Tuberculosis and the eye

INTRODUCTION — Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that can affect many organs, including the eye [1-4]. Ocular TB can involve any part of the eye and can occur with or without evidence of systemic TB. It generally develops following hematogenous spread from a primary focus but, in rare cases, it can also occur as a primary infection following an epithelial injury. Establishing the diagnosis of TB in an extrapulmonary focus is a clinical challenge.

Issues related to ocular TB will be reviewed here. Issues related to other aspects of TB, including ocular toxicities of TB medications, are discussed in detail separately. (See related topics.)

EPIDEMIOLOGY — TB is an airborne communicable disease of major public health significance in many countries. General issues related to epidemiology of TB are discussed separately. (See "Epidemiology of tuberculosis" and "Epidemiology and pathology of miliary and extrapulmonary tuberculosis" and "Epidemiology and molecular mechanisms of drug-resistant tuberculosis".)

Most TB disease involves the pulmonary system. Ocular TB usually represents extrapulmonary dissemination of infection. The incidence of ocular TB is uncertain due to difficulties in ocular sampling for microbiology and lack of definitive diagnostic criteria [5,6]. Prior to the era of HIV/AIDS, two prospective studies of patients with TB admitted to a sanatorium noted ocular disease incidence of 1 to 2 percent [7,8].

Among patients with HIV infection:

●In a cross-sectional study including 103 patients with pulmonary tuberculosis, ocular inflammation was observed in 7 cases (6.8 percent prevalence: 95% CI 2.78 to 13.5) [9].

●In a study including 98 patients with HIV infection, tuberculosis retinochoroiditis was seen in 7 percent [10].

●In a study including 85 patients with HIV and TB, ocular tuberculosis was observed in 11 patients (12.9 percent) [11].

These studies suggest that routine ocular examination is warranted in patients with suspected or proven TB, especially if eye symptoms are present.

CLINICAL MANIFESTATIONS AND DIAGNOSIS — TB of the eye may involve internal or the external structures. Three manifestations of ocular TB have been described based on mode of transmission of bacilli to the ocular tissues.

●Most commonly, ocular TB develops as a result of hematogenous spread of M. tuberculosis from pulmonary or extrapulmonary sites. The clinical manifestations consist of intraocular findings (figure 1); these include choroiditis, chorioretinitis, serpiginous choroiditis choroidal granuloma, optic neuritis, optic disc granuloma, subretinal abscess, orbital cellulitis, scleritis, necrotizing scleritis, posterior scleritis, sclerokeratouveitis, (picture 1), interstitial keratitis, and anterior chamber granuloma (picture 2) [1-4,12-15]. More recently in many patients primary intraocular tuberculosis without evidence of pulmonary or other extra pulmonary tuberculosis have been reported [13]. In these patients probably primary location of infection is mild to be symptomatic or to be traced.

●Less commonly, ocular TB can occur as a result of direct ocular infection from an exogenous source. In such cases, infection may involve the ocular adnexa, lacrimal gland, conjunctiva, sclera, or cornea.

●In rare cases, eye involvement can occur as a result of a hypersensitivity reaction to a distant focus of infection. Manifestations may include episcleritis, phlyctenular keratoconjunctivitis, nodular inflammation of the conjunctiva, episclera or sclera resulting from hypersensitivity reaction to a foreign antigen such as tuberculin protein (picture 3). Occlusive retinal vasculitis is similar hypersensitivity reaction and often named as Eales' disease. (See 'Intraocular TB' below and "Eales disease".)

Intraocular TB — Intraocular TB most commonly affects the uveal tract, which includes the iris and ciliary body (anteriorly) and the choroid (posteriorly). The choroid is a vascular layer located between the sclera and the retina; it forms the middle or vascular coat of the eye. Anatomically, tubercular uveitis may present as anterior, intermediate, posterior, or pan uveitis [1-4,12-15].

The diagnosis of intraocular TB can be challenging as the clinical manifestations are variable. Definitive diagnosis of TB is established by isolation of bacilli from the ocular tissues, which is often difficult to achieve. Therefore, a diagnosis of TB is frequently presumed in the presence of suggestive ocular findings (such as choroidal granuloma, broad-based posterior synechiae, retinal vasculitis with or without choroiditis, or serpiginous-like choroiditis) in combination with systemic findings consistent with TB (such as positive acid-fast bacilli [AFB] smear and culture, consistent radiographic findings, or a positive interferon-gamma release assay [IGRA] or tuberculin skin test [TST] in individuals with no systemic symptoms). Molecular diagnostic testing is also a useful tool. Clinical response to antituberculous therapy further supports a presumed diagnosis of ocular TB. (See 'Treatment' below.)

