Virmond MCL, Garbino JA , Cury Fo M, Delamina WFB, Almeida SND, Torquato MT

1. Virmond MCL, Garbino JA, Cury Fo M, Delamina WFB, Almeida SND, Torquato MT PROSPECTIVE AND RANDOMIZED TRIAL TO DETERMINE THE ROLE OF NERVE DECOMPRESSION IN LEPROSY NEUROPATHY – partial results INSTITUTO LAURO DE SOUZA LIMA (ILSL), BAURU - BRASIL

2. Background Leprosy patients may present damage on nerve trunks leading to deformities. The pathophysiology of this neuropathy includes edema, fibrosis with enlargement of the nerve. There is also external nerve compression – entrapment - leading to ischemia and loss of function. In spite of many publications on nerve surgery1,it is still not clear whether surgical decompression alone or combined with corticosteroids is better than corticosteroids alone. 1. Van Veen NH et al. Decompressive surgery for treating nerve damage in leprosy. A Cochrane review. Lep Rev 2009

3. Objective To conduct a prospective and randomized trial to determine the value of surgical nerve decompression of ulnar nerve at elbow tunnel, median at carpal tunnel, peroneus at retro-fibular tunnel and tibial at tarsal tunnel, in leprosy neuropathy after an attempt to treat with steroids in adequate doses.

4. Methods Design: Prospective surgical trial Inclusion criteria • Patients presenting signs of active neuropathy, clinical features, nerve function impairment and/or electrophysiologic signs of activities were included in any degree of severity Exclusion criteria • patients with other suspected cause of neuropathy, • pregnant or lactating women, • Erythema Nodosum Leprosum (ENL), • patients living too far away, • patients with long standing paralysis, • patients with steroids contraindications. Drug treatment 1 • Standard prednisone treatment: 1 mg/Kg/day. Randomization • Without improvement or worsening of nerve function, after four weeks, the case is randomized to a Clinical Group (keeping prednisone) or a Surgical Group (prednisone plus surgical decompression). Nerve function assessment (NFA) 1 • Semmes-Weinstein monofilaments - graded sensory test (GST), voluntary muscle testing (VMT), visual analog scale (VAS) for pain • nerve conduction studies along the nerves and specially across the anatomic tunnels of each nerve The follow up: is projected to be done for 5 years This study carried the approval of the ethics committee of the ILSL 1. Garbino JA, Virmond M et al. A randomized clinical trial of oral steroids for ulnar neuropathy in type 1 and type 2 reactions. Arq Neuropsiquiatr 2008

5. Nerve FunctionAssessment (NFA) Clinical score (CS) numerically summation: • VAS results, zero (no pain) to 10 (unbearable pain) for each nerve • GST from 0 (feel 0.5 g; normal) to 6 (do not feel 300g) X 2 points for each nerve, except for Tibial nerve • VMT from 0 (paralysed) to 5 (normal) inverted , in order to align to the other data X 2 muscles for each nerve except for Tibial nerve • CSwill vary from 0 to 32 in the majority of nerves, except for Tibial nerve in which the CS is compounded by four points in GST and only one muscle of VMT Motor nerve conduction (MNC) studies: • Distal latency (DL) measured over an 8 cm along segment from muscle to the wrist; the recording electrode was attached on the muscle belly. • The conduction velocity (CV) over the tunnel segments and bellow for all nerves. • The compound motor action potential (CMAP) features as amplitude and temporal dispersion (TD), was measured below and above the elbow. • The minimum value of the F wave latency, related to demyelination in all segments of the nerve, was measured over a series of 20 stimuli.

6. Surgical technique Standard surgical technique will be used to decompress involved nerves. The principles of handling peripheral nerves during surgery must be respected as stated by most authors (Fritschi, 1971; Duerksen, Virmond, 1994; Sirinivasan, Palande, 1997). The following top principles should be kept in mind: • The compressing fibrous ligaments should be always be released (Osborne, Carpal, Tarsal ligaments and at the retro-fibular tunnel • Preferably, the ulnar nerve will be kept in place after release. Only the condition of spontaneous dislocation of the nerve out of the epitrochlear-olecranon groove during passive flexion of the elbow, as tested by the surgeon, an anterior transposition may be considered. In such case, the vasanervorum should be left intact as much as possible • Anterior transposition will be recorded and these cases will be discussed in separate

7. Results Since April 2009 to 24 December 2012, 130 patients were assessed Fifteen cases (15) were excluded due to: Diabetes Hypothyroidism Sjogreen disease Type 2 reaction Eighty did not show active neuritis by nerve conduction studies (NCS) Only 35 cases with active neuritis were included for steroid treatment. Fifteen patients were lost after randomization Five patients/ 7 nerves will be followed in a Group of Modified Intention of Treatment The final total was 20 patients and 29 nerves (four patients were in both groups)

