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Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis that most commonly affects the lungs. Ocular involvement as part of extrapulmonary TB is noted in around 2-18% of cases of extrapulmonary TB. Any part of the eyes can be affected by the tubercular disease process, and a high index of suspicion is required for accurate diagnosis. Because the location is extrapulmonary, obtaining a proper sample is difficult, and the paucibacillary nature of the disease also makes microbiological detection a diagnostic challenge. Response to antitubercular therapy is usually good, and resolution of clinical features is observed in most cases. Here, we present a case report of a patient presenting with a chalazion-like lesion in the left eyelid that recurred after surgical intervention and did not respond to medical therapy. No history of past TB infection or contact was noted in the patient. An active tubercular lung infection was excluded. On further evaluation, the lesion was microbiologically proven to be of tubercular origin, and the signs and symptoms of the patient completely resolved with proper antitubercular therapy.

Tuberculosis (TB) is a leading cause of death among infectious diseases worldwide due to latent TB infection, which is the critical step for the successful pathogenic cycle. In this stage , Mycobacterium tuberculosis resides inside the host in a dormant and antibiotic-tolerant state. Latent TB infection can also lead to multisystemic diseases because M. tuberculosis invades virtually all organs, including ocular tissues. Ocular tuberculosis (OTB) occurs when the dormant bacilli within the ocular tissues reactivate, originally seeded by hematogenous spread from pulmonary TB. Histological evidence suggests that retinal pigment epithelium (RPE) cells play a central role in immune privilege and in protection from antibiotic effects, making them an anatomical niche for invading M. tuberculosis . RPE cells exhibit high tolerance to environmental redox stresses, allowing phagocytosed M. tuberculosis bacilli to maintain viability in a dormant state. However, the microbiological and metabolic mechanisms determining the interaction between the RPE intracellular environment and phagocytosed M. tuberculosis are largely unknown. Here, liquid chromatography-mass spectrometry metabolomics were used to illuminate the metabolic state within RPE cells reprogrammed to harbor dormant M. tuberculosis bacilli and enhance antibiotic tolerance. Timely and accurate diagnosis as well as efficient chemotherapies are crucial in preventing the poor visual outcomes of OTB patients. Unfortunately, the efficacy of current methods is highly limited. Thus, the results will lead to propose a novel therapeutic option to synthetically kill the dormant M. tuberculosis inside the RPE cells by modulating the phenotypic state of M. tuberculosis and laying the foundation for a new, innovative regimen for treating OTB., Importance: Understanding the metabolic environment within the retinal pigment epithelium (RPE) cells altered by infection with Mycobacterium tuberculosis and mycobacterial dormancy is crucial to identify new therapeutic methods to cure ocular tuberculosis. The present study showed that RPE cellular metabolism is altered to foster intracellular M. tuberculosis to enter into the dormant and drug-tolerant state, thereby blunting the efficacy of anti-tuberculosis chemotherapy. RPE cells serve as an anatomical niche as the cells protect invading bacilli from antibiotic treatment. LC-MS metabolomics of RPE cells after co-treatment with H 2 O 2 and M. tuberculosis infection showed that the intracellular environment within RPE cells is enriched with a greater level of oxidative stress. The antibiotic tolerance of intracellular M. tuberculosis within RPE cells can be restored by a metabolic manipulation strategy such as co-treatment of antibiotic with the most downstream glycolysis metabolite, phosphoenolpyruvate., Competing Interests: The authors declare no conflict of interest.

Purpose: To report the treatment response of a case of tubercular choroidal granuloma and subretinal abscess with intravitreal anti-vascular endothelial growth factor (anti-VEGF) and moxifloxacin., Method: Retrospective interventional case report., Results: A 34-year-old man presented with bilateral choroidal granuloma and subretinal abscess in one eye. He was a known case of spinal tuberculosis and was on anti-tubercular therapy. Patient was successfully treated with intravitreal injection of anti-VEGF and moxifloxacin., Conclusion: Intravitreal anti-VEGF and moxifloxacin combination may be beneficial in tubercular choroidal granuloma and subretinal abscess.

Background: Truenat MTB Plus assay was evaluated for diagnosing ocular tuberculosis (OTB) and detecting multi-drug resistant (MDR) and extremely-drug resistant (XDR) OTB., Methods: A total of 75 vitreous fluid specimens [five confirmed OTB, 40 clinically suspected OTB and 30 controls] were subjected to Truenat MTB Plus, multiplex PCR, and Xpert Ultra. Chips of Truenat were used for detecting rifampicin, isoniazid, fluoroquinolone and bedaquiline resistance. The performance was compared against culture, composite reference standard, and gene sequencing., Results: The overall sensitivity of TruePlus, MPCR, and Ultra in diagnosing OTB was 66.6%, 73.3%, and 55.5%, respectively. Out of six cases with mutations in rpoB gene, RifR was detected in five by TrueRif and four by Ultra. Three MDR and one XDR-OTB were reported by Truenat., Conclusion: Truenat assay along with its strategic chips is a rapid and reliable tool for diagnosis of OTB and detection of drug resistance, including MDR and XDR-OTB. Abbreviations: OTB: Ocular tuberculosis; XDR: Extremely drug resistant; Ultra: Xpert MTB/RIF Ultra; Xpert: Xpert MTB/RIF; PCR: polymerase chain reaction; NAATs: Nucleic acid amplification tests; MDR: Multi Drug Resistant; NSP: National Strategic plan for elimination of tuberculosis; FqR: Fluoroquinolone resistant; BdqR: bedaquiline resistant; TrueRif: Truenat MTB Rif Dx; TruePlus: Truenat Plus; INH: Isoniazid; DST: Drug susceptibility testing; MGIT: Mycobacterial growth indicator tube; CRF: Composite reference standard; PPV: positive predictive value; NPV: negative predictive value; EPTB: extrapulmonary tuberculosis; VF: vitreous fluid; DNA: deoxyribonucleic acid; ATT: antitubercular therapy; RifR: Rifampicin resistance; RifS: Rifampicin susceptible; RifI: Rifampicin indeterminate.

