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INTRODUCTION Tuberculosis (TB) is an air-borne disease that affects one-third of the world’s population (approximately 1.9 billion) L eading single cause of mortality and morbidity worldwide 3 million deaths annually. WHO declared global emergency Mycobacterium tuberculosis spreads by droplet infection by coughing or sneezing. Ocular tuberculosis is an extra-pulmonary form . Infection in or around the eye caused by M. tuberculosis or its related species. It may be either an active infection or an immunologic reaction, related to delayed hypersensitivity or an aseptic reaction.

Ocular TB-History:

Ocular TB-History Primary infection of the eye is rare. The recognized association of TB in 1700 iris lesions in TB Recognition of choroidal tubercles in the medical literature was first in1830 and 1844. It is estimated that 1.4% of persons with PTB develop ocular manifestations But many patients with ocular TB have no evidence of PTB Secondary ocular tuberculosis is the ocular involvement as a result of haematogenous spread from a distant site or a direct invasion from adjacent areas like the sinus or the cranial cavity. Almost every tissue of the eye and its adnexa can get affected. Course : acute , usually chronic course with exacerbations & remissions

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Rarely have overt systemic manifestations: Lead to difficulty in diagnosis. Occasionally, a history of previous TB exposure or positive skin test for TB will be found. Patients with ocular TB rarely have fever, cough, or sputum production. Chest x-ray findings in patients with ocular TB usually are normal.

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Tuberculosis and the Eye- Epidemiology


EPIDEMIOLOGY 1953 – 1984: TB cases fell, mostly in industrialized countries. 1985: Increase in number of new cases d/t occurrence of tuberculosis in persons infected with HIV. High rate of immigration from countries with a high incidence of TB and emergence of multi-drug resistance of TB Mycobacterium tuberculosis is the commonest infecting organism in HIV-infected patients worldwide and one in three people with AIDS will die of TB. 1993: new cases dropped Newer and better treatment for HIV, increased awareness, better institution of Direct Observed Therapy (DOTS) & multi-drug therapy (MDT).




CLINICAL PRESENTATION Diverse clinical spectrum The ocular disease can result from haematogenous spread, from direct local extension from the skin, mucous membranes, or sinuses Immune-mediated ocular TB can occur due to hypersensitivity to M. tuberculosis antigens from a distant focus (such as lungs). Hypersensitivity causes inflammation despite the absence of the bacterium in the eye. Symptomatic disease is most commonly observed during reactivation of dormant lesions in ocular tissue . Lesions are known to occur in all parts of the uveal tract, but choroid is most commonly involved.

Ocular findings :

Ocular findings Ocular TB is often unilateral and asymmetric. TB can cause a wide variety of ophthalmic findings, ranging from the ocular surface through the optic nerve and to the central nervous system.

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TB infection of the eyelid : Start discretely as a minute nodule and later become lupus vulgaris (soft brownish TB nodules with ulceration and scarring) Often accompanied by lymphadenopathy .

Eye in Tuberculosis:

Eye in Tuberculosis Anterior Segment:- * Phlyctenular conjunctivitis * Granuloma Conjunctiva * Keratitis (Deep) * Scleritis -Diffuse -Nodular

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Tuberculous conjunctivitis : usually unilateral, chronic, may occasionally be associated with conjunctival mass or ulceration. Preauricular lymphadenopathy is occasionally seen in these cases. TB include conjunctival granulomas , phlyctenulosis , sclerokeratitis , interstitial keratitis , anterior uveitis , and iridocyclitis . Subsequent calcification of granulomas can impede vision, and inflammation can cause irreversible damage to ocular tissue. Children and adolescents have higher rates of phlyctenular keratoconjunctivitis , which is found in 35% of children living in areas of high rates of TB.

