Methotrexate and prednisolone study in erythema nodosum leprosum (MaPs in ENL) protocol: a double-blind randomised clinical trial.

INTRODUCTION: Erythema nodosum leprosum (ENL) is an immunological complication of leprosy. ENL results in morbidity and disability and if it is not treated can lead to death. The current treatment consists of thalidomide or high doses of oral corticosteroids for prolonged periods. Thalidomide is not available in many leprosy endemic countries. The use of corticosteroids is associated with morbidity and mortality. Identifying treatment regimens that reduce the use of corticosteroids in ENL is essential. Methotrexate (MTX) is used to treat many inflammatory diseases and has been used successfully to treat patients with ENL not controlled by other drugs, including prednisolone and thalidomide. We present the protocol of the 'MTX and prednisolone study in ENL' (MaPs in ENL) a randomised controlled trial (RCT) designed to test the efficacy of MTX in the management of ENL. METHODS AND ANALYSIS: MaPs in ENL is an international multicentre RCT, which will be conducted in leprosy referral centres in Bangladesh, Brazil, Ethiopia, India, Indonesia and Nepal. Patients diagnosed with ENL who consent to participate will be randomly allocated to receive 48 weeks of weekly oral MTX plus 20 weeks of prednisolone or 48 weeks of placebo plus 20 weeks of prednisolone. Participants will be stratified by type of ENL into those with acute ENL and those with chronic and recurrent ENL. The primary objective is to determine whether MTX reduces the requirement for additional prednisolone. Patients' reported outcome measures will be used to assess the efficacy of MTX. Participants will be closely monitored for adverse events. ETHICS AND DISSEMINATION: Results will be submitted for publication in peer-reviewed journals. Ethical approval was obtained from the Observational/Interventions Research Ethics Committee of the London School of Hygiene & Tropical Medicine (15762); The Leprosy Mission International Bangladesh Institutional Research Board (in process); AHRI-ALERT Ethical Review Committee, Ethiopia; Ethics Committee of the Managing Committee of the Bombay Leprosy Project; and The Leprosy Mission Trust India Ethics Committee; the Nepal Health and Research Council and Health Research Ethics Committee Dr. Soetomo, Indonesia. This study is registered at www.clinicaltrials.gov. This is the first RCT of MTX for ENL and will contribute to the evidence for the management of ENL.Trial registration numberNCT 03775460.

A leprosy clinical severity scale for erythema nodosum leprosum: An international, multicentre validation study of the ENLIST ENL Severity Scale.

OBJECTIVES: We wished to validate our recently devised 16-item ENLIST ENL Severity Scale, a clinical tool for measuring the severity of the serious leprosy associated complication of erythema nodosum leprosum (ENL). We also wished to assess the responsiveness of the ENLIST ENL Severity Scale in detecting clinical change in patients with ENL. METHODS: Participants, recruited from seven centres in six leprosy endemic countries, were assessed using the ENLIST ENL Severity Scale by two researchers, one of whom categorised the severity of ENL. At a subsequent visit a further assessment using the scale was made and both participant and physician rated the change in ENL using the subjective categories of "Much better", "somewhat better", "somewhat worse" and "much worse" compared with "No change" or "about the same". RESULTS: 447 participants were assessed with the ENLIST ENL Severity Scale. The Cronbach alpha of the scale and each item was calculated to determine the internal consistency of the scale. The ENLIST ENL Severity Scale had good internal consistency and this improved following removal of six items to give a Cronbach's alpha of 0.77. The cut off between mild ENL and more severe disease was 9 determined using ROC curves. The minimal important difference of the scale was determined to be 5 using both participant and physician ratings of change. CONCLUSIONS: The 10-item ENLIST ENL Severity Scale is the first valid, reliable and responsive measure of ENL severity and improves our ability to assess and compare patients and their treatments in this severe and difficult to manage complication of leprosy. The ENLIST ENL Severity Scale will assist physicians in the monitoring and treatment of patients with ENL. The ENLIST ENL Severity Scale is easy to apply and will be useful as an outcome measure in treatment studies and enable the standardisation of other clinical and laboratory ENL research.

Corticosteroids for treating nerve damage in leprosy.

