Chapter 166 – Tuberculosis, Leprosy, and Brucellosis
• Tuberculous uveitis is a granulomatous infection caused by Mycobacterium tuberculosis that can involve any part of the uveal tract.
• Leprosy (Hansen’s disease) is a chronic granulomatous disease caused by the intracellular acid-fast bacillus Mycobacterium leprae.
• Brucellosis is a zoonotic disease caused by members of the genus Brucella.
– Chronic, smoldering granulomatous lesions in the choroid or iris.
– Granulomatous infection of the facial and trigeminal nerves, eyelids, and ocular tissue.
– Exposure keratitis.
– Chronic anterior uveitis.
– Granulomatous or nongranulomatous uveitis.
– Optic nerve inflammation.
– Rising titers of Brucella antibodies.
• Tuberculosis—exudative retinal detachment, hyalitis, retinal vasculitis, retinal hemorrhages, scleritis, subretinal abscess, panophthalmitis, chorioretinal atrophy.
• Leprosy—prominent or beaded corneal nerves, corneal hypoesthesia, conjunctivitis, iris pearls, iris atrophy, pinpoint pupils, ptosis, entropion.
• Brucellosis—multifocal choroiditis, chronic anterior uveitis, keratitis, conjunctivitis, posterior uveitis, cranial nerve palsies, endophthalmitis, retinal detachment.
In the past decade, tuberculosis (TB) has shown a steady decline in the United States, but the potential for debilitating ocular involvement persists. Also of concern is the emergence of drug resistance and the need for an accurate and early specific diagnosis. Newer molecular diagnostic techniques are available but are not yet standardized or universally available.
EPIDEMIOLOGY AND PATHOGENESIS
The number of tuberculosis cases has decreased during the past decade, with only 18,361 cases (6.8 cases per 100,000 population) being reported to the Centers for Disease Control and Prevention in 1998, a 34% decrease from 1990. Most of these cases occur in human immunodeficiency virus (HIV)–positive individuals or those who have immigrated from countries where TB is endemic. Resistance to the development of TB may be lowered by chronic diseases, such as diabetes mellitus or malignancy, or altered immune status, as found in malnutrition, old age, or with immunosuppressive therapy.
Unlike that of systemic TB, the diagnosis of intraocular TB in most cases is based on clinical features and investigations alone and uncommonly on histological and microbiological evaluation. This, in part, accounts for the variation in the reported incidence of ocular TB in surveys of patients who have intraocular inflammation (0–0.16%) or in those who have systemic TB (0.27–1.4%).   Some reports include assumed or proven tuberculoprotein hypersensitivity–related ocular lesions, such as phlyctenulosis and retinal vasculitis. Reports of microbiologically or histopathologically proven cases of intraocular TB are relatively rare.   
Infection with Mycobacterium (M.) tuberculosis occurs primarily by inhalation of aerosolized droplets that contain the organisms. Usually this develops into an asymptomatic, self-limited pulmonary granuloma that resolves and remains dormant but can be reactivated later. With reactivation, the bacilli may disseminate, involve any part of the body, and cause clinically active disease (TB). Sensitization to tuberculoprotein (purified protein derivative [PPD]) develops 2–10 weeks after the initial infection, and a positive skin test may persist in the absence of clinically active disease. Ocular involvement is secondary to a primary focus in the lung or alimentary tract and uncommonly a contiguous spread from adjacent structures (secondary TB). Rarely, the eye may be the portal of entry for the organisms (primary TB).
Ocular TB may have protean manifestations, as do syphilis and sarcoidosis, and may involve any part of the eye, ocular adnexae, or orbit. Also, ocular TB may present without demonstrable active TB elsewhere in the body. The most common ocular manifestations are anterior uveitis and choroiditis or chorioretinitis.
The anterior uveitis may be granulomatous or uncommonly nongranulomatous. Rarely, tubercles or an exudative mass may occur in the anterior chamber. The intensity of inflammation may vary from a mild acute iritis to a severe granulomatous reaction with granulomatous keratic precipitates and posterior synechiae.
