AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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

    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
    

    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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Skin lesions - Flat and hypopigmented
Localized scleroderma
Onchocerciasis
Pityriasis alba
Pityriasis versicolor
Post Kala-Azar dermal leishmaniasis
Vitiligo
Yaws
Skin lesions - Raised and pigmented
Acquired syphilis
Atypical necrobiosis of the face
Cutaneous leishmaniasis
Follicular mucinosis
Granuloma annulare
Granuloma multiforme
Kaposi sarcoma
Lupus vulgaris
Lupus erythematosus
Mycobacterium marinum infection
Neurofibromatosis
Pityriasis rosea
Psoriasis
Sarcoidosis
Tinea corporis
Wegener granulomatosis
Generalized thickening of skin
Myxoedema
Pachydermoperiostitis
Scleroderma

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Blood cell counts
• Blood glucose level
• Urea
• Creatinine
• Liver functions
• HIV status, especially in nonresponders
• Skin and/or nasal smears for AFB
• Family and/or contact screening for evidence of leprosy

Imaging Studies

• Chest radiography

Other Tests

• Immunologic tests
• • Lepromin test
    • Lepromin is a suspension of killed M leprae obtained from infected human or armadillo tissue. Following intradermal inoculation, early reactions (48 h, Fernandez) as well as late reactions (3-4 wk, Mitsuda) may be seen. The Mitsuda reaction, a granulomatous response to the antigen, is more consistent. Patients with TT or BT leprosy have strongly positive responses (>5 mm), whereas patients with LL do not respond.
    • The test is not useful in the diagnosis of leprosy because of the population, regardless of whether they live in an area of endemic disease, are Mitsuda positive. The test is a guide to the cell-mediated immunity of the individual. Lepromin is not available in the United States.
  • Cellular immune response against M leprae also can be studied by lymphocyte transformation test and lymphocyte migration inhibition test (LMIT). Response continuously decreases from subpolar TT to subpolar LL leprosy.
• Tests based on detection of M leprae antibodies or antigens
• • Serologic tests
    • Major serologic assays include fluorescent antibody absorption test (FLA-ABS), radioimmunoassay (RIA), ELISA, passive hemagglutination assay (PHA), serum antibody competition test (SACT), and particle agglutination assay (PAA).
    • Important serologic tests are FLA-ABS test and PGL-1 ELISA, which have been further simplified as dot ELISA and dipstick ELISA.
    • Serologic responses persist for considerable time after subsidence of disease and are not useful in assessing disease activity.
  • Estimation of M leprae–specific components in tissues
    • M leprae–specific antigens, nucleic acids, and M leprae–specific lipids are assessed with thin-layer chromatography, high-pressure liquid chromatography, gas-liquid chromatography, and mass spectrometry.
    • Lipids such as mycolic acid and phenolic glycolipid are characteristic of mycobacteria, including M leprae.
    • Tests to detect the epitope on M leprae antigens by using monoclonal antibodies or ELISA have been devised, but the frequent occurrence of false-positive reactions, especially in tropical countries, has decreased their positive predictive value for activity of the disease.
• Recombinant DNA and polymerase chain reaction (PCR)
• • Gene probes have been developed for demonstration of M leprae–specific sequences in various specimens: skin and/or nasal smears, biopsies, tissue sections, and blood.
  • DNA targeting probes have sensitivities of 10,000-100,000 organisms. Hence, they are not likely to be useful for a PB relapse. The signals may persist after bacterial death.
  • Regarding RNA (mRNA and rRNA) targeting probes because RNA has a shorter half-life and correlates better with viable organisms, these probes can detect 100-1000 bacteria.
  • PCR techniques to amplify the DNA of M leprae have been described, and these amplified sequences of target DNA can be detected by using gel electrophoresis or specific gene probes. Low bacterial loads ( <10 bacilli) can be detected. About 60-75% of smear-negative patients with PB leprosy have positive results on PCR. After chemotherapy, signals become weaker; therefore, PCR can be used to monitor treatment, diagnose relapses, or determine the need for chemotherapy. PCR methods for identifying DNA that encodes 65- and 18-kd M leprae proteins and repetitive sequences of M leprae have been developed.
• Despite the availability of several investigatory tools, the diagnosis of leprosy is essentially based on clinical grounds.
• Abnormalities on nerve conduction studies include the following:
• • Segmental slowing of conduction is seen at sites of entrapment (eg, elbow segment of the ulnar nerve), prolonged distal latencies, reduced (sensory or motor) nerve conduction velocities
  • Reduced amplitude of evoked motor responses (ie, compound muscle action potentials [CMAPs]) or absent or low-amplitude sensory potentials. The pattern of abnormalities may suggest mononeuropathy, mononeuropathy multiplex, or an entrapment neuropathy.
  • The nerves most commonly involved include the ulnar, common peroneal, median, and tibial nerves.
  • When the nerves are clinically affected, changes in nerve conduction are more obvious than they otherwise are. At times, the nerve conduction velocity may be decreased before any sensory deficit becomes apparent, and this finding can be used to detect asymptomatic nerve involvement. Conduction study in the index branch of the radial cutaneous nerve has been reported to reveal reduction in conduction velocity in people with early leprosy and even in contacts of those of leprosy.
  • Similar studies in the dorsal cutaneous branch of the ulnar and great auricular nerves may also be useful. In LL, thickening of the nerve is not correlated with impairment of nerve conduction. Although palpably enlarged nerves may function well, they may eventually fail.

