Leprosy is a chronic disease caused by Mycobacterium leprae. Its principal clinical lesions occur in the cooler tissues of the body: skin, superficial nerves, nose, pharynx, and larynx The distal portion of the eye and the testicles may also be damaged. Disfigurement and deformity owing to skin infiltration and peripheral nerve destruction in untreated patients may be extremely severe and conspicuous. The disfigurement is the principal reason for the fear and loathing historically—and tragically—attached to the disease.
Mycobacterium leprae, the cause oi leprosy, was discovered in 1873 by G. Armauer Hansen of Norway. It is an acid-fast rod about the same size as M. tuberculosis, from 1.5 to 6.0 fx long and 0.2 to 0.45 /x thick. It occurs in tissues singly, in “cigar-bundle” clusters, and in oval aggregates 15 to 25 jx in diameter called globi. Though many efforts have been made (notably by Danielssen in Norway and Mouritz in Hawaii) to infect humans by injecting bacillus-containing material into them, only’one (by Arning, in Hawaii) has been successful, and in it the possibility of prior infection of the subject by ordinary means could not be excluded. Apparent accidental inoculation of two Marines by tattooing was reported during World War II. The successful inoculation of footpads of trace, achieved in 1960, has made it possible to identify sulfone-resistant strains of M leprae.
incidence and Epidemiology.
Known of old throughout south Asia and Africa, and almost epidemic throughout Europe in the eleventh to thirteenth centuries, leprosy persists today in a patchy endemic zone encircling the world largelybetween the thirtieth parallels of latitude, but also including Japan, Korea, south China, and South Africa. Outside of these areas it does not appear to be communicable. Only a handful of cases remain inScandinaviaa and none in most European countries. In Spain and Portugal, it may be increasing in incidence. In the United States, leprosy is endemic in those states bordering on the Gulf of Mexico and in Hawaii.
The transmission of leprosy is mysterious. It is so difficult to acquire that it was believed for many decades to be hereditary rather than contagious. Yet, it is so easy to acquire that nearly half the patients with recently acquired disease are unaware of having had any contact with another diseased person. Perhaps this paradox can best be resolved by the view that leprosy is easily acquired by contact with lepromatous persons during transient periods of increased susceptibility, to which some persons are subject. Such susceptibility may be inherited, though this is unproved.
The determinants of susceptibility are not known. Hawaiians have seventy times the leprosy morbidity experienced by Caucasians in Hawaii, and similar racial differences are reported from many other areas. A family history of leprosy probably means heightened susceptibility to infection, though it is not necessarily associated with low resistance to the established disease. Persons with a negative Mitsuda reaction to injected lepromin are more susceptible to leprosy, and they are more apt to have the lepromatous form of the disease if they do become infected than persons with a positive reaction. Diet is probably unimportant.
Pathogenesis and Clinical Manifestations.
Leprosy involves principally the skin and subcutaneous nerves. It occurs in reasonably well-defined types, in both of which the disfigurement and deformity may be produced either by the disease process itself or by the consequences of t he loss of sensation or motor or trophic innervation of an affeeted area or part. The clinical picture may also be significantly modified, in the lepromatous type, by the development of systemic amyloidosis or by associated infection with tubercle bacilli. Because of these very considerable differences between types and groups, no single clinical description will usefully depict leprosy. Consequently, in the present discussion, the principal attention will be devoted to defining the individual manifestations, in themselves quite recognizable, that serve to characterize the various forms of the disease.
Types and Groups of Disease.
There are two principal types of leprosy: the lepromatous (formerly called cutaneous) type, in which the patient manifests no resistance to the disease, and the tuberculoid (formerly called neural) type, in which he manifests more or less vigorous resistance to it. Most cases of leprosy fall into one or the other of these two categories. Transition does occasionally occur from one to the other (most often
undergoing such transition may present features of both types. Nevertheless, no “mixed” form of leprosy, as such, is recognized. In Mexico and Costa Rica, a variation of the lepromatous form known as the Lucio type is encountered. In this for disease, the involvement is diffuse, no
lepromas occur, and acid-fast baciLLi ms observed in fairly large numbers in serum obtained from scraping the side of an incision in what appears to be normal skin. The Lucio form has Been observed only rarely ow\s>SAe American continent.In addition to these two relatively stable “polar” types of leprosy, two “groups” of leprosy cases are recognized, the indeterminate (I) and the borderline or dimorphous (B). The types, subtypes, groups, and subgroups, are outlined in Table 1, and the principal distinctions among these- types and groups are given in Table 2.
