Bilateral chronic central serous chorioretinopathy associated with IGRA latent tuberculosis infection: A case report and review

A 37-year-old Indian male presented with a 3-year history of right eye blurred vision. Bilateral ophthalmic examinations revealed shallow, oval areas of macular subretinal fluid containing hypopion-like precipitates and central neurosensory retinal detachments with focal early-stage fluorescein leakage consistent with central serous chorioretinopathy (CSCR). Inadequate response to Eplerenone prompted reassessment yielding a positive BCG vaccine history. Latent tuberculosis infection (LTBI) was diagnosed by a positive interferon- γ response assay (IGRA) in the absence of pulmonary symptoms. Rifampin alone yielded only modest bilateral visual acuity increases and subretinal fluid decreases. Right eye focal macular laser was performed to stabilize vision with modest subretinal fluid decrease, but peripheral retinal lesions were noted on follow up. The patient has been unavailable for follow up evaluation and supportive anti-tuberculosis treatment (ATT) to date. The unresponsiveness to anti-corticosteroid medications in our case of CSCR secondary to LTBI, the reported detection of Mycobacterium tuberculosis DNA in CSCR subretinal fluid, and the resolution CSCR post ATT in 3 previous CSCR secondary to LTBI cases support a possible association of CSCR and LTBI. To our knowledge this is the fourth case of chronic CSCR in a patient with LTBI.

We report a case of chronic CSCR in a middle-aged adult male diagnosed with asymptomatic latent M. tuberculosis infection (LTBI). A literature review of the three adult cases of CSCR secondary to LTBI supports an association of CSCR and LTBI. The CSCR associated with LTBI in our case was unresponsive to anti-corticosteroid therapies.

Case report
A 37-year-old, healthy Indian male presented with a 3-year history of blurred vision OD. His best-corrected visual acuity (BCVA) was 20/50 OD and 20/25 OS (no improvement with pinhole or refraction). External eye s and intraocular pressures were normal. Fundus examinations showed shallow, round areas of elevation involving the fovea containing white exudates that settled inferiorly in a dependent fashion in both eyes ( Figures 1A and 1B). Notably, focal areas of leakage with eventual expansion of the leakage and late pooling were detected by fluorescein fundus angiography (FFA) (Figures 1C and 1D). Bilateral retinal detachments from the RPE with similar SRF volumes (10.69 mm 3 OD and 10.03 mm 3 OS) and highest retinal prominence (HRP: 583 µm OD and 498 µm OS) were confirmed by optical coherence tomography (OCT) scans ( Figures 1E and 1F). A diagnosis of bilateral chronic CSCR was made and the patient was placed on 6-month course of Eplerenone (50 mg daily) [11].
Slight improvement in BCVA of 20/40 OD and 20/20 OS was noted after 6 months, but fundus evaluation remained unchanged with only slight decreases in SRF volume (-0.2 mm 3 OD and -0.5 mm 3 OS) and HRP (-40 µm OD and -40 µm OS). The Eplerenone treatment was discontinued due to lack of marked clinical improvement. A systemic re-evaluation by Internal Medicine found no radiological symptoms of active TBI were detected. A diagnosis of LTBI was made based upon the positive IGRA and absence of pulmonary symptoms [12]. The patient was started on rifampin 300 mg twice a day as a treatment option for LTBI and CSCR [4]. After the total 6-month course of rifampin, the BCVA was 20/40 OD and 20/20 OS, and there were only slight reductions in SRF volumes (-0.61 mm 3 and -0.1 mm 3 OS) and HRP (-46 µm OD and -8 µm OS). Based upon minimal SRF improvement, the rifampin was discontinued and focal macular laser (FML) was performed around the areas of presumed subretinal fluid leakage. FML was repeated 4 months later. The BCVA (20/40 OD and 20/20 OS) and OCT findings have remained stable, but dilated fundus exams detected some new smaller inferonasal white spot/lesion compared to previous exam. The current medical plan upon his return to clinic is to evaluate his ocular and TB status and offer ATTx4.

Review of cases
The review of the 3 previously reported cases [13][14][15] and our case of CSCR secondary to LTBI was significant for patients being middleaged adult males from diverse geographic, cultural/racial backgrounds ( Table 1). The clinical histories were significant for prolonged reduction in visual acuity (blurred vision) with two cases presenting with metamorphopsia. Fundus exams revealed bilateral areas of SRF in three cases. FFA assessment noted early and late multi-focal or diffuse hyperfluorescence in the macular area. Suspicion of TB infections in these cases were based on family history, travel from endemic area, ethnic background, and history of TB infection. Presumptive LTBI diagnoses were made based on a supportive history and a positive IGRA (T-spot test) in the absence of active pulmonary disease. Complete or significant improvement was observed in 3 cases given a ATTx4 (isoniazid, rifampin, ethambutol, and pyrazinamide) with one of the aforementioned patients maintained on rifampin. Our case has not received ATT, but rifampin alone had little therapeutic effect.

