Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 1: Guidelines for Initiating Antitubercular Therapy in Tubercular Choroiditis.

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.

Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 2: Guidelines for Initiating Antitubercular Therapy in Anterior Uveitis, Intermediate Uveitis, Panuveitis, and Retinal Vasculitis.

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.

Disconnected pancreatic duct syndrome predicts failure of percutaneous therapy in necrotizing pancreatitis.

BACKGROUND/OBJECTIVES: Minimally invasive approaches, such as percutaneous drainage (PD), are increasingly utilized as initial treatment in necrotizing pancreatitis (NP) requiring intervention. Predictors of success of PD as definitive treatment are lacking. Our aim was to assess the application, predictors of success, and natural history of PD in NP. We hypothesized that necrosis morphology patterns and disconnected pancreatic duct syndrome (DPDS) may predict the ability of PD to provide definitive therapy. METHODS: 714 NP patients were treated from 2005 to 2018. Patients achieving disease resolution with PD alone (PD) were compared to those requiring an escalation in intervention (Step). Outcomes were compared between groups using independent samples t-test, Fisher's exact test, and Pearson's correlation, as appropriate. P < 0.05 was accepted as statistically significant. RESULTS: 115 patients were initially managed with PD (42 PD, 73 Step). No difference in necrosis morphology was seen between the two groups. The PD group underwent significantly more repeat percutaneous interventions (PD, 3.2; Step, 2.0; P = 0.0006) including additional drain placement and drain upsize/reposition procedures. Patients with DPDS were more likely to require an escalation in intervention (odds ratio, 3.4; 95% confidence interval, 1.5-7.6; P = 0.003). The mean number of months to NP resolution was similar (PD, 5.7; Step, 5.8; P = 0.9). Mortality was similar (PD, 7%; Step 14%, P = 0.3). CONCLUSIONS: Necrosis morphology in and of itself does not reliably predict successful definitive treatment by percutaneous drainage. However, patients with disconnected pancreatic duct syndrome were less likely to have definitive resolution with PD alone.

Morphological differences between optic disc collaterals and neovascularization on optical coherence tomography angiography.

BACKGROUND: To study morphological features of optic disc venous collaterals (OVCs) and neovascularization of optic disc (NVD) on optical coherence tomography angiography (OCTA). METHODS: Patients with OVCs and NVDs secondary to ischemic retinal diseases were prospectively enrolled. Multimodal imaging was performed using color fundus photography, fluorescein angiography (FA), and OCTA. Morphological evaluation of en-face structural OCT, cross-sectional and en-face OCTA was performed. RESULTS: Twenty eyes (20 patients; OVCs: n = 10 and NVD: n = 10) were included. OVCs appeared as small, loopy vessels distinct from surrounding peripapillary capillaries on OCTA in the radial peripapillary capillary frame. NVDs appeared as a mesh of fine caliber, raised vessels best seen in the vitreous slab of OCTA. Flow signals in these vascular alterations correlated well with hyperfluorescence on FA. CONCLUSIONS: OCTA provides improved visualization of NVDs and OVCs in ischemic retinal diseases such as diabetic retinopathy and retinal vein occlusions compared to conventional FA.

Validation of the Online Collaborative Ocular Tuberculosis Study Calculator for Tubercular Uveitis.