Purpose: To describe a case of a macular tuberculoma in a young and healthy woman after developing a tuberculous lymphadenitis caused by Mycobacterium bovis ., Methods: Retrospective case report., Results: Tuberculous lymphadenitis caused by M. bovis was detected after biopsy and histological examination as well as polymerase chain reaction test testing of cervical lymph nodes in a 20-year-old patient. An interferon gamma was positive. Shortly starting antitubercular therapy, the patient developed visual deterioration caused by a single yellowish subretinal structure in the macula of the right eye. Optical coherence tomography showed a dome-shaped, hyperreflective, subfoveal choroidal lesion with subtle subretinal fluid. Antitubercular therapy with isoniazid, rifampicin, ethambutol, and pyrazinamide was performed, and the deescalation therapy with isoniazid and rifampicin was extended to 7 months. Further examinations showed regression of choroidal tuberculoma to a scar., Conclusion: This is the first reported case of choroidal tuberculoma after tuberculous lymphadenitis caused by M. bovis .

Tubercular uveitis (TB-uveitis) remains a conundrum in the uveitis field, which is mainly related to the diverse clinical phenotypes of TB-uveitis. Moreover, it remains difficult to differentiate whether Mycobacterium tuberculosis (Mtb) is present in the ocular tissues, elicits a heightened immune response without Mtb invasion in ocular tissues, or even induces an anti-retinal autoimmune response. Gaps in the immuno-pathological knowledge of TB-uveitis likely delay timely diagnosis and appropriate management. In the last decade, the immunopathophysiology of TB-uveitis and its clinical management, including experts' consensus to treat or not to treat certain conditions with anti-tubercular treatment (ATT), have been extensively investigated. In the meantime, research on TB treatment, in general, is shifting more toward host-directed therapies (HDT). Given the complexities of the host-Mtb interaction, enhancement of the host immune response is expected to boost the effectiveness of ATT and help overcome the rising burden of drug-resistant Mtb strains in the population. This review will summarize the current knowledge on the immunopathophysiology of TB-uveitis and recent advances in treatment modalities and outcomes of TB-uveitis, capturing results gathered from high- and low-burden TB countries with ATT as the mainstay of treatment. Moreover, we outline the recent progress of HDT development in the pulmonary TB field and discuss the possibility of its applicability to TB-uveitis. The concept of HDT might help direct future development of efficacious therapy for TB-uveitis, although more in-depth research on the immunoregulation of this disease is still necessary., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To present a case of necrotizing sclerokeratitis in a patient with multidrug-resistant tuberculosis and study the challenges in diagnosis and management of anterior tuberculous scleritis., Methods: Retrospective observational case report and review of anterior tuberculous scleritis., Results: A 28-year-old woman, previously diagnosed as presumed tubercular panuveitis, presented with necrotizing sclerokeratitis and progressed to develop panophthalmitis. Laboratory investigations revealed multidrug-resistant Mycobacterium tuberculosis as the etiological agent. We reviewed cases of anterior tuberculous scleritis published in the literature, with regards to clinical features, microbiological investigations, treatment, and outcomes. Treatment includes standard antitubercular therapy, with or without systemic corticosteroids. Poor response to treatment is seen either due to delayed diagnosis or drug resistance, and the significance of the same is highlighted in our case., Conclusion: Diagnosis of tuberculous scleritis is a challenge. Therapeutic failure must alert the clinician for drug resistance which is diagnosed early, can prevent the devastating outcomes.

Purpose : To evaluate the role of angiogenic growth factors in the pathogenesis of intraocular tuberculosis. Methods : Retinal Pigment Epithelium (RPE) cells were infected with varying dilution of Mycobacterium tuberculosis (MTB), ranging from several thousand to a few MTB bacilli to replicate paucibacillary conditions. Angiogenesis growth factors were evaluated using multiplex fluorescent bead based flow cytometry in the culture supernatant of RPE cells infected with MTB, vitreous fluids and tear samples of uveitis patients visiting retina clinic. Results : Vascular endothelial growth factor (VEGF) levels were elevated and fibroblast growth factors (FGFs) were down regulated in RPE-infected MTB cells. Similar pattern of VEGF and FGF was observed in the vitreous of IOTB patients. However, no changes were observed in tear samples. Conclusions : MTB exploits the angiogenesis growth factors for pathogenesis by decreasing FGF with concomitant surge of VEGF in MTB infected RPE as well in the vitreous of IOTB patients.

Purpose : Cytopathology of vitreous is most commonly done to diagnose vitreoretinal lymphoma in eyes with nonspecific inflammation. Vitreous cytopathology features of tuberculous intermediate uveitis have not been described in literature. Case report : We report a case of a healthy 35-year-old female who showed granulomatous inflammatory changes on vitreous cytopathology with polymerase chain reaction confirming a diagnosis of intraocular tuberculosis. Conclusion : This case highlights the role of cytopathology in determining the etiology and pathogenesis behind the elusive diagnosis of intermediate uveitis. Polymerase chain reaction can further help in confirming the diagnosis and allowing commencement of appropriate therapy.

Background: Bovine tuberculosis is a chronic inflammatory disease that causes granuloma formation mainly in retropharyngeal, tracheobronchial, mediastinal lymph nodes and lungs of bovines. The presence of these lesions in other tissues such as the eyeball is very rare and difficult to diagnose. This study describes macroscopic and microscopic pathological findings in a calf with ocular and meningeal tuberculosis., Case Presentation: March 2019, an eight-month-old Holstein Friesian calf was identified in a dairy farm located in central Mexico with a clinical cough, anorexia, incoordination, corneal opacity and vision loss. At necropsy, pneumonia, lymphadenitis, meningitis, and granulomatous iridocyclitis were observed. The histopathological examination revealed granulomatous lesions in lung tissue, lymph nodes, meninges and eyes with the presence of acid-fast bacilli associated with Mycobacterium spp., Conclusion: To the best of our knowledge, this is the first report that describes macroscopic and microscopic pathological findings of ocular tuberculosis in cattle. This report highlights the importance of considering bovine tuberculosis in the differential diagnosis of corneal opacity and loss of vision in cattle.