Discussion/Conclusion
The current number of clinical cases and basic research results support latent M. tuberculosis infection as a possible risk factor for CSCR. Accordingly, our case and the 3 previously reported cases of CSCR secondary to LTBI occurred in middle-aged males consistent with the higher intraocular TB incidence in this age-sex group [1]. Prompt CSCR improvement following ATT (therapy is based in antituberculosis drugs and corticosteroids) in 3 cases [13][14][15], suggests eradication of LTBI was associated with resolution of the CSCR. The resolution of CSCR post ATT suggests retinal M. tuberculosis infection contributes to CSCR symptoms. In this regard, M. tuberculosis DNA has been detected in the SRF of patients with tuberculosis infection [16,17] and RPE cells have been shown to survive M. tuberculosis infection suggesting RPE cells can serve as an intraocular reservoir for M. tuberculosis [18,19]. The mechanism of the CSCR secondary to LTBI is unknown, but may be due in part to pro-apoptotic and/ or pro-inflammatory effects of the M. tuberculosis infection [20,21]. Concomitantly, the duration and recurrence frequency of CSCR associated with H. pylori infection [8,10,22] is reduced by triple-drug therapy eradication of H. pylori [10]. The mechanism(s) responsible for the CSCR associated with H. pylori infection is unknown, but the CSCR appears to be a RPE disease with a general choroidal microcirculation involvement [23]. The reported CSCR resolution post antibiotic eradication of H. pylori and ATT treatment of LTBI suggests the consideration of bacteria-induced cytopathogenic mechanisms [24].
The diagnosis of LTBI in an immunocompetent person with asymptomatic disease is difficult, but important to TB prevention. A presumptive ocular TB diagnosis is supported by the combination of the ophthalmological inflammatory pattern and confirmatory tests for TB infection [25,26]. LTBI diagnosis requires a positive test for infection and a negative evaluation for active disease. A diagnosis of CSCR secondary to LTBI, in the reported cases, was made after systemic reevaluation due to worsening retinal disease with or without treatment. The LTBI diagnosis required solicitation of an accurate past medical history and confirmatory tests. In our case, failed Eplerenone treatment for bilateral CSCR prompted patient re-evaluation, which ultimately The CSCR secondary to LTBI cases presented with a longstanding history of diminished visual acuity with or without metamorphopsia. Single or multifocal retinal lesions were characterized by SRF in the macular area between the RPE and the neurosensory retina. In our case, areas of SRF with precipitate and focal "smoke stack" leakage points were identified in both eyes. The smoke stack leakage pattern occurs in 7-11% of primary CSCR eyes and 80% of recurrent leakage points generally arise within 1 mm of the primary leakage point in CSCR cases [5,6]. The appearance of new leakage points was noted in our case after failed rifampin treatment; entertaining the possibility that the M. tuberculosis was rifampin resistant. M. tuberculosis resistant to rifampin, isoniazid, and multiple drugs can arise quickly and should be considered in TB unresponsive to ATT [27]. M. tuberculosis was not isolated, thus rifampin resistance could not confirmed by Xpert MTB/ RIF assay [28].
CSCR treatment options, including photocoagulation laser therapy, have been investigated and refined due to complications such as scotoma, choroidal neo-vascularization, and persistent metamorphopsia [1,29]. More recently, clinical investigations with oral medications for acute and chronic CSCR have been reported [4,11,14,30]. Our CSCR associated LTBI case did not resolve with Eplerenone (a mineralocorticoid-specific receptor antagonist) or rifampin (potent inducer of cytochrome P450 shown to reduce circulating endogenous and exogenous steroids levels [31], in contrast to idiopathic CSCR [11,30]. Our support for rifampin therapy was predicated upon its beneficial effects against chronic CSCR [4,14,30] and anti-mycobacterial action (inhibits protein synthesis by blocking DNA-dependent RNA synthesis) [32]. Ultimately, FML (focal macular laser) was applied to the right eye as warranted following unsuccessful rifampin therapy to help preserve vision.
In conclusion, CSCR has been associated with a number of risk factors and treated in a number of different ways with mixed results. The subset of CSCR patients diagnosed with a LBTI by skin test or IGRA may fail anti-corticoid therapy and should be offered ATT to eradicate the TB infection and provide the possibility of visual acuity improvement and CSCR resolution.