BACKGROUND: Leprosy causes nerve damage that can result in nerve function impairment and disability. Corticosteroids are commonly used for treating nerve damage, although their long-term effect is uncertain. This is an update of a review first published in 2007, and previously updated in 2009 and 2011. OBJECTIVES: To assess the effects of corticosteroids on nerve damage in leprosy. SEARCH METHODS: On 16 June 2015, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL Plus, and LILACS. We also checked clinical trials registers and contacted trial authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of corticosteroids for nerve damage in leprosy. The comparators were no treatment, placebo treatment, or a different corticosteroid regimen. DATA COLLECTION AND ANALYSIS: The primary outcome was improvement in nerve function after one year. Secondary outcomes were change in nerve pain, limitations in activities of daily living, limitations in participation, and adverse events. Two review authors independently extracted data and assessed trial quality. When data were lacking, we contacted trial authors for additional information. MAIN RESULTS: We included five RCTs involving 576 people. The trials were largely at low risk of bias, but we considered the quality of the evidence from these trials as moderate to low, largely due to imprecision from small sample sizes. Two out of the five trials reported on improvement in nerve function at one year. These two trials compared prednisolone with placebo. One trial, with 84 participants, treated mild sensory impairment of less than six months' duration, and the other, with 95 participants, treated nerve function impairment of 6 to 24 months' duration. There was no significant difference in nerve function improvement after 12 months between people treated with prednisolone and those treated with placebo. Adverse events were not reported significantly more often with corticosteroids than with placebo. The other three trials did not report on the primary outcome measure. One (334 participants) compared three corticosteroid regimens for severe type 1 reactions. No serious side effects of steroids were reported in any participant during the follow-up period. Another trial (21 participants) compared low-dose prednisone with high-dose prednisone for ulnar neuropathy. Two participants on the higher dose of prednisone reported adverse effects. The last (42 participants) compared intravenous methylprednisolone and oral prednisolone with intravenous normal saline and oral prednisolone. The trial found no significant differences between the groups in the occurrence of adverse events. AUTHORS' CONCLUSIONS: Corticosteroids are used for treating acute nerve damage in leprosy, but moderate-quality evidence from two RCTs treating either longstanding or mild nerve function impairment did not show corticosteroids to have a superior effect to placebo on nerve function improvement. A third trial showed significant benefit from a five-month steroid regimen over a three-month regimen in terms of response to treatment (need for additional corticosteroids). Further RCTs are needed to establish optimal corticosteroid regimens and to examine the efficacy and safety of adjuvant or new therapies for treating nerve damage in leprosy. Future trials should address non-clinical aspects, such as costs and impact on quality of life, which are highly relevant indicators for both policymakers and participants.

Comparison of Efficacy and Safety of Ciclosporin to Prednisolone in the Treatment of Erythema Nodosum Leprosum: Two Randomised, Double Blind, Controlled Pilot Studies in Ethiopia.

BACKGROUND: Erythema Nodosum Leprosum (ENL) is a serious complication of leprosy. It is normally treated with high dose steroids, but its recurrent nature leads to prolonged steroid usage and associated side effects. There is little evidence on the efficacy of alternative treatments for ENL, especially for patients who have become steroid resistant or have steroid side effects. These two pilot studies compare the efficacy and side effect profile of ciclosporin plus prednisolone against prednisolone alone in the treatment of patients with either new ENL or chronic and recurrent ENL. METHODS AND RESULTS: Thirteen patients with new ENL and twenty patients with chronic ENL were recruited into two double-blinded randomised controlled trials. Patients were randomised to receive ciclosporin and prednisolone or prednisolone treatment only. Patients with acute ENL had a delay of 16 weeks in the occurrence of ENL flare-up episode, with less severe flare-ups and decreased requirements for additional prednisolone. Patients with chronic ENL on ciclosporin had the first episode of ENL flare-up 4 weeks earlier than those on prednisolone, as well as more severe ENL flare-ups requiring 2.5 times more additional prednisolone. Adverse events attributable to prednisolone were more common that those attributable to ciclosporin. CONCLUSIONS: This is the first clinical trial on ENL management set in the African context, and also the first trial in leprosy to use patients' assessment of outcomes. Patients on ciclosporin showed promising results in the management of acute ENL in this small pilot study. But ciclosporin, did not appear to have a significant steroid-sparing effects in patients with chronic ENL, which may have been due to the prolonged use of steroids in these patients in combination with a too rapid decrease of steroids in patients given ciclosporin. Further research is needed to determine whether the promising results of ciclosporin in acute ENL can be reproduced on a larger scale.

