Post-MDT leprosy neuropathy: differentially diagnosing reactional neuritis and relapses. Laboratory of Leprosy, Oswaldo Cruz Institute, Rio de Janeiro, RJ, Brazil

Sérgio Luiz Gomes Antunes

Márcia Rodrigues Jardim

Robson Vital Teixeira

José Augusto da Costa Nery

Anna Maria Sales, Euzenir Nunes Sarno

Introduction

• In leprosy, new nerve damage emerging after MDT poses difficulty to

medical assistance.

• Reactional neuritis, neuropathic pain, relapse can be usually cogitated as

diagnosis.

• Superimposed nonleprosy neuropathy could also be a possible hypothesis.

• The criteria for relapse diagnosis based on the aggravation or emergence of

neuropathy have not been clearly established yet.

Objectives

To ascertain the role of nerve biopsy in the differential

diagnosis of the post-MDT leprosy neuropathy based

on histological alterations across the selected groups

Patients and Methods

• Examination of 50 nerve biopsy specimens collected from patients presenting

peripheral neuropathy after leprosy MB-MDT.

• No cutaneous lesion was associated with the neuropathy.

• The patients were submitted to neurological and neuroelectrographical evaluation

previously to the biopsy.

• Serial neurological examination was performed to detect aggravating impairment of

neural symptoms.

Decision criteria for nerve biopsy • Persistence of the symptoms for more than 5 years after completion of MDT. • Aggravated neural function impairment (hyposthesia, paresthesia, motor deficit, nerve pain) after MDT. • Presence of aggravating disturbances of velocity conduction and/or action potential amplitude. • Refractoriness to anti-reactional treatment.

Histopathological analysis

• Nerve biopsy specimens were processed for routine histopathological analysis using paraffin- and

epon-embedded sections. Hematoxylin-eosin, Wade, Gomori’s trichrome and toluidin blue for

microscopy.

Histological variables analysed (yes / no)

• Presence and distribution of inflammatory infiltrate, inflammatory cell population, fibrosis,

Schwann cell proliferation, loss of myelinated nerve fibers, axonal degeneration, remyelinatiion,

and regeneration).

• A group of 50 nerve biopsy specimens from patients suffering pure neural leprosy was used for

comparison with the post-MDT neuropathy

Histological alteration Frequency

Epineurial infiltrate 25 (50%)

Perineurial infitlrate * 29 (58%)

Endoneurial infiltrate * 28 (56%)

Mononuclear cel infiltrate * 38 (76%)

Foamy macrophages * 25 (50%)

Epithelioid granuloma * 8 (16%)

Perineurial fibrosis * 30 (60%)

Endoneurial fibrosis * 32 (64%)

Schwann cell proliferation 4 (8%)

Perineurial enlargement 23 (46%)

Loss of myelinated fibers * 35 (70%)

Axonal degeneration (active) 5 (10%)

Axonal regeneration 7 (14%)

Axonal remyelination 7 (14%)

Frequency of histological alterations found in Post MDT neural leprosy

PTNL PNL

Mononuclear infiltrate 38 (76%) * 36 (53.7%)

Epithelioid granuloma 8 (16%) 14 (21.2%)

Foamy macrophages 25 (50%) * 17 (25.7%)

Perineurial fibrosis 30 (60%) * 28 (41.1%)

Endoneurial fibrosis 32 (64%) * 27 (39.7%)

Loss of myelinated fibers 35 (94.5%) 41 (83.6%)

Axonal degeneration (active) 5 (13.5%) 8 (17%)

Axonal remyelination 7 (18.9%) 3 (6.3%)

Axonal regeneration 7 (18.9%) 5 (10.4%)

Onion bulb appearance of nerve fibers 2 (5.8%) 0

Comparison of frequency of histological changes in post-treatment (PTNL) and pure neural leprosy (PNL)

Followup

• The PTNL patients demand a conduct that can relieve their disturbing symptoms and prevent severe and irreversible disability

• The risk of severe nerve damage is very high.

• Therefore, suspection of a relapse is a reasonable hypothesis.

• Decision to retreat PTNL patients was made, according to the following: o patients fit to the initially established criteria o whenever AFB are found in the nerve biopsy specimen

Relapse Reaction

Mononuclear infiltrate 24 (88.8%) * 14(60.8%)

Epithelioid granuloma 5 (18.5%) 3 (13%)

Foamy macrophages 20 (74.0%) ** 5 (21.7%)

Perineurial fibrosis 20 (74%) * 10 (43.4%)

Endoneurial fibrosis 21 (77.7%) 11 (47.8%)

Perineurial enlargement 26 (59.2%) 7 (30.4%)

Loss of myelinated fibers 25 (100%) * 10 (83.3%)

Axonal degeneration (active) 1 (4%) * 4 (33.3%)

Axonal remyelination 4 (16%) 3 (25%)

Axonal regeneration 4 (16%) 3 (25%)

Onion bulb appearance of nerve fibers 1 (4.1%) 1 (10%)

Comparison of histological changes frequency in relapse X reactional neuritis

* p< 0.05 / ** p < 0.001

After the application of the mentioned criteria, the post-MDT group of samples was sorted into relapse (27) and reactional neuritis (23) and compared in the frequency of histological alterations.

22 309 NR 22 331 NR

Inflammatory infiltrate among nerve fibers in the endoneurial space

Relapse

Microfasciculation and epithelioid granuloma in the endoneurium

Relapse

23129 Relapse 23786 NR

Fibrosis of the fascicle and close view of a microsfascicle

Reactional neuritis 23165 Relapse

Epineurial arteritis and nerve fibrosis

Relapse Relapse

Remyelinated fibers, inflammatory infiltrate and AFB-laden Schwann cells

Conclusion • The histomorphological appearance of post-MDT nerve biopsy specimens had few distinctive features compared to pure neural leprosy: gross foamy cells. • In face of the need for prevention of disability in leprosy nerve damage and of the demand to relieve patients’ neural symptoms, ….. • Given the lack of parameters for relapse diagnosis in patients presenting post-MDT leprosy neuropathy without cutaneous lesions, ….

Conclusion The following criteria for retreating post-MDT neuropathy patients were adopted and are brought for discussion as they have not been officially recommended:

• Persistence of the symptoms for more than 5 years after completion of MDT.

• Aggravated neural function impairment (hyposthesia, paresthesia, motor deficit, nerve pain) after MDT.

• Presence of aggravating disturbances of velocity conduction and/or action potential amplitude.

• Refractoriness to anti-reactional treatment.

• Presence of intact or fragmented acid-fast bacilli in the biopsy nerve specimen.

Comments

• More knowledge on the biology of the M leprae-nerve interaction must be generated in order to define reliable criteria for the leprosy relapse diagnosis.

• Dastur et al, (1991) reported the presence of AFB in the histological nerve samples after discharge.

• What is the exact meaning of the presence of AFB in nerves long time after the completion of MDT?

• The clinical followup of patients after retreatment will contribute to define the adoption of new criteria for the broad comprehension of this clinical presentation. (A study is on course in the Laboratory of Leprosy, Rio de Janeiro, Brazil).