Purpose: To describe a case of tubercular serpiginous-like choroiditis that progressed, despite antitubercular medication, corticosteroids, and immunomodulatory treatment, which ultimately quieted after two intravitreal methotrexate injections., Methods: Case report., Results: A 35-year-old woman reported a shadow in the left eye for 2 weeks. She presented with tubercular serpiginous-like choroiditis in the right eye 2 years prior. At that time, she was started on antituberculosis therapy but was noncompliant and lost to follow-up. On re-presentation, there was a new active left-eye serpiginous lesion, with repeat positive QuantiFERON gold testing. Four antituberculosis drugs were started, followed by corticosteroids and azathioprine, with continued progression despite aggressive treatment. She was finally given 2 intravitreal methotrexate injections (400 μg/0.1 cc) 1 month apart, with final arrest of lesion extension. The uveitis remained quiet for over 24 months, and the patient was able to discontinue all systemic therapy., Conclusion: Intravitreal methotrexate injections halted progression of treatment-refractory tubercular serpiginous-like choroiditis.

Purpose: To characterize the ophthalmic clinical and multimodal imaging findings of disseminated Mycobacterium chimaera infection after cardiothoracic surgery., Design: Observational case series., Participants: Four patients (8 eyes) with disseminated M. chimaera infection., Methods: Patients were evaluated with biomicroscopy, OCT and OCT angiography, fundus autofluorescence, and fluorescein and indocyanine green angiography., Main Outcome Measures: Clinical and multimodal imaging findings of patients with disseminated M. chimaera infection., Results: All 4 patients were white men with a mean age of 65.5 years (range, 60-75 years) who had aortic valve or root infection, or both, with M. chimaera diagnosed by culture, gene sequencing, or both. All 4 patients demonstrated bilateral choroidal lesions on funduscopy and evidence of osteomyelitis by imaging, culture analysis, or both at the time of ocular diagnosis. Indocyanine green and OCT angiography revealed numerous additional subclinical choroidal lesions and were used to track disease response to therapy. Fluorescein angiography and fundus autofluorescence were useful in determining lesion age and activity. All patients were treated with 3- or 4-drug antimycobacterial therapy. Three underwent revision of cardiothoracic surgery with removal of infected graft. One patient went on to demonstrate progressive ocular disease that was noted before each of his surgical revisions. Two patients showed improvement in ocular and systemic disease, however one of them developed a choroidal neovascular membrane. The final patient was a single encounter whose clinical and imaging findings showed longstanding inactive disease., Conclusions: Ophthalmologists should be aware of the systemic and ocular findings of this rare life-threatening disease. Multimodal imaging is useful in corroborating a diagnosis of ocular M. chimaera and particularly in evaluating patient response to therapy, because choroidal activity seems to mimic systemic activity. Treating physicians should be aware of the co-occurrence of choroiditis and osteomyelitis. Choroidal neovascular membrane can also be a late complication of this disease., (Copyright © 2020. Published by Elsevier Inc.)

Topic: An international, expert-led consensus initiative organized by the Collaborative Ocular Tuberculosis Study (COTS), along with the International Ocular Inflammation Society and the International Uveitis Study Group, systematically developed evidence- and experience-based recommendations for the treatment of tubercular choroiditis., Clinical Relevance: The diagnosis and management of tubercular uveitis (TBU) pose a significant challenge. Current guidelines and literature are insufficient to guide physicians regarding the initiation of antitubercular therapy (ATT) in patients with TBU., Methods: An international expert steering subcommittee of the COTS group identified clinical questions and conducted a systematic review of the published literature on the use of ATT for tubercular choroiditis. Using an interactive online questionnaire, guided by background knowledge from published literature, 81 global experts (including ophthalmologists, pulmonologists, and infectious disease physicians) generated preliminary consensus statements for initiating ATT in tubercular choroiditis, using Oxford levels of medical evidence. In total, 162 statements were identified regarding when to initiate ATT in patients with tubercular serpiginous-like choroiditis, tuberculoma, and tubercular focal or multifocal choroiditis. The COTS group members met in November 2018 to refine these statements by a 2-step modified Delphi process., Results: Seventy consensus statements addressed the initiation of ATT in the 3 subtypes of tubercular choroiditis, and in addition, 10 consensus statements were developed regarding the use of adjunctive therapy in tubercular choroiditis. Experts agreed on initiating ATT in tubercular choroiditis in the presence of positive results for any 1 of the positive immunologic tests along with radiologic features suggestive of tuberculosis. For tubercular serpiginous-like choroiditis and tuberculoma, positive results from even 1 positive immunologic test were considered sufficient to recommend ATT, even if there were no radiologic features suggestive of tuberculosis., Discussion: Consensus guidelines were developed to guide the initiation of ATT in patients with tubercular choroiditis, based on the published literature, expert opinion, and practical experience, to bridge the gap between clinical need and available medical evidence., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Topic: The Collaborative Ocular Tuberculosis Study (COTS), supported by the International Ocular Inflammation Society, International Uveitis Study Group, and Foster Ocular Immunological Society, set up an international, expert-led consensus project to develop evidence- and experience-based guidelines for the management of tubercular uveitis (TBU)., Clinical Relevance: The absence of international agreement on the use of antitubercular therapy (ATT) in patients with TBU contributes to a significant heterogeneity in the approach to the management of this condition., Methods: Consensus statements for the initiation of ATT in TBU were generated using a 2-step modified Delphi technique. In Delphi step 1, a smart web-based survey based on background evidence from published literature was prepared to collect the opinion of 81 international experts on the use of ATT in different clinical scenarios. The survey included 324 questions related to tubercular anterior uveitis (TAU), tubercular intermediate uveitis (TIU), tubercular panuveitis (TPU), and tubercular retinal vasculitis (TRV) administered by the experts, after which the COTS group met in November 2019 for a systematic and critical discussion of the statements in accordance with the second round of the modified Delphi process., Results: Forty-four consensus statements on the initiation of ATT in TAU, TIU, TPU, and TRV were obtained, based on ocular phenotypes suggestive of TBU and corroborative evidence of tuberculosis, provided by several combinations of immunologic and radiologic test results. Experts agreed on initiating ATT in recurrent TAU, TIU, TPU, and active TRV depending on the TB endemicity. In the presence of positive results for any 1 of the immunologic tests along with radiologic features suggestive of past evidence of tuberculosis infection. In patients with a first episode of TAU, consensus to initiate ATT was reached only if both immunologic and radiologic test results were positive., Discussion: The COTS consensus guidelines were generated based on the evidence from published literature, specialists' opinions, and logic construction to address the initiation of ATT in TBU. The guidelines also should inform public policy by adding specific types of TBU to the list of conditions that should be treated as tuberculosis., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To report unique retinal fundus lesions and treatment outcomes of intraocular tuberculosis in patients under anti-tumor necrosis factor treatment., Methods: Retrospective review of two patients with laboratorial evidence of tuberculosis who had bilateral ocular signs and symptoms not attributable to other diseases. Multimodal imaging was analyzed at the time of presentation and after the treatment initiation. The study patients underwent standard treatment for tuberculosis., Results: Clinical and laboratory findings were consistent with the diagnosis of presumed tuberculosis. Color fundus photograph revealed the presence of multifocal yellowish retinal spots in the study eyes. On fluorescein angiography, the retinal lesions seen on color fundus photograph showed early hypofluorescence with progressive staining of its edges. Occlusive vasculitis with peripheral nonperfusion was also observed in both cases. Spectral domain optical coherence tomography demonstrated increased reflectivity and thickness on the topography of retinitis lesions. After specific antibiotic treatment for tuberculosis, there was complete disappearance of the retinal lesions in all study eyes., Conclusion: We report two unique cases of bilateral presumed intraocular tuberculosis presenting as multifocal retinitis in patients under biologic agent treatment. Anti-tumor necrosis factor agents may be related to unusual fundus manifestations of tuberculosis.

