Neuropathy associated with leprosy

Ravindra Kumar Garg DM FRCP

Peripheral Neuropathies

Updated 12.27.2023
Released 07.14.2004
Expires For CME 12.27.2026

Neuropathy associated with leprosy

Author: Ravindra Kumar Garg DM FRCP

See Contributor Disclosures

Editor: Louis H Weimer MD

Neuropathy associated with leprosy

In This Article

Quick Link

Introduction

Overview

Leprosy is still one of the most prevalent and treatable causes of neuropathy in the world. Data suggest that 96% of new leprosy cases were reported from 14 countries and only 4% of new cases from the rest of the world. Neuropathy in leprosy is important because it is often associated with severe disability and handicap. Advances in immunology and molecular biology have led to a greater understanding of the disease as well as to hopes for improved diagnostic tests and vaccination strategies. Human genetic factors strongly influence susceptibility to leprosy as well as the severity of the disease. Toll-like receptor 2, a pattern recognition receptor of innate immune system present on human Schwann cells and other inflammatory cells, is critical in the immune response against mycobacterial infection. A group of researchers showed that the leprosy bacteria reprogram Schwann cells into programmed stem cell-like cells or programmed mesenchymal stem cells. Conversion of Schwann cells into programmed stem cell-like cells promotes bacterial spread to distant sites. Increasing numbers of patients are demonstrating lesions in the brain and spinal cord. A prospective study noted that among 29 patients with multibacillary leprosy, five patients had MRI abnormalities in CNS, spinal root ganglion, or brachial plexus. Leprosy is rare in developed countries, and unawareness of this disease often leads to misdiagnosis. Because of absent skin lesions, primary neuritic leprosy poses a great diagnostic challenge, and nerve biopsy is required for diagnosis. Every leprosy patient should be treated with the same 3-drug regimen (rifampicin, dapsone, and clofazimine) with a duration of treatment of 6 months for paucibacillary leprosy and of 12 months for multibacillary leprosy. The exact role of corticosteroids is not established and needs more data. Lately, there have been instances in which COVID-19 vaccination has led to clinical aggravation of leprosy; vaccine-induced immune alterations possibly triggered severe lepra reaction. A study in China noted that single-dose rifapentine significantly reduced leprosy incidence among household contacts, outperforming rifampin and no intervention, with no severe adverse events reported. In this article, the author describes the epidemiology, pathogenesis and pathophysiology, clinical features, differential diagnosis, and management of neuropathy associated with leprosy.

Key points

	• Leprosy is one of the oldest diseases known to mankind. Three cardinal features of leprosy are hypoesthetic skin lesions, thickened peripheral nerves, and positive skin smear for bacilli.
	• The Ridley-Jopling classification divides leprosy into three major categories: tuberculoid leprosy, lepromatous leprosy, and borderline leprosy.
	• Leprosy reactions are important acute events in the course of leprosy and are often associated with significant nerve damage.
	• Among physiological functions of a peripheral nerve, sensory functions are most severely affected in leprosy.
	• For confirmation of diagnosis, slit-skin smears, skin biopsy, and nerve biopsy are employed.
	• The World Health Organization recommends multidrug therapy regimens consisting of a combination of rifampicin, dapsone, and clofazimine for the treatment of leprosy.

Historical note and terminology

Leprosy is one of the oldest diseases known to mankind. It is a disease that has long been stigmatized, and persons afflicted with it have frequently been segregated from the rest of society. The term leprosy came from the Latin word Lepros, which means defilement. Leprosy has extensively been described in ancient Chinese, Egyptian, and Indian literature as early as 600 BC. Returning soldiers of Alexander the Great brought leprosy from India to the Mediterranean region in 237 to 326 BC (55). Using comparative genomics, it has been demonstrated that the disease seems to have originated in Eastern Africa or the Near East and spread with successive human migrations. Europeans or North Africans introduced leprosy into West Africa and the Americas within the past 500 years (65).

A Norwegian physician, GHA Hansen, discovered the causative organism of leprosy in 1873. The breakthrough in treatment of leprosy occurred in the 1940s with the development of the drug dapsone. The World Health Organization (WHO) in1982 introduced multidrug therapy, which has proved to be the most important advance in the management and control of leprosy (136). Multidrug therapy has helped in reducing the number of registered leprosy cases worldwide. During the past 3 years, the global number of new cases detected continued to decrease dramatically. In 1991 WHO and its member countries pledged to eliminate leprosy by the year 2000. Elimination was defined as a prevalence of less than one case per 10,000 population. By the end of 2003, more than 13 million patients had been cured by multidrug therapy (138).

In one major development, an observation revealed that red squirrels (Sciurus vulgaris) from around the UK and Ireland carry several strains of leprosy and possibly function as a reservoir for human leprosy. The authors found Mycobacterium lepromatosis in squirrels from England, Ireland, and Scotland, and Mycobacterium leprae in squirrels from Brownsea Island, England. Phylogenetic comparisons of British and Irish Mycobacterium lepromatosis with two Mexican strains from humans showed that they had a common ancestor around 27,000 years ago. The Mycobacterium leprae strain detected was phylogenetically similar to one that circulated in medieval England (05).

Classification. The Ridley-Jopling classification is currently the most widely accepted system of leprosy classification. According to host's immune response against mycobacterial antigen, leprosy is divided into three major categories: tuberculoid leprosy, lepromatous leprosy, and borderline leprosy (92).

	(1) Tuberculoid leprosy is characterized by active immune reaction against Mycobacterium leprae; active cell-mediated immunity restricts the disease to a few peripheral nerves or skin lesions.
	(2) Lepromatous leprosy is characterized by lack of immune response against Mycobacterium leprae, which results in extensive proliferation of bacilli in skin and nerves along with disseminated tissue infiltration.
	(3) Borderline leprosy has features of two polar forms. Borderline-tuberculoid leprosy is close to tuberculoid leprosy, whereas borderline-lepromatous leprosy is close to lepromatous leprosy.
	(4) Indeterminate leprosy is an early transitional form of disease and is characterized by smaller and fewer skin lesions. This form of leprosy often resolves spontaneously or, less frequently, may evolve into one of the definite forms of leprosy. Indeterminate leprosy is not a part of the Ridley-Jopling classification.

WHO classifies leprosy, on the basis of findings from skin smears, as paucibacillary and multibacillary leprosy. In WHO classification, patients showing negative skin smears for acid-fast bacillus at all sites examined are grouped as paucibacillary leprosy, whereas patients having positive skin smear for acid-fast bacillus from any site are grouped as multibacillary leprosy. For field surveys, patients having five or fewer skin lesions are grouped in paucibacillary leprosy, whereas patients having more than five skin lesions are grouped in multibacillary leprosy (137). According to data from the WHO, among newly detected cases in 2002, approximately 39% of patients were clinically classified as having multibacillary leprosy (138).

Clinical manifestations

Presentation and course

Skin lesions. Three cardinal features of leprosy are hypoesthetic skin lesions, thickened peripheral nerves, and positive skin smear for bacilli. In lepromatous leprosy, the skin lesions are small, numerous, widely scattered, and symmetrical in distribution. In advanced cases, diffuse thickening of skin of the face, often with thickened ear lobes, produces a typical “leonine facies.” There is often loss of eyebrows and eyelashes. In contrast, skin lesions in tuberculoid leprosy are single or few and are asymmetrical in distribution. Lesions have elevated and well-defined margins. The lesions are usually dry, erythematous, scaly, anesthetic, and hypopigmented.

Skin lesion in tuberculoid leprosy

A hypopigmented, hypoesthetic lesion of tuberculoid leprosy. The lesion has a well-defined and raised margin. (Contributed by Ravindra Kumar Garg.)

Skin lesions are commonly seen on the extensor surface of extremities, the face, and the buttocks.

Lepromatous leprosy: large skin lesion

A large typical skin lesion on extensor surface of upper limb in a patient with lepromatous leprosy. (Contributed by Ravindra Kumar Garg.)

Borderline leprosy is the most commonly encountered type of leprosy. Changes in peripheral nerves are widespread and frequently lead to crippling deformities. If untreated, this unstable type of leprosy may pass into the lepromatous end of the leprosy spectrum along with bacterial proliferation. Depending on the immunological status of the patient, skin lesions are more numerous and less well defined and have relatively symmetrical distribution as compared to tuberculoid leprosy (Table 1).

Table 1. Differences Between Three Major Types of Leprosy

	Tuberculoid	Lepromatous	Borderline
Skin lesions	Single or few, sharply demarcated, asymmetrical, hypoesthetic	Nodule, papule macule, and diffuse infiltration, symmetrical, nasal, and ocular involvement	Features of both polar forms
Nerve involvement
• Cutaneous	Common, patchy	Distal, symmetrical	Extensive, patchy
• Nerve trunks	Uncommon, often single nerve	Late, superimposed on distal neuropathy positive	Common, often multiple
Slit-skin smears	Negative	Positive	Positive in borderline-lepromatous leprosy
HLA association	HLA-DR3	HLA-DQ1	-
Reactions	Reversal reaction	Erythema nodosum leprosum	Reversal reaction, frequent
Lepromin test	Positive	Negative	Variable
Nerve biopsy	Epithelioid granuloma, no bacilli	Absent cellular reaction, bacilli present	Epithelioid granuloma, few bacilli present
Treatment with multidrug therapy	6 months	2 years	2 years for patient toward lepromatous pole
Systemic involvement	None	Nose, eye, bones, kidney, testes	None
Natural outcome	Healing	Progression	Variable

Nerve involvement. Leprosy often has an insidious protracted course and may not be recognized early. In leprosy, all physiological functions (sensory, motor, and autonomic) of a peripheral nerve are likely to be affected. Sensory functions are most severely affected. In tuberculoid leprosy, involvement of small dermal nerves of cooler parts of the body produces patchy areas of sensory loss. Pain, temperature, touch, and pressure sensations are typically impaired in affected skin areas. Vibration and proprioceptive sensations are spared until later, when nerve trunks are affected. In lepromatous leprosy there is widespread symmetrical sensory loss, particularly in cooler parts of the body. Early in the lepromatous disease, the loss of sensation is limited to knee, dorsum of the hand, forearm, and lateral legs due to infiltration of small dermal nerves. Patients with advanced lepromatous leprosy may also have progressive symmetrical, distal peripheral neuropathy; damage to nerve trunks may superimpose a picture like mononeuritis multiplex (94; 95; 68; 77; 81).

Borderline leprosy has a high propensity to involve nerve trunks, producing a picture of multiple mononeuropathies or mononeuritis multiplex. The most frequently affected peripheral nerves are peroneal and posterior tibial nerves in the lower extremities and ulnar nerve in the upper extremities. Patients with borderline leprosy have an unstable immune balance between the host’s cell-mediated immunity and bacterial replication and can progress unpredictably to either pole (10). A shift toward lepromatous pole (a downgrading reaction), with deficient immunity against Mycobacterium leprae, allows extensive proliferation of bacilli. Subsequent shift to the tuberculoid pole (an upgrading or reversal reaction), often following treatment with multidrug therapy, evokes an intense inflammatory response against Mycobacterium leprae, resulting in extensive damage to the nerve trunks (68; 15). During leprosy reactions, skin lesions often become swollen, erythematous, and tender, whereas acute neuritis leads to pain, tenderness, and loss of nerve function.

Thickened great auricular nerve (1)

Acutely inflamed great auricular nerve in a patient with borderline leprosy. The patient was on multidrug therapy. Nerve inflammation was because of type-1 leprosy reaction. (Contributed by Ravindra Kumar Garg.)

The main risk factor for the development of neuropathy is the presence of skin lesions overlying nerve trunks. Skin lesions increase the risk of sensory or motor impairment in the concerned nerve by three to four times the normal. Reactional signs in the cutaneous lesions further increase this risk to six to eight times the risk of those without such lesions. Therefore, patients with skin lesions overlying peripheral nerve trunks should be carefully monitored for development of sensory or motor impairment (125).

