Leprosy is a chronic bacterial infection, also called Hansen's disease, that damages nerves, mainly in the limbs and facial area, and may cause skin damage.
The disease is caused by a bacterium, Mycobacterium leprae, which is spread in droplets of nasal mucus. Hansen’s disease is not highly contagious; a person is infectious only in the early stages. Prolonged close contact puts people at risk. The disease is most prevalent in Asia, Central and South America, and Africa.
Symptoms and signs
Leprosy has a long incubation period – about three to five years. There are two main types: the lepromatous type, in which damage is widespread, progressive, and severe; and the tuberculoid type, which is milder. Damage is initially confined to the skin or to peripheral nerves supplying the skin and muscles. Skin areas supplied by affected nerves become lighter or darker and sensation and sweating are reduced. As the disease progresses, the peripheral nerves swell and become tender. Hands, feet, and facial skin eventually become numb and muscles become paralysed, leading to deformity. Other possible features include blindness, destruction of bone, and sterility.
Diagnosis and treatment
The presence of the causative bacteria is confirmed by a skin biopsy. Drug treatment may be with a combination of dapsone, rifampicin, and clofazimine, which kills most of the bacteria in a few days. Any damage that has occurred before treatment, however, is irreversible. Plastic surgery may be necessary to correct deformities; and nerve and tendon transplants may improve the function of damaged limbs.
Leprosy (Hansen’s disease) - detailed technical article.
- Clinical features of leprosy
- Differential diagnosis
- Education of patients
- Prevention of disability
- Social, psychological, and economic rehabilitation
- Leprosy in women
- Prevention and control
- Areas of uncertainty and controversy
- Areas where further research is needed
- Further reading
Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae, an acid-fast intracellular organism not yet cultivated in vitro. It is an important public health problem worldwide, with an estimated 4 million people disabled by the disease. Transmission of Mycobacterium leprae is only partially understood, but untreated lepromatous patients discharge abundant organisms from their nasal mucosa into the environment.
These are determined by the degree of cell-mediated immunity towards Mycobacterium leprae, with tuberculoid (paucibacillary) and lepromatous leprosy (multibacillary) being the two poles of a spectrum: (1) tuberculoid—well-expressed cell-mediated immunity effectively controls bacillary multiplication with the formation of organized epithelioid-cell granulomas; (2) lepromatous—there is cellular anergy towards M. leprae with abundant bacillary multiplication. Between these two poles is a continuum, varying from the patient with moderate cell-mediated immunity (borderline tuberculoid), through borderline, to the patient with little cellular response, borderline lepromatous.
Presenting symptoms—most commonly (1) anaesthesia—ranging from a small area of numbness on the skin due to involvement of a dermal nerve, to peripheral neuropathy with affected nerves tender and thickened; (2) skin lesions—most commonly macules or plaques; tuberculoid patients have few, hypopigmented lesions that are anaesthetic; lepromatous patients have numerous, sometimes confluent lesions.
Other manifestations—these include (1) type 1 (reversal reactions)—occur in borderline patients; characterized by acute neuritis and/or acutely inflamed skin lesions; often occur in the first 2 months after starting treatment; (2) type 2 (erythema nodosum leprosum reactions)—occur in up to 50% of patients with lepromatous leprosy; (3) neuritis—silent neuropathy is an important form of nerve damage, causing lifelong morbidity; (4) eye disease—blindness occurs in at least 2.5% of patients.
This is made by recognition of typical skin lesions or thickened peripheral nerves, supported by the finding of acid-fast bacilli on slit skin smears that should be taken from at least four sites (earlobes, and edges of active lesions).
There are six main principles of treatment: (1) stop the infection with chemotherapy—first-line antileprosy drugs are rifampicin, clofazimine, and dapsone, given in combination and duration as determined by whether disease is paucibacillary or multibacillary; these are highly effective in killing bacilli but may not halt nerve damage; (2) treat new nerve damage—a 6-month course of steroids should be given to those with nerve damage for less than 6 months; (3) treat reactions—steroids are likely to be required; (4) educate the patient about leprosy; (5) prevent disability; and (6) support the patient socially and psychologically—patients with leprosy the world over are frequently stigmatized; words such as ‘leper’ should be avoided; the disease can be referred to as ‘Hansen’s disease’.
Vaccination with bacille Calmette–Guérin (BCG) can provide some protection against leprosy (20–80% in different trials).
Leprosy is caused by Mycobacterium leprae, an acid-fast intracellular organism not yet cultivated in vitro. It was first identified in the nodules of patients with lepromatous leprosy by Hansen in 1873. M. leprae preferentially parasitizes skin macrophages and peripheral nerve Schwann cells.
In vivo cultivation of M. leprae
M. leprae can be grown in the mouse footpad, but growth is slow, taking over 6 months to produce significant yields. The nine-banded armadillo is susceptible to M. leprae infection and develops lepromatous disease. The armadillo and mouse models of M. leprae infection have been useful for producing M. leprae for biological studies and studying drug sensitivity patterns, respectively.
Mycobacterium leprae is a stable hardy organism that withstands drying for up to 5 months. It has a doubling time of 12 days (compared with 20 min for Escherichia coli). The optimum growth temperature is 27 to 30° C, consistent with the clinical observation of maximal M. leprae growth at cool superficial sites (skin, nasal mucosa, and peripheral nerves). M. leprae isolates from different parts of the world have similar biological characteristics. M. leprae possesses a complex cell wall comprising lipids and carbohydrates. It synthesizes a species-specific phenolic glycolipid and lipoarabinomannan. Antibody and T-cell screening have identified numerous protein antigens and peptides that are important immune targets.
