Continuing Education Activity

Ocular tuberculosis (TB) is a clinical disease caused by Mycobacterium tuberculosis (MTB) that can affect various ocular tissues and present with a wide range of symptoms. The condition can manifest in different parts of the eye, leading to various clinical symptoms. Consideration of ocular TB as a clinical manifestation of extrapulmonary TB, especially in immunocompromised individuals, and diagnosing and initiating treatment promptly is essential to prevent poor patient outcomes. The pathophysiological effects of MTB on the eye can vary depending on the mode of infection, including hematogenous spread from pulmonary or extrapulmonary sites affecting the uveal tract and leading to different forms of uveitis.

Ocular TB requires a thorough evaluation, including several diagnostic tests to confirm the diagnosis, especially in human immunodeficiency virus-infected persons, as these individuals are disproportionately affected by MTB. Given the complexity of ocular tuberculosis management, evidence- and experience-based recommendations have been developed that provide a framework for evaluating and treating ocular TB based on clinical findings, immunologic evidence, and radiologic findings. 

This course provides healthcare professionals with a comprehensive understanding of the evaluation, diagnosis, and management of ocular TB. Participants learn to interpret clinical, immunologic, and radiologic findings to accurately diagnose the condition. The course emphasizes the importance of interprofessional collaboration between ophthalmologists, infectious disease specialists, and radiologists to develop individualized treatment plans. By working together, the interprofessional team can optimize diagnostic accuracy and treatment effectiveness, ultimately improving patient outcomes and preventing complications related to delayed or inadequate treatment.

Objectives:

• Identify the most commonly affected eye tissues in patients with ocular tuberculosis.

• Assess immunologic, radiologic, and clinical findings to confirm a diagnosis of ocular tuberculosis.

• Implement evidence-based treatment protocols for managing ocular tuberculosis, including anti-tubercular therapy.

• Apply interprofessional team strategies to improve care coordination and outcomes in patients with ocular tuberculosis.

Introduction

Ocular tuberculosis (TB) is a clinical disease caused by or associated with Mycobacterium tuberculosis (MTB). MTB has various modes of transmission and can infect virtually any ocular tissue. Much like syphilis' ability to mimic multiple skin conditions, ocular TB should be thought of as "the great imitator" of ocular pathologies.[1] Choroidal tubercles were first anatomically described in 1855 and identified with an ophthalmoscope in 1867. A year after discovering the organism, MTB was identified in the eye in 1883.[2] An autopsy study of miliary TB in 1950 even reported that eye examination exceeded chest radiography in diagnostic sensitivity.[3] 

Since this time, TB has become increasingly rare in Western nations, and advancements in laboratory diagnostic tests have led eye examinations for choroidal tubercles to fall out of favor in current guideline recommendations. Globally, more than 1.7 billion people are estimated to be infected with TB.[4] Additionally, MTB is the leading cause of death from a single infectious agent globally and the leading cause of death among persons living with human immunodeficiency infection.[5] 

Recognition of ocular TB as a clinical manifestation of extrapulmonary TB is critical, as a timely diagnosis can lead to early initiation of antituberculosis therapy and prevent poor patient outcomes.[6] Most cases of ocular TB are presumptive, as getting histological or microbiological evidence of infection is extremely difficult. Also, the ocular disease may be due to direct infection or an immune reaction to MTB. Uniform diagnostic criteria are lacking, and the interpretation of diagnostic modalities may vary globally. However, early detection and prompt management of cases with presumed ocular tuberculosis may lead to good outcomes.[7]

Etiology

MTB can affect the eyes in multiple ways, including:

• Direct ocular infection from an exogenous source, such as contact with the eyelids or conjunctiva (primary ocular TB)
• Hematogenous spread of MTB from a pulmonary focus or extrapulmonary site (secondary ocular TB)
• A hypersensitivity reaction in eye structures exposed to MTB antigens

The most common mechanism of ocular involvement is hematogenous spread from pulmonary TB.[7] Seeding may occur from primary infection or the reactivation of a dormant lesion. MTB spreads by aerosolized droplets. Airborne bacteria are inhaled into the respiratory alveoli, where they encounter alveolar macrophages. Approximately 90% of these infected individuals never develop clinical disease and remain asymptomatic, a state termed latent TB.[8] Of the remaining 10%, approximately 5% will develop the disease within the first few years of exposure. The last 5% may develop symptoms several years later as host immunity wanes.[9] Alveolar macrophages phagocytize the bacteria and release cytokines to recruit circulating monocytes to the site of infection, but MTB escapes eradication by inhibiting the fusion of the macrophage phagolysosome.[10] This allows the bacteria to proliferate in nonactivated and partly-activated macrophages. Eventually, bacteria-laden macrophages disseminate into the lymphatics and venous circulation through erosions in the alveolar epithelium and migrate to oxygen-rich regions of the body, including the lung apex, various organs, and the eye.[11] 