●Uveitis

•Anterior – Tubercular anterior uveitis is characterized by granulomatous keratic precipitates (picture 4), iris granulomas (picture 5), and broad-based posterior synechiae; occasionally, hypopyon may be observed (picture 2). Cataract is a common complication. Unlike sarcoid uveitis, open-angle glaucoma is not common in tuberculous uveitis, although annular synechiae and iris bombe can cause secondary angle closure glaucoma. Untreated chronic anterior uveitis may result in phthisis bulbi (an atrophic, scarred globe) [15].

•Posterior – Choroidal TB is the most common form of posterior uveitis. It occurs most commonly in the presence of systemic TB and in rare cases, it is the sole manifesting presentation of TB or the initial manifestation of systemic disease. Choroidal TB may be unilateral or bilateral. Three funduscopic patterns have been described (picture 6): solitary tubercle, miliary choroidal tubercles, or tuberculoma (a single large lesion that may mimic tumor and can lead to serious retinal detachment) (picture 7) [4,10-15].

Tubercles appear as ill-defined, yellowish-white elevated nodules. They vary in size from a pinpoint to several disc diameters in size. The lesions can coalesce into larger elevated choroidal nodules. Focal choroidal granuloma or diffuse subretinal abscess may be observed as elevated lesions in the fundus [12]. Ultrasonography can demonstrate focal retinochoroidal thickening. After antituberculous treatment, the lesion becomes pigmented. In some cases, choroidal neovascular membrane develops after complete healing, which may be associated with vision loss. Such patients are further treated with intravitreal injection of antivascular endothelial growth factor (picture 6) [4]. As the lesions age, the borders become more distinct and the rim becomes pigmented (picture 7). Multifocal chorioretinitis with pigmented scars often indicates a tubercular etiology (picture 8) [4,15].

Patients with choroidal tubercle(s) near or at the macula present with diminished visual acuity. Patients with choroidal tubercle(s) at sites not adjacent to the macula are asymptomatic and lesions may be identified incidentally on screening ocular examination.

Serpiginous-like choroiditis (SLC) of presumed tubercular etiology closely mimics serpiginous choroidopathy (SC) (picture 8). Patients with SLC are more likely to develop multifocal scattered highly pigmented lesions with vitreous cells, in contrast with classic SC, which is characteristically less pigmented [16]. It is important to exclude TB as the cause of serpiginous-like choroidopathy. Optic disc granuloma may be seen, and it can mimic a sarcoid granuloma (picture 6) [4].

•Immune recovery – Immune recovery uveitis (IRU) can occur among patients with HIV and TB in the setting of immune reconstitution due to antiretroviral therapy. IRU has been described among patients with HIV and concurrent TB, cytomegalovirus retinitis, and varicella-zoster ocular infection. Severe IRU resulting in globe rupture has been reported in an HIV patient with coexisting tubercular uveitis (picture 5) [17]. Additional issues related to immune reconstitution inflammatory syndrome are discussed further separately. (See "Immune reconstitution inflammatory syndrome", section on 'Tuberculosis'.)

●Retinal TB – Tuberculous involvement of the retina alone is uncommon. More frequently, the retina is involved in the setting of choroidal TB as retinochoroiditis. The diagnosis of retinal TB is usually presumptive based upon clinical evaluation of the eye and evaluation for evidence of systemic TB disease and/or tuberculin (or IGRA) reactivity; biopsy of the retina is generally not possible. Exudative retinal hemorrhagic periphlebitis in a patient with uveitis is highly suggestive of tubercular etiology. Similarly, healed periphlebitis and perivascular healed chorioretinal scars indicate a tubercular cause (picture 2) [1,2,4]. Fundus fluorescein angiography demonstrates retinal vessel wall staining and vascular leakage. Other signs include subvascular lesions, focal vascular tortuousities, and occlusive vasculitis (picture 9) [18].

Eales' disease is a retinal perivasculitis affecting the peripheral retina of otherwise healthy adults. It is unclear whether this condition occurs as a result of TB disease or whether it reflects an independent retinal hypersensitivity reaction. In one study of 50 patients with Eales' disease, M. tuberculosis DNA was demonstrated by polymerase chain reaction in four patients (8 percent) [18]. (See "Eales disease".)

