BASICS

DESCRIPTION

• Tuberculosis (TB) is a chronic infection caused by the acid-fast bacillus, Mycobacterium tuberculosis.

– Systemic disease that mainly involves the lung

– Extrapulmonary manifestations may occur with or without pulmonary TB

– Sites include gastrointestinal tract, genito-urinary tract, cardiovascular system, skin, central nervous system, and eyes

– Uveitis is the most common ophthalmic presentation, although any part of the eye may be affected.

EPIDEMIOLOGY

Incidence

• Annual incidence of tuberculosis is ∼9.3 million patients worldwide

– Heaviest case burden in developing countries

Annual incidence rate of 363 per 100,000 in Africa

Annual incidence rate of 32 per 100,000 in the US

Prevalence

• In 2007, an estimated 13.7 million people had active TB with 1.8 million deaths

– Leading cause of death in patients with HIV and of infectious death in women of reproductive age

RISK FACTORS

• Silicosis

• Chronic renal failure

• Diabetes mellitus

• Low body weight

• Immunocompromised patients (e.g., acquired immune deficiency syndrome [AIDS], leukemia, Hodgkin’s disease)

PATHOPHYSIOLOGY

Phlyctenulosis, interstitial keratitis, and retinal vasculitis may result from a hypersensitivity reaction to mycobacterial proteins

ETIOLOGY

• Inhalation of aerosolized droplets carrying Mycobacterium tuberculosis

– 90% of infected persons never develop clinical disease.

– 5% develop disease within first few years of exposure

– 5% develop disease several years later due to altered host immunity (reactivation of latent infection)

– Infectious organisms may disseminate from lungs hematogenously, resulting in extrapulmonary manifestations

Miliary TB (1.3% of reported cases) may result, described as millet-like seeding in the lungs and extrapulmonary tissues

DIAGNOSIS

HISTORY

• Classic symptoms (pulmonary TB): chronic cough, blood-tinged sputum, fever, night sweats, and weight loss

• Vision loss, floaters, eye pain, red eye, and photophobia

• If orbital involvement is present, patient may also have diplopia and ophthalmoplegia

PHYSICAL EXAM

• Eyelid manifestations (usually in children):

– Lupus vulgaris

– Most common form of cutaneous TB

– Reddish-brown nodules which blanch an “apple-jelly” color on palpation

– May simulate a chalazion or look like a “cold abscess” (soft, fluctuant mass without inflammation)

• Tuberculous conjunctivitis:

– Unusual and more often in children

– May present with mucopurulent discharge, lid edema, and injection with marked lymphadenopathy (similar to Parinaud’s oculoglandular syndrome)

– Often chronic, which can lead to scarring

• Tuberculous episcleritis and scleritis:

– Occurs rarely

– Most common type: Focal necrotizing scleritis

– Scleral perforation may occur

– Posterior scleritis has been rarely reported

• Corneal manifestations:

– Phlyctenulosis

– Slightly raised, small, pinkish white to yellow nodules surrounded by dilated vessels, usually near limbus on conjunctiva or peripheral cornea

– Sectoral interstitial keratitis

– Typically unilateral

– Peripheral stromal infiltrate with vascularization

– Sclerosing keratitis

– Tuberculous pannus (associated with ulcerative granulomas involving conjunctiva)

– Corneal ulcer

• Anterior uveitis

– Typically granulomatous with acute or chronic presentation

– May have mutton fat keratic precipitates and posterior synechiae

– Secondary glaucoma may occur

– Iris or angle granulomas

– Small translucent nodules at pupillary margin (Koeppe’s nodules) may be seen with recurrent uveitis

– Hypopyon or mass lesion in severe cases

• Intermediate uveitis

– Chronic low-grade vitreitis, typically bilateral

– May be associated with snowball opacities, snow banking, peripheral vascular sheathing, peripheral granulomas

• Posterior uveitis

– Choroidal tubercles

– Most common manifestation of intraocular TB

– Results from hematogenous spread

– Multiple grayish white to yellow lesions with indistinct borders (<5–50 in number)

– Unilateral or bilateral

– Usually localized to posterior pole

– Size: 0.5–3 mm

– Occasionally may grow into larger mass (choroidal tuberculoma)

– Pigmented and atrophic scars upon resolution with distinct margins

– Immunocompromised patients may have no concomitant inflammation

– Choroidal tuberculoma

– Solitary subretinal mass that may mimic choroidal tumor

– Initially small, round, whitish lesion but may become yellowish

– Size: 4–14 mm

– Associated findings: hemorrhages, retinal folds, and exudative retinal detachment

– Serpiginous-like choroiditis

– Multifocal or diffuse plaque-like lesions

– Typically have progressive course despite treatment

– Retinal vasculitis

– Associated findings: vitreitis, retinal hemorrhages, perivascular choroiditis, neovascularization, and neuroretinitis

– May resemble Eales’ disease but usually has more prominent intraocular inflammation

– Eales’s disease

Retinal vasculitis that mainly affects peripheral retina with recurrent vitreous hemorrhages and fibrovascular proliferation in the relative absence of intraocular inflammation

