wellbeing” includes preventative actions, a healthy life style, satisfying emotional and social needs as well as actually managing the condition in question.9 It is helpful to consider alternative models of self-management which have been developed for various chronic conditions, to see which are most applicable in a multimorbidity situation. A person-centred collaborative approach (which captures the subjective feelings of loneliness, and of being ‘a burden to others’) is preferred to professionally-owned models of care which rely mostly on objective clinical indicators.24 One well-established approach is used by Pain Clinics, which says accepting that pain is part of one’s life and deliberately “taking control”, instead of “giving up” allows one to do things differently and live with the pain, setting realistic goals. The Recovery model from mental health suggests one should ‘look beyond mere survival’ and concentrate more on recognising and fostering one’s abilities, interests or dreams, rather than on getting rid of problems. The ‘collaborative care and support planning’ model is based on the idea that it is the people with chronic conditions who are in charge and the primary decision-makers, a health worker’s role is to support them in managing challenges. The ‘Ariadne Principle’ approach2 has been developed for identifying realistic treatment goals and preparing individualised management plans taking into account patient preferences. The cumulative complexity model25 describes a patient’s response to being overburdened when the ‘workload’ imposed on him (by being expected to manage all his multi-morbidity) exceeds his capacity to cope. If this situation arises one has to both diminish the treatment demands, and increase the capacity of the person to cope/self-manage, but it should preferably be avoided by anticipatory action. One suggestion from Hodkinson24 for thinking about people with multi-morbidity is to group them into three categories, while realising that over time people shift between groups: (i) those who, while having complex multi-morbidity are functionally fairly independent. (ii) Those who are struggling to maintain independence while receiving some level of regular intervention, or becoming more frail. (iii) Those who are definitely frail, or largely dependent, having been already assessed are currently in receipt of adequate support Research is still needed into the methods some patients use successfully, in order to learn from them how best to help those who are not coping well with their multiple prescribed medications.16

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APPLICATION TO LEPROSY

One relatively straightforward issue for leprosy clinics is handling co-Incidental, acute, illness (Tb, jaundice, neglected tropical diseases) during chemotherapy or during immunesuppressive/anti-reaction treatment,26 but not much has been written about opting not to treat new nerve function impairment in some cases, if the patient has other chronic conditions (or is very old) which would mean a disproportionate increase in the attendant risks of adverse effects of steroids. It is more difficult – for the patient as well as the clinician - to handle a second or third long-term condition superimposed on disability related to leprosy, even if he no longer needs medication for his leprosy. Often leprosy staffs do not have the knowledge or skills to advise the patient and in some places the leprosy-affected person either is not welcome when he tries to obtain medical advice/treatment for other conditions at general health services facilities, or he is unable to access the facilities for practical reasons (including transport problems or finances). Self-care problems may be compounded by other disabilities so that the person – although comprehending and motivated - is physically incapable of carrying out all advice he receives from health workers (blindness plus nerve function impairment prevents daily inspection of limbs) and some attempt has been made to develop an integrated grading system for functional limitation in the presence of leprosy/filariasis comorbidity.27 Particular overlap of leprosy with other neglected tropical diseases (NTDs) has been noted:28 both “often co-exist and often associated with poverty”. There is scope for integration of staff training, and of services (e.g. in-patient care) etc. and also for development of scales which measure ‘ability to cope’ in the face of burdensome self-care regimens for more than one chronic disease. The American Leprosy Missions has recently made available valuable teaching aids for addressing morbidity arising from various NTDs in a coordinated way.29 Considering a common non-communicable disease which often co-exists with leprosy, De Bruin & Van Brakel investigated whether health workers were willing to combine selfcare teaching for diabetes and for leprosy, by means of a questionnaire. They found a qualified readiness to undertake a joint approach provided certain barriers could be overcome.30 There have been several surveys assessing prevalence of depression amongst leprosy affected people31 but fewer studies on management of mental illness in this group. Similarly, the epidemiology of co-existent Tb and leprosy has attracted more attention than the management of these two conditions in the same patient.32 Many leprosy-affected people live in dire poverty: one needs to heed the fact that poverty itself undermines one’s ability to cope with other problems in life, including illness or disability.18,19

SUMMING UP

Since the current usual definition of multi-morbidity (two or more conditions) includes such a large proportion of the population, and some chronic conditions do not necessitate much daily attention, it may be more helpful (for planning interventions or training of health workers) to narrow it down to the working definition to those with three or more chronic conditions requiring constant attention by the sufferer. That might be residual morbidity from leprosy along with at least two other conditions. Cahill14 says “the subgroup of patients whose combination of conditions cause them a particular burden are a priority, where management is a challenge for themselves, their clinicians and their carers”. We need to think particularly

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about the burdens on older people with residual morbidity from leprosy (i.e. permanent nerve function impairment or other leprosy-related disability), who have one or more other chronic conditions requiring self-care (be it lymphatic filariasis, diabetes, depression, epilepsy or chronic obstructive pulmonary disease) and how these can be tackled in an integrated way. Finally we must keep in mind that ‘patients are more than the sum of their individual diseases’.33

References 1

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Salisbury C. Multi-morbidity: will it sink or swim general practice? Patients with multi-morbidities, from www.RCGP.org.uk website (Accessed 27th February 2015). Wallace E, Salisbury C, Guthrie B et al. Managing patients with multi-morbidity in primary care. BMJ, 2015; 350: 176. WHO, 2012, Prevention & control of non-communicable diseases. Guidelines for primary care in low resource settings Iyor FT. Reverse integration in leprosy: lessons from Mkar, Nigeria. Asia Pacific Disabil Rehab J, 2006; 17: 35–41. Guthrie B, Payne K, Alderson P et al. Adapting clinical guidelines to take account of multi-morbidity. BMJ, 2012; 345: 22 –24. Roland M, Paddison C. Better management of patients with Multi-Morbidity. BMJ, 2013; 346: 21–22. Kadam U. Should consultations for patients with multi-morbidity be different? BMJ, 2012; 345: 10. Gunn J. Designing care for people with mixed mental and physical Multi-Morbidity. BMJ, 2015; 350: 8. Ackroyd R. Diabetes and depression in general practice. BJGP, 2014; 64: 386 –387. National Institute for health and care excellence 2009, Depression in adults with a chronic physical health problem: treatment and management. Clinical guideline 91. Available from www.nice/org.uk/guidance/CG91 Sun Xin, Guyatt G. Interventions to enhance self-management support. BMJ, 2013; 346: 10. Sinnott C. What to give the patient who has everything? A qualitative study of prescribing for Multi-Morbidity in primary care. BJGP, 2015; 65: 130–131. Reeve J. Supporting expert generalist practice: the SAGE consultation model. BJGP, 2015; 65: 207–208. Cahill P. Prescribing for patients with Multi-Morbidity: aiming to tailor to patient-set goals. BJGP, 2015; 65: 114. Watt G. Looking beyond the “house of care” for long term conditions: some patients are at risk of being left outside. BMJ, 2013; 347: 8. Reeve J. Solutions to problematic polypharmacy: learning from the expertise of patients. BJGP, 2015; 65: 319– 340. Wilkie P. Really putting patients first. BJGP, 2015; 65: 108–109. Bowers R, Singh S, Kuiper P. Responding to the challenge of leprosy-rated disability and ultra-poverty. Lepr Rev, 2014; 85: 141–148. Mullainathan S & Shafir A. “Scarcity, the true cost of not having enough” published by Penguin 2014. Mercer SW. The influence of socioeconomic deprivation on Multi-morbidity at different ages: a cross sectional study. BJGP, 2014; 64: 349–350. WHO 2010. Health topics. Rehabilitation. available from www.who.int/topcs/rehabilitation/en/ Bakker L, van Brakel W. Empowerment assessment tools in people with disabilities in developing countries. A systematic literature review. Lepr Rev, 2012; 83: 129 –153. Rogers ES, Chamberlin J, Ellison ML et al. A consumer-constructed scale for measure empowerment among users of mental health services. Psychiatr Serv, 1997; 48: 1042–1047. Hodkinson I. Patients with multi-morbidities, from www.RCGP.org.uk website 2015 (Accessed 27th February 2015). Shippee ND, Shah D, May CR et al. Cumulative complexity: a functional patient centred model of patient complexity can improve research and practice. J Clin Epidem, 2012; 65: 1041–1051. Di Luca DG, de Andrade PJS, Sales AM et al. Superposition of leprosy and other neglected tropical diseases in the state of Rio de Janeiro: a case series report. Lepr Rev, 2013; 84: 302 –307. Rawson TM, Ranganadha Rao PV. Leprosy and lymphatic filariasis comorbidity: the case for an integrated functional limitation grading system. Lepr Rev, 2014; 85: 63– 67. Smith WCS, Odong DS, Ogosi AN. The importance of neglected tropical diseases in sustaining leprosy control programmes. Lepr Rev, 2012; 83: 121–124. American Leprosy Missions, A guide for health promotion and empowerment of people affected by neglected tropical diseases. 10 steps available from www.Leprosy.org/ten-steps

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De Bruin W, Dukkamp E, Post E, van Brakel W. Combining peer-led self-care interventions for people affected by leprosy or diabetes in leprosy-endemic countries. What do health care professionals think? Lepr Rev, 2013; 84: 266 –282. Senturk V, Steart R, Sagduyu A. Screening for mental disorders in leprosy patients, comparing the internal consistency and screening properties of HADS and GHQ-12. Lepr Rev, 2007; 78: 231 –242. Rawson T. Leprosy and tuberculosis concomitant infection: a poorly understood, age old relationship. Lepr Rev, 2014; 85: 288– 295. Hobbs FDR, Baker M, Davies SC. Morbidity matters. BJGP, 2015; 65: 171 –172.

Lepr Rev (2016) 87, 158– 170

Need for, and acceptability of, rapid diagnostic tests that can facilitate the diagnosis of leprosy MALCOLM S. DUTHIE*, FLORENDA M. ORCULLO**, ARMI MAGHANOY** & MARIVIC F. BALAGON** *Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102 **Cebu Skin Clinic/Leonard Wood Memorial Center for Leprosy Research, Cebu City, Philippines Accepted for publication 4 April 2016 Summary New cases of leprosy indicate that M. leprae transmission is continuing. In the first half of 2015 we sequentially diagnosed new leprosy patients attending Cebu Skin Clinic, a referral and leprosy treatment centre in Cebu City, Philippines. The great majority of patients were characterised as multibacillary (145 of 147; 98·6%), most of whom had bacterial indices 3þ (86; 58·5%) or more than 20 skin lesions (94; 63·9%). Importantly, 65·3% estimated that slightly over a year had elapsed between their initial symptoms and diagnosis, while 26·5% reported a lapse of greater than 3 years. Many patients (73·8%) and their household contacts (79·2%) reported that their lives had already been adversely affected. This indicates that improvements to expedite diagnosis are required, and rapid diagnostic tests (RDT) appear suited for this. Questionnaires were conducted among various groups to ascertain the acceptability and perception of RDT. All groups responded favourably, with 95·9% patients, 93·2% contacts and 81·4% of the general population responding that RDT would be beneficial for leprosy. The vast majority of patients (88·6%) indicated that they would ‘definitely’ submit to testing, followed by 69·4% of contacts and 72·2% of the general population. The majority of patients thought their household members should also be tested, while a subset indicated that RDT use should be extended to their respective communities. We propose that, due to their ease of use, point of care applicability and acceptability within target populations, RDT could be used as an entry point to inform the diagnostic process for leprosy. Keywords: leprosy; diagnosis; mycobacteria; serology

Correspondence to: Malcolm S. Duthie, Infectious Disease Research Institute, 1616 Eastlake Ave E, Seattle, WA 98102, U.S.A. (Tel: þ 1 206-858-6012; Fax: þ1 206-381-3678; e-mail: mduthie@idri.org)

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q Lepra

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Introduction Leprosy is the clinical consequence of infection with Mycobacterium leprae,1 manifesting as peripheral nerve damage associated with autonomic, sensory, and motor dysfunction. Loss of sensation also means that leprosy patients can unwittingly suffer damage due to ordinary hazards.2 â&#x20AC;&#x201C; 4 The disfigurement and disability that arises in advanced leprosy cases perpetuates the stigma surrounding the disease. Importantly, the earlier a patient is detected and treated, the less likely he is to suffer permanent nerve damage. Treatment in the form of a cocktail of antibiotics (multi-drug therapy; MDT) has been distributed free of charge by the World Health Organization (WHO) since 1995. This has been a major contributor to the massive reduction of registered leprosy cases, from approximately 12 million in 1985 to less than 250,000 in 2012.5,6 The new case detection rate has stabilized over recent years, however, indicating that vigilance is still required. Leprosy presents across an extremely diverse range of symptoms with varying severity and patients can be stratified into five categories based on histological examination; lepromatous leprosy (LL), borderline lepromatous (BL), mid-borderline (BB), borderline tuberculoid (BT), and pure tuberculoid (TT).7 The healthcare providers to whom patients first present typically have more limited facilities, however, so to simplify diagnosis and the initiation of treatment, WHO guidelines rely on a categorisation based on number of skin lesions and involved nerves. Patients are categorised by the sum of several criteria as either multibacillary (MB; including the LL, BL, BB and slit smear positive BT forms) or paucibacillary (PB; including TT and slit smear negative BT forms). MB patients have either greater than five skin lesions, more than one involved nerve or positive skin smears, while PB patients have at most five skin lesions, no or only one involved nerve and negative skin smears. Many leprosy patients are initially misdiagnosed and treated for other conditions, such that appropriate treatment is commonly delayed. Although difficult to accurately measure, in most regions it is estimated that extended periods of time (often years) endure from the first recognition of signs or symptoms for a patient to obtain an appropriate diagnosis.8 â&#x20AC;&#x201C; 11 Indeed, late diagnosis is indicated by reports that approximately 10% of new leprosy cases registered each year have signs of neuropathy.5 The current reliance on expert clinical recognition to achieve the correct diagnosis of leprosy presents a bottleneck that can negatively impact control programmes. Immunologically, PB patients have cellular responses that restrict bacterial dissemination and present with low or absent bacterial indices (BI; a measure of the number of acid-fast bacilli in the dermis expressed in a logarithmic scale) while MB patients skew toward antibody-mediated responses that do not control M. leprae replication and present with high BI. The measurement of M. leprae-specific antibodies can therefore serve as a proxy for infection levels and the detection of antibodies to M. leprae antigens could be used to assist in the detection, characterisation and management of leprosy cases. This has been clearly demonstrated in the controlled setting of leprosy clinics and, in retrospect, within leprosy targeted surveillance programmes.12 â&#x20AC;&#x201C; 18 This has not, however, disseminated to general health services, for which the availability of fast, easy-to-use tests would be most beneficial. To determine if delayed diagnosis was common or indicated, we analysed the characteristics of patients attending the Cebu Skin Clinic, a leprosy treatment facility of the Leonard Wood Memorial Center for Leprosy Research (LWM). We also queried the patients

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and their household contacts with regard to the acceptance and perception of rapid diagnostic tests (RDT) for leprosy, as well as questioning members of the general population. Materials and Methods SUBJECTS

Volunteers of both sexes and a range of ages were recruited at the Cebu Skin Clinic, a leprosy treatment facility of the Leonard Wood Memorial, Cebu, Philippines under a protocol approved by the local Ethics Committee. All participants signed an informed consent before inclusion. For participants below 18 years of age, the informed consent was signed by either a parent or legal guardian. Leprosy was diagnosed after a thorough clinical exam, after which each patient was fully characterised through bacteriologic examination by skin slit smear and biopsy allowing classification under the Ridley-Jopling (R-J) scale (LL; BL; BB; BT; TT). In addition to patients, two groups of control individuals were also recruited: a) healthy household contacts (HHC) were those residing in the same household with an index case for at least 6 months prior to study enrollment and b) endemic controls (EC), or community contacts, categorised as individuals with no known direct contact with leprosy patients yet residing in a highly leprosy endemic community within the Island of Cebu (Table 1). Recruitment occurred in consecutive order based on clinic attendance, with no filtering or bias toward clinical presentation, from February 2015 until June 2015. QUESTIONNAIRES

Two questionnaires were developed and used: one was designed specifically for the patients, the other was for their healthy household contacts (HHC) and the general population (endemic controls; EC). Questionnaires were configured and presented in both English and the local language/dialect, Visayan. Immediately prior to questioning, participants were shown a representative lateral flow-based rapid diagnostic test and were briefed as to how it would be conducted (i.e., addition of blood after a finger prick/venipuncture, then addition of Table 1. Characteristics of total study population.

Total Age in years (mean; range) Sex (M/F) BCG scar (present; %) MB/PB Ridley-Jopling Lesion counts (n)

Average BI (n)

Patients

Contacts

General

147 34 (10–69) 96/51 57 (38·8%) 145/2 LL (75) BL (55) BT (17) .20 (94) .5– 20 (25) 2 –5 (18) 1 (10) .4 (25) .3– 4 (61) 1 –3 (34) ,1 (27)

264 31 (12–71) 155/109

224 36 (12–78) 145/79

– –

–

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a running buffer to provide a coloured line within 20 minutes). Forms were completed by the questioner during a verbal interview of each study participant, conducted in the language with which the recruit was most comfortable. STATISTICAL ANALYSES

Graphs were generated with MS Excel (Microsoft, Richmond, WA) and correlation plots and goodness of fit were generated using GraphPad Prism (version 5). Results PATIENT CHARACTERISTICS AT TIME OF DIAGNOSIS

Based on order of clinic attendance and leprosy diagnosis, 147 leprosy patients were recruited, characterised and interviewed. Diagnosis was made based on clinical, bacteriologic and histopathologic findings. While the vast majority (145; 98·6%) were presenting with MB disease, only a few patients presented with reactional episodes (Figure 1a). Over 60% of all patients had greater than 20 skin lesions. R-J classification by histopathology demonstrated that disease presentations were skewed toward the LL polar extreme (Figures 1b and 1c). (b) 70

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Figure 1. Patient characteristics at the time of diagnosis. a. Reactional status at presentation; b. Lesion counts; c. Ridley-Jopling characterisation and; d. bacterial burden in skin slit smears.

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In agreement, skin slit smear and microscopy revealed that 86 (58·5%) of the patients were heavily infected with BI of greater than 3 (Figure 1d). These bacteriological and clinical observations suggest that many patients are detected at relatively advanced stages of disease.

ESTIMATED DELAYS IN ATTAINING DIAGNOSIS

To establish the possibility of clinical evidence suggestive of a late diagnosis, patients were asked to estimate the time that had elapsed from the appearance of signs and symptoms until clinical diagnosis. Responses were wide ranging, but it was noteworthy that almost two thirds (96; 65·3%) reported a time lapse of slightly over a year, while over one quarter (39; 26·5%) reported a time lapse of greater than 3 years (Figure 2). While these data may not be entirely reliable because they are based on estimates, this information is in agreement with clinical presentations which very well correlate with the length of time which elapsed between the first appearance of signs and symptoms and leprosy diagnosis.

OBSERVED IMPACT OF DELAYED DIAGNOSIS ON CLINICAL PRESENTATION AND INFECTION STATUS

We then cross-referenced the estimated detection delay with clinical and bacteriologic presentation to test the hypothesis that the longer the detection delay, the more severe the disease presentation. When we evaluated the correlation between detection delay against either lesion count, BI or R-J characterisation, no significant correlations were observed and poor goodness of fit were obtained for all analyses (Figure 3a, b and c, respectively). These data surprisingly indicate that estimated delays in diagnosis from the first signs of leprosy were not actually associated with infection and disease status at diagnosis.

Per cent

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Time to diagnose Figure 3. Relationship of time from first signs with clinical presentation and bacterial burden. Estimated time from first signs are plotted versus (a) lesion count, (b) BI and (c) clinical status as determined with the Ridley-Jopling scale. Each symbol represents an individual patient, while the solid line represents the correlation of results and the black dotted lines represent the 95% confidence intervals.

IMPACT OF DISEASE PRIOR TO DIAGNOSIS

User friendly leprosy diagnostic tools like RDT could easily be used by primary/untrained health personnel to facilitate immediate treatment or immediate referral for expert diagnosis. Leprosy has historically been a highly stigmatising disease, however, and stigma may limit

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Figure 4. Reported impact of previously undiagnosed leprosy and the relative ranking of impacted areas among various groups. a. Study recruits were initially asked if they considered leprosy as having impacted their lives. Those b. patients; c. contacts and; d. members of the general population answering ‘yes’, were then asked to rank the four indicated areas of their lives that had been affected, from most affected (4) to least affected (1).

the use of RDT. We therefore asked the patients how leprosy (albeit not previously diagnosed) had affected their lives. Three quarters (73·8%) of the patients reported that their lives were adversely affected, with almost half (47·5%) indicating their lives had been affected ‘a lot’ (Figure 4a). Among the house contacts, responses were comparable with that of the patients: 79·2% reported that their lives were also adversely affected. These data indicate that leprosy has an adverse impact even beyond the patient himself. Consistent with this, when asked to grade the aspects of their lives adversely affected by their illness, respondents indicated that family life was the most affected (Figure 4b). This was true especially for patients who expressed greater concern regarding family than personal life. ACCEPTABILITY OF RDT

To determine if the use of RDT would be viewed favourably or unfavourably, newly diagnosed leprosy patients, their household and community contacts/general population

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(HHC and EC) were asked if they thought it would be beneficial to have a simple and rapid diagnostic and treatment monitoring test for leprosy. All groups responded favourably, with 95·9% patients, 93·2% HHC and 81·4% of the general population responding ‘yes’ (Figure 5a). The five patients that did not respond ‘yes’ all responded ‘probably’; no patient responded negatively to the potential use of RDT. Only 1·9% and 1·3% of HHC and the general population responded ‘no’. To assess the subjects’ perspectives on the extent of benefit

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Figure 5. Acceptability and perceived beneficial uses of RDT for leprosy. Various groups were asked if a. they would participate in a study of RDT; b. they viewed RDT use as a benefit; c. the importance of RDT in leprosy control and; d. what groups should be assessed by RDT.

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associated with RDT, further questions were addressed to those in favour of RDT use. Among the patient group, 87·7% answered that RDT use would be very beneficial, with 9·9% and 2·5% thinking that it would be moderately and slightly beneficial, respectively (Figure 5b). As a secondary assessment of acceptability, we asked respondents if they would personally submit to testing. The vast majority of interviewees were in favour of testing, with 88·6% of the patient population with strongest indication of ‘definitely’, followed by 69·4% of HHC and 72·2% of EC (Figure 5c). Not surprisingly, members of the general population were least likely to submit for testing, although unwillingness was only at a level of 5·5%. The majority of the patients thought their household members should also be tested, while a subset indicated that they would like RDT use to be extended to their respective communities (Figure 5d). Only one fifth (20·5%) of patients were not in favour of using RDT to monitor their house contacts. When asked about the frequency of testing, the most common response in each group was ‘anytime as needed’ (Figure 6). Taken together, this information indicates that the use of RDT is acceptable within this study population, supported by each group’s strong willingness to participate in RDT testing.

What is your preferred frequency of testing?

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Figure 6. Frequency of use of RDT for leprosy. Participants that indicated willingness to be tested were asked how regularly this should occur, with the ability to select the answers indicated on the x-axis. Of the participants that responded “other”, specified responses were: monthly (15 respondents), every quarter (3), twice each month (2), weekly (1), daily (2) and if no conflict with work (1).

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Discussion Given the success of WHO-MDT and focused control efforts, a system of decentralised leprosy control largely based on voluntary reporting or passive detection in dermatology clinics has now been adopted in many countries.19 – 21 The lack of clinical infrastructure and material resources in many areas negatively impacts the ability to detect and report patients.10,22 Diagnosis is currently achieved by a combination of clinical, histopathological and bacteriological examinations, each of which presents a barrier to expeditious diagnosis, particularly by non-experts. Patients in our cohort, recruited without bias but rather purely on sequential attendance of the clinic, typically reported extended periods of time between the onset of signs and symptoms of leprosy and the actual diagnosis, and indicated that the undiagnosed disease had already had important social consequences. Our data document that advanced MB cases with many lesions and high infectious burdens are the predominant presentation at Cebu Skin Clinic. Patients and their contacts reported significant negative impacts on their lives, with the greatest concern surrounding its adverse impact among family members. Surprisingly, our data failed to detect any correlation of the duration of detection delay with either clinical presentation or infection level. While longer periods of time between the appearance of symptoms and receiving proper treatment extend the window for potential transmission in the community they are also typically associated with increased chance of irreversible nerve damage.23 – 25 Developmental milestones to integrate and expedite the diagnostic processes through standardised and simplified tests appear necessary. Although educational campaigns have reduced some of the stigma associated with leprosy, stigma remains a major obstacle to self-reporting and early treatment. Current control strategies are reliant on passive case detection and therefore have a limited provision for preventing leprosy confined to attempting to reduce the number of cases identified as M. leprae carriers. This deficit is compounded by the lack of clinicians with sufficient awareness and experience who can confidently recognise the symptoms of leprosy. Many patients therefore undergo multiple clinical exams and investigations from clinicians with inadequate experience or training in recognising and distinguishing the signs and symptoms of leprosy before they are finally referred to clinical experts for proper diagnosis.24,26 Consistent with estimates from other studies, our cohort indicated that the delay from the time of onset of the first discernible symptom to clinical diagnosis is anywhere from 1 –3 years in more than half of all patients.8 – 11 Most common causes of detection delay included initial misdiagnosis by non-leprosy health workers, long periods of self-medication before initiating a clinic visit and/or lack of resources for a timely visit to the leprosy clinic. These limitations arose due to work, geographic or financial constraints, but together highlight that improvements in access to health care and/or the referral system are required for potential leprosy patients in almost all leprosy endemic regions. Procedural issues also impact time for diagnosis. This is indicated in a recent Brazilian study in which the average waiting time between testing by biopsies or assessments of sensation, muscle strength and peripheral nerve enlargement, and being informed of the diagnosis of leprosy was 15 –30 days, with 10·0% reporting waiting of 2 –6 months and 3·6% waiting for over 1 year.27 A 2009 study found inadequate monitoring of an Indian policy of ‘new case validation’, in which treatment was not initiated until primary diagnosis had been verified by a leprosy expert, may have led to approximately a quarter of suspect cases awaiting confirmation of diagnosis 1 – 8 months after their initial primary health care visit.21 Such delays can have a dramatic and negative impact on nerve function impairment and response to treatment.24,25,28 Interestingly, it is reported

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that there is less self-stigmatisation among leprosy patients and less social stigma in communities where leprosy has been integrated into general health services.29 In Sri Lanka, as part of a social marketing campaign health providers were trained to diagnose leprosy and to refer people with suspicious lesions to leprosy staff. After less than a year, there was a dramatic increase in self-reporting and newly detected cases increased by 150%.30 Thus, improvements to integrate and expedite the diagnostic processes appear necessary and could dramatically enhance reporting. Standardised and simplified tests could be a relatively simple addition capable of providing significant benefit at multiple levels of leprosy control programmes. Even once prospective patients are provided different diagnostic methods that are currently available almost half of the 110 study participants in a number of Brazilian states reported being concerned what would be done in the tests to diagnose leprosy and nearly one third reported not being told anything about the tests before they were undertaken.27 Only 16Âˇ4% of participants reported being diagnosed with leprosy on the same day as being tested for it. Evaluations of CTK OnSite Leprosy Ab Rapid Test within our cohort demonstrated a sensitivity of 97Âˇ1% for leprosy patients with BI above 1 and a specificity of 96Âˇ4%.18 Accompanying this performance, a major advantage of RDT is that it is convenient and user friendly with a potential to deliver immediate results directly at the point of contact. This means that blood testing could be conducted among individuals with even the slightest suspicion of leprosy. The high levels of stigma and misconceptions associated with leprosy poses an ethical issue in divulging and explaining positive results to the person likely having leprosy or being infected with M. leprae. This is perhaps one of the reasons why RDT has not been widely implemented but could be mitigated somewhat if tests were used to direct immediate referral for proper examination, diagnosis and treatment by leprosy experts. This particular study conducted in Cebu documents high acceptability of RDT among patients including their household and community contacts/the general population, with the vast majority (over 94% in each group) indicating their willingness for RDT testing. While various factors may alter acceptability rates in different leprosy-affected regions, taken together, our data indicate that this user friendly immunodiagnostic test is an acceptable strategy to facilitate detection of cases and referral to experts in this particular setting.

Acknowledgements This work was supported by funding from Leprosy Research Initiative, Philippines Department of Health, Novartis Foundation, and American Leprosy Missions. The authors are extremely grateful to all of the participants for their cooperation, and would like to thank the field and laboratory staff of the Leonard Wood Memorial Center for Leprosy Research for their assistance.

Conflict of interest Malcolm Duthie has provided antigen to companies for fabrication of rapid diagnostic tests and is a steering committee member of BOLD (Body for the Organisation of Leprosy Diagnostics). All other authors have declared that they have no conflict of interest. We certify that this article contains the original data from our research activities and is for the first time submitted for publication.

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Ethical approval This article does not contain any studies with animals. All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

References 1

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Chen XS, Li WZ, Jiang C, Ye GY. Leprosy in China: epidemiological trends between 1949 and 1998. Bull World Health Organ, 2001; 79: 306 –312. Epub 2001/05/19. doi: S0042-96862001000400007 [pii]. PubMed PMID: 11357209; PMCID: 2566398. Pandey A, Rathod H. Integration of leprosy into GHS in India: a follow up study (2006–2007). Lepr Rev, 2010; 81: 306–317. Epub 2011/02/15. PubMed PMID: 21313976. Siddiqui MR, Velidi NR, Pati S et al. Integration of leprosy elimination into primary health care in orissa, India. PLoS One, 2009; 4: e8351. Epub 2009/12/19. doi: 10.1371/journal.pone.0008351. PubMed PMID: 20020051; PMCID: 2791232. Zhang F, Chen S, Sun Y, Chu T. Healthcare seeking behaviour and delay in diagnosis of leprosy in a low endemic area of China. Lepr Rev, 2009; 80: 416–423. PubMed PMID: 20306640. Croft RP, Nicholls PG, Steyerberg EW et al. A clinical prediction rule for nerve-function impairment in leprosy patients. Lancet, 2000; 355(9215): 1603–1606. PubMed PMID: 10821364. Nicholls PG, Croft RP, Richardus JH et al. Delay in presentation, an indicator for nerve function status at registration and for treatment outcome - the experience of the Bangladesh Acute Nerve Damage Study cohort. Lepr Rev, 2003; 74: 349 –356. PubMed PMID: 14750580. Van Veen NH, Meima A, Richardus JH. The relationship between detection delay and impairment in leprosy control: a comparison of patient cohorts from Bangladesh and Ethiopia. Lepr Rev, 2006; 77: 356– 365. PubMed PMID: 17343222. Nicholls PG, Ross L, Smith WC. Promoting early detection in leprosy–a literature review to identify proven and potential interventions addressing patient-related delay. Lepr Rev, 2006; 77: 298 –310. Epub 2007/03/09. PubMed PMID: 17343217. Teasdale K, De Wildt G, Das Pranab K et al. The patient perspective of the diagnostic process for leprosy in Brazil. An exploratory study. Lepr Rev, 2015; 86: 21–36. PubMed PMID: 26065145. Ferreira J, Mengue SS, Wagner MB, Duncan BB. Estimating hidden prevalence in Hansen’s disease through diagnosis delay and grade of disability at time of diagnosis. Int J Lepr Other Mycobact Dis, 2000; 68: 464– 473. PubMed PMID: 11332290. Arole S, Premkumar R, Arole R et al. Social stigma: a comparative qualitative study of integrated and vertical care approaches to leprosy. Lepr Rev, 2002; 73: 186–196. PubMed PMID: 12192975. Williams PG, Dewapura D, Gunawardene P, Settinayake S. Social marketing to eliminate leprosy in Sri Lanka. Soc Mar Q, 1998; 4: 27–31. doi: 10.1080/15245004.1998.9961013. PubMed PMID: 12348833.