Latent TB infection is defined as evidence of TB infection without evidence of active TB disease clinical manifestations. Detection of latent infection is only achieved by indirect testing of an individual’s immune response to MTB antigen using a tuberculin skin test (TST) or an interferon-gamma release assay (IGRA).[6] Active TB is defined by the British Thoracic Society (BTS) as the range of clinical manifestations that occur in symptomatic individuals infected with MTB. Active TB is distinct from latent TB infection, which is asymptomatic. The BTS has clarified this disease process further, stating that latent TB infection and active TB are a continuum rather than distinct clinical entities.[12][6] This clinical definition suggests that all cases of ocular TB should be considered and managed as active TB disease.[12][6]

Epidemiology

According to the World Health Organization (WHO), about 10.4 million people fall ill, and 1.8 million people die from TB each year.[13] The burden of the disease varies considerably among countries, being 8 to 12 times higher in low-resource countries compared to industrialized countries. Geographically, the majority of TB cases in 2018 were in Southeast Asia (44%), and globally, the top 5 nations were India (27%), China (9%), Indonesia (8%), the Philippines (6%), and Pakistan (6%).[14] Ocular TB cases have been estimated to be less than 1% in the United States, 4% in China, 6% in Italy, and 16% in Saudi Arabia.[15]

Historically, epidemiologic data on ocular TB has varied widely due to the lack of specific diagnostic criteria. In 1967, a study of 10,524 patients at a TB sanitarium reported an incidence of ocular TB in 1.4% of patients.[16] A 1997 study of 100 randomly selected Spanish patients with TB reported that 18% had ocular TB.[17] In patients presenting with uveitis in North India from 1996 to 2001, 9.86% of cases were caused by TB.[18] A prospective case series of 126 patients from Japan with uveitis from 1998 to 2000 reported that 7.9% were due to intraocular TB.[19]

Pathophysiology

The mode of infection can characterize the pathophysiologic effects of MTB on the eye. Patients who present with involvement of lids, lacrimal apparatus, adnexa, sclera, conjunctiva, or cornea are likely to have a primary ocular infection due to direct contact with the eye.[2][20] Hematogenous spread of MTB from pulmonary or extrapulmonary sites most commonly affects the uveal tract, consisting of the iris and ciliary body (anteriorly) and the choroid (posteriorly). Therefore, tubercular uveitis may present as anterior, intermediate, posterior, or panuveitis (granulomatous or nongranulomatous). The choroid receives the highest blood flow per unit of tissue in the body and creates an oxygen-rich environment analogous to the apex of the lung.[21] MTB-laden macrophages deposit in the first available capillary beds upon entering the eye, which leads to posterior uveitis being the most common presentation of ocular TB.[22] Bacilli multiply and incite local inflammation, which manifests as a choroidal tubercle.[23][24]

Tubercles that coalesce or grow large are reclassified as tuberculoma.[25][26] The tubercles and tuberculoma involve all layers of choroidal tissue and are surrounded by obliterated choroidal blood vessels. The lesion may liquefy into a subretinal abscess (see Image. Choroidal Tuberculosis Abscess).[26] The overlying retinal pigment epithelium remains normal in the early stages, but later, it can become disrupted with pigmentation, and the overlying retina may detach. Early intervention may completely resolve the lesion or result in an atrophic scar.[23] Hypersensitivity reactions involving the eye, including phlyctenular keratoconjunctivitis or Eales disease, are theorized to result from an immunologic response to nonviable MTB organisms in ocular tissue.[27] However, the pathophysiologic mechanism is poorly understood.[28][29]

Histopathology

In most cases, intraocular tissue involvement makes biopsy risky and impractical. In rare cases of external disease or anterior segment involvement, a biopsy may be taken for histopathologic analysis. Ziehl-Neelsen acid-fast stained bacilli or caseous necrosis with epithelioid cells and Langerhans giant cells suggests ocular TB.[30] Bacteria in multinucleated giant cells are inconsistently detected by histologic staining.[29] As a result, biopsy results and reliability may be variable.

History and Physical

Clinical History

In recent years, those at the most significant risk of developing ocular TB are immunocompromised individuals. Extrapulmonary involvement is seen in more than 50% of patients who have acquired immunodeficiency syndrome and TB.[31] Others at risk include individuals taking immunosuppressive therapy, healthcare workers, homeless and prisoner populations, immigrants from endemic countries, and patients with comorbid alcohol use disorder, chronic liver disease, chronic hemodialysis, diabetes, malignancy, or silicosis.[32]

Therefore, clinicians should obtain a comprehensive medical and social history, specifically inquiring about the patient's human immunodeficiency virus status when suspecting ocular TB. This information is especially critical when interpreted in conjunction with a history of nonspecific symptoms of pulmonary TB (eg, chest pain, chronic cough, hemoptysis, fever, anorexia, night sweats, and unexplained weight loss), travel to a TB-endemic country, interaction with an active TB patient, or prior positive radiographic findings, tuberculin skin test, or interferon-gamma release assay.