Mycobacterium leprae genome
Mycobacterium leprae has a 3.27-Mb genome that displays extreme reductive evolution. Less than one-half of the genome contains functional genes and many pseudogenes are present. One hundred and sixty-five genes are unique to M. leprae and functions can be attributed to 29 of them. These unique proteins are being identified and analysed to aid in development of new diagnostic tests. Comparison of biosynthetic pathways with Mycobacterium tuberculosis is giving new insights into M. leprae metabolism. For lipolysis Mycobacterium leprae has only two genes (Mycobacterium tuberculosis has 22); M. leprae has also lost many genes for carbon catabolism and many carbon sources (e.g. acetate and galactose) are unavailable to it. This gene loss leaves M. leprae unable to respond to different environments and underlies the impossibility of growing the organism in vitro. Using comparative genomics and analysis of single nucleotide polymorphisms it has been shown that all extant cases of leprosy can be attributed to a single clone which then disseminated worldwide. Leprosy probably originated in India or eastern Africa and spread with successive human migrations.
Leprosy continues to be an important public health problem worldwide. In 2004, 407 791 new cases were reported with high rates of childhood cases in the most endemic countries. In 2008, 249 007 new cases were registered. The highest numbers of cases were in India, Brazil, Indonesia, Nigeria and Nepal. India accounts for 64% of the global disease burden. From 1990, the World Health Organization (WHO) led a leprosy elimination campaign but this defined elimination as less than 1 case per 10 000 population. Prevalence figures are highly influenced by operational activities such as reducing the length of treatment. The global focus is now on detecting new cases and providing sustainable care for leprosy patients. An estimated 4 million people are disabled by leprosy. Leprosy has not always been a tropical disease; it was widespread in medieval Europe and was endemic in Norway until the early 20th century. In North America, small foci of infection still exist in Texas and Louisiana. Nearly all new patients now seen in Europe and North America have acquired their infection abroad.
Leprosy is a chronic disease with a long incubation period. An average incubation time of 2 to 5 years has been calculated for tuberculoid cases and 8 to 12 years for lepromatous cases. American servicemen who developed leprosy after serving in the tropics presented up to 20 years after their presumed exposure. Most leprosy patients do not have known contact with a leprosy patient. Age, sex, and household contact are important determinants of leprosy risk; incidence reaches a peak at 10 to 14 years; the excess of male cases is attributed to women’s reluctance to present to health workers with skin lesions. Poor nutritional status is cited as predisposing to leprosy but no good evidence substantiates this. Improved socioeconomic conditions, extended schooling, and good housing conditions reduce the risk of leprosy. Subclinical infection with M. leprae is probably common but the development of established disease is rare. Little work has been done on the early events in infection with M. leprae because there is no simple test that can establish whether an individual has encountered M. leprae and mounted a protective immune response.
HIV and leprosy
It was predicted that HIV infection would produce anergic, lepromatous leprosy, However HIV/leprosy coinfected patients have disease types across the leprosy spectrum with typical leprosy skin lesions and nerve involvement. Their skin lesions have typical leprosy histology with granuloma formation even in the presence of low circulating CD4 counts. Patients coinfected with HIV and leprosy appear to be at higher risk of developing leprosy reactions and nerve damage. Leprosy may also present as an immune reconstitution syndrome (IRIS) in patients who have recently started on highly active antiretroviral therapy (HAART) and have rising CD4 counts and a falling viral load. These patients have borderline leprosy which is very immunologically active with inflamed skin lesions and reactions.
The transmission of Mycobacterium leprae is only partially understood. Untreated lepromatous patients discharge abundant organisms from their nasal mucosa into the environment. Studies in Indonesia and Ethiopia using polymerase chain reaction (PCR) primers to detect Mycobacterium leprae DNA in nasal swabs have shown that up to 5% of the population in leprosy endemic areas carry M. leprae DNA in their noses. The organism is then inhaled, multiplies on the inferior turbinates, and has a brief bacteraemic phase before binding to and entering Schwann cells and macrophages. The combination of an environmentally well-adapted organism, high carriage rates, and a long incubation period means that, even with effective antibiotics, transmission will continue for a long time.
Leprosy is a bacterial infection in which the clinical features are determined by the host’s immune response (Table 1).
Immune response to M. leprae and the leprosy spectrum
The Ridley–Jopling classification places patients on a spectrum of disease according to their clinical features, bacterial load, and histological and immunological responses. The two poles of the spectrum are tuberculoid (TT; paucibacillary) and lepromatous leprosy (LL; multibacillary). At the tuberculoid pole, well-expressed cell-mediated immunity effectively controls bacillary multiplication with the formation of organized epithelioid-cell granulomas; at the lepromatous pole there is cellular anergy towards M. leprae with abundant bacillary multiplication. Between these two poles is a continuum, varying from the patient with moderate cell-mediated immunity (borderline tuberculoid, BT) through borderline (BB) to the patient with little cellular response, borderline lepromatous (BL). The polar groups (TT, LL) are stable, but within the central groups (BT, BB, BL) the disease tends to downgrade to the lepromatous pole in the absence of treatment, and upgrading towards the tuberculoid pole may occur during or after treatment.