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Conjunctival granulomas : It is a Type IV Hypersensitivity reaction, presents as an inflammatory mass on the cornea. It is usually occurs due to tuberculosis but can be associated with Staphylococcus aureus . Focal, nodular or diffuse scleritis with or without keratitis can also develop

Keratitis and scleritis:

Keratitis and scleritis Result of spread of infection and granulomatous reaction from within the eye. Biopsy-proven cases of TB scleritis . It is usually diffuse, posterior or nodular and associated with localized granuloma formation. Interstitial keratitis and sclero-keratitis is also known to occur.


ORBIT The orbit may be involved by spread of disease from within the eye. Commonly the spread occurs from orbital periosteitis . Orbital periosteal rim, dacryoadenitis , and sinus infections with a non-healing, draining fistula are typical of tuberculosis. Panophthalmitis or endophthalmitis may also occur. Tuberculosis can also present as an orbital mass, or as eyelid abscesses.

Anterior segment findings- :

Anterior segment findings- The most common anterior segment presentation is anterior uveitis which can be chronic anterior uveitis or panuveitis . Iridocyclitis shows characteristics muttonfat keratic precipitates (KPs) classically distributed inferiorly in the lower one third of the cornea which is known as the Arlt’s triangle.

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The iris usually develops posterior or anterior synechiae and/or iris granulomas . Granulomas may be seen at the angle of the iris base & over the trabecular meshwork. HIV patients on retroviral therapy can show an immune recovery uveitis associated with concomitant tuberculosis even if they are not on Rifabutin . -Long-standing inflammation can lead to cataract formation and secondary inflammatory glaucoma.

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In patients with miliary (disseminated) TB, iris nodules are often associated with anterior uveitis . Patients can also present with an intermediate uveitis pattern including ‘‘snowball’’ cellular aggregates and ‘‘snow banks’’ at the pars plana .

Posterior segment findings:

Posterior segment findings The most common finding of ocular TB is choroiditis . This is likely caused by the extensive blood supply to the choroid which makes it susceptible to hematogenous spread of M. tuberculosis. But more widespread inflammation in choroiditis and vasculitis is likely due to hypersensitivity. Multifocal choroidal granulomas being the hallmark feature. These tubercles can mimic in appearance with serpiginous choroiditis , multifocal choroiditis , or simulate the panuveitis pattern .

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Choroidal lesions, with or without inflammation, is strongly correlated with the systemic disease and is an indicator of haematogenous spread of mycobacteria . Choroidal tubercles :Unilateral or bilateral Greyish -white to yellowish in color with indistinct margins usually less than 5 or upto 100 in number. Active or inactive and are mostly unilateral but can be bilateral. Develop at the posterior pole either singly or in a multifocal pattern with sizes varying from one half to several disc diameters.

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Tubercles heal in 12-14 weeks, become pigmented with distinct margins forming an atrophic scar. b. Choroidal tuberculoma - Choroidal tubercle continues to grow, it forms a solitary mass known as tuberculoma.

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Tuberculomas may be seen anywhere in the choroid- posterior pole, macula or they maybe juxta -papillary in location Tuberculomas are subretinal masses, often mimicking a tumour , 4-14 mm in size and yellowish in color. There may be an overlying exudative retinal detachment seen in the later stages.

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C) Subretinal abscess -Large tuberculomas may undergo liquefactive necrosis and form yellowish subretinal mass lesions accompanied by exudative retinal detachment. These lesions may present with clinical signs of subretinal abscess and can be seen both in immunocompetent as immunocompromised patients. Investigated for the evidence of miliary tuberculosis. Rarely, these lesions can rupture into the vitreous cavity and may lead to endophthalmitis or panophthalmitis .

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d. Serpiginous like choroiditis - Serpiginous choroiditis is a rare, bilateral, chronic, progressive and recurrent inflammation of the outer retina and inner choroid which is of unknown etiology. Progression of disease in spite of the patient being administered systemic corticosteroids and immunosuppressants . These lesions begin in the peri -papillary area and spread centrifugally. Multifocal form where the lesions are discrete and non-contiguous initially but later in the course may form a diffuse, contiguous pattern.