ENLIST 1: An International Multi-centre Cross-sectional Study of the Clinical Features of Erythema Nodosum Leprosum.

Erythema nodosum leprosum (ENL) is a severe multisystem immune mediated complication of borderline lepromatous leprosy and lepromatous leprosy. ENL is associated with skin lesions, neuritis, arthritis, dactylitis, eye inflammation, osteitis, orchitis, lymphadenitis and nephritis. The treatment of ENL requires immunosuppression, which is often required for prolonged periods of time and may lead to serious adverse effects. ENL and its treatment is associated with increased mortality and economic hardship. Improved, evidence-based treatments for ENL are needed; however, defining the severity of ENL and outcome measures for treatment studies is difficult because of the multiple organ systems involved. A cross-sectional study was performed, by the members of the Erythema Nodosum Leprosum International STudy (ENLIST) Group, of patients with ENL attending seven leprosy referral centres in Brazil, Ethiopia, India, Nepal, the Philippines and the United Kingdom. We systematically documented the clinical features and type of ENL, its severity and the drugs used to treat it. Patients with chronic ENL were more likely to be assessed as having severe ENL. Pain, the most frequent symptom, assessed using a semi-quantitative scale was significantly worse in individuals with "severe" ENL. Our findings will determine the items to be included in a severity scale of ENL which we are developing and validating. The study also provides data on the clinical features of ENL, which can be incorporated into a definition of ENL and used for outcome measures in treatment studies.

Outcomes after unplanned admission to hospital in older people: ill-defined conditions as potential indicators of the frailty trajectory.

OBJECTIVES: To describe outcomes after unplanned hospital admission in older people and to determine whether disease trajectories in those admitted with ill-defined conditions (symptoms and signs) are distinct from other diagnostic groups and consistent with known disease trajectories. DESIGN: Longitudinal follow-up after a retrospective cross-sectional study of emergency admissions to general internal and geriatric medicine units in one hospital. SETTING: Acute hospital in southern England. PARTICIPANTS: All people aged 65 and older with unplanned admissions to general internal and geriatric medicine inpatient units during 2002 (N = 5,312). MEASUREMENTS: Age, sex, comorbidity, presence of cognitive and mood disorders, residence, and primary diagnostic group at discharge. Outcomes were death up to 36 months from admission, any readmission, and readmission for ill-defined conditions up to 36 months after discharge. RESULTS: There were significant differences in death rates between the diagnostic groups, with mortality being highest in individuals with a primary diagnosis of cancer and lowest in the ill-defined conditions group. Nearly 83% of the ill-defined conditions group survived the follow-up period. Adjusted Cox proportional hazard models indicated that, when age, sex, comorbidity, residence, and cognitive and mood disorders were accounted for, the ill-defined condition group had a lower risk of death but a higher risk of subsequent readmissions for ill-defined conditions than any other group. Overall readmission risk was highest for individuals admitted for a respiratory condition but was similar in all other diagnostic groups. CONCLUSION: The lower mortality risk associated with ill-defined conditions is consistent with chronic rather than acute needs, but the pattern of mortality and readmission is more consistent with the frailty than the chronic organ system failure illness trajectory, suggesting that functional support needs may be more important in this group of individuals.

A comparison of the change in clinical severity scale score and a retrospective physician assessment of neurological outcome in individuals with leprosy associated nerve function impairment after treatment with corticosteroids.

OBJECTIVES: To determine whether the measured change in score of a validated clinical severity scale reflected physician assessed improvement in individuals who had received corticosteroid therapy for leprosy associated nerve damage. DESIGN: Patients with nerve function impairment who participated in a randomised controlled trial of corticosteroids were classified into two groups using a retrospectively determined physician assessment of improvement. One group consisted of patients who had recovered or improved the other of patients who were unchanged or had deteriorated. The change in the clinical severity scale scores of these two groups was compared. RESULTS: The change in the clinical severity scale scores of the 34 eligible individuals in the two groups were significantly different (P = 0.003). Individuals in the group who recovered or improved had a greater change in severity score than those whose nerve function was unchanged or deteriorated. CONCLUSION: The scale for measuring the severity of leprosy Type 1 reactions (T1Rs) and/or nerve function impairment reflects the clinical improvement of individuals with leprosy associated nerve damage.