Patients with leprosy may also suffer from chronic neuropathic pain. Pain usually affects the distribution of one or more major nerves and may have a symmetrical glove and stocking distribution. Anticonvulsants and tricyclic antidepressants are effective in reducing chronic neuropathic pain (31; 29).

Thickened peripheral nerve trunks are one of the cardinal manifestations of leprosy.

Thickened great auricular nerve (2)

The photo shows a markedly thickened great auricular nerve. (Contributed by Dr. Ravindra Kumar Garg.)
Thickened supraorbital nerve

The photo shows markedly thickened bilateral supraorbital nerves. (Contributed by Dr. Ravindra Kumar Garg.)

The proportion of thickened nerve varies considerably in different endemic countries. For example, in a study from Ethiopia, 84% of new cases had at least one thickened nerve (99). Thickened nerves are more frequent in multibacillary leprosy. Ulnar and common peroneal nerves are the most frequently seen thickened nerves (Table 2).

Lepromatous leprosy: thickened lateral popliteal nerve

An unusually visibly thickened lateral popliteal nerve. (Contributed by Dr. Ravindra Kumar Garg.)

Diagnosis of leprosy in patients with a thickened nerve is made if, in addition, there is a characteristic skin lesion (01).

Table 2. Commonly Palpable Thickened Nerves in Leprosy

Supraorbital nerve
Great auricular nerve
Supraclavicular nerve
Ulnar nerve
Superficial radial nerve
Lateral popliteal nerve
Superficial peroneal nerve
Posterior tibial nerve

Above the eyebrows
Winds around sternocleidomastoid
Across the clavicle
Olecranon fossa
Lower end of radius at wrist
Neck of fibula
Front of ankle
Below medial malleolus

Delayed peripheral nerve dysfunction can be seen long after the completion of multidrug therapy. Several patients have been described with progressive, symmetrical, predominantly sensory neuropathy and acute or subacute multiple mononeuropathy developing approximately 10 years after multidrug therapy. These patients with delayed neuropathy showed limited response to corticosteroids (93). Pathogenesis of delayed nerve impairment is not properly understood. Antigens from dead bacilli can provoke immunological reactions and late manifestation.

In field surveys, sensory testing is performed with a Semmes-Weinstein monofilament and a ballpoint pen. Semmes-Weinstein nylon monofilaments are more sensitive for the detection of mild sensory impairments.

Sensory testing with nylon monofilament

Ten-gram monofilament mounted in a handheld unit for protection of the filament. The device is placed perpendicular to the skin of the sole, and pressure is applied until the filament bends. Patient is asked to respond with eyes c...

A large proportion of leprosy patients have subclinical neuropathy that is not evident when only monofilament testing and voluntary muscle testing are used. A group of authors conducted a cohort study to determine which test detects subclinical neuropathy earliest (126). One hundred and eighty-eight patients with multibacillary leprosy were selected from a cohort of 303 and followed for 2 years after diagnosis. Nerve function was evaluated at each visit using nerve conduction, quantitative thermal sensory testing and vibrometry, dynamometry, monofilament testing, and voluntary muscle testing. Study outcomes were sensory and motor impairment detected by monofilament testing or voluntary muscle testing. Seventy-four of 188 patients (39%) had a reaction, neuritis, or a new nerve function impairment event during a 2-year follow-up. Subclinical neuropathy was extensive (20% to 50%), even in patients who did not develop an outcome event. Sensory nerve action potential amplitudes, compound motor action potential velocities, and warm detection thresholds were most frequently affected, with sensory nerve action potential impairment frequencies ranging from 30% (median) to 69% (sural). Velocity was impaired in up to 43% of motor nerves. Warm detection thresholds were more frequently affected than cold detection thresholds (29% vs. 13%, ulnar nerve). Impairment of sensory nerve conduction and warm perception often preceded deterioration in monofilament testing or voluntary muscle testing scores by 12 weeks or more.

Among cranial nerves, facial and trigeminal nerves are the most frequently affected. Facial skin lesions are associated with a 10-fold increase in the risk of facial nerve involvement. Involvement of zygomatic and temporal branches of facial nerve may result in lagophthalmos. In lepromatous leprosy, facial nerve involvement is often bilateral (32). Involvement of the ophthalmic division of trigeminal nerve may result in corneal and conjunctival sensory loss. With presence of lagophthalmos and a dry and insensitive cornea, there is an increased risk of corneal trauma, ulcerations, and eventually blindness. In a series examining cranial nerve involvement, the facial nerve was the most common nerve affected, followed by olfactory, trigeminal and auditory nerves (28). Among the risk factors, facial nerve involvement was associated with facial patches and also the type-1 lepra reaction.

Motor involvement is less common than sensory involvement. Atrophy, weakness, and claw hand deformity are the most frequent motor complications seen in lepromatous leprosy. In the lower extremities, unilateral or bilateral foot drop may occur secondary to involvement of superficial peroneal nerves around neck or fibula. Posterior tibial nerve involvement may result in weakness and atrophy of intrinsic foot muscles (94; 95).

In leprosy, rheumatological involvement in form of arthritis is common and often leads to misdiagnosis. In leprosy, there is a spectrum of symptoms overlapping with rheumatologic diseases, especially seronegative rheumatoid arthritis. Most of the patients with rheumatological involvement belong to either lepromatous or borderline leprosy categories (46).

Leprosy reactions. Leprosy reactions are important acute events in the course of all forms of leprosy and are often associated with significant morbidity. Reactions in leprosy result in spontaneous acute exacerbation of existing manifestations or appearance of new symptoms and signs, especially during or after multidrug therapy. Reactions occur because of alteration in immune status of the patient. There are two types of leprosy reactions. Type-I or reversal reaction is seen in patients with tuberculoid and borderline leprosy. The reversal reaction typically occurs after initiation of leprosy treatment but may occur spontaneously before therapy. In reversal reaction, cell-mediated immunity is enhanced. In type-2 reaction or erythema nodosum leprosum, a systemic inflammatory response is secondary to deposition of circulating extravascular immune complexes in patients with lepromatous leprosy. Erythema nodosum leprosum is clinically characterized by fever and malaise, bone pain, nerve pain (often without loss of function), arthritis, lymphadenitis, epididymo-orchitis, iridocyclitis or episcleritis, edema of extremities on faces, and proteinuria.

A population-based, prospective cohort study including 640 newly diagnosed and registered leprosy patients (420 paucibacillary and 220 multibacillary patients) in Thailand observed that severe reversal reactions at the start of and during treatment were seen in 2.6% of the paucibacillary and 29% of the patients with multibacillary leprosy (100). It was shown that a statistically significant proportion of patients with severe reversal reactions had leprosy starting from borderline-tuberculoid and going toward borderline-lepromatous form. When all severe reversal reaction, severe erythema nodosum leprosum, and silent neuropathies (at the start of, during, and after treatment) were added together, 53% of the borderline-lepromatous and 42% of the lepromatous patients had a leprosy reaction that was severe enough to require steroid treatment. Several other studies have also demonstrated that reactions are more frequent in patients with borderline leprosy (53).

COVID-19 vaccine and leprosy flare-ups. Lately, there have been instances in which COVID-19 vaccination has led to clinical aggravation of leprosy. In one case, multibacillary leprosy was unmasked by the COVID-19 vaccination, and in a second case, type 2 lepra reaction following the COVID-19 vaccination manifested with acute foot drop. In both cases, vaccine-induced immune alterations possibly triggered lepra reaction (03; 78). Saraswat and colleagues reported a series of four patients who experienced severe leprosy reactions following COVID-19 vaccination. The clinical spectrum of leprosy reactions varied from skin type I reaction, ulnar neuritis, median nerve neuritis with nerve abscess, and erythema nodosum leprosum (97).

The clinical profile of the cases was varied, and precipitation of the entire spectrum of leprosy reactions was noted, which included cutaneous type I reaction, ulnar nerve neuritis, median nerve neuritis with nerve abscess, and type II reaction in the form of necrotic erythema nodosum leprosum.

Primary neuritic leprosy. The primary neuritic variety of leprosy is seen in 5% to 9% of leprosy patients in India and Nepal. This form of leprosy presents as peripheral neuropathy, but characteristic skin lesions are absent and skin smears are negative for acid-fast bacilli. Nerve biopsy is often required for diagnosis. It has been argued that primary neuritic leprosy may be an early stage in the pathogenesis of the nerve disease before the appearance of skin lesions. Some of these patients develop visible skin lesions during follow-up (112; 113; 36). In a study, authors observed that 29 individuals in a series of 182 primary neuritic leprosy patients developed visible skin lesions during follow-up (114). A skin biopsy from the newly appeared patch revealed borderline tuberculoid leprosy histology in 47% of the patients. For early diagnosis skin biopsy of a hypoesthetic area even without clinically visible lesions may be helpful. Histologic evaluation of a hypoesthetic area of skin of 42 clinically diagnosed primary neuritic leprosy patients revealed characteristic leprosy changes in 31% of the patients (60).

Tomaselli and colleagues evaluated the clinical, neurophysiological, and laboratory findings of 164 patients with primary neural leprosy (119). Authors noted that in the majority of patients, clinical findings are consistent with small-fiber neuropathy, and symptoms tend to first manifest in the upper limbs. Deep sensory modalities remain absent, but deep sensations, deep tendon reflexes, and motor disabilities, all consistent with predominant large fiber neuropathy, are present in patients with prolonged disease duration.

Silent neuritis. In silent neuritis or quiet nerve paralysis, the patient is unaware of neuropathy until late. These patients do not have any sensory complaint. There is no apparent sign of reversal reaction or erythema nodosum leprosum. In silent neuritis, there is continued presence of mycobacteria and its antigen in Schwann cells, however, initially without intraneural edema and early reactive fibrosis. Eventually, neural tissue is completely replaced by fibrous tissue (69; 124). Occasionally even in reversal reactions, nerve damage may be asymptomatic, and damage may progress silently for prolonged periods.

Late-onset neuropathy. A delayed neuropathy may develop in some patients after completion of treatment (13). This late-onset neuropathy insidiously and progressively evolves and presents with peripheral nerve symptoms not fulfilling criteria for relapse or leprosy reactions. Sensory symptoms predominate and peripheral nerve thickening is an important finding.

Central nervous system involvement. In leprosy, the central nervous system is generally thought to be free from bacilli. In a study, involvement of the central nervous system was noted in autopsy cases of clinically cured lepromatous leprosy and in nonleprosy cases (04). In this study, paraffin sections of the medulla oblongata and spinal cord were subjected to hematoxylin and eosin staining, Fite acid-fast staining, and antiphenolic glycolipid-I immunostaining. Phenolic glycolipid-I-positive areas were microdissected from selected cases and nested polymerase chain reaction targeting the Mycobacterium leprae–specific repetitive sequence was performed. In this series out of the 67 cases of leprosy, 44 had vacuolar changes of motor neurons either in medulla oblongata (nucleus ambiguous or hypoglossal nucleus) or spinal cord. Fite staining was negative, but phenolic glycolipid-l was positive in vacuolated areas. Polymerase chain reaction revealed Mycobacterium leprae–specific genomic DNA in 18 of 19 cases with vacuolated changes and five of eight without vacuolated changes. All of above findings were negative in control cases. There is additional evidence of central nervous system involvement in leprosy. In a patient with a cystic lesion of the right frontal lobe, the lesion was removed because of a presumptive diagnosis of low-grade glioma (49). Histopathology demonstrated variably thickened blood vessels and densely scattered foamy macrophages in the perivascular spaces and parenchymal stroma. Fite acid-fast staining displayed red granular inclusions suggestive of fragmented leprae bacilli. Involvement of the posterior segment or optic nerve in leprosy has also been described. A 47-year-old man presented with a mid-borderline leprosy lesion over the left periorbital region (83). The patient developed sudden and painless diminished vision in the left eye three weeks after treatment was started. There was left optic disc edema, hyperemia, and blurred disc margins. A month later, he returned with painless diminished vision in the other eye as well. Polavarapu and colleagues published a report of eight cases of leprosy demonstrating magnetic resonance imaging abnormalities of the brain and spinal cord as well as imaging abnormalities in nerve roots and plexus (80). Two patients had brainstem lesions. Two patients had imaging abnormalities in the spinal cord. Brachial plexus nerve enhancement was observed in six patients, and two patients had lumbosacral plexus involvement. In a prospective study, Verma and colleagues noted that among 29 patients with nerve-biopsy confirmed cases of multibacillary leprosy, five patients had MRI abnormalities in CNS, spinal root ganglion, or brachial plexus (131). Three patients had either myelitis or ganglionitis. One patient each had T2/FLAIR hyperintensity in the middle cerebellar peduncle or in the brachial plexus.