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Outcome of 6 months MBMDT in MB patients in Bangladesh- preliminary results C. RUTH BUTLIN*, DAVID PAHAN**, AUNG KYA JAI MAUG***, STEPHEN WITHINGTON****, PETER NICHOLLS*****, KHORSHED ALAM* & M.D. ABDUL HAMID SALIM****** *The Leprosy Mission International Bangladesh **Lepra Bangladesh ***Damien Foundation Bangladesh ****Executive Director, LAMB project, Parbatipur, Bangladesh *****Honorary Lecturer Southampton University, UK ******Advisor on Multiresistant Tb, National Tuberculosis Control Programme of Bangladesh The place where work was done: leprosy control project areas under Damien Foundation (14 districts) and The Leprosy Mission International Bangladesh (2 districts). Accepted for publication 4 April 2016 Summary Introduction: Duration of leprosy treatment remains long and difficult to complete in resource poor areas. Studies suggest that shortening duration of therapy for MB patients to 6 months may be possible. Methods: New MB patients in 2005 in two NGO projects in Bangladesh were treated with 6 months WHO MB MDT and the rate of relapse and fall in BI on slit skin smear during follow up to date were compared with a control group treated for 12 months the previous year. Results: 1612 patients were enrolled in the trial, and the average duration of follow up was over 7 years after diagnosis. During 11,425 PYAR of follow-up, no relapses were detected, by bacteriological or clinical criteria, in the 918 patients in the 6 months MB MDT group, nor in the 694 patients in the control group. Rate of decline of BI in those who were smear positive was not significantly different between groups. Conclusion: The data does not suggest that shortening duration of treatment from 12 months to 6 months MDT for MB leprosy patients leads to increased rates of relapse.

Correspondence to: Ruth Butlin, DBLM Hospital, Notkhana, PO Nilphamari, Nilphamari District 5300, Bangladesh (e-mail: drbutlin@yahoo.com) 0305-7518/16/064053+12 $1.00

q Lepra

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Introduction/Background Triple drug therapy for Multi-bacillary (MB) leprosy patients was recommended by WHO as routine first line treatment in 1981.1 Originally it was given to all leprosy cases with initial skin smear . 1þ at any one site, or those clinically classified as borderline borderline, borderline lepromatous or lepromatous (BB, BL, LL). The minimum duration of treatment advised was 24 months, but continuing ‘until smear negative’ was recommended. Over the years the definition of multibacillary has changed to include any smear positive case.2 The standard duration of multidrug therapy (MDT) for MB cases was fixed at 24 months, irrespective of smear status at that point, and then was reduced to 12 months.3 – 5 Outcomes at a population level have remained good, although some concern has been raised about the adequacy of 12 months MBMDT for initially highly smear positive cases.6,7 In 2002, it was proposed to test a shorter regimen in MB cases with a view to offering the same 6 month regimen of three drugs to both paucibacillary (PB) and MB cases, as ‘uniform multidrug therapy (U MDT)’.8 – 10 We tested the impact of the 6 month MBMDT regimen (compared with the standard 12 month regimen) on newly diagnosed adult leprosy patients in two leprosy control programmes in Bangladesh who are being followed for 10 years after diagnosis. Effectiveness of 6 months MBMDT treatment was to be assessed in terms of rate of fall of bacteriological index (BI) in initially smear positive subjects (proxy outcome measure, to reflect bacteriological killing and clearance) and of rate of relapses within the observation period (clinical outcome). In addition subjects were assessed in terms of morbidity and disability outcomes as indicated by occurrence of reactions and changes in nerve function/WHO disability grade. Information on pattern of reactions and residual morbidity data will be reported in a separate paper. Here we present a preliminary analysis of rates of relapse and fall in BI in the two groups, at which point 8 years of follow-up information was due in all patients, and a small proportion had 10 years follow-up data available. This analysis has been completed to help inform current high-level discussions on appropriate duration of MDT for leprosy patients.

Methods (Subjects etc) The study was conducted jointly by Damien Foundation Bangladesh and The Leprosy Mission International, Bangladesh, which are both partners in the National Leprosy Control Programme, and between them cover 16 districts (total population of 39 million) in central and northern parts of the country. The regimen to be tested, for adults over 45 kg, consisted of standard WHO-recommended MBMDT, i.e. monthly rifampicin (600 mg) with monthly clofazimine 300 mg (supervised), plus daily dapsone 100 mg and clofazimine 50 mg (selfadministered) for a period of 6 months, with appropriately lower doses for low body weight individuals. Comparison subjects received the same drugs and dosages but for 12 months. 6 month and 12 month courses were to be completed within a maximum 9 months and 18 months respectively as per standard WHO treatment completion requirements. New cases of MB leprosy were considered eligible if they were over 15 years old, had no known contraindications to the drugs, and consented to participation after being given full information about the trial. All cases were diagnosed by leprosy trained health workers and diagnosis was confirmed by a medical officer. Eligible subjects were enrolled sequentially in

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the study group to receive 6 month MBMDT when they were diagnosed as new cases of MB leprosy in the local clinics from early in 2005. Enrolment continued until the required number was reached. Any subjects who did not consent were given standard 12 month MBMDT treatment. The sample size required was determined pragmatically as a minimum of 1300 subjects, a number sufficient to detect a rise from a predicted baseline rate of relapse of 1% for 12 months MBMDT over 10 years to an estimated relapse rate of 5% in those treated for 6 months only, with confidence intervals of 95%. The comparison group included all consenting eligible MB patients registered as new cases in the previous year (2004). Both groups were given the same routine care and active follow-up by the same health care staff according to standard operating protocols in place. Subjects were seen monthly until released from treatment, then were reviewed annually, either at the clinic or in their own homes. At each time point they were clinically examined including assessment of nerve function. Skin smears were done at diagnosis, at RFT (whether after 6 or 12 months treatment) and bi-annually from 12 months after diagnosis. Any subject suffering ‘late’ reaction (more than 5 years after diagnosis) was carefully examined at the time of occurrence, if necessary with a skin biopsy performed, to exclude the possibility of relapse. If subjects failed to attend clinic, staff repeatedly attempted to contact them by mobile phone or home visits (within a week if still under treatment, or within 3 months if already RFT). If a skin smear was not done for any reason at the due time, it was scheduled to be done at the next annual review. Time points/periods are calculated from the point when treatment with MDT was begun (not from RFT) because of the different lengths of treatment regimens. It is assumed patients’ bacteriological status will begin to improve as soon as they start MDT. The time-specific risk of reactional episodes is also likely to be related to start of treatment rather than to end of MDT. MB Classification was assigned if patients had clinical signs of leprosy with more than five skin lesions, more than one nerve affected, or were skin smear positive at any one site, according to national guidelines, which follow those of WHO.4 Relapse was defined as: “For originally smear negative MB patients: smears becoming positive or new clinical lesions of leprosy (both skin and nerve lesions) appearing at any follow-up. New clinical lesions should be carefully differentiated from signs of a reaction; trial of steroids was advised to clarify this issue. For previously smear positive patients: average B.I. increasing by at least 2þ , compared with previous value. Histopathology of new active skin lesions was also required for diagnosis of relapse”.11 – 13 No subject was to be diagnosed as relapse without two leprosy specialists independently examining the case and agreeing that he/she met the criteria. The trial was approved by Bangladesh medical research council (BMRC/ERC/20047//1267, dated 12.04.05).

Results Enrolment continued up to about 1600 subjects to ensure that there would be adequate numbers remaining if loss to follow-up proved to be high. 1626 Subjects were finally enrolled of which 13 were excluded from the analysis as maximum Bacteriological Index (BI) at diagnosis was unavailable, and one was excluded as there was no data: leaving 918 for 6 months’ regimen and 694 for 12 months’ regimen.

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Table 1. Total subjects enrolled according to site and regimen Project site

n Male (%) Female (%) Mean age (SD)

Regimen group

DBLM

6 m cohort

12 m cohort

Total

554 408 (73·8) 145 (26·2) 38·1 (14·2)

1059 748 (70·6) 311 (29·4) 40·5 (15·4)

918 673 (73·3) 245 (26·7) 40·0 (14·7)

694 483 (69·6) 211 (30·4) 39·2 (15·4)

1612* 1156 (71·7) 456 (28·3) 39·7 (15·0)

*Excludes 13 for whom no initial BI results. There is no statistical significant difference between 6 m and 12 m group for sex ratio (chi squared 2 (1) ¼ 2·5514, P ¼ 0·110), nor for age distribution (P ¼ 0·2919).

The two groups (6 months’ and 12 months’ regimen) were similar in terms of age/sex distribution and other characteristics such as WHO disability grading. There was no major difference between subjects in each of two projects at entry into the trial (Table 1), although follow up proportion by project varied slightly (average follow up in DF and DBLM respectively was 6·4 and 8·3 years). At last recorded assessment we have follow-up of a total of 14721 person years at risk (PYAR) To date mean duration of follow up is 7·02 and 7·18 years respectively for 6 and 12 month regimes, 25% subjects have completed 9 years follow up, and 7% have completed 10 years follow up (Table 2). Subjects were classified according to their initial skin smears (maximum BI at any one site) as negative (n ¼ 941), low positive (defined as BI ¼ 1þ to 3þ) (n ¼ 291) or high positive (BI ¼ 4þ to 6þ) (n ¼ 380). The proportion with initially negative smears was slightly higher in 6 m group (Table 3), but the difference was not statistically significant. High positives were 56·63% of all positives at diagnosis. Withdrawals were classified as early or late. The 72 early withdrawals (before RFT) were mainly due to dapsone hypersensitivity syndrome (or failure to complete treatment within the Table 2. Follow-up periods: when last seen for assessment and last smear done (subjects known to be withdrawn have not been deducted from the denominator)

Years from diagnosis 0 0·5 1 2 3 4 5 6 7 8 9 10 Total subjects

Months from diagnosis

Number of subjects last seen at this time point

Percentage of total enrolled

0 6 12 24 36 48 60 72 84 96 108 120

144 31 134 12 154 23 156 31 231 179 404 113 1612

8·93% 1·92 8·31 0·74 9·55 1·43 9·68 1·92 14·33 11·10 25·06 7·01

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Table 3. Bacteriological status at entry (combined entry) Initial smear result Negative Low positive (1þ to 3þ ) High positive (4þ to 6þ ) All positive Mean BI (SD)

6 m cohort

12 m cohort

total

554 (60·35%) 171 (18·63%) 193 (21·02%) 364 (39·49%) n ¼ 918 1·31 (1·88)

387 (55·76%) 120 (17·29%) 187 (26·95%) 307 (44·23%) n ¼ 694 1·61 (2·05)

941 (58·34%) 291 (18·05%) 380 (23·57%) 671 (41·69%) n ¼ 1612 1·43 (1·96)

Difference between proportion negative in each group not statistically significant: P ,0·064, chi squared ¼ 3·42.

specified time frame). The 199 later withdrawals were for a variety of reasons including 132 deaths and one withdrawal for a protocol error. A small number of subjects were ‘lost to follow-up’, without being formally withdrawn for a specified reason (usually this appeared to be because the family had left the district). Overall losses to date were 16·8% in the 6 month group and 16·6% in the 12 month group. The numbers who died were 79/918 (8·6%) and 53/695 (7·6%) in the 6 month and 12 month cohorts respectively which is not a statistically significant difference (P ¼ 0·477). The high death rate is thought to be related to the advanced age of many of the subjects (at entry mean age ¼ 39, hence by completion of 10 years follow up mean age ¼ 49 years), considering the concurrent life expectancy in rural Bangladesh. For a subset of those who died (all 39 from two districts of RHP area, of which 17 were in the 12 month group and 22 in the 6 months group), enquiries were made about cause of death. In this subset, only three deaths appeared to be directly related to leprosy, anti-leprosy treatment or treatment of complications such as reaction (three died after prolonged steroid treatment, in two cases for chronic ENL reaction and in one case for reversal reaction). To date no subjects seen in follow-up have been confirmed as cases of leprosy relapse according to our specified criteria. Fifty-eight subjects who were noted to have had one or more episode of reaction/neuritis more than 5 years after diagnosis, were specifically assessed by a medical officer at the time for evidence of relapse, in addition to routine annual followups. One subject (originally highly smear positive and in 6 month group) had a smear report of 2þ at 72 months’ follow-up, although his previous smear report at 48 months was negative. The patient had no clinical signs of relapse then nor at later assessments and subsequent smears were all negative. At 72 months his BI was still falling in comparison with previous positive smear results, and it is possible that the 48 month smear result might have been a false negative. Except in that one subject, in no case did a negative smear become positive after RFT. Amongst the subjects who were initially smear-positive, most became negative within 5 years, and all but two became negative within 8 years. There is no significant difference in medium and long-term, for any initial smear status between those who had 6 months and those who had 12 months’ MDT, in regard to the rate of fall of BI when the two regimens are compared (Figures 1 and 2), nor in the proportion of smears becoming negative (Table 4). However, there is evidence that in the short term (at 12 months’ follow-up) there is a faster fall in positivity rate, for the 6 month regimen, in the initially low smear positive group to 29·5% still smear positive compared with 43·7% in the 12 months’ group (P ¼ 0·019). Also, the small percentage found positive at 12 months’ follow-up in those initially smear

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C.R. Butlin et al. Rates of smear negativity by regimen (6 m/12 m) at baseline and after 12, 36, 60 and 84 months 100·00 90·00 80·00 70·00 60·00 50·00 40·00 30·00 20·00 10·00 0·00 Neg (6 m)

LPOS (6 m) 12 months

HPOS (6 m) 36 months

Neg (12 m) 60 months

LPOS (12 m)

HPOS (12 m)

84 months

Figure 1. Progress to smear negativity for two regimens depending on baseline smear status. The chart shows the percentage of assessed smears which were negative, in the negative, low positive (1–3) or high positive (4–6) smear subgroups within the alternative 6 and 12 months (6 m and 12 m) MDT regimens, at each of 4 time points during follow-up – after 12 months, 36 months, 60 months and 84 months of follow-up.

negative was higher in the 12 month MBMDT group than the 6 month group (2·8% vs 1·0%; P ¼ 0·05). A possible explanation for these differences is an improvement in smear testing quality following commencement of the study.

Discussion Success of an MDT regimen in leprosy can be assessed by two sets of criteria: the bacteriological response and the clinical outcome. Bacteriological index is a proxy outcome measure which reflects both killing of bacteria and clearance from the body. Level of BI is known to be associated with risk of relapse (and also risk of ENL reaction). Any clinical relapse is assumed to be due to multiplication of endogenous bacteria not killed by the chemotherapy (although new infection from an external source is possible). Clinical outcome is also assessed by morbidity in terms of episodes of immunological reaction, amount of nerve damage sustained, and/or final ‘disability grading’. The likelihood of success according to both criteria may depend on the initial bacterial load as well as the sensitivity pattern of the bacteria and the duration of treatment.

LIMITATIONS OF STUDY

This study was not a randomised controlled trial and neither subjects nor staff were blinded to treatment regimen, however both groups received similar management and lived in the same social/epidemiological situation. Moreover the profile of two cohorts shows them to be broadly comparable in terms of age, sex ratio, proportion smear positive and WHO Grade at diagnosis. There was a slightly higher proportion of smear negative cases in the 6 month

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(a) 90·0% 6 m group % positive at follow-up

80·0%

12 m group % positive at follow-up

70·0% 60·0% 50·0% 40·0% 30·0% 20·0% 10·0% 0·0% 12 m

36 m

60 m

84 m

96 m

(b) 50·0% 45·0%

6 m group % positive at follow-up

40·0%

12 m group % positive at follow-up

35·0% 30·0% 25·0% 20·0% 15·0% 10·0% 5·0% 0·0% 12 m

36 m

60 m

84 m

96 m

Figure 2. (a) Rate of decline of BI in 6 m versus 12 m group, Initially high positive cases. (b) Rate of decline of BI in 6 m versus 12 m group, Initially low positive cases.

group than in the 12 month group: this may have occurred because subjects who knew their smear was positive could have been more likely to refuse participation in the trial. Separate analysis of smear positive and smear negative cases partially offsets this disadvantage. It is possible that the introduction of better quality control for skin smear readings, after commencing the study, had a small effect on bacteriological results; this is more likely to result in a decrease of false negatives rather than the reverse. For pragmatic reasons we did not attempt to undertake a randomised controlled trial: not least because it would have been difficult to obtain placebo MDT packs and would have entailed a long delay before starting the study. The duration of follow up might not be long enough to detect all relapses. However a ‘relapse’ due to inadequate treatment (e.g. if 6 mpnths’ MDT was not sufficiently effective) might be expected to present earlier than one due to endogenous ‘persisters’ (dormant form of M. leprae remaining in the body despite a complete course of chemotherapy to which they are expected to be sensitive). Relapses which occur very late may be attributable to re-infection,

Initially high positive

Initially low positive

Initially smear negative

496 477 424 346 304 110 137 134 109 92 25 84 112 109 102

At At At At At At At At At At At At At At At

12 m 36 m 60 m 84 m 96 m 12 m 36 m 60 m 84 m 96 m 12 m 36 m 60 m 84 m 96 m

neg

Time point from diagnosis 5 2 0 0 0 46 16 3 0 0 149 77 33 6 2

pos 1·05% 0·4% 0 0 0 29·5% 10·5% 2·2% 0 0 85·6% 47·8% 22·7% 5·2% 1·9%

% pos Of known

6 m cohort

53 75 130 208 250 15 18 34 62 79 19 32 48 78 89

n/a 554 554 554 554 554 171 171 171 171 171 193 193 193 193 193

total

Table 4. Bacteriology at different time points (based on maximum smear at baseline)

At At At At At At At At At At At At At At At

12 m 36 m 60 m 84 m 96 m 12 m 36 m 60 m 84 m 96 m 12 m 36 m 60 m 84 m 96 m

Time point from diagnosis 311 328 294 242 189 58 93 94 87 70 24 78 116 118 88

neg 9 1 0 0 0 45 12 0 0 0 139 86 28 5 0

pos 2·8% 0·3% 0 0 0 43·7% 11·4% 0 0 0 85·3% 52·4% 19·4% 4·1% 0

% pos Of known

12 m cohort

0·7 58 93 145 198 17 15 26 33 50 24 23 43 64 49

n/a

387 387 387 387 387 120 120 120 120 120 187 187 187 187 187

total

P ¼ 0·050 NS NS NS NS P ¼ 0·019 NS NS NS NS NS NS NS NS NS

Statistically significant or not, between 2 cohorts

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although at present there is no convenient method of differentiating relapse due to an endogenous source from relapse due to new infection from an external source. Considering the limited long-term data on incidence of relapse amongst large cohorts of patients treated with 12 or 24 month MBMDT, we believe that a planned follow-up duration of 10 years in this study reasonably balances the probability of finding relapse in relation to the trouble for patients and workload for staff. After 8 years many patients seen for assessment have been reluctant to continue with annual follow-up because they considered themselves ‘cured’ of leprosy. The percentage of missed assessments in some years is rather high, but if a subject was seen in the subsequent year and found to be ‘not relapsed’, it was assumed that he would not have shown signs of relapse in the previous year. If any smears were missed at due time (bi-annually) attempts were made to take another smear as soon as possible. Follow-up proportions were better in the 6 month than in the 12 month group, which may reflect the greater confidence of the subjects who had standard treatment leading them to avoid annual assessments, whereas subjects who received only 6 months’ MDT may have felt more anxious about the possibility of late complications. Alternatively, staff may have been more diligent in follow-up of those known to have had only 6 months’ MBMDT. The average duration of follow up to date is higher for the 12 months’ group as they were enrolled earlier. The examples given above of one subject with an unexplained negative smear result at 48 months’ follow-up, and the small percentage of patients initially smear negative but reported smear positive at 12 months’ follow-up (14/721 ¼ 1·9%) (whose smears subsequently became negative without further MDT) illustrates the inherent limitation of the skin smear as an indicator of activity of the disease. Even in trained hands, a slit skin smear may occasionally give a false negative result on account of choosing a different site, faults in smearing (blood staining) or fixing, the quality of the stain, or technician error in the reading. Less often a false positive may be reported. It is important to consider the whole picture (clinical assessment of skin and nerve lesions, plus histology if possible) in deciding about a suspected relapse and not rely entirely upon a single smear result. Similarly when smears are used for monitoring response to treatment, a low positive BI at RFT time in a patient whose smear was reported negative at diagnosis but is clinically improved may not indicate treatment failure. It is possible that we failed to detect a low relapse rate (or a small difference in bacteriological responses) because the number of subjects enrolled was too few. Larger population-based studies in future would be advisable. As we had no data on which to make the calculations more reliable we aimed for a large enough cohort to detect a five-fold difference in relapse rate over 10 years, if the baseline rate of relapse for 12 months’ MBMDT was about 1%.15 This was made on the pragmatic assumption that a rate of relapse of less than 5% might be acceptable at a population level if the duration of treatment could be shortened by 50%. An alternative design would be to use a ‘non-inferiority’ standard of calculating sample size. A relatively low percentage of follow ups at end of study (40·1% were not seen after 5 years follow-up, but this includes people formally withdrawn) might have meant we missed a few ‘relapse suspects’. Strenuous efforts are in progress to see as many of these as possible at the final 10 year follow-up. However, since there are almost no other leprosy services in our districts outside of those supported by our two NGOs, and government health staff routinely refer leprosy cases to our NGO services, we believe that anyone presenting with relapsed leprosy within their home area would have come to our attention. In addition it is national policy for any suspected leprosy relapse to be referred to a specialist centre for assessment,

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and the study was widely advertised at national leprosy coordination meetings. So we can expect that any relapse cases among our subjects who presented elsewhere in the country should have been referred to the DBLM hospital referral centre (a Leprosy Mission Project), where medical officers were informed about the study. In regard to relapse, it could be argued that PYAR is best calculated from completion of treatment rather than diagnosis. In this study, such an approach would decrease the overall years of follow-up, but would not alter the conclusions since no relapses were seen in either treatment or control group. As mentioned above, missed years can be ignored where a follow up assessment shows no relapse, however this assumption may not stand for reactions, where self-healing prior to the next assessment may have occurred, as documented in prior studies such as TRIPOD 3.16 Comparison with other reported studies: To date most studies published have not had very long follow up. Some studies have very low numbers. There are problems in comparison as some used different criteria for classification (e.g. all smear positive cases, and only those, were classified as MB as opposed to use of number of skin lesions in classification), and some were hospital-based rather than in the community. Not all authors performed/reported regular skin smears. Most authors count follow-up from time of RFT rather than from time of diagnosis. We consider the latter to be more logical, particularly in relation to reactional episodes and fall in BI. Although our method would have tended to underestimate relapse risk compared to the former, this is immaterial since we had no relapses in either group. Authors have different ways of describing the fall in bacteriological index over time and the temporal pattern of reactions, as well as using different criteria for diagnosis of relapse. Since diagnosis of relapse is a key issue in regard to studies of outcome of chemotherapy, there is a need for standardisation of criteria. This issue is discussed well by Kaimal.17 Preliminary results from the WHO-sponsored UMDT trial were reported after 8 years follow-up of 5000 cases: outcome was said to be ‘favourable’, but it is unclear what this means.18 Another preliminary report19 claimed that UMDT was ‘safe and effective’, since after 4 years follow up of 1302 MB cases (and 3396 PB cases) after UMDT, there had been only six relapses (at 13 – 28 months). Shen20,21 reported from a study in China, out of 114 smear positive MB patients followed up for 6 years after UMDT, there was one relapse at 13 months after RFT (a case who had been initially 3·6þ). Penna22,23 in Brazil found in a Randomised Controlled Trial of UMDT, over 1366 PYAR (max 5·2 years follow up), only one relapse (at 4·5 years) out of 323 who had received UMDT.22 In the same trial after 2139 PYAR, with a maximum 6·6 years follow up, a second relapse was found.23 Both subjects were initially Highly Smear Positive cases. Kroger24 reported four ‘clinically confirmed relapses’, from amongst 1136 MB cases (39% of all 2912 subjects in a UMDT trial). So far, it seems from these and our studies, that the relapse rate after UMDT /6 months’ MBMDT for MB cases is very low and not much higher than the rate for routine MBMDT of 12 months’ duration. Regarding Smear results: Shen20 found that amongst 75/114 initially smear positive cases given UMDT (including 21 with BI . 3þ) 73·% and 98·7% respectively were smear negative at 3·6 and 6 years of follow-up after RFT. In an open label Randomised Controlled Trial, Penna23 showed that amongst 613 MB cases (323 on UMDT for 6 months and 290 on ‘Routine’ MDT for 12 months), there was no statistically significant difference in fall of BI. Moreover the same was true if they analysed separately cases with BI ¼ 1þ to 3þ or BI ¼ 4þ to 6þ (using regression coefficient over time to assess fall in BI in each case rather than the mean of BI in all cases).

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These outcomes are consistent with our findings, where most were smear negative by 5 years, and all but two by 8 years. Whether or not the same favourable results would occur if 6 months’ MBMDT was given as routine treatment for MB leprosy in an integrated leprosy control programme, as we obtained in two well-staffed research-orientated projects, is open to question. Our subjects had documented good compliance which may not be achieved under less stringent field conditions. It is possible that the 6 months’ regimen would be less robust than a 12 month regimen, and taking the 6 months’ medication over a longer period (e.g. 9 months) might be less effective. The need for careful monitoring of subjects for leprosy reaction or nerve function impairment during and for at least 2 years after 6 months’ MB MDT, is also an important consideration; there may be an increased disability risk to subjects receiving a shorter course of chemotherapy.

Conclusion While further follow up to 10 years is pending, the early evidence from this trial of 6 months’ treatment for 918 MB leprosy patients after more than 7 years follow-up on average is that there is no excess of relapses compared with a similar cohort of 695 patients treated for 12 months. Similarly, the bacteriological response measured by rate of fall in BI in smear positive cases shows no delay in fall in the 6 months’ group, and no relapses were seen in any smear positive (or smear negative) cases. Notwithstanding limitations of this pragmatic open study with an historical control group, this study provides further support to other emerging studies that 6 months’ MB MDT could be cautiously recommended for use in all cases of MB leprosy where follow-up with quality skin smear testing is possible.

Acknowledgements Dr Marijke Becx Bleumink, and Dr Etienne Declercq for valuable advice, The Leprosy Mission International and Damien Foundation for funds, all the field staff and the data entry staff (notably, Priojit Nandi and Kallyan Kundu) who persevered for 10 years to complete this study.

Responsibilities Dr Salim, Dr Withington and Dr Butlin conceived and designed the study, and organised funding and permissions. Dr Maug, Dr Pahan and Dr Butlin aided by Khorshed Alam implemented and oversaw the work throughout most or all of the 10 years, Dr Nicholls undertook statistical analysis. All authors shared in preparing the paper. Dr Butlin is guarantor.

References 1 2

WHO study group, 1982, Chemotherapy of leprosy for control programmes, WHO technical report series 675. WHO, 1988 Expert committee on leprosy 6th report, WHO technical report series 768.

182 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

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WHO study group, 1994 Chemotherapy of leprosy, WHO technical report series 847. WHO, 1998, Expert committee on leprosy 7th report, WHO technical report series 874. WHO, 1997, Shortening duration of treatment of multibacillary leprosy. Weekly epidemiological record, b, 72, 125–132. Baohong J. Does there exist a subgroup of MB patients at greater risk of relapse after MDT? Lepr Rev, 2001; 72: 3–7. Gelber RH, Balagon MVF, Cellona RV. The relapse rate in MB leprosy patients treated with 2-years of WHOMDT is not low. Int J Lepr, 2004; 72: 493 –500. WHO, 2002, Report on 3rd meeting of WHO technical advisory group on elimination of leprosy in Brasilia, Feb 2002, WHO/CDS/CPE/CEE 2002-2009. WHO, 2003, Report of 5th meeting of TAG on EL, Yangon Feb 2003, (WHO/CDS/CPE/CEE/2003.36). WHO, 2006, Report of 7th meeting of TAG on Elimination of Leprosy, Geneva 4th –5th April 2005, (WHO/regional office for South East Asia). Becx-Bleumink M. Relapses amongst leprosy patients treated with multi-drug therapy: experience in the leprosy control programme of ALERT in Ethiopia. Int J Lepr, 1992; 60: 421 –435. WHO, 2000, Final push towards elimination of leprosy: strategic plan 2000–2005, WHO-CDS- CPE- 2000.1. WHO, 2003, The final push strategy to eliminate leprosy as a public health problem: questions and answers, 2nd edition. WHO. WHO, 1995, Action programme for elimination of leprosy 1995, A guide to elimination of leprosy as a public health problem. WHO/LEP/95.1. WHO, 2008, Report of 9th meeting of Technical advisory group on leprosy control, Leprosy review 79, p. 452– 470 (quoted report by Gupta). Richardus JH, Withington SG, Andersen A et al. Treatment with corticosteroids of longstanding nerve function impairment in leprosy: a randomized controlled trial (TRIPOD-3). Lepr Rev, 2003; 74: 311– 318. Kaimal S, Thappa DM. Relapse in leprosy. Indian J Dermatol Venereol Leprol, 2009; 75(2): 126 –135. WHO, 2010, expert committee on leprosy control 8th report, WHO technical report series 968. WHO, 2011, Report of 11th TAG meeting, New Delhi 30th September 2011. WHO publication SEA-GLP-2012.3. Shen J, Bathaliya N, Kroeger A et al. Bacteriological response and leprosy reaction amongst MB leprosy patients treated with uniform MDT in China. Lepr Rev, 2012; 83: 164– 171. Jianping Shen, Liangbin Yan, Meiwen Yu et al. Six years follow up of MB patients treated with Uniform Multidrug therapy in China. Int J Dermatol, 2015; 54(3): 315–318. (first published on line 30/9/14, doi: 10.1111/ijd. 12573). Penna MLF, Buhrer-Sekula S, Pontes MAA et al. Primary results of clinical trial of uniform Multi-drug therapy for leprosy patients in Brasil: reactions frequency in Multi-bacillary patients. Lepr Rev, 2012; 83: 309 –319. Penna MLF, Buhrer-Sekula S, Pontes MAA et al. Results from the clinical trial of uniform multidrug therapy for leprosy patients in Brasil: decrease in bacteriological index. Lepr Rev, 2014; 85: 262–266. Kroger A, Pannikar V, Htoon MT. International open trial of UMDT for all types of leprosy patients: rationale, design, and preliminary results. Trop Med Health, 2008; 13: 594 –602.

Lepr Rev (2016) 87, 183– 190

Spatial and temporal trends in new case detection of leprosy in India VASNA JOSHUA* *National Institute of Epidemiology (ICMR), Ayapakkam, Chennai-77, India Accepted for publication 6 April 2016 Summary Background: India achieved the goal of ‘leprosy elimination’ by reducing the burden of leprosy to less than one case per 10,000 inhabitants in 2005. Sustained and committed efforts by national programmes have led to a decline in the burden of leprosy to a great extent. Purpose: To examine the spatial clustering of leprosy case detection and spatiotemporal trend using Bayesian space period model. Materials: The National Leprosy Eradication Programme (NLEP) data of annual new case detection of leprosy in 34 districts of Maharashtra for eight data years 2007– 08 to 2014– 15. Methods: The presence of spatial dependency was assessed using the case detection rate for each of the eight data years spanning from 2007– 2015 using Moran’s I statistic and the variation over space and time was modeled using the Bayesian Space Period model. Results: The Moran’s I value was found to be statistically significant for each of the time period. The period effect was significantly higher than the average in the year 2007(4%), 2009(5%), 2011(6%), 2013(18%) and significantly lower than the average in 2008(7%), 2010(4%), 2012(11%), 2014(9%). The spatial effects varied between 0·579 and 1·52. There was a higher risk of leprosy (50% or more) found in districts of Garhchiroli, Raigad and Warda. The lowest risk of 0·579 was observed in the Nagpur district. Conclusion: The period effect of new case detection of leprosy using the SP model, measured in terms of relative risk shows a seesaw effect at work in districts of Maharashtra. The alternate jump in the risk of leprosy given by the model could be the actual scenario or due to expended activities in the study area. Further in depth investigation needed to ascertain the facts. Observing the spatial Bayesian effect districts Garhchiroli, Raigad and Warda are at greater risk and need priority care.