Importance: This was the first study, to the authors' knowledge, to statistically evaluate the predictive accuracy of Collaborative Ocular Tuberculosis Study (COTS) calculator in guiding initiation of antitubercular therapy (ATT) in patients with clinically suspicious tubercular uveitis (TBU) in an international cohort. Objective: To evaluate the accuracy of a score of 4 or greater on the online COTS calculator in recommending ATT initiation. Design, Setting, and Participants: This study was an evaluation of a diagnostic test or technology. Data input required for the COTS calculator were extracted from the COTS-1 study dataset, which comprised retrospective, observational records of patients with TBU who were monitored for 12 months after treatment. Patients were recruited from international ophthalmic centers. In the absence of a traditional criterion standard, the 12-month treatment response to ATT was used to classify patients as disease positive or negative. The accuracy of clinicians at the ATT decision-making stage in the COTS-1 study was set against COTS calculator scores of 4 or greater. Diagnostic accuracy metrics, including sensitivity, specificity, positive predictive value (PPV), precision, recall, and F1 score, were computed. Data collected from January 2004 to December 2014 were analyzed. Exposures: COTS calculator to guide initiation of ATT in patients with TBU. Main Outcomes and Measures: Comparison of accuracy between clinician judgment and the COTS calculator, analyzed at varying scores and further stratified by tuberculosis endemicity. Results: Of the 492 participants (mean [SD] age, 42.3 [19.0] years; 233 male [47.3%]), application of the COTS calculator identified 225 (45.7%) with high or very high probability to start ATT (score = 4 or 5) and 111 (22.5%) with very high probability alone (score = 5). COTS-5 exhibited the highest specificity (88.7%; 95% CI, 81.4%-93.8%) compared with clinician judgment (29.6%; 95% CI, 21.4%-38.8%), and clinician judgment led in sensitivity (95.5%; 95% CI, 92.9%-97.4%) compared with COTS-5 (26%; 95% CI, 21.6%-30.7%). COTS-4 and COTS-5 balanced specificity (64.3%; 95% CI, 54.9%-73.1%) and sensitivity (48.8%; 95% CI, 43.7%-54%). PPV and sensitivity were consistently higher in the endemic group for all 3 tests. Conclusions and Relevance: Results of this diagnostic study suggest that the COTS calculator (score ≥4) was more specific than clinician judgment for ATT initiation. Although clinician judgment is a good first step to identify all potential true positives (with high sensitivity), a second consultation with COTS-5 (with high PPV) may lead to less false positives. This tool, apt for high-prevalence, low-resource settings, recommends ATT more selectively for genuine TBU cases. Large prospective studies are essential to explore potential improvements in the calculator's sensitivity.

The Collaborative Ocular Tuberculosis Study (COTS) calculator-a consensus-based decision tool for initiating antitubercular therapy in ocular tuberculosis.

OBJECTIVE: To introduce the Collaborative Ocular Tuberculosis Study (COTS) Calculator, an online clinical scoring system for initiating antitubercular therapy (ATT) in patients with ocular tuberculosis (TB). METHOD: The COTS Calculator was derived from COTS Consensus (COTS CON) data, which has previously published consensus guidelines. Using a two-step Delphi method, 81 experts evaluated 486 clinical scenario-based questions, ranking their likelihood of initiating ATT in each specific scenario. Each scenario was a permutation of the results and/or availability of five following components-clinical phenotype, endemicity, two immunological (tuberculin skin test, interferon-γ release assay) and one radiological (chest X-Ray) test results-and a sixth component further stratifying three of the clinical phenotypes. The median scores and interquartile ranges (IQR) of each scenario were tabulated, representing the expert consensus on whether to initiate ATT in that scenario. The consensus table was encoded to develop the COTS Calculator. RESULTS: The COTS Calculator can be accessed online at: https://www.oculartb.net/cots-calc . The attending physician can select the conditions present in the patient, which will generate a median score from 1 to 5. 114 out of 486 scenarios (24%) deliberated had a median score of 5 indicating expert consensus to initiate ATT. CONCLUSION: The COTS Calculator is an efficient, low-cost, evidence and experience-based clinical tool to guide ATT initiation. While it holds substantial promise in improving standard-of-care for ocular-TB patients, future validation studies can help to as certain its clinical utility and reliability.

Perinatal risk factors associated with central retinal changes in former preterm children on optical coherence tomography angiography.

PURPOSE: To assess the association between perinatal risk factors for retinopathy of prematurity (ROP) and central retinal structures of former preterm children seen on optical coherence tomography angiography (OCTA). METHODS: This prospective cohort study included 40 children with a history of preterm birth and 33 healthy full-term children. We documented their birth weight, gestational age, other significant risk factors for ROP development and presence of ROP. Imaging was performed using swept-source OCTA, and quantitative evaluation was performed. Analytic parameters included the area of foveal avascular zone (FAZ), foveal depth (FD), central subfoveal retinal thickness (CSFT) and capillary density index (CDI) of the deep and superficial capillary plexus. RESULTS: Preterm children had significantly smaller FAZ, lower FD and higher CSFT compared to controls (all p < 0.001). Both groups exhibited no differences in total CDI at the superficial (p = 0.969) and deep capillary plexus (p = 0.370). The duration of mechanical ventilation correlated negatively with FAZ and FD but positively with CSFT. The duration of supplemental oxygen treatment correlated negatively with FD. The presence of intraventricular haemorrhage correlated negatively with FAZ and FD but positively with CSFT. Regression analysis found that the duration of mechanical ventilation and the presence of bronchopulmonary dysplasia were associated with lower FD (p = 0.002 and 0.01, respectively) and higher CSFT (p = 0.002 and 0.028, respectively). CONCLUSION: Central retinal anomalies were identified in former preterm children using OCTA. Macular changes were associated with several risk factors for ROP development.