Biological basis

Etiology and pathogenesis

The causative agent of leprosy, Mycobacterium leprae, is a gram positive, rod-shaped, obligate intracellular acid-fast bacillus. Mycobacteria multiply slowly, once in 12 to 14 days. Bacteria multiplies best at temperatures of 27°C to 30°C, so it prefers the cooler areas of the human body, like skin, superficial nerves, nose, eyes, and testes for multiplication. Mycobacterium leprae has never been grown in artificial bacteriological media or cell culture but has been grown in mouse footpads. The organism enters into the healthy contacts, possibly through breaches in skin or via airborne infection through nasal mucosa. Incubation period is about 2 to 5 years. Mycobacterium lepromatosis has been identified in patients with leprosy and severe erythema nodosum leprosum (82).

Genetic susceptibility. Only genetically susceptible individuals among vastly exposed populations develop leprosy. A major susceptibility locus for leprosy in India was mapped to chromosome 10p3 and in Vietnam to chromosome 6q25. Genetic factors determine the host's immune reaction against leprosy (105; 63). Further confirmation of the chromosome 6 locus in Vietnamese families was provided by high-resolution linkage mapping studies. A significant discovery narrowed the chromosome 6 susceptibility locus to the 5' regulatory promoter region shared by both the Parkinson disease gene PARK2 and its co-regulated gene PACRG. Variants in the regulatory region shared by PARK2 and PACRG have been identified as common risk factors for leprosy (62). In the Brazilian and Vietnamese populations, HLA-DRB1*10 is associated with susceptibility to leprosy and HLA-DRB1*04 is associated with resistance. These alleles possibly play an important role in the activation of cellular immune responses against Mycobacterium leprae (127). Investigations revealed that polymorphisms in the nucleotide-binding oligomerization domain containing 2 (NOD2) gene, for a cytosolic receptor known to detect mycobacteria, were associated with susceptibility to leprosy and its clinical outcomes (145; 09). A Chinese study observed genetic associations implicating IL23R and RAB32 as new susceptibility genes for leprosy (144). This genetic study suggested a potential involvement of autophagocytosis in leprosy pathogenesis.

A variety of genetic polymorphisms in innate immunity genes are known to be involved in susceptibility to leprosy. Toll-like receptor 2, a pattern recognition receptor of innate immune system present on human Schwann cells and other inflammatory cells, is critical in the immune response against mycobacterial infection. These receptors bind molecular structures that are expressed by the microbes but are not expressed by the human host like lipopolysaccharides or double-stranded RNA. Mutations in toll-like receptor 2 genes have been shown to confer susceptibility to infection with Mycobacterium leprae. Activation of toll-like receptor 2 is associated with enhanced apoptosis of Schwann cells. The toll-like receptor 2 signal pathway plays an important role in the alteration of cytokine profiles in peripheral blood mononuclear cells from leprosy patients. The toll-like receptor 2 mutation Arg677Trp, a polymorphism that is associated with lepromatous leprosy, suggests a possible mechanism for the poor cellular immune response associated with lepromatous leprosy (40; 41; 42; 44). Polymorphism N248S in the human Toll-like receptor 1 gene has also been found associated with leprosy and leprosy reactions. This polymorphism may affect the progression of leprosy from infection to disease as well as the disease course and the risk of debilitating reactional episodes (101).

Pathogenesis of nerve injury. Schwann cells of peripheral nerves are the principal target of Mycobacterium leprae. The mechanisms of bacterial entry into the nerve and subsequent nerve damage are not precisely known. Possibly, infected monocytes from broken skin and mucous membrane (eg, nasal mucosa) carry the bacilli to the peripheral nerves, and circulating mycobacteria gain entry into the nerve by breaking the blood-nerve barrier (30). Evidence from infected armadillos suggests that endothelial cells of peripheral nerve vasculature may be the entry point by which Mycobacterium leprae infect nerves (102).

Mycobacterium leprae have a great affinity for Schwann cells. A species-specific glycoprotein, phenolic glycolipid-1, which is present on outer capsule of bacilli, facilitates entry into the Schwann cells by creating a complex with G domain of alpha2 chain of laminin-2, a protein complex present on the basal lamina of Schwann cells (86). Bacterial entry into the Schwann cells occurs following binding of Mycobacterium leprae or laminin alpha2 complex with alpha-dystroglycan. Alpha-dystroglycan was shown to serve as a Schwann cell receptor for Mycobacterium leprae (87). A 21-kDa surface protein of Mycobacterium leprae also binds peripheral nerve laminin-2 and mediates Schwann cell invasion (104). Once inside the Schwann cells, Mycobacterium leprae replicates slowly. Type-1 lymphocytes play a crucial role in the pathogenesis of nerve damage. Infected Schwann cells are also actively involved in the inflammatory process (25). Schwann cells process and present Mycobacterium leprae antigens to major histocompatibility complex class-II restricted CD4 + T cells. Activated T cells, in turn, efficiently kill infected Schwann cells (111; 110). It is possible that cytokine production and apoptosis of Schwann cells directly affect nerve degeneration and regeneration, leading to injury of the myelin sheath and axon. The data from a study indicate that induction of Schwann cells death after cell interaction with Mycobacterium leprae may be implicated in the pathogenesis of nerve damage, which can most likely be modulated by in vivo cytokine production (75). Another mechanism by which T cells contribute to host defense against microbial pathogens is release of the antimicrobial protein granulysin (73). Axons are destroyed as innocent bystanders in the inflammatory process (68).

A group of researchers showed that the leprosy bacteria reprogram Schwann cells from mice into programmed stem cell–like cells or programmed mesenchymal stem cells (57). Reprogramming accompanies several genetic alterations and renders infected cells highly plastic, migratory, and immunomodulatory. The authors suggest that conversion of Schwann cells into programmed stem cell–like cells promotes bacterial spread. These cells can detach from the nerves and migrate to distal sites and re-establish a site of new infection and tissue damage through redifferentiation. At distant places, programmed stem cell–like cells start recruiting inflammatory cells and then transfer the leprosy bacteria to macrophages and, thus, spread the infection.

Tuberculoid and lepromatous forms of leprosy have different kinds of immune responses. In tuberculoid leprosy, a Th1 response causes release of interferon-gamma, TNF-alpha, and interleukin 2 and 15, which help to activate macrophages and to form an epithelioid granuloma in the skin and nerves. This type of immunological response is associated with protective immunity and destruction of Mycobacterium leprae. In lepromatous leprosy, Th 2 or suppressor response causes release of interleukins 4, 5, and 10, which inhibit the macrophages to initiate a protective response against Mycobacterium leprae, resulting in immune unresponsiveness (96; 142; 98; 130; 143).

Matrix metalloproteinases and tumor necrosis factor alpha play important and related roles in the pathogenesis of nerve injury in patients with leprosy. Matrix metalloproteinases-dependent and tumor necrosis factor alpha-dependent processes, such as blood-nerve breakdown and immune cell recruitment, are characteristic of leprosy nerve damage. One study provides evidence of the involvement of matrix metalloproteinases in the pathogenesis of pure neuritic leprosy as well (117). One study suggested that Mycobacterium leprae and tissue necrosis factor may directly induce Schwann cells to upregulate and secrete matrix metalloproteinases in leprous neuropathy (74).

In reversal reaction, there is spontaneous augmented cell-mediated response against the Mycobacterium leprae antigen. There is an enhanced influx of CD4+ T cells into the lesions. Elevated levels of cytokine mRNA and inflammatory substances TNF-alpha have been detected in situ (50). Increased levels of enzyme nitric oxide synthase are found in reactional lesions, indicating an enhanced intracellular killing capacity of macrophages. High levels of inflammatory cytokines like interferon-gamma, TNF-alpha, and interleukin 10 are associated with recurrent episodes of reversal reactions and a poor response to corticosteroids (54). Erythema nodosum leprosum is characterized by polymorphonuclear leukocytosis and a systemic inflammatory response secondary to the deposition of extravascular immune complexes. High circulating levels of TNF-alpha and other chemical mediators of inflammation have been demonstrated. In a study, the gene and protein expression of toll-like receptors 2 and toll-like receptors 4 were both shown to be significantly reduced during corticosteroid treatment (133).

Several other factors also play an important role in nerve damage. Edema, nerve entrapment, cellular infiltration, granuloma, and abscess formation may produce pressure-mediated ischemia and resultant nerve damage. Mechanical factors like repeated injuries to a superficially swollen nerve further aggravate the nerve inflammation. Recurrent ischemia and inflammatory changes eventually lead to extensive damage of the nerve. Leprosy produces an irreversible nerve damage in which fibrosis plays an important role.

Pathology. In the early stages of the disease, Schwann cells of unmyelinated nerve fibers harbor the bacilli; bacilli are rarely seen in the Schwann cells of myelinated fibers. Myelinated nerve fibers are usually resistant to Mycobacterium leprae invasion. Axons are the primary site of nerve damage preceding demyelination. In a nerve tissue culture model, Mycobacterium leprae have been shown to produce rapid demyelination of peripheral nerves by a contact-dependent mechanism, in the absence of immune cells (88).

Pathologic changes in tuberculoid leprosy are characterized by formation of epithelioid and giant cell granuloma. The granuloma consists of lymphocytes, epithelioid cells, and Langerhans giant cells.

Nerve biopsy in borderline leprosy

Nerve tissue has been replaced by an epithelioid granuloma. Epithelioid cells and lymphocytes surround Langerhans giant cell. (Hematoxylin and eosin stain, 625X) (Contributed by Ravindra Kumar Garg.)

There is extensive destruction of cutaneous nerves and large nerve trunks. Acid-fast stain does not reveal Mycobacterium leprae. In lepromatous leprosy, the structure of all affected dermal nerves is largely intact. Nerves are extensively infiltrated with Mycobacterium leprae. Macrophages and Schwann cells filled with bacilli surround the nerve endings (16; 103; 39). In the sections stained with Fite’s modification of Ziehl-Neelsen stain globi (histocytes containing acid-fast bacilli, also called Virchow cells) are found in linear arrays along the nerve fibers (81). Lymphocytic infiltration is characteristically absent. The perineurium of the peripheral nerve splits into layers by sheet of foamy cells and edema; later macrophages invade the endoneurium as well.

Nerve biopsy in lepromatous leprosy: hematoxylin and eosin stain

Longitudinal section of peripheral nerve showing absence of lymphocytic infiltration. There is splitting of perineurium in layers by sheet of foamy cells and edema. (625X) (Contributed by Ravindra Kumar Garg.)
Nerve biopsy in lepromatous leprosy: staining with Fite stain

Schwann cells with acid-fast bacilli. Bacilli stain red. (1250X) (Contributed by Ravindra Kumar Garg.)

The degenerative changes of the myelin sheaths are caused by destruction of Schwann cells. Pathological changes lead to axonal degeneration and, later, Wallerian degeneration. In borderline leprosy, fascicles of nerve trunks are destroyed by epithelioid granuloma. Few acid-fast bacilli may be demonstrated in the nerve tissues (16; 103; 39).

