eMedicine Specialties > Neurology > Neurological Infections

Leprosy

Author: Ramaratnam Sridharan, MBBS, MD, Head, Department of Neurology, Professor of Neurology, Chennai Neurospeciality and Research Institute, India
Coauthor(s): Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants; Lakshmi Narasimhan Ranganathan, MD, Tutor, Institute Of Mental Health, Chennai, India; Senior Civil Assistant Surgeon, Tamil Nadu Medical Services; Srinivasaraman Govindarajan, DMRD, DNB, Fellow in Radiology, Barnard Institute of Radiology, India
Contributor Information and Disclosures

Updated: Feb 27, 2007

Introduction

Background

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, an acid-fast, rod-shaped bacillus. Leprosy has afflicted humanity since time began. It once affected every continent and has left behind a terrifying image in history and human memory of mutilation, rejection, and exclusion from society. The highly visible nature of the debilities led to historical stigmatization of lepers. Psychological and sociologic sequelae of this stigma can be as debilitating as the disease itself and may result in delays in seeking medical attention. To combat this prejudice, leprosy also is called Hansen disease, named after G.A. Hansen, who discovered M leprae in 1873.

Clinical leprosy lies between 2 extremes: tuberculoid (TT) and lepromatous (LL). 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 reaction or erythema nodosum leprosum [ENL]). 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 grouped as having paucibacillary (PB) leprosy, whereas those showing positive smears at any site are grouped as having multibacillary (MB) leprosy. Persons with more than 5 patches and involvement of more than 1 nerve trunk are also considered to have MB leprosy. The PB group includes TT and BT types, whereas the MB group includes BB, BL, and LL.

Pathophysiology

Skin and peripheral nerves are commonly involved. Although intense bacillemia is common in LL 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 noted. Even in the most advanced cases, destructive lesions are limited to the skin, peripheral nerves, anterior chamber of the eyes, upper respiratory passages above the larynx, testes, hands, and feet.

Frequency

United States

Leprosy is found in endemic foci in the parts of Florida, Louisiana, and Texas that border the Gulf of Mexico; among Spanish-Americans of New York City; and in Asian and Mexican populations of California. At the beginning of 1998, 112 prevalent 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 prevalence 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

• Leprosy is rarely an immediate cause of death. The mortality rate for LL patients is 4 times greater than that of the general population, mainly because of the indirect effects of the disease. In patients with non-LL disease, the mortality rates are the same as for the general population or slightly higher.
• About 1-2 million people are visibly and irreversibly disabled because of past or present leprosy. Of 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 per 100 patient-years in PB leprosy and 12 per 100 patient-years in MB leprosy. The frequency of new nerve lesions during treatment is 2% in PB leprosy and 11% in MB leprosy. A worldwide study on ocular complications in leprosy revealed grade 2 visual disability or blindness due to leprosy in 10% of patients.

Race

• No racial predilection is known. Leprosy was endemic throughout the world until the late 19th century, when a striking drop in its incidence became evident in Northern Europe and North America. It is currently thought to be limited to tropical areas.
• The LL form is more prevalent in Africa, while the TT form is more frequent in Asia. Leprosy affects the poorest of the poor.

Sex

Males are affected more frequently than females, except in some areas in Africa where the prevalence in females is equal to or higher than that in males.

Age

Leprosy is known to occur at all ages, ranging from early infancy to old age. It is extremely rare in infants. About 20% of cases occur in children younger than 10 years.

Clinical

History

• Symptoms
  • Skin patch that is painless, not itchy
  • Loss of sensation over the patch: This is a characteristic feature of TT leprosy; in LL leprosy, sensations may be preserved or impaired only mildly.
  • Paresthesias or loss of sensation in the distribution of involved peripheral nerves
  • Weakness and wasting of muscles
  • Claw hand or foot drop
  • Ulcerations over feet or hands
• Symptoms seen in reactions
  • Sudden onset of redness of the skin and appearance of new skin lesions in reversal reaction
  • In 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 physical signs depend on the type of leprosy (see Table 1).

