Electrophysiological profiles of leprosy neuropathy

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1 Lepr Rev (2017) 88, Electrophysiological profiles of leprosy neuropathy SUCHANA MARAHATTA*, SABINA BHATTARAI** & BISHNU HARI PAUDEL* *B.P. Koirala Institute of Health Sciences, Dharan, Nepal **Kathmandu Medical College, Sinamangal, Kathmandu, Nepal Accepted for publication 19 July 2017 Summary Objective: To know the electrophysiological pattern of peripheral neuropathy in leprosy. Methods: We recruited consecutive, newly diagnosed leprosy patients without leprosy reactions for the study. Sensory and motor nerve conduction studies were carried out in the neuro-electrophysiology laboratory. Motor studies were done bilaterally for the median, ulnar, radial, common peroneal and tibial nerves. Likewise, sensory studies were done for the median, ulnar, radial and sural nerves. All findings were recorded on a preset pro-forma. Results: Seventy-four patients were enrolled. The mean age was ^ years, ranging between 12 and 73 years. The median duration of illness was 7 5 ( ) months. The male to female ratio was 2:1. Almost half of the patients (43%) had impaired nerve conduction at the time of diagnosis. Sensory neuropathy was more frequent (32%) compared to motor (20%). Sensory-motor axonal type was the commonest (37 5%) pattern of peripheral neuropathy. Ulnar (24%) and sural (22%) nerves were the most commonly affected motor and sensory nerves respectively. Amplitude was the most commonly affected parameter of both the sensory nerve action potential (SNAP) and the compound motor action potential (CMAP) and it was impaired in 100% of nerves having impaired nerve conduction. Conclusion: Sensory-motor axonal type was the commonest pattern of peripheral neuropathy in leprosy. From our study, amplitude can be considered as the most informative parameter, but further studies are recommended. Name of the institution where the work was undertaken: B. P. Koirala Institute of Health Sciences, Dharan, Nepal Correspondence to: Suchana Marahatta, B. P. Koirala Institute of Health Sciences, Dharan, Nepal (Tel: þ Ext 2015 (Office), 3009 (Res), Cell: þ , Fax: þ ; suchanamarahatta@yahoo.com) /17/ $1.00 q Lepra 373

2 374 S. Marahatta et al. Introduction Leprosy remains one of the commonest preventable and treatable peripheral neuropathy. It is a chronic granulomatous immune response to infection of skin and nerves with Mycobacterium leprae, which resides in macrophages and Schwann cells. It is the only bacterium known to affect myelination and cause peripheral neuropathy. 1 Global leprosy prevalence at the end of first quarter of 2015 was 0 31 per 10,000 population with 213,899 total new cases reported from 121 countries. The South East Asian Region (SEAR) is the major contributor of leprosy, accounting for 72% of the global new case load. Nepal is one of the 13 most leprosy-endemic countries in the world, where 3,046 new cases were detected in Deformities and disabilities are the worst outcome of peripheral neuropathy in leprosy and the most important goal in the management of leprosy is the prevention of disability via early detection of nerve impairment. 3 When detected and treated early, primary impairments may be reversible. So, early detection and treatment of nerve function impairment (NFI) is of paramount importance in leprosy. New Grade 2 disability is an indicator of delayed case detection. Hence the global leprosy strategy targeted the reduction of new Grade 2 disabilities by 35% ( ). Global Grade 2 disability was 0 25/1,000,000 population and in SEAR it was 0 45/100,000 population in the year In Nepal, Grade 2 disability was present in 4% of new leprosy cases in the year Visible pathological changes in the nerve are almost always preceded by a stage of functional blockade of nerve impulse conduction. 4 The role of electrophysiological evaluation of nerve function in the diagnosis and assessment of different neuropathies is well established. 5 In a study by van Brakel et al., monofilament-detected ulnar sensory abnormality was preceded by abnormal sensory nerve conduction in 100% of cases. 6 Other research groups have also found that sensory nerve action potential amplitudes are more severely affected, reinforcing the usefulness of amplitude testing for the detection of early nerve involvement. 7 Previous researchers have suggested the need for further studies to establish the role of nerve conduction studies (NCS) in leprosy neuropathy. Hence this study was conducted to show the electrophysiological pattern of peripheral nerves in leprosy in a tertiary referral hospital in eastern Nepal. Materials and methods STUDY POPULATION We enrolled all newly diagnosed leprosy patients over 12 years of age, without leprosy reactions, attending the Dermatology department from May 2011-April Inclusion criteria All newly diagnosed leprosy cases attending the Dermatology department of BPKIHS with age more than 12 years, without leprosy reactions, who were willing to participate, were included in the study.