TB of the external eye — External eye structures can be involved in ocular TB including orbit, eyelid, lacrimal gland, conjunctiva, and sclera.

●Orbit – Involvement of the orbit occurs most commonly in children, although rare cases have been reported in adults [19]. Frequent findings include a draining sinus tract and/or radiographic evidence of bony destruction [20,21].

●Eyelid – TB of the eyelid (tarsus) presents as an eyelid abscess or a chalazion-like mass. Occasionally, spontaneous drainage of the abscess forms a draining sinus tract [22]. An apparent chalazion (granuloma of an internal sebaceous gland leading to a localized swelling) that recurs despite surgical excision should prompt consideration of TB.

TB of the eyelid can also develop as an extension of cutaneous TB [22,23]. The skin disease consists of subepithelial nodules ("apple jelly nodules"), scaly plaques, or, rarely, erosive ulcers with destruction of facial features [24]. The eyelid is involved as an extension of infection from the surrounding skin. (See "Cutaneous manifestations of tuberculosis".)

●Lacrimal gland – TB of the lacrimal gland can present as symptomatic dacryoadenitis [25]; the presentation may be indistinguishable clinically from bacterial infection. Failure to respond to antibiotic treatment should prompt histopathological study of the gland.

●Conjunctiva – Primary conjunctival tuberculosis is rare, however it is reported [26]. Tuberculous infection of the conjunctiva may present as an ulcer, subconjunctival nodule, pedunculated polyp, or tuberculoma (hard, nodular, nonulcerating mass) [26]. Diagnosis requires an excisional biopsy with histopathology and culture. The number of organisms is usually small, so acid-fast bacilli may not be observed. Phlyctenular keratoconjunctivitis (picture 3) is rarely seen in patients with active TB. It appears to be associated with tuberculoprotein hypersensitivity but not with active ocular infection [27].

●Keratoconjunctivitis – Tuberculous infection of the cornea presents with pain and photophobia. Examination of the cornea may demonstrate corneal erosion with stromal infiltration (picture 1). When phlycten migrates over the cornea, it drags conjunctival vessels, and it is named as fascicular ulcer. Deep stromal keratitis is characteristic of tubercular infection of the cornea. The disease may be associated with anterior uveitis and/or conjunctivitis. Local lymph nodes may also be enlarged [27].

●Sclera – Tuberculous infection of the sclera (external or fibrous coat of the eye) results from hematogenous spread. The diagnosis can be difficult to establish and is primarily based upon evidence of scleral inflammation in a patient with active TB at another body site (picture 10) [28-31].

DIFFERENTIAL DIAGNOSIS — Granulomatous uveitis may also be seen in patients with herpes simplex or varicella-zoster infection, phacoantigenic uveitis, sarcoidosis, syphilis, leprosy, Vogt-Koyanagi-Harada disease, fungal lesions and sympathetic ophthalmia. Clinical manifestations of nontuberculous mycobacterial infections also simulate TB [4].

LABORATORY EVALUATION — Isolation of M. tuberculosis by culture is the cornerstone for diagnosis of TB, although this is not always feasible [28]. Even if a specimen can be obtained, it is often too small for all procedures, such as Ziehl-Neelsen staining for light microscopy and/or inoculation in liquid and solid media. Isolation of M. tuberculosis by culture may take 1 to 10 weeks; however, if growth is obtained, species identification and drug susceptibility testing are possible. Tuberculin skin testing and interferon-gamma release assays for TB infection may support a presumed diagnosis of ocular TB if positive; however, the test result cannot be used to confirm the diagnosis. Conversely, a negative result for any of these tests does not rule out the disease [28,32].

Biopsy specimens may be obtained for histopathologic analysis either from the iris or by retinochoroidal biopsy. However, absence of acid-fast bacilli or of caseating necrosis in the biopsy specimen does not rule out ocular TB [4,28].

Xpert MTB/RIF is a nucleic acid amplification (real-time PCR) assay rapidly detects the presence of both M. tuberculosis and rifampin resistance by PCR and it is widely used in ocular fluids [33-35]. WHO recommended Xpert MTB/RIF Ultra, based on its increased sensitivity compared to Xpert, to improve the diagnosis of paucibacillary forms of TB disease such as extrapulmonary TB [36]. Multiplex PCR can be used as a marker for detecting viable M. tuberculosis in patients with suspected intraocular TB [34]. (See "Diagnosis of pulmonary tuberculosis in adults".)