Lepromatous leprosy: lepra bacilli in nerve tissue

Wade Fite stain reveals multiple bacilli, single and in groups (arrows). Wade Fite, x1000. (Contributed by Dr. Ravindra Kumar Garg.)
Tuberculoid leprosy: histopathology

An enlarged nerve funicle showing a large central area of necrosis (*) and epithelioid cell granulomas at the periphery (arrow). Hematoxylin and Eosin stain, x200. (Contributed by Dr. Ravindra Kumar Garg.)

Axonal loss is early and extensive; evidence of regeneration of axons may also be seen (61).

Neuropathological changes of reversal reaction are characterized by marked increase in the size of epithelioid granuloma, massive fresh infiltration of lymphocytes, and extracellular edema. Occasionally, there is caseous necrosis and formation of nerve abscess. In erythema nodosum leprosum, there is massive influx of neutrophils inside the neural tissue. Vasculitis involving small arteries and arterioles produces ischemia and further damage to nerves (103; 39).

“End-stage neuritis” is a term used for all types of leprosy when neural tissues of infected nerves are completely replaced by fibrous tissue. At this stage, differentiation of leprosy from various other diseases of nerves is often impossible (39; 58).

Epidemiology

According to the World Health Organization reports received from 121 countries, the global registered prevalence of leprosy is 175,554 cases (0.24 cases per 10,000 people) at the end of 2014; during the same year 213,899 new cases (0.3 new cases per 10,000 people) were reported. In 2013, 215 to 656 new cases were reported (139). There was a marginal increase in the number of cases in 2016.

The global prevalence rate of leprosy is steadily decreasing. The latest reports from 139 countries revealed that there was a total of 127,558 newly diagnosed cases of leprosy during 2020. There were 8629 pediatric cases less than 15 years of age. The new case detection rate among the child population was 4.4 per million child population. The current prevalence of leprosy is 129,389 cases on treatment, and the prevalence rate corresponds to 16.7 per million population (140).

Data revealed that 200,808 (94%) of new leprosy cases were reported from 13 countries and only 6% of new cases from the rest of the world. Only these 13 countries reported more than 1000 new cases in 2014 (139). Pockets of high leprosy endemicity remain in some areas of Angola, Brazil, Central African Republic, Democratic Republic of Congo, India, Madagascar, Mozambique, Nepal, and the United Republic of Tanzania (139).

Leprosy is a rare disease in western countries. In 2002, only 96 new cases of leprosy were detected in United States and only 34 in Europe (14; 138). Almost all leprosy cases reported in developed countries are either immigrants or refugees from developing countries where leprosy continues to be an important health issue. Leprosy occurs in all age groups. The peak age of onset is between 10 and 20 years. The disease is rare in infancy. Leprosy affects males more frequently than females (M: F=1.5:1). Poverty, poor hygiene, and overcrowding are important risk factors for disease transmission.

There are reports that have indicated that the COVID-19 pandemic had an impact on the diagnosis and treatment of leprosy. One such report in Brazil during the year 2020 recorded a 41.4% reduction of leprosy cases; however, paradoxically during this period, the diagnosis of multibacillary leprosy increased (22). Data indicated a severe blow on leprosy control strategies in Brazil.

Studies conducted in various endemic countries have mentioned different incidence rates of nerve function impairments in patients with leprosy. Multibacillary leprosy has a higher incidence of nerve function impairments. In China, a total of 1407 patients were monitored for possible nerve function impairment through standardized clinical nerve function assessment; of these, 191 patients were found to have nerve function impairment and were put on a fixed regimen of prednisolone. In this study, 36.7% of nerve function impairment occurred before diagnosis of leprosy, 35.6% developed during multidrug therapy, and 25.7% after their release from multidrug therapy (38). In the Ethiopian All Africa Leprosy and Rehabilitation Training Center multidrug therapy field evaluation study, among 594 newly registered patients (300 multibacillary and 294 paucibacillary leprosy), 55% of patients had some degree of nerve function impairment at registration, and 73 (12%) developed new nerve function impairment after starting multidrug therapy (99). The Bangladesh Acute Nerve Damage study, a prospective follow-up study of 2664 newly diagnosed patients with leprosy, revealed that at registration approximately 12% of the cohort had sensory nerve dysfunction, and 7.4% had motor nerve dysfunction of any kind (20). Multibacillary patients had a prevalence of reactions or nerve function impairments needing treatment nearly seven times higher than paucibacillary leprosy cases. Within the observation period of three years for paucibacillary leprosy and five years for multibacillary leprosy, approximately 2.5% (54/2153) and 34% (121/357) of patients respectively developed new nerve function impairments. In 95% of patients, nerve function impairment occurred within two years of registration (89). It is assumed that all patients with leprosy will eventually develop nerve function impairment if left untreated (02). Delays in initial presentation and subsequent treatment were associated with higher incidence of nerve function impairment and WHO grade-2 disability (71) (Table 3).

Table 3. WHO Grading System of Leprosy-Associated Disability

Grade	Disability
0 1 2	No anesthesia No visible deformity or damage Anesthesia present No visible deformity or damage Visible deformity or damage present

Patients with multibacillary leprosy and existing nerve function loss at registration had a high risk of developing new nerve function impairment. On the contrary, patients with paucibacillary leprosy but without nerve function loss had the least risk (18; 19). Most of the nerve damage in leprosy takes place during leprosy reactions, both in reversal reaction and erythema nodosum leprosum.

Prevention

Bacillus Calmette-Guerin vaccination provides some protection against both types of leprosy. A combination of killed Mycobacterium leprae and bacillus Calmette-Guerin further increases the protective effect of the vaccination. Dapsone prophylaxis in high-risk contacts is of no proven value, hence, is not recommended. A program of leprosy chemoprophylaxis, employing a supervised, single 25 mg/kg dose of rifampicin, was implemented in the Southern Marquesas Islands; the effectiveness of the chemoprophylaxis was only 35% to 40% (70). As per current World Health Organization recommendation, single-dose rifampicin may be used for contacts of leprosy patients (141).

Wang and colleagues conducted a randomized controlled trial in China and assessed the efficacy of single-dose rifapentine in preventing leprosy among household contacts of leprosy patients (134). The trial included 207 clusters with a total of 7450 participants, divided into three groups: rifapentine, rifampin, and a control group with no intervention. Over a 4-year period, 24 new leprosy cases were noted. The cumulative incidence of leprosy was significantly lower in the rifapentine group (0.09%, or two cases) compared to the control group (0.55%, or 13 cases), indicating an 84% reduction in incidence. The rifampin group showed a nonsignificant difference from the control group, with a 0.33% incidence (nine cases). In a per-protocol analysis, the incidence rates were even lower for the rifapentine and rifampin groups. No severe adverse events were reported. These results suggest that a single dose of rifapentine is more effective in reducing the incidence of leprosy among household contacts compared to no intervention.

Educating the patients about self-care is of paramount importance in preventing disability. For example, anesthetic foot requires protective footwear to prevent trauma, ulcers, and infections.

Differential diagnosis

Confusing conditions

The precise diagnosis of leprosy is of great importance as early diagnosis and treatment will prevent disabilities. In western countries, unawareness about leprosy often results in delay in diagnosis (52; 76). Whenever a patient from an endemic country is seen with chronic skin disease and peripheral neuropathy, leprosy must be included in the differential diagnosis. The diagnosis of leprosy depends on presence of three cardinal features: anesthetic skin lesions, thickened peripheral nerve, and acid-fast bacilli in skin smears. In a patient with peripheral neuropathy, a characteristic sensory loss (involvement of pain and temperature, sparing of proprioceptive and vibration sensations), preserved deep tendon reflexes, and thickened nerves are highly suggestive of leprosy. Distinctive temperature-linked pattern of sensory loss helps in differentiating lepromatous leprosy from other polyneuropathies. In lepromatous leprosy, there is often disproportionate sensory loss in the upper extremities, whereas in most toxic, metabolic, and familial polyneuropathies, as the longest nerve fibers degenerate early, sensory manifestations are more marked in lower extremities. In lepromatous leprosy, there is often early loss of sensations in the ears and face, but sensations of palm and sole remain unaffected until later (94; 95; 15). In absence of sensory manifestations, diagnosis of leprosy should be made with great caution. Deep pain on percussion of lesions over bone in tuberculoid leprosy, in spite of superficial sensory impairment, has been described as the "Tap sign.” The Tap is a useful clinical sign in diagnosis of tuberculoid and borderline tuberculoid leprosy where a lesion overlies a bone (sensitivity 66.7%) (45).

Anhidrosis in skin is another hallmark of leprosy, attributed to early invasion by Mycobacterium leprae of Schwann cells related to unmyelinated nerve fibers (Table 4) (121).

Table 4. Differential Diagnosis of Neuropathy Associated with Leprosy

Cranial nerves
	Bell palsy
Spinal cord
	Cervical spondylosis Syringomyelia Cervical cord tumor Amyotrophic lateral sclerosis Spinal muscular atrophy
Peripheral nerves
	Mononeuropathy
		Carpal tunnel syndrome Traumatic neuropathy Neurofibromatosis Meralgia paresthetica Diabetic neuropathy
	Mononeuritis multiplex
		Vasculitis Amyloidosis Diabetes Lyme disease Toxic neuropathy
	Sensory neuropathy
		Hereditary sensory autonomic neuropathy Tabes dorsalis Paraneoplastic ganglionopathy Postinfectious small fiber sensory neuropathy
	Sensory-motor neuropathy
		Tangier disease Chronic inflammatory demyelinating neuropathy
	Thickened nerves
		Amyloidosis Diabetes Neurofibromatosis
Other disorders
	Lambert Eaton syndrome

In endemic areas, leprosy is an important cause of bilateral facial palsy. Lyme disease, Guillain-Barré syndrome, Bell palsy, leukemia, sarcoidosis, bacterial meningitis, syphilis, infectious mononucleosis, and skull fracture are the common causes of bilateral facial paralysis and require differentiation. When the facial nerve is affected in leprosy, the earliest sign is of involvement of the lower lid because of selective involvement of the zygomatic branch of the facial nerve. Involvement of the lower lid can be demonstrated by asking the patient to close the eyes slowly and gently; this method will reveal that defective eye closure is because of weakness of the lower lid. This phenomenon helps in differentiating facial palsy due to leprosy from other causes of facial palsy.

Trophic ulcers are often seen in patients with sensory or autonomic neuropathy. In addition to leprosy, other common diseases associated with trophic ulcers are diabetic neuropathy, vasculitic neuropathy, hereditary sensory autonomic neuropathies, and Tangier disease. In areas endemic for Hansen disease, patients with trophic ulcers often receive anti-leprosy treatment without a definite diagnosis. For example, Sinha and colleagues reported a patient with Tangier disease who took anti-leprosy treatment for several years before the correct diagnosis was established (107).

Diagnostic workup

Electrophysiology. Electrophysiological assessment in leprosy indicates both axonal loss and demyelination. Nerve conduction studies often reveal slowed nerve conduction velocities. Amplitudes of compound action potentials may be prominently reduced. Focal slowing, across thickened nerve segments and sites of focal involvement, is present (85). Partial conduction block suggestive of segmental demyelination has been demonstrated (27). Sensory nerve action potentials are either absent or reduced. Axonal involvement can also be demonstrated by needle EMG. Abnormal spontaneous activity and large motor unit potentials may be recorded from involved muscles. An electrophysiological study revealed that leprosy causes a predominantly axonal polyneuropathy (109). Changes are more severe in the lower extremities. Sensory nerve damage is accompanied by autonomic involvement (109). Reversal reactions cause greater electrophysiological abnormalities both in clinically and subclinically affected nerves (118). Near nerve potential recording increases the sensitivity of nerve conduction studies (56). Electrophysiological assessment of the autonomic nervous system reveals abnormalities in fingertip blood flow velocity, sympathetic skin response, and heart rate (RR) interval variation (135; 121). Blink reflex testing can provide useful and objective information for the diagnosis of trigeminal and facial cranial nerves lesions (120).