Choroidal TB may present as tubercles or tuberculomas (large solitary masses). Choroidal tubercles occur predominantly in the posterior pole as solitary or multiple lesions (multifocal choroiditis) of various sizes, in the range 0.3–3.0?mm in diameter; appear yellowish, grayish, or whitish in color; and may have overlying serous retinal detachment. The anterior segment may be normal with minimal or no hyalitis, particularly in HIV-positive individuals. On fluorescein angiography (FA), these lesions are hypofluorescent initially with progressive hyperfluorescence in the late phases. Indocyanine green angiography may sometimes detect
Figure 166-1 Choroidal tuberculoma. A large, yellow-white, subretinal mass occupies almost one quadrant of the retina in this 13-year-old child. A differential diagnosis of subretinal cysticercosis was entertained because of the presence of a coin-shaped lesion in the brain ( Fig. 166-2 ). Chorioretinal biopsy confirmed tuberculosis ( Fig. 166-3 ).
Differential Diagnosis of Tuberculosis
Chronic granulomatous disease
subclinical lesions or those missed by FA. Choroidal tuberculomas ( Fig. 166-1 ) present as solitary grayish white, raised lesions of area 2–3 disc diameters or larger, with indistinct margins, an overlying exudative retinal detachment, and sometimes intraretinal exudation. FA in choroidal tuberculomas may show early hyperfluorescence, with leakage around the margins in the later phases. Ultrasonography shows an acoustically dense lesion with no choroidal excavation. Low internal reflectivity and high vascularity may simulate a melanoma. Isolated retinal TB is very rare. Retinal involvement is secondary to adjacent choroidal lesions, and subretinal abscess associated with TB has also been reported.
Other intraocular manifestations attributed to TB include retinal vasculitis and Eales’ disease. These are not the result of direct invasion by tubercle bacilli but instead are presumed to be an immunological response to the mycobacteria. This association is based on increased prevalence of tuberculoprotein hypersensitivity or concurrent active pulmonary TB in such patients. Reports of retinal vasculitis from direct infection are rare and are based on a positive response to antituberculous therapy or detection of M. tuberculosis DNA by polymerase chain reaction (PCR).
Laboratory evidence of M. tuberculosis, using smears, cultures, and histopathology on chorioretinal, iris, or vitreous tissue, is diagnostic. Newer techniques for diagnosis such as PCR  and serological assays (to detect anticord factor antibodies) are yet to be standardized and not universally available. Other ancillary tests, such as tuberculin skin testing, chest radiography, and therapeutic trials, provide only presumptive evidence for a clinical diagnosis of intraocular TB, particularly in areas endemic for TB. In immunosuppressed individuals, other species of Mycobacterium (e.g., M. avium-intracellulare) may cause opportunistic infection.
Figure 166-2 Tuberculoma of the left temporal lobe. Coin-shaped hyperdense lesion seen on computed tomographic scan in the same patient as shown in Figure 166-1 .
Interpretation of the diagnostic value of the Mantoux test using PPD is difficult,  but a negative reaction is more important than a positive one. Induration >5?mm indicates prior exposure rather than an active infection, and indurations >10?mm in a high-risk population and >15?mm in a low-risk population are significant. The specificity of the PPD skin test is interpreted from the size of the reaction, contact history, regional prevalence of TB, and age and immune status of the patient. Because TB is a rare cause of uveitis, a positive PPD in a patient who has uveitis but no other signs of TB is more misleading than helpful.
Various entities that may mimic tuberculous uveitis are given in Box 166-1 .
In addition to the eye, TB can involve any part of the body. Choroidal tubercles indicate hematogenous spread of bacilli and may be associated with miliary TB.  Uncommonly, ocular involvement may occur with concurrent extraocular TB, such as pulmonary TB, tuberculous lymphadenitis, TB of the alimentary tract, and tuberculoma of the brain ( Fig. 166-2 ).
A characteristic caseating, granulomatous inflammation results from infection by M. tuberculosis ( Fig. 166-3 ), which consists of a central caseation surrounded by epithelioid cells, multinucleated giant cells of the Langerhans type, and lymphocytes. Absence of giant cells and caseation, however, does not exclude the diagnosis of TB. In immunocompromised individuals, histopathology may reveal mononuclear cells only, with no epithelioid cells and giant cells, but with abundant acid-fast bacilli (nonreactive TB).
Treatment of intraocular TB is often problematic because it is difficult to establish the cause conclusively, particularly for the patient who has uveitis compatible with TB, a positive PPD, and no other systemic evidence of TB. In such cases the use of a 2- to 3-week therapeutic trial with single or multiple drugs is recommended, with ocular evaluation each week. If ocular inflammation improves, the patient is considered to have a positive test response and a full course of anti-TB therapy is advised. However,
Figure 166-3 Tuberculous granuloma with central caseation. Chorioretinal biopsy from the choroidal lesion shown in Figure 166-1 . Hematoxylin-eosin–stained sections show multiple granulomas with caseation and multinucleated giant cells. Acid-fast stains did not reveal any organisms.
concurrent use of anti-inflammatory agents or a natural temporary regression of inflammation may reduce the value of this test. Alternatively, if anti-inflammatory therapy alone fails to control the inflammation, an anterior chamber tap, vitreous aspirate, or chorioretinal biopsy may be carried out to obtain a definitive laboratory diagnosis.