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A. Scrofula. B. Accompanying choroidal granuloma

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The retina may show features of retinitis, vasculitis , vascular occlusions or serous retinal detachment. Retinal periphlebitis is rarely caused by the direct invasion of the retina by tubercle bacilli . Retinal tuberculosis usually occurs secondary to underlying choroiditis . Cystoid macular edema can accompany intraocular inflammation in ocular tuberculosis

Eye in Tuberculosis…Contd…:

Eye in Tuberculosis…Contd… Complications of Ocu TB - Cataract -Glaucoma -Cystoid Macular edema -Retinal detachment -Corneal Scarring Complication of Anti TB therapy - Retro bulbar Neuritis

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There are two other ocular entities that are related to Tuberculosis- Reactions to tuberculin- Allergic reaction have occurred in patients with bilateral, granulomatous anterior uveitis associated with tuberculin skin testing. - Severe choroiditis progressing to serous retinal detachment has been reported with intra-dermal injection of purified protein derivative (PPD) in patients with preexisting tuberculous uveitis 2. Eales ’ disease - The disease is characterized by recurrent vitreous haemorrhages and retinal periphlebitis in young adult males.

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Eales disease. A)Multifocal areas of periphlebitis with associated intraretinal flameshaped hemorrhages, secondary lipid maculopathy , and subtle choroidal folds within the papillomacular bundle are present. B) Peripheral vaso -occlusive arterial inflammation coexistant with venous involvement and secondary intraretinal hemorrhage Late neovascularization with vitreous hemorrhage is a common sequelae C) Fluroescein angiography demonstrates staining of venous walls and blockage of background fluorescence by intraretinal blood

Diagnosis :

Diagnosis Based upon clinical presentation, systemic evaluation and response to treatment. Choroiditis is the most common ocular manifestation in patients with pulmonary and systemic tuberculosis and in the absence of ocular biopsies the diagnosis remains presumptive.

Diagnosis :

Diagnosis Suggested guidelines for diagnosis of intraocular tuberculosis: I. Clinical signs Presence of features of any one of the following: Uveitis Cyclitis Choroiditis Retinitis Retinal vasculitis , Neuro -retinitis ,optic neuropathy Endophthalmitis , pan- ophthalmitis An intractable disease course with multiple recurrences on nonspecific treatment (corticosteroids) is a clue suggesting a possible tubercular etiology.

Laboratory Diagnosis of Tuberculosis:

Laboratory Diagnosis of Tuberculosis

Laboratory Diagnosis:

Laboratory Diagnosis 1- Sputum smears stained by Z-N stain Three morning successive mucopurulent sputum samples are needed to diagnoise pulmonary TB . Advantage : - cheap – rapid - Easy to perform - High predictive value > 90% - Specificity of 98% Disadvantages: - sputum ( need to contain 5000-10000 AFB/ ml.) - Young children, elderly & HIV infected persons may not produce cavities & sputum containing AFB.

Interpretation of sputum stained by Z N Stain (WHO ):

Interpretation of sputum stained by Z N Stain (WHO ) More than 10 bacilli / field ------- +++ From 1 – 10 bacilli / field ------- ++ From 10 – 99 bacilli / 100 fields ----- + From 1 -9 bacilli/100 fields ------ write the no. No bacilli seen ---------- negative

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2 - Detecting AFB by fluorochrome stain using fluorescence microscopy: The smear may be stained by auramine -O dye. In this method the TB bacilli are stained yellow against dark background & easily visualized using florescent microscope . Advantages: - More sensitive - Rapid Disadvantages: - Hazards of dye toxicity - more expensive - must be confirmed by Z-N stain LED microscopy is recommended over conventional fluorescence

LED Fluorescence Microscopy:

Advantages : increase in performance increase in lamp lifetime reduces initial, operating and maintenance costs No need for dark room LED Fluorescence Microscopy

We still dependent on culturing MTB but has limitations ???:

We still dependent on culturing MTB but has limitations ??? Culture of M. tuberculosis in clinical specimens is substantially more sensitive than smear microscopy. Culture can be performed using solid media, such as Lowenstein-Jensen, or liquid media, such as that used in commercially available automated systems. Dr.T.V.Rao MD 41

3- Cultures on L J media Lowenstein –Jensen medium is an egg based media with addition of salts, 5 % glycerol, Malachite green & penicillin. :

3- Cultures on L J media Lowenstein –Jensen medium is an egg based media with addition of salts, 5 % glycerol, Malachite green & penicillin. Advantages : - Specificity about 99 % - More sensitive ( need lower no. of bacilli 10-100 / ml) Disadvantages :- Slowly growing ( up to 8 weeks )

Recent Methods for Diagnosis:

Recent Methods for Diagnosis I – BACTEC 460 ( rapid radiometric culture system ) Specimens are cultured in a liquid medium (Middle brook7H9 broth base )containing C 14 – labelled palmitic acid & PANTA antibiotic mixture. Growing mycobacteria utilize the acid, releasing radioactive CO 2 which is measured as growth index (GI) in the BACTEC instrument.

The PANTA antibiotic mixture:

The PANTA antibiotic mixture P ---- Polymyxin B A ---- Amphotericin B N ---- Nalidixic acid T ---- Trimethoprim A ---- Azlocillin The antibiotic mixture inhibits the growth of contaminating bacteria.

Advantages : :

Advantages : - Rapid ( mycobacteria can be detected within 12 days.) Determining drug susceptibility . - Specificity is very high Disadvantages: - Expensive - Hazards of using radioactive material.

II Mycobacteria Growth Indicator Tube (MGIT):

II Mycobacteria Growth Indicator Tube (MGIT) Tube contains modified Middlebrook 7H9 broth base with OADC enrichment & PANTA antibiotic mixture. All types of clinical specimens, pulmonary as well as extra-pulmonary ( except blood ) could be cultured on this type of media.

The OADC supplement :

The OADC supplement O ----- Oleic acid ( Metabolic stimulant) A ----- Albumin ( to bind toxic free fatty acid) D ---- Dextrose (Energy source ) C ----- Catalase ( Destroy toxic peroxides that may be present in the medium )

Mycobacterial Growth Indicator Tube (MGIT):

Rapid Method. Consists of round bottom tubes containing 4 ml of modified Middlebrooks 7H9 broth which has an oxygen sensitive fluorescent sensor at the bottom .* When mycobacteria grow, they deplete the dissolve oxygen in the broth & allow the indicator to fluoresce brightly in a 365nm UV light . Mycobacterial Growth Indicator Tube (MGIT) 49

The MGIT 960 System:

The MGIT 960 System The MGIT 960 system is a non- radiometeric automated system that uses the MGIT media & sensors to detect the fluorescence. Advantages: -The system holds 960 plastic tubes which are continuously monitored. - Early detection as the machine monitoring & reading the tubes every hour.

Detection and identification of mycobacteria directly from clinical samples:

Detection and identification of mycobacteria directly from clinical samples Genotypic Methods : PCR LAMP TMA / NAA Ligase chain reaction Phenotypic Methods : FAST Plaque TB Dr.T.V.Rao MD 51

•PCR-based genetic tests:

• PCR-based genetic tests Detection is based on multiplication not of whole bacilli, as in culture, but of their genetic material, chromosomal DNA or ribosomal RNA. Provided all ingredients are present in the reaction tube, this will only take place when the target genetic sequences to which the added primers can bind are found in the sample. 52

Polymerase Chain Reaction (PCR):

