A diagnosis of bilateral panuveitis was made based on the history and ocular examination. The differential diagnosis at this time was broad and consisted of predominately infectious and inflammatory etiologies including: Lyme disease; syphilis; tuberculosis; toxoplasmosis; sarcoidosis; Vogt-Koyanagi-Harada syndrome; and white dot syndromes such as serpiginous chorioretinopathy. Further office-based testing was pursued. An OCT of the macula demonstrated cystoid macular edema in both eyes, the left greater than the right. On fluorescein angiography there was blocking over the peripapillary lesions with late hyperfluorescence of the lesion borders in the right eye. In the left eye, late leakage in the macula was noted. A-V transit time was normal. Systemic workup was also done, including chest X-ray, toxoplasmosis antibody, Lyme antibody, syphilis enzyme immunoassay and an interferon gamma releasing assay. All testing was within normal limits, except the interferon gamma releasing assay, which was positive. A diagnosis of ocular tuberculosis was made given our patient’s clinical presentation and ocular exam, demographic risk factors and lab testing. He was referred to the health department and started on four-drug therapy per current guidelines.1
Tuberculosis represents a massive burden to public health globally and it is a leading cause of morbidity and mortality worldwide.2 The disease’s prevalence varies, and the majority of tuberculosis cases occur in low- or middle-income countries. In 2012, there were more than 9,900 new tuberculosis cases reported in the United States.3 While the majority of cases manifest as pulmonary tuberculosis, 16 percent of cases in the United States were extrapulmonary in one World Health Organization study of the disease.2 In the United States, risk factors for tuberculosis infection include homelessness, imprisonment and emigration from or recent travel to an area of endemic disease. Of all cases of uveitis in this country, tuberculosis uveitis has an incidence of 0.5 percent.4
The pathogenesis of tuberculosis uveitis has not been fully elucidated by researchers. It is likely a manifestation of both primary active infection and secondary immune reaction to the latent mycobacterium tuberculosis organism. Primary ocular lesions are rare and are typically located on the conjunctiva, cornea or sclera. More often, ocular tuberculosis represents hematogenous spread of the mycobacteria from another site. For this reason, the highly vascularized uvea is most commonly affected.
The gold standard of diagnosis is isolation of the M. tuberculosis organism from ocular fluid or culture; however, this is rarely practical from a clinical standpoint. For this reason, it’s typically a presumptive diagnosis. As suggested in a 2016 paper on the disease by Marcus Ang and his colleagues at the Singapore National Eye Centre,5 a stepwise process is helpful in making the diagnosis.
Factors to support the diagnosis include the presence of ocular and systemic findings suggestive of tuberculosis infection, a positive interferon gamma release assay, a positive tuberculin skin test and improvement following anti-tuberculosis therapy.5 However, in many reported cases of ocular tuberculosis in non-endemic areas, the eye was the only site of infection.6 Ocular findings consistent with tuberculosis uveitis include a diverse array of pathology, but certain signs are more predictive of tuberculosis. In one study, India’s Amod Gupta and co-workers found that the clinical signs most predictive of ocular tuberculosis were broad-based posterior synechiae and serpiginous-like choroiditis with or without vasculitis.7 Consideration of these factors in a stepwise fashion can be used to aid in the diagnosis of ocular tuberculosis.
Tuberculosis skin testing and an interferon gamma releasing assay can also aid the diagnosis. However, there are no definitive guidelines on the use of these tests in the setting of uveitis, and there’s wide variability in clinical practice. In a survey of members of the American Uveitis Society, 25 percent of respondents reported obtaining tuberculosis testing in all patients presenting with uveitis.8 In a case similar to our patient, uveitis in a person with tuberculosis risk factors, 71 percent of respondents reported they would order a tuberculosis screening test.8 In the same paper, 23 percent of those responding reported that they would treat a panuveitis patient with tuberculosis risk factors even if their tuberculosis screening tests were negative. This highlights the limitations of the currently available tests (interferon gamma releasing assay, tuberculin skin tests and chest X-ray).
Additionally, it is important to note that even though these tests may help make the diagnosis, they don’t differentiate between active and latent infection. Furthermore, these tests’ positive and negative predictive values will vary widely given the dramatic variability in tuberculosis prevalence globally. While TB screening tests can be useful adjuncts, the importance of clinical correlation is especially critical in making this challenging diagnosis. The most typical presentations include “sticky” iridocyclitis, panuveitis, serpiginous-like choroiditis or chorioretinitis, choroidal tubercles and a choroidal mass; any of these findings with the appropriate history should raise suspicion of ocular tuberculosis.
While no formal treatment algorithm exists for ocular tuberculosis, most authors recommend six to 12 months of four-drug therapy for extrapulmonary tuberculosis.9,10 From the previously mentioned survey of uveitis specialists, 26 percent of respondents reported they would treat a uveitis patient with TB risk factors for 12 months.7 Concurrent corticosteroid therapy9 or immunosuppressive therapy in steroid-intolerant patients11 may be necessary to control any associated inflammation.
In summary, tuberculosis uveitis represents an uncommon entity in the United States but an important manifestation of a disease with a significant global burden. Proper diagnosis of tuberculosis uveitis presents multiple challenges, with no gold standard in most clinical settings. As in our patient, the absence of pulmonary or other systemic symptoms or findings of tuberculosis is common. While tuberculosis screening tests are valuable, there is significant variability in when and how these tests are used, even among uveitis specialists. Similarly, treatment is not standardized, and most providers rely on our infectious disease colleagues and Centers for Disease Control and Prevention guidelines on extrapulmonary tuberculosis to help guide their treatment.
1. Nahid P, Dorman SE, Alipanah N, et al. Executive summary: Official American Thoracic Society/CDC/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of drug-susceptible tuberculosis. Clin Infect Dis 2016;63:7:853-67.
2. World Health Organization (WHO). Global tuberculosis report 2013. Geneva: WHO; 23 Oct 2013.
3. Centers for Disease Control and Prevention (CDC). Trends in tuberculosis—United States, 2012. MMWR 2012;62:11: 201.
4. Henderly DE, Genstler AJ, Smith RE, Rao NA. Changing patterns of uveitis. Am J Ophthalmol 1987;103:2:131–136.
5. Ang M, Vasconcelos-Santos DV, Sharma K, et al. Diagnosis of ocular tuberculosis. Ocul Immunol Inflamm 2016;5:1-9.
6. Patel SS, Saraiya NV, Tessler HH, Goldstein DA. Mycobacterial ocular inflammation: Delay in diagnosis and other factors impacting morbidity. JAMA Ophthalmol 2013;131:6:752-8.
7. Gupta A, Bansal R, Gupta V, et al. Ocular signs predictive of tubercular uveitis. Am J Ophthalmol 2010;149:4:562-70.
8. Lou S M, Larkin K L, Winthrop K, et al. Lack of consensus in the diagnosis and treatment for ocular tuberculosis among uveitis specialists. Ocul Immunol Inflamm 2015;23:1:25-31.
9. Cutrufello NJ, Petros C. Karakousis PC, et al. Intraocular tuberculosis. Ocul Immunol Inflamm 2010;18:281-91.
10. Ang M, Hedayatfar A, Wong W, et al. Duration of anti-tubercular therapy in uveitis associated with latent tuberculosis: A case–control study. Br J Ophthalmol 2012;96:3:332-6.
11. Chin EK, Almeida DR, Mahajan VB. Management of choroidal granulomas involving the macula in corticosteroid-intolerant patients. JAMA Ophthalmol. 2015;133:11:1351-2.
