some authorities have suggested rifabutin in place of rifampicin.

Ocular tuberculosis is also a common infection in patients following renal and other solid organ transplants or those on long-term immunosuppressive agents. The majority of reports describe Mycobacterium tuberculosis as the causative agent.

Ocular Tuberculosis Associated with Mycobacterium bovis

M. bovis has been identified as the causative agent in isolated cases. Kurup et al. reported a 33-year- old female with nodular scleritis and a choroidal mass. She had undergone partial treatment for abdominal tuberculosis 6 years earlier. Investigations revealed M. bovis and intake of bacillicontaminated unpasteurized milk was thought to be the initiating agent [12].

Rare Presentations

A review of the literature reveals several uncommon presentations.

Isolated Macular Edema

In a case described by Torres, a 61-year-old woman who presented with unilateral defective vision underwent a complete ophthalmologic evaluation. The only significant ocular finding was cystoid macular edema which was confirmed on fluorescein angiography. Systemic evaluation revealed a positive Mantoux test, and tubercle bacilli were detected in her sputum. There was a positive response in terms of reduction of the edema and visual recovery on completion of antitubercular therapy [42].

Isolated Ocular Tuberculosis

Systemic tuberculosis is normally present in most cases of ocular tuberculosis that have been described in worldwide literature. Only a handful of patients have been described with isolated

ocular tuberculosis without evidence of systemic disease. Of these five patients, four had choroidal tuberculomas and one had a vitritis/ retinitis. In the absence of chest pathology as determined by normal radiography, a conclusive diagnosis was based on Mantoux testing, PCR of the aqueous fluid, or histopathology of the enucleated globe [43].

Intraocular Infection with Pigmented Hypopyon

A 38-year-old female patient undergoing immunosuppressive treatment (cyclophosphamide) for membranous glomerulonephropathy noticed severe visual loss. Examination revealed acute uveitis with a pigmented hypopyon. An aspiration and subsequent pathological examination revealed acid-fast bacilli on culture and staining. Multiple scleral abscesses developed despite a course of antitubercular therapy, and the eye had to be enucleated [44].

Ocular Tuberculosis After Corticosteroid Therapy

Rosen et al. have described the clinical course of a 35-year-old male patient who presented with unilateral anterior uveitis along with bilateral vitritis and periphlebitis. He was prescribed systemic corticosteroid therapy—following which he improved. After a period of 8 months, he presented again with miliary tuberculosis and choroidal tubercles. According to the authors, the earlier inflammation may have been a purely hypersensitivity phenomenon that was steroid sensitive. The steroid therapy may have led to a reactivation of the tuberculosis following which he developed miliary tuberculosis and choroidal tubercles [28].

Investigations and Diagnosis

of Ocular Tuberculosis

The diagnostic workup of patients with suspected ocular tuberculosis has both systemic and ocular components.

Systemic Investigations

As the majority of cases of ocular tuberculosis are associated with systemic disease, these investigations are of importance in all patients of ocular inflammatory disease. Evidence of systemic tuberculosis in the presence of ocular inflammation suggests ocular tuberculosis but does not confirm it.

1.Radiography—Chest X-rays may reveal active pulmonary tuberculosis in the form of infiltrates and cavitation in apical or posterior segments of the upper lobe or occasionally lower lobe infiltrates. At times, pleural effusions may be seen. Hilar lymphadenopathy as the only feature of pulmonary tuberculosis is common in patients of South Asian origin, and computed tomography may be a better chest imaging modality in these patients [45]. Hilar lymphadenopathy is also a common feature of patients with coexistent HIV. Abdominal CT scan or ultrasonography may reveal mesenteric, periportal, or retroperitoneal lymphadenopathy suggestive of isolated abdominal tuberculosis or as a component of disseminated tuberculosis.

2.Mantoux Testing—The Mantoux test assesses the patient’s response to a stimulus of PPD (purified protein derivative). Three strengths available are 1, 5, or 250 tuberculin units, and 0.1 cc is injected intradermally into the volar forearm to produce a wheal of 6–10 mm diameter. After 48–72 h, the induration is measured in millimeters at the point of injection and interpreted according to current guidelines. The Mantoux test is a delayedtype hypersensitivity reaction and merely suggests tuberculous infection but not active clinical disease. Common false-negatives include poor test techniques, miliary tuberculosis, sarcoidosis, HIV infection, or active malignancies.