Procedures

• Skin smears for AFB
• • These smears are made by nicking the skin with a sharp scalpel and scraping it. Obtained fluid and tissue are thickly spread on a slide, stained by using the Ziehl-Neelsen method, and partially decolorized with 1% acid alcohol.
  • Two indices (bacillary index and morphologic index), which depend on observation of M leprae in smears from skin or nasal discharge, are useful in assessing amount of infection, viability of organisms, and patient progress.
  • The bacillary index is an expression of the extent of bacterial loads. It is calculated by counting 6-8 stained smears under the X100 oil immersion lens. The depth of the skin incision, the thoroughness of the scrape, and the thickness of the film affect the bacillary index. Results are expressed on a logarithmic scale, as follows:
    • 1+ indicates 1-10 bacilli in 100 fields.
    • 2+ indicates 1-10 bacilli in 10 fields.
    • 3+ indicates 1-10 bacilli in every field.
    • 4+ indicates 10-100 bacilli in every field.
    • 5+ indicates 100-1000 bacilli in every field.
    • 6+ indicates more than 1000 bacilli in every field.
    • A more accurate and reliable index of the bacillary content of a lesion is given by the logarithmic index of biopsy results. These indices help to assess a patient's infection at the beginning of treatment and to assess progress.
  • The morphologic index is calculated by counting solid-staining acid-fast rods. Leprosy bacilli that stain with carbol-fuchsin as solid, acid-fast rods are believed to be viable; bacilli that stain irregularly are probably dead and degenerating. Measurement of the morphologic index is affected by observer variations and therefore not always reliable.
  • Fluorescent diacetate-ethidium bromide (FDA-EB) staining, laser microprobe mass analysis (LAMMA), bioluminescent technology, and macrophage-based assays may also be useful in detecting viable organisms.
• Nasal smears for AFB
• Skin biopsy
• • Skin biopsy should include the dermis and the epidermis, and samples are usually obtained from the edge of the lesion. A biopsy punch or scalpel may be used.
  • Skin biopsy is useful for the diagnosis and proper classification of leprosy.
• Nerve biopsy
• • Nerve biopsy occasionally reveals abnormalities even in contacts of patients with leprosy. The results may rule out other diseases such as polyarteritis nodosa, hereditary neuropathies, or chronic inflammatory demyelinating polyradiculoneuropathy. Recognizing that not all people with thickened nerves, even those of in regions of endemic disease, have leprosy is important. In purely neuropathic forms, nerve biopsy is the only way to confirm the diagnosis.
  • Nerve biopsy is probably more sensitive than skin biopsy, though false-negative histologic results may be seen when clinically uninvolved nerves are sampled. Skin and nerve histologic results are often incongruous; results in patients with MB leprosy in nerve may show PB leprosy in skin. The best results of nerve biopsy are obtained when the findings are interpreted in laboratories with special expertise in such diseases.

Histologic Findings

Histologic findings of skin obtained from leprosy-involved areas may be helpful. Histologic findings vary according to the type of leprosy. Indeterminate leprosy is characterized by a few cells cuffing the dermal appendages and neurovascular bundles and a few M leprae within cutaneous nerves.

In TT leprosy, epithelioid cells, lymphocytes, and perhaps giant cells form noncaseating granulomas. Dermal nerves are destroyed. Normal skin organs (eg, sweat glands, hair follicles) are lost. Bacilli are frequently absent or difficult to demonstrate.

In LL leprosy, the epidermis is normal and the rete flattened. A clear space separates the epidermis from diffuse granulomatous reaction with macrophages; large, foamy histiocytes (Virchow or lepra cells); and many intracellular AFB, which are frequently in spheroidal masses (ie, globi). Epithelioid cells and giant cells are not found. Granulomas are most numerous around blood vessels, nerves, and skin appendages. In some cases, many plasma cells are found. Dermal nerves are easily visible.