3 Electrophysiological profiles of leprosy neuropathy 375 Exclusion criteria Patients aged less than 12 years, those not willing to participate in the study, those with nonleprosy peripheral neuropathies (diabetic neuropathy, alcohol induced neuropathy, etc.) and those unable to cooperate with the nerve conduction examination, were excluded from the study. Sample size We included 74 newly diagnosed leprosy patients, based on a previous report. 8 ENROLLMENT All newly diagnosed leprosy patients were evaluated thoroughly at baseline. Details of history and examination were noted in standardised pro-forma. Slit-skin smear examination was performed in all cases. We classified all patients as per the Ridley-Jopling classification. For treatment purposes, lepromatous, borderline lepromatous and mid-borderline leprosy were classified as multibacillary leprosy and tuberculoid and borderline-tuberculoid leprosy were classified as paucibacillary leprosy. 9 Informed, written consent was taken from all the patients. NERVE CONDUCTION STUDY (NCS) Nerve conduction studies were performed at the Neuro-electrophysiology laboratory in the Physiology department of BPKIHS using a Digital Nihon Kohden Machine (NM-420S, H636, Japan). We commented on the functional impairment of the nerves based on standard criteria. 10 The required set up was checked before starting the test. Room temperature was maintained at the thermo-neutral zone i.e. 26 ^ 28C. It was ensured that all subjects were relaxed during the recording and were made comfortable with the laboratory set up prior to the recording. Recording procedure Motor and sensory nerve conduction studies of the relevant peripheral nerves were done as mentioned in detail in the previous study. 11 Statistical analysis Data were entered in MS-Excel, and were transferred into Statistical Package for the Social Sciences software (SPSS version 11.5) for statistical analysis. For descriptive statistics, frequency, percentage, proportion, mean, standard deviation, median, IQR (inter quartile range) were calculated. For inferential statistics, the chi square test was applied at the level of significance (P ¼ 0 05, where confidence interval (CI) ¼ 95%. Ethical clearance Ethical clearance was obtained from institutional ethical review board (IERB). This is the second part of a primary study entitled Early detection of neuropathy in leprosy - comparing clinical tests with nerve conduction study.

