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

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

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.

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.

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).

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

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.

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.

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.

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).

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

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

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.

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.

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

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).

Special considerations

Pregnancy

Pregnancy-induced immunosuppression allows Mycobacterium leprae to proliferate and may result in the worsening of leprosy. Reversal reactions are often precipitated by pregnancy and parturition. Erythema nodosum leprosum may appear in pregnancy and during lactation. Erythema nodosum leprosum in pregnancy is associated with severe loss of nerve function. A high potential of teratogenicity with thalidomide makes management of erythema nodosum leprosum in pregnancy difficult. Multidrug therapy is safe during pregnancy (48; 66). Babies of mothers with leprosy weigh less than those of healthy mothers. The babies of the mothers with leprosy grow more slowly than those of the healthy mothers, and these findings are most marked in the babies of mothers with lepromatous leprosy (24).

Anesthesia

General anesthesia is not a contraindication for surgery in leprosy; however, because lepromatous leprosy affects every organ and system of the body, a preanesthetic workup of these systems is required (64). Methemoglobinemia, an uncommon side effect of dapsone, may get precipitated during induction of general anesthesia (115).