Neuropathic pain in Leprosy even after successful therapy


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I seems that consensus is not yet definitive in this field as well...

Abstract 1

Neural pain is a frequent symptom in leprosy disease. There is a paucity of data regarding neural pain diagnostics resulting in common prescriptive errors when neuritis is confused with neuropathic or mixed nociceptive–neuropathic pain.

The present study identified important demographic, clinical, and neurophysiological features of 42 leprosy neuropathy patients presenting neuropathic pain (NP).

During routine evaluations, patients were selected asking if they had ever experienced neural pain. Data analyses of their pain characteristics, clinical examination results, and both the Douleur Neuropathique 4 Questionnaire and Hamilton Depression Scale scores were used to classify these patients.

The most common word they used to describe the sensation of pain for 25 (60%) of these patients was “burning.”

In the early stages of the disease and before leprosy diagnosis, 19 (45%) had already complained about NP and leprosy treatment was unable to prevent its occurrence in 15 (36%).

Leprosy reactions, considered NP risk factors, occurred in 32 (76%) cases.

Knowledge of typical NP characteristics could be used to develop more effective therapeutic approaches for a notoriously difficult-to-treat pain condition.
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Despite widespread implementation of effective multidrug therapy (MDT), leprosy has not been eliminated. In spite of treatment, a third of newly diagnosed patients have nerve damage and might later develop disabilities and delayed nerve impairment.1

Moreover, different types of pain related to nerve injury may occur during the course of the disease, contributing to patient morbidity.

In leprosy, a variety of physiopathological mechanisms are directly related to neural pain. Nociceptive pain is initiated by a noxious stimulus such as neuritis, an inflammatory process affecting the nerves.

Neuritis differs from neuropathic pain (NP), a nonexclusive condition of leprosy that occurs in abnormal functioning of the peripheral and central nervous systems in several associated etiologies (e.g., cancer, diabetes, and herpes zoster).24

It is common for neuritis to be associated with certain features of NP, making it difficult to reach correct differential diagnostic and to decide the best treatment.5

During neuritis, deterioration of the nerve function associated with pain usually recovers after administration of oral steroids.6
On the other hand, NP relief most often occurs as a result of tricyclic antidepressives, dual reuptake inhibitors of serotonin and norepinephrine, anticonvulsivant drugs, and topical anesthetics.
Previous reactions in leprosy before evaluation occurred in 32 patients (76%). Twenty-three (55%) of these patients had previously more than one type of reaction.
Previous neuritis occurred in 50% of 32 patients, as erythema nodosum leprosum. Erythema multiforme occurred in 19 (59%) and reversal reaction in 12 (38%).
Nine of them had had the first acute neuritis before starting NP.
Pain started before treatment in 19 (45%) patients and after MDT in 15 (36%).
As neurological impairment, leprosy reactions are considered risk factors to NP and occurred in 32 (76%) cases.17,22 Even more prevalent in our evaluation, a history of type 2 reactions also showed a significant association.20,22
It is known that NP can occur without an obvious neurological impairment, as in small-fiber neuropathies.

In this connection, normal neural conduction was identified in 14 (33%) patients, reinforcing the integrity of large diameter fibers.
Whereas large fibers are affected in a relatively late stage of infection, small unmyelinated and lightly myelinated nerve fibers (the C and Aδ nerve fibers) are particularly vulnerable to early damage from Mycobacterium leprae.3234
NP is more prevalent in neuropathies associated with the prominent involvement of C and Aδ nerve fibers.

However, it is not unusual to find NP in patients with mixed large-fiber and small-fiber neuropathies and even in those with predominantly large-fiber involvement.35


Leprosy is a chronic infectious peripheral neuropathy caused by Mycobacterium leprae.

The different clinical presentations of the disease are determined by the quality of the host immune response.

Early detection of leprosy and treatment by multidrug therapy are the most important steps in preventing deformity and disability.

Thus the early recognition of the clinical leprosy presentation is essential. Mononeuritis, mononeuritis multiplex (MM), polyneuritis (MM summation) are the most frequent.
The frequent anesthetic skin lesions are absent in the pure neuritic leprosy presentation form.
Isolated peripheral nerve involvement is common, including the cranial ones. Arthritic presentation is occasionally seen, usually misdiagnosed as rheumatoid arthritis.