Correspondence to: Vasna Joshua, National Institute of Epidemiology (ICMR), Ayapakkam, Chennai-77, Tamil Nadu, India (e-mail: vasnajoshua@yahoo.com) 0305-7518/16/064053+08 $1.00

q Lepra

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Background India achieved the goal of ‘leprosy elimination’ by reducing the burden of leprosy to less than one case per 10,000 inhabitants in 2005.1 There has been a dramatic fall in the prevalence rate (PR) of leprosy, but the new case-detection rate (NCDR) has not been reduced concurrently.2 According to the World Health Organization (WHO), 65% of all new cases of leprosy globally are from India.3 Sustained and committed efforts by national programmes have led to a decline in the burden of leprosy to a great extent. The National Leprosy Eradication Programme (NLEP) envisages a ‘leprosy free India’, and is striving to achieve the Neglected Tropical Diseases (NTD) goal of elimination of leprosy by 2020.4 Also, the Bangkok Declaration emphasises the ambition to achieve the global target of reducing the occurrence of new cases with visible deformity (Grade 2 disabilities) to less than one case per million population by the year 2020.5 For many infectious diseases, cases are not spread uniformly in a geographical area, but occur in clusters. In fact, leprosy epidemiology shows a markedly uneven distribution in different geographic areas such as in China,6 Indonesia,7 in the state of Sa˜o Paulo, Brazil,8 and in India9 where leprosy cases were extensively clustered. It has been observed that the distribution of leprosy is uneven even within the smallest community groups such as villages, right down to the household level.10 In the literature, high rates of leprosy are generally observed in economically poorer strata, and situations of overcrowding and urbanisation.9 In some cases, this could also relate to more efficient health services, enabling them to detect new cases of leprosy. Geographical or spatial analysis comes into play due to the existence of spatial dependence in the data. Therefore, data analyses and interpretation should not ignore spatial dependency.11 The Bayesian method lends itself to representing spatial dependence during the estimation of model parameters. The objectives of the study are i) To examine spatial clustering of leprosy using Moran’s I statistic in the data set. ii) To assess spatio-temporal trends using the Bayesian space-period model. Materials According to the annual reports of NLEP (which run from 1st April to 31st March every year), Maharashtra and Orissa are the two states which consistently showed an increasing new case Table 1. Period effects and 95% credibility intervals, relative risk of Leprosy in Maharashtra Bayesian Space Period model. Period 2007–08 2008–09 2009–10 2010–11 2011–12 2012–13 2013–14 2014–15

Mid year

RR (95% CI)

Increase/Decrease in risk

2007 2008 2009 2010 2011 2012 2013 2014

1·04 [1·03, 1·06] 0·93 [0·91, 0·95] 1·05 [1·03, 1·05] 0·96 [0·95, 0·98] 1·06 [1·04, 1·08] 0·89 [0·87, 0·90] 1·18 [1·16, 1·20] 0·91 [0·90, 0·93]

4% 27% 5% 24% 6% 211% 18% 29%

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detection rate (NCDR) every year from 2007 –2015. Therefore, an attempt was made to explore the variations in leprosy incidence in Maharashtra which is an endemic state, comprising of 34 districts [Mumbai and Mumbai Suburban combined as one district, Mumbai, and Thane and Palghar combined as one district, Thane, in the analysis, due to missing data], as reported under NLEP within the defined timeframe. Methods The presence of spatial dependency was assessed using the case detection rate for each of the eight data years spanning from 2007 –2008 to 2014– 2015 using the Moran’s I statistic.13 The formula is described in Appendix 1. To examine the variation in the detection of leprosy, Bayesian models described by Arbyn et al.14 proposed earlier by Lagazio et al.15 were used. The variation over space and time was modeled using the Bayesian Space Period model during the time periods 2007– 2008 to 2014 –2015 over 34 districts. The average of all periods was used as the reference. Table 2. District effects and 95% credibility intervals, relative risk of NCDR of leprosy estimated from the SP model. District AHMADNAGAR AKOLA AMRAVATI AURANGABAD BEED BHANDARA BOMBAY CITY BULDANA CHANDRAPUR DHULE GARHCHIROLI GONDIYA HINGOLI JALGAON JALNA KOLHAPUR LATUR NAGPUR NANDED NANDURBAR NASHIK OSMANABAD PARBHANI PUNE RAIGAD RATNAGIRI SANGLI SATARA SINDHUDURG SOLAPUR THANE WARDHA WASHIM YAVATMAL

Median RR 0·6950 1·4915 0·9040 1·1345 1·1507 0·8701 0·9056 0·7638 1·1200 1·2964 1·5176 0·8170 1·0904 1·0128 1·0470 0·9817 1·1727 0·5790 1·4907 0·8584 1·2964 0·8620 1·1943 0·9634 1·5106 0·7147 1·1606 1·0222 0·8660 1·0745 0·9817 1·5039 0·9558 1·0446

95% CI 0·6471 1·3907 0·8430 1·0590 1·0755 0·8085 0·8443 0·7108 1·0472 1·2122 1·1239 0·7626 1·0184 0·9461 0·9755 0·9159 1·0963 0·5397 1·4309 0·8021 1·2141 0·8031 1·1182 0·9007 1·2555 0·6666 1·0845 0·9545 0·8085 1·0050 0·9174 1·4077 0·8927 0·9765

0·7496 1·6108 0·9755 1·2230 1·2389 0·9416 0·9771 0·8251 1·2068 1·3957 1·6218 0·8812 1·1741 1·0906 1·1305 1·0576 1·2628 0·6243 1·6476 0·9244 1·3938 0·9305 1·2845 1·0362 1·6535 0·7714 1·2499 1·1018 0·9321 1·1558 1·0564 1·6933 1·0299 1·1243

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Figure 1. The median relative risk of detection of leprosy across 34 districts of Maharashtra estimated from the Space Period model [2007–08 to 2014–15].

Posterior distributions of the parameters of interest were obtained using Gibbs sampling in WinBUGS.16 The description of the model is given in Appendix 2. The spatial effects of the relative risk of leprosy given by the SP model were used to portray geographical variations within the districts.

Results The spatial pattern of clustering of the case detection rate was confirmed using Moran’s I value, a measure of spatial autocorrelation. It was found to be statistically significant over all the time periods (Moran’s I . 0·58; P , 0·05).

PERIOD EFFECT USING THE SPACE PERIOD (SP) MODEL

The period effect of case detection of leprosy using the SP model is shown in Table 1. The period effect measured in terms of relative risk, significantly declined from a higher than average of 4% during the (mid) year 2007, to a reduction in risk of 9% during 2014. The trend pattern was not uniform. There is a leap up and down alternately. The period effect was

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significantly higher than the average in the years 2007, 2009, 2011 and, 2013 and significantly lower than the average during 2008, 2010, 2012 and 2014. SPATIAL EFFECT USING THE SP MODEL

The spatial effects of different districts are listed in Table 2 and can be further visualised in the Choropleth map (Figure 1). The spatial effects of relative risk varied between 0·579 and 1·52. The Bayesian model identified 15 districts that had a significantly higher risk of detection of leprosy. There was a higher risk of leprosy (50% or more) found in 3 districts of Maharashtra namely Garhchiroli, Raigad and Wardha. The lowest risk (relative risk 0·579) was observed in the Nagpur district.

Discussion Leprosy case detection rates in Maharashtra show a strong spatial dependency. The period effect of detection of leprosy using the SP model, measured in terms of relative risk shows a seesaw effect at work in districts of Maharashtra. It might be a true oscillation in the incidence rate or, as seems more likely, it could be due to the effect of the application of special programme case-finding efforts, such as: selective special drives, leprosy detection drives in endemic blocks, house to house surveys for new case detection, mass awareness campaigns, etc., which identify larger numbers of new cases during certain time periods.17 – 19 The reduction in risk of leprosy detection at other times may be due to reduced active case-finding activities, operational shifts in leprosy control activities, or, over a longer time-frame, changes in urbanistion, better hygiene or an improved standard of living.9,20 Similar patterns were previously observed in the NCDR of rural Satara district of Maharashtra.21 The authors state that the effect may be due to training and retraining of peripheral health care workers, adequate and proper placement of workers, periodic evaluation of their work, Modified Leprosy Elimination Campaigns (MLEC), or intensified IEC (Information, Education, and Communication) activities. The marginal increased risk of 4% in 2007 may be due to the ‘Block Leprosy Awareness Campaign’ (BLAC-IV) focused on high priority districts, the Situational Activity Plan (SAP 2007) and the ‘Urban Leprosy Sensitisation and Awareness Campaign’ (ULSAC) in urban areas.22 Special efforts for leprosy case detection by the DPMR (Disability Prevention and Medical Rehabilitation) programme in 2009 could be a reason for the 5% increased risk in the corresponding period. The increased risk of 6% in 2011 may be due to focused special drives in the endemic regions of Maharashtra. The prominent increased risk of 18% in new cases detected during 2013 may be attributable to the NLEP strategy of carrying out extensive house to house surveys for new case detection in 2012 – 13, capacity building of staff, awareness drives, enhanced monitoring and supervision, and treatment of identified new cases with Multidrug Therapy (MDT) to cut down the transmission potential in 2013 – 2014,18 obviously the outcome being a reduction in risk of 9% in 2014. The spatial effect using the SP model shows the variation in the geographical distribution of leprosy detection in the state of Maharashtra. Observing the spatial Bayesian effect, districts Garhchiroli, Raigad and Wardha are at greater risk and need priority care. These

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districts have been already labeled as high endemic districts by NLEP. Moreover the NLEP conducts extensive leprosy drives twice every year in endemic blocks and cases are treated with MDT.22 The alternating jump in the detection of leprosy should be further explored by removing the effects expended by various programmes in the study area. This would help us to ascertain whether the pattern is an artefact.

Limitation If the data had been readily available at micro level (block or village) then the centroid points would have been much finer and the leprosy high-risk pockets would have been pinpointed more precisely for remedial measures. The results are dependent on the data reported under NLEP, which could have missed some new cases in the study area. Since the analysis was done using only NLEP data the outcome was related to NLEP activities and there could be other organisations that might also have contributed to the impact.

Acknowledgements I thank Mr. P. Kamaraj, Technical Officer, National Institute of Epidemiology, Chennai, India, for his suggestions during the development of the manuscript. My sincere thanks, to Dr. Sanjay Mehendale, Director, National Institute of Epidemiology, Chennai, India, for his intellectual inputs for improvement of this paper.

References 1 2

4 5 6

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http://nlep.nic.in/about.html (Accessed on 5th September 2015). Subramanian M, Ali MKS, Thorat DM et al. Leprosy situation in endemic states of India and prospects of elimination of the disease. Indian J Lepr, 2003; 75: 335–345. http://timesofindia.indiatimes.com/india/65-new-global-leprosy-cases-from-India/articleshow/9499477.cms (Accessed on 5th September 2015). http://www.who.int/bulletin/volumes/88/3/09-072322/en/ (Accessed on 5th September 2015). http://www.searo.who.int/entity/global_leprosy_programme/bangkok_declaration.pdf (Accessed on 5th September 2015). Chen XS, Li WZ, Jiang C, Ye GY. Leprosy in China: epidemiological trends between 1949 and 1998. Bull World Health Organ, 2001; 79: 306 –312. Bakker MI, Hatta M, Kwenang A et al. Epidemiology of leprosy on five isolated islands in the Flores Sea, Indonesia. Trop Med Int Health, 2002; 7: 780 –787. Paschoal JAA, Paschoal VAA, Nardi SMT et al. Identification of urban leprosy clusters. The Scientific World Journal, 2013; vol. 2013, Article ID 219143, 6 pages. doi:10.1155/2013/219143. Joshua V, Gupte MD, Bhagavandas M. A Bayesian approach to study the space time variation of leprosy in an endemic area of Tamil Nadu, South India. IJHG, 2008; DOI: 10.1186/1476-072x-7-40. Gupte MD. Leprosy Epidemiology. Text Book and Atlas of Dermatology (II) second edition (chapter 65). 2001; 1543–1552. Anselin L, Griffith DA. Do spatial effects really matter in regression analysis? Papers of the Regional Science Association, 1988; 65: 11–34. http://nlep.nic.in/data.html (Accessed on 5th September 2015). https://en.wikipedia.org/wiki/Moran%27s_I (Accessed on 5th September 2015). Arbyn M, Capet F, Komarek A, Lesaffre E, Hierarchical Bayesian models for space-time variation of cervical cancer mortality - (Belgium, 1969-1994) 2003; REF: D/2003/2505/24,2003, https://www.wiv-isp.be/epidemio/ epien/cervixen/space_time.pdf (Accessed on 25th December 2006).

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Lagazio C, Dreassi E, Biggeri A. A hierarchical Bayesian model for space-time variation of disease risk. Statistical Modelling, 2001; 1: 17 –29. Spiegelhalter D, Thomas A, Best N, WINBUGS: Bayesian Inference Using Gibs Sampling. http://www.mrc-bsu. cam.ac.uk/bugs (Accessed on 1th January 2014). Shetty VP, Pandya SS, Arora S, Capadia GD. Observations from a ‘special selective drive’ conducted under National Leprosy Elimination Programme in Karjat taluka and Gadchiroli district of Maharashtra. Indian J Lepr, 2009; 81: 189– 193. http://lep.nic.in/pdf/Progress%20report%2031st%20March%202013-14.pdf (Accessed on 5th September 2015). http://nlep.nic.in/pdf/Final%20PIP,on%203%20May%202013.pdf (Accessed on 5th September 2015). Saunderson PR. Leprosy Elimination: Not as Straightforward as It Seemed. Public Health Rep, 2008; 123: 213 –216. Mohite RV, Mohite VR, Durgawale PM. Differential Trend of Leprosy in Rural and Urban Area of Western Maharashtra. Indian J Lepr, 2013; 85: 11–18. http://indianexpress.com/article/cities/mumbai/leprosy-detection-drive-in-222-blocks-in-state/ Geweke J. Evaluating the Accuracy of Sampling– Based Approaches to the Calculation of Posterior Moments. In: Berger JO, Bernardo JM, Dawid AP, Smith AFM (eds). Proceedings of the Fourth Valencia International Meeting on Bayesian Statistics, Oxford: Oxford University Press, 1992; pp. 169–194. Gelman A, Rubin DB. Inference from iterative simulation using multiple sequences. Statistical Science, 1992; 7: 457 –511.

Appendix-1 Moran’s I statistic The Moran’s I statistic provides a test of spatial dependence. Data with a spatial independence give an expected value of I close to zero, spatial aggregation or clustering leads to positive values, with an upper limit of Moran’s I statistic near to one but its precise value of the upper limit depends on the neighborhood structure. The Moran’s I statistic is given by PP n wij ðxi 2 x Þðxj 2 x Þ i

I¼

PP i

wij

ðxi 2 x Þ2

Under the null hypothesis of spatial random data, mean and variance of I is EðIÞ ¼ 21=ðn 2 1Þ; var ðIÞ ¼ n 2 S1 2 nS2 þ 3S20 =S20 ðn 2 2 1Þ 2 E 2 ðIÞ 0 12 XX XX X X @ ðwij þ wji ÞA wij ; S1 ¼ 1=2 ðwij þ wji Þ2 ; S2 ¼ S0 ¼ i

Appendix-2 Bayesian Space period model Let Yit denote the observed count of leprosy incidence cases in district i (i ¼ 1, 2, : : : , 34) and during the time period t (t ¼ 1, 2, : : : , 8). The expected value is based on the overall incidence value.

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Yit be the observed number of leprosy cases in the ith district at time period t. Eit be the expected number of leprosy cases in the ith district at time period t. Yit , Poisson (mit) With mit ¼ Rit Eit , where i ¼ 1, 2, : : : , 34 districts t ¼ 1, 2 : : : , 8 time period mit log ¼ log ðRRit Þ ¼ hit Eit where hit is a linear predictor, and RRit is the relative risk of the ith district and the time t. The linear predictor hit is specified as. For the model hit ¼ a þ bstruct þ bunstruct þ bperiod i i t Where a is the intercept term Where bstruct represents structured spatial variability i bunstruct represents unstructured spatial variability i bperiod represents the effect of the tth time period t The prior distribution of all effects are multivariate normals bstruct , N 0; ðtstruct K struct Þ21 bunstruct , N 0; ðtunstruct I 34 Þ21 21 bperiod , N 0; tperiod K period The structured spatial term is assigned the Gaussian Conditional Autoregression (CAR) prior distribution and period effect is assigned the Gaussian prior. The prior values were assigned to the precision terms tstruct ; tunstruct and tperiod ; for detailed specification of matrices K struct and K period and the algorithmic steps for the model using WINBUGS are discussed in detail elsewhere.14 In the model the spatial effect (autocorrelation) depends on (i) whether any two districts share a common boundary and (ii) number of shared neighbors (districts). For fitting the models without interactions with a burn-in of 5 000 iterations and an additional 10 000 iterations and Convergence was checked using standard procedures.23,24

Lepr Rev (2016) 87, 191– 200

Is the WHO disability grading system for leprosy related to the level of functional activity and social participation? VIVIAN TAI´ S CUNHA DE SOUZA*, WALDERI ´ NIOR**, AME´ LIA MARIA MONTEIRO DA SILVA JU RIBEIRO DE JESUS**, DANIELA TELES DE OLIVEIRA**, HELLI ALKISTI RAPTIS***, PAULO HENRIQUE LUIZ DE FREITAS* & SHEILA SCHNEIBERG* *Universidade Federal de Sergipe, Lagarto, Sergipe, Brazil **Universidade Federal de Sergipe, Saõ Cristovaõ, Sergipe, Brazil ***Research Center of Institut Universitaire de Ge´riatrie de Montreál, Montreál, Que´bec, Canada Accepted for publication 6 April 2016 Summary To investigate the relationship between the WHO disability grading system for leprosy with the limitations to perform daily functional activities and the decrease in social participation in participants with leprosy. Participants with a diagnosis of leprosy were recruited at the dermatology ambulatory clinic of the University Hospital of Sergipe. In order to investigate the association of WHO disability grading system for leprosy with activities of daily living measured with the Screening Activity Limitation and Safety Awareness (SALSA) scale and with the social participation (P-scale), we performed an analysis with the Kruskal-Wallis test and the Spearman coefficient. Thirty-six patients diagnosed with leprosy participated in the study. Most of participants had mild to moderate daily activity limitations and 58% of participants did not have any restriction participation. The findings demonstrated that the WHO grading is associated with the level of activity (P , 0·0001; r ¼ 0·58), but not with the level of participation (P . 0·05; r ¼ 0·27). Although the WHO grading system is used in Brazil and worldwide as an epidemiological indicator to explain the burden of leprosy, the results of this study demonstrated that in our sample the WHO grading system was not associated with participation. Participation is a complex construct with the influence of different psychosocial factors. In order to determine social participation damage of infectious diseases such as leprosy, it is necessary to develop new index of classification based

Correspondence to: Sheila Schneiberg, Universidade Federal de Sergipe, Campus Lagarto, Physical Therapy Department, Centro, Lagarto, Sergipe, Brazil, CEP: 49400-970. (Tel: þ 011-55-79-3024-0875; e-mail: sheilaschneiberg@gmail.com) 0305-7518/16/064053+10 $1.00

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V.T.C. de Souza et al. on a broader definition of disability. Health professionals should consider the international classification of function and health (ICF) to develop such index.

Keywords: Disability, Participation, Impairment, Activity, ICF

Introduction Leprosy is still considered a public health problem in some countries, because of its high incidence and complications (physical impairment due to nerve damages, and psychosocial repercussions) associated to this disease.1 Interventions to effectively eliminate leprosy and reduce its consequences include early diagnosis, medical treatment, impairment prevention, as well as motor and psychosocial rehabilitation care.2 According to the International Classification of Function, Disability and Health (ICF WHO, 2001),3 disability can be defined as a difficulty in functioning at the body (biological), activity, personal (psychological aspects), environmental or societal (context and participation) levels, which can be experienced by an individual affected by a disease or a special health condition.4 The World Health Organization (WHO) classifies leprosy according to the WHO disability grading system, where Grade 0 means no impairment, Grade 1 means loss of sensation in the hand, eyes or foot, and Grade 2 means visible impairment.5 Leprosy impairment can also be quantified with the Eyes, Hands, Feet (EHF) score, a score combining indicators of physical impairment. The EHF Sum Score is obtained by adding the maximum grade for each of six body sites (eyes, hands and feet), and it can range from 0 to 12.5 The WHO disability grading system for leprosy is simple and practical and it has been used as an epidemiological indicator to assess the efficacy of a public health programme.6 The inter-rater reliability for the grading test was reported as excellent when used by health specialists, with a Kappa coefficient 0·89 (95% CI, 0·84 – 0·94).7 While being useful, the WHO disability grading classification system for leprosy has some limitations. One of those limitations is that it is not sensitive to change after treatment (considering that it is a three ordinal scale); therefore it cannot be used in rehabilitation practice to assess the effectiveness of a treatment, nor to evaluate general disability. As presented previously, the term disability includes more than just impairment, and, indeed, impairment is the main concept evaluated in the WHO grading system. In 2004, Nienhuis et al. suggested that the ‘WHO disability grading system’ should be renamed ‘WHO impairment grading system’, using the terminology defined by the ICF.7 Recently (2014), a Delphi list was formed to propose improvements in the WHO grading system.5 Limitations in daily activities and restrictions to social participation are variables that need to be taken into account in analyses of the social and economic burden of leprosy, as well as in evaluations of the general disability or in the implementation of strategies aimed at the eradication of leprosy.4 The instruments currently available to evaluate these variables in patients with leprosy are the Scale of Activity Limitation and Safety Awareness and the Scale of participation.8 Previous studies have shown that patients with leprosy who were in treatment or after discharge presented limitations in the performance of some daily activities, which ranged from mild to severe. These studies also detected patients with restriction in social participation.3,9,10

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Certainly, the neuropathies caused by leprosy may give rise to physical impairments and diverse disabilities, especially for activities involving the use of hands, feet and eyes. Moreover, these disabilities may impact on social participation of affected individuals.11 – 13 However, it is not clear to what extent impairments can impact on the social participation of individuals with leprosy, since no previous study has investigated the association between the WHO grading system scores obtained with these patients, their level of activity measured with SALSA and their participation, measured with the Participation scale. Therefore, the objective of this study was to determine if the impairment grading classification system proposed by WHO is related with the performance of these patients in daily functional activities, as measured with the SALSA,14 and with their social participation (Participation scale).15

Methodology A cross-sectional design was used to investigate the association between the WHO disability grading system with activity (SALSA) and participation (Participation scale) measures.

PARTICIPANTS

Participants were recruited between May and November 2014 among ambulatory outpatients seen for the treatment of leprosy, leprosy reactions or sequels at the dermatology clinic of the University Hospital of Sergipe (Aracaju, Brazil), which is a reference service in leprosy care in the state of Sergipe. The following inclusion criteria were established: age over 18 years and score . 26 at the Modified Mini Mental State Exam (to avoid patients with cognitive deficits that might not understand or respond to the questionnaires). Subjects with arm or leg amputations not related to leprosy or diagnosis of other diseases resulting in physical disabilities (e.g., neurological or rheumatologic diseases) were excluded from the study. Patients were characterised according to the type and clinical from of leprosy (paucibacillary or multibacillary; tuberculoid, lepromatous, undefined, pure borderline or neural). The degree of impairment was measured according to the simplified neurological assessment form of the WHO disability three grading system, which classifies the degrees as following: 0, no impairment in the eyes, hands and feet; 1, decrease or loss of sensation in the eyes, hands and feet; and 2, visible impairment. The Ethic Research Committee of the Federal University of Sergipe had previously approved this study and all participants signed the consent form.

MAIN OUTCOMES

Activity was assessed with the Screening Activity Limitation and Safety Awareness scale.14 The SALSA measures limitations in activities and patients’ awareness towards the risks associated with diabetes mellitus, leprosy or other peripheral neuropathies. The SALSA scale consists of 20 items, based on the ICF activity domain. It is divided into areas related to mobility, self-care, work and dexterity, with scores ranging from 0 to 80; the higher the score, the greater are the activity limitations. If the final score is less than 25, it is considered that the subject does not have significant limitations in activity, whereas scores between 25 – 39 are

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associated with mild limitations, 40 – 49 with moderate, 50– 59 with severe and 60 – 80 with extreme limitations.8 The limitations related to social participation were evaluated with the Participation scale,15 in which the participant has to compare his answers with those of a peer (someone whose condition is similar to him in all aspects except for illness or disability). The scale consists of 18 items addressing, for example, the possibility to find employment, job performance, mobility in public places and involvement in social activities. The scores range from 0 to 90, and are categorised in different levels of limitation: no significant limitation (0 – 12), mild (13 – 22), moderate (23 – 32), severe (33 – 52) or extremely severe (53 –90) limitations.8 DATA ANALYSIS

The SPSS Statistical Package for the Social Sciences version 23·0 (Chicago, IL) was used for statistical analysis. Descriptive statistics (mean, standard deviation, median and range) are reported for all analysed variables. To test if the data was normally distributed, a Kolmogorov-Smirnov test was performed. In order to evaluate the associations between the WHO grading system for impairment (ordinal data) and the activity limitation measured by the SALSA scale (continuous data), and between the WHO grading system and restriction to participation, as measured by the Participation scale (continuous data), a Kruskal-Wallis test and correlation analyses (Spearman coefficient) were performed. Results After screening, 40 participants were eligible to participate in the study. During the evaluation process, four of them were excluded: one participant was excluded because he could not understand some of the questions asked during the evaluation, and the three others were excluded because significant information was missing in their records (Figure 1). Participants’ demographic and clinical characteristics are presented in Table 1. The participant’s age, leprosy type and classification did not influence the results in activity and participation, with no association as investigated with separate analysis with the correspondent stratification of groups.

40 Participants eligible 1 Participant excluded due to lack of understanding of evaluation 3 Participants excluded due to missing information in medical records 36 Participants included in the study Figure 1. Participants’ recruitment flowchart.

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Table 1. Demographic and clinical characteristics of participants Variables

Participants (n ¼ 36)

(%)

20 16 47 ^ 17

(56) (44)

Gender Female Male Age Marital status Married Single, divorced, widowed Employment/Occupation Employed Unemployed Retired Student Education Illiterate Elementary school High school University Operational classification Paucibacillary Multibacillary Clinical form Borderline Lepromatous Tuberculoid Neural Undefined WHO impairment grading Grade 0 Grade 1 Grade 2 EHF Score

23 13

(64) (36)

19 8 7 2

(53) (22) (19) (6)

6 17 11 2

(17) (47) (30) (6)

4 32

(11) (89)

13 10 5 4 4

(36) (28) (14) (11) (11)

10 15 11 2·36

(28) (42) (30) (1·94)*

*Mean and standard deviation (SD).

ACTIVITY AND PARTICIPATION MEASURES

The results for activity, as measured with the SALSA scale, demonstrated that 33·3% of participants did not present significant activity limitation. A third of participants reported a mild limitation, while 14% were moderately limited, 11·1%, severely limited and 8·3% showed extremely severe limitations (Figure 2a). Regarding restriction to participation, as measured with the Participation scale, the results indicated that 58% of participants did not have any restriction to participation, while 14% showed mild restriction, 8% moderate restriction and 20% severe restriction (Figure 2b).

DEGREE OF IMPAIRMENT £ ACTIVITY AND PARTICIPATION

In order to explore possible associations between participants’ degree of impairment and limitations in activity or restriction to participation, we stratified the SALSA and Participation scores according to participants’ degree of impairment (from 0 to 2) (Table 2). A Kruskal-Wallis ANOVA was performed for SALSA and Participation scale values for each

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V.T.C. de Souza et al. Activity limitation A

% participants

70 60 50 40 30 20 10 0 None

Mild

Moderate

Severe

Extreme

Restriction to participation B

% participants

70 60 50 40 30 20 10 0 None

Mild

Moderate

Severe

Figure 2. (a) Results for activity limitation measured with the SALSA scale. (b) Restriction to participation measured with Participation scale.

degree of impairment. The SALSA scores were associated with the degree of impairment, P , 0·01, where high score on SALSA had higher impairment classification. However, no association was found between Participation scores and degree of impairment, P . 0·05 (Table 2). To further quantify the association between impairment and activity, and impairment and participation, we performed a Spearman correlation test. The SALSA scale scores where highly correlated with the level of disability (r ¼ 0·58; P , 0·0001; Figure 3a), but not with the Participation scores (r ¼ 0·27; P . 0·05; Figure 3b). Table 2. Results of SALSA scale and Participation scale in each degree of impairment WHO disability three-grading system Results SALSA scale Activity Participation scale Social participation

Grade 0 (n ¼ 10)

Grade 1 (n ¼ 15)

Grade 2 (n ¼ 11)

Kruskal-Wallis Test

21 (18–47)

26 (20–60)

40 (26–70)

P ¼ 0·002*

4 (0–48)

7 (0–47)

16 (1–47)

P ¼ 0·28

Median, minimum and maximum; *Significant between-group difference at P , 0·05.

Impairment level ÂŁ Activity and participation in leprosy

SALSA scale

197

75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0 0

WHO disability three grading system

60 55 50

Participation scale

45 40 35 30 25 20 15 10 5 0 0

WHO disability three grading system Figure 3. (a) Association between SALSA scale and WHO disability three grading system. (b) Association between Participation scale and WHO disability three grading system.