• Early or indeterminate leprosy is characterized by a solitary macule, usually hypopigmented, with some alteration of sensation. It may heal spontaneously or evolve into the TT type or rarely into the LL type of leprosy.
• TT leprosy
  • Skin lesions (1 or several) are circular, ovoid, or serpiginous, sharply demarcated, often hypopigmented, with a tendency to slow enlargement and central healing. Lesions may have elevated and erythematous borders and dry scaly appearance in the center with complete anesthesia.
  • Skin lesions commonly occur on extensor surfaces of limbs, face, or buttocks (cool parts); they do not involve the perineum, axilla, or scalp. Cutaneous sensory nerves are thickened (see Image 1).
  • Larger peripheral nerves—especially the ulnar, peroneal, and great auricular nerves—may be enlarged palpably and visibly, particularly those closest to the skin lesion. Muscle atrophy or sensory loss is due to neural involvement.
• LL leprosy
  • The skin has extensive, bilaterally symmetric, nonanesthetic skin lesions comprising macules, nodules, plaques, or papules (see Image 2). Occasionally, bullous or ulcerated lesions are seen. Borders of lesion are ill defined, and the centers of lesion are raised and indurated. The skin lesions are most severe over the cooler parts of the body.
  • The lateral portions of the eyebrows may be lost. Skin of the face and forehead becomes thickened and corrugated (ie, leonine facies). Ear, nose, and throat findings include pendulous ear lobes (see Image 3), nasal mucosal involvement, laryngitis, hoarseness of voice, septal perforation, and nasal collapse.
  • Ocular examination may reveal evidence of keratitis, iridocyclitis, or glaucoma due to involvement of the ciliary body. Systemic problems may include painless inguinal and axillary adenopathy, as well as infiltration and scarring of testes leading to sterility and gynecomastia.
  • Neural issues include diffuse hypesthesia involving peripheral parts of extremities. Although peripheral nerves are heavily infected, visibly thickened, and symmetrically enlarged, they function well until the late stages.
• BT leprosy
  • Skin lesions are few or moderate in number and asymmetric, with nearly complete anesthesia.
  • Cutaneous nerve enlargement may occur; peripheral nerves are thickened and involved asymmetrically.
• MB leprosy
  • Skin lesions are moderate in number and asymmetrical with moderate anesthesia.
  • Cutaneous nerves are not enlarged, but peripheral nerves may be enlarged symmetrically.
• BL leprosy
  • Skin lesions are moderate to numerous and slightly asymmetrical with slight or no anesthesia.
  • Cutaneous sensory nerves are not enlarged; peripheral nerves are enlarged moderately and symmetrically.
• 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.
• Erythema nodosum leprosum reaction
  • This 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, or lateral popliteal at the fibular head—becomes tender and increases in size.
  • Other features include multiple acute tender skin nodules, arthritis, edema, hepatosplenomegaly, lymphadenopathy, orchitis, and iridocyclitis. Table 1. Differences Between TT and LL Leprosy

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    Table

    Clinical Features or Test	TT Form	LL Form
    Skin lesions Number Sensation Surface Hair growth in lesions	One or few Absent Dry or scaly Absent	Numerous Not affected Shiny Not affected
    Nerve enlargement Cutaneous nerves Larger peripheral nerves	Common Very rare	Not enlarged Symmetrically enlarged
    ENL reaction	Does not occur	Common
    Lepromin test	Strongly positive	Negative
    Bacillary index	0	5 or 6
    Skin histology Granuloma cell Lymphocytes Dermal nerves	Epithelioid +++ Destroyed	Foamy histiocyte +/- Easily visible
    Prognosis	Good	Poor

    Clinical Features or Test	TT Form	LL Form
    Skin lesions Number Sensation Surface Hair growth in lesions	One or few Absent Dry or scaly Absent	Numerous Not affected Shiny Not affected
    Nerve enlargement Cutaneous nerves Larger peripheral nerves	Common Very rare	Not enlarged Symmetrically enlarged
    ENL reaction	Does not occur	Common
    Lepromin test	Strongly positive	Negative
    Bacillary index	0	5 or 6
    Skin histology Granuloma cell Lymphocytes Dermal nerves	Epithelioid +++ Destroyed	Foamy histiocyte +/- Easily visible
    Prognosis	Good	Poor

Causes

Leprosy is a chronic infectious disease caused by M leprae.