Unclear pathogenic mechanisms underlying the ocular tuberculosis (OTB) has resulted in perplexity related to the diagnosis and management of the disease. Developments in experimental research and innovations in molecular diagnostics have recently provided a new understanding of disease pathogenesis and natural history. The current review focuses on the new insights into OTB pathogenesis, derived from in vivo and in vitro studies on Mycobacterium tuberculosis dissemination and localization into the eye, in combination with histopathological studies on chorioretinal tissue and vascular network. Advances in the knowledge of OTB have influenced disease management in the clinical setting and lead to reconsideration of the role of existing treatments and suggesting potential new therapeutic approaches., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The spread of tuberculosis is directly related to the processes of globalization and migration. Tuberculosis has also been the main cause of fatality associated with antimicrobial resistance and also the main cause of death in people who have HIV infection. Additionally, tuberculosis smites the lungs in 80% of patients, and in the remaining 20% of patients the tuberculosis may smites other organs, such as the vision/eye. Ocular tuberculosis is a specific infectious disease of bacterial etiology with a chronic and persistent course, the prognosis of which is extremely doubtful. Even effective chemotherapy can be accompanied by a decrease in visual acuity, and clinical recovery is not always persistent. Ocular tuberculosis often leads to permanent disability and, as a result, the quality of life of patients decreases. A statistical reporting of this disease does not always reflect the true picture, since ocular tuberculosis sometimes develops against the background of an existing specific lesion in the lung tissue. Currently, ocular tuberculosis remains substantially a conjectural clinical diagnosis. This review paper presents an analytical review of the literature on the epidemiology, clinical features, and diagnosis methods of ocular tuberculosis. The results of recent studies that focused on the modern clinical manifestations of this pathology, its diagnosis, and complex therapy are systematized. The development of new rational regimens and pathogenetic treatment methods are also highlighted in this review., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Ocular tuberculosis (OTB) encompasses all forms of intra- and extra-ocular inflammation associated with Mycobacterium tuberculosis (Mtb) infection. However, the organism is rarely found in ocular fluid samples of diseased eyes, rendering the pathomechanisms of the disease unclear. This confounds clinical decision-making in diagnosis and treatment of OTB. Here, we critically review existing human and animal data related to ocular inflammation and TB pathogenesis to unravel likely pathomechanisms of OTB. Broadly there appear to be two fundamental mechanisms that may underlie the development of TB-associated ocular inflammation: a. inflammatory response to live/replicating Mtb in the eye, and b. immune mediated ocular inflammation induced by non-viable Mtb or its components in the eye. This distinction is significant as in direct Mtb-driven mechanisms, diagnosis and treatment would be aimed at detection of Mtb-infection and its elimination; while indirect mechanisms would primarily require anti-inflammatory therapy with adjunctive anti-TB therapy. Further, we discuss how that most clinical phenotypes of OTB likely represent a combination of both mechanisms, with one being predominant than the other., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: To report on the prevalence and clinical implications of positive QuantiFERON-Gold (QFT-G) test results in the diagnostic evaluation of a large cohort of consecutive patients with uveitis in the Netherlands., Design: Retrospective cross-sectional study., Methods: This study included 710 consecutive patients who all underwent evaluation for uveitis including QFT-G testing. The ocular features, comorbidity, and abnormalities in diagnostic imaging and laboratory tests were registered for QFT-G-positive patients with uveitis., Results: Of all patients, 13% (92/710) were positive for QFT-G. Previously treated tuberculosis (TB) was documented in 2 patients. Of all 92 QFT-G-positive patients, culture-proven active TB was observed in 1 case. The proportion of patients with uveitis of unknown etiology was higher in QFT-G-positive than in the QFT-G-negative patients (54/92, 59% vs 238/618, 39%; P = .0004). The uveitis features of QFT-G-positive patients were mainly nonspecific. Of all QFT-G-positive patients with uveitis, 17 patients had chest imaging changes suggesting either TB or sarcoidosis. Twenty-nine QFT-G-positive patients with otherwise unexplained uveitis completed antituberculous therapy (29/710; 4% of all included patients) with beneficial effect in most cases., Conclusion: The QFT-G tested positive in 13% of patients with uveitis in the Netherlands, whereas only sporadic patients had a documented previous or active TB infection. The proportion of patients with unexplained uveitis was higher in QFT-G-positive patients. Though the association between uveitis and a positive QFT-G test might be coincidental, the majority of treated QFT-G-positive patients with otherwise unexplained severe uveitis cause had a beneficial response to antituberculous therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Mycobacterium tuberculosis (MTB) in latent infection has been demonstrated in pulmonary/extra-pulmonary locations (lung, spleen, liver, kidney, adipose tissue) in autopsy studies, but its presence in ocular tissues in the latent state is not known., Methods: We conducted molecular and histopathological study of 100 cadaver eyes (50 humans) who died from causes other than tuberculosis (TB) (and were potential candidates for corneal transplantation) to detect MTB in ocular tissues in an endemic setting. After removal of the corneal button, an 8 to 10 mm block of tissue (choroid, retina and part of the vitreous) was excised from the remaining globe for DNA isolation. Gel-based IS6110 and devR3 polymerase chain reaction (PCR) assays were done, followed by real-time PCR using beta actin gene as an internal control. Sixteen randomly selected DNA samples were double checked using a commercial kit for MTB and non-tuberculous mycobacteria (NTM) DNA. The remaining larger part of the globe was subjected to histopathology., Results: The mean age was 65.14 ± 18 years. All 100 samples were negative for both IS6110 and devR, and all 16 samples were negative with NTM MTB commercial kit. All samples were negative with Ziehl-Neelsen stain for acid fast bacilli and none showed any inflammation or granulomatous pathology., Conclusions: MTB could not be detected in human ocular tissues in latent state in India, a TB-endemic country. This may suggest the inability of MTB to seed ocular tissues in the latent state, unlike other organs which serve as reservoirs for the bacilli in the absence of manifest disease., (© 2019 Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: To evaluate the potential clinical utility of wide-field swept source optical coherence tomography angiography (SS-OCTA) using a prototype device compared to a wide-field fundus autofluorescence (FAF) for analysis of the disease activity in eyes with tubercular serpiginous-like choroiditis (TBSLC)., Methods: Using a prototype SS-OCTA device (PLEX Elite, Carl Zeiss Meditec, Dublin, CA), 17 eyes of 12 consecutive patients with TBSLC were imaged and multiple 12 mm × 12 mm OCTA scans were captured, which were montaged to create wide-field montage OCTA images scans. A wide- FAF (Eidon, CenterVue, Padova, Italy) was performed in the same sitting. Two masked graders independently analyzed OCTA and FAF images for the presence of choroidal lesions, recorded the number of lesions identifiable, and provided a subjective grading for the activity of individual lesion, which were then compared., Results: The total number of lesions identified on FAF were 282 (posterior pole lesions, n = 129 and peripheral lesions n = 153) and on wide-field SS-OCTA were 230 (posterior pole lesions, n = 108 and peripheral lesions n = 122). Active choroidal lesions were comparable on the two machines (n = 28 on FAF and n = 28 on SS-OCTA, respectively); whereas numerous healed lesions were identified on FAF (n = 219) as compared to SS-OCTA (n = 170). There was good correlation among the devices for healed lesions (Pearson correlation, r = 0.82) and active lesions (r = 0.88)., Conclusion: There was good correlation between FAF and wide-field SS-OCTA for detection of disease activity in TBSLC; however, FAF depicted greater number of healed lesions compared to wide-field SS-OCTA., Competing Interests: None

