Clinical findings

From 50% to 70% of patients with leprosy have the tuberculoid form, which tends to be localized to the skin and nerves. The disease in these patients is characterized by granuloma formation and the absence of a large number of bacilli because of their active cell-mediated immune response. The skin test with lepromin is highly positive (Mitsuda reaction). The lepromatous form of the disease is characterized by a severe generalized condition with massive bacterial infection. In contrast to patients with tuberculoid leprosy, these patients have a poor cellular immune response, and macrophages are predominantly found on histologic examination. Intraocular inflammatory disease occurs more commonly in this form of leprosy. In addition, the severe disfiguring changes of the limbs and face are associated with lepromatous leprosy. In patients with borderline groupings of leprosy, a sudden shift to the lepromatous state can occur.

A list of the ocular complications of leprosy is given in Box 9-1 . In one study, over half of patients with multibacillary leprosy had ocular involvement. Structural damage to the eyelids, poor lid closure as a result of facial nerve involvement, and impaired corneal sensation often lead to exposure of the cornea. Loss of the temporal portion of the eyebrows (madarosis) is a typical finding and a stigma to those affected. It is important to remember, however, that trachoma can exist in the same population with leprosy and can compound the external disease in these patients. The keratitis associated with leprosy starts superiorly and first appears as subepithelial chalky infiltrates surrounded by gray stromal opacifications. Corneal exposure predisposes patients to development of corneal ulcers ( Fig. 9-2 ) that are often difficult to manage.

Severe bacterial corneal ulcer in patient with leprosy.

(Courtesy R. Christopher Walton, MD.)

Intraocular inflammatory disease is a known complication of leprosy. In a retrospective study of 531 leprosy patients, 4% had iritis. The organisms can directly invade the iris and ciliary body, and chronic anterior uveitis is commonly seen in these patients. If the uveitis is not aggressively treated, cataract and hypotony frequently result. Less frequently, patients present with an acute anterior uveitis. In a study of 100 patients with leprosy in Brazil, 72 had ocular complications. Seventeen had a chronic anterior uveitis, whereas only two had an acute anterior uveitis. In a study in Nepal, 8% of patients with tuberculoid leprosy had uveitis, whereas 16% of patients with lepromatous leprosy had anterior chamber inflammatory disease. Spaide and colleagues found that uveitis was uncommon in leprosy patients in the United States, which possibly reflects the results of more aggressive treatment with antilepromatous and antiinflammatory agents. Granulomas form in the iris and appear as iris ‘pearls’ on the anterior surface ( Fig. 9-3 ). Iris atrophy also occurs in many patients ( Fig. 9-4 ).

A, Iris ‘pearl’ of leprosy seen as small white object on iris edge. In B, many of these can be seen just right of the slit beam.

(Courtesy Khalid Tabbara, MD.)

Multiple areas of iris atrophy (arrowhead) in patient with iritis caused by leprosy.

(Courtesy Fernando Orefice, MD.)

Although less common, changes to the retina have been described in patients with leprosy. Patients with long-standing lepromatous leprosy can have large numbers of organisms that invade not only the anterior segment but also the adjoining peripheral pars plana and retina. Pars planitis has been reported in patients with leprosy. Chovet and colleagues demonstrated segmental vasculitis in the posterior pole on fluorescein angiography in patients with lepromatous disease. Blindness can occur from a number of the ocular complications of leprosy.

Immunology and pathology

Humans are the only natural host for M. leprae . After entering the host, the organism reproduces in mononuclear cells, particularly skin histiocytes. The doubling time for the organisms is extraordinarily long – about 20 days – and attempts to culture the organism in a cell-free environment have not been successful. Some work has centered on the use of the nine-banded armadillo as an experimental model. This animal has a low basal temperature that seems to permit large numbers of M. leprae to propagate.