• Microbiology
  • M leprae, the only mycobacterium known to infect nervous tissue, was the first bacterial pathogen to be associated with a specific human disease. The Koch postulates have never been fulfilled for this bacterium, since it has not been cultivated in vitro. It 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, measuring 1-8 microns in length and 0.2-0.5 micron 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 lipoarabinomannan, both of which are produced in large amounts by M leprae.
  • PGL-1, a prominent surface lipid specific to M leprae, is the best-characterized virulence factor. PGL-1 binds to complement component C3, which in turn mediates phagocytosis of the bacterium by mononuclear phagocytes by means of 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 among all 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 following treatment.
    • The mouse footpad model has been used to test the minimum required concentration of drugs and sensitivity of bacilli to new drugs.
  • 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.
• Reservoirs of infection
  • 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, however, constitute the most important reservoir of infection.
• Portals: Portals of exit for M leprae are skin and nasal mucosa. Portals of entry of M leprae are the skin and upper respiratory tract.
• Method of transmission
  • Skin-to-skin contact
  • Respiratory route: Evidence in favor of this route are the following findings:
    • The organism has not been detected 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
    • Experimentally, 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 actually transmit the infection remains unanswered.
• Molecular biology
  • DNA technology now allows cloning of M leprae genes. The genome of M leprae is represented by 4 contigs of overlapping clones, which together account for nearly 2.8 Mb of DNA. The major proteic antigens of M leprae include the 65-kd heat shock proteins and 18-kd heat shock proteins. Another major antigen is represented by a 28-kd protein that is the superoxide dismutase of M leprae. The genes that code for these antigens have been identified.
  • levels of antibodies to 65-, 28-, and 18-kd stress proteins are increased in all patients with leprosy compared with healthy individuals. The 65-kd antigen may induce an antibody response in the initial phase of infection; this does not change during various stages of disease, including reactional states. Antibody responses against the 28-kd antigen are higher in LL than in TT, and the response is even greater in type 1 reactions. The antigen has recently been suggested as a potential candidate for initiating the type 1 reaction because it was found in macrophages and Schwann cells of skin and nerve biopsy samples. Whether the antibody response is the cause or result of the reaction is not certain. All patients with leprosy except those with TT have a high level of antibodies to the 18-kd antigen. The 18-kd protein is one of the important antigens and produces significant B- and T-cell immune responses in leprosy.
  • Single point mutations within an 81-bp region in the rpoB gene involving 5 codons (Gly-513, Asp-516, His-526, Ser-531, and Leu-533) have been proved to lead to rifampin resistance
  • Recombinant proteins, the target of intense study, are available as purified products with known protein sequences. The T- and B-cell epitopes of such proteins can be defined by means of synthetic peptides. LSR/A15 antigen mimics the native bacillus in the cellular humoral responses elicited, and its B-cell epitopes have been identified. A major T-cell antigen has been cloned.Table 2. Immunologic Differences Between TT and LL Leprosy
    

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    Table

    Features or Test	TT	LL
    Host immunity	Good	Poor
    HLA association	DR2, especially DRB1 1501 and 1502	DQ1, MT1
    T cells	CD4 helper/inducer T cells, few CD8 cells	Negligible, mostly CD8
    T-cell subtype	Type 1 (Th1)	Type 2 (Th2)
    Response to mitogens and M leprae antigens	Strong	Poor
    Cytokines	Interferon gamma, IL-2	IL-4, IL-10
    Antibodies to M leprae antigens	Not prominent	Abundant

    Features or Test	TT	LL
    Host immunity	Good	Poor
    HLA association	DR2, especially DRB1 1501 and 1502	DQ1, MT1
    T cells	CD4 helper/inducer T cells, few CD8 cells	Negligible, mostly CD8
    T-cell subtype	Type 1 (Th1)	Type 2 (Th2)
    Response to mitogens and M leprae antigens	Strong	Poor
    Cytokines	Interferon gamma, IL-2	IL-4, IL-10
    Antibodies to M leprae antigens	Not prominent	Abundant