Mycobacterium tuberculosis can spread through the entire body but rarely involves the eye. We report a patient with endophthalmitis in one eye and simultaneous retinal vasculitis in the fellow eye. Systemic work-up suggested infective endopericarditis. Polymerase chain reaction analyses of the vitreous and pericardial fluid were positive for M. tuberculosis . We initiated a four-drug antituberculous treatment regimen (isoniazid, ethambutol, pyrazinamide, and rifampin). After two weeks, we discontinued all the medications due to drug-induced hepatitis. We restarted isoniazid and rifampin, but hepatitis recurred. Finally, we chose isoniazid/ethambutol combination for 18 months, and also administered short-term systemic corticosteroid. His vision improved considerably with no recurrence of hepatitis or tuberculosis for 3 years after completion of treatment. Ocular tuberculosis can masquerade as other causes of intraocular inflammation, and a medical team consisting of an ophthalmologist and an infectious disease specialist might be needed for the diagnosis and management.

Competing Interests: There are no conflicts of interest.

Purpose: To present a rare case of bilateral endogenous chorioretinitis and unilateral endophthalmitis due to Mycobacterium bovis in a patient who received intravesical bacillus Calmette-Guerin (BCG) treatment., Methods: We present a case of a single male patient with bilateral endogenous chorioretinitis due to Mycobacterium bovis in a patient who received intravesical BCG, an attenuated strain of M. bovis widely used to treat superficial bladder cancer. The patient underwent intravitreal tap, vitrectomy, and chorioretinal biopsy with histologic examination., Results: The patient presented with a visual acuity of light perception in the right eye and 20/25 in the left eye. Examination of the right eye revealed dense vitreous haze, whereas the left eye demonstrated multifocal, yellow, round subretinal pigment epithelial lesions in the macula. The patient underwent a vitreous tap with injection of antibiotics and was admitted to the hospital for empiric systemic antibacterial and antifungal treatment along with an endogenous endophthalmitis workup. His systemic evaluation and vitreous tap did not identify a causal organism, and the eyes failed to improve on empiric therapies. He underwent pars plana vitrectomy and retinal biopsy of the right eye that revealed vitreal and infiltrative retinal acid-fast bacilli. Cultures confirmed M. bovis to be susceptible to ethambutol, rifampin, and isoniazid. After starting antimycobacterials, his vision improved to finger counting in the right eye, and his vision and appearance of the lesions remained stable in the left eye at postoperative month one., Conclusion: Intravesical BCG stimulates a local cell-mediated response that destroys malignant cells. It is generally well tolerated, although it rarely can result in secondary systemic infection. Intravesical BCG-related endophthalmitis is rare and should be considered in the setting of ocular inflammation in patients with a history of bladder cancer who may not disclose previous treatment with BCG.

