Introduction

Tuberculosis or human infection with mycobacterium species has been reported since prehistoric times, but it needed the development of modern ocular diagnostic tools to identify ocular tuberculosis. Uveal tuberculosis in the form of tubercles was recognized in 1830 by Gueneau de Mussy and by Jaeger, who in 1855 described similar findings. Fraenkel (1867) described the clinical appearance of tubercles, and this work was carried on by Bouchut, Fraenkel, and Weiss. In the early twentieth century, Hoeve (1925), Bollack (1927), and Baldenweck (1938) laid the groundwork for the continued use of fundus examination in the diagnosis of miliary tuberculosis.

Treatment for tuberculosis in the pre-antibiotic era consisted of admission in sanatoriums, fresh air, exercise, and various pneumothorax surgeries, and these institutions reported large numbers of patients of ocular tuberculosis. Of the 10,524 patients that Donoghue examined in the period 1940–1966, he reported that 1.4% of them needed treatment for ocular tuberculosis [1]. Similarly, Illingworth, in an early meta-analysis of publications from 1913 to 1947, noted 206 cases of choroidal tubercles in 737 patients (28%) [2].

Simultaneously, tuberculosis was also the single most common etiological diagnosis in ophthalmology outpatient departments. In 1960, Woods suggested that at least 21.8% of patients presenting with posterior uveitis had ocular tuberculosis.

The advent of improved public health measures and antitubercular therapy has led to a marked reduction in the rates of tuberculosis over the world, and this parallels the reported decline in the incidence of ocular tuberculosis. These declines are more marked in the developed world as compared to the developing world.

Data from several studies in recent times have documented the prevalence of ocular lesions in patients with systemic, largely pulmonary, tuberculosis. In a study from Spain, Bouza et al. examined 100 patients with culture-positive tuberculosis and found tubercular choroiditis (commonly), papillitis, retinitis, vitritis, and vasculitis in 18 patients, suggesting a prevalence of as much as 18%, but 11 of these patients had additional human immunodeficiency virus (HIV) infection [3]. In India, lower prevalence rates were seen in a study of 1,005 patients, of whom 1.39% had ocular lesions [4]. Systemic dissemination has been reported to significantly increase the likelihood of ocular lesions to as much as up to 60% [5].

Tuberculosis is also less prevalent as an etiologic agent in patients with intraocular inflammation in developed countries. This may result from a reduced prevalence of tuberculosis but is also due in part to awareness of other etiologies and better diagnostic techniques. Tuberculosis was found to be responsible for 0.2% of cases of posterior uveitis and in no cases of anterior uveitis in Southern California [6].

Schlaegel and O’Connor reported that tuberculosis was responsible for 0.28% of uveitis cases in the 1970s, which had fallen from an incidence of 8.6% in the 1950s. In developing countries with a still high prevalence of tuberculosis, it remains a relatively common etiologic agent. Studies from North India have estimated that it is the etiological agent in 7.9% of cases of anterior uveitis, 4% of cases of intermediate uveitis, 8.95% of cases of posterior uveitis, and 26% of cases of panuveitis. Overall, 125 patients of 1,233 (10.1%) cases had a tuberculous etiology [7]. Interestingly, a study from Italy revealed tuberculosis as the etiological agent in 3.6% of cases of anterior uveitis, 2.5% of cases of posterior uveitis, and 0.7% of cases of panuveitis [8], suggesting that a diagnosis of ocular tuberculosis is becoming increasingly common in developed countries.

The advent of the HIV epidemic has led to an increase in the prevalence of ocular tuberculosis in patients with systemic HIV-TB (HIVtuberculosis) coinfection, but large studies are few. In a study of 307 patients in Malawi, choroidal granulomas were seen in 2.8% of patients with mycobacteremia and acquired immunodeficiency syndrome (AIDS) [9]. However, another study showed no lesions suggestive of ocular tuberculosis in 154 patients of AIDS in Burundi [10]. In a prospective study from Mumbai, India, 23.5% of AIDS patients with systemic tuberculosis had ocular lesions [11], but a much lower prevalence was seen in a neighboring city, where although as many as 66% of 1,268 patients had systemic tuberculosis, only 1% of patients had ocular tuberculosis [12].

