Leprosy is caused by Mycobacterium leprae, a gram-positive and strongly acid-fast bacillus. The organism was first recognized by Hansen in 1874 but has never been cultured on artificial media. It is an obligate intracellular parasite, primarily of macrophages and Schwann cells and is the only mycobacterium that infects peripheral nerves. It was first shown to replicate in the foot pads of mice in 1960 by Shepard.¹ Recently, three species of monkeys have been infected, and one of these species was probably infected naturally.^2,3 The organism grows slowly, requiring about 12.5 days’ generation time (doubling time)⁴ compared to 14 to 15 hours for Mycobacterium tuberculosis⁵ and 20 minutes for Escherichia coli.⁶ One result of this extremely slow growth is the long incubation period for leprosy of 1 to 10 years.⁷ It may be 20 or more years after exposure before the diagnosis is made.

Leprosy is a chronic, granulomatous infection of the skin, mucous membranes, nerves, eyes, and adnexal tissues of the eyes. The major organs involved are the skin and peripheral nerves, although any organ can be affected, especially later in the disease. Although the bacillus prefers tissues that are cooler than 37°C, bacilli have been found in almost every organ.⁸

The immunologic defect in leprosy is caused by the selective anergy of T cells to M. leprae and its antigens. This immunodeficiency is either hereditary or acquired through an infection that leads to tolerance from gradual exposure of the patient to the organism. Consequently, cell-mediated immunity is inadequate, and the host is unable to mount an effective response.

Using the Madrid classification scheme, there are basically three forms of Hansen’s disease: tuberculoid, borderline, and lepromatous, depending on the immune response of the host.⁹ Diagnosis of these three forms of the disease is made on clinical and histologic findings. The Ridley and Jopling classification includes two polar forms (tuberculoid TT and lepromatous LL), the intermediate form (borderline BB), and a continuum between the two polar forms, giving five disease states (polar lepromatous LL, borderline lepromatous BL, intermediate II, borderline tuberculoid, BT and polar tuberculoid TT).^10,11 The disease in any one patient may evolve from one form to another, depending on duration of treatment and immunity.

In tuberculoid leprosy, the granulomatous lesions resemble those of tuberculosis, with epithelioid cells, lymphocytes, and giant cells. Acid-fast staining reveals few bacilli in the affected tissues. Clinically, tuberculoid leprosy exhibits only a few discrete skin lesions because of localization of the bacilli. The early skin lesions are sharply demarcated, hypopigmented, and hypoesthetic. The dermal nerves and skin are affected, often symmetrically, with few bacilli being present. Although sensory deficits are a prominent feature, there is little, if any, internal involvement.

In lepromatous leprosy, the patient has multiple diffuse lesions. The skin and, to a somewhat lesser degree, the peripheral nerves of the cooler portions of the body are affected early in this form, but sensory changes appear late in the disease process. The skin lesions are less clearly outlined and may be elevated. Later, the skin of the face becomes thickened, producing leonine facies. The internal organs and the eye are more frequently affected than in the tuberculoid form. There appears to be a defect in cell-mediated immunity,¹² and the replication of the bacillus is poorly constrained. Histologically, numerous acid-fast bacilli may be seen intracellularly and extracellularly. The lesions typically have many lipid-laden macrophages and many histiocytes. The acid-fast bacilli surround and are within vessel walls. There may also be a mild inflammatory perivascular infiltrate.

Borderline leprosy has some characteristics of both the tuberculoid and lepromatous forms of leprosy. The patient may evolve toward either of the polar forms or may remain borderline throughout the course of the disease. The lesions of intermediate leprosy may have variable presentations of skin and peripheral nerve involvement, as well as internal organ and ocular manifestations. The skin lesions are often multiple with either discrete or irregular margins. The histology has characteristics of both polar forms of the disease, with a mixture of epithelioid cells, histiocytes, and some lymphocytes. Acid-fast staining reveals several to many acid-fast bacilli, often found in the nerves. Although the immune status is less well defined, it probably lies between the two polar forms, with some abnormality in cell-mediated immune function but not the profound defect found in lepromatous leprosy.¹²

Occasionally, one sees reactional states during the course of the disease. These episodes may cause deformities from nerve and soft tissue inflammation and destruction. The reactional states are reversal (type I lepra reactions) and erythema nodosum leprosum (ENL) (type II lepra reactions).

In a type I reaction, the reversal reaction represents a delayed hypersensitivity reaction and is directed toward bacillary antigens. The surrounding tissue is damaged as a result of the reaction. This reaction usually occurs in the borderline and unstable states of leprosy and usually after initiation of treatment; it rarely occurs without treatment. A reversal reaction usually arises from an abrupt increase in cell-mediated immunity, and there is a shift of the disease toward the tuberculoid end (called upgrading reaction). It is clinically characterized as fever, edema, hyperemia, infiltration of skin lesions, and severe peripheral neuritis. In borderline disease, it is responsible for loss of nerve function and deformity. A downgrading reaction indicates development of decreased immunity. In this form of reversal reaction, borderline leprosy drifts toward the lepromatous pole. It generally occurs in the absence of treatment.

ENL, a type II reaction, is an immune-complex reaction. It occurs in lepromatous or borderline lepromatous patients as a result of immune complex deposition in skin. ENL is characterized by painful erythematous nodules or plaques on the face, arms, and thighs. Fever, malaise, arthritis, orchitis, iridocyclitis, lymphadenopathy, and proteinuria may all occur. The reaction is triggered by a transient imbalance in the patient’s immunoregulatory mechanisms. There is an increase in the CD4:CD8 (T helper/suppressor) ratio resulting in release of bacillary antigens from macrophages, which sets the stage for antibody and antigen to combine, fix complement, and attract neutrophils.