In BT leprosy, granulomas are epithelioid, with a preponderance of lymphocytes. Dermal nerves are mostly destroyed. Bacilli may be scanty or absent.

In BB leprosy, granulomas are epithelioid, dermal nerves may be visible, and bacilli are seen more often than in BT leprosy.

In BL leprosy, histiocytes form granulomas, dermal nerves are visible, and bacilli are seen in greater numbers than in other types.

In a reversal reaction, epithelioid cells and lymphocytes form granulomas. Extracellular edema is noted in the collagen of the dermis with dilated lymphatics or a proliferation of fibrocytes. As reactions clear, lesions heal with reduction or eradication of bacilli.

ENL reaction is characterized by a massive influx of polymorphonuclear cells. Complement and immunoglobulin may be deposited in a granular pattern around dermal vessels. Bacilli become more numerous. Histologic studies are not useful for assessing clinical activity because granuloma persists for a long time after clinical activity subsides.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• US regimens
• • PB disease: Dapsone 100 mg/d plus rifampin 600 mg/d for 1 year, then stop treatment
  • MB disease: Dapsone 100 mg/d plus rifampin 600 mg/d plus clofazimine 50 mg/d for 2 years, then stop treatment. Some US physicians prescribe dapsone indefinitely as prophylaxis to reduce any risk of relapse. This approach appears logical but difficult to maintain in all patients. The National Hansen's Disease Programs (NHDP) believes that stopping therapy after 2 years should be safe if close follow-up can be maintained for the recommended intervals during which relapse is most likely to occur so that therapy can promptly be restarted if necessary. Furthermore, the use of daily rifampin in the United States may also decrease the risk of reactivation in patients with MB leprosy. In the event of intolerance or toxicity to the usual drugs, the NHDP may be contacted regarding recommendations for alternative regimens
• Practitioners in many countries follow the multidrug therapy (MDT) regimen of the World Health Organization (WHO). A WHO study group first recommended MDT in 1981.
  • For adults with MB leprosy, rifampin (rifampicin) 600 mg once monthly, dapsone 100 mg daily, clofazimine 300 mg once monthly, and 50 mg daily are recommended for 12 months. In the rare patient who has evidence of deterioration after MDT for 12 months, he or she can be treated with an additional 12 months of MDT, as for MB leprosy.
  • For PB leprosy in adults, rifampin 600 mg once monthly and dapsone 100 mg daily is given for 6 months. In adults, PB leprosy in a single skin lesion can be treated with single doses of rifampin 600 mg, ofloxacin 400 mg, and minocycline 100 mg. This recommendation is based on the results of a large multicenter trial.
  • For children, the dosage of dapsone is 2 mg/kg/day. Clofazimine 6 mg/kg is given once a month under supervision, and 1 mg/kg daily is self-administered. Rifampin 10 mg/kg is administered once a month.
• Treatment of reactions
  • Reactions require urgent treatment because they can lead to irreversible deformities. Therefore, early diagnosis and timely initiation of anti-inflammatory measures are crucial. MDT should not be stopped but continued at full doses without interruption.
  • Mild cases of reversal reaction may respond to salicylates, chloroquine, or nonsteroidal anti-inflammatory drugs (NSAIDs).
    • Corticosteroids are used when the patient has severe nerve involvement, nerve abscess, or impending paralysis or extensive and acutely inflamed skin lesions. Prednisolone should be prescribed as follows: 40 mg daily for weeks 1 and 2, 30 mg daily for weeks 3 and 4, 20 mg daily for weeks 5 and 6, 15 mg daily for weeks 7 and 8, 10 mg daily for weeks 9 and 10, and 5 mg daily for weeks 11 and 12.
    • The patient should be examined every week, and the dose of corticosteroids should be reduced every 2 weeks. The maximum dosage of prednisolone is 1 mg per kilogram of body weight.
    • Rest, splints, and physiotherapeutic measures are advised.
    • Thalidomide is not useful for reversal reactions.
  • Mild ENL reactions are treated with salicylates, chloroquine, or NSAIDs. Severe ENL reaction is often recurrent and chronic and may vary in its presentation. The management of severe ENL is best undertaken by physician at a referral center. The physician can adjust the dose and duration of antireaction drugs treatment according to the needs of the individual patient. WHO guidelines for the management of severe ENL reaction are given below.
    • If the patient is still receiving antileprosy treatment, continue the standard course of MDT. If MDT is already completed, it need not be restarted.
    • Give adequate doses of analgesics to control fever and pain.
    • Use a standard course of prednisolone at a dosage not exceeding 1 mg/kg/day for a total of 12 weeks.
    • In patients with severe ENL whose disease is not responding satisfactorily to treatment with corticosteroids or in whom the risk of toxicity with corticosteroids is high, a combination of clofazimine and corticosteroids may be used. Start clofazimine 100 mg 2 times a day and continue for a maximum of 12 weeks, along with a standard course of prednisolone. Then, taper clofazimine to 100 mg twice a day for 12 weeks and then 100 mg once a day for 12-24 weeks.
    • Management with clofazimine (dose given above) alone is indicated in patients with severe ENL when corticosteroids are contraindicated: The total duration of treatment with high-dose clofazimine should not exceed 12 months. About 4-6 weeks is needed for clofazimine to take full effect in controlling ENL.
    • Other drug reported to be useful in treating ENL is pentoxifylline, alone or combined with clofazimine and prednisolone.
    • Because of its well-known teratogenic adverse effects, thalidomide should not be used as first-line treatment for ENL associated with leprosy.