Discussion Leprosy is considered a neglected disease. While it is no longer a health problem in developed nations, it is still endemic in some African, Asian and Latin American developing countries.2,16 The fact that leprosy is particularly affecting populations with lower social status and level of education led researchers to investigate its association with psychosocial factors; these factors have been neglected in actual control and eradication programmes.17,18

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The application of ICF to leprosy offers new opportunities to evaluate its burden, as well as the mechanisms underlying its high incidence in middle and low-income countries.4 The currently available epidemiological data related to the classification of leprosy cases is mainly based on the WHO disability grading system, which solely evaluates the level of impairment, and do not takes into account effects of the disease on social participation. The findings of this study demonstrated that the WHO disability grading system is associated with the level of activity (measured with the SALSA scale) in patients with leprosy, but not with the level of participation. The ICF defines that impairment are problems in structure or body function such as significant deviation or loss of biological function. Activity is defined in the ICF concept as the execution of a task or action by an individual. And, participation is considered by the ICF as the involvement in a life situations.19 From these definitions, it is expected that activity measurements that are based on ICF’s definition of activity would be associated with impairment measurements. In the present study, the activity measurement was the SALSA scale, whose questions can be related to ICF’s definition.4 For example, SALSA’s questions such as “Can you see (enough to carry out your daily activities)?”, “Do you walk on uneven ground?”, “Do you open/close screw capped bottles?” are directly related to specific structures and functions of the body; therefore, it is expected that limitations in those activities would be associated with impairments.14 Our results, showing association between impairment and activity, are consistent with previous studies12,17,18 that demonstrated moderate to strong association between limitations of activity and impairments. Our results can be contrasted with those of a previous study involving elderly patients with leprosy20 that investigated the association between the WHO disability grading system and two activity types: basic activities of daily living (BADL) and instrumental activities of daily living (IADL). They found a weak association between the WHO disability grading system and IADL, and no association with BADL. The weakness of the association between grading of impairment and IADL might stem from the fact that questions used in the IADL scale (which was developed around 20 years before the ICF) address aspects related not only to activity, but also to participation. It should be noted that participation is a much more complex concept than activity, which does not only involve activity, but also life contexts such as environment and psychosocial aspects. Indeed, in our study, participation levels were not associated with the WHO disability grading system. Social participation is a relatively new construct, which appeared during the revision of the International Classification of Impairments, Disabilities and Handicaps (ICIDH); it is highly influenced by environmental and cultural factors.15 In the latest definitions of activity and participation proposed by the ICF, participation is not only related to activity; it is also determined by contextual factors including environment and personal characteristics. For example, the individual with a disability due to leprosy can have the capacity to walk home; however, he avoids going to work because he does not want to take public transportation or show himself in public, being afraid of discrimination. Studies have demonstrated the correlation between participation restriction and stigma in patients with leprosy.3,21 – 24 Social stigma and discrimination are environmental factors that have significant impacts on the incidence and prevalence of leprosy, especially in developing countries, where most patients diagnosed with leprosy come from the poorest socioeconomic groups.25 In the present study, the results related to social participation demonstrated a high variability, with a wide range of scores, which contrasted with the narrow range of scores observed in the results related to activity limitations. Despite the high variability in

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participation scores, our results can be compared to the others studies that identify participation as a complex construct related to environmental and personal factors and then not directly related to the degree of impairment.26 – 28 It will be interesting to investigate the relation of social participation and education, to understand if education determine in some way the level of social participation in individuals with leprosy. In Brazil the WHO grading system is the most used measurement, it is used to classify impairment at the time of diagnosis and in the epidemiological notification. There is no doubt that the WHO grading system is a valid, reliable, practical and simple indicator to classify leprosy severity. However, the WHO grading system is based only on physical impairment. Therefore, many other dysfunctions can be underestimated when only the WHO grading system is applied, even social participation. Moreover, evaluating patients with leprosy only with the WHO grading system can harm the primary health assistance to refer patients to a more specialised treatments such as psychologists. In order to eradicate leprosy it is urgent and necessary to develop new classification indexes based on a broader definition of disability. The ICF could be used as a model to develop such an index. Limitations The results from this study should be interpreted within their limitations. Indeed, our sample was small and was local to the state of Sergipe, Brazil. Cultural and environmental aspects may play an important role in social participation. Conclusion The WHO disability grading system is associated with activity limitations in patients with leprosy, but not with restrictions to participation. Participation is a complex construct which is influenced by different psychosocial factors that can also impact health-seeking behaviours, which can have an impact on the control of the disease. The countries where leprosy is endemic are facing the challenge of making a more holistic report of problems experienced by patients; these reports should include not only the grade of impairment, but also assessments related to activity and participation, which are important variables in the design of efficient local public health strategies aiming to prevent and treat leprosy.

Acknowledgements The authors thank nurses and staff from University Hospital in Aracaju for their help in data collection and the Coordination Office for Improvement of Higher Education Personnel in Brazil (Coordenaçaõ de Aperfeiçoamento de Pessoal de Nı´vel Superior, CAPES) for the master’s degree scholarship of Vivian Taı´s Cunha de Souza.

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Nerve conduction study in leprosy: a hearty need or a customary practice? SUCHANA MARAHATTA*, SABINA BHATTARAI**, BISHNU HARI PAUDEL* & DILIP THAKUR* *B. P. Koirala Institute of Health Sciences, Dharan, Nepal **Kathmandu Medical College, Sinamangal, Kathmandu, Nepal Accepted for publication 2 May 2016 Summary Objective: To determine the diagnostic accuracy of the clinical tests like nerve palpation, monofilament test and voluntary muscle test for assessing peripheral nerve function impairment in leprosy. Methods: In this comparative cross-sectional study, 74 newly diagnosed leprosy patients without lepra reaction were enrolled. They underwent a thorough evaluation for peripheral nerve function using the above-mentioned clinical tests and nerve conduction study. The diagnostic accuracy of the clinical tests was determined by sensitivity, specificity, positive predictive value and negative predictive value considering nerve conduction study as a gold standard test. Data analysis was performed using SPSS version 11.5. Results: All clinical tests (nerve palpation, monofilament test and voluntary muscle test) were more specific but less sensitive. Amongst all, monofilament testing was the most specific one. Its specificity ranged between 93·54 –100%, whereas its sensitivity was 38·46 –68·75% only. Both nerve palpation and voluntary muscle testing had high specificity (. 90%) for all nerves, except nerve palpation for ulnar nerve; whereas both the tests had very low sensitivity (, 70%) for all the tested nerves. Conclusion: Though these clinical tests had higher specificity, their sensitivity was very low. So, along with clinical tests, nerve conduction study should be considered in leprosy patients for early detection of nerve function impairment whenever feasible.

Introduction Leprosy is one of the common causes of treatable peripheral neuropathy. Although leprosy has been eliminated from developed countries, it is still considered to be a major public health problem in developing countries of Africa, Asia, and Latin America. Every year thousands of Correspondence to: Suchana Marahatta, B. P. Koirala Institute of Health Sciences, Dharan, Nepal (Tel: þ977-25525555 Ext 2015 (Office), 3009 (Res); Mobile: þ 977-9862023236; Fax: þ 977-25-520251; e-mail: suchanamarahatta@yahoo.com) 0305-7518/16/064053+10 $1.00

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patients develop nerve damage as a result of leprosy.1 A total of 6,332 patients presented with Grade-2 disability in South East Asia during the year 2013, which is approximately half of the world’s data of 14,403.2 In Nepal, 3·38% of new leprosy cases presented with Grade-2 disability in a year.3 Peripheral nerve enlargement is one of the cardinal signs and the most common physical finding in leprosy, which may even proceed to sensory-motor deficits.4 Monofilament testing and voluntary muscle testing (VMT) are two established tests for assessing sensory and motor functions of peripheral nerves respectively.5 The role of electrophysiological evaluation of nerve function in the diagnosis and assessment of different neuropathies is well established.6 A stage of functional blockade of nerve conduction almost always precedes visible pathological changes in the nerve. A significant decline of motor nerve conduction velocities has been reported in clinically normal nerves in leprosy.7 In less sophisticated settings where newer modalities of nerve function assessments are not available, nerve conduction study (NCS) is supposed to be a reliable technique.8 In a country like ours, where the majority of people live below the poverty line, we cannot impose NCS as a routine investigation. Therefore we conducted this study to determine the sensitivity and specificity of each of the clinical tests done in leprosy, considering nerve conduction study as a gold standard test.

Materials and Methods STUDY POPULATION

All newly diagnosed leprosy patients of age . 12 years without lepra reaction attending the Dermatology department from May 2011 – April 2012 were enrolled in the study.

SAMPLE SIZE

Based on the previous study9 the sample size was taken as 74. For this odds ratio between two measurements (NCS and clinical assessment) was calculated as 2·66. Then we calculated the sample size for the study at 95% confidence interval (CI) and 80% power by using Epi Info software.

Methods The patients were assessed at baseline for nerve function impairment using three clinical methods (nerve palpation, monofilaments testing and VMT). Informed written consent was taken from them. All the clinical tests were performed for bilateral sensory (ulnar, median and sural) as well as motor nerves (ulnar, median, common peroneal and posterior tibial). The results were compared with the obtained sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) by sensory and motor NCS respectively. The findings of relevant examination were entered in the standardised pro-forma.

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NERVE FUNCTION ASSESSMENTS

Clinical assessments (a) Touch sensibility testing using monofilaments (MF) Touch sensibility was tested with a standard set of five coloured Semmes – Weinstein monofilaments (MF) as described by Bell Krotoski.10 In our study, weight up to 200 mg for the hands and 2 gm for the foot were considered as normal values of the monofilament test.11

TEST SITES

(1) (2) (3) (4)

Ulnar nerve – at hypothenar eminence, 5th metacarpal head and volar surface of the distal phalanx of the little finger Median nerve – at thenar eminence, volar surface of distal phalanx of the thumb and volar surface of distal phalanx of the index finger Radial nerve – over dorsum of the thumb at the site of motor point Sural –at dorsal lateral aspect of the foot

(b) Nerve palpation (NP) All the major nerves listed above were palpated bilaterally to record the enlargement and were graded as normal or enlarged. (c) Voluntary muscle testing (VMT) Voluntary muscle testing was done using the modified Medical Research Council (MRC) scale.12 VMT score less than 4 was set as the criteria for motor impairment. Motor functions of all the nerves were categorised into: normal or impaired. All the clinical tests were confirmed by the consultant dermatologist. Muscles tested according to the nerves were: a) ulnar nerve (abductor digiti minimi), b) median nerve (abductor pollicis brevis), c) radial nerve (extensor carpi radialis and extensor carpi ulnaris), d) common peroneal nerve (tibialis anterior, peroneus longus and brevis) and e) posterior tibial nerve (small intrinsic muscles of feet).

ELECTROPHYSIOLOGICAL ASSESSMENTS

Nerve conduction study (NCS) Nerve conduction study was performed at the Neuroelectrophysiology laboratory of Physiology department of BPKIHS using Digital Nihon Kohden Machine (NM-420S, H636, Japan). We commented on the functional impairment of the nerves based on standard criteria.13 Room temperature was maintained at the thermo neutral zone (26 ^ 28C). It was ensured that all the patients were relaxed and comfortable with the laboratory set up prior to the recording.

RECORDING PROCEDURE

(a) Motor nerve conduction study (MNCS) Stimulator with water soaked felt tips were placed on the skin overlying the nerve at proximal and distal sites. The recording and reference electrodes were placed using belly tendon montage. The gain was set at 2 –5 mV per division and stimulation duration in the range of

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50– 300 msec. The nerves were stimulated with short burst of direct current, not exceeding 50 mA since it was the upper limit available in the machine. The current was initially set to zero, then gradually increased with successive stimuli up to the point that compound motor action potential (CMAP) no longer increases in size. Further, it was increased by another 20% to ensure the supra-maximal stimulation. For each stimulation site, CMAP latency, amplitude, duration and conduction velocity of median, ulnar, radial, common peroneal and posterior tibial nerves were recorded. F-waves were also recorded for all nerves except radial nerve. (b) Sensory nerve conduction study (SNCS) Ring and surface stimulating electrodes were used for orthodromic and antidromic (sural nerve) stimulation respectively. Electrodes were placed over a purely sensory portion of the nerves. Gain was set at 10 –20 mV per division and an electrical pulse of either 100 or 200 msec of duration was used. Current was slowly increased from a base line of 0 mA, usually by 3– 5 mA at a time until the supra maximal stimulation of nerve was ensured. For each stimulation site, sensory nerve action potential (SNAP) amplitude, latency, duration and conduction velocity were measured. STATISTICAL ANALYSIS

Data were entered in MS- Excel 2007, and were transferred into SPSS version 11.5 for statistical analysis. For descriptive statistics, percentage, proportion, median were calculated. The diagnostic accuracy of clinical tests was determined by sensitivity, specificity, positive predictive value and negative predictive value. ETHICAL CLEARANCE

Ethical clearance was obtained from institutional ethical review board. CONFLICT OF INTEREST

All authors declare that the answer to the question on competing interest form are all ‘No’, and therefore have nothing to declare. FUNDING SOURCE

There was no funding source for the study – the Institute considered free process for patients who couldn’t afford the procedural fees.

Results SOCIO-DEMOGRAPHIC PROFILE

Out of a total of 74 patients, the maximum (27·0%) were in the age group 30 –39 years, with the mean age 35·09 ^ 14·92 years. Males predominated with the ratio being 2:1. About 77·1% patients were literate, among which only one fifth 15/74 (20·3%) had studied more than 10th grade. The subjects in the study group had different occupations, but the majority

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were housewives 15/74 (20·3%). Out of 74 subjects included in the study, 58/74 (78·4%) were of the multibacillary group and 16/74 (21·6%) were of the paucibacillary group. The presenting complaint of the maximum patients (50·0%) was loss of sensation, followed by hypopigmentation in 44·6% of patients. Most of the patients (31·0%) had 6 – 10 months of illness duration.

SUMMARY OF CLINICO-ELECTROPHYSIOLOGICAL FINDINGS

All the patients were subjected to a thorough examination, including clinical (i.e. nerve palpation, monofilament testing, VMT assessment) and NCS tests. Among the sensory nerves the sural nerve was found to be maximally affected (21·6%) followed by the ulnar (17·6%), radial (16·2%) and median (9·5%). Similarly, among the motor nerves, the ulnar was maximally affected (18%) followed by the common peroneal (16·2%), posterior tibial (13·5%), median (8·1%) and radial (8·1%) as detected by NCS (Table 1).

DIAGNOSTIC ACCURACY OF CLINICAL TESTS

For the calculation of diagnostic accuracy, nerve wise sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of clinical tests were calculated and nerve conduction study was taken as reference test. (a) Monofilament test: It was found to be important for its negative predictive value. Its specificity was high whereas sensitivity was low for all tested sensory nerves. Its overall specificity was 83·63%, sensitivity was 78·94%, negative predictive value was 92·00% and positive predictive value was 62·5%. Among all the tested sensory nerves, highest specificity was for monofilament test of the sural nerve (Table 2). Table 1. No (%) of patients showing enlarged nerves, impaired clinical (monofilament test, VMT assessment) and nerve conduction (sensory and motor) tests

Patients Sensory Nerves Ulnar Median Radial Sural Motor Nerves Ulnar Median Radial Common Peroneal Posterior Tibial

Enlarged nerves on NP (%)

Impaired MF test (%)

Impaired VMT (%)

Impaired SNCS (%)

Impaired MNCS (%)

43 (58·1)

19 (25·7)

7 (9·4)

24 (32·4)

15 (20·3)

32 (43·2) 6 (8·1) 6 (8·1) 4 (5·4)

7 (9·1) 5 (6·8) 9 (12·1) 11 (14·9)

NA NA NA NA

13 (17·6) 7 (9·5) 12 (16·2) 16 (21·6)

NA NA NA NA

32 (43·2) 6 (8·1) 6 (8·1) 20 (27·0) 13 (17·5)

NA NA NA NA NA

6 (8·1) 3 (4·1) 2 (2·75) 1 (1·4) 1 (1·4)

NA NA NA NA NA

18 6 6 12 10

(24·3) (8·1) (8·1) (16·2) (13·5)

(Abbreviation: NA ¼ Not applicable, NP ¼ Nerve palpation, MF ¼ Monofilament, VMT ¼ Voluntary muscle test, SNCS ¼ Sensory nerve conduction, MNCS ¼ Motor nerve conduction).

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Table 2. Diagnostic accuracy of monofilament test (sensory nerves) Nerves Ulnar Median Radial Sural

Sensitivity (%) 38·46 42·85 41·66 68·75

(15·13–67·72) (11·80–79·76) (16·49–71·40) (41·48–87·87)

Specificity (%)

PPV (%)

NPV (%)

96·72 (87·64–99·43) 97·01 (88·68–99·48) 93·54 (83·50–97·91) 100 (92·26–100)

71·42 60·00 55·55 100

88·05 94·20 89·23 92·06

(Abbreviation: PPV ¼ positive predictive value, NPV ¼ negative predictive value).

(b) Nerve palpation test It was also found to be important for its specificity and higher negative predictive value when individual nerves were considered. The overall sensitivity and specificity were 64·00% & 65·30% for sensory nerves; and 48·57% & 80·64% for motor nerves respectively (Table 3). (c) Voluntary muscle testing Overall, VMT has sensitivity: 14·28%, specificity: 79·10%, PPV: 6·66% and NPV: 89·83%. Here, median and radial nerves had high negative predictive value whereas common peroneal and posterior tibial nerves had 100% specificity and PPV (Table 4).

LOGISTIC REGRESSION ANALYSIS

On five step logistic regression analysis, a combination of occupation, monofilament test and nerve palpation test were found to be important determinants of abnormal nerve conduction study in leprosy patients. Variables intered in the first step of the analysis were occupation, monofilament testing, nerve palpation, voluntary muscle testing of ulnar nerve, grade of disability and bacillary index.

Discussion Leprosy is a common treatable disease of peripheral nerves, but still remains a devastating disease in the developing world because of the potential deformities, disabilities and morbidity associated with it. It can be minimised if nerve damage is detected and treated early. Monofilament testing is an inexpensive, easy-to-use and portable test for assessing the loss of protective sensation. Previous study had said that the monofilament testing can be one of the valid and standard screening tests for sensory nerve function assessment.14 While testing touch sensation by monofilament, out of 74 patients in our study, only 19 (25·7%) patients had impaired test, which is less (41%) then that found in a previous study.9 In our study, the sural nerve showed maximum impairment 11/74 (14·9%), followed by radial 9/74 (12·1%), ulnar 7/74 (9·1%), median 5/74 (6·8%) and the sequence was comparable to a previous study9 but frequency of impairment was less in our patients. It could be because of the inclusion of both paucibacillary and multibacillary patients in our study unlike in the study by Khambati et al. where only multibacillary patients were included.9

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Table 3. Diagnostic accuracy of nerves palpation Nerves Sensory nerves Ulnar Median Radial Sural Motor nerves Ulnar Median Radial Common peroneal Posterior tibial

Sensitivity (%)

Specificity (%)

PPV (%)

NPV (%)

69·23 (38·88 –89·64) 57·14 (20·23 –88·19) 33·33 (11·27 –64·56) 12·50 (2·19 –39·58)

62·29 97·01 96·77 98·27

(48·93–74·10) (88·68–99·48) (87·82–99·43) (89·53–99·90)

28·12 66·66 66·66 66·66

90·47 95·58 88·23 80·28

61·11 (36·14 –81·73) 33·33 (5·99 –75·89) 33·33 (5·99 –75·89) 66·66 (35·43 –88·72) 70·00 (35·36 –91·90)

62·50 96·96 96·96 80·64 90·62

(48·51–74·76) (88·52–99·47) (88·52–99·47) (68·25–89·18) (80·05–96·13)

34·37 50·00 50·00 40·00 53·84

83·33 94·11 94·11 92·59 95·08

(Abbreviation: PPV ¼ positive predictive value, NPV ¼ negative predictive value).

An effective diagnostic test requires an acceptable sensitivity and specificity. To find the accuracy of the monofilament test, we calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Overall sensitivity was 78·94% (53·9093·02%), specificity was 83·63% (70·69– 91·79%), PPV was 62·5% (40·75 –80·44%) and NPV was 92·00% (79·89 – 97·40%). Sensitivity of the monofilament test was very low with a wide range for all nerves, whereas it showed good specificity and NPV. Among the individual nerves, the sural nerve was found to have the maximum specificity (100%). The PPV of the monofilament test was good only for the sural nerve (100%). So there is a high chance of missing patients with neuropathy if we rely only on the monofilament test. A similar result was found when Dros et al. conducted one systematic review for the accuracy of the 5/10 gram monofilament using nerve conduction as a reference standard in diabetic neuropathy; in which sensitivity ranged from 41% to 93% and specificity ranged from 68% to 100%.15 The authors stressed that monofilament testing should not be used as the sole test to diagnose peripheral neuropathy, whereas nerve conduction study could be of great help for the detection of peripheral neuropathy. In our study, more than half of the patients (58·1%) had enlarged peripheral nerves. The ulnar nerve was the most commonly enlarged nerve in most of the patients (43·2%) followed by the common peroneal (27·0%), posterior tibial (17·5%) radial (8·1%), median (8·1%) and sural (5·4%) nerves. In another study done in Bangladesh, the most commonly affected nerve

Table 4. Diagnostic accuracy of voluntary muscle testing Nerves Ulnar Median Radial Common peroneal Posterior tibial

Sensitivity (%) 11·11 16·66 16·66 8·33 10·00

(1·94–36·07) (0·87–63·51) (0·87–63·51) (0·43–40·24) (0·53–45·88)

Specificity (%)

PPV (%)

NPV (%)

92·85 (81·87–97·68) 97·05 (88·83–99·48) 98·52 (90·98–99·92) 100 (92·73–100) 100 (92·94–100)

33·33 33·33 50·00 100 100

76·47 92·95 93·05 84·93 87·67

(Abbreviation: PPV ¼ positive predictive value, NPV ¼ negative predictive value).

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was the posterior tibial nerve (9·38%), followed by the ulnar nerve (5·56%), median and common peroneal nerves.16 The ulnar nerve, however, being the most commonly involved nerve in our study, could be explained by the maximum number of patients having skin lesions on the forearm and hand. Assessment using voluntary motor testing showed impaired motor nerve function only in seven (9·4%) patients. The ulnar nerve showed maximum impairment in 6/74 (8·1%) patients followed by the median in 3/74 (4·1%), the radial in 2/74 (2·7%), the common peroneal in 1/74 (1·4%) and the posterior tibial 1/74 (1·4%) patients. In a study by van Brakel et al. concordance between VMT results and motor nerve conduction was good for the ulnar nerve, but very few median and common peroneal nerves with abnormal conduction had an abnormal VMT.14 So they recommended that a more sensitive manual motor test may be needed for these nerves. Both nerve palpation and VMT had a high specificity (. 90%) for all nerves, except nerve palpation for the ulnar nerve (sensory as well as motor i.e. 66% for both). But both tests had very low sensitivity with wide range. These findings also suggest that we should not depend only on these clinical tests; and these tests alone are not sufficient enough to detect peripheral neuropathy in the early stages. The Nerve conduction study (NCS) is one of the established tools for the assessment of various peripheral neuropathies, including leprosy. van Brakel et al. reported that half of the INFIR cohort without clinical evidence of neuropathy had impaired NCS for the superficial radial and sural nerves. Similarly, monofilament-detected ulnar sensory neuropathy was preceded by abnormal SNCS in 100% of cases.17 Hence NCS may play an important role for the early detection of Leprosy neuropathy compared to clinical tests. This statement has also been supported by few other studies.9,18 In our study 32/74 patients (43·2%) had impaired nerve conduction study at the time of disease diagnosis. However in a previous study more than 50% of the patients had NFI at the baseline.19 A lesser percentage of baseline neuropathy in our study could be because of: i) exclusion of patients in lepra reaction and ii) non-exclusion of paucibacillary leprosy patients. Out of them, 24/74 (32·4%) patients had abnormal sensory NCS and 15/74 (20·3%) patients had abnormal motor NCS. So sensory neuropathy was found to be more common in leprosy patients. One of the studies from western Nepal also found more of sensory neuropathy (11·90%) then the motor one (7·39%).20 Similar was the report from Brown et al. with sensory neuropathy in 42·89% and motor neuropathy in 21·42% of the leprosy patients.21 In contrast to our study, in the study by Ramadan et al. motor nerve conduction was found to be more impaired than the sensory one.22 When concordance was assessed between different clinical tests and the gold standard test in our study; between nerve palpation and NCS tests, the maximum concordance was observed for ulnar nerve (motor-14·9%, sensory-12·2%), followed by the common peroneal nerve (10·8%). Between monofilament test and SNC tests, concordance was maximum for the sural nerve (14·9%). Similarly between VMT assessment and MNC, concordance was maximum for the ulnar nerve (2·7%). Hence 4·1– 18·9% of patients with impaired nerve conduction can be missed by nerve palpation. Similarly, subclinical neuropathy ranging from 6·7– 21·6% can be missed by VMT and that from 5·4– 10·8% may be missed by monofilament test. For the peripheral nerves (both sensory and motor), the impairment observed by SNC as well as MNC may be preclinical and may translate into obvious weakness (i.e. sensory and motor respectively) late in the disease. Similar opinion was given by the authors in few of the previous studies.21,23

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Conclusion Though all the clinical tests i.e. monofilament testing, nerve palpation and voluntary muscle testing assessment have higher specificity, they have very low sensitivity for assessing peripheral nerve damage in leprosy. So along with clinical tests, nerve conduction studies should also be considered in leprosy patients for the early detection of nerve function impairment whenever feasible.

Acknowledgements The authors are grateful to all the patients who participated in this study. We would like to express our deepest appreciation and sincere thanks to Prof Dr Sudha Agrawal for her kind help and inspiration during the dissertation of this work. We would like to extend our thanks to Mr. D. D. Baral, the Biostatistician of the department of Community Medicine, B. P. Koirala Institute of Health Sciences for statistical guidance. Also, we are immensely pleased to thank all the consultants, residents and entire supporting staffs of Dermatology department and Nerve Conduction Study unit of B. P. Koirala Institute of Health Sciences.

References 1 2 3 4 5 6 7 8 9

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Van Veen NH, Meima A, Richardus JH. The relationship between detection delay and impairment in leprosy control: a comparison of patient cohorts from Bangladesh and Ethiopia. Lepr Rev, 2006; 77: 356 –365. World Health Organization. Weekly Epidemiological Record. 2014, 89, 389–400. Department of Health services, Nepal. Leprosy control program. Annual report, 2012/13; 137–143. McDougall AC. The clinical examination of peripheral nerves in leprosy. Ind J Lepr, 1996; 68: 378 –379. Roberts AE, Nicholls PG, Maddali P, Van Brakel WH. Ensuring inter-tester reliability of voluntary muscle testing and monofilament sensory testing in the INFIR cohort study. Lepr Rev, 2007; 78: 122–130. Campion D. Electrodiagnostic testing in hand surgery. J Hand Surg, 1996; 21: 947–956. Hackett ER, Shipley DE, Livengood R. Motor nerve conduction velocity studies of ulnar nerve in patients with leprosy. Int J Lepr, 1968; 36: 282–287. Chaudhry V, Cornblath DR, Mellits ED et al. Inter and intra examiner reliability of nerve conduction measurements in normal subjects. Ann Neurol, 1991; 30: 841 –843. Khambati FA, Shetty VP, Ghate SD, Capadia GD. Sensitivity and specificity of nerve palpation, monofilament testing and voluntary muscle testing in detecting peripheral nerve abnormality, using nerve conduction studies as gold standard; A study in 357 patients. Lepr Rev, 2009; 80: 34–50. Bell-Krotoski JA. “Pocket” filaments and specifications for the Semmes-Weinstein monofilaments. J Hand Ther, 1990; 3: 26–31. Anderson AM, Croft RP. Reliability of Semmes Weinstein monofilament and ballpoint sensory testing and voluntary muscle testing in Bangladesh. Lepr Rev, 1999; 70: 305 –313. Brandsma JW. Monitoring motor nerves function in leprosy patients. Lepr Rev, 2000; 71: 258– 267. Preston DC, Shapiro BE. Fundamentals of nerve conduction studies and electromyography. In: David C, Preston DC, Shapiro BE (eds). Electromyography and Neuromuscular Disorders, 8th ed. Butterworth-Heinemann, 1998; pp. 561–564. van Brakel WH, Nicholls PG, Das L et al. The INFIR cohort study: investigating prediction, detection and pathogenesis of neuropathy and reactions in leprosy. Methods and baseline results of a cohort of multibacillary leprosy patients in north India. Lepr Rev, 2005; 76: 14–34. Dros J, Wewerinke A, Bindels P, Weert H. Accuracy of monofilament testing to diagnose peripheral neuropathy: a systematic review. Ann Fam Med, 2009; 7: 555–558. Croft RP, Richardus JH, Nicholls PG et al. Nerve function impairment in leprosy: design, methodology and intake status of a prospective cohort study of 2664 new leprosy cases in Bangladesh: the Bangladesh acute nerve damage study. Lepr Rev, 1999; 70: 140 –159. van Brakel WH, Peter G, Nicholls PG et al. Early diagnosis of neuropathy in leprosy—comparing diagnostic tests in a large prospective study (the INFIR cohort study). PLoS Negl Trop Dis, 2008; 2: 212–224.

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Shetty VP, Khambati FA, Ghate SD et al. The effect of corticosteroids usage on bacterial killing, clearance and nerve damage in leprosy; part 3- study of two comparable groups of 100 multibacillary (MB) patients each, treated with MDT þ steroids vs MDT alone, assessed at 6 month post – release from 12 months MDT. Lepr Rev, 2010; 81: 41–58. van Brakel WH, Nicholls PG, Das L et al. The INFIR cohort study: assessment of sensory and motor neuropathy in leprosy at baseline. Lepr Rev, 2005; 76: 277–295. van Brakel WH, Khawas IB. Nerve damage in leprosy: an epidemiological study of 396 patients in West Nepal, part 1: definitions, methods and frequencies. Lepr Rev, 1994; 65: 204– 221. Brown TR, Kovindha A, Wathanadilokkol U et al. Leprosy neuropathy: correlation of clinical and eletrophysiological tests. Indian J Lepr, 1996; 68: 1– 14. Ramadan W, Mourad B, Fadel W et al. Clinical, electrophysiological and immunological study of peripheral nerves in Hansen’s disease. Lepr Rev, 2001; 72: 35 –49. Dyck PJ, Zimmerman IR, O’Brien PC et al. Introduction of automated systems to evaluate touch pressure, vibration and thermal cutaneous sensation in man. Ann Neurol, 1978; 4: 502 –510.

Lepr Rev (2016) 87, 211– 220

Experiences with Thalidomide for Erythema Nodosum Leprosum – a retrospective study JOYDEEPA DARLONG*, PITCHAIMANI GOVINDHARAJ*, DUKE EBENEZER CHARLES*, ALASDAIR MENZIES* & SURESH MANI** *The Leprosy Mission Home and Hospital, PO Box 9, Purulia 723101 West Bengal, India **Physiotherapy Programe, School of Rehabilitation Sciences, Faculty of Health Sciences, University Kebangsaan Malaysia, Malaysia Accepted for publication 6 April 2016 Summary Background: Thalidomide is well known as a steroid sparing drug in Erythema Nodosum leprosum (ENL) reaction in leprosy. There is no guideline as to when it should be offered to patients. Documentation of ENL presentation with its morbidity before and after with patient profile can be a baseline to develop a selection criteria as to when thalidomide should be started to reduce steroid related morbidly. Method: Chart and electronic record review was done. Result: 427 ENL patients attended the hospital from 2010 to 2014. 73 patients (67 males six females) were treated with thalidomide. 77% (56) patients were in the age group of 16 – 45 yrs. 16% (12) were dependent and 39% (29) were taking steroids at presentation. 82% (60) became dependent while on treatment. Ninety five percent were chronic or recurrent ENLs and 73% (53) had moderate to severe ENLs over 49 median months. Steroid induced morbidities were (Cushingoid features 42%, diabetes 21%, infections GI 42%, genitourinary 26%, cataract 23%). There was 11% mortality. Conclusion: Further studies are recommended to diagnose steroid dependence early to prevent serious adverse effects.