Multidrug anti-TB therapy is preferably administered by an internist well versed in current treatment recommendations and drug resistance. The duration of therapy and drug combination depend on the type of extraocular TB, immune status of the individual, and drug resistance. The concomitant use of corticosteroids is still controversial because of fear of exacerbation of the infection, but in vision-threatening cases corticosteroid may be used in low doses with a careful follow-up.
COURSE AND OUTCOME
Early diagnosis and treatment appears to be associated with a good prognosis. One series reported a good response to anti-TB treatment in only 3 of 12 patients who had suspected intraocular TB, whereas others noted improvement in only 2 of 5 and 2 of 4 histologically or microbiologically proved cases. Spread of TB choroiditis to involve the retina may occur, and iridocyclitis (if untreated) may involve the sclera with a resultant uveal tissue prolapse and glaucoma. Extraocular spread may result in panophthalmitis ( Fig. 166-4 ).
EPIDEMIOLOGY AND PATHOGENESIS
Leprosy affects 10 million to 12 million people worldwide, 3–7% of whom are blind. A total of 108 cases of Hansen’s disease were reported in the United States in 1998. The highest prevalence of leprosy occurs in the Indian subcontinent, sub-Saharan Africa, and Southeast Asia.
Mycobacterium (M.) leprae has a tropism for body areas that have low temperatures, particularly the skin, peripheral nerves, nasal mucosa, and the eye. The mode of transmission is probably through the mucous membrane of the upper respiratory tract or the skin. Leprosy is divided into two major subtypes on the basis of the host immune response. In the tuberculoid type, an active, cell-mediated immune response is seen, whereas in the lepromatous type patients have a poor cellular immune response. In addition to this, acute reactional states (type I and type II) that arise from acute changes in the immune status are
Figure 166-4 Tuberculous panophthalmitis. Conjunctival granuloma with chemosis and yellow-white pupillary reflex in an 11-year-old girl, initially treated as infective endophthalmitis. Conjunctival biopsy showed multiple caseating granulomas and giant cells. The inflammation responded positively to a three-drug antituberculosis regimen.
described. Intraocular inflammatory disease occurs more commonly in the lepromatous type. Ocular manifestations depend on the duration of infection, the immune response, and the time of initiation and type of treatment. Paralysis of the trigeminal and facial nerve results in lid abnormalities and corneal hypoesthesia, which results in corneal damage. Direct bacterial invasion of the external eye results in keratitis, scleritis, and iritis, which may also occur during the reactional stages of the disease. Destruction of the autonomic nerve fibers that supply the eye results in pinpoint pupil and a low-grade iridocyclitis.
Comprehensive ocular evaluations of leprosy patients show that uveitis occurs in about 7%,  whereas other reports indicate an incidence of 5.3–63%. Iritis or iridocyclitis is the main complication. Acute anterior iridocyclitis is uncommon, occurs bilaterally, and develops during the reactional state (type II), especially with therapy or sometimes after cessation of therapy. This granulomatous anterior uveitis may be associated with a hyphema or hypopyon. A chronic, low-grade bilateral uveitis with minimal or no symptoms until late in the disease process is more common. It is associated with few, scattered, fine, white keratic precipitates, few anterior chamber cells, mild to moderate flare, and minimal ciliary or conjunctival congestion. Posterior synechiae are uncommon. If not aggressively treated, pinpoint pupils, glaucoma or hypotony, iris atrophy, ciliary body damage, and cataract occur insidiously and result in loss of vision. Iris pearls are characteristic of leprosy ( Fig. 166-5 ) and are seen on the anterior surface of the iris or at the pupillary border as creamy white particles. After several years, they may coalesce and drop into the inferior angle, where they may be observed by gonioscopy. Rarely, choroiditis, pars planitis, and uveal effusion associated with overlying scleral inflammation have been reported.
Diagnosis is usually made easily on the basis of a thorough clinical evaluation but must be confirmed by histology of the skin lesions or skin biopsy. Iris pearls are characteristic. Skin tests with lepromin may be highly positive (Mitsuda reaction) in the tuberculoid type.