Sonography. Ultrasonography of nerve can provide useful information about nerve morphologic alterations regarding the echo texture and location of nerve enlargement (34; 07). High-resolution ultrasonography is emerging as an important tool to diagnose primary neuritic leprosy and nerve abscesses. Ultrasound in nerve abscess shows diffuse thickening of the nerve with hypoechoic texture and a cystic lesion with internal debris (35; 84).

Slit-skin smears. For bacteriological confirmation and to assess the response of multidrug therapy, slit-skin smears are invaluable. With the help of a scalpel, skin slit is made at six sites while holding the edges firmly so there is no bleeding; expressed fluid is taken over a glass slide. Four smears are taken from edges of active skin lesion and two from ear lobes. Smears are stained with Ziehl-Neelsen stain, and the density of acid-fast bacilli is assessed.

Lepromatous leprosy: positive slit-skin smears examination

A Slit-skin smear stained with Ziehl-Neelsen stain showing globi of acid-fast bacilli in a patient with lepromatous leprosy. (Contributed by Dr. Ravindra Kumar Garg.)

Skin biopsy. Skin biopsy is performed when diagnosis is in doubt, as in patients with tuberculoid leprosy. Biopsy is also used in order to demonstrate the characteristic histopathology for classification of leprosy type. Skin biopsy should include the full depth of dermis and should be taken from the active edge of a lesion. The sections are usually stained with hematoxylin and eosin stain. For demonstration of Mycobacterium leprae, Fite’s modification of Ziehl-Neelsen stain is used. Fine needle aspiration cytology of a skin lesion is an excellent alternative to skin biopsy.

Nerve biopsy. Nerve biopsy is indicated in patients with unexplained mononeuropathy, mononeuritis multiplex, or distal sensory motor neuropathy. Because of absent skin lesions, primary neuritic leprosy poses a great diagnostic challenge, and diagnosis requires nerve biopsy (23). Cutaneous sensory nerves suitable for biopsy are the sural nerve at the back of leg, a superficial peroneal nerve on the dorsum of foot, and radial cutaneous nerve just above the wrist. Because these nerves do not contain motor fibers, there is no risk of motor damage. Fine needle aspiration cytology is an effective alternative to open nerve biopsy (106). Immunohistochemical staining technique, if applied to skin and nerve biopsy samples, may increase the sensitivity and specificity of the histological diagnosis of leprosy.

Skin biopsy in borderline leprosy: immunohistochemical staining

Skin lesion stained with antibacillus Calmette-Guerin for Mycobacterium leprae and counterstained with hematoxylin. The presence of antigen (stained dark brown) in epithelioid cells can be noted. (Contributed by Ravindra Ku...

Lepromin test. The lepromin test assesses the patient’s cell-mediated immunity against Mycobacterium leprae and helps in classifying the leprosy in two polar forms. Lepromin is a suspension of autoclaved Mycobacterium leprae obtained from human or armadillo; 0.1 ml is injected intradermally, and skin responses are recorded at 48 to 72 hours (Fernandez reaction) and induction of skin after three weeks to four weeks (Mitsuda reaction). Late Mitsuda reaction is an indication to the cell-mediated immunity against leprosy. Lepromin test is strongly positive in tuberculoid leprosy, whereas in lepromatous leprosy patients, the response is negative.

Serological tests. A simple dipstick assay based on the detection of antibodies to the Mycobacterium leprae-specific phenolic glycolipid-I antigen can be used as a tool for classification of patients in paucibacillary leprosy and multibacillary leprosy categories for treatment purposes. The sensitivity of the dipstick test for detection of multibacillary leprosy patients was 85.1%, the specificity 77.7% (12). Antiphenolic glycolipid-I assay using Mycobacterium leprae particle agglutination assay and ELISA has also been reported to be helpful in early detection of relapses in multibacillary leprosy. Detection of antibodies against phenolic glycolipid-I in patients with peripheral neuropathy is useful for the diagnosis of pure neural leprosy (37).

Polymerase chain reaction. Various PCR techniques to amplify DNA of Mycobacterium leprae and detection of amplified sequences of target DNA, at times, can confirm the diagnosis. PCR-based methods have been useful in confirming the diagnosis in paucibacillary leprosy (where few bacilli are present). Bacteriological confirmation in primary neuritic leprosy may not be possible even after histopathology; in a study, presence of Mycobacterium leprae in nerve was demonstrated by PCR techniques (36).

Artificial intelligence for the diagnosis of leprosy. A study has presented AI4Leprosy, an artificial intelligence diagnostic tool combining skin images and clinical data for leprosy diagnosis (06). In 222 patients at a Brazilian referral center, the study compiled an open-source dataset of 1229 images and 585 metadata sets. Using convolutional neural network algorithms, the study tested three artificial intelligence models, analyzing the data both individually and collectively. Key diagnostic indicators identified included thermal sensitivity loss, nodules, papules, feet paresthesia, lesion count, and gender. The models achieved a 90% accuracy and an area under curve of 96.46%.

Management

Multidrug therapy. For the treatment of leprosy, WHO recommends multidrug therapy regimens consisting of a combination of rifampicin, dapsone, and clofazimine. Rifampicin is a bactericidal drug and is administered once a month because Mycobacterium leprae multiplies slowly. Dapsone is a bacteriostatic drug, which is given daily. Monotherapy, especially in suboptimal doses, and irregular treatment with dapsone may result in drug resistance. Clofazimine is a weak bactericidal drug with antiinflammatory properties. The drug is effective in controlling systemic inflammation of erythema nodosum leprosum in patients with lepromatous leprosy. Every leprosy patient should be treated with the same three-drug regimen (rifampicin, dapsone, and clofazimine) with a duration of treatment of six months for paucibacillary leprosy and of 12 months for multibacillary leprosy (141) (Table 5).

Rifampicin-resistant leprosy patients require at least two of the second-line drugs: clarithromycin, minocycline, or a quinolone (ofloxacin, levofloxacin, or moxifloxacin), plus clofazimine daily for six months, followed by clofazimine plus one of the second-line drugs daily for an additional 18 months. Patients resistant to both rifampicin and ofloxacin may be treated with clarithromycin, minocycline, and clofazimine for six months, followed by clarithromycin or minocycline plus clofazimine for an additional 18 months (141).

All treated patients should be followed for reactions or relapse for at least 5 to 10 years after multidrug therapy is complete.

Table 5. Leprosy: WHO-Recommended Treatment Regimens

		Dapsone (per day)	Rifampicin (per month)	Clofazimine
• Adult • Children		100 mg	600 mg	50 mg daily + (300 mg once a month)
	- 10 to 14 years - Younger than 10 years	50 mg 2 mg/kg	450 mg 10 mg/kg	50 mg daily + (150 once a month) 1 mg/kg daily + (6 mg/kg once a month)
Duration: 6 months for paucibacillary and 1 year for multibacillary leprosy (141).

According to the National Hansen disease program in the United States, rifampicin needs to be given daily, and total duration of paucibacillary leprosy is of 1 year (68; 76).

Reactions in leprosy are treated with oral corticosteroids. Reversal reaction is treated with 40 to 60 mg prednisolone per day; doses may be tapered once reaction begins to subside. If neuritis (nerve tenderness, anesthesia, or motor loss) is present, three to six months of prednisolone administration is required (67). Erythema nodosum leprosum is best treated with prednisolone or thalidomide. Thalidomide (an anti-TNF-alpha agent) in starting doses of 300 to 400 mg per day effectively controls systemic manifestations of erythema nodosum leprosum within a few days; then for maintenance, 100 mg per day is sufficient. Thalidomide is an expensive drug and has a great teratogenic potential. Pentoxifylline and colchicine may be effective in mild cases. Neuritis in erythema nodosum leprosum requires use of prednisolone (76; 33).

Leprosy and HIV infection. Immunodeficiency caused by HIV infection does not alter the course of leprosy (26). Leprosy management is similar to that of non-HIV infected persons. Several reports described that the immune reconstitution inflammatory syndrome following antiretroviral therapy may lead to either unmasking or paradoxical worsening of leprosy in HIV-infected patients (47; 17; 79; 59). One such report described three cases of leprosy occurring in patients treated with combination antiretroviral drugs. The patients fulfilled the criteria for an immune reconstitution inflammatory syndrome (IRIS). A reactional state occurred in all three cases. Two of the three patients developed unusual ulcerous progression of the lesions not generally observed in cases of leprosy (17). Upgrading shifting of leprosy clinical forms after initiation of highly active antiretroviral therapy leads to a reactional state (116).

Leprosy and tuberculosis. In endemic areas, leprosy and tuberculosis may coexist. Patients taking antituberculous treatment do not require taking monthly rifampicin of multidrug therapy.

Treatment of neuropathy. In addition to multidrug therapy, leprosy patients with recent nerve function impairment should promptly be treated with oral corticosteroids (02; 51). Approximately 60% of patients treated with corticosteroids regain nerve function. In endemic countries, under field conditions, a fixed-dose standardized regimen of prednisolone is administered by paramedical workers. Total recommended duration of prednisolone treatment is 12 weeks for paucibacillary leprosy and 20 weeks for multibacillary leprosy. Prednisolone is initially administered in doses of 40 mg daily, which is gradually tapered off within the treatment period (21). However, in patients with longstanding (longer than six months) nerve function impairment, corticosteroids have no definite role, as the nerve is considered to be damaged irreversibly. In a study of patients with longstanding nerve function impairment, no demonstrable benefit of corticosteroids was observed (90). On the contrary, 50% of patients of both prednisolone and placebo groups showed spontaneous improvement of nerve function. Corticosteroids are used in patients with silent neuropathy. Prednisolone is given in doses of 50 mg daily with tapering over four months (11). Treatment of recent facial nerve damage with lagophthalmos, using a semistandardized steroid regimen, demonstrated that after completion of the steroid course, 75% of the eyes had complete closure or only a slight gap of less than or equal to two mm on gentle closure. Steroids were found to be beneficial and safe in patients with lagophthalmos (43). According to the latest Cochrane analysis, at the present time, there is not enough evidence from randomized controlled trials to suggest a significant long-term benefit of corticosteroids in treatment of neuropathy associated with leprosy. Moderate-quality evidence from two randomized controlled studies 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 5-month steroid regimen over a 3-month regimen in terms of response to treatment (need for additional corticosteroids). It was felt that more quality randomized controlled studies are needed to establish optimal corticosteroid regimens for the treatment of nerve damage in leprosy (128).

A study observed a beneficial role of methylprednisolone in patients with leprosy who experienced type 1 reactions or nerve function impairment. In this study, 42 patients with leprosy were randomized to receive methylprednisolone followed by oral prednisolone or oral prednisolone alone. Patients 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 or nerve function impairment required additional prednisolone despite treatment with 16 weeks of corticosteroids (132).

Prophylactic use of prednisolone (along with multidrug therapy) is less well established. In a double-blind randomized controlled trial, new multibacillary leprosy patients either received prednisolone (20 mg daily for first three months, tapered off for the four months) or placebo. Corticosteroids significantly prevented episodes of reaction and new nerve function impairments during a prophylaxis period of four months; however, the protective effect of corticosteroids was lost at the end of 12 months (108). Even in patients with mild sensory impairment, corticosteroids were not helpful in preventing further deterioration in sensory function (123). Standardized regimens of corticosteroids are generally safe under field conditions (91). The effects of prednisolone treatment on the cellularity and cytokine (gamma-interferon, interleukin-12, and inducible nitric oxide synthase) profiles, in skin lesions with type-1 (reversal) reactions, were studied using immunohistochemistry. Prednisolone treatment had little effect at day 7, but by day 28 significant decreases were found in cytokine levels. Some patients maintained decreased cytokine production at days 28 and 180 (50).

Surgical decompression of the nerve may be required if medical treatment fails to provide adequate relief from painful neuritis. Surgery is expected to prevent further damages of nerve fibers from intraneural or extraneural compression (08). However, evidence from randomized controlled trials does not show a significant added benefit of decompressive surgery over steroid treatment alone (129).