Definition of these types and groups adopted by the Sixth International Congress of Leprosy in’ Madrid in 1953 were as follows:
Lepromatous type (L).
A malign type, especially stable, strongly positive on bacteriologic examination, presenting more or less infiltrated skin lesions, and negative to lepromin. The peripheral nerve trunks become manifestly involved as the disease progresses, habitually in symmetrical fashion and often with neural sequelae in advanced stages.
Tuberculoid type (T). Usually benign, very stable; generally negative on bacteriologic examination; presenting in most cases erythematous skin lesions which, are elevated marginally or more extensively; positive to lepromin. Sequelae of peripheral nerve trunk involvement may develop in some cases, and this may give rise to serious ar z disabling deformity. This frequently appears to occur as a result of extension from or through cutaneous nerve branches, rather than of systemic dissemination, and consequently it is oft*- asymmetrical and unilateral.
More or less transitory states of exacerbation or reactivation known as reactions may occur once or repeatedly in all forms of leprosy. In lepromatous leprosy, these are known as “lepra reactions and two principal forms are recognized. The ordinary lepra reaction consists of aggravation of existing skin lesions, development of new ones, and usually fever, neuralgia, and malaise or prostration lasting for hours, days, or weeks. This may or may not be accompanied by erythema multiforme of either the ordinary or bullous variety. The lepra reaction may take the form of an atypical, sparse, generalized erythema- nodosum-like reaction, erythema nodosum leprosum, which characteristically occurs when the proportion of dead to living M. leprae rises above a critical ratio.
In tuberculoid or borderline leprosy, reactions, consist of aggravation of previous lesions or the appearance of succulent, elevated new plaques; painful swellings of nerves may occur; M. leprae may become numerous in the lesions: and the lepromin reaction may decrease in intensity. Fever and constitutional symptoms (including erythema multiforme) do not occur in tuberculoid cases.
An advanced case of leprosy with the combination of skin lesions and obvious nerve lesions should be readily recognized by the reasonably alert physician. It is in the early cases, in which the nerve involvement is not readily apparent, that the diagnosis of leprosy may be missed. In certain forms of the disease, the diagnosis can be definitely established by demonstration of the presence of M. leprae in material obtained from the patient’s lesions. It is important to realize, however, that a clinical impression or suspicion of leprosy, as such, cannot be excluded by any one diagnostic procedure. A suspicion of lepromatous leprosy can be excluded by finding no acid-fast bacilli in the lesions, but such a negative finding will not exclude the indeterminate or tuberculoid variety. A suspicion of tuberculoid leprosy can be eliminated by excluding all evidence of nerve damage in the lesions, but such a finding will not exclude the indeterminate or lepromatous type.
Nasal scrapings, though they will show acid- fast bacilli in perhaps one third of early lepromatous cases and in all advanced ones, may be either positive or negative in either type of leprosy, and cannot be relied upon either to confirm or to exclude the diagnosis. Nonpathogenic acid-fast diphtheroid bacilli indistinguishable, from M. leprae may be found even in a normal nose.
A simple and trustworthy method of looking for bacilli in skin lesions is Wade’s “scraped incision” procedure. The point of a scalpel, or, better still, the corner of a safety razor blade, is inserted 3 or 4 mm. deep into a pinched-up fold of involved skin, or even uninvolved skin, e.g., an ear lobe. It is then rotated about an axis perpendicular to the skin surface so that its edge scrapes the side of the cut, and a small drop of tissue pulp and lymph is obtained. Blood does not interfere seriously.
This drop is spread in a dime-sized area on a clean slide, dried, and stained by the Ziehl- Neelsen method, destaining with, preferably, Gab- bett’s solution. The carbolfuchsin should be used cold, not warm, for fifteen minutes. The preparation should not be subjected to decolorization too long because M. leprae is much less acid-fast than M. tuberculosis. A count of bacilli may be made in high-power fields per bacillus (or bacilli per high- power field) for comparison with future counts.