Introduction Erythema Nodosum Leprosum (ENL) reaction is a complication of multibacillary (MB) leprosy, occurring before, during and after multidrug therapy. Managing severe recurrent and chronic ENL reactions in leprosy-affected patients can be extremely difficult. These patients Correspondence to: Joydeepa Darlong, Deputy Superintendent, The leprosy Mission Home and Hospital, PO Box 9, Purulia 72310, West Bengal, India (Tel: Mobile: þ91 9434885198; e-mail: jddarlong@gmail.com) 0305-7518/16/064053+10 $1.00

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develop fever; skin lesions occur as crops of painful and tender papules or nodules, lasting for several days. Lesions may be pustular or bullous which may ulcerate and necrotize, resulting in disfiguring scars and keloids. Ophthalmic complications such as iridocyclitis may lead to severe episodes which may be life threatening, and with features mimicking septic shock.1 The Operational Guidelines of the Global Strategy for Further Reducing the Leprosy Burden published by WHO in 2006 describes ENL as a syndrome of ‘complex medical problems requiring careful management by experienced clinicians’.2,3 ENL treatment requires prolonged immunosuppression;3 corticosteroids, the mainstay of treatment can rapidly improve symptoms, leading to improved quality of life.4,5 There is no fixed regime for the use of prednisolone in ENL. In patients with recurrent ENL the dose may have to be increased and/or maintained for an indefinite period of time. Such patients may require a minimum daily prednisolone dose of 15– 20 mg to keep them free of ENL for prolonged periods. However steroids are not indicated to keep ENL at bay, it only treats active ENL, it does not prevent ENLs and by continuous intake of steroids the situation is worsened. Chronic use of high doses of glucocorticoids has been associated with many adverse systemic effects. Steroids may be responsible for diabetes, hypertension, and impaired wound healing and increased risk of infections. Serious complications include increased risk of fracture, gastrointestinal ulcers, even leading to gastrointestinal hemorrhage. Steroids may mask other diseases and so make them difficult to diagnose. Patients taking steroids have a significant risk of Adrenal suppression caused due to suppression of hypothalamic pituitary axis leading to adrenal insufficiency. It is defined as decreased or inadequate cortisol production that results from exposure of the hypothalamic pituitary- adrenal (HPA) axis to exogenous glucocorticoids. It is an under-recognised complication of glucocorticoid therapy (e.g. inhaled, oral, intramuscular, intranasal, and intravenous) that can persist for up to 1 year after cessation of corticosteroid treatment. If adrenal suppression is unrecognised and the body undergoes physiological stress, such as injury, surgery or a severe infection, the condition can lead to an adrenal crisis.6 – 12 Adrenal crisis is defined as severe, life-threatening adrenal insufficiency characterised by severe hypotension and/or hypoglycaemia which may lead to seizures and even coma.13 The patients’ ‘total steroid load’ must be considered when evaluating the risk of adrenal suppression. The full recovery of the HPA axis varies from 1 week to several months after discontinuation of therapy, so patient continues to beat risk of adrenal crisis.14 Notably steroids may be bought over the counter without prescription in some countries including India, and patients may self-medicate without prescription. Thus extreme caution should be taken to monitor patients for possible adverse events due to prolonged use of steroids even long after they have successfully completed their steroid course and are free of signs & symptoms of ENL reactions. Accordingly, there is a call to use steroid sparing agents with few side effects. Thalidomide has been advocated as a good alternative to steroid dependence and side effects. It markedly reduces morbidity, improves quality of life and in some case is life-saving in patients with chronic or recurrent Type 2 reaction. The World Health Organization (WHO) has issued conflicting statements with respect to the use of thalidomide.15 The drug is acknowledged as an effective treatment for ENL by the WHO Expert Committee on Leprosy, but other publications state that WHO does not support the use of thalidomide in ENL or even more emphatically that there is no role for thalidomide in the management of leprosy. This view does not concur with the published evidence on the importance of ENL, albeit to small

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numbers of patients and provoked a vigorous response from leprosy workers around the world arguing for the place of thalidomide in the management of ENL. It is, however, not available in all areas and there are strict regulations governing the use of thalidomide. We have used thalidomide at The Leprosy Mission Hospital, a tertiary leprosy referral centre in Purulia (West Bengal, India) for treating patients who have steroid dependence, serious steroid side effects and comorbidities preventing the use of steroids. This retrospective study compares the use of thalidomide with steroids in the treatment of ENL, and discusses the advantages and downfalls of steroid usage.

Method PATIENTS

For the retrospective study, 423 patients who had been treated for ENL reaction (from 2009 â&#x20AC;&#x201C; 2013) with either steroids or thalidomide, or both, were recruited. Data of the demographics, Ridley-Jopling classification, multi-drug therapy (MDT) status, disease duration in months was recorded in either within the inpatient or outpatient department. Seventy-three patients were treated with thalidomide. These patients were studied in detail with respect to their steroid side effects. Follow up was recorded until after 1 year of completing thalidomide. Patients who did not visit the hospital for follow up were consulted by telephone to obtain patient details. Home visits were carried out for those without a telephone number. The definitions of ENL reaction and of types of ENL according to ENLIST consensus were used16 (see section â&#x20AC;&#x2DC;definitionsâ&#x20AC;&#x2122;). The study was approved by The Leprosy Mission Trust India (TLMTI) ethics committee.

THALIDOMIDE PROTOCOL

We used The Leprosy Mission protocol for treatment purposes. Thalidomide treatment requires mandatory admission to ensure close monitoring of patients. Only males and postmenopausal females may be treated with thalidomide, although females of childbearing age may be treated in extenuating circumstances, requiring special recommendation and close monitoring. One designated physician will treat and monitor patients with strict adherence to protocol; informed consent, investigations and the correct documentation must be completed. Biweekly sensory testing of the palms and soles are conducted to ascertain thalidomide induced sensory loss or leprosy neuritis. Patients are further evaluated if they have any complaints of numbness, tingling, burning on their palms and soles. The standard regimen is for 4 months, although there is flexibility when steroids cannot be tapered soon enough. The System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) monitoring protocol of thalidomide is used.17 The starting dose is 300 mg to 400 mg each day, which is tapered once the reaction subsides until the patient is maintained on 100 mg given on alternate days as required. The dosing schedule can be altered according to the clinical response of the patient. Patients may be treated for a maximum of 1 year. All patients on thalidomide are prescribed 75 mgs of aspirin daily to prevent thrombosis. A list of indications for prescribing thalidomide is shown in Table 1.

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Table 1. The indications for treatment of ENL with thalidomide Indication Steroid Dependent Serious adverse effects (SAE) of steroids Co morbidity preventing steroid use Steroid Dependent & SAE of steroids SAE of steroids & Co morbidity preventing steroid use Steroid Dependent & Co morbidity preventing steroid use Steroid Dependent, SAE of steroids & Co morbidity preventing steroid use

Frequency (%) 12 (16·2) 3 (4·1) 4 (5·0) 17 (23·3) 7 (10·0) 1 (1·4) 29 (40·0)

DEFINITONS

Acute ENL: ENL with less than 24 weeks duration. Recurrent ENL: ENLs are considered recurrent if they occur more than 28 days after completing treatment for ENL. Chronic ENL: ENL with greater than 24 weeks duration.16 Steroid dependence: when steroids cannot be discontinued due to recurrent symptoms even when steroid doses are tapered gradually. Adrenal insufficiency: the inability of the adrenal glands to secrete sufficient cortisol, which can be a result of any pathological process.10 Adrenal suppression: decreased or inadequate cortisol secretion resulting from exposure of the hypothalamic-pituitary adrenal axis to exogenous glucocorticoids.10

Results Data was collected for 73 patients treated with thalidomide for ENL reaction. Sixty-seven males and six females were recruited. The mean age was 31·9 years and the mean leprosy duration was 31 months ranging from 2 – 300 months. The mean bacteriological index, a measure of density of acid fast bacilli (AFB) within skin smears, was 4·1, ranging from 0·66 to 5·66. Around 30·1% were BL and 70% were LL (Table 2). The mean duration of ENL reaction was 30·8 months with a range of 1 to 300 months. Episodes ranged from single to as many as 20 with a median of six episodes with median disease duration of 12 months. Around 95% of patients had recurrent or chronic ENL reaction. Twenty one (28·7%) individuals presented with ENL at the time of their leprosy diagnosis, 36 (49·5%) developed ENL during treatment with MDT and 12 (16·4%) developed ENL after having completed a 24 month course of MDT. Four patients (5·5%) relapsed after a becoming BI negative on MDT treatment. The ENL reactions were classified as acute in four (5%) patients, recurrent in 56 (77%), and chronic in 13 (18%). Physician assessment for severity diagnosed 53% as moderate to severe ENLs. The most common lesions were nodular eruptions (77%), although 23% experienced ulcerating and necrotizing lesions as well. See Table 3 for a complete list of patient ENL data. Forty percent of patients were treated with steroids before presentation to the hospital. Around 16% were on steroids and 49% were already steroid dependent at presentation to our centre, from treatment previously received elsewhere. About 80% were steroid-dependent by the time they were treated with thalidomide. The doses of steroids ranged from 10 mg – 60 mg

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Table 2. Table describes the disease and treatment status of individuals prescribed thalidomide Total number of patients prescribed thalidomide Male: Female ratio Age (years) RJ classification

BL LL ,4 .4 Naı¨ve Current Completed Relapse ,6 6 to 12 12 to 24 24 to 48 to .60

Bacteriological index MDT status

Disease duration in months

73 67:06 14–58 22 51 24 43 21 (28·7%) 36 (49·4%) 12 (16·4%) 04 (5·5%) 7 32 20 4 2 8

per day. The average duration of steroid usage was 684·71, ranging from 22 to 2,950 days with a median of 572 days. Cumulative steroid doses ranged from 142 mg to 30,164 mg with a median of 8,360 mg, and an average of 10,385 mg. Adverse events recorded were features such as moon facies, striae, thinning of extremities, bruising tendency, hypotension and inability to wean off steroids. Commonly encountered morbidities were respiratory (11), gastrointestinal (26), genitourinary and soft tissue infections, and worsening of ulcers. Diabetes and hypertension occurred in 15 and six patients respectively. Tuberculosis was detected in six individuals. These morbidities may have been either caused or exacerbated by prolonged steroid use. Table 3. Details of the ENL episodes n (%) ENL duration in months

Number of ENL episodes

Type Severity Skin Lesions

,6 6 to 12 12 to 24 24 to 48 48 to 60 .60 ,5 5 to 10 10 to 15 .15 Acute Recurrent Chronic Mild Moderate Severe Nodular Ulcerating Necrotizing

15 (20·6%) 11 (15·1%) 28 (38·4%) 10 (13·7%) 4 (5·5%) 5 (6·9%) 32 (44%) 24 (33%) 9 (12%) 8 (11%) 4 (5%) 56 (77%) 13 (18%) 20 (27%) 26 (36%) 27 (37%) 59 (77%) 14 (18%) 4 (5%)

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At 1 year follow up after completion of thalidomide therapy; there were 33 healthy patients who did not have ENL reaction. Twenty-three required additional steroids to control the reaction; four patients were restarted on thalidomide and six patients were untraceable. After receiving thalidomide the proportion of adverse effects of steroid was reduced (Figure 1). The number of infections (including systemic, respiratory and genitourinary) fell by an absolute number of 27, which was considered significant (P ¼ , 0·05). Orthopaedic complications such as pre-tibial tenderness and joint pains were reduced significantly (P ¼ , 0·05). Anemia though not a side effect of steroids but rather due to chronic inflammation associated with ENL reaction, improved in 28 patients, which was considered significant (P ¼ 0·001). Thalidomide-related side effects were increased drowsiness and constipation. There were no reports of peripheral neuropathy or venous thromboembolism. Bi-weekly nerve function assessments were conducted and there were no such impairment reported in our patients.

Before Thalidomide

After Thalidomide

40 35 30 25 20 15 10 5 ns io at

N cc

Tu b

ve s

sis

n In

te H

s te be ia D

di op ae

as tro

O rth

in es

tin

Adverse reaction

Before Thalidomide

After Thalidomide

p-value

Cushingoid features

34 (46.6%)

5 (6.8%)

<0.0001

Gastrointestinal complications

31 (42.5%)

20 (27.4%)

0.056

Diabetes

15 (20.5%)

3 (4.1%)

0.003

6 (8.2%)

0 (0.0%)

0.012

38 (52.1%)

11 (15.1%)

0.000

6 (8.2%)

2 (2.7%)

0.146

Nerves

27 (37.0%)

13 (17.8%)

0.009

Orthopaedic complications

33 (45.2%)

6 (8.2%)

0.000

Hypertension Infection Tuberculosis

Figure 1. Reduction in the steroid induced adverse effects before and after thalidomide treatment.

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During the review period, eight patients were known to have died with conditions attributed to steroid usage (Table 4). No patients were known to have died from adverse effects associated with thalidomide use.

Discussion This is the first attempt to study the profile of a larger series of patients treated with thalidomide for ENL reaction in rural India. We investigated the steroid intake history and its adverse events in great detail. The course of recurrent and chronic ENLs are difficult to predict. Since it is an acute, extremely painful and febrile episode, there is no alternative that will bring down the symptoms as rapidly as steroids. Clinicians may find it frustrating to decide the minimum effective dose of steroids that will keep ENLs at bay. Even if such a steroid dose is identified, the question arises as to how long it should be continued. From this study, TLM Purulia, being a tertiary referral centre, we found 49% of patients presenting to the hospital with clinical features of steroid dependence and 80% developed steroid dependence before they were offered thalidomide treatment. Steroid dependence occurs due to adrenal insufficiency resulting from prolonged ingestion of high dose steroids. It is an elusive diagnosis. Clinically, it signifies flaring of ENL lesions or appearance of new lesions when prednisolone is tapered to below 10mg. Physical findings in patients with steroid dependence and adrenal insufficiency are subtle and nonspecific. Patients with mineralocorticoid insufficiency may show signs sodium and volume depletion (e.g., orthostatic hypotension, tachycardia).10,18 There are tests that are available to detect adrenal suppression in patients who are on long-term steroids for other conditions but have not been made available to leprosy-affected patients. There are no screening guidelines for patients at risk. Steroid induced mortality is a serious and significant issue. Until a globally acceptable safe and effective steroid sparing agent is discovered, clinicians will have to depend on steroids for the treatment of ENLs. We need to rethink and redraft steroid protocols and policies for better clinical practice. Chronic adrenal suppression often takes a long time to recover, sometimes up to a year. Stressors like minor illnesses, surgeries and emotional stresses can push the patient to adrenal crisis.10 Acute medical emergencies such as this need prompt diagnosis and management. In rural settings it is difficult for patients to reach the hospital, especially within a short timeframe, and even more difficult for clinicians to diagnose and treat the condition. Patients who are lost to follow-up or died due to undiagnosed reasons potentially may have been victims of adrenal crisis. Thalidomide, in contrast, appears to be associated with significant reductions in steroidassociated adverse effects, such as diabetes, hypertension and susceptibility to infections. Although there are some adverse effects such as sedation and constipation, thalidomide appears to be well-tolerated and an effective treatment for ENL. Obviously, caution should be taken when used within the premenopausal patient population. Some countries, which have a high incidence of leprosy, such as Brazil, advocate the usage of thalidomide as a first-line treatment for ENL.19 Thalidomide may offer an economic advantage; use of thalidomide may avoid costs associated with treatment of steroid-induced morbidity. Due to repeated hospital visits, the burden of treatment of morbidities and in-patient treatment length, the patient may be economically disadvantaged due to prolonged treatment costs, hospital trips and loss of working days.20

DM, Neuritis, Anaemia

Gastritis, recurrent infections

None

DM2 /TB

Recurrent infections

Gastric ulcer

Sputum- positive cavitating PTB None

51 27

Acute gastroenteritis, fluctuating sugars, hypotension, and electrolyte imbalance. Severe abdominal pain and distension, fever, jaundice, hyperglycemia, hypotension, hypokalemia, disorientation, arthritis with effusion. Necrotizing fasciitis until mid-thigh, unconscious in septicemia. High fever, hypotension, uncontrolled sugars, congestive cardiac failure, sputum positive, cavitating PTB, septic shock. Ulcerating ENLs, pedal oedema, massive, tender lymphadenopathy, orchitis. Fluctuant sugars, hypotension, dyspnea. Uncontrolled haematemesis, melaena, hypotension, shock. Managed Conservatively. Continued to bleed; referred, refused treatment? Died at home Died at home

Disease course

DM Âź Diabetes Mellitus, PTB Âź Pulmonary tuberculosis.

Comorbidities

Age

Table 4. Analysis of the causes of the deaths of those prescribed steroids

Unknown TB

Hypovolaemic shock secondary to hematemesis

Chronic adrenal suppression

Pyothorax associated with PTB

Septicaemia

Cardiorespiratory arrest secondary to adrenal crisis Suspected acute Pancreatitis resulting in cardiorespiratory failure

Cause of death

Steroid Steroid

Steroid

Attributed to

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Currently, there is little knowledge about the optimum initiation time, length of treatment, and tapering protocol for thalidomide treatment to treat ENL reaction in leprosy. Several studies have suggested different regimes. Studies have reported difficulty in switching to thalidomide when patient is already on steroids and may take several weeks of controlled tapering.1 It is also suggested that thalidomide is used as a first line treatment in ENL reaction to ensure a better control and outcome. Furthermore, there are no proven methods to identify patients most at risk of recurrent or chronic ENLs, making it difficult to identify those who would most benefit from thalidomide treatment. Large, multi-centric studies need to be conducted to determine the optimum initiation time, risk versus benefit over steroids, duration of treatment and overall efficacy of thalidomide. Information gained may help more accurately guide local and national guidance on the usage of thalidomide in treatment of leprosy. This may only benefit a small group of leprosy-affected people but we must remember that they belong to the productive age group, mostly males, with dependent families. It is the clinicianâ&#x20AC;&#x2122;s responsibility to ensure a faster relief from ENL reaction, free of adverse events and not financially draining.

Conclusion ENL reaction is a dreaded complication of leprosy and steroids are the most effective antiinflammatory agents available. When high doses are used for prolonged periods, serious adverse events including adrenal suppression are possible. The risk of adrenal suppression can be minimised through increased awareness, early recognition of at-risk patients, regular patient follow up and ensuring that the minimal effective dose are utilised. Thalidomide is a double-edged weapon; although its use has been associated with devastating consequences such as phocomelia (when used in pregnant women), is extremely useful as a steroid-sparing agent. There are other side-effects like sensory loss and peripheral neuropathy that have been documented. Regular sensory testing of patients on thalidomide can pick up those who suffer sensory loss. However it is difficult to establish the cause of sensory loss as a thalidomide side-effect or leprosy neuritis. Clinicians using thalidomide must keep this side-effect in mind and take appropriate measure if it happens. Proper and timely identification of individuals who are at risk for steroid dependence and offering them thalidomide can reduce morbidity and mortality in them, thus enabling them to enjoy a better quality of life.

Contribution of each author Joydeepa Darlong was involved in conceptualisation and study design, interpretation of the results and preparation of manuscript. Pitchaimani Govindharaj was involved in data analysis and interpretation of data. Duke Ebenezer Charles was contributed in data collection and compilation. Alasdair Menzies contributed in manuscript writing. Suresh Mani was involved proof reading and finalising the final draft for submission.

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3 4 5 6

7 8

9 10

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13 14

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Walker SL, Waters MFR, Lockwood DNJ. The role of thalidomide in the management of erythema nodosum leprosum. Lepr Rev, 2007; 78: 197–215. http://www.ncbi.nlm.nih.gov/pubmed/18035771. Organization WH. Enhanced global strategy for further reducing the disease burden due to Leprosy: plan period: 2011–2015. 2009. https://scholar.google.com/scholar?hl¼en&as_sdt¼0,5&q¼EnhancedþGlobalþ Strategyþ forþ furtherþ reducingþ theþdiseaseþ burdenþdueþ toþ leprosy#1. Accessed October 27, 2015. Pocaterra L, Jain S, Reddy R. Clinical course of erythema nodosum leprosum: an 11-year cohort study in Hyderabad, India. Am J Trop Med Hygiene, 2006; 74: 868–879. WHO. Guidelines for the management of severe erythema nodosum leprosum (ENL) reactions. who.int. http://www.who.int/entity/lep/research/WHOenlguide.pdf?ua¼1. Accessed October 27, 2015. Suresh M, Joydeepa D, Annamma J, Pitchaimani G. Non-Adherence to steroid therapy in leprosy reaction and neuritis. Lepr Rev, 2015; 86: 356–367. Dullaart RP, Pasterkamp SH, Beentjes JA, Sluiter WJ. Evaluation of adrenal function in patients with hypothalamic and pituitary disorders: comparison of serum cortisol, urinary free cortisol and the humancorticotrophin releasing hormone test with the insulin tolerance test. Clin Endocrinol (Oxf), 1999; 50: 465– 471. http://www.ncbi.nlm.nih.gov/pubmed/10468905. Accessed October 27, 2015. Agwu JC, Spoudeas H, Hindmarsh PC et al. Tests of adrenal insufficiency. Arch Dis Child, 1999; 80: 330– 333. doi:10.1136/adc.80.4.330. Schmidt IL, Lahner H, Mann K, Petersenn S. Diagnosis of adrenal insufficiency: Evaluation of the corticotropinreleasing hormone test and Basal serum cortisol in comparison to the insulin tolerance test in patients with hypothalamic-pituitary-adrenal disease. J Clin Endocrinol Metab, 2003; 88: 4193–4198. doi:10.1210/jc.2002021897. Renu Virk. Clinical Chemistry - Adrenal insufficiency. Univ Massachusetts Meml Hosp. 2009. http://www. pathologyoutlines.com/topic/chemistryadrenalinsufficiency.html. Accessed October 27, 2015. Ahmet A, Kim H, Spier S. Adrenal suppression: A practical guide to the screening and management of this underrecognized complication of inhaled corticosteroid therapy. Allergy Asthma Clin Immunol, 2011; 7 doi:10.1186/1710-1492-7-13. Guinot M, Duclos M, Idres N et al. Value of basal serum cortisol to detect corticosteroid-induced adrenal insufficiency in elite cyclists. Eur J Appl Physiol, 2007; 99: 205 –216. doi:10.1007/s00421-006-0332-4. Portner MM, Thayer KH, Harter JG et al. Successful initiation of alternate-day prednisone in chronic steroiddependent asthmatic patients. J Allergy Clin Immunol, 1972; 49: 16–26. http://www.ncbi.nlm.nih.gov/pubmed/ 4331972. Accessed October 27, 2015. Lynnette KN. Adrenal insufficiency (Addison’s disease). Uptodata, Wolters Kluwer. 2015. http://www.uptodate. com/contents/adrenal-insufficiency-addisons-diseasebeyond-the-basics. Accessed October 27, 2015. Brown PH, Blundell G, Greening AP, Crompton GK. Hypothalamo-pituitary-adrenal axis suppression in asthmatics inhaling high dose corticosteroids. Respir Med, 1991; 85: 501 –510. http://www.ncbi.nlm.nih.gov/ pubmed/1775677. Accessed October 27, 2015. Crawford CL. No role for thalidomide in the treatment of leprosy. J Infect Dis, 2006; 193: 1743–1744. author reply 1744–1745. doi:10.1086/504295. Walker SL, Balagon M, Darlong J et al. ENLIST 1: An International Multi-centre Cross-sectional Study of the Clinical Features of Erythema Nodosum Leprosum. PLoS Negl Trop Dis, 2015; 9: e0004065. doi:10.1371/journal.pntd.0004065. Zeldis JB, Williams BA, Thomas SD, Elsayed ME. S.T.E.P.S.: a comprehensive program for controlling and monitoring access to thalidomide. Clin Ther, 1999; 21: 319 –330. http://www.ncbi.nlm.nih.gov/pubmed/ 10211535. Accessed September 15, 2015. Schreuder PAM, Naafs B. Chronic recurrent ENL, steroid dependent: long-term treatment with high dose clofazimine. Lepr Rev, 2003; 74: 386–389. http://www.ncbi.nlm.nih.gov/pubmed/14750585. Accessed October 27, 2015. Walker SL, Saunderson P, Kahawita IP, Lockwood DNJ. International workshop on erythema nodosum leprosum (ENL) - consensus report; the formation of ENLIST, the ENL international study group. Lepr Rev, 2012; 83: 396– 407. http://www.ncbi.nlm.nih.gov/pubmed/23614260. Chandler DJ, Hansen KS, Mahato B et al. Household costs of leprosy reactions (ENL) in rural India. PLoS Negl Trop Dis, 2015; 9: e0003431. doi:10.1371/journal.pntd.0003431.

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The use of steroids and thalidomide in the management of Erythema Nodosum Leprosum; 17 years at the Hospital for Tropical Diseases, London LAURA E.B. NABARRO*, DINESH AGGARWAL*, MARGARET ARMSTRONG* & DIANA N.J. LOCKWOOD* , ** *The Hospital for Tropical Diseases, London UK **London School of Hygiene and Tropical Medicine, London, UK Accepted for publication 9 May 2016 Summary Objectives: Prednisolone and thalidomide are commonly used in the management of erythema nodosum leprosum (ENL) and bring relief to patients with this condition worldwide. However, both ENL and its treatments can cause significant morbidity. This study describes the spectrum of ENL seen at The Hospital for Tropical Diseases, London (HTD), the use of steroids and thalidomide in its management and the complications of their use. Study Design: We conducted a retrospective audit of patients diagnosed with ENL between 1996 and 2013. Data were obtained from hospital records including severity and length of disease, together with treatments received and adverse effects. Results: Between 1996 and 2013, 30 patients were diagnosed with ENL. The median bacillary index (BI) at diagnosis was 4·65, higher than in previous studies. Most patients developed ENL during leprosy treatment (67%) and had chronic ENL (57%). The median length of ENL was 60 months (range 9 – 192); patients with BI . 4·5 had significantly longer duration of disease. 87% patients received prednisolone for median nine months; 35% developed adverse effects including diabetes and hypertension. 87% patients received thalidomide for median 16 months; 65% complained of side effects. There were no pregnancies or venous thromboembolisms. 77% patients stopped prednisolone within two months of starting thalidomide. There were no deaths in our cohort. Conclusion: We describe the clinical course of ENL in a non-endemic country with access to thalidomide and prednisolone. ENL may last far longer than previously described and has significant impact on a patient’s health. In the UK, thalidomide is essential as a steroid-sparing agent, to prevent the adverse effects and mortality of long-term steroids which have been documented elsewhere.

Correspondence to: Laura Nabarro, The Hospital for Tropical Diseases, Mortimer Market, Capper Street, London, WC1E 6JB (Tel: þ 44 7595 354 297/þ91 95 66 908966; e-mail: Laura.nabarro@nhs.net) 0305-7518/16/064053+11 $1.00

q Lepra

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Introduction ENL is a multisystem, relapsing and remitting disorder occurring in patients with lepromatous and borderline lepromatous leprosy. Although its pathogenesis is not fully understood, it is characterized by immune complex deposition and T cell activation with high levels of TNFa and IL6.1 This manifests clinically as tender erythematous skin lesions with or without systemic symptoms such as fever, neuritis, orchitis and bone pain. The incidence of ENL varies from 5%2 to 49%3 in cohorts worldwide. Risk factors include having lepromatous leprosy or a bacillary index (BI) over 4.3 The management of ENL is difficult. Anti-inflammatory agents are rarely sufficient for symptomatic control. Prednisolone rapidly controls symptoms but risks the complications of long-term steroid treatment.4 Thalidomide is effective but associated with side effects including tiredness, constipation and neuropathy. It is unavailable in many countries due to concern about teratogenic risk.5 Clofazimine can be effective as an anti-inflammatory agent at a dose of 300 mg/day. However, it takes four weeks to work and the associated skin pigmentation can be stigmatizing for patients in leprosy endemic areas.6 Other disease modifying agents have been tried with varying success. Case reports7,8 and a small case series suggest azathioprine may reduce the frequency and severity of ENL episodes and may be effective as a steroid sparing agent.9 Both etanercept and infliximab, tumour necrosis factor- alpha (TNFa) inhibitors, have been reported to be effective in individual patients with severe ENL. 10,11 The utility and safety of expensive immunosuppressive agents in resource poor settings where tuberculosis is endemic has yet to be established. The Hospital for Tropical Diseases, London, (HTD) is a tertiary centre for tropical disease and runs the leprosy referral clinic for the UK National Health Service. The majority of patients diagnosed with leprosy in the UK are referred to this clinic. Most patients receive the WHO recommended multidrug therapy (MDT) of rifampicin, clofazimine and dapsone in blister packs provided by WHO. Patients who have adverse effects to first line treatment are given alternative regimens, such as monthly rifampicin, ofloxacin and minocycline (ROM). Prednisolone, clofazimine and azathioprine are available for the management of ENL. Thalidomide is prescribed through the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.). TNFa inhibitors are not currently available for patients with ENL. This retrospective case note review aims to describe the spectrum of ENL seen at HTD, the use of steroids and thalidomide in its management and the complications of their use. Although this manuscript describes the side effects of drugs used in ENL treatment, we emphasise that these drugs bring relief to ENL patients worldwide.

Method We conducted a retrospective audit of the management of patients with ENL seen at the Hospital for Tropical Diseases, London, between January 1996 and December 2013. Ethical approval was not required as this was an audit of our current practice. Data were obtained from hospital records including case notes from consultations and inpatient admissions, electronic letters and laboratory records. Data collected included age, sex, country of origin, country where leprosy was acquired, Ridley-Jopling classification, BI at diagnosis, treatment regimen, treatment length and occurrence of ENL. Further data were

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Table 1. Case definitions. Type and severity of ENL have been adapted from previous studies looking at the clinical course of ENL in Ethiopia2 and India18. Case Definitions Reactions

Erythema nodosum leprosum 2

Type of ENL

Acute Recurrent Chronic

Severity of ENL18

Mild Moderate Severe

Onset of ENL

Before MDT

ENL treatment

During MDT After MDT High dose clofazimine Self-directed therapy Duration of ENL treatment Complications of steroid use Complications of thalidomide use

The presence of tender skin nodules with or without other systemic symptoms Episode of ENL lasting less than 6 months in which treatment was slowly withdrawn with no recurrence of ENL whilst on treatment At least one further episode of ENL occurring 28 days or more after withdrawal of treatment for ENL Episode of ENL lasting longer than 6 months during which patient is on continuous ENL treatment or any treatment free periods are less than 28 days. A few mildly tender lesions with or without mild aches and pain or low grade fevers without neuritis Mild ENL with neuritis or with more than three systemic symptoms such as joint pain, bone pain, anorexia, malaise, lymphadenopathy Multiple skin nodules with high grade fever and organ involvement (iritis, orchitis, severe neuritis) History of ENL onset before MDT was started or presence of ENL when MDT was started ENL which started during MDT ENL which started after MDT had finished More than 50 mg per day of clofazimine OR clofazimine prescribed independently of MDT. Rescue packs of prednisolone or thalidomide kept by the patient and taken in short course when the patient experienced a flare-up of ENL. Time from initial ENL symptoms until termination of symptoms OR the patient stopped taking treatment for ENL (whichever was latest) Hypertension, steroid induced diabetes, cataracts, osteoporosis, weight gain, infection Tiredness, constipation, unplanned pregnancy, dizziness, abdominal pain, venous thromboembolism

collected about ENL including timing, pattern, severity and length of disease together with treatments used. Adverse effects of steroids were recorded including weight gain, diabetes, hypertension, osteoporosis, cataracts and occurrence of infections. Adverse effects of thalidomide were also recorded including tiredness, constipation, dizziness, abdominal pain, unplanned pregnancy and venous thromboembolism. The neurological outcomes of thalidomide treatment are currently being collected and will be reported separately. As these data were collected retrospectively from notes, letters and laboratory records rather than from systematic patient interview, the occurrence of adverse events may be underestimated. Table 1 details the case definitions used.

Results Between 1996 and 2014, 18 patients with BL and 46 patients with LL were seen at HTD. Four (22%) patients with BL and 26 (56%) patients with LL developed ENL.

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3 received rifampicin, ofloxacin and minocycline 22 completed therapy 1 received rifampicin, ofloxacin, minocycline and clofazimine

28 received rifampicin, clofazimine and dapsone. 6 changed regimenc 30 patients

1 received rifampicin, ofloxacin and minocyclinea

1 received rifampicin and clofazimine

1 received rifampicin and dapsoneb

1 received rifampicin, dapsone, ofloxacin

Median length of treatment 30 monthsd

aThis

patient had previously been partially treated in India but had developed severe clofazimine pigmentation hence was started on a clofazimine free regimen.

bThis patient received rifampicin and dapsone alone as treatment had been started elsewhere and the BI was low. c6

(20%) patients changed regimen due to complications of therapy; 5 due to severe clofazimine pigmentation and one to enable directly observed treatment with the ROM regimen.

dThe median duration of treatment is longer than advised by the WHO as patients with a BI≥4 are treated for 2 years or until their BI falls below 2, due to the higher rate of relapse in these patients.

Figure 1. Treatment regimens of patients with ENL.

