eMedicine Specialties > Neurology > Neuromuscular Diseases

Neuropathy of Leprosy

Author: Ramaratnam Sridharan, MD, FRCP, FAAN, Head of the Department of Neurology, Professor, Neurology, Chennai Neurospeciality & Research Institute
Coauthor(s): Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants; Lakshmi Narasimhan Ranganathan, MD, Assistant Professor, Department of Neurology, Stanley Medical College, India; Srinivasaraman Govindarajan, DMRD, DNB, Staff Physician, Barnard Institute of Radiology, Madras Medical College, India
Contributor Information and Disclosures

Updated: Feb 27, 2007

Introduction

Background

Leprosy is the most common treatable cause of neuropathy in the world. In all patients with leprosy, the nerve tissue is involved. The dermal nerves are infected in all skin lesions, including those due to indeterminate leprosy of childhood. Clinical examination is often sufficient to reliably diagnose leprous neuropathy.

Clinical leprosy lies between 2 extremes: tuberculoid (TT) and lepromatous (LL) disease. Between the 2 ends of the spectrum lies a broad group designated as borderline and subclassified as borderline tuberculoid (BT), midborderline (BB), and borderline lepromatous (BL). The disease does not remain static but evolves spontaneously or in response to therapy. Transition toward the TT pole is referred to as upgrading (and may lead to a reversal or type I reaction), and transition toward the LL pole as downgrading (leading to type II or erythema nodosum leprosum [ENL] reaction). The reactions reflect abrupt changes in the host-parasite immunologic balance and are associated with acute clinical exacerbations.

In classification based on skin smears, patients with negative smears at all sites are classified as having paucibacillary (PB) leprosy, whereas those with a positive smear at any site are classified as having MB leprosy. Persons with more than 5 skin patches and involvement of more than 1 nerve trunk also are considered to have MB leprosy. The PB group includes TT and BT types, whereas the MB group includes BB, BL, and LL types.

Leprosy is a common cause of neuropathy in developing countries, although it also is seen in developed countries. In the United States, the prevalence of leprosy may increase with increasing immigration from regions in which the disease is endemic.

Pathophysiology

Peripheral nerves and skin are affected most commonly. Although intense bacillemia is common in LL disease, and though organisms can be seen in stained smears of peripheral blood or buffy coats, high temperature or systemic signs of toxicity are absent. Bacilli are also found in the liver, spleen, and bone marrow; however, no clinical signs of visceral organ dysfunction are apparent. Even in the most advanced cases, destructive lesions are limited to the skin; peripheral nerves; anterior aspects of the eyes; and the upper respiratory passages above the larynx, testes, hands, and feet.

Frequency

United States

Leprosy is found in endemic foci in parts of Florida, Louisiana, and Texas that border the Gulf of Mexico. It is also seen in the Spanish-American population of New York City, and in the Asian and Mexican populations of California. As of 1998, 112 cases of leprosy had been reported.

International

The prevalence of leprosy is gradually declining. The registered prevalence as of December 2005 was 219,826 cases, of which 133,119 are from Asia. Brazil, Democratic Republic of Congo, Madagascar, Nepal, Mozambique, and Tanzania have prevalences of greater than 1 case per 10.000 inhabitants. The number of new cases worldwide in 2005 was 296,499, of which nearly two thirds are from Asia. Most cases are concentrated in Southeast Asia, Africa, and South America. Brazil accounts for more than 80% of all cases in Latin America.

Mortality/Morbidity

• Death is rarely immediate. The mortality rate of patients with LL disease is 4 times greater than that of the general population owing to the indirect effects of leprosy. In patients with non-LL leprosy, mortality rates are the same or slightly higher than that of the general population.
• Worldwide, 1-2 million people are visibly and irreversibly disabled because of past and present leprosy. Of these patients with LL disease, 70-75% have eye, hand, and/or foot disabilities.
• According to 1 study, the frequency of nerve function impairment at presentation in regions of endemic disease is 1.7 cases per 100 patient-years at risk in PB leprosy and 12 cases per 100 patient-years at risk in MB leprosy.
• Frequency of new nerve lesions during treatment is 2% in PB leprosy and 11% in MB leprosy.

Race

Leprosy has no racial predilection. Leprosy was endemic throughout the world until the late 19th century, when the incidence in Northern Europe and North America strikingly decreased. At present, leprosy is mostly limited to tropical areas. The LL form is most prevalent in Africa, while the TT form is most frequent in Asia.