Both T cells and macrophages play important roles in the processing, recognition, and response to M. leprae antigens. In tuberculoid leprosy, in vitro tests of T-cell function such as lymphocyte transformation tests show a strong response to M. leprae protein antigens with the production of Th1-type cytokines such as interferon-γ and interleukin 2 (IL-2). Skin tests with lepromin, a heat-killed M. leprae preparation, are strongly positive. Staining of skin biopsies from tuberculoid lesions with T-cell markers shows highly organized granulomas composed predominantly of CD4 cells and macrophages with a peripheral mantle of CD8 cells. This strong cell-mediated immune response clears bacilli but with concomitant local tissue destruction, especially in nerves.
Patients with lepromatous leprosy have no cell-mediated immunity to M. leprae with a failure of the T-cell and macrophage response. Tests for lepromin are negative. This anergy is specific for M. leprae. Patients with lepromatous disease respond to other mycobacteria such as M. tuberculosis, both in vitro and in skin tests. Identification of cell types in lepromatous granulomas shows a disorganized mixture of macrophages and T cells, mainly CD8 cells. The T-cell failure may be due to clonal anergy or active suppression. Defects in cytokine production have been demonstrated; intralesional injections of recombinant IL-2 reconstitute the local immune response with elimination of M. leprae from macrophages. There is low production of Th2-type cytokines. Macrophage defects described in lepromatous disease include defective antigen presentation and recognition, defective IL-1 production, a failure of macrophages to kill M. leprae, and a macrophage suppression of the T-cell response. Patients with lepromatous leprosy produce a range of autoantibodies that are both organ specific (against thyroid, nerve, testis, and gastric mucosa) and nonspecific, such as rheumatoid factors, anti-DNA, cryoglobulins, and cardiolipin.
|Table 1 Major clinical features of the disease spectrum in leprosy|
|Tuberculoid (TT)||Borderline tuberculoid (BT)||Borderline (BB)||Borderline lepromatous (BL)||Lepromatous (LL)|
|Infiltrated lesions||Defined plaques, healing centres||Irregular plaques with partially raised edges||Polymorphic, ‘punched out centres’||Papules, nodules||Diffuse thickening|
|Macular lesions||Single, small||Several, any size, ‘geographical’||Multiple, all sizes, bizarre||Innumerable, small||Innumerable, confluent|
|Peripheral nerve||Solitary enlarged nerves||Several nerves, asymmetrical||Many nerves, asymmetrical pattern||Late neural thickening, asymmetrical, anaesthesia and paresis||Slow symmetrical loss, glove and stocking anaesthesia|
|Antibody, anti-M. leprae||–/+||–/++||+||++||++|
+, present, ++, present strongly, –, absent.
In lepromatous leprosy, bacilli spread haematogenously to cool superficial sites including eyes, upper respiratory mucosa, testes, small muscles, and bones of the hands, feet, and face as well as to peripheral nerves and skin. The heavy bacterial load causes structural damage at all these sites. In tuberculoid leprosy, bacilli are not readily found.
Neural inflammation is pathognomonic of leprosy. Nerve damage occurs in small nerve fibres, both sensory and autonomic, in the skin and in peripheral nerve trunks. Nerve damage occurs before diagnosis, during treatment, and after treatment. In lepromatous infection, almost all the cutaneous nerves and peripheral nerve trunks are involved. Bacilli are found in Schwann, perineural, and endothelial cells. Extensive demyelination occurs and later wallerian degeneration. Despite large numbers of organisms in the nerve there is only a small inflammatory response, but ultimately the nerve becomes fibrotic and is hyalinized. At the tuberculoid end of the spectrum nerve damage is secondary to a granulomatous response to M. leprae antigens. Perineural inflammation and epithelioid granulomas destroy the Schwann cells and axons. In borderline leprosy the combination of M. leprae antigens and a cell-mediated immune response results in small granulomas abutting strands of normal-looking but heavily bacillated Schwann cells giving rise to the widespread nerve damage in borderline leprosy. The persistence of M. leprae antigens in Schwann cells means that immune-mediated nerve damage can occur after successful antibacterial treatment.
Leprosy reactions are events superimposed on the Ridley–Jopling spectrum. Type 1 (reversal reactions) occur in borderline patients (BT, BB, BL) and are delayed hypersensitivity reactions caused by increased recognition of M. leprae antigens in skin and nerve sites. They are characterized by an increase in lymphocytes (CD4 and IL-2-producing cells) within lesions, severe oedema with disruption of the granuloma, and giant cell formation. There is local production of Th1-type cytokines such as interferon-γ and tumour necrosis factor-α.
Clinical features of leprosy
Patients commonly present with skin lesions, weakness or numbness due to a peripheral nerve lesion, or a burn or ulcer on an anaesthetic hand or foot. Borderline patients may present in reaction with nerve pain, sudden palsy, multiple new skin lesions, pain in the eye, or a systemic febrile illness. The cardinal signs are:
- typical skin lesions, anaesthetic at the tuberculoid end of the spectrum
- thickened peripheral nerves
- acid-fast bacilli on skin smears or biopsy
The commonest early lesion is an area of numbness on the skin or a visible skin lesion. The classic early skin lesion is indeterminate leprosy, which is commonly found on the face, extensor surface of the limbs, buttocks, or trunk. Indeterminate lesions consist of one or more slightly hypopigmented or erythematous macules, a few centimetres in diameter, with poorly defined margins. Hair growth and nerve function are unimpaired. A biopsy may show the perineurovascular infiltrate and only scanty acid-fast bacilli. The indeterminate phase may last for months or years before resolving or developing into one of the determinate types of leprosy.
