Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis. Recent evidence supports the hypothesis that targeting both VEGF and Ang-2 may improve clinical outcomes in DME and nAMD compared with targeting VEGF alone by enhancing vascular stability, resulting in reduced macular leakage, prevention of neovascularization, and diminished inflammation. Faricimab, a novel bispecific antibody that targets VEGF-A and Ang-2, has been evaluated in clinical trials for DME (YOSEMITE/RHINE) and nAMD (TENAYA/LUCERNE). These trials evaluated faricimab against the anti-VEGFA/B and anti-placental growth factor fusion protein aflibercept, both administered by intravitreal injection. In addition to faricimab efficacy, safety, and pharmacokinetics, durability was evaluated during the trials using a treat-and-extend regimen. At 1 year, faricimab demonstrated non-inferior vision gains versus aflibercept across YOSEMITE/RHINE and TENAYA/LUCERNE. In YOSEMITE/RHINE, faricimab improved anatomic parameters versus aflibercept. Reduction of central subfield thickness (CST), and absence of both DME and intraretinal fluid were greater in faricimab- versus aflibercept-treated eyes. In TENAYA/LUCERNE, CST reductions were greater for faricimab than aflibercept at the end of the head-to-head phase (0-12 weeks), and were comparable with aflibercept at year 1, but with less frequent dosing. CST and vision gains were maintained during year 2 of both YOSEMITE/RHINE and TENAYA/LUCERNE. These findings suggest that dual Ang-2/VEGF-A pathway inhibition may result in greater disease control versus anti-VEGF alone, potentially addressing the unmet needs and reducing treatment burden, and improving real-world outcomes and compliance in retinal vascular diseases. Long-term extension studies (RHONE-X, AVONELLE-X) are ongoing. Current evidence suggests that dual inhibition with faricimab heralds the beginning of multitargeted treatment strategies inhibiting multiple, independent components of retinal pathology, with faricimab providing opportunities to reduce treatment burden and improve outcomes compared with anti-VEGF monotherapy.

Repeatability of a Virtual Reality Headset Perimeter in Glaucoma and Ocular Hypertensive Patients.

Purpose: The VisuALL S is an automated, static threshold, virtual reality-based perimeter for mobile evaluation of the visual field. We examined same-day and 3-month repeatability. Methods: Adult participants with a diagnosis of glaucoma or ocular hypertension underwent two VisuALL 24-2 Normal T- Full threshold strategy tests at baseline and one additional exam at 3 months for each eligible eye. Spearman, intraclass correlation coefficients (ICCs), and Bland-Altman plots were used to assess the correlation of individual point sensitivities and mean deviation (MD) among three tests. Results: Eighty-eight eyes (44 participants) were included. Average age was 68.1 ± 14.3 years, and 60.7% were male. VisuALL MD was highly correlated between tests (intravisit: r = 0.89, intervisit: r = 0.82; P < 0.001 for both). Bland-Altman analysis showed an average difference in intravisit MD of -0.67 dB (95% confidence interval [CI], -6.04 to 4.71 dB) and -0.15 dB (95% CI, -8.04 to 7.73 dB) for intervisit exams. Eight-five percent of pointwise intravisit ICCs were above 0.75 (range, 0.63 to 0.93), and 65% of pointwise intervisit ICCs were above 0.75 (range, 0.55 to 0.91). Conclusions: VisuALL demonstrated high correlation of MD between tests and good repeatability for individual point sensitivities among three tests in 3 months, except at the points around the blind spot and superiorly. Translational Relevance: The preliminary reproducibility results for VisuALL are encouraging. Its portable design makes it a potentially useful tool for patients with glaucoma, enabling more frequent assessments both at home and in clinical settings.

Report From the 2022 Mary Tyler Moore Vision Initiative Diabetic Retinal Disease Clinical Endpoints Workshop.

The Mary Tyler Moore Vision Initiative Diabetic Retinal Disease (DRD) Clinical Endpoints Workshop was held on October 22, 2022 to accelerate progress toward establishment of useful clinical and research endpoints and development of new therapeutics that have important relevance across the full spectrum of DRD pathology. More than 90 patient representatives, clinicians, scientists, funding and regulatory agencies, diagnostic, therapeutic and biotech industry representatives discussed the needs for new diagnostic and therapeutic approaches to prevent and restore retinal neurovascular unit integrity. Phase I of the MTM Vision Initiative plans, notably updating the DRD staging system and severity scale, establishing a human ocular biorepository and resource, and clinical endpoints and biomarker development and validation, was emphasized.

Participant Experience Using Novel Perimetry Tests to Monitor Glaucoma Progression.