The differential diagnosis of leprosy-associated uveitis is given in Box 166-2 .
Figure 166-5 Iris pearls in a patient who has leprosy. (Courtesy of Dr. G.C. Sekhar.)
Differential Diagnosis of Leprosy-Associated Uveitis
Idiopathic anterior uveitis
The common systemic manifestations of leprosy consist of hypopigmented skin lesions, skin anesthesia, thickened peripheral nerves, deformed hands and feet, and leonine facies.
The tuberculoid form of disease is characterized by granuloma formation and the lack of a large number of bacilli because of an active cell-mediated immune response. In contrast to this, lesions in the lepromatous form are composed predominantly of macrophages with numerous acid-fast bacilli ( Fig. 166-6 ). Iris pearls consist of macrophages filled with bacilli.
Because of the chronicity and insidious nature of this anterior uveitis, early screening for ocular complications, to detect asymptomatic disease, is advisable. Once detected, regular (every 1–6 months) eye examinations are advisable, depending on the severity of the uveitis and its response to therapy. Supervision of continuous corticosteroid and mydriatic therapy at home is necessary,  along with appropriate antimicrobial therapy. Multidrug treatment (MDT) instituted in 1982 by the World Health Organization has resulted in sustained high microbiological cure rates. However, leprosy-related ocular pathology such as lagophthalmos, posterior synechiae, and keratitis continues to develop after a microbiological cure and therefore regular monitoring is required.
EPIDEMIOLOGY AND PATHOGENESIS
The disease has a very low incidence in the United States (total of 79 cases reported in 1998), with higher rates in the less developed countries. Brucella (Bru.) is a bacterium that infects the genitourinary tract of domestic animals such as sheep (Bru. melitensis), cattle (Bru. abortus), swine (Bru. suis), and dogs (Bru. canis).
Figure 166-6 Cells teem with acid-fast leprous organisms (red color), seen with the Ziehl-Neelsen method. The patient had lepromatous leprosy. (Courtesy of Dr. P. Henkind. In Yanoff M, Fine BS. Ocular pathology, ed 4. London, Mosby, 1996.)
Human beings become infected by direct contact or by airborne spread after exposure to infected animals, contaminated meat, or dairy products. Infection occurs mostly among farmers and abattoir workers.
Brucellosis may affect all the ocular structures, but uveitis with or without optic nerve involvement appears to be the most common result.  The uveitis may be granulomatous or nongranulomatous and unilateral or bilateral. Anterior, intermediate, and posterior uveitis may occur in patients who have brucellosis. Anterior uveitis may result in hypopyon, which responds well to topical corticosteroids. Rarely, acute brucellosis may manifest as endophthalmitis with sudden loss of vision.  Choroiditis that results from brucellosis is usually multifocal and either nodular or geographic. Optic nerve involvement appears as hyperemia, retrobulbar neuritis, papilledema, or arachnoiditis of the chiasm. Vitreous exudates, cystoid macular edema, and retinal detachment have also been reported.
For a definitive etiological diagnosis, laboratory investigations are necessary in addition to the ocular and systemic clinical manifestations. Blood, vitreous, or aqueous cultures may give positive results in the acute stages. In chronic stages, it is more difficult to isolate the organisms. To be cultured, Brucella species require careful laboratory processing. Serological investigations for the detection of brucella antibodies vary in sensitivity and specificity. Serum antibody titers are high in chronic stages, whereas recent infections are associated with low titers. The standard agglutination test can also be carried out using vitreous and aqueous samples. 
The entities listed in Box 166-3 are considered in the differential diagnosis of brucellosis.
In the acute stage, systemic infection is characterized by fever, headache, arthralgia, generalized aches, chills, sweating, malaise, anorexia, and weight loss. More than 90% of patients have intermittent fever with a characteristic diurnal variation as the fever tends to peak daily in the afternoon.  Splenomegaly and diffuse lymphadenopathy occur in as many as 30% of patients.  Pneumonia, hepatitis, splenic abscess, epididymo-orchitis, prostatitis,
Differential Diagnosis of Brucellosis
endocarditis, arthritis, osteomyelitis, and meningoencephalitis have been reported.
It is not clear whether antibiotic therapy is helpful for uveitis associated with brucellosis. The treatment of brucellosis requires more than one agent to decrease the incidence of relapses. Therapy with combinations of tetracyclines, cephalosporins, rifampin, trimethoprim-sulfamethoxazole, and aminoglycosides has been employed. Effective treatment often requires prolonged therapy (4–8 weeks).