Correlation between Subfoveal Choroidal Thickness and Anterior Segment Inflammation in Patients with Chronic Stage of Vogt-Koyanagi-Harada Disease.

PURPOSE: To correlate changes in subfoveal choroidal thickness (SCT) with the degree of anterior inflammatory activity in chronic Vogt-Koyanagi-Harada (VKH) disease. METHODS: Anterior segment inflammation was assessed using SUN anterior chamber cell grading criteria, and SCT was measured using EDI-OCT in patients with VKH at multiple visits. ANOVA was used to compare the mean SCT for each anterior chamber cell grade. Regression analysis was used to correlate the anterior segment cell grade and the SCT. RESULTS: 14 patients were included in the study. A total of 432 data points consisting of SCT and anterior segment cell values were analyzed. ANOVA demonstrated significant difference between the mean SCT for different anterior chamber cell grades (p < .0001). Regression analysis demonstrated significant correlation between SCT and grade of anterior chamber cells (R2 = 0.37, p < .001). CONCLUSIONS: Chronic VKH is characterized by a dynamic change in SCT that correlates with anterior segment inflammatory activity.

Reversibility of retinochoroidal vascular alteration in patients with obstructive sleep apnea after continuous positive air pressure and surgical intervention.

Purpose: The aim of this work was to study various retinochoroidal parameters in patients with obstructive sleep apnea syndrome (OSAS) and the effect of interventions on these parameters at 6 months follow-up. Methods: A total of 36 patients were recruited prospectively from the otorhinolaryngology clinics of a large tertiary center between September 2018 to March 2020. The subjects were divided into three groups depending upon intervention chosen for OSAS: Group A (surgery, i.e., uvulopalatopharyngoplasty), group B (medical therapy, i.e., continuous positive air pressure) and group C (no intervention). Various retinochoroidal parameters which were studied included retinal thickness (RT), choroidal thickness (CT), choroidal vascularity index (CVI), arteriovenous ratio (AVR), capillary density index (CDI) in superficial and deep retina, at baseline and 6 months of follow-up after the intervention. Results: In group A, CT increased significantly at 6 months (332.76 ± 86.41 um) compared to baseline (306.28 ± 78.19) (P = 0.0004). Similarly, CDI at both superficial and deep capillary plexus increased significantly at 6 months (superficial CDI: 0.65 ± 0.04, deep CDI: 0.38 ± 0.01) compared to baseline (superficial CDI: 0.62 ± 0.03, deep CDI: 0.36 ± 0.02) (P = 0.004 and 0.002 respectively). In group B, CT increased significantly at 6 months (361.38 ± 78.63 um) compared to baseline (324.21 ± 76.97 um) (P = 0.008). Also, CVI showed a significant decrease at 6 months (65.74 ± 1.84%) compared to baseline (67.36 ± 1.57%) (P = 0.019). In group C, all except CDI in deep capillary plexus showed a significant decrease at 6 months (0.35 ± 0.01) compared to baseline (0.36 ± 0.02) (P = 0.003). Conclusion: OSAS alters various retinochoroidal parameters and timely intervention in patients with OSAS can prevent these alterations. Also, these retinochoroidal parameters could serve as one of the markers to monitor the disease progression.

Fungal Endogenous Endophthalmitis during Pregnancy as a Complication of In-Vitro Fertilization.

Purpose: To report a Candida endogenous endophthalmitis in a pregnant woman with a prior history of in-vitro fertilization (IVF).Methods: Case report.Results: 21-year-old healthy woman within the first trimester of her pregnancy of a successful IVF developed a focal retinitis and panuveitis. Ocular findings suggested fungal endophthalmitis. The patient was treated with pars plana vitrectomy and repeated intravitreal antifungal injections. No systemic therapy was given. Cultures showed Candida albicans. IVF procedure was the only identifiable risk factor for endogenous endophthalmitis.Conclusions: In-vitro fertilization appeared as a possible risk factor for endogenous endophthalmitis during pregnancy. In the absence of systemic fungal infection, local intravitreal antifungal injections seem to be effective options to treat endogenous candida endophthalmitis, especially in the first trimester.