Effectiveness of mindfulness-based stress reduction in mood, breast- and endocrine-related quality of life, and well-being in stage 0 to III breast cancer: a randomized, controlled trial.

PURPOSE: To assess the effectiveness of mindfulness-based stress reduction (MBSR) for mood, breast- and endocrine-specific quality of life, and well-being after hospital treatment in women with stage 0 to III breast cancer. PATIENTS AND METHODS: A randomized, wait-listed, controlled trial was carried out in 229 women after surgery, chemotherapy, and radiotherapy for breast cancer. Patients were randomly assigned to the 8-week MBSR program or standard care. Profile of Mood States (POMS; primary outcome), Functional Assessment of Cancer Therapy-Breast (FACT-B), Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) scales and the WHO five-item well-being questionnaire (WHO-5) evaluated mood, quality of life, and well-being at weeks 0, 8, and 12. For each outcome measure, a repeated-measures analysis of variance model, which incorporated week 0 measurements as a covariate, was used to compare treatment groups at 8 and 12 weeks. RESULTS: There were statistically significant improvements in outcome in the experimental group compared with control group at both 8 and 12 weeks (except as indicated) for POMS total mood disturbance (and its subscales of anxiety, depression [8 weeks only], anger [12 weeks only], vigor, fatigue, and confusion [8 weeks only]), FACT-B, FACT-ES, (and Functional Assessment of Cancer Therapy subscales of physical, social [8 weeks only], emotional, and functional well-being), and WHO-5. CONCLUSION: MSBR improved mood, breast- and endocrine-related quality of life, and well-being more effectively than standard care in women with stage 0 to III breast cancer, and these results persisted at three months. To our knowledge, this study provided novel evidence that MBSR can help alleviate long-term emotional and physical adverse effects of medical treatments, including endocrine treatments. MBSR is recommended to support survivors of breast cancer.

Features and outcomes of unplanned hospital admissions of older people due to ill-defined (R-coded) conditions: retrospective analysis of hospital admissions data in England.

BACKGROUND: Rising rates of unplanned admissions among older people are placing unprecedented demand on health services internationally. Unplanned hospital admissions for ill-defined conditions (coded with an R prefix within Chapter XVIII of the International Classification of Diseases-10) have been targeted for admission avoidance strategies, but little is known about these admissions. The aim of this study was to determine the incidence and factors predicting ill-defined (R-coded) hospital admissions of older people and their association with health outcomes. METHODS: Retrospective analysis of unplanned hospital admissions to general internal and geriatric medicine wards in one hospital over 12 months (2002) with follow-up for 36 months. The study was carried out in an acute teaching hospital in England. The participants were all people aged 65 and over with unplanned hospital admissions to general internal and geriatric medicine. Independent variables included time of admission, residence at admission, route of admission to hospital, age, gender, comorbidity measured by count of diagnoses. Main outcome measures were primary diagnosis (ill-defined versus other diagnostic code), death during the hospital stay, deaths to 36 months, readmissions within 36 months, discharge destination and length of hospital stay. RESULTS: Incidence of R-codes at discharge was 21.6%, but was higher in general internal than geriatric medicine (25.6% v 14.1% respectively). Age, gender and co-morbidity were not significant predictors of R-code diagnoses. Admission via the emergency department (ED), out of normal general practitioner (GP) hours, under the care of general medicine and from non-residential care settings increased the risk of receiving R-codes. R-coded patients had a significantly shorter length of stay (5.91 days difference, 95% CI 4.47, 7.35), were less likely to die (hazard ratio 0.71, 95%CI 0.59, 0.85) at any point, but were as likely to be readmitted as other patients (hazard ratio 0.96 (95% CI 0.88, 1.05). CONCLUSIONS: R-coded diagnoses accounted for 1/5 of emergency admission episodes, higher than anticipated from total English hospital admissions, but comparable with rates reported in similar settings in other countries. Unexpectedly, age did not predict R-coded diagnosis at discharge. Lower mortality and length of stay support the view that these are avoidable admissions, but readmission rates particularly for further R-coded admissions indicate on-going health care needs. Patient characteristics did not predict R-coding, but organisational features, particularly admission via the ED, out of normal GP hours and via general internal medicine, were important and may offer opportunity for admission reduction strategies.