Of 30 patients with ENL, 20 (67%) were male. Ten (33%) patients acquired leprosy in South Asia, ten (33%) in South America and seven (23%) in West Africa. The median age at leprosy diagnosis was 33 years; 29 (97%) patients were of working age and 24 (80%) were between 20 and 40 years old. Patients had a median of 18 months of symptoms before the diagnosis of leprosy was made. The median BI at diagnosis was 4·65 (4·7 in patients with LL and 2·6 in patients with BL leprosy). Twenty-two (73%) patients had a BI over 4. All patients received multi-drug therapy (see Figure 1). Nine (30%) patients developed ENL before starting leprosy treatment, 20 (67%) during treatment and one (3%) after treatment. Thirteen (43%) patients had recurrent ENL and 17 (57%) patients had chronic ENL. No patients had acute ENL. The median length of ENL was 60 months (range: 9 to 192 months). Four (13%) patients had ENL for more than 10 years (see Figure 2). Those with an initial BI over 4·5 had a median length of ENL of 76 months in comparison to 40 months in patients with a BI of 4·5 or less (Mann Whitney u test, P 0·043). Sixteen (53%) patients had moderate disease with four (13%) experiencing severe disease. There were no deaths in this cohort.

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28 25

Patient

Median 60 months Range 9–192 months

19 16 13

BI>4·5: median length 76 months BI<4·5: median length 40 months (P 0·0043)

10 7 4 1 0

100 150 Time (months)

200

250

Figure 2. Duration of ENL.

Twenty six (87%) patients received prednisolone, 26 (87%) received thalidomide, five (17%) received high dose clofazimine and four (13%) received a further disease modifying agent. Figure 3 shows the combinations of treatments that patients received. Prednisolone was given for a median of 9 months (range 1 week to 74 months) at a dose range of 5 mg to 80 mg/day. The median maximum dose of prednisolone was 40 mg/day; patients were initially started at this dose and the dose was then reduced as their ENL was controlled. Of note, three (11%) patients were already on prednisolone for neuritis or Type 1 reaction when they developed symptoms of ENL. Nine (35%) patients developed side effects whilst on treatment; seven (27%) gained weight, four (15%) developed Cushingoid features and three (11%) developed steroid-induced diabetes. One patient developed a Listeria monocytogenes meningitis which was attributed to steroid use. Six (23%) had self-directed treatment at the end of therapy; these patients kept rescue packs of prednisolone at home and took a short course if they experienced an ENL flare-up. Thalidomide was given for a median of 16 months (range 2 weeks to 175 months) at a dose range of 12.5 mg to 500 mg/day. The median maximum dose of thalidomide was 400 mg

Clofazimine 0

4 Prednisolone 3

Thalidomide 3

1 patient had all four treatments 1 patient had no treatments

Azathioprine 0

Figure 3. Combinations of treatments that patients received.

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per day. Twenty (77%) patients were on prednisolone when thalidomide was started. The median time from developing ENL to starting thalidomide was 5 months in men and 8 months in women. Twenty (77%) were weaned off prednisolone whilst taking thalidomide in a median of 2 months. Seventeen (65%) patients had side effects on thalidomide: 16 (61%) felt tired, four (15%) felt dizziness and four (15%) complained of constipation. There were no unplanned pregnancies or venous thromboembolisms. Ten women received thalidomide. Two of these women were post-menopausal and thus did not require contraception. Of seven patients whose contraception was documented, six (86%) used condoms, four (57%) used the oral contraceptive pill, three (43%) used a coil and one (14%) used the Depo contraceptive injection. One patient was documented to be using contraception but the type was not recorded in the patientâ&#x20AC;&#x2122;s records. Of five women who received thalidomide after the introduction of the S.T.E.P.S. programme, all had a negative pregnancy test documented at over 90% of appointments at which thalidomide was prescribed. Four patients received clofazimine at doses between 100 mg and 300 mg per day. Three patients received azathioprine for between 8 and 44 months at a dose between 200 mg and 300 mg per day. These three patients had ENL of moderate severity that was not controlled on 40 mg prednisolone per day. In the first patient, introduction of azathioprine allowed a reduction in prednisolone to 10 mg per day at 2 months but the patient continued to require

MDT

ROM

Prednisolone Thalidomide

350 Clofazimine pigmentation 300

Dose (mg/d)

250 Hypertension

200 150

Strongyloides 100 DM2 50 0 0

30 Time (months)

New nerve damage Type 1 reaction ENL Figure 4. The clinical course of a patient with ENL, type 1 reaction and neuritis. The patient was treated with prednisolone and thalidomide and developed steroid induced diabetes and hypertension as a complication of treatment.

The use of steroids and thalidomide in ENL 450

227

400

60 50

300 250

200

150

Prednisolone (mg/d)

Thalidomide (mg/d)

350

100 10

50 0

0 0

100

Time (months) Figure 5. The clinical course of a patient with chronic severe ENL maintained on thalidomide with intermittent prednisolone.

2·5– 10 mg prednisolone daily for a further 22 months before prednisolone could be stopped permanently. In the second patient, prednisolone was reduced to less than 10 mg per day at 11 months and then stopped completely at 23 months. The third patient did not respond to 8 months of azathioprine and required increased doses of prednisolone to control the symptoms of ENL. The median length of follow up after ENL had terminated was 29 months (range 1– 144 months). In 10 patients for whom electronic documentation of outpatient appointments was available, the median number of attended appointments was 49. Figures 4 and 5 show the clinical course of two patients with ENL.

Discussion This is the first study to describe the clinical course of ENL in a clinic where patients can be treated with thalidomide and prednisolone in a non-endemic region. Compared to other cohorts, the rate of ENL in our study is high: 56% of our patients with LL leprosy developed ENL compared to 49% of LL patients in a hospital-based study with similar inclusion criteria and case definitions in Hyderabad, India.3 Other studies have found lower rates of ENL; 31% in multibacillary patients in Brazil12 and 5% in field studies of multibacillary patients in Ethiopia. The differing inclusion criteria, case definitions and clinical settings may account for the variation between studies.13 However, the median BI at diagnosis in our cohort was 4·65 compared to 3·5 in Hyderabad;3 63% of our patients had over 12 months of symptoms before being diagnosed with leprosy compared to 52% of patients in Nepal.14 We postulate that delay in diagnosis may result in a higher BI and, as a high BI is a known risk factor for ENL,3 increased rates of ENL in our cohort. The UK is a non-endemic area with an average of 10 new leprosy diagnoses per year. Awareness of leprosy is low

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outside the specialties of dermatology, infectious disease and neurology. This may contribute to delays in diagnosis. As in previous studies3,14 most of our patients developed ENL whilst on leprosy treatment. However, our patients had a longer duration of ENL (median 60 months, range 9-192 months) than previously reported. In Hyderabad, the median duration of ENL was 18·5 months.3 In Nepal, the range was 1 to 62 months. The longest case of ENL previously documented in the literature is 96 months,15 far shorter than our maximum ENL duration of 192 months. Figure 5 shows the clinical course and treatment of a patient with chronic severe ENL for 105 months. It is unclear why our cohort has a longer median duration of ENL than previously recorded but we suspect that it is a combination of three factors. Firstly, it may be due to delay in leprosy diagnosis; our patients had a higher BI at diagnosis resulting in a longer time to clear M. leprae antigen from skin, thus a prolonged period of immune complex deposition causing symptoms of ENL. In our cohort, patients with a BI over 4·5 had a significantly longer duration of disease than those with a BI of 4·5 or less. Secondly, there may be some patients with no adverse effects from thalidomide who received extended courses of treatment because thalidomide kept them symptom free, thus artificially prolonging the estimated duration of their ENL. Finally, it may be due to the prolonged follow up of our patients. We reviewed patients for a median 29 months after their last episode of ENL hence we would expect to identify late recurrences or prolonged mild ENL. As HTD is the main leprosy clinic in the UK, loss to follow-up is rare and patients who developed recurrent ENL after discharge would be referred back to our clinic. Previous studies have not documented duration of follow-up or number of patients lost to follow-up3,14,15 so may have underestimated the true duration of disease. The extended duration of ENL has both social and medical implications for patients. Most of our patients were of child-bearing and working age. In the UK, people whose health is poor earn 7 – 15% less and are 34% less likely to be in employment than those in average health.16 In West Bengal, the household cost of ENL was 28% of monthly income and 11% of households faced catastrophic health expenditure.17 In addition, ENL is often treated with long courses of steroids putting patients at considerable risk of adverse events; 13% of patients treated with steroids developed steroidinduced diabetes (SID) compared to 21% and 26% in two studies in India.4,18 The increased rate may be due to a higher incidence of Type 2 diabetes in South Asia. However, until recently we did not routinely check patients’ blood sugars or HbA1C, hence our data may underestimate the true incidence of SID in our cohort. Sugurmaran investigated complications of steroid therapy in leprosy reactions and found that 23% of patients developed cataracts and 3% developed TB.4 These complications were not seen in our small cohort. However, this highlights the importance of systematic recording of side-effects in patients on steroids, particularly in areas without access to thalidomide. Figure 4 shows the clinical course and treatment of a patient with ENL and a Type 1 reaction. She developed SID and hypertension, gained weight and developed a Cushingoid habitus, which she found particularly distressing. There were no deaths in our cohort. Walker et al. found a mortality rate of 7·9% in patients hospitalised for ENL in Ethiopia, where thalidomide is not available. In 50% of deaths, steroids were identified as a definite contributing factor; these patients died of TB or septic shock.19 We postulate that the zero mortality in our cohort was due to the availability of thalidomide.

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Thalidomide allowed 75% of patients to be weaned off steroids in a median of 2 months. However, it may need to be taken for years and many patients complain of side-effects, particularly tiredness, which negatively affects their working and social lives. Thalidomide is prothrombotic; the risk of deep vein thrombosis (DVT) in patients with myeloma on thalidomide and dexamethasone is 17%20 and there are increasing reports amongst leprosy patients on thalidomide. None of our patients developed DVT. The occurrence of thalidomide-induced neuropathy in this cohort is currently being investigated and will be reported separately. Eighty percent of female patients were of childbearing age. Use of thalidomide precludes pregnancy and the S.T.E.P.S. programme mandates that women use two forms of contraception and attend clinic monthly for pregnancy testing. Although this is effective at reducing unplanned pregnancy21 it is disruptive to the patientâ&#x20AC;&#x2122;s working and family life. Finally, the length of ENL has implications for health care provision. Patients with ENL attended many outpatient appointments and eight patients required hospital stay. They received long courses of treatment, some of which resulted in adverse events which themselves required treatment. As it is impossible to predict the likely length or severity of ENL at the outset, it is difficult to plan healthcare provision for these patients. Although this is unlikely to be problematic in the UK where the number of patients with ENL is small, it may have a significant impact on health care provision in countries where leprosy is highly endemic. There were a number of limitations to our study. Notably the small sample size and nonrandomised nature of this study limit the potential to generalise the data to other cohorts of patients. Most patients received both thalidomide and prednisolone and so it was not possible to evaluate their individual therapeutic effect. Furthermore, we have not discussed the neurological toxicity of thalidomide. This will be reported in a separate paper due to the large amount of data and complexity of this important topic. As this was a retrospective review of patient records, it was limited by clinical documentation. In particular, side-effects of treatment were not systematically documented in notes but only documented if they occurred. Furthermore, our patients did not routinely have blood sugar, HbA1C and blood pressure measurements performed in clinic and so we may have underestimated treatment related side-effects.

Conclusion This study highlights the significant effect that ENL has on patientsâ&#x20AC;&#x2122; lives even in a developed country with access to prednisolone, thalidomide and other disease modifying agents. In particular, it shows that ENL can last far longer than was previously suspected. This has implications on the working, social and family life of our patients and on health care provision. It underscores the importance of using thalidomide as a steroid-sparing agent to prevent adverse events associated with long-term steroid use. Further work is needed to investigate predictors of ENL severity and length of disease so that patients can be started on appropriate therapy early on in the illness. In addition, ongoing investigations into effective steroid-sparing agents in ENL should be supported and further advocacy is needed in leprosy endemic regions where thalidomide is not available.

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Acknowledgements M. Armstrong is supported by the Special Trustees of the Hospital for Tropical Diseases. All authors were supported by the University College London Hospitals Comprehensive Biomedical Research Centre Infection Theme. The supporting agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Presentation: This paper was presented in part at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2015, 26th April 2015 by LEB Nabarro. Competing Interests: Diana Lockwood is on the editorial board of Leprosy Review. All authors declare that the answer to the question on competing interest form are all ‘No’, and therefore have nothing to declare. Contributorship: LEB Nabarro designed the study, collected and analysed the data and wrote the manuscript. D Aggarwal and M Armstrong collected data. DNJ Lockwood conceived of and designed the study, reviewed the data and helped to write the final manuscript.

References 1

Kahawita IP, Lockwood DN. Towards understanding the pathology of erythema nodosum leprosum. Trans R Soc Trop Med Hyg, 2008; 102: 329–337. Saunderson P, Gebre S, Byass P. ENL reactions in the multibacillary cases of the AMFES cohort in central Ethiopia: incidence and risk factors. Lepr Rev, 2000; 71: 318–324. Pocaterra L, Jain S, Reddy R et al. Clinical course of erythema nodosum leprosum: an 11-year cohort study in Hyderabad, India. Am J Trop Med Hyg, 2006; 74: 868–879. Sugumaran DS. Leprosy reactions - complications of steroid therapy. Int J Lepr Other Mycobact Dis, 1998; 66: 10–15. Walker SL, Waters MF, Lockwood DN. The role of thalidomide in the management of erythema nodosum leprosum. Lepr Rev, 2007; 78: 197–215. Van Veen NH, Lockwood DN, Van Brakel WH et al. Interventions for erythema nodosum leprosum. A Cochrane review. Lepr Rev, 2009; 80: 355–372. Verma KK, Srivastava P, Minz A, Verma K. Role of azathioprine in preventing recurrences in a patient of recurrent erythema nodosum leprosum. Lepr Rev, 2006; 77: 225–229. Mahajan VK, Sharma NL, Sharma RC, Sharma A. Pulse dexamethasone, oral steroids and azathioprine in the management of erythema nodosum leprosum. Lepr Rev, 2003; 74: 171 –174. Dura˜es SM, Salles SeA, Leite VR, Gazzeta MO. Azathioprine as a steroid sparing agent in leprosy type 2 reactions: report of nine cases. Lepr Rev, 2011; 82: 304–309. Ramien ML, Wong A, Keystone JS. Severe refractory erythema nodosum leprosum successfully treated with the tumor necrosis factor inhibitor etanercept. Clin Infect Dis, 2011; 52: e133–135. Faber WR, Jensema AJ, Goldschmidt WF. Treatment of recurrent erythema nodosum leprosum with infliximab. N Engl J Med, 2006; 355: 739. Nery JA, Vieira LM, de Matos HJ et al. Reactional states in multibacillary Hansen disease patients during multidrug therapy. Rev Inst Med Trop Sao Paulo, 1998; 40: 363–370. Voorend CG, Post EB. A systematic review on the epidemiological data of erythema nodosum leprosum, a type 2 leprosy reaction. PLoS Negl Trop Dis, 2013; 7: e2440. Feuth M, Brandsma JW, Faber WR et al. Erythema nodosum leprosum in Nepal: a retrospective study of clinical features and response to treatment with prednisolone or thalidomide. Lepr Rev, 2008; 79: 254–269. Kumar B, Dogra S, Kaur I. Epidemiological characteristics of leprosy reactions: 15 years experience from north India. Int J Lepr Other Mycobact Dis, 2004; 72: 125–133. Bell M, Ridge M, Kossykh Y, Woolley N. An empirical analysis of the effect of health and condomic growth in the UK. Health and Safety Executive (HSE) Research Report. 2008. Chandler DJ, Hansen KS, Mahato B et al. Household costs of leprosy reactions (ENL) in rural India. PLoS Negl Trop Dis, 2015; 9: e0003431.

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Papang R, John AS, Abraham S, Rao PS. A study of steroid-induced diabetes mellitus in leprosy. Indian J Lepr, 2009; 81: 125– 129. Walker SL, Lebas E, Doni SN et al. The mortality associated with erythema nodosum leprosum in ethiopia: a retrospective hospital-based study. PLoS Negl Trop Dis, 2014; 8: e2690. Rajkumar SV, Blood E, Vesole D et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol, 2006; 24: 431 –436. Uhl K, Cox E, Rogan R et al. Thalidomide use in the US: experience with pregnancy testing in the S.T.E.P.S. programme. Drug Saf, 2006; 29: 321–329.

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Is nullity for Glutathione S-transferase genes GSTT1 and GSTM1 protective against leprosy? CARLA RENATA GRAC ¸ A*, ROSA MARIA CORDEIRO-SOUBHIA*, SUSILENE MARIA TONELLI-NARDI**,***, EDIS BELINI JUNIOR****, CLAUDIA REGINA BONINI-DOMINGOS****, CAMILA RAVAZZI GAUCH*, ELISABETH MARTINS DA SILVA DA ROCHA*****, ˆ NIA DEL´ ARCO PASCHOAL*, JOA Õ VA ARIS KOUYOUMDJIAN* & ANDREA REGINA DE SOUZA BAPTISTA***** *Faculdade de Medicina de Saõ Jose´ do Rio Preto (FAMERP), Saõ Paulo, Brazil **Instituto Lauro de Souza Lima, Bauru, Saõ Paulo, Brazil ***Centro de Laborato´rio Regional – Instituto Adolfo Lutz Saõ Jose´ do Rio Preto, Saõ Paulo, Brazil ****Departamento de Biologia, Laborato´rio de Hemoglobinas e Gene´ticas das Doenças Hematologicas, Universidade do estado de Saõ Paulo (UNESP), Saõ Jose do Rio Preto, Saõ Paulo, Brazil *****Departamento de Microbiologia e Parasitologia, Instituto Biome´dico, Universidade Federal Fluminense (UFF), Niteroí, Rio de Janeiro, Brazil Accepted for publication 12 May 2016 Summary Introduction: Leprosy is a slow and progressive infectious disease caused by Mycobacterium leprae. The generation of free radicals called reactive oxygen species (ROS), which promote destruction of the bacillus within macrophages, is an effective defence mechanism developed by the host. In parallel, the glutathione S-transferase (GST) multifamily of enzymes constitutes an important antioxidant system for ROS detoxification and protection against toxicity. Therefore, GST null genotype individuals could reduce the detoxification of ROS, increasing host effectiveness for M. leprae destruction. Objectives: To evaluate polymorphisms in the GSTT1 and GSTM1 genes as human leprosy susceptibility modulators. Correspondence to: Carla Renata Graça, Laborato´rio de Investigaçaõ Neuromuscular (LIN) Av. Brigadeiro Faria Lima 5416, 15090-000 Saõ Jose´ do Rio Preto SP, Brasil (Tel: þ 55 17 3201-5911; e-mail: cgraca@hotmail.com)

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0305-7518/16/064053+07 $1.00

q Lepra

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Methods: GSTT1 and GSTM1 polymorphisms were genotyped by a multiplex polymerase chain reaction (PCR) in 218 leprosy patients and 244 non-leprosy subjects (control group). Results: The occurrence of the GSTT1/GSTM1 null genotype was significantly higher among control subjects than amongst leprosy patients (P ¼ 0·01). The GSTT1 positive genotype frequency was significantly increased in leprosy patients when compared with control subjects (P ¼ 0·01). Conclusions: The results suggest that GSTT1/M1 nullity may play an important role in leprosy pathogenesis. Significance: Despite these findings, further studies will be necessary to ascertain the exact role of these genes in leprosy and to design any future prevention measures or contributions to drug therapy.

Keywords: Glutathione S-transferase; Leprosy; Reactive Oxygen Species; Mycobacterium leprae

Introduction Leprosy is a slow and progressive infectious disease caused by Mycobacterium leprae, an obligate intracellular bacillus, with a broad clinical and immunological spectrum of disease. The tuberculoid form (TT) is characterised by isolated skin lesions with or without occasional intracellular bacilli (paucibacillary form) and a lymphocyte T helper 1 (Th1) cellular immune response. On the other hand, lepromatous leprosy (LL) is characterised by the presence of profuse bacilli (multibacillary form) in the skin and a lymphocyte T helper 2 (Th2) humoral immune response. In addition, four intermediate forms, borderline tuberculoid (BT), midborderline (BB), borderline lepromatous (BL) and indeterminate (I), are observed.1 The major defence against infection by any microorganisms is the macrophage system. The generation of free radicals produced by phagocytes, called reactive oxygen species (ROS), which promote the destruction of M. leprae, is an effective defence mechanism developed by the host.2 In parallel, cells have a comprehensive system of antioxidant defences to prevent free radical formation, and the glutathione S-transferase (GST) multifamily of enzymes constitutes an important antioxidant system for ROS detoxification and protection against toxicity. Therefore, GST null genotypes could reduce the detoxification of ROS, increasing its effectiveness for microorganism destruction.3,4 Glutathione S-transferases (GSTs) constitute a multifunctional family of enzymes that are coded by at least eight distinct loci: a (GSTA), m (GSTM), u (GSTT), p (GSTP), s (GSTS), k (GSTK), v (GSTO), and z (GSTZ); GSTT1 and GSTM1 are the most studied.5 The GSTT1 gene is located on chromosome 22 (22p 11·2), while the GSTM1 gene is located on chromosome 1 (1p 13·3). The GSTT1 and GSTM1 enzyme activity deficiency results from the inherited absence of the GSTT1 or GSTM1 genes (GSTT1 or GSTM1 null genotypes).6,7 In this context, several authors sought to investigate the possible correlation between human cancer susceptibility and GST gene polymorphisms, including bladder, kidney, liver, gastric, tobacco-related (lung and oral cavity), colorectal, brain and skin tumours, among others, with contradictory results.8 Some of these disparities seem to be related to differential xenobiotic exposure or even to the frequency of the GSTM1 and GSTT1 polymorphisms, since both can be influenced by population ethnicity.9

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The purpose of the present study was to evaluate whether GSTT1 and GSTM1 genes polymorphisms (presence or absence) can influence human susceptibility to leprosy and/or modulate the severity of this disease in a Southeast Brazilian population.

Materials and methods SUBJECTS

The study population was composed of subjects older than 18 years, belonging to any ethnic group. They were invited to participate after signing an informed consent form, approved by the Ethical Research Board from the Faculdade de Medicina de Sa˜o Jose´ do Rio Preto – FAMERP (number 3898/2006).

PATIENTS

This study represents a case-control investigation of 218 leprosy patients (n ¼ 218), 103 female and 115 male, recruited from two leprosy treatment reference centres in Saõ Jose´ do Rio Preto city, located in the Northwestern region of Saõ Paulo state, Southeast Brazil: the Nućleo de Gestaõ Assistencial 60 (NGA-60) and the Sanitary Dermatological Service of the Hospital de Base Outpatients Clinic (HB-DAS), FUNFARME Foundation. The Hospital de Base (HB) is a tertiary care hospital catering to a large population from the Northwestern region of Saõ Paulo State, Brazil, representing, along with the NGA 60, the regional reference centre for leprosy diagnosis and treatment. Together, these two centres concentrate leprosy health care in the Saõ Paulo State Health Regional Department XV (DRS XV), which includes 101 cities. All patients were invited to participate among those who started leprosy treatment in the municipality from November 2006 until April 2010. Leprosy diagnosis was based on clinical assessment as evaluated by physicians, and detection of acid-fast bacilli either in skin-slit smears or in skin biopsies. Patients were classified according to the RidleyJopling Scale1 and also as paucibacillary (PB) or multibacillary (MB), with subsequent treatment according to World Health Organization (WHO) specifications.10 The PB group (BT, TT and I) included 96 cases, while the MB group (LL, BL and BB) included 122 cases. General characteristics of the patient groups are summarised in Table 1. Table 1. General characteristics of patient groups Total N (%) Classification used for treatment Clinical forms (Ridley and Jopling)

Paucibacillary Multibacillary LL BL BB BT TT I

96 (44·0) 122 (56·0) 90 (41·3) 13 (6·0) 19 (8·7) 19 (8·7) 63 (28·9) 14 (6·4)

LL, lepromatous leprosy; BL, borderline lepromatous; BB, borderline; BT, tuberculoid leprosy; TT, tuberculoid leprosy; I, indeterminate.

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CONTROL GROUP

Two hundred and forty four (n ¼ 244) unrelated subjects, 110 female and 134 male, from the same endemic area as the patients, were selected among blood bank donors from the HB Blood Bank, in the same municipality, as controls. They were matched with leprosy patients by age (^ 5 years) and gender. None of them was under continuous medication.

DNA EXTRACTION AND GSTT1 AND GSTM1 GENOTYPING

The genomic DNA was obtained from peripheral blood according to Miller et al.11 with modifications. The genotyping of the GSTT1 and GSTM1 polymorphisms was performed by using a multiplex polymerase chain reaction (PCR) with co-amplification of the CYP1A1 gene as an internal control for successful amplification.12 Briefly, PCR amplifications were carried out in 50 ml reactions using 25 –100 ng of genomic DNA as template in tubes containing 1·0 U Taq DNA polymerase with 1X of the buffer as supplied by the manufacturer (Invitrogen, CA, USA), 1·5 mM of MgCl2, 0·2 mM of each dNTP and 0·3 mM of each primer. Amplification cycles included a denaturing step at 94 8C for 5 minutes followed by 35 cycles set at 94 8C for 2 minutes, 62 8C for 1 minute and 72 8C for 1 minute and a final extension at 72 8C for 5 minutes. The PCR products were electrophoresed in 2% agarose gel and visualized by ethidium bromide staining. DNA from samples positive for GSTM1 and GSTT1 genotypes yielded bands of 215 bp and 480 bp, respectively, while the internal positive control (CYP1A1) PCR product corresponded to 315 bp. The associations of the GSTT1 and GSTM1 polymorphisms in patients and control subjects were carried out by weighted logistic regression models. Results are shown as odds ratios (OR) with 95% confidence intervals (95% IC). The significance of the allele frequency difference between the MB and PB groups and GSTT1, GSTM1 genotypes was analysed using Pearson’s Chi-square test. P-values , 0·05 were considered statistically significant.

Results The mean age of patients and controls were 55 years ^ 14·2 and 51·4 years ^ 16·6 (mean ^ standard deviation), respectively. There were no statistically significant differences between cases and controls, indicating a well-matched population. After comparing the genotypes obtained for both study groups, we could detect that the presence of both genes (GSTM1 and GSTT1 positive genotype) enhanced the risk for leprosy (OR 1·824, 95% CI 1·197 –2·779) whereas the frequency of the GSTT1/GSTM1 null genotypes was significantly higher among control subjects than among patients (P ¼ 0·0223). The GSTT1 positive genotype frequency was significantly increased in leprosy patients when compared with control subjects (P ¼ 0·0067), a phenomenon that was not observed when the GSTM1 positive genotype frequency was considered (P ¼ 0·5482). The distribution of GSTT1 and GSTM1 alleles in patients and control subjects is shown in Table 2. The same results were obtained when the variables gender and age were included in the logistic regression model. In addition, no differences were observed in the frequency of the GSTT1/GSTM1 genotypes between MB and PB groups (P . 0·05).

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Table 2. Genotypic frequencies among patients versus controls, and MB versus PB forms of leprosy Frequency Genotype GSTT1/GSTM1 null GSTT1 GSTM1

Frequency

Patients (n ¼ 218)

Controls (n ¼ 244)

P-value

MB (n ¼ 122)

PB (n ¼ 96)

P-value

0·100 0·788 0·495

0·188 0·672 0·463

0·0223* 0·0067* 0·548

0·090 0·795 0·500

0·0114 0·781 0·489

0·7958 0·9352 0·9870

n ¼ number of individuals; P ¼ significance level P, 0·05; Comparisons between cases and controls, multibacillary (MB) and paucibacillary (PB) were performed using Chi-square test. *P , 0·05 is significant.

Discussion Several studies in different populations around the world have investigated leprosy susceptibility and disease severity through human genetic susceptibility.13,14 The majority aimed at determining the role of proteins and enzymes involved in Th 1 and Th 2 immune responses,15 vitamin D receptor gene variations,13,16 Parkin (PARK2) and parkin coregulated genes (PACRG),17,18 and also the Toll-like receptor gene polymorphisms, with conflicting results. As far as we know, our study is the first to investigate the GST gene polymorphisms as possible modulators of susceptibility and/or severity in leprosy. Therefore, it is not an easy task to discuss the results here obtained, which will be explained based on the GST enzymes function versus the well-recognised mechanism of M. leprae elimination - the macrophage defense through ROS. In the present investigation, we analysed the combined genotypes of GSTM1 and GSTT1 genes to evaluate the possibility of a contribution to the severity of leprosy or to a modulation of the human susceptibility to this disease. In fact, the combination of the GSTTM1 and GSTT1 null genotypes was more frequent in the control group than in the leprosy group. We also suggest an association of GSTT1 positive genotype and susceptibility to developing leprosy. As a matter of fact, GSTs are a class of abundant proteins that promote cellular defence against different artificial and naturally occurring environmental agents by catalysing the conjugation of glutathione to various electrophiles and xenobiotics, including ROS.19 Recently, Kawamura et al.20 targeting cancer treatment, by a combination of proteomic profiling and affinity purification, together with subsequent biochemical assays, described that the mechanism by which a small molecule induces ROS is the depletion of cellular glutathione. Together, our data led us to the proposition that the absence of GSTs, with a consequent maintenance of high levels of intracellular ROS, can contribute to M. leprae elimination and, therefore, reduce leprosy susceptibility. On the other hand, we could not establish any statistically significant association between these polymorphisms and clinical subtypes of leprosy. Indeed, if GST nullity plays an important role in bacilli destruction, as suggested, this could be more likely a protective effect, which would act before the establishment of a multi or paucibacillary forms of the disease. GST gene polymorphisms were extensively studied in case-control studies which investigated human susceptibility to several types of cancer in different populations with both positive and negative associations, mainly attributed to particularities concerning

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environmental exposure to carcinogens and populations with diverse ethnic composition.6,21 While the first do not seem to represent an important issue in the present study, the bias generated in case-control studies based on polymorphisms investigated in human admixed populations can be of major concern. The lack of individual genotyping of ethnicity markers before case-control matching was a limitation of this study that we acknowledge. Further studies with a large cohort and a careful case-control match according to ancestry informative markers to control ethnicity will shed additional light on the role of GSTM1 and GSTT1 in leprosy.

Acknowledgements This study was partially supported by the BAP-FAMERP (022/2010) and Fundaçaõ Paulista Contra a Hansenıáse (123/2008 and 136/2010) grants and by a Scientific Initiation scholarship from FAPESP – IC/FAPESP (2008/11626-0).