3.Interferon-g(gamma) Release Assays (IGRA)—

The IGRA tests are the in vitro assays that measure interferon-g(gamma). This is secreted by previously sensitized T cells after they are stimulated by Mycobacterium tuberculosis antigens. The antigens include early secreted

antigen target (ESAT) 6 and culture filtrate protein (CFP)-10 that are specific for M. tuberculosis and make false-positive readings with BCG vaccine strains unlikely. The commonly used kits are T-SPOT.TB test (Oxford Immunotec Ltd.) and the QuantiFERON-TB Gold (Cellestis Ltd., Australia). Positive IGRA tests suggest latent tuberculosis.

Ocular Investigations

Following a detailed clinical examination, the isolation of M. tuberculosis from ocular tissues is often necessary to establish a diagnosis of confirmed ocular tuberculosis. Samples may be obtained from the aqueous humor, vitreous humor, subretinal fluid, specific tissue biopsies (eyelid tissue, conjunctiva, cornea, sclera, retina, or uvea) or the enucleated globe. However, these are often of small volume and pose a risk of ocular morbidity, especially the risks of endophthalmitis and retinal detachment. These samples once obtained may undergo the following:

1.Microscopy—This is the easiest test but needs densities of 5,000–10,000 bacilli per ml for a positive result. The success rate may be increased by centrifugation of samples. Tissue sections may be stained after formalin fixation. Stains in use include conventional acid-fast stains (e.g., Ziehl-Neelsen) or fluorescent acid-fast stains.

2.Culture—Culturing is more sensitive and is reported to be capable of detecting densities of 10–100 bacilli per ml. Drawbacks include prolonged incubation of up to 8 weeks. Commonly used culture media includes Lowenstein-Jensen.

3.PCR (Polymerase Chain Reaction) Techniques—These are becoming the technique of choice in the diagnosis of ocular tuberculosis. They are capable of detecting mycobacterial DNA from all samples and are ideally suited for ocular diagnostic work because they require small volumes and are extremely specific. In one case series of 53 patients, the specificity was 100% and the sensitivity was 37% [46].

Guidelines and Suggested Treatment

of Ocular Tuberculosis

The purpose of the investigations (clinical, radiological, and laboratory) is to permit understanding of the specific manifestation in each patient and allow the appropriate therapy. Specific points that need to be elucidated are as follows:

1.Specific Ocular Etiopathogenesis—Whether the ocular lesions are a hypersensitivity reaction or a direct infection or both.

2.Specific Systemic Findings—A positive Mantoux test or IGRA test indicates previous mycobacterial infection and, in the absence of evidence of systemic infection, suggests latent tuberculosis. In contrast, active systemic tuberculosis is diagnosed by radiological or laboratory evidence of tubercular infection elsewhere in the body.

Some authors have suggested that cases of ocu-

lar tuberculosis be classified as (1) presumed when there is only indirect evidence that M. tuberculosis is the causative organism (e.g., suggestive ocular disease and evidence of systemic tuberculosis) or

(2) confirmed when M. tuberculosis bacilli are isolated from ocular tissue or fluids.

Regardless of classification, patients with a diagnosis of presumed or proven tubercular infection in the eye and concomitant systemic or latent tuberculosis (positive Mantoux and/or IGRA tests) need antitubercular therapy with or without corticosteroid therapy. Patients with hypersensitivity reaction alone (e.g., phlyctenulosis), negative Mantoux/IGRA tests, and negative systemic imaging may be treated with corticosteroid therapy alone.

Corticosteroid Therapy

Manifestations that are due to a purely hypersensitivity phenomena such as phlyctenulosis need only corticosteroid therapy. Most direct infections such as anterior or posterior uveitis, retinal vasculitis, or panophthalmitis also need adjunct corticosteroid therapy due to the inflammation

they induce. Depending on the site of involvement and severity of the inflammation, topical, periocular, or systemic corticosteroids may be used.

Antitubercular Therapy

Systemic antitubercular therapy must be prescribed in cases of ocular direct infections as well as in cases where a systemic focus is present. At present, there is no commercially available topical antitubercular therapy. Following systemic treatment, all ocular tissues, especially the commonly affected posterior uvea, receive adequate drug concentrations. Schlaegel first suggested a therapeutic trial of isoniazid in suspect cases of ocular tuberculosis, but this has historical value and may actually promote drug resistance. As no randomized controlled trials have been done specifically for ocular tuberculosis, current recommendations rely on the guidelines for pulmonary and extrapulmonary tuberculosis.