4 376 S. Marahatta et al. Table 1. Demographic and clinical characteristics of the patients (n ¼ 74) Characteristics Multibacillary (n ¼ 58) Paucibacillary (n ¼ 16) P-value Age in years (mean ^ SD) ^ ^ Male (n ¼ 49) 41 (55%) 8 (11%) 0 12 Female (n ¼ 25) 17 (23%) 8 (11%) Duration of Illness in months: 0 91 Median (IQR) 6 5 ( ) 11 ( ) Range ( ) ( ) Funding source There was no funding source for the study. Results DEMOGRAPHIC PROFILE The mean age of the patients was ^ years, ranging between 12 and 73 years. The male to female ratio was 2:1 (66% and 34% respectively). The median duration of illness was 7 5 (IQR ¼ ) months. Out of 74 subjects included in the study, 58/74 (78%) were of the multibacillary group and 16/74 (22%) were of the paucibacillary group. Other demographic characteristics are shown in Table 1. PATTERN OF NERVE CONDUCTION (NC) Less than half of the patients (43%) had impaired nerve conduction at the time of diagnosis. When considered separately, sensory neuropathy was more common (32%) compared to motor neuropathy (20%). Sensory-motor axonal type was the commonest pattern of peripheral neuropathy in our patients, as shown in Table 2. Correlation of NC with patient characteristics More than half of the multibacillary patients 32/58 (55%) had abnormal NC. However, none of the paucibacillary patients had abnormal NC (P-value, ). Patients with. 12 Table 2. Pattern of nerve conduction in leprosy patients (n ¼ 74) Category No (%) Normal NCS 42 (57) Abnormal NCS 32 (43) 1 Motor axonal 6 (8) 2 Sensory axonal 6 (8) 3 Sensory axonal & demyelinating 1 (1) 4 Sensory-motor axonal 12 (16) 5 Sensory-motor axonal & demylinating 7 (9)

5 Table 3. Correlation of nerve conduction with patient characteristics Electrophysiological profiles of leprosy neuropathy 377 Nerve Conduction Category Abnormal Normal P-value WHO classification (n ¼ 74) Multibacillary (¼58) 32 (55%) 26 (45%), Paucibacillary (¼16) 0 16 (100%) Bacterial Index (n ¼ 74) BI Positive (¼12) 9 (75%) 3 (25%) 0 01 BI Negative (¼62) 23 (38%) 39 (62%) Disease duration (n ¼ 74),6 months (¼26) 11 (42%) 15 (58%) months (¼29) 11 (38%) 18 (62%).12 months (¼19) 10 (53%) 9 (47%) Age group (n ¼ 74) 15 years and below (¼6) 1 (17%) 5 (83%) years (¼68) 31 (46%) 37 (54%) months disease duration seemed likely to have more abnormal NC, but this difference was not significant (P-value ¼ 0 54). Children (15 years and below) comprised of 8% (6/74) of total leprosy patients. Among them, one child had abnormal NC (Table 3). NC of individual nerves The sural nerve was the most commonly affected 16/74 (22%) nerve on sensory nerve conduction study. While, ulnar nerve was maximally affected 18/74 (24%) on motor nerve conduction study. Frequency of NCS parameters Amplitude was the most commonly affected parameter for both SNAP and CMAP, and it was impaired in 100% of nerves having impaired NC (Table 4). Table 4. Frequency of abnormal nerve conduction parameters (n ¼ 74) Parameters of nerve conduction Amplitude Duration Latency CV F-latency Nerves Reduced NR Reduced NR Reduced NR Reduced NR Reduced NR Sensory nerves Median NA NA Ulnar NA NA Radial NA NA Sural NA NA Motor nerves Median Ulnar Radial Common peroneal Posterior tibial [CV ¼ Conduction Velocity, NR: No response, NA: Not Applicable]

6 378 S. Marahatta et al. Discussion For the peripheral nerves (both sensory and motor), impairment may be preclinical and may translate into obvious weakness (i.e. sensory and motor respectively) late in the disease. A similar opinion was given by authors in previous studies. 12,13 NCS may be an important modality for early detection of peripheral neuropathy in leprosy. In this study, out of 74 subjects included in the study, 78% were multibacillary and 22% were paucibacillary. Less than half of the patients (43%) had impaired nerve conduction at the time of diagnosis, and sensory neuropathy was more common than motor neuropathy. More than half of the MB patients, but none of the PB patients had abnormal NC. NC was impaired more in patients with positive BI status. Sensory-motor axonal type was the commonest pattern of peripheral neuropathy in our patients followed by sensory-motor axonal and demyelinating (i.e. mixed neuropathy) type. Sural and ulnar nerves were the most commonly affected sensory and motor nerves on NCS. Amplitude was the most commonly affected parameter of both SNAP and CMAP, and it was impaired in all nerves having impaired NC. Duration was the least affected parameter of NCS (mainly of SNAP). In the INFIR cohort, 38% of the patients had nerve damage as diagnosed by NCS at the time of leprosy diagnosis, 14 which is very similar to the finding in our study (43%). The highest rates of clinical nerve function impairment were reported from Ethiopia (55%), 15 while studies in Thailand and Bangladesh reported rates of 18% and 12% respectively. 