Although any part of the eye can be involved, some signs are more likely to represent intraocular TB.9,10 The most common clinical presentation appears to be posterior uveitis, followed by anterior uveitis, panuveitis, and intermediate uveitis.1,11 According to Gupta and colleagues,12 who are from a TB endemic area, ocular signs consistent with intraocular TB may be assumed in the presence of cells in anterior chamber or vitreous along with:

• 1.

  Broad posterior synechiae;

• 2.

  Retinal perivasculitis with or without discrete choroiditis/scars;

• 3.

  Multifocal serpiginoid choroiditis;

• 4.

  Choroidal granuloma (single or multifocal);

• 5.

  Optic disk granuloma;

• 6.

  Optic neuropathy.

Of all the signs listed above, broad posterior synechiae, retinal vasculitis with or without choroiditis/scars and tuberculous multifocal serpiginoid choroiditis showed high specificity.12

Intraocular TB may present with a wide spectrum of clinical findings,5 many of which are less suggestive than those mentioned above. In non-endemic areas, there were no uveitis features characteristic of TB uveitis and a wide range of manifestations was seen ranging from non-granulomatous anterior uveitis to occlusive retinal vasculitis.13

In non-TB-endemic areas, broad or extensive posterior synechiae occur much more frequently in eyes with HLA-B27 or sarcoid-associated uveitis than intraocular TB and so make this particular sign may be less predictive in such contexts.14 In non-endemic areas, the most common ocular features described were diverse but retinal occlusive vasculitis and serpiginoid choroiditis were common.15,16

Multifocal serpiginoid choroiditis and Eales’ disease (a form or retinal vasculitis) are two entities which are closely associated with a tuberculous etiology.17–20

According to the clinical symptoms and the probability of the disease we propose:

Not to routinely include tuberculosis screening in the following situations:

• 1.

  Patients with a known diagnosis (HLA B27 positive, VKH, etc.), unless prolonged immunosuppression or biologic treatment is anticipated;

• 2.

  First episode of anterior mild uveitis;

To include tuberculosis screening:

• 1.

  Uveitis of unknown etiology, recurrent or not responding to conventional therapy;

• 2.

  Ocular findings highly suggestive of ocular TB;

• 3.

  Before immunosuppression, particularly before biologic agents.

When tuberculosis diagnosis is considered, the screening process for active tuberculosis requires a combination of a detailed medical history, chest radiology and sputum collection facing respiratory symptoms or abnormal radiology suggestive of pulmonary tuberculosis.

If there are no other signs of active tuberculosis, immunological memory tests against M. tuberculosis (tuberculin skin and/or interferon gamma test) should be performed in the same way as screening for latent tuberculosis.26

Ocular diagnosis is confirmed following the identification of M. tuberculosis in one of the ocular products collected.

When that is not possible and the patient presents signs suggestive of ocular tuberculosis in association with IGRA or TST positivity (≥10mm in immunocompetent patients and ≥5mm in immunocompromised patients) or chest CT suggestive of untreated TB sequelae, active TB should be assumed and patients should start an anti-tuberculosis regimen.27

Gupta proposed a classification of intraocular tuberculosis divided in “Confirmed IOTB”, Probable IOTB” and “Possible IOTB” (Table 4).12

A 4-drug anti-tuberculosis treatment (isoniazid, rifampicin, ethambutol, and pyrazinamide) is proposed over a period of 6–9 months. Factors affecting the treatment outcome in patients with presumed ocular tuberculosis on anti-tubercular therapy (ATT) were analyzed in a retrospective review (the largest on this subject, involving 175 patients) at a tertiary referral eye care center in a low endemic area. Failure was defined as recurrence of inflammation within 6 months of completion of ATT. It was found that patients with intermediate uveitis or panuveitis and those on immunosuppressive therapy had greater tendency for treatment failure while those with more than 9 months of ATT had a lower likelihood of failure.28 A decision to start treatment implies that it is maintained for a period of at least six months, even if there seems to be no clinical response after two months.19

From the moment a decision to treat is made, treatment should not be stopped because of lack of response, unless other diagnosis has been made.29 The lack of response can be due to an immune reaction that needs anti-inflammatory treatment.

There seems to be no benefit in TB prophylaxis in regard to uveitis control.30

Treatment efficacy versus failure has been difficult to define. Recent studies31 have proposed that failure be defined as inability to taper oral corticosteroids to less than 10mg/day or topical steroids to less than twice/day, inability to stop oral immunosuppressive agents as well as persistence/recurrence of inflammation within the first 6 months of completion of tuberculosis treatment.

Patients should be reviewed at the end of the initiation phase (two months) and at the end of treatment (6–9 months).13 The revision should include:

• 1.

  Obvious TB lesions (e.g. conjunctival or choroidal granuloma), looking for indications of lesion reduction with progressive atrophy and pigment mobilization.10

• 2.

  Any uveitis compatible with TB (positive TST or IGRA tests) but no obvious ocular TB lesion and no evidence of systemic disease, signs of reduction in inflammatory response and/or ease of titration of anti-inflammatory drugs (e.g. corticosteroids):32,33

  • a.

    patients with idiopathic uveitis and a positive IGRA test have been shown to react favorably to antituberculosis treatment with improvement in ocular inflammation, even though only a small minority had documented (prior) tuberculosis or a history of exposure14;

  • b.

    previous work has shown resolution of inflammation after TB treatment in about 70% of patients, a change in the nature of their inflammation in 18% and no benefit in 11%13;

  • c.

    in the example of serpiginous-like choroiditis, antitubercular therapy significantly reduced recurrences. Lesions responded to combined antitubercular and steroid therapy, usually spared the fovea and had good final visual acuity.18

• 3.