Attention should be given to autonomic dysfunctions in leprosy. There are clinical presentations with severe neuropathic pain - painful small-fiber neuropathy. Leprous late-onset neuropathy (LLON) clinical presentation should be considered facing a patient who develop an inflammatory neuropathy many years after a previous skin leprosy treatment.

Leprosy classification

The current accepted classification for leprosy was made by Ridley and Jopling in 1966. It was based on clinical, histological and immunological criteria. It subdivided leprosy in groups: tuberculoid (T), borderline tuberculoid (BT), borderline (BB), borderline lepromatous (BL) and lepromatous (L). A minor form was added later: indeterminate (I). As it is well known, leprosy forms does not depend of the bacilli itself but on the immune response of the host. In LL macrophages are unable to kill bacilli; on the other hand, in BL there is an intense cell-mediated immunity response able to destroy bacilli. There is also a clinical presentation of leprosy without any skin lesions known as pure neuritic form (PNL)6. There is also a condition known as “silent neuropathy” (SN). It is characterized by the impairment of sensory and motor functions without skin signs, nerve tenderness, pain, paraesthesia or numbness symptoms of neuritis. It is also called “quiet nerve paralysis”1.

Autonomic dysfunction in leprosy

Regional autonomic signals and symptoms, most involving sweating process, are seen in leprosy. Vasomotor reflex was impaired in at least one finger in 33/76 (43%) patients by means of laser Doppler velocimetry in 76 Brazilian patients19. Autonomic nerve lesion was more frequent than somatic lesions and was strongly related to the immune-inflammatory reaction against M. Leprae.

Compared with controls, in a series of 25 leprosy patients the R-R interval variations were found to be reduced during both resting and deep forced hyperventilation. The authors concluded that sensory nerve damage is accompanied by autonomic involvement20. Autonomic function and NCS were significantly more altered in MB than PB patients in a prospective clinical study we have recently reported including 10 PB and 12 MB patients evaluated at diagnosis and one year after cessation of MDT21.

Leprosy reactions

Leprous patients may develop hypersensibility host responses, thus interrupting the stable and chronic course of the disease. These are known as leprosy reactions.

Type 1 reaction or reversal reaction (RR) is a late cellular hypersensibility reaction type IV. It occurs in B and Border line Lepromatous form.
The reaction usually appears during the first months of treatment. Previous lesions become steadily more swelled up, reddened and even ulcerate resulting in pain upon minor trauma. Fever, malaise and anorexia may be present. Facial swelling as well as swelling of the legs and upper limbs is characteristic.

Type 2 reaction or erithema nodosum leprosum (ENL) is an acute inflammatory condition involving a TNF-alfa and immune complex mediated immune response with infiltration of Th2-cells. It occurs most frequently in L patients, less frequently in BL patients and is more commonly seen in patients with high bacterial index. Nodules and painful, raised red papules are characteristic. These nodules may be accompanied by uveitis, iridocyclitis, episcleritis, neuritis, arthritis, dactilitis, lympohadenitis and orchitis. Fever, prostration, anorexia as well as other symptoms are frequent22.
Leprosy late-onset neuropathy

Relapse in leprosy is a reoccurrence of the disease at any time after the completion of MDT.
There are different causes of relapses: an inadequate MDT due to misclassification of the disease, a premature stop of MDT or a poor compliance.
Sometimes even with adequate MDT the relapse is due to multiplication of persistent bacilli, or drug resistance. The relapse may be in the form of late reversal reaction or due to reinfection.

Occasionally there are patients who developed delayed nerve impairment years after MDT, which could not be explained by relapses or reactions.

They may have acute mononeuropathy or a chronic and slowly progressive form of multiple mononeuropathy or polyneuropathy. There was no activity of leprosy. We have considered this form as a leprosy late-onset neuropathy (LLON)23.

New cases were included and recently reported by our group emphasizing LLON presentation form24.

Probably it represents an immune reaction due to the persistence of the bacillus antigen25. Recently we also reported two LLON cases presenting as an ataxic polyneuropathy (LLON – ataxic presentation) (Peripheral Nerve Society Meeting, Saint Malo, Fr, June 2013). A better understanding of LLON clinical features and physiopathology is needed for a better management.

This european neurologist suggested in 2003 that the late onset form could be an immune mediated chronic Reversal Reaction for a subset, and similar to the post Polio syndrome for the other subset (thus he called it the Post Leprosy Syndrome);

He suggest agressive immunosuppression for the first subset (Chronic RR)