All recent consensus statements and institutional guidelines—the American Thoracic Society (ATS), the Centers for Disease Control (CDC), and the Infectious Diseases Society of America (IDSA)—suggest an initial four-drug regime (isoniazid [INH], pyrazinamide [PZA], ethambutol [ETB], and rifampicin [RIF]) for an initial 8 weeks followed by INH and RIF either 7 days a week (Regimen 1a) or twice weekly (Regimen 1b) for a minimum duration of 18 weeks. These guidelines also apply to extrapulmonary forms of the disease or HIV-infected patients, with some data suggesting that similar regimens of four drugs for 6–9 months are equally effective [47].

The World Health Organization (WHO) suggests the use of four drugs (INH/RIF/PZA/ETB) for an initial 2 months followed by INH/RIF for 4 months for category I patients (new sputum positive patients, new sputum negative patients with extensive lung parenchymal disease, and those with severe extrapulmonary disease) and category III patients (new smear negative patients

with lesser lung parenchymal involvement and patients with less severe extrapulmonary disease) [48].

Therapeutic failures may occur and may be due to primary resistance (infection or reactivation of bacilli that are resistant to one or more drugs at the onset of disease itself) or secondary resistance where bacilli develop resistance due to faulty compliance or poor drug selection. Reports of drug-resistant ocular tuberculosis are rare but may be a problem in the future, as the multidrug tuberculosis epidemic expands.

Ocular Toxicity in Antitubercular

Therapy

Antitubercular therapy–induced ocular toxicity is rare, and ethambutol is usually the offending drug. The observed toxicity is an optic neuropathy that may be seen in up to 2% of patients on the current recommended dose of 15 mg/kg. Patients present with bilateral visual loss and a normal-appearing fundus. Rarely, hyperemic or edematous discs have been seen. A primary optic atrophy may supervene after 4–6 weeks. Visual field studies may show central, paracentral, or peripheral scotomas. Defective color vision is common, especially in the red-green axis. Patients with acute or chronic renal failure may be at an added risk and need close monitoring or reduced dosages of ethambutol. The neuropathy is usually reversible, but complete recovery may take several months.

Controversies and Perspectives

1.Use of Antitubercular Drugs—While the use of antitubercular drugs is mandatory, until recently no large series studied its exact role. Bansal et al. [49] studied 360 patients with at least a 1-year follow-up after starting antitubercular therapy. They studied patients who received four-drug antitubercular therapy and corticosteroids and those that received corticosteroids alone and observed inflammatory recurrences in each group. Significantly fewer

recurrences were seen in the first group as compared to the second. The authors estimate that the use of antitubercular therapy reduces the chance of recurrence by up to two-thirds.

2.Use of 18 FDG-PET (Fluorodeoxyglucose– Positron Emission Tomography) Scans in the Management of Ocular Tuberculosis—These utilize a radioactive tracer (18 FDG) that accumulates in tissues that rapidly utilize glucose, such as malignancies as well as inflammatory foci. Potentially, use of these scans may help to detect foci of systemic tubercular inflammation. Mehta et al. [50] recently have described the utility of 18 FDG-PET scan in a 35-year-old female patient with recurrent posterior uveitis in whom chest imaging studies of the chest were normal. Increased tracer activity was seen in the right paratracheal, precarinal, and bilateral hilar nodes and in the left choroid. The authors suggest that a FDG-PET/ CT scan may be a better choice in detecting coexisting pulmonary tuberculosis as compared to conventional imaging techniques.

3.Use of an Animal Model—Histopathological and immunological studies into ocular tuberculosis have been limited by the relative lack of intraocular tissue and fluids. Recent developments of an animal model may change this. Rao et al. [51] have recently used Hartley strain guinea pigs that were infected via an aerosol route. Some animals were infected with low doses of bacteria and were merely observed. Another group received a high-dose infection and was treated with the standard antitubercular regimen. Animal tissues were studied via histopathology and PCR techniques. Uveal granulomatous lesions were found to have acid-fast bacteria and M. tuberculosis DNA. The presence of treatment was found to have a protective effect to the development of tubercular uveitis.

Focal Points

The prevalence of ocular tuberculosis has reduced in the twentieth century worldwide, but it is still a common etiological agent in the developing world.