Ocular Tuberculosis Presentation

Ocular TB can have multiple manifestations. Patients may report acute or chronic inflammation that is unilateral or bilateral. Patients may also report headaches, flashes, floaters, or red eyes. Choroidal tubercles near the macula may present with diminished visual acuity and photosensitivity. The lack of visual symptoms does not rule out ocular TB, as small tubercles in the peripheral fundus may be asymptomatic.[23][33]

Ocular TB is a great imitator of various ocular pathologies. Therefore, a clinician should consider ocular TB along with other differential diagnoses in patients presenting with ocular symptoms. Ocular TB may be extraocular, involving structures on or around the eye, or intraocular, involving structures inside the eye. Extraocular and intraocular clinical signs of ocular TB are findings that may be observed according to the anatomical location.

Extraocular Tuberculosis

Orbit clinical features

The involvement of the orbit is most common in children.[20] Patients may present with proptosis, eyelid swelling, intermittent periorbital swelling, headache, epistaxis, decreased vision, visual field abnormalities, chemosis, Marcus Gunn pupil(s), epiphora, and increased orbital resistance to retropulsion.[34][35] Other orbital features include cold abscess, orbital periostitis, bony destruction, extraocular muscle involvement, soft tissue tuberculoma, and orbital apex syndrome.[36][37]

Eyelid and lacrimal gland clinical features

Eyelid involvement is also most common in children. Eyelid TB can present as lupus vulgaris with reddish-brown "apple-jelly" nodules, a lid abscess, chronic blepharitis, or atypical chalazion.[15][38] Other features include recurrent chalazion, chronic blepharitis, and diffuse infiltration simulating preseptal cellulitis.[37] TB involving the lacrimal gland presents as symptomatic dacryoadenitis or lacrimal gland abscess indistinguishable from other bacterial infections.[39]

Conjunctivae clinical features 

Primary tuberculous conjunctivitis is a chronic disease leading to scarring. Patients present with ocular redness, discomfort, and mucopurulent discharge with regional lymphadenopathy.[40] Other conjunctival manifestations include subconjunctival nodules, phlycten, ulcers, tuberculomas, and polyps.[39]

Corneal and scleral clinical features

Phlyctenular keratoconjunctivitis, an inflammatory nodule at the limbus, or interstitial keratitis are frequent clinical presentations associated with corneal TB. The phlyctenule is believed to be a hypersensitivity reaction to MTB antigen, and it may erode the epithelia and create photophobia, redness, and tearing. Tuberculous interstitial keratitis presents as a unilateral sectoral, peripheral stromal infiltrate with vascularization.[41] Other features include disciform keratitis, corneal erosion, and corneal ulcer.[42]

Tuberculous scleritis is challenging to diagnose outside the context of active systemic TB. Scleritis is usually chronic, does not respond to anti-inflammatory treatment, can be necrotizing, and usually presents anteriorly; posterior scleritis involvement is rare.[43] Other manifestations include nodular or diffuse anterior scleritis, sclerouveitis, sclerokeratitis, and scleromalacia.[39]

Intraocular Tuberculosis

Anterior and intermediate uveitis clinical features

TB involving the uvea is usually granulomatous. Anterior uveitis may present with iris granulomas with broad-based posterior synechiae, Koeppe and Busacca nodules, mutton-fat keratic precipitates on the posterior aspect of the cornea, or a complicated cataract.[44][45] In children, band keratopathy can occur. Intermediate uveitis usually presents with unilateral or bilateral asymmetry and resembles par planitis.[46] Features include mild-to-moderate vitritis with snowballs, cystoid macular edema, snow banking, peripheral vascular sheathing, or peripheral retinochoroidal granulomas.[23][47]

Posterior uveitis clinical features

Ocular TB most commonly presents as posterior uveitis. Common patterns include a solitary tubercle (see Image. Choroidal Tubercle), multiple tubercles, miliary choroidal tubercles, tuberculoma, tubercular subretinal abscess, and multifocal choroiditis (see Image. Tubercular Choroidal Granuloma). Tubercles are white-yellow nodules that typically reside in the posterior pole. Usually, fewer than 5 tubercles are present, but there may be as many as 50 or 60. Choroidal tubercles, tuberculoma, and subretinal abscess are thought to be caused by direct infection by MTB.[46] A patient with choroidal tuberculomas due to military TB, diabetic macular edema, and proliferative diabetic retinopathy who responded well to anti-vascular endothelial growth factor therapy, pan-retinal photocoagulation, and ATT has been reported.[24] 