8. Statisticalstrategy The tests were chosen in order to compare: • the previous clinical and neurophysiological parameters in order to assess the similarity between Groups • the recovering degree of nerves of Surgical (S)and Clinical (C)Groups in the 3rd evaluation (3-6 month) and in the last that varied from 3-6 m to 2-3 years • Severity grade: moderate + mild Xpronounced + complete • ulnar and tibial, which are the more frequent, between both Groups • the parameters variation during the nerve improvement • Complete nerve lesions were followed separately

9. StatisticalResults: surgical (s) x clinical (c) allnerves For Clinical Score (CS) For Motor nerve conduction (MNC) studies In the 1st eval: no statistical differences 3rd eval(3-6 month): F wave, P: 0,057 1st/Last eval: F wave, P = 0,049 Positive Pearson correlations : CMAP distal amplitude X proximal X CVs • In the 1st eval: statistical differences, though the S Group shows more severe nerves, P = 0,018 • 1st/3rd eval(3-6 month): no statistical differences • 1st/Last eval: no statistical differences • VSA ↑pron+compl > mod+mild • VMT ↑mod+mild > pron+compl • S-W↑ “ = “

10. StatisticalResults: Surgical (S) X Clinical (C) for Ulnar and Tibial nerves Ulnar nerves of S and C groups: Tibial nerves of S and C groups: GroupS: 4 and C: 1 No comparisonswerepossible • GroupS: 9 and C: 4 - 1st/Last comparison • No significance in CS values • According NFA severity :VMTshowedP= 0,015 for moderate group • F wave showed P = 0,077 for GrupoS • CMAPproximal amplitude: P= 0,044 for moderate group

11. Discussion • Surgical and Clinical Groups presented statistical differences of the mean values in the nerves of the Surgical Group in the 1st evaluation. Suggesting a trend towards more severity in this Group that could be equalize with increased samples. • The majority of nerves improved (80%) or maintained the CS in the final evaluation, except a peroneus nerve with a complete lesion. But there were no statistical significances in the CS and isolated: VSA, S-W monofilaments and VMT between both groups (S and C) in the two times of comparison, 3rd and the Last follow-up. • The CS improvement according the severity grade : VSA improved more in the group: pronounced+ complete, VMT improved more in moderate + mild group and S-W improved in both groups. • One of the neurophysiologic parameters (NP), F wave, that is actually a result of a global motor conduction, the statistical results were significant for Surgical Group. • Studying NP correlation (Pearson) a positive correlation was found for distalCMAP amplitude with proximal CMAP amplitudes and CVs. These findings reflect partial resolutions of TD, CBs and myelin regeneration (Garbino JA et al. 2010). Thus, improvements of other parameters can be expected : DL, CMAP amplitudes, CV and TD, along the time. As the majority of nerves were followed just to the 3rd evaluation at this time.

12. Conclusion In other non-leprosy entrapment syndromes, such as tarsal tunnel and ulnar neuropathy at the elbow, many of the nerves do not change after surgery. The worst results are assumed to be due to other underlying conditions and systemic diseases. Thus the authors supported that surgery should be restricted to nerves with space-occupying lesions (Mondelli M et al. 1998, 2004). However, in other genetic and progressive neuropathies (Charcot-Marie-Tooth), i.e. underlying condition, the nerves can be protected by the surgery (Chaleskson CP et al 1999). The nerves with space-occupying leprosy nerve lesions are the subject of this study. Despite this chronic and progressive underlying disease, nerve improvement or protection can be observed with nerve release in leprosy. Key-words: Leprosy; Nerve damage; Entrapment ; Nerve decompression; Surgery.

13. Aknowledgements • Dr. Wladimir Bonilha Delanina: DirectorofDermatology inthe ILSL • Dr. Somei Ura: DirectorfoResearchBranch inthe ILSL • Dr. Flavio Badin Marques: assistantdermatologistofthe ILSL • Prof. Dr. JaisonAntonio Barreto: assistantdermatologistofthe ILSL • Dra. Paula Levatti Alexandre: assistantneurologistandneurophysiologistofthe ILSL ClinicalNeurophysiology • Dr. Marco A M Robles: ILSL ClinicalNeurophysiologyformerstudent– in memorium • Dra. Cristina MichelonBaldisseroto: ILSL ClinicalNeurophysiologyformerstudent • Dr. Gustavo G Robinson: ILSL ClinicalNeurophysiologyformerstudent • Dr. Dante G V Hardoim: ILSL ClinicalNeurophysiologyformerstudent • Dra. Aline S M Souza: ILSL ClinicalNeurophysiologystudent • Dr. Daniel Rocco Kirchner: ILSL ClinicalNeurophysiologystudent • Florinda da Costa Faria: Techniqueauxiliary in ILSL ClinicalNeurophysiologyLab • FumikoTokuhara: Techniqueauxiliary in ILSL ClinicalNeurophysiologyLab