    • In exceptional cases, thalidomide may be used in male patients in countries where the drug is licensed for use. The initial regimen is 100 mg 3-4 times daily, which usually controls the reaction within 48-72 hours. The dosage is then tapered over 2 weeks to a maintenance level, usually 50-100 mg/d. Regular attempts should be made to taper or discontinue the drug, but patients may need to continue taking thalidomide for months to years before ENL reactions no longer recur.
    • Other agents, such as intravenous methylprednisolone, plasma exchange, intravenous immunoglobulin, cyclosporine A, alpha-TNF, pentoxifylline oral zinc, and immunotherapy have been used in difficult cases. However, these agents have not been systematically studied.
• Highlights of WHO MDT
  • MDT has been highly successful in controlling leprosy under various conditions since 1982. Relapse with MDT is 0.1% per year for PB and 0.06% per year for MB on average, with a low frequency of adverse effects. Patients with MB leprosy who are taking MDT have significantly reduced frequency and severity of ENL reactions, an effect that may be attributed to the anti-inflammatory effect of clofazimine. MDT can prevent resistance of M leprae to antileprosy drugs because organisms that are resistant to 1 drug are susceptible to other drugs in MDT. Even in the few patients whose leprosy relapses after MDT, retreatment with the WHO MDT regimen has been effective in all.
  • The WHO considers treatment with dapsone or any other antileprosy drug as monotherapy is considered unethical. For patients with PB leprosy, giving MDT until the infection becomes clinically inactive is not necessary because clinical activity does not necessarily imply direct correlation with bacterial multiplication. Nevertheless, the accuracy of the initial classification of patients designated as having PB leprosy is important. Hence, patients with more than 5 skin lesions are treated as if they had MB leprosy. Most patients with MB with a high bacillary index continue to improve even after 12 months without further treatment.
• Future treatment - Drugs under evaluation
  • Minocycline, ofloxacin, and clarithromycin are promising agents being investigated for use in leprosy. These agents have less bactericidal activity than rifampin but are more effective than dapsone or clofazimine and may help to reduce the duration of treatment. Treatment with rifampicin 600 mg/d daily and ofloxacin 400 mg/d for 1 month is being evaluated in both PB and MB leprosy.
  • Ethionamide, prothionamide, thiambutosine, and amithiozone are also under evaluation. They have significant toxic effects.
  • Fusidic acid, ampicillin combined with clavulanic acid, and brodimoprim also have activity against M leprae in vitro or in mice.
  • Clinical trials of many of these new drugs are underway, but the US Food and Drug Administration (FDA) has not approved these drugs for the treatment of leprosy.
  • Levels of tumor necrosis factor (TNF) are increased in leprosy reactions. Thalidomide, which relieves ENL, inhibits TNF release. Analogues of thalidomide without teratogenic effects would have an important role in future therapeutic regimens.
  • PCR may be useful to diagnose early skin lesions, to detect rifampin-resistant strains, and to monitor viability and response to treatment.
• Immunoprophylaxis and immunotherapy
  • No specific and effective vaccine against leprosy is available.
  • Trials of bacille Calmette-Guérin (BCG) plus killed M leprae vaccine, and International Committee of the Red Cross (ICRC) bacillus vaccine yielded 65-70% protective efficacy in trials in India. Other candidate vaccines have been tested, including those against Mycobacterium welchii, Mycobacterium habana, Mycobacterium vaccae, and others. However, none of the candidates or combinations provide a level of efficacy that can be considered a cost-effective intervention for a public health program.
  • BCG immunoprophylactic trials have revealed 20% protection in Burma and 80% in Uganda; India, Papua, New Guinea, and Malawi report rates between these. Endemicity of leprosy in the area, background saprophytic mycobacterial flora, and the age at vaccination may all be relevant factors. Because vaccination may precipitate the clinical appearance of TT leprosy in apparently healthy contacts, immunoprophylaxis is best initiated at an early age.
  • A recent meta-analysis of 7 experimental studies revealed an overall protective effect of 26% (95% confidence interval [CI], 14-37%). The analysis of 19 observational studies overestimated the protective effect at 61% (95% CI, 51-70%). The age at vaccination did not predict the protective effect of BCG. An additional dose of BCG was more protective in the prevention of leprosy compared with a single dose. An additional dose of BCG may be warranted for contacts of leprosy patients in areas where leprosy continues to be a public health problem.
  • India has approved a leprosy vaccine prepared from a killed, nonpathogenic mycobacterial strain for limited clinical use. The intradermal vaccine is designed to be used as an adjunct to standard MDT, to accelerate healing, and to reduce the duration and cost of treatment. Genetically engineered products are likely to replace this first-generation product. A live, nonpathogenic bacillus that replicates in the host is more likely than a killed one to induce cellular immunity.
  • Other immunotherapeutic agents under investigation are immunomodulatory drugs, transfer factor, gamma interferons and IL-2, acetoacetylated M leprae, and delipidified cell components of M leprae. Combined immunotherapy and chemotherapy did not increase the incidence of reactions, was well tolerated, and was beneficial. Modification of defective cell-mediated immunity may be associated with efficient killing and fast clearance of dead bacilli.