Patients should be trained to promptly recognize signs and symptoms of reversal reactions and acute nerve function impairment. Patients with a planter ulcer should not be allowed to wear the weight until the ulcer is healed. Contractures of the hand, foot, lagophthalmos, and other ocular deformities need reconstructive surgery. Socioeconomic rehabilitation of the patient with participation of government, family, and community is invaluable (02).

Outcomes

Multidrug therapy is effective both in multibacillary and paucibacillary leprosy. Multidrug therapy helps in preventing disabilities (02). Nerve function may partially improve with early treatment. Skin lesions of paucibacillary leprosy resolve within one year; however, in patients with multibacillary leprosy, skin lesions persist longer. Relapse rate in both types of leprosy is low. One paper reports on relapses 20 years after patients were inducted into the WHO field trial. Between 1981 and 1982, 1067 borderline lepromatous and lepromatous patients were inducted into the trial for multidrug therapy. Among them, 357 patients were skin-smear positive. During the follow-up in 2002 (mean duration of follow-up 16.4 +/- 1.83 years), 173 of the skin-smear positive patients could be traced and assessed. Two patients relapsed 14 and 15 years after completion of treatment, the relapse rate being 0.07 per 100 person years follow-up (72).

Complications of neuropathy. Use of anesthetic hands may result in repeated injuries, burns, recurrent infections, and, subsequently, mutilation and shortening of digits. Late complications of nerve damage include vasomotor and trophic changes, nonhealing planter ulcers, gangrene, skin cracks, pyogenic osteomyelitis, muscle wasting, and resorption of soft tissues and bones (122).

Planter ulcer in leprosy

A nonhealing planter ulcer in a patient borderline leprosy. (Contributed by Ravindra Kumar Garg.)
Vitiligo in leprosy

This patient with borderline leprosy who had an episode of ulnar neuritis (as a manifestation of leprosy reaction) developed vitiligo in affected the region. (Contributed by Ravindra Kumar Garg.)
Severe trauma in lepromatous leprosy

This lepromatous leprosy patient experienced severe trauma (Contributed by Ravindra Kumar Garg.)
Gangrene in a patient with leprosy

Gangrene of the little finger in patient of leprosy. Patient also has a hypoesthetic skin lesion in the lateral aspect of the dorsum of the hand as well. (Contributed by Dr. Ravindra Kumar Garg.)