The commonest skin lesions are macules or plaques; papules and nodules are more rare. Lesions may be found anywhere although rarely in the axillae, perineum, or hairy scalp. Skin lesions should be assessed for inflammation, colour, and sensation. Tuberculoid patients have few granulomatous hypopigmented lesions while lepromatous patients have numerous, sometimes confluent lesions. The few tuberculoid lesions are usually asymmetrical; more numerous lesions are likely to be distributed symmetrically.
Anaesthesia may occur in skin lesions when dermal nerves are involved or in the distribution of a large peripheral nerve. In skin lesions the small dermal sensory and autonomic nerve fibres supplying dermal and subcutaneous structures are damaged causing local sensory loss and loss of sweating within that area.
Peripheral nerve trunks are vulnerable at sites where they are superficial or are in fibro-osseous tunnels. At these points a small increase in nerve diameter raises intraneural pressure causing neural compression and ischaemia. Damage to peripheral nerve trunks produces characteristic signs with dermatomal sensory loss and dysfunction of muscles supplied by that peripheral nerve. The predilection sites for peripheral nerve involvement are ulnar nerve (at the elbow), median nerve (at the wrist), radial nerve, radial cutaneous nerve (at the wrist), common peroneal nerve (at the knee), posterior tibial and sural nerves at the ankle, facial nerve as it crosses the zygomatic arch, and great auricular nerve in the posterior triangle of the neck. All these nerves should be examined for enlargement and tenderness. Peripheral nerve function should be assessed by testing the motor function of the small muscles of the hands and feet using the Medical Research Council (MRC) grading scale. Sensory function is best assessed using graded nylon monofilaments (Semmes–Weinstein) as in diabetic screening. Patients should be asked about symptoms of neuropathy.
Tuberculoid leprosy (TT)
Infection is localized and asymmetrical. A typical tuberculoid skin lesion is a macule or plaque, single, erythematous, or purple, with raised and clear-cut edges sloping towards a flattened hypopigmented centre. The surface is anaesthetized, dry, and hairless. Sensory impairment may be difficult to demonstrate on the face where there are abundant nerve endings. If peripheral nerve trunk involvement is present, only one nerve trunk is enlarged. No M. leprae are found in skin smears. True tuberculoid leprosy has a good prognosis, many infections resolve without treatment, and peripheral nerve trunk damage is limited.
Borderline tuberculoid leprosy (BT)
The skin lesions are similar to tuberculoid leprosy and there may be few or many lesions. The margins are less well defined and there may be satellite lesions. Damage to peripheral nerves is widespread and severe, usually with several thickened nerve trunks. It is important to recognize borderline tuberculoid leprosy because these patients are at risk of reversal reactions leading to rapid deterioration in nerve function with consequent deformities.
Borderline leprosy (BB)
Borderline disease is the most unstable part of the spectrum and patients usually downgrade towards lepromatous leprosy if they are not treated or upgrade towards tuberculoid leprosy as part of a reversal reaction. There are numerous skin lesions which may be macules, papules, or plaques and they vary in size, shape, and distribution. The edges of the lesions may have streaming, irregular borders. Annular lesions with a broad irregular edge and a sharply defined punched-out centre are characteristic of borderline disease. Nerve damage is variable.
Borderline lepromatous leprosy (BL)
This is characterized by widespread variable asymmetrical skin lesions. There may be erythematous or hyperpigmented papules, succulent nodules or plaques, and sensation in the lesions may be normal. Peripheral nerve involvement is widespread. While patients with borderline lepromatous leprosy do not have the extreme consequences of bacillary multiplication that are seen in lepromatous disease, they may experience either or both reversal and ENL reactions.
Lepromatous leprosy (LL)
The patient with untreated polar lepromatous leprosy may be carrying 1011 leprosy bacilli. The onset of disease is frequently insidious, the earliest lesions being ill-defined, shiny, hypopigmented, or erythematous macules. Gradually the skin becomes infiltrated and thickened and nodules develop; facial skin thickening causes the characteristic leonine facies. Hair is lost, especially the lateral third of the eyebrows (madarosis). Dermal nerves are destroyed leading to a progressive glove and stocking anaesthesia. Position sense is preserved. Sweating is lost, which is uncomfortable in the tropics as compensatory sweating occurs in the remaining intact areas. Damage to peripheral nerves is symmetrical and occurs late in the disease. Infiltration of the corneal nerves causes anaesthesia of the cornea, which predisposes to injury, secondary infection, and blindness.
Nasal symptoms can often be elicited early in the disease. Septal perforation may occur. There may be papules on the lips and nodules on the palate, uvula, tongue, and gums. Bone involvement is common, with absorption of the terminal phalanges and pencilling of the heads and shafts of the metatarsals. Testicular atrophy results from diffuse infiltration compounded by acute orchitis that may occur during ENL reactions. The consequent loss of testosterone leads to azoospermia and gynaecomastia. The extremities become oedematous. The skin of the legs becomes ichthyotic and ulcerates easily.