Noncontiguous, multifocal choroiditis may progress to a diffuse, contiguous pattern called a serpiginous-like lesion. This lesion resembles serpiginous choroiditis (multifocal serpiginous choroiditis); in contrast to classic serpiginous choroiditis, it does not extend to the disc, tends to spare the fovea even when the macula is involved, and it is more multifocal and pigmented (see Image. Tubercular Serpigionous-Like Choroiditis). The vitreous in tuberculous serpiginous-like choroiditis (TBSLC) is usually inflamed, whereas no vitreous inflammation is present in serpiginous choroiditis.[7][48] Gupta and colleagues described presumed TBSLC as having 3 morphological variants.[49] The "multifocal progressive choroiditis" started as multiple distinct patches of choroiditis that had "wave-like progression," and these eventually coalesced, resulting in diffuse choroiditis simulating serpiginous choroiditis. Some of these cases had retinal vasculitis.[49] 

The second variant of presumed TBSLC manifested with diffuse plaque-like or ameboid choroiditis that initially resembled serpiginous choroiditis. Some of these patients may have optic disc edema and vitreous snowballs.[49] The mixed variant has a different presentation in the opposite eye. All such patients had strong TST, an induration of 20 mm or more after the Mantoux test using 5 tuberculin units or necrosis, and chest x-ray findings such as hilar lymphadenopathy or infiltrates.[49] A few such patients also had acid-fast bacilli on sputum examination, and histopathology of biopsied hilar or cervical lymph nodes showed caseation necrosis. The polymerase chain reaction for IS6110 in aqueous (ie, eyes with significant anterior chamber reaction) or vitreous was positive in patients with presumed TBSLC who underwent this test.[49] All such patients responded favorably with antituberculin therapy and oral corticosteroids.[49] However, whether TBSLC is due to direct infection of choroid by MTB (needing ATT) or a hypersensitivity reaction to TB (needing systemic steroids and or immunomodulatory therapy) is still being explored.[50] Choroiditis and tuberculoma may be associated with choroidal neovascular membranes.[51]

Retina clinical features

TB of the retina is almost always a result of the extension from choroidal disease. Rarely does hematogenous spread affect the retina before the choroid. Retinal lesions may include focal tubercles, subretinal abscesses, focal retinitis, or diffuse retinitis. Occlusive retinal vasculitis may occur and induce neovascularization. Exudative retinal hemorrhagic periphlebitis with uveitis is highly suggestive of intraocular TB.[52] Gupta et al reported approximately 50% of patients with tubercular retinal vasculitis have active or healed choroiditis patches under retinal vessels. Patients may also have snowball opacities in the inferior vitreous cavity, optic disc edema, or macular star.[40] Patients with tubercular retinitis may have periarterial plaques (ie, Kyrieleis arteriolitis).[53]

Optic nerve clinical features

Optic neuropathy develops from direct infection induced by TB or a hypersensitivity reaction to the infectious agent. This condition may present as an optic nerve tubercle, papillitis, neuroretinitis, or papilledema. Optic nerve swelling and posterior tuberculous scleritis have been reported.[54] The optic nerves of both eyes may be affected by toxic optic neuropathy due to ethambutol or isoniazid.[55] Papilledema and secondary optic atrophy in both eyes may result from increased intracranial pressure due to tubercular meningitis, obstructive hydrocephalus, or edema due to multiple tuberculomas in the brain.[56]

Endophthalmitis

Tubercular subretinal abscesses may burst into the vitreous cavity and present as endophthalmitis. Panophthalmitis and orbital cellulitis may also occur.[23][33][23]

Evaluation

Due to the various ocular TB manifestations, a clinical diagnosis is quite challenging. Diagnosing ocular TB begins with a complete history, physical examination, and fundoscopic exam. Gupta et al identified broad-based posterior synechiae, retinal vasculitis without choroiditis, retinal vasculitis with choroiditis, and serpiginous-like choroiditis as features of ocular TB with specificities of 93%, 97%, 99%, and 98%, respectively. However, all these findings have poor sensitivities.[52] Other highly suspicious lesions include choroidal granulomas (granulomatous uveitis), multifocal serpiginous choroiditis, occlusive retinal periphlebitis, or vasculitis.[7][41][43][48][52][54][57][58] 

The evaluation of ocular TB should include:

• Ocular investigations: Ocular imaging includes anterior segment photography, optical coherence tomography of the macula, fundus fluorescein angiography (FFA), indocyanine green angiography, and ocular ultrasound.[59][60] Diagnosing ocular tuberculosis often depends heavily on the clinical features and the ocular findings.
  • Optical coherence tomography of the macula can reveal intraretinal fluid in cystoid macular edema associated with intermediate uveitis. Inflammatory choroidal neovascular membranes may be associated with subretinal fluid and finger-like projection from choroidal neovascular membranes to the outer retina (pitchfork sign).[61] Bacillary layer detachment has also been reported in TBSLC.[62] The tubercular choroidal granuloma may show the characteristic contact sign adjacent to it, denoted by contact between the outer retina and the retinal pigment epithelium near an area with subretinal fluid.[63] 
  • FFA shows early hypofluorescence and late hyperfluorescence in active choroiditis. Window defects and block fluorescence denote healed choroiditis. FFA helps to rule out other differential diagnoses.
  • Ocular ultrasound helps rule out posterior scleritis (subtenon fluid) and ocular malignancies (eg, amelanotic choroidal melanoma).
  • Fundus autofluorescence shows hyperautofluorescence with ill-defined margins in areas of active choroiditis, whereas healed choroiditis shows hypoautofluorescence with sharp borders.[64][65] 
  • Anterior chamber fluid or vitreous humor sample can be used in molecular diagnostic testing via polymerase chain reaction (PCR). The most common target for PCR to diagnose tuberculosis is IS6110. Other targets include MPB64 or MPT64 and protein B.[66][67] PCR is becoming the testing method of choice because of better accuracy and faster test results than culture. Results from a case-control study of 22 patients with known TB uveitis demonstrated a 77.2% sensitivity and 92.1% specificity for PCR detection of MTB in aqueous and vitreous aspirates.[68] The positivity of PCR may not signify the presence of actively multiplying live microorganisms. PCR for tuberculosis was positive in the subretinal fluid of cases with retinal detachment and those with tuberculin skin test (TST) positivity.[69] Thus, the results of PCR have to be correlated with clinical features, specifically in countries with high endemicity.

• Laboratory studies: TST and IGRA evaluate the patient's cellular immune response to MTB; both tests have strengths and limitations.[70] 
  • TST can be falsely positive after Bacille Calmette-Guérin (BCG) vaccinations and other mycobacteria infections.[71] Skin induration at the injection site is checked 48 to 72 hours after intradermal injection of tuberculin.
  • Tests for interferon-gamma release assay (eg, T-SPOT and QauntiFERON-TB Gold) are more specific, but false-positive cases can occur in low-endemic areas.[72] Contrary to the tuberculin skin test, IGRA is an in vitro test. The WHO noted that "there is insufficient data and low-quality evidence on the performance of IGRAs in low- and middle-income countries, typically those with a high TB and/or HIV burden."[73] The same WHO policy statement also mentions that "neither IGRAs nor the TST should be used for the diagnosis of active TB disease."[73] 
  • In patients from tuberculosis-endemic countries, the role of TST and IGRA is debatable as most of such patients already have exposure to MTB and BCG vaccination. The positivity of these tests suggests latent TB with exposure to MTB and does not denote a diagnosis of active tuberculosis in a patient from an endemic country.[73] 
  • The WHO recommends using GeneXpert MTB/RIF assay, an automated real-time PCR, to rapidly and simultaneously detect TB and rifampicin resistance in <2 hours. This is a nucleic acid amplification technique. Xpert MTB/RIF assay is currently used with sputum samples; the Food and Drug Administration has not approved it for use with ocular fluids.[20][58]

• Imaging studies: Up to 60% of cases with extrapulmonary TB may not have evidence of lung TB and may have a normal chest x-ray.[74][75][50] Chest x-ray or high-resolution computed tomography (CT) of the chest demonstrates findings of pulmonary TB, including hilar lymph node enlargement, pulmonary infiltrates, and cavitation.[76] 
  • High-resolution computed tomography (HRCT) chest has a better sensitivity (96%) of picking up active pulmonary tuberculosis than chest x-rays (48%).[77][78] Another study noted that "the sensitivity, specificity, positive predictive value, negative predictive values of thorax HRCT in determining the activity of the illness (pulmonary tuberculosis) were found as 97%, 86.7%, 94.2%, and 92.9%, respectively."[77] 
  • Magnetic resonance imaging is preferred for TB of central nervous system and tuberculous spondylitis.[78] 
  • Positron emission tomography-computed tomography (PET-CT) may help in evaluating the response of pulmonary and extrapulmonary TB to antitubercular therapy.[79] 
  • Neuroimaging should be done in patients with choroidal tuberculoma to rule out brain involvement.[80] 

• Biopsy: A fine-needle aspiration biopsy or tissue biopsy attempt may be made as the culture of MTB is the gold-standard diagnosis.[23] Demonstration of acid-fast bacilli also confirms the diagnosis of tuberculosis. However, samples are difficult to collect, impose significant risk on patients, and culture results may take up to 10 weeks.[81]

Presumptive Intraocular Tuberculosis Criteria

A definitive diagnosis of TB uveitis is only made when MTB, or its deoxyribonucleic acid, is isolated from ocular fluids. In most cases, ophthalmologists are unable to make a definitive diagnosis. Still, the patient may have ophthalmological features consistent with ocular TB, confirmed TB exposure (positive TST or IGRA), or evidence of a tubercular lesion on a chest x-ray or CT scan. If 1 of these features is present, the diagnosis of "presumed ocular TB" should be made, and treatment should be offered.[19][70][82][83] However, a negative result on these tests does not rule out the disease. TSTs often yield negative results in patients with disseminated TB [84] and about 60% of patients with extrapulmonary TB have no evidence of pulmonary TB.[85] Gupta and colleagues classified intraocular TB into 3 types of presumptive intraocular TB, comprising confirmed, probable, and possible criteria.