Media

References

01: Anonymous. Diagnosis and classification of leprosy. Lepr Rev 2002a;73:S17-26.
02: Anonymous. Prevention of disabilities and rehabilitation. Lepr Rev 2002b;73:S35-48.
03: Aponso S, Hoou LC, Wei YY, Salahuddin SA, Yit PJ. Multibacillary leprosy unmasked by COVID-19 vaccination. JAAD Case Rep 2022;19:87-9. PMID 34841026
04: Aung T, Kitajima S, Nomoto M, et al. Mycobacterium leprae in neurons of the medulla oblongata and spinal cord in leprosy. J Neuropathol Exp Neurol 2007;66(4):284-94. PMID 17413319
05: Avanzi C, Del-Pozo J, Benjak A, et al. Red squirrels in the British Isles are infected with leprosy bacilli. Science 2016;354(6313):744-7. PMID 27846605
06: Barbieri RR, Xu Y, Setian L, et al. Reimagining leprosy elimination with AI analysis of a combination of skin lesion images with demographic and clinical data. Lancet Reg Health Am 2022;9:100192. PMID 36776278
07: Bathala L, Kumar K, Pathapati R, Jain S, Visser LH. Ulnar neuropathy in Hansen disease: clinical, high-resolution ultrasound and electrophysiologic correlations. J Clin Neurophysiol 2012;29(2):190-3. PMID 22469686
08: Bernardin R, Thomas B. Surgery for neuritis in leprosy: indications for and results of different types of procedures. Lepr Rev 1997;68:147-54. PMID 9217354
09: Berrington WR, Macdonald M, Khadge S, et al. Common polymorphisms in the NOD2 gene region are associated with leprosy and its reactive states. J Infect Dis 2010;201(9):1422-35. PMID 20350193
10: Boggild AK, Keystone JS, Kain KC. Leprosy: a primer for Canadian physicians. CMAJ 2004;170:71-8. PMID 14707226
11: Britton WJ, Lockwood DN. Leprosy. Lancet 2004;363:1209-19. PMID 15081655
12: Buhrer-Sekula S, Cunha MG, Foss NT, Oskam L, Faber WR, Klatser PR. Dipstick assay to identify leprosy patients who have an increased risk of relapse. Trop Med Int Health 2001;6:317-23. PMID 11348523
13: Cardoso Fde M, De Freitas MR, Escada TM, Nevares MT, Nascimento OJ. Late onset neuropathy in leprosy patients released from treatment: not all due to reactions. Lepr Rev 2013;84(2):128-35. PMID 24171238
14: Centers for Disease control and Prevention. Hansen’s disease (Leprosy)- Technical information. http://www.cdc.gov/nczved/divisions/dfbmd/. Accessed April 27, 2004.
15: Chad DA, Hedley-Whyte ET. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 1-2004. A 49-year-old woman with asymmetric painful neuropathy. N Engl J Med 2004;350:166-76. PMID 14711916
16: Chimelli L, Freitas M, Nascimento O. Value of nerve biopsy in the diagnosis and follow-up of leprosy: the role of vascular lesions and usefulness of nerve studies in the detection of persistent bacilli. J Neurol 1997;244:318-23. PMID 9178158
17: Couppie P, Abel S, Voinchet H, et al. Immune reconstitution inflammatory syndrome associated with HIV and leprosy. Arch Dermatol 2004;140(8):997-1000. PMID 15313818
18: Croft RP, Nicholls PG, Richardus JH, Smith WC. The treatment of acute nerve function impairment in leprosy: results from a prospective cohort study in Bangladesh. Lepr Rev 2000;7:154-68. PMID 10920611
19: Croft RP, Nicholls PG, Steyerberg EW, Richardus JH, Withington SG, Smith WC. A clinical prediction rule for nerve function impairment in leprosy patients-revisited after 5 years of follow-up. Lepr Rev 2003;74:35-41. PMID 12669931
20: Croft RP, Richardus JH, Nicholls PG, Smith WC. 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;70:140-59. PMID 10464433
21: Croft RP, Richardus JH, Smith WC. Field treatment of acute nerve function impairment in leprosy using a standardized corticosteroid regimen--first year's experience with 100 patients. Lepr Rev 1997;68:316-25. PMID 9503867
22: da Paz WS, Souza MDR, Tavares DDS, et al. Impact of the COVID-19 pandemic on the diagnosis of leprosy in Brazil: an ecological and population-based study. Lancet Reg Health Am 2022;100181. PMID 35072147
23: Dos Santos DF, Antunes DE, Dornelas BC, et al. Peripheral nerve biopsy: a tool still needed in the early diagnosis of neural leprosy? Trans R Soc Trop Med Hyg 2020;114(11):792-7. PMID 32710545
24: Duncan ME. Babies of mothers with leprosy have small placentae, low birth weights and grow slowly. Br J Obstet Gynaecol 1980;87:471-9. PMID 7397079
25: Ford AL, Britton WJ, Armati PJ. Schwann cells are able to present exogenous mycobacterial hsp70 to antigen-specific T lymphocytes. J Neuroimmunol 1993;43:151-9. PMID 7681446
26: Gebre S, Saunderson P, Messele T, Byass P. The effect of HIV status on the clinical picture of leprosy: a prospective study in Ethiopia. Lepr Rev 2000;71:338-43. PMID 11105493
27: Ghiglione E, Beronio A, Reni L, Abruzzese M. Leprous neuropathy: a clinical and neurophysiological study. J Peripher Nerv Syst 2004;9:120-1.
28: Gopinath DV, Thappa DM, Jaishankar TJ. A clinical study of the involvement of cranial nerves in leprosy. Indian J Lepr 2004;76(1):1-9. PMID 15527054
29: Haanpaa M, Lockwood DN, Hietaharju A. Neuropathic pain in leprosy. Lepr Rev 2004;75:7-18. PMID 15072122
30: Haimanot RT, Melaku Z. Leprosy. Curr Opin Neurol 2000;13:317-22. PMID 10871258
31: Hietaharju A, Croft R, Alam R, Birch P, Mong A, Haanpaa M. Chronic neuropathic pain in treated leprosy. Lancet 2000;356:1080-1. PMID 11009148
32: Inamadar AC, Palit A. Bilateral facial palsy in Hansen's disease. Lepr Rev 2003;74:383-5. PMID 14750584
33: Ishii N. Recent advances in the treatment of leprosy. Dermatol Online J 2003;9:5. PMID 12639458
34: Jain S, Visser LH, Praveen TL, et al. High-resolution sonography: a new technique to detect nerve damage in leprosy. PLoS Negl Trop Dis 2009;3(8):e498. PMID 19668356
35: Jain S, Visser LH, Yerasu MR, et al. Use of high resolution ultrasonography as an additional tool in the diagnosis of primary neuritic leprosy: a case report. Lepr Rev 2013;84(2):161-5. PMID 24171244
36: Jardim MR, Antunes SL, Santos AR, et al. Criteria for diagnosis of pure neural leprosy. J Neurol 2003;250:806-9. PMID 12883921
37: Jardim MR, Antunes SL, Simons B, et al. Role of PGL-I antibody detection in the diagnosis of pure neural leprosy. Lepr Rev 2005;76(3):232-40. PMID 16248210
38: Jiang J, Watson JM, Zhang GC, Wei XY. A field trial of detection and treatment of nerve function impairment in leprosy--report from national POD pilot project. Lepr Rev 1998;69:367-75. PMID 9927809
39: Job CK. Pathology and pathogenesis of leprous neuritis; a preventable and treatable complication. Int J Lepr Other Mycobact Dis 2001;69(2 Suppl):S19-29. PMID 11757175
40: Kang TJ, Chae GT. Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol Med Microbiol 2001;31:53-8. PMID 11476982
41: Kang TJ, Lee SB, Chae GT. A polymorphism in the toll-like receptor 2 is associated with IL-12 production from monocyte in lepromatous leprosy. Cytokine 2002;20:56-62. PMID 12445799
42: Kang TJ, Yeum CE, Kim BC, You EY, Chae GT. Differential production of interleukin-10 and interleukin-12 in mononuclear cells from leprosy patients with a Toll-like receptor 2 mutation. Immunology 2004;112(4):674-80. PMID 15270740
43: Kiran KU, Hogeweg M, Suneetha S. Treatment of recent facial nerve damage with lagophthalmos, using a semistandardized steroid regimen. Lepr Rev 1991;62:150-4. PMID 1870377
44: Krutzik SR, Ochoa MT, Sieling PA, et al. Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat Med 2003;9:525-32. PMID 12692544
45: Kumarasinghe SP, Kumarasinghe MP, Amarasinghe UT. "Tap sign" in tuberculoid and borderline tuberculoid leprosy. Int J Lepr Other Mycobact Dis 2004;72(3):291-5. PMID 15485286
46: Labuda SM, Schieffelin JS, Shaffer JG, Stryjewska BM. Hansen's disease and rheumatoid arthritis crossover of clinical symptoms: a case series of 18 patients in the United States. Am J Trop Med Hyg 2017;97(6):1726-30. PMID 29141716
47: Lawn SD, Wood C, Lockwood DN. Borderline tuberculoid leprosy: an immune reconstitution phenomenon in a human immunodeficiency virus-infected person. Clin Infect Dis 2003;36(1):e5-6. PMID 12491222
48: Le Grand A. Women and leprosy: a review. Lepr Rev 1997;68:203-11. PMID 9364820
49: Lee KH, Moon KS, Yun SJ, et al. Brain involvement by leprosy presenting as a frontal cystic lesion. J Neurosurg 2014;121(1):184-8. PMID 24527821
50: Little D, Khanolkar-Young S, Coulthart A, Suneetha S, Lockwood DN. Immunohistochemical analysis of cellular infiltrate and gamma interferon, interleukin-12, and inducible nitric oxide synthase expression in leprosy type 1 (reversal) reactions before and during prednisolone treatment. Infect Immun 2001;69:3413-7. PMID 11292765
51: Lockwood DN, Kumar B. Treatment of leprosy. BMJ 2004;328:1447-8. PMID 15205269
52: Lockwood DN, Reid AJ. The diagnosis of leprosy is delayed in the United Kingdom. QJM 2001;94:207-12. PMID 11294963
53: Lockwood DN, Vinayakumar S, Stanley JN, McAdam KP, Colston MJ. Clinical features and outcome of reversal (type 1) reactions in Hyderabad India. Int J Lepr Other Mycobact Dis 1993;61:8-15. PMID 8326184
54: Manandhar R, Shrestha N, Butlin CR, Roche PW. High levels of inflammatory cytokines are associated with poor clinical response to steroid treatment and recurrent episodes of type 1 reactions in leprosy. Clin Exp Immunol 2002;128:333-8. PMID 11985524
55: Mark S. Alexander the Great, seafaring, and the spread of leprosy. J Hist Med Allied Sci 2002;57:285-311. PMID 12211973
56: Marques W Jr, Foss NT, Arruda AP, Barreira AA. Near-nerve potential in lepromatous leprosy. Muscle Nerve 2003;28:460-3. PMID 14506718
57: Masaki T, Qu J, Cholewa-Waclaw J, Burr K, Raaum R, Rambukkana A. Reprogramming adult Schwann cells to stem cell-like cells by leprosy bacilli promotes dissemination of infection. Cell 2013;152(1-2):51-67. PMID 23332746
58: Massa R, Morello M, Sancesario G, Bernardi G. Sural nerve without nerve fibers in leprous neuropathy. Arch Neurol 2002;59:306. PMID 11843705
59: Menezes VM, Sales AM, Illarramendi X, et al. Leprosy reaction as a manifestation of immune reconstitution inflammatory syndrome: a case series of a Brazilian cohort. AIDS 2009;23(5):641-3. PMID 19525622
60: Menicucci LA, Miranda A, Antunes SL, et al. Microscopic leprosy skin lesions in primary neuritic leprosy. J Am Acad Dermatol 2005;52:648-52. PMID 15793516
61: Miko TL, Le Maitre C, Kinfu Y. Damage and regeneration of peripheral nerves in advanced treated leprosy. Lancet 1993;342:521-5. PMID 8102668
62: Mira MT, Alcais A, Nguyen VT, et al. Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 2004;427(6975):636-40. PMID 14737177
63: Mira MT, Alcais A, Van Thuc N, et al. Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat Genet 2003;33:412-5. PMID 12577057
64: Mitra S, Gombar KK. Leprosy and the anesthesiologist. Can J Anaesth 2000;47:1001-7. PMID 11032278
65: Monot M, Honore N, Garnier T, et al. On the origin of leprosy. Science 2005;308(5724):1040-2. PMID 15894530
66: Morrison A. A woman with leprosy is in double jeopardy. Lepr Rev 2000;71:128-43. PMID 10920609
67: Naafs B. Treatment duration of reversal reaction: a reappraisal. Back to the past. Lepr Rev 2003;74:328-36. PMID 14750578
68: Nations SP, Katz JS, Lyde CB, Barohn RJ. Leprous neuropathy: an American perspective. Semin Neurol 1998;18:113-24. PMID 9562673
69: Negesse Y. Comment: “silently arising clinical neuropathy” and extended indication of steroid therapy in leprosy neuropathy. Lepr Rev 1996;67:230-1. PMID 8885621
70: Nguyen LN, Cartel JL, Grosset JH. Chemoprophylaxis of leprosy in the southern Marquesas with a single 25 mg/kg dose of rifampicin. Results after 10 years. Lepr Rev 2000;71 Suppl:S33-5. PMID 11201884
71: Nicholls PG, Croft RP, Richardus JH, Withington SG, Smith WC. Delay in presentation, an indicator for nerve function status at registration and for treatment outcome--the experience of the Bangladesh Acute Nerve Damage Study cohort. Lepr Rev 2003;74:349-56. PMID 14750580
72: Norman G, Joseph G, Richard J. Relapses in multibacillary patients treated with multi-drug therapy until smear negativity: findings after twenty years. Int J Lepr Other Mycobact Dis 2004;72:1-7. PMID 15217321
73: Ochoa MT, Stenger S, Sieling PA, et al. T-cell release of granulysin contributes to host defense in leprosy. Nat Med 2001;7:174-9. PMID 11175847
74: Oliveira AL, Antunes SL, Teles RM, et al. Schwann cells producing matrix metalloproteinases under Mycobacterium leprae stimulation may play a role in the outcome of leprous neuropathy. J Neuropathol Exp Neurol 2010;69(1):27-39. PMID 20010305
75: Oliveira RB, Sampaio EP, Aarestrup F, et al. Cytokines and Mycobacterium leprae induce apoptosis in human Schwann cells. J Neuropathol Exp Neurol 2005;64(10):882-90. PMID 16215460
76: Ooi WW, Moschella SL. Update on leprosy in immigrants in the United States: status in the year 2000. Clin Infect Dis 2001;32:930-7. PMID 11247715
77: Ooi WW, Srinivasan J. Leprosy and the peripheral nervous system: basic and clinical aspects. Muscle Nerve 2004;30(4):393-409. PMID 15372437
78: Panda AK, Begum F, Panda M, Jena AK. Trigger of type 2 lepra reaction with acute foot drop following Covid-19 vaccination. J Eur Acad Dermatol Venereol 2022;36(5):e334-5. PMID 35015915
79: Pignataro P, Da Silva Rocha A, Nery JA, et al. Leprosy and AIDS: two cases of increasing inflammatory reactions at the start of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 2004;23:408-11. PMID 15112073
80: Polavarapu K, Preethish-Kumar V, Vengalil S, et al. Brain and spinal cord lesions in leprosy: a magnetic resonance imaging-based study. Am J Trop Med Hyg 2019;100(4):921-31. PMID 30761984
81: Polston DW, Dyck PJ, Dyck PJ, Litchy WJ, Keegan BM. A 46-year-old man with numbness and shock-like sensations in hands, feet, and jaw. Lancet Neurol 2004;3:63-7. PMID 14693113
82: Polycarpou A, Walker SL, Lockwood DN. New findings in the pathogenesis of leprosy and implications for the management of leprosy. Curr Opin Infect Dis 2013;26(5):413-9. PMID 23982232
83: Prabha N, Mahajan VK, Sharma SK, et al. Optic nerve involvement in a borderline lepromatous leprosy patient on multidrug therapy. Lepr Rev 2013;84(4):316-21. PMID 24745131
84: Rai D, Malhotra HS, Garg RK, et al. Nerve abscess in primary neuritic leprosy. Lepr Rev 2013;84(2):136-40. PMID 24171239
85: Ramadan W, Mourad B, Fadel W, Ghoraba E. Clinical, electrophysiological, and immunopathological study of peripheral nerves in Hansen's disease. Lepr Rev 2001;72:35-49. PMID 11355517
86: Rambukkana A, Salzer JL, Yurchenco PD, Tuomanen EI. Neural targeting of Mycobacterium leprae mediated by the G domain of the laminin-alpha2 chain. Cell 1997;88:811-21. PMID 9118224
87: Rambukkana A, Yamada H, Zanazzi G, et al. Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium leprae. Science 1998;282:2076-9. PMID 9851927
88: Rambukkana A, Zanazzi G, Tapinos N, Salzer JL. Contact-dependent demyelination by Mycobacterium leprae in the absence of immune cells. Science 2002;296:927-31. PMID 11988579
89: Richardus JH, Nicholls PG, Croft RP, Withington SG, Smith WC. Incidence of acute nerve function impairment and reactions in leprosy: a prospective cohort analysis after 5 years of follow-up. Int J Epidemiol 2004;33:337-43. PMID 15082636
90: Richardus JH, Withington SG, Anderson AM, et al. Treatment with corticosteroids of long-standing nerve function impairment in leprosy: a randomized controlled trial (TRIPOD 3). Lepr Rev 2003a;74:311-8. PMID 14750576
91: Richardus JH, Withington SG, Anderson AM, et al. Adverse events of standardized regimens of corticosteroids for prophylaxis and treatment of nerve function impairment in leprosy: results from the TRIPOD trials. Lepr Rev 2003b;74:319-27. PMID 14750577
92: Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis 1966;34:255-73. PMID 5950347
93: Rosenberg NR, Faber WR, Vermeulen M. Unexplained delayed nerve impairment in leprosy after treatment. Lepr Rev 2003;74:357-65. PMID 14750581
94: Sabin TD. Temperature-linked sensory loss: a unique pattern in leprosy. Arch Neurol 1969;20:257-62. PMID 5766490
95: Sabin TD, Swift TR, Jacobson RR. Leprosy. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF, editors. Peripheral Neuropathy. 3rd ed. Vol. 2. Philadelphia: WB Saunders, 1993:1354-79.
96: Salgame P, Abrams JS, Clayberger C, et al. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 1991;254:279-82. PMID 1681588
97: Saraswat N, Tripathy DM, Kumar S, Awasthi P, Gopal MM. A spectrum of leprosy reactions triggered by Covid-19 vaccination: a series of four cases. J Eur Acad Dermatol Venereol 2022;36(11):e858-60. PMID 35766884
98: Sasiain MC, de la Barrera S, Minnucci F, Valdez R, de Elizalde de Bracco MM, Balina LM. T-cell-mediated cytotoxicity against Mycobacterium antigen-pulsed autologous macrophages in leprosy patients. Infect Immun 1992;60:3389-95. PMID 1639507
99: Saunderson P, Gebre S, Desta K, Byass P, Lockwood DN. The pattern of leprosy-related neuropathy in the AMFES patients in Ethiopia: definitions, incidence, risk factors and outcome. Lepr Rev 2000;71:285-308. PMID 11105488
100: Schreuder PA. The occurrence of reactions and impairments in leprosy: experience in the leprosy control program of three provinces in northeastern Thailand, 1987-1995 [correction of 1978-1995]. II. Reactions. Int J Lepr Other Mycobact Dis 1998;66:159-69. PMID 9728448
101: Schuring RP, Hamann L, Faber WR, et al. Polymorphism N248S in the human Toll-like receptor 1 gene is related to leprosy and leprosy reactions. J Infect Dis 2009;199:1816-9. PMID 19456232
102: Scollard DM, McCormick G, Allen JL. Localization of Mycobacterium leprae to endothelial cells of epineurial and perineurial blood vessels and lymphatics. Am J Pathol 1999;154:1611-20. PMID 10329613
103: Shetty VP, Antia NH. Pathology of nerve damage in leprosy. In: The peripheral nerve in leprosy and other neuropathies. Antia NH, Shetty VP, editors. Delhi: Oxford University Press, 1997:79-137.
104: Shimoji Y, Ng V, Matsumura K, Fischetti VA, Rambukkana A. A 21-kDa surface protein of Mycobacterium leprae binds peripheral nerve laminin-2 and mediates Schwann cell invasion. Proc Natl Acad Sci U S A 1999;96:9857-62. PMID 10449784
105: Siddiqui MR, Meisner S, Tosh K, et al. A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nat Genet 2001;27:439-41. PMID 11279529
106: Singh N, Malik A, Arora VK, Bhatia A. Fine needle aspiration cytology of leprous neuritis. Acta Cytol 2003;47:368-72. PMID 12789916
107: Sinha S, Mahadevan A, Lokesh L, et al. Tangier disease--a diagnostic challenge in countries endemic for leprosy. J Neurol Neurosurg Psychiatry 2004;75:301-4. PMID 14742612
108: Smith WC, Anderson AM, Withington SG, et al. Steroid prophylaxis for prevention of nerve function impairment in leprosy: randomised placebo controlled trial (TRIPOD 1). BMJ 2004;328:1459-62. PMID 15159285
109: Soysal A, Atay T, Ozu T, Arpaci B. Electrophysiological evaluation of peripheral and autonomic involvement in leprosy. Can J Neurol Sci 2004;31(3):357-62. PMID 15376480
110: Spierings E, de Boer T, Wieles B, Adams LB, Marani E, Ottenhoff TH. Mycobacterium leprae-specific, HLA class II-restricted killing of human Schwann cells by CD4+ Th1 cells: a novel immunopathogenic mechanism of nerve damage in leprosy. J Immunol 2001;166:5883-8. PMID 11342602
111: Spierings E, De Boer T, Zulianello L, Ottenhoff TH. The role of Schwann cells, T cells and Mycobacterium leprae in the immunopathogenesis of nerve damage in leprosy. Lepr Rev 2000;71 Suppl:S121-9. PMID 11201869
112: Suneetha S, Arunthathi S, Chandi S, Kurian N, Chacko CJ. Histological studies in primary neuritic leprosy: changes in the apparently normal skin. Lepr Rev 1998;69:351-7. PMID 9927807
113: Suneetha S, Arunthathi S, Kurian N, Chacko CJ. Histological changes in the nerve, skin and nasal mucosa of patients with primary neuritic leprosy. Acta Leprol 2001;12:11-8. PMID 11526636
114: Suneetha S, Sigamoni A, Kurian N, Chacko CJ. The development of cutaneous lesions during follow-up of patients with primary neuritic leprosy. Int J Dermatol 2005;44(3):224-9. PMID 15807731
115: Szeremeta W, Dohar JE. Dapsone-induced methemoglobinemia: an anesthetic risk. Int J Pediatr Otorhinolaryngol 1995;33:75-80. PMID 7558644
116: Talhari C, Mira MT, Massone C, et al. Leprosy and HIV coinfection: a clinical, pathological, immunological, and therapeutic study of a cohort from a Brazilian referral center for infectious diseases. J Infect Dis 2010;202(3):345-54. PMID 20565258
117: Teles RM, Antunes SL, Jardim MR, et al. Expression of metalloproteinases (MMP-2, MMP-9, and TACE) and TNF-alpha in the nerves of leprosy patients. J Peripher Nerv Syst 2007;12(3):195-204. PMID 17868246
118: Thacker AK, Chandra S, Mukhija RD, Sarkari NB. Electro-physiological evaluation of nerves during reactions in leprosy. J Neurol 1996;243:530-5. PMID 8836943
119: Tomaselli PJ, Dos Santos DF, Dos Santos ACJ, et al. Primary neural leprosy: clinical, neurophysiological and pathological presentation and progression. Brain 2022;145(4):1499-506. PMID 34664630
120: Ulvi H, Yigiter R, Yoldas T, Aygul R, Varoglu AO, Deniz O. Using the blink reflex as measured by electromyogram to assess cranial nerve involvement in people affected by leprosy. Int J Lepr Other Mycobact Dis 2004;72(4):486-91. PMID 15755205
121: Ulvi H, Yoldas T, Yigiter R, Mungen B. R-R interval variation and the sympathetic skin response in the assessment of the autonomic nervous system in leprosy patients. Acta Neurol Scand 2003;107:42-9. PMID 12542512
122: van Brakel WH. Peripheral neuropathy in leprosy and its consequences. Lepr Rev 2000;71 Suppl:S146-53. PMID 11201872
123: van Brakel WH, Anderson AM, Withington SG, et al. The prognostic importance of detecting mild sensory impairment in leprosy: a randomized controlled trial (TRIPOD 2). Lepr Rev 2003;74:300-10. PMID 14750575
124: van Brakel WH, Khawas IB. Nerve function impairment in leprosy: an epidemiological and clinical study--Part 2: Results of steroid treatment. Lepr Rev 1996;67:104-18. PMID 8684251
125: 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(1):14-34. Erratum in: Lepr Rev 2005 Sep;76(3):264. PMID 15881033
126: 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(4):e212. PMID 18382604
127: Vanderborght PR, Pacheco AG, Moraes ME, et al. HLA-DRB104 and DRB110 are associated with resistance and susceptibility, respectively, in Brazilian and Vietnamese leprosy patients. Genes Immun 2007;8(4):320-4. PMID 17396103
128: Van Veen NH, Nicholls PG, Smith WC, Richardus JH. Corticosteroids for treating nerve damage in leprosy. Cochrane Database Syst Rev 2016;(5):CD005491. PMID 27210895
129: Van Veen NH, Schreuders TA, Theuvenet WJ, et al. Decompressive surgery for treating nerve damage in leprosy. Cochrane Database Syst Rev 2009;(1):CD006983. PMID 19160310
130: Verhagen CE, van der Pouw Kraan TC, Buffing AA, et al. Type 1- and type 2-like lesional skin-derived Mycobacterium leprae-responsive T cell clones are characterized by coexpression of IFN-gamma/TNF-alpha and IL-4/IL-5/IL-13, respectively. J Immunol 1998;160:2380-7. PMID 9498780
131: Verma S, Garg RK, Rizvi I, et al. Central nervous system, spinal root ganglion and brachial plexus involvement in leprosy: a prospective study. J Cent Nerv Syst Dis 2022;14:11795735221135477. PMID 36277272
132: Walker SL, Nicholls PG, Dhakal S, et al. 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. PLoS Negl Trop Dis 2011;5(4):e1041. PMID 21532737
133: Walker SL, Roberts CH, Atkinson SE, et al. The effect of systemic corticosteroid therapy on the expression of toll-like receptor 2 and toll-like receptor 4 in the cutaneous lesions of leprosy Type 1 reactions. Br J Dermatol 2012;167(1):In 29-35. PMID 22348338
134: Wang L, Wang H, Yan L, et al. Single-dose rifapentine in household contacts of patients with leprosy. N Engl J Med 2023;388(20):1843-52. PMID 37195940
135: Wilder-Smith A, Wilder-Smith E. Electrophysiological evaluation of peripheral autonomic function in leprosy patients, leprosy contacts and controls. Int J Lepr Other Mycobact Dis 1996;64:433-40. PMID 9030110
136: World Health Organization. Chemotherapy of leprosy for control programmes. Geneva: WHO, 1982. (Technical Report Series, 675).
137: World Health Organization. Expert Committee on leprosy. Seventh report. Geneva, World Health Organization, 1998. (Technical Report Series, 874).
138: World Health Organization. World Health Organization, Leprosy Elimination Project. Geneva 2004. Status reports 2003. http://www.who.int/lep. Accessed April 27, 2004.
139: World Health Organization. Leprosy, Fact sheet, Updated April 2016. http://www.who.int/mediacentre/factsheets/fs101/en/index.html. Accessed June 2, 2016.
140: World Health Organization. Leprosy, Fact sheet, Key facts, Updated January 2022. https://www.who.int/news-room/fact-sheets/detail/leprosy/. Accessed March 7, 2022.
141: World Health Organization. Guidelines for the diagnosis, treatment and prevention of leprosy. Accessed March 14, 2019. https://www.who.int/publications/i/item/9789290226383. World Health Organization 2018b.
142: Yamamura M, Uyemura K, Deans RJ, et al. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science 1991;254:277-9. PMID 1925582
143: Yoshimoto T, Mizutani H, Tsutsui H, et al. IL-18 induction of IgE: dependence on CD4+ T cells, IL-4 and STAT6. Nat Immunol 2000;1:132-7. PMID 11248805
144: Zhang F, Liu H, Chen S, et al. Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy. Nat Genet 2011;43(12):1247-51. PMID 22019778
145: Zhang FR, Huang W, Chen SM, et al. Genomewide association study of leprosy. N Engl J Med 2009;361(27):2609-18. PMID 20018961