Surgical Care

• Surgery improves sensation in selected patients with sensory impairment, and most often prevents further deterioration. Optimal timing for nerve decompression must be established. A multidisciplinary team comprising a leprologist, a neurologist, physical and occupational therapists, and a surgeon with experience in peripheral nerve surgery is needed.
• Surgical treatment of acute nerve abscess consists of careful incision of the nerve sheath and draining the abscess. Surgical neurolysis or even fascicular dissection has been advocated to relieve intraneural pressure. Sensory loss, though generally irreversible, can often be ameliorated by simple longitudinal epineurotomy.
• Surgical treatments for eliminating anatomic constrictions include medial epicondylectomy, anterior transposition of ulnar nerve, deroofing of the carpal tunnel, and decompression of the posterior tibial nerve at the flexor retinaculum.
• • Nerve decompression is undertaken when signs of entrapment have not cleared after 3-4 weeks of steroid therapy, when the patient's neurologic status deteriorates despite steroid therapy, and when signs of nerve abscess or chronic entrapment are noted.
  • Posterior tibial neurovascular decompression by release of the flexor retinaculum with systemic administration of steroids may be beneficial in early acute and silent neuritis. Distal compression of the plantar branches should be relieved by slitting the calcaneal bands and ensuring free passage of the plantar branches to the sole of the foot. Nerve function, particularly autonomic and sensory modalities, recovers to a considerable extent. Some authors believe that, even in long-standing cases, vascular decompression may help in healing chronic plantar ulcers and prevent their recurrence.
• Peripheral nerve reconstruction using denatured muscle autografts may help to restore protective sensation in hands and feet. Nerve grafts may be helpful for patients with localized nerve lesions.
• Cosmetic Surgery in leprosy may be contemplated after medical control of the disease. The procedures include excision of redundant skin in ear lobes and eyelids, excision of excessive breast tissue in gynecomastia, implantation of islands of scalp hair to replace lost eyebrows, and nasal reconstruction.
• Tenodesis may be done to stabilize joints, and arthrodesis may be performed to correct clawing.
• Tendon transfer procedures may be used to replace paralytic muscles with functioning ones, especially to restore dorsiflexion of foot, abduction-opponens action of thumb, extension of the proximal interphalangeal joint, and flexion at the metacarpophalangeal joint.
• Lagophthalmos may be corrected with tarsorrhaphy and canthoplasty or by tunneling a slip of temporalis muscle attached to tendon through the lid and attaching it to the inner canthus. Re-education involves closing jaws to effect eye closure.
• Hopelessly diseased tissue may require surgical amputation.