Confirmed intraocular tuberculosis

Both of the following findings should be present:

• A minimum of 1 clinical sign suggestive of intraocular tuberculosis should be present. The clinical signs include:
  • Anterior chamber or vitreous cells with or without posterior synechia
  • Vitreous snowballs
  • Perivascular cuffing
  • Single or multiple choroidal tuberculoma with or without subretinal fluid
  • Optic nerve head granuloma with or without neuroretinitis
  • Subretinal abscess
• Microbiological confirmation of tuberculosis bacilli in the sample for ocular fluids or tissue [57] 

Probable intraocular tuberculosis

All 3 criteria must be present together, including:

• A minimum of 1 clinical sign suggestive of intraocular tuberculosis should be present. Other causes should be excluded.
• Evidence of chest x-ray consistent with TB infection or clinical evidence of extraocular TB or microbiological confirmation from sputum or extraocular sites
• At least 1 of the following:
  • Documented exposure to TB
  • Immunological evidence of TB infection [57]

Possible intraocular tuberculosis

This category requires the presence of all of the following first, second, and third criteria or both the first and fourth criteria:

1. At least 1 clinical sign suggestive of intraocular TB with other etiologies excluded
2. Chest x-ray not consistent with TB infection and no clinical evidence of extraocular TB
3. At least 1 of the following:
   • Documented exposure to TB
   • Immunological evidence of TB infection
4. Evidence of chest x-ray consistent with TB infection or clinical evidence of extraocular TB but none of the characteristics given in the third criterion [57]

Presumptive intraocular tuberculosis treatment

Treatment of presumed ocular tuberculosis begins with an ATT trial. Patients are evaluated for response to a 4-drug course of isoniazid, rifampicin, ethambutol, and pyrazinamide. After 4 to 6 weeks of treatment, a positive response is taken as evidence for ocular TB, and treatment should be continued.[23] The possible side effects of ATT, including hepatotoxicity and toxic optic neuropathy, make the clinical decision to start ATT challenging, particularly when a definitive diagnosis of TB is not reached.[86]

Treatment / Management

In general, treating ocular tuberculosis is the same as treating extrapulmonary TB. Treatment consists of a 4-drug regimen administered in 2 phases: rifampicin, isoniazid, pyrazinamide, and ethambutol daily for 2 months, followed by rifampicin and isoniazid for 4 or more months. The total duration of ATT for ocular TB varies from 6 to 19 months.[87] ATT for at least 9 months in ocular TB may reduce the likelihood of recurrence by 11 times.[88] Bansal and colleagues evaluated 360 patients with active uveitis (ie, cellular reaction in the anterior chamber with or without keratic precipitates and active vitreous inflammation, retinal vasculitis, choroiditis, or neuro-retinitis) and positive TST (induration of ≥10 mm), for whom causes other than TB were excluded.[89] They found that adding corticosteroids to ATT reduced the chances of recurrence of ocular inflammation.[89]

If the patient fails to respond in 3 to 4 weeks, multidrug-resistant TB should be considered, and management should continue in conjunction with an infectious disease specialist.[90] Multidrug-resistant TB is defined as resistance to at least isoniazid and rifampicin. Preextensively drug-resistant tuberculosis is defined by the United States Centers for Disease Control (CDC) as TB "caused by an organism that is resistant to isoniazid, rifampin, and a fluoroquinolone OR by an organism that is resistant to isoniazid, rifampin, and a second-line injectable (eg, amikacin, capreomycin, and kanamycin)." Extensively drug-resistant tuberculosis is defined by CDC as TB "caused by an organism that is resistant to isoniazid, rifampin, a fluoroquinolone, and a second-line injectable (eg, amikacin, capreomycin, and kanamycin) OR by an organism that is resistant to isoniazid, rifampin, a fluoroquinolone, and bedaquiline or linezolid."

Most authorities agree that choroidal tubercle, tuberculoma, and subretinal abscess need ATT as they are considered direct infections by MTB.[7][91] Usually, these will regress with ATT alone.[92] Sometimes, oral corticosteroids are added to reduce inflammation. However, whether other forms of presumed ocular TB, including TBSLC, vitritis, retinal vasculitis, and neuroretinitis, are due to active invasion by MTB or a hypersensitivity reaction to MTB or due to remote immune priming is still being explored.[93] Rao et al described the acid-fast bacilli in the retinal pigment epithelium in a patient with panuveitis; the real-time PCR was positive for IS6110.[94]

Steroids are given to reverse insult from granulomatous inflammation and to help prevent a delayed-type hypersensitivity response to TB antigens.[95] They must be used judiciously with ATT, not alone, due to the concern of inducing latent disease reactivation or prolonging the active growth of bacilli in the eye.[23] Rifampicin induces hepatic steroid metabolizing enzymes and will suppress the therapeutic effect of corticosteroids. Increasing the corticosteroid dosage when in concomitant use with rifampicin may be necessary to maintain effectiveness.[96]