When such techniques are not possible and while awaiting culture information, the diagnosis of TB is presumptive based on ocular examination and evidence of systemic infection. (See "Diagnosis of pulmonary tuberculosis in adults".)

Multimodal imaging has greatly enhanced the characterization of ocular TB lesions. Fundus autofluorescence, optical coherence tomography (OCT), and OCT angiography have all been used for the identification of disease pattern and response to treatment in serpiginous-like choroiditis [37].

TREATMENT — The approach to treatment of ocular TB is generally the same as that for pulmonary TB. These issues are discussed in detail separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Treatment of drug-resistant pulmonary tuberculosis in adults".)

In general, for circumstances in which ocular TB is considered strongly as a clinical diagnosis, treatment should not be delayed until culture data become available [38]. Rifampicin-resistant tubercular choroidal granuloma has been reported to be treated successfully with second line antitubercular drugs. Early recognition of drug-resistant TB and appropriate treatment improves prognosis. Ethambutol and linezolid appear to have similar ocular adverse reaction resulting in optic neuropathy, and careful follow-up is needed for early recognition and intervention [39].

The response to therapy can usually be assessed by the clinical examination and resolution of inflammation. In the setting of choroidal TB, lesions can resolve completely with treatment. Paramacular and optic nerve head TB is managed with antituberculous therapy together with systemic corticosteroids (prednisone 40 to 60 mg orally once daily) followed by a taper depending on the clinical response [40]. Development of neovascularization warrants photocoagulation of the retina (picture 9).

Some favor administration of antituberculous treatment for two to four weeks without steroids, followed by assessment for clinical improvement and subsequent determination regarding addition of steroids. However, for cases in which a lesion is present near the macula or optic disc, administration of concomitant steroids is mandatory to save these delicate structures from rebound inflammation that may occur with antituberculous therapy alone. In such situations, absence of recurrence following completion of the treatment supports a clinical diagnosis [40].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of tuberculosis".)

SUMMARY

●Ocular tuberculosis (TB) can involve any part of the eye and can occur with or without evidence of pulmonary or extrapulmonary TB. Ocular TB usually arises after hematogenous spread from a primary focus. (See 'Introduction' above.)

●Three forms of ocular TB have been described based on mode of transmission of bacilli to the ocular tissues. Most commonly, ocular TB develops as a result of hematogenous spread of Mycobacterium tuberculosis from pulmonary or extrapulmonary sites. Less commonly, ocular TB can occur as a result of direct ocular infection from an exogenous source. In rare cases, eye involvement can occur as a result of a hypersensitivity reaction to a distant focus of infection. (See 'Clinical manifestations and diagnosis' above.)

●The most common manifestation of intraocular TB is choroidal tubercles. External eye structures that can be involved in ocular TB include the orbit, eyelid, lacrimal gland, conjunctiva, and sclera. TB of these structures can occur as a result of hematogenous spread or via extension of adjacent infection involving the skin or the sinuses. (See 'Clinical manifestations and diagnosis' above.)

●A diagnosis of ocular TB is most often a clinical diagnosis, with ocular findings supported by a consistent risk history, evidence for TB elsewhere (such as the lungs), and/or a positive test for TB infection such as the tuberculin skin test (TST) or an interferon-gamma release assay (IGRA), since culture of eye tissue or fluid is often not possible. A positive TST or IGRA may support a clinical diagnosis of TB, but it does not establish the diagnosis. Conversely, a negative test result does not rule out active TB. (See 'Laboratory evaluation' above.)

●Biopsy specimens may be obtained for histopathologic analysis either from the iris or by retinochoroidal biopsy. Absence of acid-fast bacilli or of caseating necrosis in the biopsy specimen does not rule out ocular TB; in such circumstances, nucleic acid amplification may be useful. (See 'Laboratory evaluation' above.)

●The approach to treatment of ocular TB is generally the same as that for pulmonary TB. In general, for circumstances in which TB is considered strongly as a clinical diagnosis, treatment should not be delayed until culture data become available. The response to therapy can be assessed by the clinical examination and resolution of objective sites of clinical involvement. (See 'Treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Michele Trucksis, who contributed to an earlier version of this topic review.