Other forms of leprosy
There are several variant forms of leprosy. Pure neural leprosy occurs principally in India where it is the presenting form for 10% of patients. There is asymmetrical involvement of peripheral nerve trunks and no visible skin lesions. On nerve biopsy all types of leprosy have been found.
Histoid lesions are distinctive nodules occurring in lepromatous patients who have relapsed due to dapsone resistance or noncompliance with chemotherapy.
Lucio’s leprosy is a form of lepromatous leprosy found only in Latin Americans; it is characterized by a uniform diffuse shiny skin infiltration.
Eye disease in leprosy
Blindness due to leprosy, which occurs in at least 2.5% of patients, is a devastating complication for a patient with anaesthesia of the hands and feet. Eye damage results from both nerve damage and bacillary invasion. Lagophthalmos results from paresis of the orbicularis oculi due to involvement of the zygomatic and temporal branches of the facial (VIIth) nerve. These superficial branches are frequently involved in borderline tuberculoid cases, particularly if there are facial skin lesions. In lepromatous disease, lagophthalmos occurs later and is usually bilateral. Damage to the ophthalmic branch of the trigeminal (Vth) nerve causes anaesthesia of the cornea and conjunctiva resulting in drying of the cornea and making the cornea susceptible to trauma and ulceration. Lepromatous infiltration in corneal nerves produces punctate keratitis and corneal lepromas. Invasion of the iris and ciliary body makes them extremely susceptible to reactions.
Type 1 (reversal reactions)
These are characterized by acute neuritis and/or acutely inflamed skin lesions. Nerves become tender with new loss of sensation or motor weakness. Existing skin lesions become erythematous or oedematous; new lesions may appear. Occasionally oedema of the hands, face, or feet is the presenting symptom, but constitutional symptoms are unusual. Type 1 reactions occur in borderline patients; 35% of borderline lepromatous patients will experience a type 1 reaction. Patients often present with a skin lesion in reaction since a previously quiescent lesion has become active and visible. The peak time for reactions in the first 2 months after starting treatment and in the puerperium. Late reactions may occur years after finishing multidrug treatment. Some patient experience repeated reactions.
Type 2 (ENL reactions)
These occur in lepromatous and borderline lepromatous patients. Up to 50% of lepromatous patients will experience ENL reactions and 5 to 10% of borderline lepromatous patients. Attacks are acute and may recur over several years. ENL manifests most commonly as painful red nodules on the face and extensor surfaces of limbs. The lesions may be superficial or deep, with suppuration or brawny induration when chronic. Acute lesions crop and desquamate, fading over several days. ENL is a systemic disorder producing fever and malaise and may be accompanied by uveitis, dactylitis, arthritis, neuritis, lymphadenitis, and orchitis. ENL is often not recognized as a complication of leprosy outside endemic areas.
Silent neuropathy is an important form of nerve damage and presents as a functional neural deficit without a manifest acute or subacute neuritis. An Indian study following a cohort of 2608 patients found that 75% of those developing deformity had no history of reactions. In Ethiopian and Bangladeshi cohort studies, silent neuritis accounted for most neuritis. This emphasizes the importance of regular nerve function testing so that new deficits can be detected.
The diagnosis is made on the clinical findings of one or more of the cardinal signs of leprosy and supported by the finding of acid-fast bacilli on slit skin smears. The whole body should be inspected in a good light otherwise lesions may be missed, particularly on the buttocks. Skin lesions should be tested for anaesthesia to light touch, pin prick, and temperature. The peripheral nerves should be palpated systematically examining for thickening and tenderness and peripheral nerve function should be assessed. Histological examination of a biopsy taken from the active edge of a lesion is helpful to support the diagnosis and confirm the classification. The pathologist should be asked to examine for neural inflammation which will differentiate leprosy from other granulomatous conditions. Serology is not usually helpful diagnostically because antibodies to the species-specific glycolipid PGL-1 are present in 90% of untreated lepromatous patients but only 40 to 50% of paucibacillary patients and 5 to 10% of healthy controls. Polymerase chain reaction for detecting M. leprae DNA has not proved sensitive or specific enough for routine diagnosis.
Outside leprosy endemic areas, doctors frequently fail to consider the diagnosis of leprosy. Of new patients seen from 1995 to 1999 at The Hospital for Tropical Diseases, London, diagnosis had been delayed in over 80% of cases. Patients had been misdiagnosed by dermatologists, neurologists, orthopaedic surgeons, and rheumatologists. A common problem was failure to consider leprosy as a cause of peripheral neuropathy in patients from leprosy endemic countries. These delays had serious consequences for patients; over one-half of them had nerve damage and disability.
Slit skin smears
The bacterial load is assessed by making a small incision through the epidermis, scraping dermal material, and smearing evenly onto a glass slide. At least four sites should be sampled (earlobes and edges of active lesions). The smears are then stained and acid-fast bacilli are counted. Scoring is done on a logarithmic scale per high-power field. A score of 1+ indicates 1 to 10 bacilli in 100 fields, 6+ over 1000 per field. Smears are useful for confirming the diagnosis and should be done annually to monitor response to treatment.
Doctors should be aware of the normal range of skin colour and texture in their local population, and also of the common endemic skin diseases, such as onchocerciasis, that may coexist or mimic leprosy.