A phase two randomised controlled double blind trial of high dose intravenous methylprednisolone and oral prednisolone versus intravenous normal saline and oral prednisolone in individuals with leprosy type 1 reactions and/or nerve function impairment.

BACKGROUND: Leprosy Type 1 reactions are a major cause of nerve damage and the preventable disability that results. Type 1 reactions are treated with oral corticosteroids and there are few data to support the optimal dose and duration of treatment. Type 1 reactions have a Th1 immune profile: cells in cutaneous and neural lesions expressing interferon-γ and interleukin-12. Methylprednisolone has been used in other Th1 mediated diseases such as rheumatoid arthritis in an attempt to switch off the immune response and so we investigated the efficacy of three days of high dose (1 g) intravenous methylprednisolone at the start of prednisolone therapy in leprosy Type 1 reactions and nerve function impairment. RESULTS: Forty-two individuals were randomised to receive methylprednisolone followed by oral prednisolone (n = 20) or oral prednisolone alone (n = 22). There were no significant differences in the rate of adverse events or clinical improvement at the completion of the study. However individuals treated with methylprednisolone were less likely than those treated with prednisolone alone to experience deterioration in sensory function between day 29 and day 113 of the study. The study also demonstrated that 50% of individuals with Type 1 reactions and/or nerve function impairment required additional prednisolone despite treatment with 16 weeks of corticosteroids. CONCLUSIONS: The study lends further support to the use of more prolonged courses of corticosteroid to treat Type 1 reactions and the investigation of risk factors for the recurrence of Type 1 reaction and nerve function impairment during and after a corticosteroid treatment. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN31894035.

Analysis of antibody and cytokine markers for leprosy nerve damage and reactions in the INFIR cohort in India.

BACKGROUND: The ILEP Nerve Function Impairment in Reaction (INFIR) is a cohort study designed to identify predictors of reactions and nerve function impairment (NFI) in leprosy. AIM OF THE STUDY: Antibodies to mycobacteria, nerve components and serum cytokine were measured as potential markers for their possible association with reactions and NFI. PATIENTS AND METHODS: 303 newly diagnosed leprosy patients from two centres in North India were enrolled. Antibodies to PGL-1, LAM (IgG1 and IgG3), ceramide, S100 and TNFα levels were measured using ELISA techniques. RESULTS: S-100, PGL IgG and IgM antibody levels were lowest in patients with BT leprosy and highest in patients with lepromatous leprosy. LAM IgG1 and LAM IgG3 antibody levels were highest in patients with BL leprosy. Ceramide antibody levels were not correlated with type of leprosy. Levels of all the antibodies tested and TNF α were lowest in patients with only skin reaction. PGL IgM antibody levels were elevated in patients with skin reactions and NFI. Old sensory NFI is associated with significant elevation of PGL IgG, LAM IgG and S100 antibody levels. CONCLUSION: These results reveal that the antibody response to mycobacterial antigens, nerve antigens and cytokines are in a dynamic flux and could collectively contribute to NFI in leprosy. The association of multiple markers with old NFI may indicate the contribution of different pathological processes.

Predicting neuropathy and reactions in leprosy at diagnosis and before incident events-results from the INFIR cohort study.

BACKGROUND: Leprosy is a disease of skin and peripheral nerves. The process of nerve injury occurs gradually through the course of the disease as well as acutely in association with reactions. The INFIR (ILEP Nerve Function Impairment and Reactions) Cohort was established to identify clinically relevant neurological and immunological predictors for nerve injury and reactions. METHODOLOGY/PRINCIPAL FINDINGS: The study, in two centres in India, recruited 188 new, previously untreated patients with multi-bacillary leprosy who had no recent nerve damage. These patients underwent a series of novel blood tests and nerve function testing including motor and sensory nerve conduction, warm and cold detection thresholds, vibrometry, dynamometry, monofilament sensory testing and voluntary muscle testing at diagnosis and at monthly follow up for the first year and every second month for the second year. During the 2 year follow up a total of 74 incident events were detected. Sub-clinical changes to nerve function at diagnosis and during follow-up predicted these new nerve events. Serological assays at baseline and immediately before an event were not predictive; however, change in TNF alpha before an event was a statistically significant predictor of that event. CONCLUSIONS/SIGNIFICANCE: These findings increase our understanding of the processes of nerve damage in leprosy showing that nerve function impairment is more widespread than previously appreciated. Any nerve involvement, including sub-clinical changes, is predictive of further nerve function impairment. These new factors could be used to identify patients at high risk of developing impairment and disability.