Purpose: To study optical coherence tomography angiography (OCTA) and multimodal imaging features of Type 1 inflammatory choroidal neovascularization (CNV) in tubercular serpiginous-like choroiditis and response to anti-vascular endothelial growth factor therapy., Methods: In this study, multimodal imaging was performed using OCTA, enhanced-depth imaging optical coherence tomography, fluorescein angiography, and indocyanine green angiography. Correlation of OCTA with other imaging modalities in the detection of CNV was performed. The changes in CNV configuration after anti-vascular endothelial growth factor therapy were assessed., Results: In this study, nine eyes (8 patients; 5 females; mean age: 32.5 ± 11.57 years) with diagnosis of tubercular serpiginous-like choroiditis were included. All the eyes had presence of low-lying pigment epithelial detachments on enhanced-depth imaging optical coherence tomography. Using OCTA, it was possible to detect Type 1 CNV in all eyes. Type 1 CNV networks comprised fine anastomotic network of vessels, some of which had a hairpin loop configuration. After anti-vascular endothelial growth factor therapy, there was a decrease in branching and anastomosis. The visual acuity significantly improved from 0.49 ± 0.26 (20/60 Snellen equivalent) at baseline to 0.26 ± 0.17 (20/36 Snellen equivalent) (P = 0.03) in all eyes., Conclusion: Type 1 CNV can occur among patients with tubercular serpiginous-like choroiditis, leading to significant visual loss even in the healed stages of the disease. Optical coherence tomography angiography can help in the detection of Type 1 CNV where conventional multimodal imaging, including fluorescein angiography and OCT, fails to make a definitive diagnosis and thereby guide the initiation of anti-vascular endothelial growth factor therapy.

Tuberculosis is an airborne communicable disease primarily affecting lungs. Primary tuberculosis of the lacrimal sac is very rare. A 15-year-old girl presented with bilateral epiphora for 8 months. Examination revealed bilateral nasolacrimal duct obstruction. During dacryocystorhinostomy, bone over lacrimal sac was found partially eroded. Lacrimal sac was found filled with caseous white material. Biopsy from the lacrimal sac revealed tubercular granulomas. Patient improved after anti-tubercular therapy. Abbreviations: PCR: polymerase chain reaction; NAAT: nucleic acid amplification test.

A 47-year-old female presented with optic disc oedema, peripapillary subretinal fluid and scattered areas of choroiditis. Her ultrasound B-scan showed sclerochoroidal thickening with widening of sub-Tenon space. Subsequent investigations revealed a positive Mantoux test and high-resolution computed tomography of the chest was suggestive of pulmonary involvement. She responded well to antitubercular treatment and systemic corticosteroid. A review of the literature was conducted to identify additional reports on similar cases and discussed. A high index of suspicion and appropriate laboratory work-up can aid in the diagnosis of tuberculous posterior scleritis., Competing Interests: There are no conflicts of interest

Purpose: Tubercular retinal vasculitis (TRV) is a heterogeneous disease that can be difficult to manage because of nonspecific presentation and limitations of confirmatory tests for tuberculosis. This is a big data analysis on phenotypes and treatment outcomes for TRV., Methods: Multicentre retrospective study of patients with TRV between January 2004 and December 2014 and a minimum follow-up of 1 year., Results: Two hundred and fifty-one patients with TRV with a mean age of 38.9 ± 14.4 years (range, 9-86 years) were included. The patients were predominantly males (n = 167/251; 66.5%) of Asian ethnicity (n = 174/246; 70.7%), and geographical origin (n = 137/251; 54.6%). Most patients had features of occlusive type of RV (n = 113/185; 61.1%) except Caucasians (n = 11; 28.2%). There was no significant difference in treatment failure whether patients received antitubercular therapy (ATT) (P = 0.29), although treatment failure was less frequent in patients who received ATT (13.6%; n = 31/228) compared with those who did not (21.7%, n = 5/23). Less treatment failures were observed in patients with occlusive type RV who received ATT; however, this was not significant on survival analysis (P = 0.09). Treatment with ATT was associated with higher failure rates in patients of Hispanic and African American race and those with TRV associated with panuveitis (compared with posterior uveitis)., Conclusion: In this multinational study of TRV, there was no significant therapeutic effect of ATT. However, a definitive conclusion about the role of ATT could not be made because of a few patients who did not receive ATT. Because this is a retrospective study with a limited 1-year follow-up, the effect of ATT may have been overestimated (or underestimated) in the duration of follow-up.

Background: Studies on human intraocular tuberculosis (IOTB) are extremely challenging. For understanding the pathogenesis of IOTB, it is important to investigate the mycobacterial transcriptional changes in ocular environment., Methods: Mice were challenged intravenously with Mycobacterium tuberculosis H37Rv and at 45 days post-infection, experimental IOTB was confirmed based on bacteriological and molecular assays. M. tuberculosis transcriptome was analyzed in the infected eyes using microarray technology. The identified M. tuberculosis signature genes were further validated and investigated in human IOTB samples using real-time polymerase chain reaction., Results: Following intravenous challenge with M. tuberculosis, 45% (5/12) mice showed bacilli in the eyes with positivity for M. tuberculosis ribonucleic acid in 100% (12/12), thus confirming the paucibacillary nature of IOTB similar to human IOTB. M. tuberculosis transcriptome in these infected eyes showed significant upregulation of 12 M. tuberculosis genes and five of these transcripts (Rv0962c, Rv0984, Rv2612c, Rv0974c and Rv0971c) were also identified in human clinically confirmed cases of IOTB., Conclusions: Differentially expressed mycobacterial genes identified in an intravenously challenged paucibacillary mouse IOTB model and presence of these transcripts in human IOTB samples highlight the possible role of these genes for survival of M. tuberculosis in the ocular environment, thus contributing to pathogenesis of IOTB., (© FEMS 2019.)