The Lucio phenomenon, which has occurred in a few lepromatous patients from Mexico and Central America, is probably a variant of ENL. It represents an acute allergic vasculitis from immune-complex formation and deposition within the vascular walls caused by release of antigens from infected endothelial cells. The Lucio phenomenon results in infarction of the overlying skin.

Humans are the only known natural host of M. leprae. Patients with untreated lepromatous leprosy are most likely the source of this infection with organisms being shed in nasal secretions and discharge from skin ulcers. The port of entry is probably the mucous membrane of the upper respiratory system and the skin. The disease process begins with bacillary infiltration, during a bacillemia, of predisposed cool and dopa-rich nerve and pigmented tissues¹³ (e.g., skin, nasal mucosa, the eye, and ocular adnexa), followed by an inflammatory response leading to functional loss with eventual atrophy and deformity of the involved structures.

Leprosy continues to remain a public health problem in some 14 countries in Africa, Asia, and Latin America, both in the tropical and subtropical regions. For some 20 years, WHO has focused on a global strategy to eliminate leprosy as a public health problem as defined by a prevalence rate, on the global level, of less than 1 case per 10,000 persons. During this period, more than 12 million patients have been diagnosed with leprosy, treated, bacteriologically cured, and discharged from leprosy control programs. The prevalence rate of the disease has decreased by 90% and active reportable leprosy has been eliminated from 108 of the 122 countries where leprosy was considered a public health problem in 1985. Approximately 755,000 new cases were detected in 2001. Intensive efforts are still needed to reach the leprosy elimination targets in Brazil, India, Madagascar, Mozambique, Myanmar, and Nepal; these countries accounted for 90% of the prevalence of the disease in the world in early 2002.^14,15 However, complications and disabilities associated with this disease continue to be a major challenge facing leprosy control efforts all over the world.

The worldwide distribution of leprosy does not parallel patterns of ocular complications seen in the disease, which is influenced by type of leprosy, age distribution, implementation of multidrug therapy (MDT) in the area, socioeconomic status, and eye care services available to patients.¹⁶ The available data on ocular leprosy and its complications rely almost exclusively on institutionalized patients. These data, therefore, include mainly the more advanced cases with serious debilities but rarely include earlier and milder cases living in their own communities. A worldwide study on ocular complications of leprosy has revealed blindness caused by leprosy in 3.2% and grade 2 visual disability in 7.1% of the sample analyzed.¹⁷ There are approximately 1.5 million patients with leprosy undergoing MDT treatment and another 10 million have completed and been released from MDT treatment. It is estimated that 1.5% to 2% are blind from leprosy-related causes and another 2% are blind from nonleprosy causes, mostly age related cataracts (defined as vision less than 20/400 [3/60] in the better eye; the metric equivalent is given after Snellen notation).^18,19

Major causes of blindness in this group include corneal opacity from exposure, iridocyclitis and its sequelae, and cataract. Because these causes may be considered in other categories of blindness (e.g., cataract is recognized as a major worldwide blinding condition), leprosy is largely ignored in blindness prevention efforts. Yet, this group of patients is clearly at high risk to have an avoidable blindness whatever the cause.

The apparent susceptibility of persons to infection and the expression it takes varies according to the gender, race, and geographic distribution of the involved population. The disease occurs in clusters and in families, probably because of shared environment, genetics, and contact. A history of prolonged exposure to the disease is common in new cases. Within families, the disease is spread by untreated lepromatous cases where the attack rate among the spouses is 5% to 10%.²⁰ Among young children exposed to untreated lepromatous cases, 30% to 50% develop a mild episode (usually a single lesion) that heals spontaneously.²¹ Documented cases in previously healthy adults (e.g., exposed medical personnel) are uncommon.

In most prevalence studies, males outnumber females by 2:1 or 3:1,^{22,23,24,25,26} but this may represent a reporting bias instead of an increased male susceptibility. Race or climate also appears to be important in determining the disease pattern. Prevalence studies suggest that lepromatous leprosy is more common in the temperate climates of Asia, South America, Northern India, and Nepal,²⁷ while tuberculoid leprosy is more common in tropical central Africa.^28,29 However, racial differences may play some role in this differing distribution. Some workers believe that the Mongolian races are more susceptible to lepromatous leprosy and that climate plays a less important role.^30,31 The diffuse form of lepromatous leprosy with skin ulcers (Lucio reaction),³² which occurs principally in Mexico, has been cited as an example of genetic influence.

Ocular involvement and blindness differ according to the type of leprosy. In lepromatous leprosy, there is a higher rate of intraocular complications, particularly in the various forms of uveitis.^33,34 Patients with tuberculoid leprosy, on the other hand, have more problems of the outer eye such as lagophthalmos, exposure keratitis, and corneal opacities.^21,28 A study in Egypt, however, indicated a higher rate of intraocular disease (uveitis) than expected in patients with long-term tuberculoid leprosy.³⁵

Although a great deal of data has been collected on leprosy and to a lesser extent on ocular leprosy, caution should be used in comparing the data because of the vast differences in reporting, examination techniques, equipment used, and background and training of the observers. Ocular involvement has been reported in 6% to 90% of patients, and some workers believe that all leprosy patients eventually develop eye diseases.^{28,36,37,38,39} Estimates of blindness among patients with leprosy also vary. For example, a study of 466 patients with leprosy in Nepal revealed that the prevalence of blindness, defined as a visual acuity of less than 20/200 (6/60), depended on the duration and type of disease. Of patients with leprosy of less than 10 years’ duration, 8.3% were blind, but of those who had had leprosy more than 20 years, 30% were blind.⁴⁰ Data on blindness in patients with Hansen’s disease are notoriously incomplete and often unreliable. There simply are many problems in obtaining representative population-based estimates.