Consultations

• The Gillis W. Long Hansen's Disease Center, formerly the National Hansen's Disease Center, in Carville, LA, and its regional centers provide consultation and assistance in patient care.
• • In the United States, patients are eligible for treatment by means of the public health service. Contact the Gillis W. Long Hansen's Disease Center, Bureau of Primary Health Care, HRSA 1770 Physician Park Drive, Baton Rouge, LA 70816. Telephone 800-642-2477 (toll free) or 225-642-4736, fax 225-642-4748.
  • In the United States and in countries where leprosy is uncommon, patients with leprosy are best referred to specialized centers with expertise in leprosy management.
  • In areas of endemic leprosy, individual physicians may adhere to policies of local health authorities. Even in these areas, referral to a specialized center would be indicated in nonresponders, patients who do not tolerate the MDT regime, those with severe reactions, or those in whom other diagnoses have not been excluded.
• Consultation with an ophthalmologist is recommended for management of ocular complications.
• Consultation with an otorhinolaryngologist may be helpful for patients who have nasal symptoms.
• Consultation with an orthopedic surgeon is recommended for management of trophic ulcers and tendon transfer surgery.
• A cosmetic surgeon should be consulted for correction of facial deformities.
• Consultation with a specialist in physical medicine and orthotics may be helpful.
• • Physiotherapy is essential in patients with paralysis due to neural involvement. In patients who undergo rehabilitative surgery, such as tendon transfers, muscle reeducation exercises are essential.
  • The most effective healing tools for plantar ulceration are the total contact cast (TCC) and the posterior walking splint (PWS).
  • If the TCC and PWS are not appropriate, alternative pressure relieving devices or healing devices such as the Carville custom sandal, Plastizote boot, and prefabricated healing sandals or shoes can be made, modified, or augmented to remove the load from the foot. The footbed of the Plastizote boot is molded the same way as a Carville sandal, but the upper part is made of Plastizote and rises to just below the gastrocnemius muscle belly. This device adds support for moderately to severely deformed feet, such as resolved Charcot fractures, during showering, bathing, or household activities.
  • Heel ulcers are common in patients with insensitive feet because of long-term bedrest or positioning during surgery. These ulcers can be on the medial, lateral, or posterior aspect, with some plantar component. The boot is cut out to appropriately relieve the affected area. The boot should be worn at all times, especially when the involved foot is in contact with any surface (eg, bed, recliner, foot stool, sofa).
  • When the wound closes, permanent footwear and orthotics are fitted to prevent reulceration.
  • All options used for the wound-healing phase and initial ambulation after wound closure must include an assistive device for partial weight bearing, preferably crutches or a walker.

Diet

Most patients can have a normal diet. In undernourished patients, a high-protein diet may be beneficial.

Activity

Normal activities are appropriate, except for patients with sensory loss and at risk for trophic ulcers.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Leprostatic agents

These agents have antibiotic properties against M leprae.

Drug Category: Antitubercular agents

The drug of choice is rifampin.

Drug Category: Antibiotics

Therapy should cover all likely pathogens in the context of the clinical setting.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Deterrence/Prevention:

• Periodic examination of the contacts of persons with MB leprosy is essential to detect the disease in the early stages and start therapy.
• Several studies of 1 or more antileprosy drugs (dapsone, long-acting injectable dapsone, acedapsone, rifampicin) as chemoprophylaxis against leprosy failed to demonstrate any significant protection against leprosy. Therefore, at present, the only practical method of prevention is early detection and MDT for all patients with leprosy.
• BCG or other antileprosy vaccines may increase the immunity to the disease and help in prevention.
• Isolation of patients (eg, in a leprosarium) is not necessary because the viability of bacteria in skin biopsy samples falls sharply within 3 weeks of therapy with dapsone and rifampin is begun. This rapid drop in infectivity and the fact that family members already have had prolonged exposure to the patient before diagnosis makes physical isolation of patients unnecessary.

Complications:

• Deformities and trophic changes
• • Deformities may be due to direct effects of proliferation of M leprae. Examples are collapse of the nasal septum and, in rare cases, direct invasion of the phalanges with pathologic fractures of the fingers.
  • Deformities are most often due to neuropathy. The effects include crippling deformities of the hand, contractures due to paralysis, and recurrent injuries to the hands, feet, and eyes due to insensitivity, leading to progressive absorption of the extremities and blindness.
  • Common problems include ulcerations on the plantar surfaces and sides of the feet and toes and on the hands. Lacerations, burns, abrasions, and hematomas are common on the hands. Shortening of digits on feet and hands may occur as a result of destructive osteomyelitis, and fragments of bone may be discharged through ulcerated areas. Amputations may occur traumatically. Impairments are graded as follows (WHO, 1982):
    • Grade 0 - Normal, no impairments
    • Grade 1 - Peripheral anesthesia over the hands and/or feet
    • Grade 2 - Trophic ulcers over the hands and/or feet, mobile clawing of fingers or toes, minimal absorption of the fingers and/or toes and wrist and/or foot
    • Grade 3 - Fixed deformities of the fingers and/or toes, more than minimal absorption of the fingers and/or toes, and nasal collapse
• Lucio phenomenon
• • This phenomenon is seen in certain Latin American patients with diffuse infiltrative LL leprosy.
  • The condition characterized by thrombosis of the deep subcutaneous arteries resulting in necrosis of the skin and subcutaneous fat. The underlying tendons and muscles may be exposed.
  • The outcome is often fatal.
• Secondary amyloidosis is a complication of severe LL disease, especially in chronic ENL reactions.