16,17 One study from western Nepal also showed that sensory nerves were more frequently impaired (12%) in comparison to motor nerves (7%) as in our study. 18 In contrast, in a study by Ramadan et al. motor nerve conduction was impaired more than sensory. More than half of the MB patients 32/58 (55%), but none of the PB patients had abnormal NCS. 19 However, in a previous study, 92% of multibacillary patients had abnormal NCS. 5 In contrast to our study, a study by Chaurasia et al. showed that even paucibacillary patients had extensive neurological involvement. 20 Sensory-motor axonal type was the commonest (37 5%) pattern of peripheral neuropathy followed by sensory-motor axonal and demyelinating (i.e. mixed neuropathy) type (22%) in our patients. However, mixed axonal and demyelinating pattern of peripheral neuropathy was the most frequent finding in a previous study. 20 The sural nerve was the most frequently impaired (22%) among the sensory nerves, and it was followed by ulnar (18%) nerve. Similar to our study, many previous studies found the sural nerve to be the most frequently affected sensory nerve in leprosy. 8,14 The electrophysiological function of the nerve trunk is evaluated on the basis of amplitude, conduction velocity, latency and duration. Amplitude represents the summation of axonal activity in a nerve trunk. Sensory nerve action potential (SNAP) amplitude was the most commonly affected parameter and it was impaired in all sensory nerves (100%) having abnormal nerve conduction in our study. Duration, latency and conduction velocity of the sural nerve SNAP were also impaired in 82% patients with abnormal sural nerve conduction. However, they were not significantly impaired in other nerves. Unlike our study, some studies have observed that in a significant proportion of cases, sensory velocity was at the lower limit of normal or slightly delayed while amplitude and duration of action potential were within the normal range in electrophysiological studies. 21 In a past study, sensory NC of the ulnar nerve showed significant reduction of conduction velocity, prolongation of distal latency, reduction of amplitude in 77 5% patients. 19 However, ulnar sensory latency and amplitude were abnormal in very few subjects (13% and 31% respectively) in a study by van Brakel et al. 14

7 Electrophysiological profiles of leprosy neuropathy 379 Among the motor nerves, the ulnar nerve was the most likely to be impaired (24%), and it was followed by the common peroneal (16%) nerve. Studies by Kumar et al. noted that paralysis was more common in the ulnar nerve distribution than other nerves in leprosy. 22 This also suggests that the ulnar nerve is the most frequently affected motor nerve in leprosy. Cooler temperature facilitating bacterial multiplication, repetitive trauma and bony impingement can be implicated as some of the underlying causes. Similar was the finding in the study by Husain et al. 23 As in SNCS, the amplitude of the compound motor action potential (CMAP) was also affected in all nerves (100%) with abnormal motor nerve conduction. Other parameters of CMAP i.e. duration, latency, conduction velocity and F-wave latency were impaired in a few patients only. However in a previous study, ulnar motor latency, conduction velocity and amplitudes were abnormal in 35%, 38% and 31% respectively. Ulnar sensory latency and amplitude were abnormal in 13% and 31% of subjects. 14 In the study by Ramadan et al. significant reduction in motor nerve conduction velocity, prolongation of distal latency and reduction of amplitude was 72%, 70% and 80% for median, ulnar and common peroneal nerves respectively. 19 It has been shown in many past studies that electrophysiological examination can detect leprosy neuropathy very early as compared to other clinical assessment modalities. 