Sex

Male individuals are affected more frequently than female individuals, except in some areas in Africa, where prevalence in females is equal or higher than of males.

Age

Leprosy occurs in people of all ages from early infancy to old age, though the disease is extremely rare in infants. About 20% of cases occur in children younger than 10 years.

Clinical

History

Signs and symptoms vary depending on the type of leprosy.

• General features of leprous neuropathy
• • Sensory neuropathy is far more common than motor neuropathy, but pure motor neuropathy can occur.
  • Mononeuropathy and mononeuritis multiplex can occur, with the ulnar and common peroneal nerves most often involved.
  • Symmetric peripheral neuropathy also may occur.
• Symptoms of leprous neuropathy usually include the following:
• • Anesthetic, painless, nonitchy skin patches: Patients with skin lesions overlying peripheral nerve trunks are at high risk for the development of sensory or motor impairment.
  • Deformities due to weakness and wasting of muscles innervated by the affected peripheral nerves (eg, claw hand or foot drop secondary to muscle weakness)
  • Sensory symptoms such as diminution to complete loss of sensation, paresthesias in the distribution of affected nerves, and neuralgic pain when the nerve is struck or stretched
  • Spontaneous blisters and trophic ulcers consequent to sensory loss
• Symptoms seen in reactions
• • Reversal reaction - Sudden onset of redness of the skin and appearance of new skin lesions
  • ENL reaction - Multiple skin nodules, fever, joint pains, muscle pains, and redness of eyes
  • Severe neuritic pain and rapid evolution of peripheral nerve damage resulting in claw hand or foot drop

Physical

The type of leprosy determines the evolution, pattern, and extent of sensory loss and paralysis. Distinction between TT and LL leprosy is discussed in detail in Leprosy. The Table below highlights the salient differences between the 2 extremes of the spectrum constituting clinical leprosy. Physical signs due to intracutaneous nerve damage may differ from those due to involvement of major nerve trunks.

Differences between TT and LL Leprosy

Open table in new window

• Cutaneous (or integumentary system): Characteristic cutaneous lesions confirm the diagnosis in more than 50% of patients.
• Peripheral nerve hypertrophy
• • Nerve trunks are enlarged palpably in 40-55% of patients; this sometimes predates sensory loss in the corresponding nerve territory.
  • Nerve hypertrophy must be differentiated from a healthy nerve that may be palpable.
  • Sensory cutaneous nerves running to the proximal edge of a skin lesion may be thickened in TT and BT leprosy.
    
    
    • Nerves with a predilection for thickening include the great auricular nerves, supraclavicular nerves as they cross the clavicle, ulnar nerves just above the elbow, dorsal cutaneous branches of the ulnar nerve at the wrist, the median and superficial radial nerves, the femoral cutaneous and lateral popliteal (common peroneal) nerves as they wind round the neck of the fibula, the superficial peroneal nerves in front of the ankles, the posterior tibial nerves immediately below the internal malleoli, and the sural nerves. The ulnar nerve is most commonly thickened.
    • Thickening is usually confined to 1 nerve in TT disease.
    • In LL disease, increase in nerve size is symmetrical. However, degree of nerve thickening may differ between the 2 sides. The enlargement often may be segmental rather than diffuse and uniform.
    • Disparity may be noted between specific areas of thickened nerves and distribution of sensory/motor signs.
• Cranial nerves
• • Facial nerve palsy due to involvement of branches to the frontalis or orbicularis oculi leads to frontalis weakness or lagophthalmos. It may be unilateral or bilateral but spares other muscles innervated by the facial nerve.
  • Sensory loss may occur in the malar region and cornea.
• Motor system
• • Wasting and weakness usually progress pari passu (ie, at the same rate). In some patients, however, wasting is more prominent than weakness.
  • These signs involve predominantly the ulnar nerve at the elbow, median nerve at the wrist, and common peroneal nerve at the fibular head.
• Sensory modalities
• • Thermal sensation is affected first, followed by pain and touch. Proprioception and vibration modalities often are preserved.
  • Topographical distribution of sensory loss is variable.
  • Graded sensory testing with standardized nylon microfilaments or computer-assisted sensory examination (CASE) may be helpful to detect early sensory loss.
• Deep tendon reflexes: These are generally preserved because the muscle spindles and large-fiber nerves are not involved.
• Extremities, deformities, and trophic changes
• • Claw-hand deformity (usually indicating ulnar nerve involvement) is most common, though it is a nonspecific manifestation of leprosy (see Media file 1).
  • Trophic ulcers, a common, nonspecific complication of pain sensation loss, occur on the sole of the foot and the hands/fingers (see Media file 2).
  • Absorption of fingers and toes may be noted.
• Autonomic system
• • Autonomic nerve involvement is manifest clinically as varying degrees of impaired sweating and possible anhidrosis.
  • Visceral autonomic nerves are not involved generally, though conflicting experiences with cardiac dysautonomia have been reported.
• Reversal reaction
• • Physical findings include erythema and edema in skin lesions. New skin lesions appear.
  • Affected nerves increase in size and become tender with signs of damage of involved nerves.
• ENL reaction
• • Reaction is characterized by acute peripheral nerve damage leading to claw hand or foot drop.
  • The involved nerve trunk—usually ulnar just above the elbow, median at the wrist, lateral popliteal at the fibular head—becomes tender and increases in size.
  • Other features include multiple acute and tender skin nodules, arthritis, edema, hepatosplenomegaly, lymphadenopathy, orchitis, and iridocyclitis.