Seen in young, healthy adults

Perivascular exudates and hemorrhages may progress to venous thrombosis, neovascularization, and traction retinal detachment

• Endophthalmitis/panophthalmitis

– Usually in children or severely ill adults in the setting of systemic TB and chronic illness, poor nutrition, or intravenous drug abuse

– Severe inflammation may cause widespread destruction of ocular tissues

– Anterior segment:

– Corneal infiltrates

– Hypopyon

– Posterior segment:

Vitreitis

Choroidal detachment

Globe perforation may occur typically near equator in cases of panophthalmitis

• Tuberculous optic neuropathy and neuroretinitis

– Optic nerve involvement may manifest as an optic nerve tubercle, papillitis, papilledema, optic neuritis, retrobulbar neuritis, neuroretinitis, or opticochiasmatic arachnoiditis

• Orbital manifestations:

– Rare case reports

– Clinical presentations:

Periostitis: Chronic ulceration or discharging sinus in periorbital region with discolored/thickened/edematous surrounding skin often adherent to underlying bone

Orbital soft-tissue tuberculoma or cold abscess without bony destruction: Proptosis and palpable orbital mass

Orbital TB with evidence of bony involvement: Proptosis, ophthalmoplegia, and palpable orbital mass

Orbital spread from paranasal sinuses: Proptosis, significant globe dystopia, palpable mass, ophthalmoplegia, and epistaxis

Dacryoadenitis: Limitation of eye movements, ptosis, proptosis, globe displacement, mass in region of lacrimal gland, and regional lymphadenopathy

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

• Tuberculin skin test (PPD)

– High-risk groups (e.g., medical personnel, intravenous drug abusers): Induration >10 mm considered positive

– Immunocompromised: Induration >5 mm considered positive

– Low-risk groups: Induration >15 mm considered positive

– False positives may occur in patients with prior BCG vaccination

– Note that vaccination-induced reactions wane over time and are unlikely to persist for >10 years

– May be falsely negative in up to 30% of patients with active TB, especially if immunocompromised

• Interferon-gamma release assays (e.g., QuantiFERON-TB test): Detects cellular response to TB antigens through measurement of interferon-gamma release

– Reduced false positive rate in patients with prior BCG vaccination

• Sputum culture (if pulmonary symptoms)

Follow-up & special considerations

• In select cases, consider vitreous biopsy or diagnostic anterior chamber paracentesis:

– May see acid-fast bacilli on smear or culture

– May be falsely negative due to low yield of organisms from intraocular fluids

– Polymerase chain reaction testing may improve detection and can be performed on even small samples.

Imaging

Initial approach

Chest X-ray (PA and lateral)

Follow-up & special considerations

Chest CT if chest X-ray is inconclusive

Diagnostic Procedures/Other

• Fluorescein angiography

– Choroidal tubercles:

– Hypofluorescent during transit phase with late hyperfluorescence

– May also confirm a choroidal neovascular membrane or retinal angiomatous proliferation associated with a choroidal tubercle (acute phase or inactive lesion)

– Choroidal tuberculoma:

– Early hyperfluorescence with dilated capillary bed → leakage and pooling in late phase if there is surrounding exudative detachment

– Serpiginous-like choroiditis:

– Active edge with early hypofluorescence and late hyperfluorescence with diffuse staining

– Healed lesions show transmission hyperfluorescence or blocked fluorescence from pigment epithelial proliferation

– Retinal vasculitis:

Staining and leakage from vessel walls, primarily veins

Peripheral sweeps helpful for documenting capillary nonperfusion and neovascularization

• Indocyanine green angiography

– Choroidal tubercles/tuberculoma

– Active lesions hypofluorescent → iso- or hyperfluorescent border present in late phase

– Resolving lesions become less hypofluorescent

– Helpful in detecting subclinical lesions

– Serpiginous-like choroiditis:

Active lesions are hypofluorescent throughout angiogram

• Optical coherence tomography

– May be helpful if a choroidal neovascular membrane or cystoid macular edema is suspected

• B-scan ultrasonography

– Choroidal tuberculoma:

Solid, elevated mass

Low to medium internal reflectivity

• Ultrasound biomicroscopy: May show ciliary body granulomas

• If orbital TB is suspected, CT head/orbit is the preferred imaging modality.

– Biopsy confirmation is typically recommended (either open biopsy or fine needle aspiration biopsy)

Pathological Findings

• Granulomas with central caseous necrosis surrounded by epithelioid cells, Langerhans’ giant cells, lymphocytes, and plasma cells

• Immunocompromised patients:

– More of a purulent infection with necrotic and viable neutrophils, macrophages, and numerous bacteria

DIFFERENTIAL DIAGNOSIS

• Infectious

– Toxoplasmosis

– Syphilis

– Lyme’s disease

– Cat scratch disease

– Toxocariasis

– Nocardiasis

– Coccidiomycosis

– Candidiasis

– Brucellosis

– Leptospirosis

– Leprosy

• Noninfectious

– Sarcoidosis

– Behçet’s disease

– Autoimmune vasculitis

– Tumors

– Metastasis

TREATMENT

MEDICATION

First Line

• Multidrug anti-TB regimen is required to avoid resistance.