References 1

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Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis, 1966; 34: 255– 273. Jyothi P, Riyaz N, Nandakumar G, Binitha MP. A study of oxidative stress in paucibacillary and multibacillary leprosy. Indian J Dermatol Venereol Leprol, 2008; 74: 80. Mittal RD, Manchanda PK, Bid HK, Ghoshal UC. Analysis of polymorphisms of tumor necrosis factor-alpha and polymorphic xenobiotic metabolizing enzymes in inflammatory bowel disease: study from northern India. J Gastroenterol Hepatol, 2007; 22: 920–924. Prasad CV, Kodliwadmath MV, Kodliwadmath GB. Erythrocyte glutathione peroxidase, glutathione reductase activities and blood glutathione content in leprosy. J Infect, 2008; 56: 469–473. Silva DG, Belini Junior E, Torres Lde S et al. Relationship between oxidative stress, glutathione S-transferase polymorphisms and hydroxyurea treatment in sickle cell anemia. Blood Cells Mol Dis, 2011; 47: 23–28. Bathi RJ, Rao R, Mutalik S. GST null genotype and antioxidants: risk indicators for oral pre-cancer and cancer. Indian J Dent Res, 2009; 20: 298–303. Sharma V, Kumar B, Saxena R. Glutathione S-transferase gene deletions and their effect on iron status in HbE/beta thalassemia patients. Ann Hematol, 2010; 89: 411–414. McIlwain CC, Townsend DM, Tew KD. Glutathione S-transferase polymorphisms:cancer incidence and therapy. Oncogene, 2006; 25: 1639–1648. Moyer AM, Salavaggione OE, Hebbring SJ et al. Glutathione S-transferase T1 and M1: gene sequence variation and functional genomics. Clin Cancer Res, 2007; 13: 7207– 7216. WHO Expert Committee on Leprosy (1998) Seventh report. World Health Organ Tech Rep Ser. 874:20. Miller SA, Dykes DD, Poleski HF. A simple salting out procedure for extrating DNA from human nucleated cells. Nucleic Acids Research, 1988; 16: 1215. Abdel-Rahman SZ, El-Zein RA, Anwar NA. A Multiplex PCR procedure for polymorphic analysis of GSTM1 and GSTT1 genes in population studies. Cancer Lett, 1996; 107: 229– 233. Roy S, Frodsham A, Saha B et al. Association of vitamin D receptor genotype with leprosy type. J Infect Dis, 1999; 179: 187 –191. Grac¸a CR, Paschoal VD, Cordeiro-Soubhia RM et al. NINJURIN1 single nucleotide polymorphism and nerve damage in leprosy. Infect Genet Evol, 2012; 12: 597–600. Hagge DA, Saunders BM, Ebenezer GJ et al. Lymphotoxin-alpha and TNF have essential but independent roles in the evolution of the granulomatous response in experimental leprosy. Am J Pathol, 2009; 174: 1379–1389. Goulart LR, Ferreira FR, Goulart IM. Interaction of TaqI polymorphism at exon 9 of the vitamin D receptor gene with the negative lepromin response may favor the occurrence of leprosy. FEMS Immunol Med Microbiol, 2006; 48: 91– 98. Schurr E, Alcais A, Singh M et al. Mycobacterial infections: PARK2 and PACRG associations in leprosy. Tissue Antigens, 2007; 69: 231 –233.

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Malhotra D, Darvishi K, Lohra M et al. Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population. Eur J Hum Genet, 2006; 14: 438–442. Ketterer B. A bird’s eye view of the glutathione transferase field. Chem Biol Interact, 2001; 138: 27–42. Kawamura T, Kondoh Y, Muroi M et al. A small molecule that induces reactive oxygen species via cellular glutathione depletion. Biochem J, 2014; 463: 53–63. Kwon DD, Lee JW, Han DY et al. Relationship between the Glutathione-S-Transferase P1, M1, and T1 Genotypes and Prostate Cancer Risk in Korean Subjects. Korean J Urol, 2011; 52: 247 –252.

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Autonomic neuropathy impairing quality of life after completion of MDT: Are we managing enough? VIKAS ANAND*, SWETALINA PRADHAN** & PIYUSH KUMAR* *Katihar Medical College and Hospital, Bihar, India **All India Institute of Medical Sciences, Bhubhneshwar, India Accepted for publication 6 April 2016 Summary A 26 year old male, treated case of lepromatous leprosy, presented with severe heat intolerance, loss of sensation and sweating over distal parts of both upper and lower limb of 12 years’ duration. On examination, there was definite sensory loss over the extremities in glove and stocking pattern and thickening of the bilateral ulnar, common peroneal and radial nerves. There were three trophic ulcers over the plantar aspect of the right foot, atrophy of the small muscles of hand, reabsorption of the distal index, middle and ring fingers along with total clawing of both hands. A slit skin smear for acid fast bacilli revealed fragmented granular bacilli. A starch-iodine test was used to document the pattern of sweating which coincided with the glove and stocking pattern of sensory loss found in lepromatous leprosy. Even though the patient had completed WHO MDT and bacilli were dead, the damage to the autonomic system was extensive in the patient leading to widespread loss of sweating and severe heat intolerance affecting his quality of life. Also the patient had motor deformity in the form of total clawing which added to his disability. Therefore all cases should be followed up even after completion of MDT, counselled regarding the course of the disease, and trained to tackle the consequences of nerve damage in their daily life. We report the case as autonomic dysfunction that has been rarely documented in leprosy patients and also we emphasise the use of the starch-iodine test in such cases along with management of the disease in part by using hydro-oleo therapy.

Case report A 26 year old male patient presented to the skin Outpatient Department with a loss of sweating over distal parts of both his upper and lower limbs for which he couldn’t work during the day due to heat intolerance, and he had to wet his body repeatedly to gain some comfort. He was a treated case of lepromatous leprosy and had completed a 1 year course of Correspondence to: Swetalina Pradhan, All India institute of Medical Sciences, Bhubaneswar, India (e-mail: dr.swetalinapradhan@gmail.com) 0305-7518/16/064053+04 $1.00

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WHO MDT MB regimen 4 years after the onset of disease. Other personal and family histories were unremarkable. Other than a tender right inguinal lymphadenopathy, other general physical and systemic examinations were normal. Dermatological examination revealed a hypopigmented anaesthetic patch on his right antero- lateral arm. Both upper and lower extremities showed glove and stocking anaesthesia. The bilateral ulnar, common peroneal and radial nerves were enlarged clinically with the left side being more pronounced than the right. There were three trophic ulcers with a sero-purulent discharge present over the plantar aspect of his right foot. Motor deformities in the form of atrophy of small muscles of his hands, and bilateral total ulnar clawing were present along with reabsorption of the distal index, middle and ring fingers. All routine laboratory tests were normal. Both the pattern and absence of sweating was documented by using the starch-iodine test which followed the similar glove and stocking distribution (Figures 1 and 2). A slit skin smear showed fragmented granular dead bacilli. Therefore the patient was diagnosed as a case of autonomic dysfunction subsequent to lepromatous leprosy. The patient was treated with oral antibiotics to treat the secondary infection in his ulcer and appropriate steps were taken for ulcer management. He was taught to practise hydro-oleo therapy using any vegetable oil to keep the area hydrated, along with passive exercises for ulnar clawing. The patient is now in the follow-up period and his quality of life with regard to heat intolerance is improving with hydro-oleo therapy.

Figure 1. Starch-iodine test â&#x20AC;&#x201C; white area denotes absence of sweating and black area denotes presence of sweating.

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Figure 2. Starch-iodine test – white area denotes absence of sweating and black area denotes presence of sweating.

Discussion Leprosy neuropathy is complex, with the superposition of acute and chronic sensory, motor and/or autonomic events. In many leprosy patients, nerve damage may occur with or without symptoms from the very beginning of infection and multibacillary leprosy cases are more susceptible to nerve damge.1 – 3 Leprosy has been shown to affect almost all systems of the human body and abnormalities in function of autonomic nerves innervating various parts have been observed in several studies.1,4 – 5 Autonomic nervous system (ANS) dysfunction manifests as anhidrosis, impaired sweat response and localised alopecia. Peripheral dysautonomia leads to damage of vascular autonomic innervations in the skin followed by a loss of vascular tone which results in stasis of capillary blood flow and consequently delayed ulcer healing. Anhidrotic skin fissures easily, thereby contributing to the vicious circle of

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secondary infection and ulceration. Sensory loss and motor paralysis are the leading causes of morbidity and permanent severe disability in leprosy patients, and therefore remains the prime focus of clinical concern and research; but reports on the impact of autonomic neuropathy in leprosy in literature are scarce. In the lepromatous pole, sensory loss has a ‘glove and stocking’ pattern and not much literature is available on the pattern of anhidrosis. Our case here shows a similar pattern of loss of sensation and sweating in the lepromatous pole which has been pictographically documented by the use of a starch-iodine test. The patient had heat intolerance due to the loss of his ability to sweat which impaired his quality of life. This case is a definite indicator that the long-term sequel of autonomic nerve dysfunction cannot be managed just by completing a full course of anti-leprosy treatment as seen in this case who has had leprosy for 12 years and had completed a full course of treatment 4 years after the onset of his illness. This conclusion brings us to another issue: that completing the full course of MDT might not be of benefit in the long run in preventing the sequel of damage that has already occurred while the disease was active. Though sensory and/or motor impairment may be partially or completely reversible with adequate and early treatment, due to lack of data, no conclusion could be made till now regarding the reversibility of autonomic dysfunction. Reversal of autonomic function is not achieved just by use of anti-leprosy drugs.6,7 Those cases with autonomic dysfunction should be counselled and trained regarding hydro-oleo therapy, care of their hands and feet to improve their quality of life.

References 1 2

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Vital RT, Illarramendi X, Nascimento O et al. Progression of leprosy neuropathy: a case series study. Brain Behav, 2012; 2: 249– 255. Capadia GD, Shetty VP, Khambati FA et al. Effect of corticosteroid usage combined with multidrug therapy on nerve damage assessed using nerve conduction studies: a prospective cohort study of 365 untreated multibacillary leprosy patients. J. Clin. Neurophysiol, 2010; 27: 38– 47. Richardus JH, Finlay KM, Croft RP et al. Nerve function impairment in leprosy at diagnosis and at completion of MDT: a retrospective cohort study of 786 patients in Bangladesh. Lepr Rev, 1996; 67: 297– 305. Illarramendi X, Bu¨hrer-Se´kula S, Sales AM et al. High prevalence of vasomotor reflex impairment in newly diagnosed leprosy patients. Eur J Clin Invest, 2005; 35: 658–665. Soysal A, Atay T, Ozu T, Arpaci B. Electrophysiological evaluation of peripheral and autonomic involvement in leprosy. Can J Neurol Sci, 2004; 31: 357– 362. Yawalkar SJ, Saajana HB. Effect of DDS therapy on the acetylcholine sweat function test in fifty cases of tuberculoid and maculoanaesthetic leprosy. Int J Lepr, 1974; : 4255– 4257. Brute NP, Chandorkar AG, Muley MP et al. Effect of one year clofazimine therapy on autonomic functions in lepromatous leprosy with lepra (ENL) reaction. Lepr India, 1983; 55: 278–285.

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Pseudoathetosis and ataxia – a rare presentation of multibacillary leprosy in a non-endemic area ¨ STENBAUER* & HANNAH KEMPTON* JAKOB KO *University of New South Wales, Wagga Wagga, Australia Accepted for publication 4 April 2016

Introduction This report details the case of a patient with pseudoathetosis and sensory ataxia secondary to multibacillary leprosy. To the best of our knowledge there is only one previously reported incident of pseudoathetosis associated with leprosy. Case Report A 51 year old female presented to an aged-care facility in North-Western Panama, where for the last three decades the prevalence and incidence rate of leprosy has been similar to most OECD countries at below 20 new cases per year.1 Symptoms arose at the age of 29 and progressed over decades. Medical assessment revealed a malnourished, cognitively intact and otherwise healthy post-menopausal woman on no medications. Her neurological examination was significant for the following: Marked athetoid writhing of the trunk, arms and legs - worse distally and with eyes closed, disappearing while asleep; an ataxic, wide-based gait with left foot drop (power 2/5); a complete right peripheral facial nerve palsy; right-sided fixed-flexion deformity of the first, third and fourth digits and fixed extension of the wrist (Figure 1); anaesthesia of the lower limbs to the level of the mid-tibia, with preservation of sensation on the dorsum of the right foot and loss of proprioception and vibration in the upper limbs to the elbow and in the left lower limb to the knee. Numerous (more than five) hypopigmented, anaesthetic lesions were noted around the trunk, knees, and hands, with sparing of the fifth digit of the left hand. Deep tendon reflexes were absent at the left ankle, right elbow and wrist. The right plantar reflex was down-going. Finger-nose and heel-shin tests were impaired in all limbs more-so in the right. The right great auricular and left common fibular nerves were markedly thickened. Additional findings Correspondence to: Jakob Ko¨stenbauer, University of New South Wales, Wagga Wagga, Australia. (e-mail: jakobkuba@gmail.com) 0305-7518/16/064053+03 $1.00

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Figure 1. Fixed flexion deformity of the first, third and fourth digits, impaired flexion of the right hand and an irregularly shaped anaesthetic, hypopigmentated lesion on the volar surface of the forearm.

included the absence and/or deformity of multiple digits; a deep, painless, 2 £ 2 £ 3 cm ulcer on the medial volar aspect of the right foot, immediately proximal to the first digit; a painless 3·5 £ 2·5 cm decubitus ulcer over the left ischial tuberosity; wasting of the right periocular muscles and a right-sided cataract. Differential diagnoses included Friedreich’s ataxia, multiple sclerosis and diabetic, alcoholic, autoimmune or toxic peripheral neuropathy. After 2 weeks the diagnosis of multibacillary leprosy was made on clinical findings and smears collected from both ulcers and hypopigmented lesions, which stained positive for acid-fast bacilli.

Discussion In this case, signs pathognomonic for leprosy included the hypopigmented, anaesthetic lesions; slowly erosive ulcers and distal loss of digits; thickened peripheral nerves with corresponding neuropathy and a cataract. Involvement of the facial, greater auricular and fibular nerves in particular is typical, as these traverse bony prominences, providing the relatively cooler environments preferred by M. leprae. Of note in this case was the presence of pseudoathetosis. The only previously reported incident of leprous pseudoathetosis was an acute case of paucibacillary leprosy, with rapid deterioration, pain and Type-1 lepra reaction following 12 days of anti-leprosy treatment.2 Although a similar pattern of pseudoathetosis and sensory ataxia was described in our patient, the development of her symptoms occurred over a longer time-course, without pain, and was not associated with the administration of antibiotics. The cause of pseudoathetosis is significant proprioceptive deafferentation at any stage of the sensory pathway from peripheral sensory nerves to the parietal cortex. In the case of leprosy the pathology is limited to peripheral nerves. The patient’s ataxic gait is proposed to have similar origins, as described in previous reports of patients with polyneuritic leprosy,

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absent tendon reflexes in the ataxic limbs and no other cause for ataxia. Follow-up after 4 months of MDT treatment showed moderate improvement of ulcers and foot drop (left ankle dorsiflexion power increased to 4/5) but all other symptoms persisted. Due to the late diagnosis, the facility’s location in a non-endemic area and limited supplies, appropriate antibiotic therapy was delayed for several weeks. Transmission becomes negligible within 24 hours of therapy.4 This prompted questions regarding confidentiality, and the need for personal protection and/or patient isolation to protect staff and residents of the aged-care facility. Current research suggests that transmission requires a genetic susceptibility coupled with sustained close proximity to a patient with active disease.5,6 As such, isolation and use of respiratory precautions was deemed unnecessary. Confidentiality was strictly enforced.

Conclusion This case presented with unusually severe neurological symptoms, masking an otherwise obvious diagnosis. This case adds to the spectrum of clinical presentations of leprosy, however medical practitioners should also remain mindful of the disease’s stigma and social implications.

References 1 2 3 4 5 6

World Health Organization. Global Leprosy: update on the 2012 situation. Geneva: 2013 30 August 2013. Report No. Misra UKJ, Mahadevan A, Shankar S. Pseudoathetosis in a patient with leprosy. Movement disorders, 2003; 18: 598–601. Pandya SBS. Severe pan-sensory neuropathy in leprosy. International journal of leprosy & other mycobacterial diseases, 1994; 62: 24–31. Rodrigues LC, Lockwood DNJ. Leprosy now: epidemiology, progress, challenges, and research gaps. The Lancet Infectious Diseases 11: 464–470. Alter A, Grant A, Abel L et al. Leprosy as a genetic disease. Mammalian Genome, 2011; 22: 19 –31. Han XY, Seo Y-H, Sizer KC et al. A new Mycobacterium species causing diffuse lepromatous leprosy. American journal of clinical pathology, 2008; 130: 856–864.

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Uncommon clinical presentations of leprosy: apropos of three cases RASHMI JINDAL* & NADIA SHIRAZI** *Department of Dermatology, Venereology & Leprosy, Himalayan Institute of Medical Sciences, SRHU, Dehradun, India **Department of Pathology, Himalayan Institute of Medical Sciences, SRHU, Dehradun, India Accepted for publication 4 April 2016 Summary Leprosy has been labelled as a great imitator since times immemorial. This mainly is because of the wide range of its clinical presentations. In endemic regions it is important to entertain the possibility of leprosy even in atypical presentations so as to avoid misdiagnosis. Here we report three cases of leprosy with uncommon disease presentations. First case had presented with eczematous morphology of cutaneous lesions without sensory loss and nerve thickening. Second case had localized type-2 reaction and third case had presented initially with only rheumatologic manifestations. Histopathology is an important tool in arriving at correct diagnosis and thus should be done in all suspected cases.

Introduction Leprosy is a great mimic and can have varied clinical presentations. The most remarkable thing about leprosy is the wide variations in the way it affects different people. Apart from the common presentations, which can be easily identified, certain uncommon clinical presentations can delay diagnosis. In those circumstances, histopathology comes to the rescue by aiding with accurate and timely diagnosis. Further patients of lepromatous leprosy can also be diagnosed with the help of slit skin smear examination. We here present three cases having uncommon clinical presentations of leprosy where histopathology was key in establishing the correct diagnosis.

Correspondence to Rashmi Jindal, Department of Dermatology, Venereology & Leprosy, Himalayan Institute of Medical Sciences, SRHU, Swami Ram Nagar, Doiwala, Dehradun 248 140, India (Tel: Ăž91 0135 2471376; e-mail: rashmijindal98@gmail.com)

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Figure 1. (A, B): (Case 1) Erythematous to hyper-pigmented scaly papules and plaques over extremities.

Case series CASE 1

A 45 year old man sought dermatology consultation for multiple asymptomatic erythematous to hyper-pigmented scaly papules and plaques over his face, trunk and extremities predominantly involving extensors for 112 years (Figure 1). The patient correlated the onset of lesions with the spray of insecticides in the fields. He also complained of nasal stuffiness and pain in his legs. There were no sensory symptoms or peripheral nerve enlargement. The patient was investigated with a provisional clinical diagnosis of air-borne contact dermatitis. Nasal endoscopy revealed a gross left sided deviated nasal septum and septal perforation. A skin biopsy taken from the erythematous plaques showed mildly atrophic epidermis with multiple foamy macrophages and lymphocytes in the dermis. On fite stain abundant acid-fast bacilli were demonstrated (Figure 2). A slit skin smear and nasal smear taken subsequently showed acid-fast bacilli in globi. Thus a final diagnosis of lepromatous leprosy was established and the patient was started on multidrug therapy. CASE 2

A 25 year old man presented to the dermatology outpatient department with chief complaints of erythema, edema and tenderness of his right hand with 3 â&#x20AC;&#x201C; 4 overlying pustules for the past 112 months. He also had two subcutaneous nodules of 2 ÂŁ 2 cm over the right side of his chest wall and right arm medial side (Figures 3A & 3C).

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Figure 2. (Case 1) Mildly atrophic epidermis with superficial dermis showing many telangiectatic blood vessels surrounded by many foamy macrophages, lymphocytes and neutrophils (Figure 2A: H&E £ 4). Fite stain demonstrates many acid fast bacilli (Figure 2B: Fite stain £ 40).

Figure 3. (Case 2) Erythema & edema of right hand with 3–4 overlying pustules (Figure 3A), subcutaneous nodules of size 2 £ 2 cm over right arm medial side (Figure 3C). Erythematous papules and plaques over forehead (Figure 3B).

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Figure 4. (Case 2) Atrophic epidermis with dense dermal chronic inflammatory infiltrate around pilosebaceous units and nerve fibrils (Figure 4A: H&E ÂŁ 10). Fite stain shows numerous lepra bacilli (Figure 4B: Fite stain ÂŁ 100).

For the past week the patient had experienced fever. With the provisional clinical diagnosis of pyoderma, the patient was started on intravenous antibiotics but there was no improvement after one week of therapy. Further he developed a few erythematous papules and plaques over his back and forehead (Figure 3B). Fine needle aspiration cytology from the nodule over his arm showed multiple acid-fast bacilli. A skin biopsy taken from the plaque on his back revealed an atrophic epidermis with dense dermal inflammatory infiltrate of lymphocytes and foamy macrophages. Fite stain showed numerous lepra bacilli in stacks and dispersed singly (Figure 4). Thus a final diagnosis of lepromatous leprosy with localised Type 2 reaction was made. The patient responded well to multidrug therapy and oral corticosteroids.

CASE 3

A 52 year old man presented with a one-month history of polyarthritis, fever and testicular pain. On investigation he was found to be Hepatitis C virus (HCV) seropositive. The patient was given non-steroidal anti-inflammatory drugs and investigations for HCV viral load were sent. The patient was lost to follow-up and reported back after 2 weeks with multiple erythematous, tender, subcutaneous nodules over both legs. A skin biopsy taken from these nodules revealed the presence of multiple foamy macrophages surrounding pilosebaceous units (Figure 5A). Fite stain was positive for the presence of acid-fast bacilli (Figure 5B). The final diagnosis established was lepromatous leprosy with Type 2 reaction. The patient was started on multidrug therapy and oral corticosteroids and he responded well to treatment.

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Figure 5. (Case 3) Foamy macrophages surrounding pilosebaceous units (Figure 5A: H&E ÂŁ 10), fite stain showing few fragmented acid fast bacilli (Figure 5B: Fite stain ÂŁ 100).

Discussion Leprosy can be diagnosed fairly accurately on the basis of its three cardinal signs. However, as it is a spectral disease, its range of clinical presentations is wide. The uncommon disease presentations include localized lepromatous disease presenting with single nodule or localized area of papules and nodules, histoid leprosy, lucio leprosy and spontaneous ulcerations seen in long-standing untreated lepromatous leprosy. First case of our series had presented with atypical morphology resembling eczematous disorder. Further history of development of lesions following insecticide spray, absence of sensory symptoms and absence of nerve enlargement was misleading. However subtle clues to point towards diagnosis of leprosy were nasal stuffiness, pain in legs and absence of pruritus in the lesions. In the second case initial absence of cutaneous lesions suggestive of leprosy, short duration of symptoms, absence of sensory symptoms and nerve enlargement and localization of disease to right upper limb delayed the diagnosis of leprosy. Ankad BS et al have reported a case of pure neural leprosy involving isolated cutaneous radial nerve as multiple abscesses along the course of nerve.1 Other atypical manifestations reported previously include verrucous lepromatous leprosy, leprosy presenting initially with myositis followed by skin lesions and lymphadenopathy and leprosy presenting as erythema multiforme like Type 2 reaction.2 â&#x20AC;&#x201C; 4 There are also few case reports of leprosy mimicking common rheumatologic entities.5 Our third case was also initially misdiagnosed as polyarteritis nodosa due to absence of cutaneous lesions and sensory symptoms. The presence of fever, arthritis and testicular pain in view of a positive HCV serology pointed towards the possible diagnosis of polyarteritis nodosa.

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The possibility of leprosy was entertained only after the development of erythema nodosum lesions. In all the three cases presented histopathology was central in establishing the correct diagnosis. Thus all suspected cases, especially in endemic regions, should be subjected to histopathologic examination. Further various clinical presentations of leprosy, common as well as uncommon, must be kept in mind to avoid untoward delay in diagnosis. Conclusion Skin and nerves affected by leprosy is quite common. However, it is a great mimic of many conditions. In areas endemic for leprosy it is imperative to keep in mind the diverse presentations of leprosy. Leprosy should be actively ruled out in all suspected cases so as to prevent misdiagnosis. As none of the patients are identifiable in the clinical photographs no patient consent form was required. This being a case report containing retrospective data without any drug trial, ethical clearance was not required.

References 1 2 3 4 5

Ankad BS, Jawalgi A, Dombale VD, Telkar S. Multiple nerve abscesses on cutaneous radial nerve - a case of pure neural leprosy. Ind J Lepr, 2013; 85: 79–81. Medeiros MZ, Takita LC, Barbosa AB et al. Verrucous lepromatous leprosy: a rare form of presentation - report on two cases. An Bras Dermatol, 2014; 89: 481–484. Gupta S, Mehta A, Lakhtakia R, Nema SK. An unusual presentation of lepromatous leprosy. Med J Armed Forces India, 2006; 62: 392– 393. Sgambatti S, Andrade JG, Sousa ALM et al. An unusual presentation of leprosy at diagnosis: erythema multiforme like Type 2 rection. Revista de Pathologia Tropical, 2010; 39: 221– 227. Rath D, Bhargava S, Kundu BK. Leprosy mimicking common rheumatologic entities: A trial for clinicians in the era of biologics. Case reports in Rheumatology 2014. http://dx.doi.org/10.1155/2014/429698

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Leukemia cutis in a patient of relapsed leprosy- Coincidence or predisposition? SUGA REDDY*, A R SHASHIKIRAN*, RASHMI BASAVARAJ* & MURUGESH SHAMANUR* *Department of dermatology, JJM Medical College, Davangere Accepted for publication 4 April 2016 Introduction Leprosy, a disease of skin and peripheral nerves has varied manifestations which principally affect the immune status of the host. Leukemic skin infiltrations in patients with leukemia are referred to as leukemia cutis. It can be seen in all types of leukemia, especially in patients with acute myelomonocytic leukemia (AML). In majority of cases, the cutaneous lesions are nonspecific manifestations associated with an impaired immune system.1 Though various malignancies have been documented with leprosy, no case of borderline-tuberculoid (BT) Hansen’s disease with coexisting leukemia cutis has ever been reported in literature to the best of our knowledge.

Case report A 79 year old male presented with multiple asymptomatic skin coloured to brownish well-defined plaques over the face, neck, back, forearm and thighs of 15 days duration (Figures 1 and 2). The patient was a known case of BT Hansen’s disease, released from treatment 3 years ago. The patient reported an increase in the size of his previous leprosy patches as well as the appearance of new lesions (Figure 3). Both the ulnar nerves were asymmetrically thickened and tender. Sensory deficit was noted over both palms without motor deficit. Cervical lymphadenopathy was present. After 2 weeks of admission, the lesions over the back disappeared. On the day of presentation, we considered either relapse or Type 1 lepra reaction in our differentials, and the patient underwent a skin biopsy and slit skin smear which came back positive with a BI of 2þ . Histopathology showed diffuse lymphocytic infiltration with epitheloid granulomas in the upper dermis with a clear Grenz zone (Figure 4). Correspondence to: A.R. Shashikiran, JJM Medical College, Davangere, Karnataka, India (e-mail: shashikims1988@gmail.com)

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Figure 1. Multiple non-tender erythematous papules and plaques on nape of the neck. The lesions disappeared after two weeks.

Fite-Faraco staining revealed the presence of solid staining bacilli. We therefore diagnosed the patient as a ‘relapse’ BT Hansen’s disease and MDT-MB was started. During routine blood investigations, the haemoglobin was 11·2 gm% and the total leucocyte count was 76,000 cells/cumm. A peripheral blood smear and bone marrow biopsy showed features of chronic lymphocytic leukemia (CLL). The patient also showed hepatosplenomegaly with diffuse hyperechoic shadows on ultrasound examination with elevated liver enzymes and a normal renal panel. Following this, immunohistochemistry was done which showed T cells positive for CD3/CD45RO with the histiocytes immunoreactive for CD68 in upper dermis suggestive of leprosy (Figures 5 and 6) and lower dermis with B-cells immunoreactive for CD20/CD5/CD23 suggestive of leukemic infiltrate (Figures 7 and 8). Based on this, we revised our diagnosis to BT Hansen’s with Leukemia cutis secondary to B cell CLL. The patient was advised to continue with MDT-MB and referred to oncologist, who started the patient on cyclophosphamide and fludarabine for the management of B-Cell CLL.

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Figure 2. Solitary well defined, non tender erythematous nodule on the nasal bridge.

Discussion According to WHO (1995), a case of relapse is defined as â&#x20AC;&#x153;A patient who successfully completes an adequate course of MDT, but subsequently develops new signs and symptoms of the disease either during the surveillance period or thereafterâ&#x20AC;?.2 The criterion for leprosy was given by Becx-Bleumink (Table 1) which has been adapted by WHO.3 Lesions found in BT and tuberculoid (TT) leprosy are the direct result of a hypersensitive granulomatous response to the antigens of M. leprae. Introduction of multidrug therapy (MDT) leads to resolution of the granuloma over time. However, a few bacilli may get buried alive in the fibrosed nerves and arrector pili muscles, thereby serving as a nidus for relapse.4 The association of leprosy with various cancers though recognised is not well established in the literature. In a series of 252 autopsies done in leprosy patients, 85 cases (33Âˇ7%) were reported to have malignancies, among which carcinoma of the alimentary system was the most common. Of the non-epithelial malignancies, malignant lymphoma was the most common.5 In our case, the patient initially developed leprosy and though he was adequately treated, immunodeficiency associated with leukemia may have allowed multiplication of dormant persisters resulting in his current presentation. This is similar to the case of lepromatous leprosy with B-cell lymphoma reported by Sutjita6 and that of large-cell anaplastic lymphoma in a lepromatous leprosy.7

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Figure 3. Ill defined erythematous plaque with hyperpigmented border over the right ante-cubital fossa, with mild scaling present over the site of a healed leprosy lesion.

Leukemia cutis refers to the infiltration of the skin by neoplastic leukocytes (myeloid or lymphoid), resulting in clinically identifiable cutaneous lesions. It is most often reported in congenital leukemia and AML. It occurs in 10% –15% of patients with AML, and has been reported in 4% to 20% of patients with chronic lymphocytic leukemia (CLL).8 Leukemia cutis has a wide range of cutaneous manifestations, including single or multiple violaceous to hemorrhagic papules, nodules, bulla, and plaques of varying sizes. The presence of leukemia cutis suggests extramedullary involvement, thereby indicating a poorer prognosis. In the setting of AML, leukemia cutis presents as a firm nodule with a greenish hue, known as a chloroma or granulocytic sarcoma. In the neonate, it often presents as sites of extramedullary hematopoiesis in the skin, imparting a ‘blueberry muffin’ appearance.8

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Figure 4. H&E staining under scanner view showing diffuse lymphocytic infilteration of the papillary dermis, focal nodular infiltration of the deeper dermis with a clear grenz zone. (inset) H&E staining under 40x showing diffuse lymphocytic infiltration with epitheloid granulomas and occasional Langhanâ&#x20AC;&#x2122;s ginat cells.

More than 90% of cases of leukemia cutis occur after a diagnosis of leukemia has been established. Concomitant involvement of skin and systemic leukemia have been observed in up to one third of the cases, and, in , 10% of cases, skin infiltration can occur before bone marrow or peripheral blood involvement and in the absence of systemic symptoms9 as in this case. Cutaneous involvement by CLL may represent a reactive process triggered by antigenic stimuli such as infections. Cutaneous leukemic infiltration has been associated with sites of previous or concomitant inflammatory or infectious conditions, including borrelia burgdorferi, leishmaniasis, herpes zoster, and herpes simplex.10 This is the first case report to our knowledge where there is cutaneous localisation to previous leprosy lesions. The underlying molecular basis responsible for the migration of leukemic cells to the skin is not defined. The expression of cutaneous lymphocyte associated antigen (CLA) on circulating immunoglobulin-secreting B cells may relate, at least in part, to skin homing of some of these cells after antigen stimulation.11 In leukemia cutis, histopathology reveals three main architectural patterns, viz, perivascular and periadnexal, nodular & diffuse, and band-like with sparing of upper papillary dermis with a relatively monotonous population of small lymphoid cells with round nuclear contours.8 This is in contrast to a relapsed case of leprosy which shows well defined

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Figure 5 and 6. Immunohistochemistry showing diffuse lymphocytic infiltrate reactive for CD3/CD45RO with the histiocytes immunoreactive for CD68 in upper dermis suggestive of borderline tuberculoid leprosy.

granulomas made of lymphoid and epitheloid cells initially focused around the fibrosed nerve bundles and progress later to invade larger portions of dermis. The well-defined granulomas are often indistinguishable from the original lesions.4 A Grenz zone is often appreciated in BT Hansenâ&#x20AC;&#x2122;s disease.12

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Figure 7 and 8. The reticular dermis shows focal nodular aggregates of lymphocytes immunoreactive for CD20/CD5/CD23 suggestive of leukemia cutis.