4,6 Hence it can detect subclinical leprosy neuropathy, which may be helpful for the prevention of clinical neuropathies. Until now there has been no evidence to prove that the development of clinical neuropathy can be prevented in individuals with subclinical leprosy neuropathy. However an international multicenter randomised controlled trial (TENLEP) in six centres of Asia, including Nepal, is testing the efficacy of prednisolone therapy for the prevention of the progression to clinical impairment. 24 Conclusion Sensory-motor axonal type is the commonest pattern of peripheral neuropathy. Amplitude can be considered as one of the important indicators of abnormal nerve conduction. Further studies are recommended in order to allow this method of assessment to be more widely applied. Acknowledgements We would like to thank everyone involved directly or indirectly in this study. We would like to extend our thanks to Mr. D. D. Baral, the Biostatistician (Department of Community Medicine, BPKIHS) for statistical guidance. Likewise, we are immensely pleased to thank all the consultants, residents and entire supporting staffs of Dermatology department and Nerve Conduction Study unit of BPKIHS. References 1 Jopling WH, Mc Dougall AC. Definition, Epidemiology and World Distribution. In: Handbook of leprosy, CBS Publishers; 2000; 5: World Health Organization. Weekly epidemiological record. 2015; 90:

8 380 S. Marahatta et al. 3 Einar PW, Van Brakel WH. Nerve damage in leprosy. Nature Clin Pract Neurol, 2008; 4: Hackett ER, Shipley DE, Livengood R. Motor nerve conduction velocity studies of ulnar nerve in patients with leprosy. Int J Lepr, 1968; 36: 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 untrated multibacillary leprosy patients. J Clin Neurophysiol, 2010; 27: Van Brakel WH, Nicholls PG, Wilder-Smith EP 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: Ramakrishnan AG, Srinivasan TM. Electrophysiological correlates of hanseniasis. Int J Lepr Other Mycobact Dis, 1995; 63: 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: Bartt RE. Leprosy (Hansen s Disease). Curr Treat Options Neurol, 2004; 6: 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 Marahatta S, Bhattarai S, Paudel BH. Nerve conduction study in leprosy: a hearty need or a customary practice? Lepr Rev, 2016; 87: Brown TR, Kovindha A, Wathanadilokkol U et al. Leprosy neuropathy: Correlation of clinical and eletrophysiological tests. Indian J Lepr, 1996; 68: 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: 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: Saunderson P, Gebre S, Meima A et al. The pattern of leprosy related neuropathy in the AMFES patients in Ethiopia: definitions, incidence, risk factors and outcome. Lepr Rev, 2000; 71: Schreuder PA. The occurrence of reactions and impairments in leprosy: experience in the leprosy control program of three provinces in northeastern Thailand, III. Neural and other impairments. Int J Lepr Other Mycobact Dis, 1998; 66: 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: 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: Ramadan W, Mourad B, Fadel W, Ghoraba E. Clinical, electrophysiological and immunopathological study of peripheral nerves in Hansen s disease. Lepr Rev, 2001; 72: Chaurasia RN, Garg RK, Singh MK et al. Nerve conduction studies in paucibacillary and multibacillary leprosy: a comparative evaluation. Indian J Lepr, 2011; 83: Antic NH, Mehta L, Shetty V et al. Clinical, electro-physiological, quantitative histologic and ultra-structural studies of the index branch of the radial nerve in leprosy. Preliminary Report. Int J Lepr, 1975; 43: Kumar A, Girdhar A, Girdhar BK. Nerve thickening in leprosy patients and risk of paralytic deformities: a field based study in Agra, India. Lepr Rev, 2004; 75: Husain S, Malaviya GN. Early nerve damage in leprosy: an electrophysiological study of ulnar and median nerves in patients with and without clinical neural deficits. Neurol India, 2007; 55: Wagenaar I, Brandsma W, Post E et al. Two randomized controlled clinical trials to study the effectiveness of prednisolone treatment in preventing and restoring clinical nerve function loss in leprosy: the TENLEP study protocols. BMC Neurol, 2012; 12: 159.