Essentially PCR is a way to make millions of identical copies of a specific DNA sequence , which may be a gene , or a part of a gene, or simply a stretch of nucleotides with a known DNA sequence, the function of which may be unknown Polymerase Chain Reaction (PCR) 53

III Polymerase Chain Reaction (PCR) & Gene probe:

III Polymerase Chain Reaction (PCR) & Gene probe Nuclic acid probes & nucleic acid amplification tests in which polymerase enzymes are used to amplify ( make many copies of specific DNA or RNA sequences extracted from mycobacterial cells. Advantages: - Rapid procedure - High sensitivity (1-10 ( 3 – 4 hours) bacilli / ml sputum)

Disadvantages: :

Disadvantages : - Very expensive. - Require specialist training & equipments. - False positive results. - Can not differentiate between living & dead bacilli.

Loop-mediated isothermal amplification. LAMP*:

Loop-mediated isothermal amplification. LAMP* It is a novel nucleic acid amplification method in which reagents react under isothermal conditions with high specificity , efficiency, and rapidity . LAMP is used for detection of M.tb complex, M.avium, and M.intracellulare directly from sputum specimens as well as for detection of culture isolates grown in a liquid medium (MGIT) or on a solid medium ( Ogawa’s medium ). * Iwamoto T et al J Clin Microbiol 2003;41 :2616- 57

LAMP*: principle:

LAMP *: principle This method employs a DNA polymerase and a set of four specially designed primers that recognize a total of six distinct sequences on the target DNA . Species-specific primers were designed by targeting the gyrB gene . Simple procedure, starting with the mixing of all reagent in a single tube, followed by an isothermal reaction during which the reaction mixture is held at 63°C 60-min incubation time. Dr.T.V.Rao MD 58

Ligase Chain Reaction:

It is a variant of PCR, in which a pair of oligonucleotides are made to bind to one of the DNA target strands, so that they are adjacent to each other. A second pair of oligonucleotides is designed to hybridize to the same regions on the complementary DNA . Ligase Chain Reaction 59

IV FASTplaque TB Test :

IV FASTplaque TB Test - Patient’ s sputum is mixed with myco-bactriophage. - A virucide is added which destroy any phages outside the TB bacilli. - Lysis of cells & release of phages after replication within the tubercle bacilli. - Non-pathogenic mycobacteria are added & the sample incorporated in agar mixture( over night incubation) - Zones of clearing indicate that patient’ s sputum contained viable M. tuberculosis.

Interferon –γ Tests:

Interferon – γ Tests An in vitro T-cell-based assays tests for diagnosis of latent TB infection : - QuantiFERON TB gold Test - T-Spot Test. These whole-blood assays measure IFN- γ production by previously sensitised lymphocytes in response to M.tuberculosis -specific protein antigens ESAT6 and CFP-10

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Some studies have shown that: -Compared with TST these tests have higher specificity. -Correlate better with exposure to tuberculosis. -Have less cross-reactivity with the BCG vaccine & environmental mycobacteria. NB: Yet there is no evidence for the use of these tests in young children at present.

Evaluation of different methods of diagnosis:

Evaluation of different methods of diagnosis As regards the time: The MGIT had the shortest mean time to positivity at 13.3 days, compared with 14.8 days for the BACTEC 460 system & 25.6 days for L J medium.

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As regards the no. of culture yield : The best yield, was with BACTEC 460, followed by BACTEC MGIT 960 , & then with L J medium. As regards contamination rate: L J medium (17%) had the highest contamination rate (Tortoli E, Cichero P,Et al. 1999) then the MGIT 960 ( 10.0% ) Compared with radiometeric system (3.7%)

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V. Therapeutic test A positive response to 4-drug ATT ( isoniazid , rifampicin , ethambutol , and pyrazinamide ) over a period of 4 to 6 weeks can be diagnostic. Therapeutic trial with single drug isoniazid should be avoided due to risk of development of resistance


TREATMENT Medical M. tuberculosis requires a bacteriocidal agent and a sterilizing agent, owing to the complex lifecycle of the tubercle bacilli, including a dormant, replicating, and intracellular phase. Isoniazid initially decreases bacterial load by bacteriocidal activity, while rifampin and pyrazinamide may be used for sterilization. The CDC recommends the use of all four drugs ( isoniazid , rifampicin , pyrazinamide , and ethambutol ) for an initial 2-Month period followed by a choice of different Options over next 4 to 7 months for treatment of Tuberculosis (Centers for Disease Control, 2003).