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Ravindra Kumar Garg DM FRCP

Dr. Garg of King George's Medical University in Lucknow, India, has no relevant financial relationships to disclose.
See Profile

Editor

Louis H Weimer MD

Dr. Weimer of Columbia University has no relevant financial relationships to disclose.
See Profile

Patient Profile

Age range of presentation: 6 to 64 years
Sex preponderance: male>female, >1:1
Heredity: none
Population groups selectively affected: None selectively affected.
Occupation groups selectively affected: None selectively affected.

ICD & OMIM codes

ICD-9: Leprosy [Hansen disease]: 030

Lepromatous: 030.0

Tuberculoid: 030.1

Indeterminate: 030.2

Borderline: 030.3

Other specified leprosy: 030.8

Leprosy, unspecified: 030.9
ICD-10: Leprosy [Hansen disease]: A30

Indeterminate leprosy: A30.0

Tuberculoid leprosy: A30.1

Borderline tuberculoid leprosy: A30.2

Borderline leprosy: A30.3

Borderline lepromatous leprosy: A30.4

Lepromatous leprosy: A30.5

Other forms of leprosy: A30.8

Leprosy, unspecified: A30.9

Mononeuropathy in leprosy: G59.8*

Polyneuropathy in leprosy: G63.0*

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Neuropathy associated with leprosy

Associated Disorders

Blood: hemolytic anemia, megaloblastic anemia
Bone: osteomyelitis, osteoporosis, osteoperiostitis
Eyes: uveitis, iritis, iridocyclitis, corneal ulcers, blindness
Kidney: nephrotic syndrome, renal amyloidosis, glomerulonephritis
Larynx: fibrosis of vocal cords, laryngeal ulcer, hoarseness of voice
- Nose: rhinitis, crusting, epistaxis, anosmia, nasal collapse
- Testes: acute orchitis, testicular atrophy, azoospermia, hypogonadism
- Antineutrophil cytoplasmic autoantibodies in serum
- Arthritis
- Asymptomatic hepatic infiltration
- Dapsone hypersensitivity syndrome
- Dapsone-related motor neuropathy
- Generalized lymphadenopathy
- Gynecomastia
- High serum antiphospholipid antibodies
- Neuropathic osteoarthropathy
- Palatal perforation
- Plantar ulcer
- Thalidomide neuropathy
- Ulnar neuritis
- Vitiligo

Differential Diagnosis

Bell palsy
cervical spondylosis
syringomyelia
cervical cord tumor
amyotrophic lateral sclerosis
- spinal muscular atrophy
- carpal tunnel syndrome
- traumatic neuropathy
- neurofibromatosis
- meralgia paresthetica
- diabetic neuropathy
- vasculitis
- amyloidosis
- diabetes
- Lyme disease
- toxic neuropathy
- hereditary sensory autonomic neuropathy
- Tabes dorsalis
- paraneoplastic ganglionopathy
- postinfectious small fiber sensory neuropathy
- Tangier disease
- chronic inflammatory demyelinating neuropathy
- Lambert Eaton syndrome

Also Relevant

Clinical evaluation of peripheral neuropathies
Neuromuscular pathology: overview
Radial neuropathy
Spinal accessory neuropathy
Vaccines for neurologic disorders

Clinical Categories

Peripheral Neuropathies

Neuropathy associated with leprosy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Differences Between Three Major Types of Leprosy

Table 2. Commonly Palpable Thickened Nerves in Leprosy

Biological basis

Etiology and pathogenesis

Epidemiology

Table 3. WHO Grading System of Leprosy-Associated Disability

Prevention

Differential diagnosis

Confusing conditions

Table 4. Differential Diagnosis of Neuropathy Associated with Leprosy

Diagnostic workup

Management

Table 5. Leprosy: WHO-Recommended Treatment Regimens

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Chronic inflammatory demyelinating polyradiculoneuropathy

Amyotrophic lateral sclerosis

Amiodarone neuropathy

Autoimmune autonomic neuropathy

Leukodystrophies

Neuroacanthocytosis

Peripheral nerve injuries

This is an article preview.
Start a Free Account
to access the full version.