Causes

• Microbiology
• • The agent that causes leprosy, Mycobacterium leprae, is the only mycobacterium known to infect nervous tissue; it was the first bacterial pathogen to be associated with a specific human disease.
  • The Koch postulates have never been fulfilled because the bacterium has not been cultured in vitro.
  • M leprae is an obligate intracellular organism that preferentially proliferates in tissues of cooler temperature.
  • M leprae is a strongly acid fast, rod-shaped organism. It has parallel sides and rounded ends, measures 1-8 µm in length and 0.2-0.5 µm in diameter, and closely resembles the tubercle bacillus.
  • Under an electron microscope, M leprae is seen as dark, osmiophilic inclusions located in a cytoplasmic vacuole containing a phenolic glycolipid-1 (PGL-1) and liporabinomannan, both of which M leprae produces in large amounts.
  • PGL-1 is the best-characterized virulence factor; it is a prominent surface lipid specific to M leprae.
    • PGL-1 binds to complement component C3, which in turn mediates phagocytosis of the bacterium by mononuclear phagocytes via CR1, CR3, and CR4 receptors on their cell surfaces.
    • Once inside the phagocyte, PGL-1 helps to protect the bacterium from oxidative killing by chemically scavenging hydroxyl radicals and superoxide anions.
  • M leprae exhibits the longest reproduction time of any bacteria, requiring 13 days to double in experimentally infected mice.
  • M leprae has been cultured in vivo using the mouse footpad inoculation method (Shepherd) or by inoculating thymectomized irradiated (TR) mice.
    • The TR mouse has been used to detect small numbers of viable organisms and is used to detect persistent disease after treatment.
    • The mouse footpad model has been used to test the minimum required concentration of drugs and sensitivity of bacilli to new drugs.
  • Reservoirs of infections
    • The 9-banded armadillo (Dasypus novemcinctus) also can be infected with M leprae. This animal has become the main source of M leprae for genetic, biochemical, and immunological research, including development of a vaccine.
    • Approximately 5% of armadillos in Louisiana have naturally occurring clinical disease. About 20% have serologic evidence of infection with organisms indistinguishable from M leprae. However, only occasional cases are reported among individuals handling armadillos. Naturally occurring infection also has been reported in the African chimpanzee, sooty mangabey, and cynomolgus macaque.
    • Persons with MB leprosy are the most important reservoir of infection.
  • Portals of entry and exit
    • Portal of exit of M leprae - Skin and nasal mucosa
    • Portal of entry of M leprae - Skin and upper respiratory tract
  • Method of transmission of leprosy
    • Skin-to-skin contact
    • Respiratory route: Evidence in favor is inability to detect the organism on the surface of the skin.
    • Large numbers of morphologically intact organisms can be demonstrated in the nasal discharge.
    • M leprae may survive outside the human host for several hours or days.
    • Experimental transmission of leprosy has been accomplished through aerosols containing M leprae and by topical application in immune-suppressed mice.
  • Vectors
    • In experimental studies, acid-fast bacilli (AFB) have been demonstrated in biting insects.
    • Successful transmission of M leprae by intracutaneous inoculation in the mouse footpad model has been reported.
    • However, the question whether insects transmit the infection remains unanswered.
• The following mechanisms may explain the entry of M leprae into the nerves.
• • Bacilli may enter through naked nerve filaments in the epidermis and travel through the axon. However, intra-axonal bacilli are detected rarely.
  • Bacilli may be phagocytosed by Schwann cells in the skin, where they multiply and are passed to adjacent Schwann cells.
  • Macrophages in the upper dermis take up M leprae, which then aggregate around nerve bundles. They may release bacilli, which are ingested by perineurial cells (which pass the bacilli to Schwann cells), or M leprae –laden macrophages themselves infiltrate the perineurium.
  • Perivascular intraneural granulomata may be found in TT Hansen neuritis; therefore, bacilli may spread through the bloodstream and reach the nerve by means of the intraneural capillaries.