The immune characteristics of patients with this disorder have been extensively studied. Imbalances in T cells, antigen-specific suppressor T cells, and defective production of monocyte-activating cytokines have all been described. CD4+ T cells predominate in tuberculoid lesions, but CD8+ T cells are almost exclusively found in lepromatous lesions. Family studies with HLA typing have suggested that there is an HLA-linked recessive gene that may predispose patients to the tuberculoid form of the disease.

The reactional states of leprosy have been divided into two categories: type I and type II. The type I reaction is also known as the reversal reaction and is a delayed hypersensitivity response directed against bacillary antigens. The type II reaction is also known as erythema nodosum leprosum and is an immune-complex reaction. Patients with the reversal reaction (type I) may be more likely to present with orbicularis oculi weakness and lagophthalmos.

Therapy

Dapsone, rifampin, and clofazimine are the principal antileprosy agents used. The World Health Organization recommends multidrug treatment regimens because of the existence of dapsone-resistant strains of M. leprae . More aggressive therapy may be warranted in patients with multibacillary disease. The use of thalidomide has been useful in patients with recurring and persistant erythema nodosum leprosum. Attempts to develop a vaccine are currently under way. Ocular care of patients with leprosy requires careful management of the external disease, including surgical management of eyelid deformities and judicial use of ocular lubrication. If intraocular surgery is planned, great care must be taken to be sure that the eye has no active inflammation.

Systemic disease

Infection in the United States is transmitted predominantly in aerosolized droplets. Most patients develop an asymptomatic, self-limited pneumonia that usually heals with granuloma formation. Sensitization develops 2–10 weeks after infection and is manifested by a positive skin test to an extract of the tuberculous bacillus (purified protein derivative, PPD). The granulomas usually calcify and remain inactive. However, onset of symptoms can occur after a breakdown of the patient’s immune system associated with age, disease, or the use of immunosuppressive therapy for other conditions.

Ocular disease

Ocular involvement occurs in about 1–2% of patients with TB. The ocular manifestations of TB are listed in Box 9-2 . TB can involve both the anterior and posterior segments of the eye as well as the ocular adnexa and orbit. In miliary TB tubercles can be seen in the choroid, giving the impression of a unifocal or multifocal choroiditis ( Fig. 9-5 ). There has been debate about whether at least some cases of serpiginous choroiditis may be caused by tuberculosis. ^, Choroidal tubercles have also been associated with the development of subretinal neovascularization. More rarely, tubercles occur in the anterior chamber and may elicit a severe inflammatory response ( Fig. 9-6 ). In addition, tubercle formation of the lids conjunctiva, cornea, and sclera have been reported. Granulomatous iritis is the inflammatory condition most often associated with TB. Coles wrote that TB should be suspected not only in cases of granulomatous uveitis but also in cases of intense nongranulomatous anterior uveitis of short duration, mild relapsing uveitis, or chronic smoldering inflammatory disease.

Two large choroidal lesions (arrowheads) caused by miliary tuberculosis.

(Courtesy Fernando Orefice, MD.)

Patient with systemic tuberculosis who presented with a large floccular mass in anterior chamber.

(Courtesy Roberto Neufeld, MD.)

Interstitial keratitis and phylactenular keratoconjunctivitis are common findings in patients with ocular TB; however, they are not thought to result from direct invasion of organisms but instead to represent an immunologic response to the mycobacteria. Eales’ disease, a disorder characterized by retinal vasculitis and vitreous hemorrhage, is also associated with TB (see Fig. 27-2, A and B ). Finally, optic nerve involvement and cataracts have also been reported in patients with ocular TB. ^, A number of infectious and noninfectious disorders may cause ocular disease similar to TB. For example, the retinal periphlebitis that results from TB can mimic the ocular disease associated with sarcoidosis and syphilis. Finally, an underlying immunosuppressive state, such as AIDS, should always be considered in patients with ocular TB.