COURSE AND PROGNOSIS
The severity and chronicity of disease in humans vary with the species and strain. Most of the infections with Bru. abortus involve a self-limited disease, whereas Bru. melitensis or Bru. suis may cause more severe or chronic disease. As with tuberculosis, the disease may become chronic and the organism may persist in tissue for years.
1. Summary of notifiable diseases, United States, 1998. MMWR Morb Mortal Wkly Rep. 1999;53:1–93.
2. Copeland RA Jr. The classics: tuberculosis, syphilis, and sarcoidosis. Ophthalmol Clin North Am. 1993;6:69–80.
3. Helm CJ, Holland GN. Ocular tuberculosis. Surv Ophthalmol. 1993;38:229–56.
4. Biswas JB, Madhavan HN, Gopal L, Badrinath SS. Intraocular tuberculosis. Clinicopathologic study of five cases. Retina. 1995;15:461–8.
5. Morinelli EN, Dugel RU, Riffenburgh R, Rao NA. Infectious multifocal choroiditis in patients with acquired immune deficiency syndrome. Ophthalmology. 1993;100:1014–21.
6. Sheu SJ, Shyu SJ, Chen LM, et al. Ocular manifestations of tuberculosis. Ophthalmology. 2001;108:1580–5.
7. DiLoreto DA Jr, Rao NA. Solitary nonreactive choroidal tuberculoma in a patient with acquired immune deficiency syndrome. Am J Ophthalmol. 2001;131: 138–40.
8. Wolfensberger TJ, Piguet B, Herbort CP. Indocyanine green angiographic features in tuberculous chorioretinitis. Am J Ophthalmol. 1999;127:350–3.
9. Madhavan HN, Therese KL, Gunisha P, et al. Polymerase chain reaction for detection of Mycobacterium tuberculosis in epiretinal membrane in Eales’ disease. Invest Ophthalmol Vis Sci. 2000;41:822–5.
10. Kotake S, Kimura K, Yoshikawa K, et al. Polymerase chain reaction for the detection of Mycobacterium tuberculosis in ocular tuberculosis. Am J Ophthalmol. 1994;117:805–6.
11. Sakai J, Matsuzawa S, Usui M, et al. New diagnostic approach for ocular tuberculosis by ELISA using the cord factor as antigen. Br J Ophthalmol. 2001;85:130–3.
12. Croxatto JO, Mestre C, Puente S, Gonzalez G. Nonreactive tuberculosis in a patient with acquired immune deficiency syndrome. Am J Ophthalmol. 1986; 102:659–60.
13. Rosen PH, Spalton DJ, Graham EM. Intraocular tuberculosis. Eye. 1990;4: 486–92.
14. Dana MR, Hochman MA, Viana MAG, et al. Ocular manifestations of leprosy in a noninstitutionalized community in the United States. Arch Ophthalmol. 1994;112:626–9.
15. Schwab IR, Ostler HB, Dawson CR. Hansen’s disease of the eye (ocular leprosy). In: Tasman W, Jaeger EA, eds. Duane’s clinical ophthalmology, Vol 5. Philadelphia: JB Lippincott; 2000.
16. Sekhar GC, Vance G, Otton S, et al. Ocular manifestations of Hansen’s disease. Doc Ophthalmol. 1994;87:211–21.
17. Espiritu CG, Gelber R, Ostler HB. Chronic anterior uveitis in leprosy: an insidious cause of blindness. Br J Ophthalmol. 1991;75:273–5.
18. Lewallen S, Tungpakorn NC, Kim SH, et al. Progression of eye disease in “cured” leprosy patients: implications for understanding the pathophysiology of ocular disease and for addressing eyecare needs. Br J Ophthalmol. 2000;84:817–21.
19. Al-Kaff AS. Ocular brucellosis. In: Tabbara KF, ed. Posterior uveitis—Part II. Int Ophthalmol Clin. 1995;35:139–45.
20. Puig-Solanes M, Heatley J, Arenas F, et al. Ocular complications in brucellosis. Am J Ophthalmol. 1953;36:675–89.
21. Al-Faran MF. Brucella melitensis endogenous endophthalmitis. Ophthalmologica. 1990;201:19–22.
22. Akduman L, Or M, Hasenreisoglu B, Kurtark K. A case of ocular brucellosis: importance of ocular specimen. Acta Ophthalmol. 1993;71:130–2.