Consensus Recommendations for the Diagnosis of Vitreoretinal Lymphoma.

PURPOSE: To provide recommendations for diagnosis of vitreoretinal lymphoma (VRL). METHODS: Literature was reviewed for reports supporting the diagnosis of VRL. A questionnaire (Delphi 1 round) was distributed to 28 participants. In the second round (Delphi 2), items of the questionnaire not reaching consensus (75% agreement) were discussed to finalize the recommendations. RESULTS: Presenting symptoms include floaters and painless loss of vision, vitreous cells organized into sheets or clumps. Retinal lesions are usually multifocal creamy/white in the outer retina. Other findings include retinal lesions with "leopard-skin" appearance and retinal pigment epithelium atrophy. Severe vitreous infiltration without macular edema is the most likely presentation. Diagnostic vitrectomy should be performed. Systemic corticosteroid should be discontinued at least 2 weeks before surgery. An interleukin (IL)-10:IL-6 ratio > 1, positive mutation for the myeloid differentiation primary response 88 gene and monoclonality are indicators of VRL. Multi-modal imaging (optical coherence tomography, fundus autofluorescence) are recommended. CONCLUSIONS: A consensus meeting allowed the establishment of recommendations important for the diagnosis of VRL.

Drug-induced Uveitis in HIV Patients with Ocular Opportunistic Infections.

Purpose: To describe drug-induced uveitis in immunocompromised patients diagnosed with Human Immunodeficiency Virus (HIV) infection Methods: Narrative Review Results: Systemic and intraocular medications administered for the treatment of acquired immune deficiency syndrome (AIDS)-associated diseases in patients infected with HIV are a well-known cause of uveitis. Conclusions: Cidofovir and rifabutin, among other novel anti-retroviral therapies, are strongly associated with drug-induced uveitis. It is imperative to understand the pathogenesis, clinical findings, and management of HIV patients with uveitis induced by these agents.

Choroidal structural changes in preterm children with and without retinopathy of prematurity.

PURPOSE: Evaluate choroidal structural changes in preterm children with and without retinopathy of prematurity (ROP) using image binarization technique on swept-source optical coherence tomography (SS-OCT) scans. METHODS: Prospective case-control study. Forty-one (79 eyes) children aged 5-15 years with a history of preterm birth and 33 (63 eyes) age-matched full-term children were recruited. Demographics including gestational age at birth, birth weight and history of ROP were documented. All subjects had undergone complete eye examinations, including best-corrected visual acuity and SS-OCT imaging. Subfoveal choroidal thickness (SFCT) was calculated, and images were binarized to obtain stromal and luminal areas (LA). The choroidal vascularity index (CVI) was derived from the proportion of LA to the total subfoveal choroidal area. RESULTS: There were no significant differences in SFCT between the preterm children with (286.63 ± 83.98 µm) or without (306.59 ± 77.29 µm) ROP and the full-term children (311.82 ± 42.87; p = 0.20 and 0.67, respectively). The CVI was significantly reduced in the preterm children with ROP (68.66 ± 3.24%; p = 0.005) compared with the CVI in the full-term control group (71.37 ± 3.63%); however, the CVI in the preterm children without ROP (71.68 ± 3.09%; p = 0.93) was not significantly affected. CONCLUSION: The reduced CVI in preterm children with ROP may indicate compromised choroidal vascularity. The CVI was found to be a more sensitive OCT biomarker than the SFCT and may be helpful in evaluating associated choroidal structural changes in preterm children, especially those with a history of ROP.

Lessons in Digital Epidemiology from COTS-1: Coordinating Multicentre Research across 10 Countries Using Operational and Technology Innovation to Overcome Funding Deficiencies.