The variety of leprosy skin lesions means that a potentially wide range of skin conditions are in the differential diagnosis. At the tuberculoid end of the spectrum, anaesthesia differentiates leprosy from fungal infections, vitiligo, and eczema. At the lepromatous end the presence of acid-fast bacilli in smears differentiates leprosy nodules from onchocerciasis, Kaposi’s sarcoma, and post-kala-azar dermal leishmaniasis.
Peripheral nerve thickening is rarely seen except in leprosy. Hereditary sensory motor neuropathy type III is associated with palpable peripheral nerve hypertrophy. Amyloidosis, which can also complicate leprosy, causes thickening of peripheral nerves. Charcot–Marie–Tooth disease is an inherited neuropathy that causes distal atrophy and weakness. The causes of other polyneuropathies such as HIV, diabetes, alcoholism, vasculitides, and heavy metal poisoning should all be considered where appropriate.
There are six main principles of treatment:
- Stop the infection with chemotherapy.
- Treat new nerve damage.
- Treat reactions.
- Educate the patient about leprosy.
- Prevent disability.
- Support the patient socially and psychologically.
These objectives need the patient’s cooperation and confidence and can be achieved through the leprosy outpatient clinic with appropriate support and patient education. On the first visit there should be a careful assessment of skin and mucosal involvement and accurate evaluation of nerve and eye function. Each patient should be classified using the Ridley–Jopling classification and assessed for evidence of a reaction of new nerve damage.
All patients with leprosy should be given an appropriate multidrug combination. The first-line antileprosy drugs are rifampicin, clofazimine, and dapsone. The drug combination and duration are determined by the classification of the patient. The WHO has recommended a simple classification for use in the field determined only by the number of skin lesions. Patients are classified as paucibacillary if they have up to five skin lesions and as multibacillary if they have six or more skin lesions. In the specialist clinic setting, where skin smears and skin biopsies can be combined with clinical data, patients can be classified into paucibacillary (skin smear-negative TT and BT) and multibacillary (skin smear-positive BT, all BB, BL, and LL). Table 2 gives the drug combinations, doses, and duration of treatment. Patients with multibacillary disease and an initial bacterial index greater than 4 will need longer treatment, and the duration should be guided by their clinical status and bacterial index.
Rifampicin is a potent bactericide for Mycobacterium leprae. Four days after a single 600-mg dose, bacilli from a previously untreated patient with multibacillary disease were no longer viable in a mouse footpad test. It acts by inhibiting DNA-dependent RNA polymerase. Because M. leprae can develop resistance to rifampicin as a one-step process, this drug should always be given in combination with other antileprotics.
|Table 2 WHO recommended multidrug therapy regimens|
|Type of leprosya||Drug treatment|
|Monthly supervised||Daily self-administered||Duration of treatment|
|Paucibacillary||Rifampicin 600 mg||Dapsone 100 mg||6 months|
|Multibacillary||Rifampicin 600 mg||Clofazimine 50 mg||12 months|
|Clofazimine 300 mg||Dapsone 100 mg|
a WHO classification for field use when slit skin smears are not available: paucibacillary—up to five skin lesions; multibacillary—more than six skin lesions.
Dapsone (DDS, 4,4-diaminodiphenylsulphone) is weakly bactericidal. Oral absorption is good and it has a long half-life, averaging 28 h. It commonly causes mild haemolysis, but rarely anaemia. Glucose-6-phosphate dehydrogenase deficiency is seldom a problem. The ‘DDS syndrome’, which is occasionally seen in leprosy, begins 6 weeks after starting dapsone and manifests as exfoliative dermatitis associated with lymphadenopathy, hepatosplenomegaly, fever, and hepatitis. Clofazimine is a red fat-soluble crystalline dye. The mechanism of its weakly bactericidal action against M. leprae remains unknown. The most troublesome side effect is skin discoloration, ranging from red to purple-black, the degree depending on the drug dose and extent of leprous infiltration. The pigmentation usually fades within 6 to 12 months of stopping clofazimine, although traces of discoloration may remain for up to 4 years. Urine, sputum, and sweat may become pink. Clofazimine also produces a characteristic ichthyosis on the shins and forearms.
Other drugs bactericidal for M. leprae include the fluoroquinolones pefloxacin and ofloxacin, minocycline, and clarithromycin. These agents are now established second-line drugs. Minocycline causes a black pigmentation of skin lesions and so may not be an appropriate substitute for clofazimine if pigmentation is to be avoided.
A single-dose triple-drug combination (rifampicin, ofloxacin, and minocycline) has been tested in India for patients with single skin lesions and improved 98% of patients. This regimen can also be used in patients who experience adverse effects of dapsone or clofazimine, even in patients with a high BI. Although the study had major flaws and single-dose treatment is less effective than the conventional 6-month treatment for paucibacillary leprosy, it is an operationally attractive field regimen or for use in patients with migrant lifestyles.
The principal outcome of treatment is improvement of skin lesions; nerve damage may also improve but to a lesser extent. At the end of a 6-month treatment of borderline disease there may still be signs of inflammation, which should not be mistaken for active infection. Relapse is uncommon with a cumulative relapse rate of 1.07% for paucibacillary leprosy and 0.77% for multibacillary leprosy at 9 years after completion of multidrug therapy. M. leprae is such a slow-growing organism that relapse only occurs after many years. M. leprae isolates from relapsed patients who have received multidrug therapy are fully drug sensitive and patients can be retreated with the same regimen. The distinction between relapse and reaction may be difficult.