The standard Ziehl-Neelsen staining procedure is not sensitive enough to be used on paraffin sections of tissue if bacilli are at all scarce. Wade’s modification of the Fite-Faraco stain (Amer. J. Path., 28:157, 1952) should be used to prevent defatting the bacilli.
In the absence of bacilli, a suspicion of leprosy needs confirmation by demonstration of nerve damage. Such damage may consist of anesthesia or anhidrosis (usually coextensive with a skin lesion in tuberculoid cases, often on feet or hands in lepromatous disease), thickening of superficial nerves, muscular weakness or atrophy, especially in the face and hands, or histologic changes in a biopsy specimen.
Leprous neuritis often produces sensory dissociation similar to that seen in syringomyelia: sense of touch may be preserved, but that of heat and cold, or pain, or both, may be lost. Each should be tested separately. Palpation of the great auricular nerves where they cross the sternocleidomastoid muscles, of the ulnar nerves just above and behind the internal humeral epicondyles, or of the peroneal nerves behind the heads of the fibulas may reveal thickening, nodularity, stiffness, or tenderness, any or all of which cause suspicion of leprous neuritis. Drooping of one or both
lower eyelids or oral commissures, or weakness of elevation of one eyebrow may disclose the patchy weakness of facial muscles, which Monrad-Krohn has said is the most distinctive single neurologic sign of leprosy. Contracture of a fifth finger, or flattening of a hypothenar or thenar eminence, or the grooving produced by atrophy of the interosseous muscles of the hands, may betray the presence of leprous ulnar or median neuritis. Actual “claw” hand deformity or foot drop may ultimately occur.
Biopsy of a thickened great auricular nerve or of other skin nerves that subserve no important motor function is a practicable procedure of value if a diagnostic biopsy of skin is not possible. The histologic changes are usually characteristic, and, in tuberculoid leprosy, bacilli are much more readily found in the nerves than in the skin.
Roentgenograms of hands and feet may show concentric absorption of phalangeal or metatarsal shafts, a characteristic “trophic” lesion that leads ultimately to loss of continuity of the bone and shortening of digits or of the whole foot. Rarely, diabetic peripheral neuritis may produce such changes, but without anesthesia. “Dropping off” of digits is a myth.
Painless trophic plantar ulceration, identical with that seen in tabes dorsalis and in syringomyelia, may also occur. Such ulcers are not primarily leprous, and no bacteriologic or histologic evidence of leprosy is to be found in them. They often lead to osteomyelitis of metatarsal bones.
The lepromin test is performed by the intradermal injection of 0.1 ml. of a boiled or autoclaved, gauze-filtered suspension of M. leprae and human tissue, prepared by grinding lepromatous granulation tissue in a mortar and suspending it in saline solution. Mitsuda reported in 1919 that such an injection was followed by no reaction in patients with lepromatous leprosy, but that in tuberculoid cases an inflammatory nodule resulted, reaching its height in about three weeks and sometimes ulcerating.
Fernandez later described a 48-hour Mantoux-like reaction, fairly well correlated with the Mitsuda response. A positive lepromin reaction does not denote the presence of leprosy. It is positive in roughly half the population in many areas in which leprosy does not even occur. It apparently denotes resistance to leprosy. Its high correlation with a positive Mantoux reaction, especially in persons without leprosy, and the regularity with which BCG vaccine causes negative Mitsuda reactors to “convert” to positive suggest a relationship with exposure to tuberculosis that has not yet been explained or even fully evaluated. The use of BCG vaccine to protect susceptible contacts against leprosy is still undergoing extensive experimental testing, and its value is still moot.
Without treatment, patients with lepromatous leprosy tend to suffer steady progression of their disease and to die of tuberculosis, amyloid nephrosis, intercurrent infection, or leprosy. Patients with tuberculoid leprosy, untreated, tend to recover completely, except for residual nerve damage, within a year or two if only one or a few annular plaques are present. If their skin lesions are numerous and widespread, the disease may run a rather protracted course, with repeated relapses, but the patients still tend to recover completely if the lepromin reaction is strongly positive.