Purpose: There is controversy regarding the diagnosis and management of ocular tuberculosis (TB) due to lack of robust evidence. The Collaborative Ocular Tuberculosis Study (COTS) was conducted in stages to enable swift, accurate data collection across 25 participating centers.Method: Data collection was facilitated by a cloud-based data aggregation platform with programmed logic based on anecdotal evidence from uveitis experts corroborated with literature review.Results: The platform enabled standardization of interpretation and collection of data from patient medical records. The pre-programmed logic also ensured the platform only prompted the entry of relevant data based on initial data entered for each unit of analysis. This enabled collection of the vast amounts of data without compromising either of the breadth nor the depth of data collection.Conclusion: The final output from this effort was an in-depth retrospective analysis to facilitate the design of future prospective investigations on ocular TB and develop best practice guidelines.

Ocular surface manifestations of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis.

PURPOSE: This study was performed to determine the occurrence of ocular surface manifestations in patients diagnosed with coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: A systematic search of electronic databases i.e. PubMed, Web of Science, CINAHL, OVID and Google scholar was performed using a comprehensive search strategy. The searches were current through 31st May 2020. Pooled data from cross-sectional studies was used for meta-analysis and a narrative synthesis was conducted for studies where a meta-analysis was not feasible. RESULTS: A total of 16 studies reporting 2347 confirmed COVID-19 cases were included. Pooled data showed that 11.64% of COVID-19 patients had ocular surface manifestations. Ocular pain (31.2%), discharge (19.2%), redness (10.8%), and follicular conjunctivitis (7.7%) were the main features. 6.9% patients with ocular manifestations had severe pneumonia. Viral RNA was detected from the ocular specimens in 3.5% patients. CONCLUSION: The most common reported ocular presentations of COVID-19 included ocular pain, redness, discharge, and follicular conjunctivitis. A small proportion of patients had viral RNA in their conjunctival/tear samples. The available studies show significant publication bias and heterogeneity. Prospective studies with methodical collection and data reporting are needed for evaluation of ocular involvement in COVID-19.

Effect of weight loss on the retinochoroidal structural alterations among patients with exogenous obesity.

PURPOSE: To evaluate the changes in the retinochoroidal vasculature in patients with exogenous obesity using swept-source optical coherence tomography (SS-OCT) and OCT angiography (OCTA). METHODS: In this prospective study, 60 patients diagnosed with obesity (47 males) (mean age: 46.47±10.9 years) were included, of which 30 patients underwent bariatric surgery (Group A), and 30 patients underwent conservative management (exercise/diet) (Group B). Parameters including choroidal thickness (CT), choroidal vascularity index (CVI) and retinal capillary density index (CDI) and arteriovenous ratio (AVR) were measured at the baseline and three months follow up. 30 eyes (30 age and gender-matched) of normal participants were included for comparison. RESULTS: Baseline CT was lower in 60 participants with obesity compared to controls. Compared with normal subjects, subjects with obesity had higher mean CVI (0.66±0.02 versus 0.63±0.04; p<0.01), smaller FAZ area (0.26±0.07 versus 0.45±0.32; p<0.01), higher CDI (superficial plexus: 0.7±0.04 versus 0.68±0.06; p = 0.04, deep plexus: 0.38±0.02 versus 0.35±0.06; p = 0.01), and lower AVR (0.68±0.05 versus 0.70±0.03 versus; p<0.01). At 3-month after intervention, CT showed a significant increase in participants from Group A (329.27±79µm; p<0.01) but not in Group B from baseline. No significant change was noted in CVI or CDI at 3-month in either group compared to baseline. AVR significantly increased in Group B (p = 0.03). CONCLUSION: Subclinical changes in retinochoroidal vasculature occurs in participants with exogenous obesity compared to healthy subjects. Surgical intervention (bariatric surgery) may have a favorable outcome on the choroidal thickness in these patients.

Management of Intraocular Infections in HIV.

Purpose: Overview of treatment options for the most common intraocular opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS), including ocular syphilis, ocular tuberculosis, toxoplasmic chorioretinitis, and viral retinitis. Method: Narrative Review. Results: Despite the huge advances in the development of combined antiretroviral therapy (cART) for the management of patients with human immunodeficiency virus (HIV) infection, opportunistic infections still represent a significant diagnostic dilemma and cause of ocular morbidity in patients with HIV. Conclusion: Although the treatment of intraocular infections in patients with AIDS may be challenging, prompt assessment of the clinical features and appropriate aggressive management of the underlying etiology are critical to avoid life and vision threatening.