Since the introduction of multidrug therapy more than 14 million patients have been treated successfully. Clinical improvement has been rapid and toxicity rare. Monthly supervision of the rifampicin component has been crucial to success. Other benefits are reduced deformity rates and increased compliance in control schemes. Reactions may develop months or years after stopping chemotherapy, especially in patients with borderline lepromatous or lepromatous leprosy. It is therefore vital when discharging patients to warn them to return should new symptoms appear, especially in hands, feet, or eyes. Patients with reactions or physical or psychological complications will need long-term care.
Treatment of new nerve damage
Patients with nerve damage present for less than 6 months (assessed by patient history or testing) should receive a 6-month course of steroids starting at a dose of 40 mg prednisolone per day. A randomized controlled trial has shown that nerve damage present for more than 6 months is not improved by steroid treatment.
Management of reactions
Awareness of the early symptoms of reversal reactions by both patient and physician is important because, if left untreated, severe nerve damage may develop. The peak time for reversal reactions is in the first 2 months of treatment. Patients should be warned about reactions because the sudden appearance of reactional lesions after starting treatment is distressing and undermines confidence. The treatment of reactions is aimed at controlling acute inflammation, easing pain, reversing nerve and eye damage, and reassuring the patient. Multidrug therapy should be continued.
Type 1 (reversal) reactions
Simple anti-inflammatory drugs are rarely sufficient to control symptoms. If there is any evidence of neuritis (nerve tenderness, new anaesthesia, and/or motor loss), corticosteroid treatment should be started. Prednisolone should be given, starting at 40 to 60 mg/day, reducing to 40 mg after a few days, and then by 5 mg every 2 to 4 weeks. Patients with borderline tuberculoid leprosy in reaction commonly need 4 months of steroids while borderline lepromatous reactions may need 6 months or more.
Type 2 (ENL) reactions
This is a difficult condition to treat and frequently requires treatment with high-dose steroids (80 mg/day, tapered down rapidly) or thalidomide. Since ENL frequently recurs, steroid dependency can easily develop. Thalidomide (400 mg/day) is superior to steroids in controlling ENL and is the drug of choice for young men with severe ENL. Women with severe ENL may benefit from thalidomide treatment. This is a difficult decision for the woman and her physician and needs careful discussion of the benefits and risks (phocomelia when thalidomide is taken in the first trimester). Women should use double contraception and report immediately if menstruation is delayed. Unfortunately, the problems with thalidomide mean that it is unavailable in several leprosy endemic countries despite its undoubted value. Clofazimine has a useful anti-inflammatory effect in ENL but takes 6 weeks to become effective and can be used at 300 mg/day for several months. Low-grade chronic erythema nodosum with iritis or neuritis will require long-term suppression, preferably with thalidomide or clofazimine. Acute iridocyclitis is treated with 1% hydrocortisone eye drops given 4 hourly and 1% atropine drops twice daily.
Silent neuritis should be treated similarly to reversal reactions with prednisolone at a dose of 40 mg/day which should be reduced slowly over a period of months.
Education of patients
Stigmatization due to leprosy occurs worldwide. Patients are frightened of social ostracization, physical rejection, and the development of deformities. It is often useful to ask them about their fears so that these can be addressed. They should be reassured that having started treatment they are not infectious to family or friends and can have a sex life. The importance of compliance with antibiotic therapy needs to be emphasized. The patient needs a careful explanation of the diagnosis, aetiology, and prognosis.
Prevention of disability
The morbidity and disability associated with leprosy is secondary to nerve damage. A major goal in prevention of disability is to create patient self-awareness so that damage is minimized. Monitoring sensation and muscle power in patient’s hands, feet, and eyes should be part of the routine follow-up so that new nerve damage is detected early. The patient with an anaesthetized hand or foot needs to understand the importance of daily self-care, especially protection when doing potentially dangerous tasks and inspection for trauma. It is helpful to identify for each patient potentially dangerous situations, such as cooking, car repairs, or smoking. Soaking dry hands and feet followed by rubbing with oil keeps the skin moist and supple.
An anaesthetized foot needs the protection of an appropriate shoe. For anaesthesia alone, a well-fitting ‘trainer’ with firm soles and shock-absorbing inners will provide adequate protection. Once there is deformity, such as clawing, shoes must be made specially to ensure protection of pressure points and even weight distribution.
The patient should be taught to question the cause of an injury so that the risk can be avoided in the future. Plantar ulceration occurs secondary to increased pressure over bony prominences. Ulceration is treated by rest. Unlike ulcers in the feet of patients with diabetes or ischaemia, ulcers in leprosy heal if they are protected from weight-bearing. No weight-bearing is permitted until the ulcer has healed. Appropriate footwear should be provided to prevent recurrence.
Physiotherapy exercises should be taught to maximize function of weak muscles and prevent contracture. Contractures of hands and feet, foot drop, lagophthalmos, entropion, and ectropion are amenable to surgery.
Social, psychological, and economic rehabilitation
The social and cultural background of the patient determine the nature of many of the problems that may be encountered. The patient may have difficulty in coming to terms with leprosy. The community may reject the patient. Education, gainful employment, confidence from family, friends, and doctor, and plastic surgery to correct stigmatizing deformity all have a role to play.