Competing Interests: None

Tubercular uveitis is a common manifestation of tuberculosis (TB) in TB-endemic countries. Due to lack of gold standard diagnostic tests for confirming intraocular TB, it is often either underdiagnosed or rarely over diagnosed. We report a case of a 28-year-old woman with diminution of vision in the left eye. She was started on antitubercular treatment (ATT) and steroids but she did not comply with the treatment. She developed progressive painful loss of vision consequently and was treated with vitrectomy and silicone oil tamponade. After a complete course of ATT, she recovered, salvaging of eye and restoration of some vision was possible. Mycobacterium tuberculosis is rarely demonstrated in the ocular fluid samples of the suspected cases of TB due to the paucibacillary nature of the disease. A vitreous sample can be obtained from these patients. Surgical intervention in the form of vitrectomy and silicone oil tamponade can help in avoiding enucleation/evisceration., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose : To analyze the role of polymerase chain reaction (PCR) of ocular fluids in management of tubercular (TB) anterior, intermediate, posterior, and panuveitis. Methods: In Collaborative Ocular Tuberculosis Study (COTS)-1 (25 centers, n  = 962), patients with TB-related uveitis were included. 59 patients undergoing PCR of intraocular fluids (18 females; 53 Asian Indians) were included. Results: 59 (6.13%) of COTS-1 underwent PCR analysis. PCR was positive for Mycobacterium TB in 33 patients (23 males; all Asian Indians). 26 patients were PCR negative (18 males). Eight patients with negative PCR had systemic TB. Anti-TB therapy was given in 18 negative and 31 PCR cases. At 1-year follow-up, five patients with positive PCR (15.15%) and three with negative PCR (11.54%) had persistence/worsening of inflammation. Conclusions : Data from COTS-1 suggest that PCR is not commonly done for diagnosing intraocular TB and positive/negative results may not influence management or treatment outcomes in the real world scenario.

Purpose : To describe the clinico-radiological features and long-term outcomes in patients with tubercular dacryoadenitis (TbD) Methods : Retrospective, observational study of TbD patients who underwent a thorough clinical examination, orbital imaging study, and tailored ancillary investigations. Polymerase chain reaction (PCR) and microscopy were done in specific cases. A 4-drug anti-tubercular therapy (ATT) was started and clinical response was monitored in all. Patients with a minimum follow-up of 6 months "off-ATT" were included. Results : All patients were women and three presented with pain, blepharoptosis, and bilateral involvement. In all, ESR was raised, Mantoux test was positive and orbital imaging revealed enlarged lacrimal gland/s. Positive PCR and granulomatous inflammation on microscopy were seen in two patients. At a mean follow-up of 17.25 months, all women responded with no relapse or clinical recurrence. Conclusion : Bilateral lacrimal gland enlargement, positive Mantoux & PCR with early response to ATT may provide sufficient evidence for diagnosing TbD.

Purpose : To describe tuberculous uveitis (TU) presenting as a bullous retinal detachment (RD) and to perform a comprehensive literature review on TU with similar features. Methods : Observational case report and systematic literature review. Results : An 84-year-old woman presented with bilateral granulomatous uveitis and bullous RD in the left eye. The interferon gamma release assay was strongly positive, but all other tests were unremarkable. The patient was diagnosed with TU and started on anti-tubercular therapy (ATT) and systemic steroids with excellent treatment response. Twenty-six articles (32 cases) reported TU with exudative RD. Choroidal tuberculoma was the most common clinical manifestation, followed by optic disc edema and retinal exudate. Systemic steroids with ATT improved vision in more patients (78.6%) than ATT alone (50.0%) or oral steroids followed by ATT (50.0%). Conclusion : Atypical presentations of TU make diagnosis and treatment difficult. A high level of suspicion for TU is needed to minimize ocular morbidity.

Purpose: To assess cellular composition and local cytokine response in vitreous humor of tubercular uveitis., Methods: Cells were collected from vitreous cassettes and peripheral blood of 8 tubercular uveitis and 5 control subjects, undergoing vitrectomy and analyzed by flow cytometry for cellular composition, activation status, proinflammatory cytokine expression, and uptake of TLR9 ligand, CpG ODN 2216., Results: CD3 + T cells with equal proportion of CD4+ and CD8 + T cells formed major fraction of infiltrating cells. The vitreous humor showed higher expression of recent activation marker, CD69, and proinflammatory cytokines, IFN-γ and IL-17A, in CD4 + T cells as compared to peripheral blood. Lastly, intraocular CD4 + T cells showed reduced uptake of ODN 2216 than peripheral blood., Conclusions: Our results indicate that local antigenic stimuli trigger T cell infiltration and activation of CD4 + T cells that are hyporesponsive to TLR9 stimulation. These infiltrating T cells might be responsible in further aggravating ocular inflammation.