To summarise, leukemia cutis, like leprosy has a varied clinical presentation. Leprosy occurring together with leukemia is rare. Leukemia cutis can also be confused for reactions in leprosy. In our case, immunohistochemistry confirmed the presence of both T cell and B cell markers and thus established the diagnosis of concurrent leukemia cutis and leprosy. The occurrence of leprosy in our patient may be coincidental, but the possibility of reduced immunity leading to reactivation of persister leprosy bacilli should be considered.

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Table 1. Becx-Bleumink criteria a. New skin lesions b. New activity in previously existing skin lesions c. Bacteriological index (BI) 2þ or more in two sets of skin smears d. New nerve function loss e. Histological evidence of relapse in skin or nerve biopsy f. Lepromatous activity in the eye(s)

Conclusion CLL rarely presents with skin lesions as the initial manifestation. In leprosy endemic areas, it is important for dermatologists to recognise the subtle clinical differences between these two entities. When in doubt, investigations like immunohistochemistry prove to be a valuable tool to accurately diagnose and differentiate these two conditions with similar clinical and histological presentation. Further, reduced immunity in leukemia predisposing to relapse of leprosy should be further investigated. Acknowledgements We sincerely thank Dr. Prakash Kumar and Dr. Vardendra Kulkarni, Department of Pathology, JJM Medical college, Davangere and Dr. Sanjay Navani, Surgical pathologist and immunohistochemist, Mumbai for their support. References 1 2 3

4 5 6 7 8 9 10 11 12

Lu C, Li L, Qiao Q et al. Cutaneous Manifestations in a Patient with Chronic Lymphocytic Leukemia Involving the Head, Neck and Distal Extremities. Exper Therap Med, 2015; 9: 877–879. The Leprosy Unit, WHO. Risk of relapse in leprosy. Indian J Lepr, 1995; 67: 13–26. Becx-Bleumink M. Relapses among leprosy patients treated with multidrug therapy: Experience in the leprosy control programme of the All Africa Leprosy and Rehabilitation and Training Centre (ALERT) in Ethiopia; Practical difficulties with diagnosing relapses, operational procedures and criteria for diagnosing relapses. Int J Lepr, 1992; 60: 421– 435. Kaimal S, Thappa DM. Relapse in leprosy. Ind J Dermatol Venereol Leprol, 2009; 75: 126–135. Furuta M, Obara A, Ishida Y et al. Leprosy and malignancy: autopsy findings of 252 leprosy patients. Int J Lepr, 1990; 58: 697–702. Sutjita M, Jenouri G, Holden MD et al. Lepromatous Leprosy in a Patient with B-Cell Lymphoma and Tubulointerstitial Nephritis. Hospital Physician, January, 1999: 51–54. Mahajan N, Rao S, Sobti P et al. Coexisting Anaplastic Large Cell Lymphoma and Lepromatous Leprosy. Lepr Rev, 2012; 83: 104–107. Cho-Vega JH, Medeiros LJ, Prieto VG et al. Leukemia cutis. Am J Clin Pathol, 2008; 129: 130–142. Su WP. Clinical, histopathologic, and immunohistochemical correlations in leukemia cutis. Sem in Dermatol, 1994; 13: 223–230. Cerroni L, Zenahlik P, Kerl H. Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia arising at the site of herpes zoster and herpes simplex scars. Cancer, 1995; 76: 26–31. Ferenczi K, Fuhlbrigge RC, Pinkus J et al. Increased CCR4 expression in cutaneous T cell lymphoma. J Invest Dermatol, 2002; 119: 1405–1410. Singh A, Ramesh V. Histopathological features in leprosy, post-kala-azar dermal leishmaniasis, and cutaneous leishmaniasis. Indian J Dermatol Venereol Leprol, 2013; 79: 360–366.

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SHORT REPORT

Disability aid compliance in people affected by leprosy in urban and rural Maharashtra, India – a need for comprehensive study MARK DAVID BAKER*, VIVEK VASUDEV PAI**, NANDA AJAYAN*** & CHANDRAKANT DHAMALE**** *Nurse Volunteer, Promise Nepal/Bombay Leprosy Project, Mumbai, Maharashtra, India **Director, Bombay Leprosy Project, 11, Vidnyan Bhavan, VN Purav Marg, Sion, Chunabhatti, Mumbai – 400 022, India ***Non Medical Supervisor, Bombay Leprosy Project, 11, Vidnyan Bhavan, VN Purav Marg, Sion - Chunabhatti, Mumbai – 400 022, India ****Voluntary Physiotherapist, Bombay Leprosy Project, 11, Vidnyan Bhavan, VN Purav Marg, Sion - Chunabhatti, Mumbai – 400 022, India Accepted for publication 4 April 2016

Introduction If the predictions of Richardous1 are correct, then leprosy is the biggest cause of preventable disability in India today. Data from the National Leprosy Eradication Programme, (NLEP), also indicates rising numbers of Grade II deformities in newly detected cases since 2005.2 In a recent communication, the draft Leprosy Strategy 2016 to 2020 from the World Health Organisation (WHO) also underlines the need for a global research agenda to reduce the disability burden in communities affected by leprosy.3 Key to this is the assessment of disability aid compliance in such communities, a research topic which unfortunately shows a paucity of up to date and relevant data. As a result we believe that there is a greater need for more research on this subject and hence we present our preliminary findings arising out of a recent assessment in Maharashtra, India. Correspondence to Mark David Baker, Promise Nepal/Bombay Leprosy Project, Mumbai, Maharashtra, India (e-mail: markbaker3433@hotmail.com)

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Materials and Methods As part of leprosy patientsâ&#x20AC;&#x2122; ongoing treatment, monitoring and follow-up, an informal questionnaire was designed to assess disability aid compliance. Patients were interviewed at the Referral centre and satellite clinics of the Bombay Leprosy Project (BLP) operations in both urban and rural locations. For the purpose of this assessment and due to the paucity of information, we defined disability aid compliance as patients who have taken up a disability aid or aids and report whether there was a positive outcome of the intervention. Conversely, patients who reported on non-usage or no positive outcome were classified as non-compliance. Patients were asked how often they used the disability aids, how long the aids were used for and whether they felt they had helped to improve their symptoms. Patients were also asked if they had any difficulties with the disability aids.

Results Seventy interviews were carried out in rural and urban areas with a 3:1 male to female ratio, aged between 15 and 81, with mean age 44 years. The results are based on 64 responders as six people did not answer the questionnaire. Among the patients interviewed a large majority of them (87%), have been affected by leprosy for 3 years or more and 81% of them showed Grade II deformities. The remainder of patients had been affected by leprosy for less than 3 years and had Grade I deformities. The disability and disability aid information collected is summarised in Table 1. Over 90% of patients answered questions relating to frequency and time of aid use, and whether they felt the intervention had improved their functional ability. Overall, 60% reported that this was a positive intervention using the aid during the daytime, (MCR footwear) or once per day for 10 â&#x20AC;&#x201C;20 minutes for FLS, (finger loop splints). Some patients used the FLS for up to three times a day and were generally the younger patients on the assessment. Uniformly, the AD, (abductor band), was used at night during sleep. Some 32% of patients felt there was no improvement in their symptoms and had limited their use of the aid as a result. Many patients reported pain as a limiting factor, especially with FGS, (finger gutter splints), or the fact that the aid was broken, lost or unavailable. Some identified lack of time to use the aid, due to work and family caring commitments. A small number of patients didnâ&#x20AC;&#x2122;t like the aid and preferred to wear normal footwear, had not taken up the treatment even though it was given, or had not requested replacement of damaged or lost disability aids. A small number of patients with multiple deformities reported non-compliance, where their illness had lasted 7 years and less than 6 months; 8% of patients were uncertain about the question or did not answer.

Discussion The majority of patients using disability aids showed good compliance leading to an improvement in their symptoms. This suggests they were committed to self-care and understood the education they were given, correlating with the observations of Joshi and Revankar.4 The 60% compliance rate shows patients reporting with fixed to mobile claw correction and greater hand dexterity or feet free of ulceration and showing foot drop

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Table 1. Disability aid compliance

Disability

No of disabilities reported

Mobile Claw

Plantar Neuropathy Plantar Ulcer Hand Neuropathy/Muscle Atrophy

32 15 8

Claw Toe Fixed Claw Foot Drop Abductor Deformity Chronic Deformity/Surgery

3 3 2 4 8

Disability aid used FLS FGS AB MCR footwear MCR footwear AB FGS FLS MCR FLS FDS AB MCR

No. of Disability aids utilised

Compliance rate (%)

25 4 5 32 15 2 2 5 3 2 1 4 8

60 100 100 62 53 100 0 80 65 100 100 100 62

Note: Many patients reported multiple disabilities and disability aids used. % compliance calculated by the number of disability aids utilised and whether a positive outcome was reported for example, 29 people reported having a mobile claw deformity and 25 reported using a finger loop splint. 60% reported a positive outcome. FLS – Finger Loop Splint; FGS – Finger Gutter Splint; AB – Abductor Band; MCR – Micro-cellular Footwear; FDS – Foot Drop Splint.

improvements. When patients take up the services voluntarily and understand how to use them the result is generally positive - a fact also noted by Ganapati et. al.5 This assessment has also shown that non-compliance in using disability aids remains relatively common, both in rural and urban districts, through all ages and by people new to the disease, or those that have been affected by leprosy for many years. Joshi et al.6 reported a compliance rate of less than 50% in 2000, supporting the 32% non-compliance revealed in this assessment. While this may be due to a lack of patient motivation or difficult personal circumstances, it also shows the need for continued education and training for people affected by leprosy set against a backdrop of structured long-term care management. Ganapati et al.7 indicated that the problem posed by leprosy patients with disabilities is highly challenging and without further research into this issue, we may not know how challenging it may be. However, it is certain that research into disability aid compliance is needed to reduce the rate of non-compliance discovered and to improve the prevention of disability among leprosy affected people. Acknowledgements The authors are grateful to all the patients who participated in the study and are thankful to all the donors for supporting leprosy relief work and research investigations. References 1 2

Richardous JH. Leprosy remains an important public health challenge in India. Ind J Med Res, 2013; 137: 878–879. Available online at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734677 (Accessed 1st October 2014). National Leprosy Elimination Programme, (NLEP). Progress Report 2014–2015, 2014; http://nlep.nic.in/pdf/ Progress%20report%2031st%20March%202014-15%20-pdf (Accessed 11th November 2015).

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World Health Organisation (WHO). Universal Elimination of Leprosy: Towards zero disabilities among new child cases, Plan period: 2016– 2020 (Draft), 2015; downloaded from http://english.aifo.it/leprosy/mailing_list/2015/ 20151108.pdf 20th November 2015. Joshi AN, Revankar CR. Improving compliance of leprosy patients with disabilities for disability care and prevention of disability services. Ind J Lepr, 1998; 70: 39–45. Ganapati R, Pai VV, Kingsley S. Disability prevention and management in leprosy: A field experience. Ind J Dermatol, Venereol and Lepr, 2003; 69: 369 –374. Joshi AN, Kingsley S, Ganapati R, Revenkar CR. Improving Compliance of Leprosy patients for disability care. Proceedings of the Asian Leprosy Conference (Agra), 2000; 203–204. Ganapati R. Community care of the physically disabled due to leprosy. Indian Dermatology Online Journal, 2011; 2: 70 –74. doi: 10.4103/2229-5178.85994 downloaded 11th December 2015.

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LETTER TO THE EDITOR

Prevalence of leprosy-related disability in Bangladesh CYNTHIA RUTH BUTLIN*, KALLYAN KUNDU*, DELWAR HOSSAIN*, SUREN SINGH* & THOMAS STUART WARRENDER* *Rural Health Programmes, DBLM hospital, Notkhana, Nilphmari district, 5300 Bangladesh Accepted for publication 11 April 2016 Summary Disability due to leprosy often lasts lifelong, so estimates of the burden of leprosy in a community based on ‘registered prevalence of leprosy cases’ or on ‘proportion with Grade 2 disability amongst new cases in past year’ will seriously underestimate the number of disabled people in the community needing support or services. In a previously highly endemic are of Bangladesh, the accumulated prevalence of disability due to leprosy amongst adults was 45·35/100,000 population.

Leprosy-related disability is often a life-long problem which may progress over time to a more severe level, and people with disability resulting from leprosy may also have many other health problems. There is little data on community-based cumulative prevalence rates for leprosy-related disability in areas which were recently highly endemic for leprosy. We reviewed (over a 6 month period in 2015) all known leprosy-disabled adults in four districts of North West Bangladesh. In addition to a physical examination to establish current disability level -WHO grade and EyeHandFoot score (EHF) - they were asked about a history of diabetes and had a random blood sugar test done. According to leprosy control unit records, dating back to 1977, there were 4,603 individuals eligible for annual disability follow-up as they had received a full course of anti-leprosy treatment and their WHO grade at RFT was 1 or 2. After deducting 816 who were found to have died, 209 who were not found at home for various reasons, and five who did not wish to be seen, there were 3,753 individuals reviewed (95% eligible people). In our population of 7,878,854 (2015 figure), 3,753 disabled individuals corresponds to a cumulative prevalence rate of 45·35/100,000 (current Disability Grade 1 or 2). Amongst the disabled people assessed in the survey, 62·7% had Grade 2 disability: if only these with current disability Grade 2 are counted, the cumulative prevalence rate is 28·43/100,000. Amongst the leprosy-disabled individuals the average EHF score was 3·2, and 17·9% had EHF . ¼ 6, which represents severe disability. Table 1 Correspondence to C. Ruth Butlin, The Leprosy Mission Bangladesh, Polegate, East Sussex, U.K. (e-mail: drbutlin@yahoo.com)

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All subjects

All ages

All subjects Diagnosed 0 –5 yrs ago Diagnosed 5 – , 10 yrs ago Diagnosed 10 – , 20 yrs ago Diagnosed .20 yrs ago People aged 15 to ,25 yrs People aged 25 to ,50 yrs People aged . ¼ 50 yrs

Table 1. characteristics of leprosy disabled people

3573 317 405 951 1900 37 1115 2421

No. of Subjects 3·26 2·71 2·57 2·88 3·68 2·19 2·81 3·48

Average EHF Score 427 18/317 18/405 72/951 319/1900 1 86 340

Number with EHF .6 12·0% 6% 4% 8% 17% 2·7% 7·7% 14·0%

% with EHF .6

2240 155/317 206/405 546/951 1333/1900 20/37 640/1115 1580/2421

Number with WHO Grade 2

62·7% 49% 51% 57% 70% 54·1% 57·4% 65·3%

% with WHO Grade 2

Prevalence of leprosy-related disability in Bangladesh 265

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Table 2. indicators over past decade

Population covered Registered prevalence rates (reg. cases/10,000 pop) Total new cases found in year Total new cases detection rate/100,000 Total Disability grade 2 proportion among all new cases as %

Range 2005–2014

Average 2005 to 2014

2015

0·65– 1·11 572– 1098 7·70– 16·10 4·91– 16·26%

7273725 0·94 854·2 11·74 8·35%

7878854 0·78 801 10·1 7·9

0·96

0·80

0·64– 1·16

There was a prevalence of diabetes of 4%. In addition, as 35·6% individuals were elderly (. ¼ 60 years) and 3·2% very old (. ¼ 80 years), and their average BMI was low (22·56% had a BMI , ¼ 18), it is likely many of these leprosy-disabled people would have had other chronic long-term health conditions (for which we were not screening on this occasion). In this area lymphatic filariaisis is a common co-morbidity, as is tuberculosis and intestinal helminth infestation. Our calculated prevalence rates will slightly underestimate the true prevalence for two reasons (a) we excluded children from the review, (b) a small number of other people, who have taken anti-leprosy treatment outside the four districts (e.g. while working in a distant city) then returned to live in our catchment area, might also have disability due to leprosy. The prevalence of leprosy-related disability in the community is far higher than one would guess if only considering registered prevalence rates for leprosy (current cases on MDT) or recent data on disability amongst newly detected cases. Table 2. In order to provide adequate services for these disabled people, whether through a specialised organisation or in an integrated way through government general health services, it is necessary to know the size of the problem. We are planning a further study of disability in people who were diagnosed with leprosy as children. Other parts of Bangladesh may have a lower leprosyrelated disability prevalence on account of lower prevalence of leprosy infection in the past. Detailed analysis of data, which is collected at regional/national level for the purpose of routine monitoring of the National Leprosy Elimination Programme, can enable managers to estimate the disability burden in the population covered. When estimating the global disability burden, or when comparing the impact of leprosy with that of other neglected tropical diseases or of non-communicable diseases, using Disability-adjusted life years (DALYs), one should look at cumulative disability prevalence not only at the ‘rate of disability Grade 2 in newly diagnosed leprosy cases per 100,000 population’ (WHO indicator).

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Obituary

Robert Jacobson, M.D., Ph.D. Dr. Robert R. Jacobson age 83, died in Woodstock, GA on December 1, 2015. Dr. Jacobson, known to his friends and colleagues as “Jake,” was a physician and international authority on clinical leprosy. Dr. Jacobson received his undergraduate degree in chemistry from the University of Minnesota, his PH.D. in organic chemistry from the University of Wisconsin and his M.D. from the University of Minnesota. As a commissioned officer in the U.S. Public Health Service’s (U.S.P.H.S.) commissioned corps, he practiced at the Gillis W. Long Hansen’s Disease Center in Carville, LA for 34 years where he served as a staff physician, becoming Chief of the Clinical Branch and rising to Director of the Center. He was an outstanding physician beloved by the hundreds of patients at Carville for his caring expertise and quiet gentle manner. During his career he carried out long term toxicity studies on clofazamine and pioneered work on rifampicin resistance in leprosy, fostering the introduction of this potent bactericidal component into the multi-drug therapy regimen for the disease. He was a member of the World Health Organization THELEP scientific working group and traveled extensively to leprosy endemic areas of the world as a researcher and consultant for WHO, foreign governments and non-government organizations to train and help treat the disease worldwide. Dr. Jacobson loved his work and received numerous commendations from the U.S.P.H.S., including the Meritorious Service, and Distinguished Service Medals. Jake was a cautious and evidence-based researcher. When the 1991 WHO Assembly targeted elimination of leprosy by the year 2000 he was a strong but unsuccessful advocate for reduction in incidence of new cases as a marker of success rather than reduced prevalence of existing cases. As Director of the Center in the 1990s he oversaw the relocation of the Laboratory Research Branch (LRB) from its outmoded labs at Carville to modern facilities in the nearby Louisiana State University School of Veterinary Medicine. When a budgetslashing Congress targeted basic biomedical research as non-essential to patient care at Carville, Jake vigorously supported efforts to maintain the LRB, its multidisciplinary group of investigators and its unique research resources as vital to the Center’s mission. Finally, before retiring in 1999, he oversaw the relocation of the clinical, rehabilitation and training programs from the 105 year old historic site at Carville to a medical center campus in Baton Rouge, where it became the National Hansen’s Disease Programs (NHDP). The remaining 120 elderly residents received either a stipend, were moved to the chronic care facility at 0305-7518/16/064053+02 $1.00

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NHDP or were permitted to remain under assisted living conditions at Carville, now operated by the state of Louisiana. The change was dictated by severe budget constraints and assured the continuance of the program at a new site but it had to be a bittersweet necessity to a man who had spent his entire medical career at Carville. In his retirement years Dr. Jacobson continued to travel, lecture and share his vast knowledge of clinical leprosy. James L. Krahenbuhl, Ph.D. Director, National Hansenâ&#x20AC;&#x2122;s Disease Programs (retired)

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NEWS AND NOTES

19th International Leprosy Congress: Welcome Note Dear Colleagues The International Leprosy Association is glad to announce that the last details are being arranged by the Scientific Committee and the China Organizing Committee to finalize the preparation of the 19th International Leprosy Congress. From September 18 to 20, 2016, Beijing will be the center of leprosy science making the 19th ILC the largest scientific gathering around the world to discuss exciting themes related to the congress moto: Unfinished business: stopping leprosy transmission, preventing disability and promoting inclusion. There will be 2 special presentations; 60 years of leprosy control in China by the Professor Zhang Guocheng and The immune response at the site of infection in leprosy by Robert Modlin (USA). There will be four stimulating Plenary Sessions focused on A Global Strategy for Leprosy Control fit for Purpose, Innovations to reduce transmission, Advances in clinical management of leprosy and Promoting inclusion of people affected by leprosy. A remarkable number of 730 abstracts were submitted. After the peer review 470 abstract were approved for poster presentation and around 260 titles were selected for oral presentation by the Scientific Committee. The presentations will be organized into the following sessions: Best clinical practice, health systems, training and referral, Chemotherapy, Reactions and nerve injury, Dermatology. Ophthalmology. History, Human rights and Discrimination, Social aspects, Participation, Immunology and vaccines, Microbiology, Molecular biology and Genetics, Epidemiology, Leprosy Control, Prevention – prophylaxis, Transmission and diagnostics, Neglected Tropical Diseases and other mycobacterial diseases, Nerve function and impairments, Prevention of disability and Rehabilitation. There will also be 16 Workshops on focused topics such as U-MDT, Diagnostic Tests, GIS and Mapping, Leprosy Control in Francophone Africa, ENL, Discriminatory Legislation, Drug Resistance, Enabling Participation, Data Systems, Leprosy and Migration in the United States, and 3 Symposia from the Leprosy Research Initiative. The International Leprosy Association is one of the oldest scientific associations and its aim is to encourage collaboration between persons of all nationalities concerned in leprosy work; to facilitate the dissemination of knowledge of leprosy and its control and to help in any other practicable manner the fight against the leprosy endemic throughout the world. In this connection, the 19th International Leprosy Congress is being organized to offer opportunities of interaction and live discussion to a variety of participants from many areas involved in the efforts to help those affected by leprosy and in the challenge of preventing further transmission of the disease. You are cordially invited to participate in this exciting congress1. We aim to provide a scientifically stimulating and socially enjoyable forum to meet and discuss results and ideas aiming to achieve world without leprosy related problems. Marcos Virmond ILA President W. Cairns Smith Chair – Scientific Committee 19th ILC Guacheng Zhang President – China Leprosy Association 1

For registration, please, connect to http://ciccst.org.cn/ILC2016/reg.html

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IAL Textbook of Leprosy In the December, 2015 issue we published a review of the new IAL Textbook of Leprosy (Second Edition), edited by Professors Bhushan Kumar and Hemanta Kumar Kar. The book can be obtained directly from the publisher, Jaypee Brothers Medical Publishers (P) Ltd, New Delhi. The following link may be used ,http://www.jaypeebrothers.com/pgDetails.aspx?cat=s&book_id=9789351529910. The book is also available through Amazon.com.

Desautels Faculty of Management, McGill University, 1001 Sherbrooke Street West, Suite 640, Montreal (Quebec), Canada H3A 1G5 Telephone: þ514 398 8811 Fax: þ514 221 4700 Email: info.imhl@mcgill.ca Website: www.mcgill.ca/imhl The International Masters for Health Leadership (IMHL) began in 2006 as part of the quest to become a world leader in health care management education. The IMHL is a collaborative effort of McGill’s Faculty of Medicine and Management that builds upon the two Faculties’ worldwide reputation and acts as an agent of change in health care. “The IMHL is uniquely designed to educate health professionals – physicians, nurses and other allied health workers – to obtain a stronger understanding of modern health care and to develop the advanced management skills needed to deliver quality health care solutions to diverse segments of the public.” (Dr. Abraham Fuks, former Dean, Faculty of Medicine, McGill University and cofounder of the IMHL). Participants hold positions of responsibility in health care; many have a clinical background (physicians, nurses, pharmacists, social workers, psychologists) while some have other backgrounds (hospital administrators/managers, economists, lawyers, etc.). They work in all manner of health organizations (hospitals, community care, public health, government ministries, private sector, international agencies, foundations, others) and in all areas of health - from health promotion, to disease prevention to treatment. They come from all over the world.

Background and Purpose Health systems are in disarray in many parts of the world, including Canada. And they are experiencing monumental changes. The demands in today’s health care environment are such that it appears crucial not only to reinforce the quality and the sustainability of health systems, but also their resilience throughout the transformation process. Health care delivery systems are called upon to offer more quality services, in all circumstances, with enhanced technology, to more patients, at lower costs, and in a sustainable manner. Prioritization is another major issue of health care. As health care is becoming increasingly complex, interactive, and team-oriented, a thorough understanding of the entire continuum – from health promotion, disease prevention to treatment – and of all aspects of delivery, is essential to improve the patient experience. In this regard, the need for increased clinical access, quality care and decreased costs goes hand in hand with the need to acknowledge in all spheres of health care that the patient is not at the ‘centre’ surrounded by external decision-makers, but is rather an integral part, a ‘partner’ in the realm of decision-making.

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Only then can the path to transformation become a truly meaningful one. This transformation dictates that those who have been clinically prepared must have managerial and leadership skills that are learned neither in a traditional classroom nor in most health care organizations. The IMHL pedagogy demands that the learning be applied in real time, between classroom modules, so that managerial practices can be developed and improved during the course of the program. To be true partners, the clinicians must understand the managerial side. The same is true for other stakeholders who are driven by accountability. Few in today’s health care institutions understand the managerial side, and too few managers fully appreciate the needs of the providers. For the type of collaboration that is required to confront the future, it is a minimum imperative that all must extend themselves to learn the trade of the others. Future leaders must appreciate the nature of their health systems if they are to succeed in transforming them to serve emerging needs. The program encourages participants to share their experiences, delving into each other’s issues to provide innovative solutions to the challenges they face in their respective work environments. Our participants report increased confidence in undertaking challenges they previously found daunting. This is achieved through five modules in which participants explore different aspects of health care leadership and management: reflection, analysis, worldly perspectives, collaboration and change. These are the managerial mindsets upon which our program’s pedagogy is built.

Structure of the Program While modular in delivery, the program is full-time with regard to what is expected between and among the five classroom modules. The program features academics and practitioners from Management, Medicine, Political Science and other fields from the University, as well as universities and organizations around the world. The Faculty use a large range of teaching and learning methods to maximize the experience and transfer of skills, as well as to ensure a meaningful and sustainable impact for the individual, organization and greater community. The formal evaluation throughout the program is based on the reflection papers written between modules as well as on the final master’s paper, the latter of which reflects the conceptual material from the modules, the direct application to the participant’s work, and an indication of the impact pursued between modules. The final paper is a research-based paper with a required literature review. Presented in a modular format, the IMHL provides participants with an unparalleled opportunity to draw on personal experience in putting theory into practice, developing a far deeper understanding of health challenges and concrete solutions to them. The fundamental assumption of the IMHL program is that leadership in the complex health system requires the ability to transform people, organizations, systems and their contexts. Accordingly, the IMHL is built around five 12-day “managerial mindsets” over 15 months aimed at exploring the possibilities of transformation within different realms of management: 1. 2. 3. 4. 5.

The The The The The

Reflective Mindset – Broadening Perspectives and Managing Self Analytic Mindset – Leading and Managing Organizations Worldly Mindset – Navigating the System and Managing Context Collaborative Mindset – Appreciating and Managing Work Relationships Catalytic Mindset – Achieving and Managing Change

Between modules, participants return to the workplace where they apply the pedagogy and insights of the program to practice. They also write their reflection papers between modules where they bring the learning to their own practices and use the program’s frameworks and theories to create impact.

Module 1: The Reflective Mindset – Broadening Perspectives and Managing Self The Reflective Mindset is designed to help participants gain a better understanding of their personal management style - how they present themselves to others, their strengths and weaknesses, and their

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current leadership skills. Participants learn how to be thoughtful and reflective, to step back from always doing, to see familiar experiences from a new perspective. This, in turn, fosters innovation and change, rather than repeating similar patterns and mistakes. Some areas of focus in the Reflective Mindset are: the nature of managerial work, leadership, management styles, ethical practices and the power of daily reflection.

Module 2: The Analytic Mindset – Leading and Managing Organizations The Analytic Mindset provides an overview of today’s principal health care organizations including health promoting hospitals, community agencies, health maintenance organizations, etc. Participants gain insight into the operation of these organizations by analyzing their intrinsic similarities and differences. Participants are also introduced to the analytical tools used to manage specific organizations and to formal approaches that improve managerial effectiveness. Key concepts in financial management, operations management, and organizational strategy stimulate participants to diagnose the strengths and weaknesses of their own organization. Strategy, structure, sourcing and delivery are explored in a systematic way that allows participants to view the managing process as a melding of science, art and craft. Discussions are reinforced by field studies at the many health sector institutions available in the Montreal area. In the Analytic Mindset we explore the strengths and limitations of analysis in organizations through new perspectives on analytical tools, going beyond quantitative data (the yin and the yang of analysis), new approaches to decision-making, how to avoid paralysis by analysis, and how to consider complex issues.

Module 3: The Worldly Mindset – Navigating the System and Managing Context The delivery of health care is rooted within highly complex systems that vary enormously across the world - from fully socialized to market-driven. Yet every system struggles with where it should sit on this continuum. Because most practitioners - whether managers or clinicians - typically spend their careers within a single system, they rarely have the opportunity to appreciate the alternatives. Managers need to develop the cultural and social insights essential to operating in diverse regions, serving varied customer segments, partnering with other organizations. The third module focuses on these contextual “systems”, exploring the various social institutions within the health care field and their interactions with economic, political and social forces. The goal is to increase understanding of the dynamics of “system change”. Participants are encouraged to seek creative solutions based on an integrated, rather than a fragmented understanding of health care. Participants also explore in greater depth the interactions between economics and health, and the possibilities for leveraging change within complex systems. In the Worldly Mindset we explore looking outward, to see inward, values, habits, and cultures in other systems, managing context, economic and financial aspects of health systems in other parts of the world.

Module 4: The Collaborative Mindset – Appreciating and Managing Work Relationships In this module, participants focus on managing relationships with patients, professionals, health advocates, administrators, the government, the media and many other groups. Skill development includes collaborative relationship building, negotiation, stakeholder coordination, and knowledge management. The managing of professional relationships is emphasized, with participants developing the advanced skills necessary to build and lead complex networks rather than simple organizations. The integration of knowledge from multiple disciplines and perspectives is also examined. Effective

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managers manage, not from the top down, but from within. They create the environment and attitudes that encourage teamwork. In the Collaborative Mindset we explore: collaborative arrangements at the intra-firm, inter-firm, and societal levels, identifying the requirements and implications of effective collaboration, managing teams, strategic alliances, and juxtaposing competition, collaboration, compromise, avoidance and accommodation, all with a focus on conflict.

Module 5: The Catalytic Mindset – Achieving and Managing Change The final module is action-focused, integrative in nature, focusing on the achievement of change. The impact initiatives on which participants have worked throughout the program are given considerable attention. Successful health management cases are reviewed and the action implications of adaptive management are explored. Other key areas of study include: integrated and sustainable approach to health, the notion of prevention and its applied dissemination, effective intervention within the policy environment, positive/negative outcomes of media exposure in health policy, and the notions of evaluation and accountability. Participants integrate and synthesize the knowledge they have acquired during the preceding modules. The program closes with in-depth consideration of the process of transformation leadership and what it means to lead comprehensively, analytically, collaboratively, contextually, catalytically and reflectively. A key principle of the program is “use work, don’t make work”. Participants bring their actual work challenges to the program, rather than using more traditional case studies and theory. Experienced managers not only enjoy delving into each other’s issues, but also prove especially adept at doing so in a way that provides innovative solutions and strategies to the challenges they face in their own work. Throughout the program we encourage the application to practice of the concepts, theories and frameworks used in the classroom. In many organizations, our participants form teams so that the learning can be shared in the context of embracing challenges. Participants are supported and challenged throughout the program by internationally renowned faculty from Management, Medicine, Political Science and other faculties and departments at McGill, as well as from universities and organizations around the world. We have an excellent mix of academic and professional faculty, all with the experience of teaching using our pedagogical approach. For further information and application forms, please e-mail: info.imhl@mcgill.ca or visit the website: www.mcgill.ca/imhl