The majority of patients, especially those who have no nerve damage at the time of diagnosis, do well on multidrug treatment with resolution of skin lesions. Left untreated, borderline patients will downgrade towards the lepromatous end of the spectrum and lepromatous patients will have the consequences of bacillary invasion. Borderline patients are at risk of developing type 1 reactions, which may result in devastating nerve damage. Treatment of the neuritis is currently unsatisfactory and patients with neuritis may develop permanent nerve damage despite corticosteroid treatment. It is not possible to predict which patients will develop reactions or nerve damage. Nerve damage and its complications may be severely disabling, especially when all four limbs and both eyes are affected.
Leprosy in women
Women with leprosy are in double jeopardy; not only may they develop postpartum nerve damage but also they are at particular risk of social ostracization with rejection by spouses and family.
Pregnancy and leprosy
There is little good evidence that pregnancy causes new disease or relapse. However, there is a clear temporal association between parturition and the development of type 1 reactions and neuritis when cell-mediated immunity returns to prepregnancy levels. In an Ethiopian study, 42% of pregnancies in borderline lepromatous patients were complicated by a type 1 reaction in the postpartum period. In the same cohort, patients with lepromatous leprosy experienced ENL reactions throughout pregnancy and lactation. ENL in pregnancy is associated with early loss of nerve function compared with nonpregnant individuals. Pregnant and newly delivered women should have regular neurological examination and steroid treatment instituted for neuritis. Rifampicin, dapsone, and clofazimine are safe during pregnancy. Clofazimine crosses the placenta and babies may be born with mild clofazimine pigmentation. Reactions can be managed with the steroid regimens given above but with a more rapid reduction in dose. Women should be warned before becoming pregnant of the risk that their condition may deteriorate after delivery. Ideally pregnancies should be planned when leprosy is well controlled.
Prevention and control
Leprosy control is now becoming more integrated into general services. Different models of providing leprosy control are used depending on the local facilities. In some endemic countries largely vertical programmes are being retained; in others such as Brazil leprosy services are provided within dermatological services. Effective treatment is not merely restricted to chemotherapy but also involves good case management with effective monitoring and supervision and prevention of disabilities. Treating patients with leprosy is a long-term enterprise involving patients, their families, and health workers.
Vaccines against leprosy
The substantial cross-reactivity between bacille Calmette–Guérin (BCG) and M. leprae has been exploited in attempts to develop a vaccine against leprosy. Trials of BCG as a vaccine against leprosy in Uganda, New Guinea, Burma, and South India showed it to confer statistically significant but variable protection, ranging from 80% in Uganda to 20% in Burma and this protective effect has been confirmed in a meta-analysis. A case-control study in Venezuela showed BCG vaccination to give 56% protection to the household contacts of patients with leprosy. Combining BCG and killed M. leprae has been tried, but in both a large population-based trial in Malawi and an immunoprophylactic trial in Venezuela there was no advantage for BCG plus M. leprae over BCG alone.
Areas of uncertainty and controversy
The optimum duration of treatment is a controversial area. The duration of treatment for multibacillary (MB) patients was reduced from 24 months to 12 months without good evidence. However, this occurred after the definition of LL patients was broadened and in India up to 60% of LL patients are smear-negative borderline tuberculoid patients. The concern regards patients with a high initial bacterial load. Data from India show that patients with a high initial bacterial load (bacterial index >4) treated with 2 years of rifampicin, clofazimine, and dapsone had a relapse rate of 8/100 person years, whereas patients treated to smear negativity had a relapse rate of 2/100 person years. The dilemma is that since skin smears are abandoned in many programmes those patients in need of longer treatment courses cannot be identified. A new treatment, uniform multidrug treatment (U-MDT), in which all leprosy patients are given 6-months of rifampicin, dapsone, and clofazimine are taking place. The problem is that this regimen adds in clofazimine for many patients who do not need it and will probably be inadequate for the same number of lepromatous leprosy patients with high bacterial loads who also maintain the infection in the community. These arguments illustrate the difficulty in providing sound evidence for policy decisions when a decade-long wait to establish relapse rates is needed.
Areas where further research is needed
The epidemiology of leprosy still poses unanswered questions. Why are 64% of all patients with leprosy in India? Is this due to living conditions, genetic susceptibility, or particular environmental conditions in India?
Early detection of cases is vital at both an individual and a population level. It is now recognized that substantial nerve damage occurs before diagnosis. A test for early infection might help detect individual cases before nerve damage is established and before the spread of infection. Leprosy-specific peptides for skin tests have been generated and are being evaluated.
The medical management of reactions and nerve damage is currently limited to steroids. These are not effective for about 30% of patients. Trials to determine the effectiveness of established and out-of-patent immunosuppressants such as azathioprine and ciclosporin are taking place.
The WHO started the 1990s with the bold slogan of ‘Eliminating leprosy as a public health problem by 2000’. This initiative galvanized leprosy control programmes worldwide, but the unique biology of M. leprae and its interaction with the human host rendered this target unattainable. However, there is a strong perception that leprosy has been eliminated and this has hindered research and planning. The WHO policy for 2011–2015 focuses on sustaining leprosy work. Leprosy is a bacterial disease with challenging immunological complications and will be a global and individual problem for many decades. It is unlikely to be eradicated until there is considerable improvement in general health, wealth, living conditions, and education.
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