With chemotherapy, most patients experience immediate arrest of the disease and steady improvement. Recovery (except for residual nerve destruction) is usually complete in a year or two if bacilli were initially few or absent, or in three to perhaps six or eight years if bacilli were initially abundant and the lesions widespread The problem of longer persistence of disease in some lepromatous cases remains unsolved
The sulfones are the major specific chemotherapy of leprosy Diaminodiphenylsulfone (DDS, Avlosulfon, dapsone has preempted the field. Many leprologists start with 25 mg. once a week and raise the dose to a 100 mg. daily maximum in weekly 25-mg. increments, although some start and continue with 50 or 100 mg. orally two days a week. The duration of treatment in tuberculoid cases is determined by the clinical response; as bacilli are usually lacking from the start, a clinically satisfactory result is likely to require a year or two. In lepromatous cases, treatment is continued until the skin lesions and nasal mucosa are healed and virtual devoid of acid-fast bacilli — usually at least two or three years in early cases, and perhaps as long as six or eight years in heavily involved cases. Maintenance therapy for prevention of relapse is necessary for many patients and advisable for most. Patients with a strongly positive reaction to lepromin, however, usually remain well indefinitely without maintenance therapy.
Reactions are mild and infrequent with small doses of sulfones. Moderate overdosage may cause headache, anorexia, nausea, dizziness, insomnia, or tachycardia. Anemia, which may occur at any dose level, is the most common potentially serious reaction, and should be watched for by hemoglobin determinations weekly and, later, monthly. Toxic psychosis, agranulocytosis, hematuria, or erythema nodosum may be seen with larger doses of any sulfone and require interruption of treatment or reduction of the dose.
In the event of complete intolerance for even small doses of sulfones, amithi ozone is probably the best substitute. The dose is 25 mg. a day initially, increased slowly to a maximum of 100 to 150 mg a day, by mouth Dihydrostreptomycin, 1.0 gram intramuscularly three times a week, is. much less effective, according to most observers, though controlled studies over short periods in the Philippines and South Africa under Doull’s direction (1956) suggest that it is almost as good a» the sulfones (For discussion of dihydrostreptomycin toxicity, see Pulmonary Tuberculosis.)
Isoniazid and para-aminosalicylic acid are not reliable in their effects upon the disease.
During lepra reactions?, bed rest is indicated, and aspirin and antihistamines may be helpful. The sulfone dosage may have to be reduced, but need not be if symptoms respond well to intramuscularly injected triamcinolone acetonide (Kenalog IM) suspension. Erythema multiforme, ordinary or bullous, or erythema nodosum may be controlled with steroids as a rule.
Keratitis, iritis, or iridocyclitis may occur in lepromatous cases and may require treatmem with 1 per cent hydrocortisone drops or ora or better, intramuscular triamcinolone Atropmiza tion is indicated for iridocyclitis. In advanced cases, eyelid paralysis may lead to exposure keratitis.
Although lepromatous neuritis is slowly progressive, tuberculoid leprous neuritis may cause rapid swelling of one or more nerve trunks, sometimes with such intense and persistent pain as to require surgical decortication of the nerve involved. Nerve abscesses, which occur rarely, may require incision and drainage.
Orthopedic procedures aimed at rehabilitation of patients with “claw” hand resulting from ulnar neuritis, or foot drop from peroneal palsy, differ in no essential respect from those devised for similar lesions due to other diseases.
Prevention of leprosy is promoted best by protecting uninfected persons, especially children, from exposure to untreated, lepromatous patients. In nonendemic areas adults are probably as susceptible as children. Mouse footpad inoculation studies by Shepard (1960) and by Levy and Fasal (1968) suggest that infectivity of lepra bacilli is reduced to nearly zero after 60 to 90 days of sulfone therapy.
A recent retrospective study of Hong Kong families by Worth (1968) showed that infection occurred in more than IQ per cent of children exposed to an untreated lepromatous parent, but none had been infected (up to seven years’ observation) when exposure to such a parent had occurred after treatment had been started. Isolation is no longer regarded as playing a role of any importance —even in endemic areas — in the prevention of leprosy. The emphasis is all on early diagnosis and treatment. Hospitalization is desirable for initiation of treatment in most lepromatous cases, but it should be voluntary and usually need not exceed two or three months.