Prognosis:

• Progression of tissue and nerve damage can be limited, but recovery of lost sensory and motor function is variable and generally incomplete.
• Hyperpigmentation, hypopigmentation, and loss of skin organs persist.
• Intercurrent reactional states, poor compliance, and emergence of dapsone resistance all can lead to clinical exacerbations or relapses, necessitating close follow-up.
• Much of the chronic debility results from repeated trauma to anesthetic digits and limbs. Careful counseling and consultations with physical and occupational therapy services are essential for an optimal outcome.
• Rejection and isolation by community and even family members lead to social and economic dislocation. Even when the disease is controlled fully, the stigma and social isolation persist.

Patient Education:

• All of the activities and advice listed below should be explained, and patient adherence should be monitored on follow-up visits.
• Education of the patient about the disease, its bacterial origin, low communicability, and possibilities for successful treatment improves their self-esteem and motivation to take medical treatment.
• Educate the patients about the condition, the consequences of neuropathy.
• • Periodic screening is recommended to detect signs and symptoms of neuropathic feet.
  • Any change in status may require a change in treatment protocol (possibly a different style of shoe or orthotic).
• If any new injury or redness, swelling or temperature are noted, it should be brought to the attention of a healthcare professional.
• Patients should be educated about proper self-care techniques. The patient must be told the importance of taking responsibility for self-care to ensure healthy feet.
• • Patients should be advised to cut their toenails straight across. If the nails are large or irregular in shape, professional care may be necessary. Patients should not cut calluses or corns or use corn removers; these are problems that a healthcare professional should address.
  • For dry skin, use a lotion that does not contain alcohol.
  • Patients should never use heating pads or hot water bottles, and they should not stand too close to a heater or fireplace. Insensitive feet and lower legs may not detect when temperatures reach dangerous levels that can cause burns.
  • A person with insensitive feet must always wear shoes and not walk barefoot, but the shoes must be appropriate. The shape of the shoe must match the shape of the foot, and patients should always have the feet measured when buying shoes.
    • The space between the tip of the longest toe and the shoe should be at least 0.5 in. The person should be able to pinch a small area at the widest part of the shoe to determine sufficient width. The toe box (end of the shoe) should be roomy enough to accommodate the toes.
    • Leather uppers are preferred because they conforms to the shape of the foot over time.
    • Patients should purchase shoes with a wedge and soft rubber sole.
    • Shoes should have a closure system. Clogs, slip-ons or loose-fitting shoes may easily come off the foot or rub red areas.
    • Patients should gradually break in new shoes. They should begin by wearing new shoes for no more than 2 hours the first time and then gradually wear them longer if they have no problems.
  • Patients should always wear socks with shoes and inspect them daily. White cotton socks are preferred because they are most absorbent and because white easily shows evidence of skin breakdown and drainage.
  • Patients should inspect their shoes before and after wear to ensure that no objects have accidentally fallen into the shoe and that no sharp items have penetrated the soles. Patients should not wear high-heeled shoes, as they tend to put pressure on the forefoot.
  • Patients should inspect their feet daily for redness, warmth, swelling or any other new injury. They should use a mirror to check the bottom of their feet.
• Educating the patient's family, friends, and employers of the items listed above facilitates acceptance of the patient in his or her family and in society.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• In areas in which the disease is not endemic, always confirm diagnosis by smears or biopsy; if possible, mouse footpad cultures also should be done.
• Consult local health authorities regarding treatment policies and seek help from referral centers in difficult situations such as differentiation of relapse from reactions, treatment during pregnancy, treatment of persons who cannot tolerate standard drugs, and patients with associated hepatic or renal disease or HIV infection.
• Special attention should be paid to prevent deformities, blindness, and injuries to insensitive parts.