Paradoxical worsening after initiation of ATT has been reported. This phenomenon is thought to result from a Jarisch-Herxheimer-like reaction as the immune system gains increased exposure to bacterial antigens after treatment, releasing pro-inflammatory cytokines.[97] Cotreatment with corticosteroids can circumvent this phenomenon.[23] 

Agarwal et al found that tubercular serpiginous-like choroiditis with poor initial best-corrected visual acuity and foveal and optic disc involvement was associated with inadequate response to therapy. They also noted that a higher grade of lesion opacity at baseline may be associated with a higher risk of poor therapeutic response and paradoxical worsening with treatment.[98] In addition to ATT, TB delayed hypersensitivity retinal vasculitis (Eales disease) patients with retinal new vessels also benefit from peripheral scatter retinal laser treatment to decrease the ischemic drive for retinal neovascularization.[27] Choroidal neovascular membranes associated with choroidal tuberculosis may respond well to anti-vascular endothelial growth factor agents.[51] Large choroidal tuberculomas may also respond well to intravitreal anti-vascular endothelial growth factor agents.[99]

The Collaborative Ocular Tuberculosis Study Recommendations

Due to a lack of high-level evidence to guide clinicians in the management of tubercular uveitis, the Collaborative Ocular Tuberculosis Study (COTS), an international expert-led consensus initiative, developed evidence- and experience-based recommendations regarding initiation of antitubercular treatment ATT and adjunctive anti-inflammatory and immunosuppressive therapy for the various subtypes of tubercular choroiditis (eg, TBSLC, tuberculoma, and tubercular unifocal or multifocal choroiditis). However, it must be noted that most of these are opinions of various experts and are not a result of randomized control trials or studies.[100][101][102][103][104]

Due to its high association with TB, TBSLC can be treated with ATT with only a single positive immunologic test, either a TST or IGRA, without radiologic evidence of TB. However, the patient's background should be factored into the clinical evaluation. In a TB-endemic region, an isolated positive TST, despite negative IGRA, is sufficient to initiate ATT. This is a testament to the strong predictive value of a positive TST for ocular TB in patients of endemic areas with the serpiginous-like choroiditis phenotype. However, the positivity rate of TST in such areas may be too high, and the side effects of ATT must be considered before starting.[50][72][105] Another factor that complicates the clinical judgment to start ATT in TBSLC is its very similar clinical appearance to serpiginous choroiditis, which is an autoimmune phenomenon and needs immunosuppression alone as therapy.

In non endemic regions, however, a positive IGRA is required to initiate ATT because of its increased specificity for TB. COTS guidelines further suggest that a tuberculoma is highly representative of tubercular uveitis. As such, ATT should be initiated if there is any immunologic evidence for TB. In endemic regions, radiographic evidence alone may be sufficient to support treatment initiation.[104] In contrast to TBSLC and tuberculoma, the unifocal and multifocal choroiditis phenotypes have a relatively weaker association with TB. As such, immunologic evidence and radiologic findings suggestive of healed or active pulmonary TB are necessary to support the initiation of ATT for these phenotypes.[104]

Furthermore, the COTS recommends that oral corticosteroids be started concomitantly with or soon after initiation of ATT to control the inflammatory response of infection in patients with TBSLC, tuberculoma (except in the setting of active systemic TB), and tubercular unifocal or multifocal choroiditis. Clinicians can justify starting systemic corticosteroid-sparing immunosuppressive therapy for patients with TBSLC and tubercular unifocal or multifocal choroiditis who have recurrent inflammation while tapering the dose of oral corticosteroids. Potential drug interactions when combining ATT with immunosuppressive agents must always be considered.[104]

The COTS developed the COTS Calculator, an online clinical scoring system for initiation of ATT in patients with ocular TB, which was derived from expert consensus data. This scoring system can be accessed online at https://www.oculartb.net/cots-calc. The calculator will generate a score of 1 to 5 by inputting patient details and relevant clinical findings.[100] Interpretation of generated scores is as follows:

• 1: Very low probability for most experts to initiate ATT (<20%)
• 2: Low probability for most experts to initiate ATT (21% to 40%)
• 3: Mixed probability for most experts to initiate ATT (41% to 60%)
• 4: High probability for most experts to initiate ATT (61% to 80%)
• 5: Very high probability for most experts to initiate AT (81% to 100%)

Differential Diagnosis

Sarcoidosis, syphilis, toxoplasmosis, toxocariasis, and fungal infections can present as panuveitis with choroidal involvement and should be considered in the differential diagnosis of tubercular uveitis.[106] Tubercular anterior uveitis in children may mimic juvenile idiopathic uveitis. In patients presenting predominantly with retinal vasculitis, Eales disease should be considered. Eales disease is characterized by overlapping stages of retinal vasculitis, vascular occlusion, and retinal neovascularization (see Image. Eales Disease). The cause of Eales disease remains unknown, but there is speculation it is a delayed retinal hypersensitivity reaction to MTB. Prior study results have shown patients with Eales disease have consistently been found more likely to test positive for MTB than control populations.[107]