Development and validation of a severity scale for leprosy type 1 reactions.

OBJECTIVES: To develop a valid and reliable quantitative measure of leprosy Type 1 reactions. METHODS: A scale was developed from previous scales which had not been validated. The face and content validity were assessed following consultation with recognised experts in the field. The construct validity was determined by applying the scale to patients in Bangladesh and Brazil who had been diagnosed with leprosy Type 1 reaction. An expert categorized each patient's reaction as mild or moderate or severe. Another worker applied the scale. This was done independently. In a subsequent stage of the study the agreement between two observers was assessed. RESULTS: The scale had good internal consistency demonstrated by a Cronbach's alpha >0.8. Removal of three items from the original scale resulted in better discrimination between disease severity categories. Cut off points for Type 1 reaction severities were determined using Receiver Operating Characteristic curves. A mild Type 1 reaction is characterized using the final scale by a score of 4 or less. A moderate reaction is a score of between 4.5 and 8.5. A severe reaction is a score of 9 or more. CONCLUSIONS: We have developed a valid and reliable tool for quantifying leprosy Type 1 reaction severity and believe this will be a useful tool in research of this condition, in observational and intervention studies, and in the comparison of clinical and laboratory parameters.

Voluntary muscle testing and dynamometry in diagnosis of motor impairment in leprosy: a comparative study within the INFIR Cohort Study.

AIM: To evaluate hand muscle weakness detected through dynamometry as an indicator for change in motor nerve function detected by Voluntary Muscle Testing (VMT) of ulnar and median nerves. DESIGN: The research was carried out as part of the INFIR Cohort Study among 303 subjects newly diagnosed with MB leprosy in two centres in UP state, northern India. METHODS: To assess grip strength, key pinch and pulp-to-pulp pinch we adapted the cuffs of adult and neonatal sphygmomanometers. The testing was carried out at diagnosis and at each visit during a 2-year follow-up. RESULTS: 303 subjects with newly diagnosed MB leprosy were included in the study. We found statistically significant differences in grip strength, key pinch and pulp-to-pulp pinch between groups defined by ulnar VMT grades at time of diagnosis. There was also a statistically significant difference in hand grip between groups defined by median VMT at diagnosis. In each case, strength tended to reduce with increasing motor involvement. We explored reduction in grip strength, key pinch or pulp-to-pulp pinch as indicators of change in ulnar VMT during follow-up. A 25% reduction over two visits was the most effective indicator. Changes were also associated with marginal changes in motor and sensory nerve function, most commonly associated with Type I reactions. CONCLUSION: Dynamometry is recommended as an additional method that may be used to monitor changes in nerve function in leprosy, particularly in subjects with early motor impairment of the ulnar nerve.

Early diagnosis of neuropathy in leprosy--comparing diagnostic tests in a large prospective study (the INFIR cohort study).

BACKGROUND: Leprosy is the most frequent treatable neuromuscular disease. Yet, every year, thousands of patients develop permanent peripheral nerve damage as a result of leprosy. Since early detection and treatment of neuropathy in leprosy has strong preventive potential, we conducted a cohort study to determine which test detects this neuropathy earliest. METHODS AND FINDINGS: One hundred and eighty-eight multibacillary (MB) leprosy patients were selected from a cohort of 303 and followed for 2 years after diagnosis. Nerve function was evaluated at each visit using nerve conduction (NC), quantitative thermal sensory testing and vibrometry, dynamometry, monofilament testing (MFT), and voluntary muscle testing (VMT). Study outcomes were sensory and motor impairment detected by MFT or VMT. Seventy-four of 188 patients (39%) had a reaction, neuritis, or new nerve function impairment (NFI) event during a 2-year follow-up. Sub-clinical neuropathy was extensive (20%-50%), even in patients who did not develop an outcome event. Sensory nerve action potential (SNAP) amplitudes, compound motor action potential (CMAP) velocities, and warm detection thresholds (WDT) were most frequently affected, with SNAP impairment frequencies ranging from 30% (median) to 69% (sural). Velocity was impaired in up to 43% of motor nerves. WDTs were more frequently affected than cold detection thresholds (29% versus 13%, ulnar nerve). Impairment of SNC and warm perception often preceded deterioration in MF or VMT scores by 12 weeks or more. CONCLUSIONS: A large proportion of leprosy patients have subclinical neuropathy that was not evident when only MFT and VMT were used. SNC was the most frequently and earliest affected test, closely followed by WDT. They are promising tests for improving early detection of neuropathy, as they often became abnormal 12 weeks or more before an abnormal monofilament test. Changes in MFT and VMT score mirrored changes in neurophysiology, confirming their validity as screening tests.