Special Concerns

• Patients who do not tolerate MDT because of adverse reactions or contraindications
• • These patients pose a difficult clinical problem. Once adverse events are conclusively established to be due to antileprosy drugs, other new antileprosy drugs can be used under direct supervision in a referral center. For patients who refuse to take clofazimine, educate the patient about the advantages of the drug, particularly the reversible nature of the discoloration produced by the drug; this information should be sufficient to encourage the patient to continue with clofazimine. In exceptional cases, ofloxacin 400 mg or minocycline 100 mg/d may be used under supervision in place of clofazimine.
  • As an alternative, patients may be treated with the monthly administration of 600 mg rifampin, 400 mg ofloxacin, and 100 mg minocycline (ie, ROM therapy) for 24 months.
  • For adults with MB leprosy who do not tolerate rifampin, clofazimine 50 mg/d with ofloxacin 400 mg and minocycline 100 mg for 6 months is recommended; this is followed by clofazimine 50 mg/d with minocycline 100 mg or ofloxacin 400 mg for at least an additional 18 months is recommended.
  • If the toxic effects of dapsone are severe in patients with PB, dapsone may be substituted with clofazimine at the same dose as that used for patients with MB but for 6 months. In patients with MB, dapsone should be stopped, and treatment should be continued with rifampin and clofazimine at the standard doses.
• Patients who default during treatment
• • If for any reason a patient cannot complete the required number of doses in time, the treatment regimen should be resumed from the point at which the patient stopped, and the full course should be completed.
  • Adequate efforts should be made to trace and persuade the patient to return for assessment and treatment.
  • A patient who returns for treatment and who has new skin lesions, new nerve involvement, LL nodules, or signs of ENL reaction should be given a new course of MDT.
• Patients with no response to therapy
  • Nonresponse may be due to poor drug compliance or other concomitant and debilitating intercurrent infections (including that due to HIV).
  • When the patient does not improve despite supervised drug therapy, health education, and thorough investigation and management of intercurrent infections, seeking an expert opinion may be necessary.
• Patients who have a relapse
  • In MB leprosy, relapse is defined as the multiplication of M leprae, as suggested by the marked increase (at least 2+ over the previous value) in the bacillary index at any single site, usually with evidence of clinical deterioration (new skin patches or nodules and/or new nerve damage). In most cases, relapse can be confirmed by the growth of M leprae in the mouse footpad system.
  • Recognition of relapse in PB leprosy is somewhat difficult because it is hard to distinguish from a reversal reaction. In theory, a therapeutic test with corticosteroids may be able to distinguish the 2 phenomena; definite improvement within 4 weeks of corticosteroid therapy indicates a reversal reaction, whereas no response to corticosteroids within 4 weeks suggests clinical relapse.
• Steroid therapy and leprosy
  • Indications for steroid use in people with leprosy include neuritis, impending nerve palsies, iridocyclitis, epididymoorchitis, severe reversal reaction, ENL reaction, or systemic involvement. No evidence suggests that immunosuppressive drugs, such as corticosteroids, accelerate the multiplication of organisms located in dormant foci or cause reactivation of leprosy.
  • Whenever the duration of steroid therapy (eg, for a late reversal reaction or other medical conditions) is expected to exceed 4 months, clofazimine 50 mg/d can be started as a prophylactic measure. This treatment should be continued until the course of steroids is complete.
• HIV infection and leprosy
  • Unlike tuberculosis and atypical mycobacteriosis, leprosy is not significantly associated with HIV infection in any case-controlled studies. HIV serodiagnostic tests based on ELISA and/or Western blotting may have a significantly increased rate of false-positive results among sera from patients with LL leprosy. The treatment of patients with leprosy and HIV infection is the same as that of any other patient with leprosy, including the treatment of reactions.
  • HIV-associated neuropathy might be confused with or exacerbate leprosy neuritis. Neuropathy due to antiretroviral chemotherapy might be confused with leprosy. Nonleprosy mycobacterioses in HIV-positive people might be diagnostically confused with leprosy.
  • National policies on BCG vaccination might be amended because of endemic HIV infection.
  • Slit-skin smear taking could spread HIV infection if proper precautions are not taken.
  • Leprosy workers in countries where leprosy is endemic may become increasingly involved with problems of HIV counseling.
• Women, pregnancy, and leprosy
  • Hormonal changes in puberty and pregnancy cause nonspecific suppression of cell-mediated immunity with worsening of leprosy. Pregnancy also can be associated with reactions. Deterioration usually occurs in the second half of pregnancy or the first 3 months after delivery. Late nerve damage has been recorded even in women released from treatment with MDT in relation to childbirth. Therefore, WHO recommends that MDT be continued during pregnancy.
  • Dapsone is not known to have any adverse effects on mother or fetus. Clofazimine, prednisolone, and thalidomide may affect both mother and fetus. Rifampin is not recommended in the first trimester. A small quantity of antileprosy drugs are excreted through breast milk, but no adverse reactions have been reported as a result of this except for mild discoloration of infants due to clofazimine. Infants of mothers with leprosy have decreased birth weights and an increased risk of the disease.
• Tuberculosis and leprosy
  • MDT for leprosy is not adequate for treatment of tuberculosis. Therefore, an appropriate antitubercular regimen should be given, in addition to antileprosy MDT, to patients with both leprosy and tube