• Immunology of leprosy
  • In LL leprosy, the lack of cellular immunity relates specifically to the causal organism. These patients show normal responses to other mycobacteria, such as Mycobacterium tuberculosis. They do not suffer increased morbidity from viral, fungal, or protozoal infections for which cellular immunity is essential. This may be related to any of the following:
    • Host factors
    • Inhibition of T-cell functions by bacillary products such as PGL-1 and lipoarabinomannan
    • Macrophage defects
    • Release of monocyte factors such as prostaglandin E2 and interleukin (IL)-10
  • Many patients also have a generalized T-cell defect, which is secondary to bacillary load and reverts to normal with effective chemotherapy.
  • Subsets of T cells and cytokines
    • Patients with LL leprosy have Th2 T cells and IL-4 but not interferon gamma, whereas patients with TT leprosy have (Th1 cells and interferon gamma but not IL-4.
    • A network of immune cells communicating through cytokine molecules possibly determines the final expression of host immune response to intracellular pathogens.
    • Three consecutive daily intradermal injections of 10 mcg of interferon gamma led to rapid clearance of the bacilli from the lesion in 3-4 weeks. IL-2 injections have similar favorable effects.
    • Cytokine treatment may prove useful in recalcitrant and drug-resistant cases.
• Immunogenetics of leprosy
  • Human leukocyte antigen (HLA) class II serologic typing has revealed an association of TT leprosy with DR2 in ethnically diverse populations of Asian Indians. The predominant subtypes of DR2 associated with TT leprosy are DRB1 1501 and 1502. DRB1 1501 and 1502 alleles probably are implicated selectively in presentation of pathogenic peptides of mycobacteria. LL and BL leprosy show increased frequency of DQ1, suggesting that DQ1 may be associated with an immunosuppression gene for the organism.
  • From existing data, immunogenetic aspects of M leprae infection can be explained on the model of major histocompatibility complex (MHC)-peptide interaction. In TT, a Th1-like response is generated to mycobacterial heat shock proteins whenever the major antigen presenting allele is HLA-DR2. Peptides originating from M leprae probably bind preferentially to HLA allelic forms (HLA-DR2 as well as other positively associated DR antigens), characterized by arginine at positions 13, 70, and 71, and stimulate T-cell clones that result in a detrimental immune response. In LL, complete anergy to native heat shock proteins is the rule.
  • Using a postgenomic HLA-based approach, 12 candidate genes have been identified that are unique to M leprae and predicted to contain T-cell epitopes restricted via several major HLA-DR alleles. Five of these antigens (ML0576, ML1989, ML1990, ML2283, ML2567) induced significant T-cell responses in paucibacillary leprosy patients and M leprae –exposed healthy controls, but not in most multibacillary leprosy patients, tuberculosis patients, or endemic controls. Of M leprae –exposed healthy control subjects that did not have antibodies to the M leprae –specific phenolic glycolipid-I, 70% responded to one or more M leprae antigen(s), highlighting the potential added value of these unique M leprae proteins in diagnosing early infection. State-of-the-art HLA immunogenetics may provide new tools for specific diagnosis of M leprae infection.
• Factors determining clinical expression after infection
  • About 90% of the population is not susceptible to infection. 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 also has been reported in TT leprosy.
  • When host cell-mediated immunity functions perfectly, organisms are routed and no disease develops. If the individual has good immunity, organisms are contained and TT disease occurs. In subjects with moderate immunity, a seesaw battle occurs and results in borderline types of leprosy. In persons with poor immunity, LL occurs.
  • Route of entry of the organism
  • Prior infection with other mycobacteria
  • Genetic factors (HLA type)
• Incubation period
  • The incubation period is difficult to define because of lack of adequate immunologic tools and because of the insidious nature of the onset of leprosy, which usually occurs over 3 or more years in TT and over 8 or more years in LL.
  • 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 infection but otherwise living in areas in which the disease is not endemic.
• Subclinical infection in leprosy
  • Evidence for subclinical infection in leprosy has come mainly from limited studies with in vitro tests for cell-mediated immunity such as the lymphocyte transformation test and serologic tests for detecting humoral antibodies such as PGL-1–based enzyme-linked immunosorbent assay ELISA.
  • Skin tests with various preparations of lepromin, and more recently with soluble antigens from M leprae, also have provided useful information on occurrence of subclinical infection.
  • The specificity of these tests, however, particularly of integral lepromin, is questionable.

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