Corticosteroids for treating nerve damage in leprosy. A Cochrane review.

OBJECTIVE: Corticosteroids are commonly used for treating nerve damage in leprosy. We assessed the effectiveness of corticosteroids for treating nerve damage due to leprosy. METHODS: A systematic search was undertaken to identify randomised controlled trials (RCTs) comparing corticosteroids with placebo or with no treatment. Two authors independently assessed quality and extracted data. Where it was not possible to perform a meta-analysis, the data for each trial was summarised. RESULTS: Three RCTs involving 513 people were found. Two trials compared prednisolone with placebo. One trial treated mild sensory impairment of less than 6 months duration and the other trial treated nerve function impairment of 6 to 24 months duration. Both trials examined nerve function improvement 12 months from the start of treatment, but found no significant difference between the two groups. The third trial compared three corticosteroid regimens for severe type 1 reactions. After 12 months, a significantly higher proportion of individuals on a 3 month course required extra corticosteroids compared to the groups with a high-dose and low-dose regimen of 5 months duration. Diabetes and peptic or infected ulcers were not significantly more often reported in the corticosteroid compared to the placebo group. CONCLUSIONS: Evidence from RCTs does not show a significant long-term effect for either long-standing nerve function impairment or mild sensory impairment. A 5 month corticosteroid regimen was significantly more beneficial than a 3 month corticosteroid regimen. Further RCTs are needed to establish the effectiveness and optimal regimens of corticosteroids and to examine new therapies.

Ensuring inter-tester reliability of voluntary muscle and monofilament sensory testing in the INFIR Cohort Study.

OBJECTIVE: To assess the reliability of monofilament (MF) and voluntary muscle strength (VMT) testing carried out by nine physiotherapy staff recruited for the ILEP Nerve Function Impairment & Reaction (INFIR) Cohort Study in India. DESIGN: A multiple pair inter-tester reliability study was carried out in Uttar Pradesh, India. Newly trained testers were paired up with an experienced physiotherapist, whose assessment served as the gold standard. Each pair completed a series of assessments. All testers had undertaken a week of specific VMT and MF training, followed by a month of practice in the hospital setting. Reliability was assessed by calculating weighted Kappa (Kw) statistics, which may be interpreted as the chance-corrected proportion of agreement between testers. RESULTS: Eight newly-trained physiotherapists and one physiotechnician took part in the study. In the early stages of the study some areas of weak agreement were identified and correct assessment technique was reviewed, particularly for the eye. Good to very good reliability (Kw 0.62 to 0.99) was found for all sensory tests and most muscle strength tests. The only lower Kw scores (0-48 to 0-59, suggesting only moderate reliability) were for the VMT of muscles supplied by the median nerve in one of the study's two field centres. Even in this case, testers never varied by more than one grade, but calculation of Kw was negatively influenced by a lack of variation among the subjects. In addition, testers never varied by more than one grade from the gold standard. CONCLUSION: Even though all testers were professionally trained and received additional specific training and practice in MF and VMT testing, discrepancies in technique required an early review and correction. This fact highlights the need for careful training and formal reliability testing. This should extend to referral centres where staff are involved in assessing the symptoms of reaction and monitoring response to treatment. Reliability testing provides the opportunity to address important discrepancies in technique that may persist even in the presence of protocols and qualified and trained staff. It is therefore a valuable tool as part of a training procedure for situations, where patients may be assessed by different testers. Overall, our results were deemed good enough to proceed with the INFIR study, using VMT and MF testing as a baseline against which to compare more sophisticated methods of nerve function testing.