Etiopathogenesis of Ocular

Tuberculosis

Several members of the Mycobacterium tuberculosis complex, namely, M. tuberculosis, M. bovis, and M. africanum, are responsible for the majority of systemic and ocular tuberculous disease. The most important agent is M. tuberculosis, which spreads as airborne droplets that are released into the air by patients with pulmonary (usually cavitatory) tuberculosis. Inhalation of these droplets

leads to an initial infection where the bacilli multiply and are spread hematogenously to several areas that usually include the lung apices, skeletal system, and the choroid. In most individuals, immune responses prevent the establishment of clinical disease, but a small number develop clinical (primary) disease at this stage. The bacillus in the remaining patients remains in a latent state, but a number of triggers, commonly HIV infection, cancer, or any other immune deficiency state, can produce active clinical disease in 5–10% of patients at some point in their lives. This is termed as reactivation or secondary tuberculosis.

Ocular tuberculosis may occur at both the primary and secondary stages of clinical disease; thus, patients may range in age from childhood to late adulthood. Earlier classifications have described ocular tuberculosis as primary (from direct inoculation of bacilli) or secondary (as a result of hematogenous spread). Current thought holds that virtually all ocular and orbital diseases are a result of hematogenous spread, and thus, this classification is obsolete.

Specific Ocular Manifestations

Ocular tuberculosis can have myriad manifestations and can affect virtually all ocular tissue. These are summarized in Table 5.1.

Eyelid Tuberculosis

This is commonly seen in childhood and is thought to be lupus vulgaris (cutaneous tuberculosis). The clinical appearance includes reddishbrown nodules that exhibit an apple-jelly color on pressure or as erosive skin lesions. Eyelid tuberculosis also commonly mimics chalazia, and unusual or atypical chalazia should be carefully investigated, preferably with a histopathological study. Globe or orbital extensions have been reported [13, 14]. Several authors have described abscesses and cellulitis of the eyelids resulting from tuberculous infection. Raina et al. reported seven children who presented with

preseptal cellulitis and had evidence of systemic tuberculosis. Spontaneous fistulization was common [15]. Increasingly, atypical mycobacteria have been implicated in periocular infections. Chang et al. described six patients with

Mycobacterium chelonae or Mycobacterium fortuitum. Immunosuppression, nasolacrimal duct obstruction, the presence of a foreign body, and a history of recent surgery were identified as risk factors [16].

Conjunctival Tuberculosis

Conjunctival tuberculosis was initially described by Arlt. An early meta-analysis (Eyre 1912) discussed 177 cases in published literature and 29 of his own who had histology or animal inoculation proven disease. The disease patterns identified included a propensity to affect young adults (<20 years), unilateral disease, and a predilection for involvement of the upper palpebral conjunctiva. Variants identified included ulcerative, hypertrophic, miliary tubercle, lupus, and pedunculated tumor. Only seven of these 160 patients had evidence of systemic tuberculosis.

Recent reviews have described primary tuberculous conjunctivitis presenting as a mucopurulent conjunctivitis with lid edema accompanied by lymphadenopathy that tends to caseate or undergo fistula formation. Conjunctival smears show the presence of acid-fast bacilli on the appropriate stain. Lamba et al. have reported the case of a 30-year-old female patient with miliary tuberculosis who presented with two reddish

yellow, soft, nontender conjunctival nodules that revealed acid-fast bacilli on Ziehl-Neelsen stain with subsequent positive cultures [17].

Scleral Tuberculosis

Verhoeff (1907) identified tuberculosis as the etiological agent in patients with scleritis based on histopathological findings. Only 3 of these 13 patients had systemic disease, but the authors concluded that its presence was necessary. Tuberculosis may present as a dark red focal area of necrotizing scleritis that shows chronic granulomatous inflammation with caseating necrosis on histopathology. In rare cases, scleral necrosis can occur. This diagnosis, though rare, is a differential diagnosis in patients unresponsive to traditional methods of treatment. Welldocumented scleral tuberculosis was reported by Bloomfield et al. in an 82-year-old female patient whose tissue sections showed acid-fast bacilli, and M. tuberculosis was grown on culture. Oral isoniazid and rifampicin, along with topical and subconjunctival streptomycin, led to a complete cure [18]. In a solitary case, Gupta et al. have presented the findings of a 45-year-old female patient of posterior scleritis with a clinical presentation of optic disc edema and choroidal folds. Sclerochoroidal thickening with fluid in the sub-Tenon’s space was seen on ultrasonography. Systemic investigations revealed a positive Mantoux test and right upper lobe infiltrates. The patient responded to systemic corticosteroids and antitubercular therapy [19].