Purpose: To describe the clinical features of patients with uveitis associated with latent tuberculosis (TB) and examine the effect of anti-TB treatment (ATT) on uveitis outcome., Design: Retrospective cohort study., Methods: One hundred ninety-nine eyes of 129 patients diagnosed with uveitis associated with latent TB were evaluated for recurrence of disease following treatment. Eighty-nine of the patients (69%) received ATT and information was gathered retrospectively regarding clinical outcome, vision, and treatment. Outcome measures included best-corrected visual acuity (BCVA) and rate of disease recurrence., Results: This study included 89 patients (69%) who received ATT and 40 patients who did not. The uveitis was treated with local and systemic anti-inflammatory and immunosuppressive therapy in all patients. The mean change in BCVA following treatment was 4.5 ± 1.4 letters over the follow-up period, with no difference between eyes of patients receiving ATT and those who did not. Sixty-eight eyes (34.9%) had a recurrence of uveitis (0.64 ± 0.08 recurrences per year), with eyes of patients receiving ATT less likely to develop a recurrence compared to those not receiving ATT (29.5% vs 48.2%, odds ratio 0.47, 95% confidence interval 0.29-0.77, P = .003). Eyes treated with ATT recurred at an estimated median of 120 months, compared with 51 months in eyes with no treatment (P = .005)., Conclusions: Treatment with ATT halved the risk of uveitis recurrence and delayed the onset of the first recurrence in eyes with uveitis associated with latent TB., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Mycobacterium tuberculosis (Mtb) bacilli have been found in retinal pigment epithelial (RPE) cells from uveitis patients without signs of systemic tuberculosis (TB) infection. RPE cells are important for ocular immune privilege and uveitis development., Methods: To address a potential role for Mtb-infected RPE cells in the development of uveitis, we delineated the response to Mtb infection in human RPE cells and primary human macrophages, the main target cell of Mtb. Primary human RPE cells, the human RPE cell line ARPE-19, and monocyte-derived proinflammatory M1 and anti-inflammatory M2 macrophages were infected with DsRed-expressing Mtb strain H37Rv. Infection rates and clearance were addressed along with RNA sequencing analysis, a confirmation analysis by dual-color reverse-transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA) and cytokine secretion., Results: RPE cells robustly controlled intracellular outgrowth of Mtb early after infection. The response in RPE cells to control Mtb survival was dominated by interferon (IFN) signaling and further characterized by prominent regulation of cell death/survival-associated genes and low-level production of Th1-associated cytokines. In contrast, macrophages engaged a plethora of responses including IFN signaling and communication between innate and adaptive immune cells to induce granuloma formation., Conclusions: Together, our data demonstrate that RPE cells display a strong response to Mtb infection that appears, however, incomplete in comparison to the macrophage response to Mtb. The RPE response might reflect a balance between mechanisms aimed at Mtb eradication and mechanisms that limit retinal inflammation.

PurposeTimely diagnosis of intraocular tuberculosis (IOTB) along with detection of drug resistance can save many eyes from visual impairment. With the growing incidence of IOTB and rising drug resistance, a reliable diagnostic platform for simultaneous detection of the agent and mutated gene is urgently needed. The MTBDRplus assay was evaluated directly on vitreous fluid samples for the same.Patients and methodsIn a prospective study, The MTBDRplus assay was performed on 127 vitreous fluid samples (77 'study group' comprising cases of presumed ocular tuberculosis and 50 'control group' cases of disease controls (n=25) and non-uveitic controls (n=25)). All samples positive by MTBDRplus assay were subjected to gene sequencing to confirm the mutations for rifampicin and isoniazid resistance.ResultsThe MTBDRplus assay produced a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 36.36%, 100%, 100%, and 50.50%, respectively, for the detection of IOTB. Among the 28 cases from study group that were positive by MTBDRplus assay, rifampicin resistance was reported in six and isoniazid resistance in two cases. On sequencing of rpoB and katG gene, one case of false rifampicin-resistant by MTBDRplus was found. The other resistant isolates showed concordant mutations between MTBDRplus assay and sequencing.ConclusionThe MTBDRplus assay is an effective tool for the rapid diagnosis of IOTB along with detection of drug resistance, thereby improving the outcome in IOTB.

Purpose: To retrospectively analyze clinical features, laboratory investigations, treatment and visual outcomes in patients with tubercular subretinal abscess., Methods: A total of 12 eyes of 12 patients receiving a diagnosis of subretinal abscess, between 2004 and 2014, were included for this retrospective study., Results: The mean age of the presentation was 29.75 ± 16.72 years (range: 14-62 years) and seven (58.3%) were male. The most common anterior segment presentation was anterior uveitis (75%). The mean BCVA at presentation was 1.62 (in logMAR). A tuberculin skin test was positive in seven patients (58.3%) and five patients had a history of pulmonary tuberculosis. Polymerase chain reaction for the Mycobacterium tuberculosis genome was positive in 6 of 11 eyes from aqueous aspirate (54%) and 4 of 7 eyes from vitreous aspirates (57.14%). All patients were started on systemic steroids and an anti-tubercular regimen. The mean duration of follow-up was 134.28 days. The mean BCVA at final presentation was 1.19 (in logMAR). Chorioretinal scar was the most common finding after resolution., Conclusions: Subretinal abscess is a rare manifestation of ocular tuberculosis. A high degree of suspicion and timely management of the condition can prevent loss of vision.

Purpose: To report on the prevalence of ocular TB and positive QuantiFERON ® -TB Gold (QFT-G) test in uveitis patients and describe their clinical manifestations., Methods: We performed a prospective study of 108 new human immunodeficiency virus-negative uveitis patients. All patients underwent a tailored screening protocol for uveitis and received QFT-G test and tuberculin skin tests (TST)., Results: QFT-G test was positive in 39/108 (36%) of patients, while TST ≥15 mm was positive in 16/108 (15%) patients. None of the patients were identified with active systemic TB. Out of 39 QFT-G-positive patients, 25 (64%) were of unknown cause, which represents a higher proportion than encountered in QFT-G-negative cases (29/69; 42%; p<0.03). Retinal occlusive vasculitis was frequently observed in patients with positive QFT-G outcomes (10/39 vs 3/69; p = 0.001) and was commonly associated with high QFT-G levels, young age, and male gender., Conclusions: Out of all patients with uveitis, none had active systemic TB but 36% were positive for QFT-G test. QFT-G-positive patients frequently had uveitis of unknown cause and exhibited clinical features of occlusive retinal vasculitis.