  In any case, bear in mind:

  • d.

    response to TB treatment may be masked by concomitant anti-inflammatory treatment1;

  • e.

    the natural course of this ocular disease may be indolent or characterized by an alternating exacerbation-remission course.

In addition to the aforementioned and mandatory reviews at two months after initiation of ATT and at the end of treatment, patients should also be assessed every two to three months for:

• 1.

  Maintenance of inflammatory control–remission;

• 2.

  Absence of corticosteroid dependence;

• 3.

  Reduction in disease flare-up or recurrence rate (lower severity, longer disease-free periods).18

Follow-up is otherwise identical to uveitis entities unrelated to TB, being based essentially on disease severity.34 Such involvement may be assessed in the following terms:

• 1.

  Is there any threat to central vision?

• 2.

  Is the disease progressing?

• 3.

  What is the patient's immune status (immunocompetent/immunosuppressed)?

• 4.

  Is there the possibility of a masquerade syndrome (e.g. other infectious disease or neoplasm)?

Drug-associated toxic optic neuropathy is a rare but vision-threatening condition. Diagnosis is made based on an extensive case history and careful clinical examination. The examination findings include varying decrease in vision, normal pupillary reflexes and extraocular muscle function, and unremarkable fundoscopy, although swollen optic discs may be found in the acute stage of the optic neuropathy. Other important findings suggestive of toxic optic neuropathy include decreased color vision and cecocentral visual field defects. It is therefore of paramount importance to identify any contributing factor for optic nerve toxicity so that they may be properly addressed in any patient with worsening or non improving signs or symptoms of visual disfunction.35

Prospective studies of ocular toxicity in patients receiving ethambutol have been conducted as a part of directly observed treatment strategy. Ethambutol has been shown to cause ocular toxicity at standard doses (>15mg/kg/day), making early recognition of ocular symptoms a priority to prevent unnecessary delay in diagnosis and irreversible visual loss.36

The incidence and prognostic factors of ethambutol-related optic neuropathy (EON) have been addressed in retrospective studies. One such study found a prevalence of 1.29% (62 out of 1004 patients) with visual impairment and subsequent diagnosis of EON. Sixteen patients (26%) were being followed for over 6 months when symptoms developed. Of these, eight patients (50%) showed visual improvement (an increase in visual acuity of ≥2 Snellen lines) after ethambutol was discontinued. The other eight patients (50%) showed no visual improvement. When analyzing multiple factors between the patients with and without visual improvement (body weight, daily dose of ethambutol, duration of ethambutol use, cumulative dose of ethambutol, renal function, underlying disease such as diabetes mellitus or hypertension, and initial visual acuity) there was no statistically significant difference and as such no obvious prognostic factors were found to facilitate visual recovery.31

It is advisable to obtain informed consent – toxicity may occur with any treatment dose despite regular ophthalmic follow-up, and subsequent visual loss may be severe, bilateral and irreversible.

• 1.

  Perform baseline (pre-treatment) ophthalmic examination including assessment of visual acuity, confrontation visual field testing, color vision and dilated fundus observation.

• 2.

  Perform optic coherence tomography (OCT) because of a higher likelihood of early toxicity detection (especially if normal baseline examination). Decreased retinal ganglion-cell layer (RGL) thickness and volume suggest optic nerve toxicity. RGL analysis may thus contribute to early diagnosis and management of EON.37,38

• 3.

  Contrast sensitivity testing, pattern visual evoked potentials (VEP) and multifocal electroretinography (ERG) are sensitive tests to detect ethambutol toxicity in subclinical stages and hence useful for monitoring patients under ethambutol therapy for ocular toxicity. These may be considered complementary to the baseline examination, should they be available, particularly in dubious cases.39,40

• 4.

  Ethambutol should be discontinued as soon as EON is suspected, and as soon as visual symptoms develop (visual acuity loss, color vision disturbance, scotomata). The patient should be referred promptly to ophthalmic evaluation.31

• 5.

  Frequency of ophthalmic screenings should be every two months for standard ethambutol doses (equal or higher than 15mg/kg/day), or monthly if additional risk factors for toxicity are present such as:

• a.

  diabetes mellitus

• b.

  chronic renal disease

• c.

  alcoholism

• d.

  elderly patients

• e.

  children

• f.

  other ocular diseases (other than the uveitis)

• g.

  ethambutol-induced peripheral neuropathy

• h.

  linezolid-related optic neuropathy35,41

• 6.

  Systematic close monitoring (probably monthly) with VEP is advisable in children younger than 5 years old since ethambutol-related visual impairment has also been shown in this age group, and such alterations in visual function are most likely underestimated.42

When another etiology for the uveitis has been identified, and the patient has immunological tests such as tuberculin skin or IGRA test positive or evidence of untreated past tuberculosis and being considered for immunosuppressive therapy.43,44

The authors declare that no experiments were performed on humans or animals for this investigation.

The authors declare that no patient data appears in this article.

The authors declare that no patient data appears in this article.