Diagnosis

The diagnosis of ocular TB is usually difficult to make. We have spent countless hours debating the diagnostic approach to patients with possible TB-associated uveitis. Definitive diagnosis requires the identification of Mycobacterium tuberculosis organisms in ocular tissues or fluids, but samples are often difficult to obtain, and biopsy may be hard to justify in a patient who has only a small chance of having the disease. Patients with suspected ocular TB should have a systemic evaluation for evidence of the disease. A chest X-ray should be obtained and tuberculin skin tests performed. If the clinical findings support a diagnosis of TB, a complete course of antituberculosis therapy should be considered. In a study in Japanese patients with intraocular inflammation, 26 of 126 had a positive tuberculin skin test result. Ten of these 26 patients had clinical findings consistent with TB and had a favorable response to antituberculosis therapy.

An intermediate-strength tuberculin skin test should be used for most patients. However, if a patient has a history of TB or has had a positive PPD test result in the past, an intermediate-strength PPD may cause a severe dermatologic response and a lower-strength one should be used. The PPD test is not 100% sensitive or specific for the disease. One patient with numerous tubercle bacilli in the eye was reported to have a negative PPD test result and no systemic manifestations of disease. Importantly, a positive PPD test result in a patient with uveitis does not mean that the uveitis is caused by TB, because TB is a very rare cause of inflammatory eye disease. In fact, without other signs of TB, a positive PPD test result in a patient with uveitis is probably more misleading than helpful. Interferon-γ-release assays are new alternatives to the tuberculin skin test. These new assays, especially QuantiFERON-TB Gold, have excellent specificity and are unaffected by BCG vaccination.

Although many patients with ocular TB will have evidence of systemic disease, TB infection limited to specific organs, including the eye, may occur. Microscopic examination of ocular tissues or fluids may show bacilli; however, culture is more sensitive. The polymerase chain reaction (PCR) has also been used to diagnose TB infection, but in most laboratories this is currently only experimental.

Therapy

Because of the development of treatment-resistant TB, recommended treatment regimens have become more aggressive. Previously the recommended treatment was regimens of isoniazid and ethambutol for 1.5 to 2 years. Since the late 1960s, however, a number of studies have demonstrated that short-course treatment regimens can be effective. Most regimens contain isoniazid and rifampin for 9 months. A third drug – ethambutol, streptomycin, or pyrazinamide – was usually added for the first 3 months to prevent resistance. Most regimens now include at least a 2-month course of four drugs, including isoniazid, rifampin, pyrazinamide, and ethambutol, followed by an additional 4 months of isoniazid and rifampin. Clearly, therapy should be administered by a practitioner well versed in the current treatment recommendations. ^,

The difficult decision is whether antituberculous therapy is warranted for the patient with uveitis compatible with TB, no evidence of systemic disease, and a positive PPD test result. Schlaegel and Weber have recommended an isoniazid therapeutic test for these patients. This involves giving isoniazid at 300 mg/day and examining the patient every week. If ocular inflammation improves after 1–2 weeks of therapy, the patient is considered to have a positive test response. Schlaegel and Weber suggested that these patients should then receive a full course of therapy. There are several problems with this test, however. From a practical point of view, many patients with presumed tuberculous uveitis are concomitantly treated with corticosteroids, which makes it difficult to determine whether the antituberculous or the antiinflammatory therapy had the principal effect. The disease course may wax and wane; therefore, improvement may be due to the natural course of the disorder and be unrelated to antituberculous drugs. Importantly, a randomized double-masked study of isoniazid in the treatment of uveitis showed no significant difference between the treated and placebo groups. Our current recommendation is to treat patients with uveitis and a positive PPD test result only if there are other findings to support the diagnosis of TB. The addition of antitubercular therapy to corticosteroids in uveitis patients with underlying latent or manifest TB appears to reduce the recurrences of uveitis. Although hematogenous seeding of organisms from the lung is the most common mode of ocular infection, results on the chest X-ray may be normal, and disease is occasionally limited to a specific organ. A history of exposure to TB, a history of inadequately treated TB, a positive PPD test result with a large area of induration, or positive culture results all greatly increase the likelihood of disease. Once a decision to treat is made, the patient should receive at least two drugs for at least 3–6 months before a decision about efficacy is made.