Ophthalmologists should also consider the diagnosis of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) or classic serpiginous choroiditis in patients presenting with TBSC. APMPPE is a rare and poorly understood inflammatory chorioretinopathy that predominantly affects the macula. Evidence supports a primary vasculitis or a delayed-type hypersensitivity reaction to various pathogens, including MTB.[108] The acute phase of APMPPE presents with multifocal flat, gray-white lesions with a placoid appearance found at the level of the posterior pole in the retinal pigmented epithelium.[109] 

Fluorescein angiography reveals early hypofluorescence and late, irregular hyperfluorescence. Similarly, the early stages of TBSC can resemble APMPPE as it may present with yellowish-white plaque-like lesions that appear hypofluorescent early and hyperfluorescent late on fluorescein angiography.[49] However, the individual discrete lesions of TBSC progressively enlarge and converge into diffuse, contiguous choroiditis with an active leading edge.

Prognosis

The immediate use of ATT in ocular TB is associated with good outcomes. ATT was noted to reduce the recurrence of TBSLC in a study.[48] Most lesions completely regress and leave minimal residual damage. Depending on the ocular TB, some lesions resolve as focal chorioretinal scars. However, lesions in the context of acquired immunodeficiency syndrome have been reported to progress despite ATT.[106]

Complications

Clinicians should also know that ATT medications are associated with adverse ocular effects. Ethambutol causes dose-dependent ocular toxicity, eg, optic neuritis, photophobia, extraocular muscle paresis, red-green dyschromatopsia, central scotomas, and disc edema.[110] Patients receiving doses of more than 15 mg/kg/day require an ophthalmic evaluation every 4 weeks. Symptoms that occur typically resolve in 3 to 12 months.[34] Most patients with TBSLC have pigmented scars over the posterior pole after healing from choroiditis. However, the visual acuity and the fovea may be preserved till late disease. Recurrence is another issue with TBSLC. Healed ocular choroidal tuberculosis may be associated with a choroidal neovascular membrane that may respond well to anti-VEGF agents.[51] 

Deterrence and Patient Education

Patients diagnosed with ocular TB should be counseled on the 6-month duration of treatment and the health consequences if not completed. Directly observed treatment is a strategy WHO recommends to increase treatment adherence, where a clinician or family member witnesses the patient taking treatment.

Pearls and Other Issues

Clinicians should bear in mind the following factors when managing ocular TB:

• The most common mechanism of ocular involvement is hematogenous spread from pulmonary TB.
• Ocular TB can involve any part of the eye and can occur with or without evidence of pulmonary or extrapulmonary TB disease.
• The most common ocular TB manifestation is granulomatous uveitis; the most common presentation is posterior uveitis.
• Choroidal granulomas, occlusive retinal vasculitis, and multifocal serpiginous-like choroiditis are the most typical lesions related to ocular TB.
• The gold standard for diagnosis is the identification of MTB in culture. However, this is rarely possible. PCR of ocular fluid is a recent alternative to cultures but is not widely available. Diagnosis, in most cases, is “presumed ocular TB.” Ocular findings must be supported in context with risk factor history, chest radiography findings, and TST or IGRA testing. Negative tests do not rule out ocular TB.
• Treatment of ocular TB is the same as for pulmonary TB, and concomitant steroid therapy is often required.

Enhancing Healthcare Team Outcomes

A management approach involving physicians, advanced practitioners, nurses, pharmacists, and other health professionals is essential to enhance patient-centered care, outcomes, patient safety, and team performance related to ocular TB. Given that MTB is the leading infectious disease killer of individuals with human immunodeficiency virus/acquired immunodeficiency syndrome worldwide, healthcare professionals should be cognizant of the potential extrapulmonary complication of TB, particularly its spread to ocular tissue.

Physicians and ophthalmologists play a pivotal role in educating fellow clinicians and healthcare professionals about the possibility of ocular TB and its visual implications if undiagnosed. They should ensure that the retinal examination becomes a part of the initial workup for all patients with a CD4 count of less than 100 cells/µL. Furthermore, interprofessional communication and care coordination among healthcare clinicians are critical in referring TB and HIV-infected individuals to infectious disease specialists for managing medical treatment. Nurses and pharmacists also have vital roles in administering TST to HIV-infected patients and should be actively involved in the care team.

Local health officials should be contacted if an individual with HIV or any patient tests positive for TB infection, as the majority of states mandate reporting confirmed TB to the proper authorities within 24 hours. By leveraging the expertise of physicians, ophthalmologists, advanced clinicians, nurses, pharmacists, and other health professionals, a collaborative and proactive approach can be established to enhance patient-centered care, improve outcomes, prioritize patient safety, and optimize overall team performance in addressing ocular TB and its implications for individuals coinfected with HIV/AIDS.