– Typically: Isoniazid, rifampin, pyrazinamide, and ethambutol for 2–4 months

– Subsequently: Isoniazid and rifampin for another 4–7 months

– In cases of isolated ocular TB, some advocate the above therapy without ethambutol

• Systemic corticosteroids may limit damage from delayed-type hypersensitivity

– Consider 4- to 6-week course

– Must be used with anti-TB medications or could lead to panophthalmitis and systemic TB due to activation of latent infection

• Conjunctivitis: Anti-TB therapy

• Scleritis/episcleritis: Anti-TB therapy; systemic steroids may be used depending on severity

• Interstitial keratitis: Topical steroids, systemic with or without topical anti-TB therapy, and cycloplegics

• Phlyctenulosis: Topical steroids, anti-TB therapy, and cycloplegics

• Uveitis:

– Use of anti-TB therapy decreases recurrence of uveitis

– Anterior uveitis: Cycloplegics and topical steroids in addition to anti-TB therapy

– Intermediate uveitis: Topical, periocular and/or oral steroids after anti-TB therapy is initiated

– Posterior uveitis: Oral steroids after anti-TB is therapy initiated

– May have paradoxical worsening of serpiginous-like choroiditis after initiation of anti-TB therapy

– Eales’ disease: Anti-TB therapy, when associated with clinical evidence of TB infection

If cystoid macular edema is present, intravitreal triamcinolone or bevacizumab may be used

Intravitreal bevacizumab helps induce regression of neovascularization

• Tuberculous optic neuropathy: Anti-TB therapy and oral steroids after anti-TB therapy is initiated

• Orbital TB: Anti-TB therapy

Second Line

• Streptomycin

• Rifabutin and rifapentine may be alternatives to rifampin

• Drugs that may be useful for drug-resistant TB:

– Cycloserine, levofloxacin, moxifloxacin, gatifloxacin, amikacin, kanamycin, ethionamide, and capreomycin

SURGERY/OTHER PROCEDURES

• Retinal vasculitis/Eales’ disease:

– Laser photocoagulation of ischemic nonperfused retina

– If non-clearing vitreous hemorrhage, may consider pars plana vitrectomy

• Orbital TB: Surgical intervention may be diagnostic, therapeutic (e.g., excision of bone and fistulous tract), or both (e.g., excisional biopsy)

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Infectious disease specialist or internist experienced in managing TB

• Pulmonologist: In cases of suspected associated pulmonary TB

• Ophthalmologist: In cases with ocular or orbital involvement, or with ethambutol therapy to evaluate for toxicity

Patient Monitoring

• Local public health officials may need to be notified

– In some locations, directly observed therapy (DOTS) is recommended to increase compliance with anti-TB therapy and to lower the risk of drug resistance

• Ocular side effects of anti-TB drugs

– Isoniazid, pyrazinamide, and rifampin carry risk of hepatotoxicity

– Liver function needs to be monitored during therapy

– Ethambutol

Toxic effects: Optic neuritis, photophobia, and extraocular muscle paresis

Onset is usually 3–6 months after initiation of therapy

Dose dependent: Occurs in 1–2% of patients receiving 25 mg/kg/day but is rare with daily dose <15 mg/kg

Recommendation: Baseline ophthalmologic exam with visual field and color plate testing followed by monthly exams and testing if dose >15 mg/kg or every 3–6 months if lower dose

Self-monitoring with vision card: Instruct patient to stop ethambutol and undergo ophthalmic exam if visual acuity decreases

If no vision improvement 10–15 weeks after ethambutol is discontinued, consider parenteral hydroxocobalamin 40 mg/day for 10–28 weeks

PROGNOSIS

• With appropriate diagnosis and timely treatment, prognosis is often good

– In advanced, neglected, or aggressive cases, the outcome may be poor despite appropriate therapy

• Orbital TB: Rarely, deaths have been reported due to extension of an orbital focus into the brain

– Visual loss may occur in some cases due to optic atrophy

ADDITIONAL READING

• Thompson MJ, Albert DM. Ocular tuberculosis. Arch Ophthalmol 2005;123:844–849.

• Madge SN, Prabhakaran VC, Shome D, et al. Orbital tuberculosis: A review of the literature. Orbit 2008;27:267–277.

• Bansal R, Gupta A, Gupta V, et al. Role of anti-tubercular therapy in uveitis with latent/manifest tuberculosis. Am J Ophthalmol 2008;146:772–779.

• Gupta V, Gupta A, Arora S, et al. Presumed tubercular serpiginous-like choroiditis. Ophthalmology 2003;110:1744–1749.

• Gupta V, Gupta A, Rao NA. Intraocular tuberculosis—an update. Surv Ophthalmol 2007;52:561–587.

CODES

ICD9

• 017.30 Tuberculosis of eye, unspecified examination

• 363.13 Disseminated choroiditis and chorioretinitis, generalized

• 370.31 Phlyctenular keratoconjunctivitis

CLINICAL PEARLS

• Ocular TB can mimic various other eye diseases, necessitating a high level of clinical suspicion in order to make the correct diagnosis

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