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In patients who cannot take ethambutol , this can be substituted with moxifloxacin 400mg orally once daily. Ethambutol is discontinued after 2 months to prevent optic neuropathy and ganglion cell loss. The CDC recommends prolonged therapy Patients with uveitis who have a suggestive pattern of ocular inflammation for TB, a positive TB skin test with no systemic associations, and negative chest x-ray and laboratory findings for TB found on extensive testing are Controversial in their management.

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If the uveitis is severe, progressive, or difficult to manage with local immunosuppressive drugs , or in patients who have retinal vasculitis :Systemic immunosuppressive drugs Addition of anti-tubercular therapy to corticosteroids in uveitis patients with latent/manifest TB also leads to significant reduction in recurrences of uveitis ( Bansal et al 2008). After the TB uveitis has clearly responded to antibiotic therapy, topical or depot corticosteroids may be considered to decrease the local ocular inflammatory response and improve visual function.

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Topical therapy of anterior uveitis in patients with ocular tuberculosis consists of topical prednisolone acetate and cyclopentolate eye drops. For elevated intraocular pressure, topical beta blockers and carbonic anhydrase inhibitors may be given. Rifabutin used for the treatment of pulmonary tuberculosis may in itself cause anterior uveitis


DRUG TOXICITY The ethambutol toxicity is dose-related and is rare if the daily dose does not exceed 15 mg/kg. Ocular toxicity is experienced by less than 2% of patients receiving daily dose of 25 mg/kg or more of ethambutol (Albert et al 1999). Optic neuritis, acquired red-green dyschromatopsia (Rizzo, 1993), scotomas , disc edema, disc hyperemia (Barron et al 1974) Peripapillary splinter haemorrhages , optic atrophy, rarely, retinal edema and foveal pigmentary changes.

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Toxicity is reported to be mediated through an excitotoxic pathway whereby the drug disturbs the mitochondrial function; and its toxicity depends on decreased ATPase activity and mitochondrial homeostasis ( Heng et al 1999) The optic neuritis is abrupt in onset and is generally seen at 3—6 months of the onset of treatment. Baseline ophthalmic examination including visual acuity, visual field, and color vision. Examined every 2 to 4 weeks, Lower doses, follow-up every 3-6 months is adequate.

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In case of any ocular side effect, the drug should be stopped immediately; following which the vision should improve within 10— 15 weeks. Where vision does not improve following discontinuation of therapy, parenteral hydroxycobalamine , 40 mg/day over a 10- to 28-week period should be considered. Majority of symptoms resolve over a period of 3—12 months, permanent visual loss may also be seen.

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Rifabutin : Spiropiperidyl derivative of rifamycin , is more effective than rifampicin against slow-growing mycobacteria , including M. avium-intracellulare , and has been extensively used in HIV-infected patients. This agent, especially when combined with clarithromycin or fluconazole , can cause severe acute anterior uveitis , including hypopyon uveitis ( Fineman et al 2001), corneal endothelial deposits ( Golchin & McClellan, 2003) and inflammatory vitreous exudates and opacities (Khan et al 2000).

Surgical management :

Surgical management Generally, surgery is not required in treating ocular TB and is usually directed to treating adverse effects of disease or treatment for the rehabilitation of vision. Cataract surgery should not be performed in a patient with tuberculous uveitis until all inflammation has been completely controlled for at least 3 months.

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