  • Inside the nerves, the bacillus is offered immunological protection by the Schwann cell basement membrane, multilayering of the perineurium, absence of lymphocyte recirculation within the fascicles, and the blood-nerve barrier.
• Possible factors in mechanism of nerve damage
• • Temperature: Nerves in cool body parts are involved preferentially.
  • Mechanical factors
    • Affected nerves are usually superficial nerve trunks, those commonly prone to compression, or those situated in confined spaces.
    • Angulation stresses due to joint movement and external pressure also contribute.
    • Edema, inflammation, and swelling at sites of predilection for entrapment result in increased intraneural pressure.
  • Vascular factors
    • Histologic studies have identified vasculitic changes in small-sized arteries and arterioles (intraneural blood vessels).
    • Angiographic studies have revealed abnormalities in medium-sized vessels as well.
    • The consequent ischemia may be one of the factors leading to neuropathy.
  • Genetic and immunologic factors
    • These are discussed in detail in the article Leprosy.
    • The basis for the conspicuous destruction of nerve structure is thought to be a delayed hypersensitivity reaction with specific helper T cells reacting with M leprae.
    • Leprae antigens are presented in the endoneurium by macrophages.
    • Activation of macrophages leads to release of secretory products including neural proteases, potent oxidizing agents, and free radicals.
    • A delayed hypersensitivity reaction in the endoneurium can cause major damage or even necrosis and intraneural abscesses.
  • Cytokines and chemical factors
    • Roles of interferon-gamma and interleukins are discussed in detail in the article Leprosy.
    • Tumor necrosis factor (TNF) has been shown to induce demyelination; therefore, chronic production of TNF in lesions of leprosy may be related to some aspects of nerve damage.
• Factors determining clinical expression after infection
• • Susceptibility
    • About 90% of the population is not susceptible. Children are more susceptible than adults.
    • Immunologic and epidemiologic studies suggest that only 10-20% of those exposed to M leprae develop signs of indeterminate Hansen disease; only 50% of those with indeterminate disease develop full-blown clinical leprosy.
    • Spontaneous healing has also been reported in TT leprosy.
  • Host immunity
    • When host immunity is intact, organisms are routed and no disease occurs.
    • If immunity is good, organisms are contained, and TT disease occurs.
    • In subjects with moderately good immunity, a seesaw battle occurs and results in borderline types of leprosy.
    • In persons with poor immunity, LL disease occurs.
  • Route of entry of the organism
  • Previous infection with other mycobacteria
  • Genetic factors (type of human leukocyte antigen)
• Incubation period
• • This period is difficult to define because of the lack of adequate immunologic tools and because of the insidious nature of the onset of leprosy, which is usually 3 or more years in TT disease and 8 or more years in LL disease.
  • The minimum incubation period reported is as short as a few weeks; this is based on the rare occurrence of leprosy among infants just 3 weeks old.
  • The maximum incubation period reported is as long as 30 years or more, as observed among war veterans exposed for short periods in areas of endemic disease but otherwise living in areas where the disease is not endemic.
• Other diagnostic considerations
• • Diseases characterized by wasting of small muscles of the hand
    • Syringomyelia
    • Motor neuron disease
    • Cervical myeloradiculopathies
    • Carpal tunnel syndrome
    • Ulnar nerve entrapment at elbow
  • Mononeuropathy multiplex
    • Rheumatoid arthritis
    • Polyarteritis nodosa
    • Diabetes
  • Symmetric polyneuropathy due to other causes
  • Small-fiber neuropathies due to amyloid or hereditary sensory neuropathy
  • Entrapment neuropathies
  • Dapsone-induced motor polyneuropathy
  • Sensory perineuritis affecting subcutaneous sensory nerves
  • Hypertrophic neuropathies
    • Amyloidosis
    • Hereditary motor sensory neuropathies
    • Refsum syndrome
    • Neurofibromatosis
    • Recurrent trauma
  • Diseases characterized by trophic ulcers
    • Tabes
    • Diabetic neuropathy
  • Congenital indifference to pain
  • Hereditary sensory neuropathy
  • Hysterical and/or functional disease

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