PRCIS: Participant surveys taken after using tablet-based and smart visual function analyzer (SVFA) perimetry tests suggest that patients may prefer novel perimetry tests over traditional visual field machines. PURPOSE: Compare patient experience using the IMOvifa SVFA and the tablet-based Melbourne Rapid Fields visual field (VF) tests to the Humphrey Field 24-2 Swedish Interactive Threshold Algorithm Standard. PATIENTS AND METHODS: Prospective observational cohort study on adult participants with diagnoses of glaucoma suspect, ocular hypertension, or glaucoma. Participants attended 2 study visits ~3 months apart. During the first visit, participants were trained to use the 2 novel perimeters, took 1 test on both new devices and the Humphrey Field Analyzer, then were surveyed. Participants received tablets and performed weekly tablet VF tests at home between study visits. At the final study visit, participants re-took the VF tests and completed the same surveys. RESULTS: Eighty-one participants were surveyed twice. At the baseline survey, participants preferred the SVFA (71.7%) and tablet tests (69.2%) over the Humphrey VF. Most were willing to perform weekly monitoring at home on the SVFA (69.1%) and tablet (75.4%). Participants generally had a "very good" overall experience when testing on the SVFA (71.6%) and tablet (90.1%). At the final visit, fewer participants were willing to test on the tablet daily (23.5% to 9.9%; P = 0.02 for change) and more were willing to test monthly (18.5% to 33.3%; P = 0.03 for change). CONCLUSION: Users reported a preference for novel VF devices. Overall participant experience using these devices was positive, supporting the feasibility of home monitoring of VFs from an experience perspective.

Lens extraction versus laser peripheral iridotomy for acute primary angle closure.

BACKGROUND: Acute primary angle closure (APAC) is a potentially blinding condition. It is one of the few ophthalmic emergencies and carries high rates of visual morbidity in the absence of timely intervention. Laser peripheral iridotomy (LPI) has been the standard of care thus far. However, LPI does not eliminate the long-term risk of chronic angle closure glaucoma and other associated sequelae. There has been increasing interest in lens extraction as the primary treatment for the spectrum of primary angle closure disease, and it is as yet unclear whether these results can be extrapolated to APAC, and whether lens extraction provides better long-term outcomes. We therefore sought to evaluate the effectiveness of lens extraction in APAC to help inform the decision-making process.  OBJECTIVES: To assess the effect of lens extraction compared to LPI in the treatment of APAC. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2022, Issue 1), Ovid MEDLINE, Ovid MEDLINE E-pub Ahead of Print, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily (January 1946 to 10 January 2022), Embase (January 1947 to 10 January 2022), PubMed (1946 to 10 January 2022), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to 10 January 2022), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search. We last searched the electronic databases on 10 January 2022. SELECTION CRITERIA: We included randomized controlled clinical trials comparing lens extraction against LPI in adult participants ( ≥ 35 years) with APAC in one or both eyes. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and assessed the certainty of the body of evidence for prespecified outcomes using the GRADE approach. MAIN RESULTS: We included two studies conducted in Hong Kong and Singapore, comprising 99 eyes (99 participants) of predominantly Chinese origin. The two studies compared LPI with phacoemulsification performed by experienced surgeons. We assessed that both studies were at high risk of bias. There were no studies evaluating other types of lens extraction procedures.  Phacoemulsification may result in an increased proportion of participants with intraocular pressure (IOP) control compared with LPI at 18 to 24 months (risk ratio (RR) 1.66, 95% confidence interval (CI) 1.28 to 2.15; 2 studies, n = 97; low certainty evidence) and may reduce the need for further IOP-lowering surgery within 24 months (RR 0.07, 96% CI 0.01 to 0.51; 2 studies, n = 99; very low certainty evidence). Phacoemulsification may result in a lower mean IOP at 12 months compared to LPI (mean difference (MD) -3.20, 95% CI -4.79 to -1.61; 1 study, n = 62; low certainty evidence) and a slightly lower mean number of IOP-lowering medications at 18 months (MD -0.87, 95% CI -1.28 to -0.46; 1 study, n = 60; low certainty evidence), but this may not be clinically significant. Phacoemulsification may have little to no effect on the proportion of participants with one or more recurrent APAC episodes in the same eye (RR 0.32, 95% CI 0.01 to 7.30; 1 study, n = 37; very low certainty evidence). Phacoemulsification may result in a wider iridocorneal angle assessed by Shaffer grading at six months (MD 1.15, 95% CI 0.83 to 1.47; 1 study, n = 62; very low certainty evidence). Phacoemulsification may have little to no effect on logMAR best-corrected visual acuity (BCVA) at six months (MD -0.09, 95% CI -0.20 to 0.02; 2 studies, n = 94; very low certainty evidence). There was no evidence of a difference in the extent of peripheral anterior synechiae (PAS) (clock hours) between intervention arms at 6 months (MD -1.86, 95% CI -7.03 to 3.32; 2 studies, n = 94; very low certainty evidence), although the phacoemulsification group may have less PAS (degrees) at 12 months (MD -94.20, 95% CI -140.37 to -48.03; 1 study, n = 62) and 18 months (MD -127.30, 95% CI -168.91 to -85.69; 1 study, n = 60).  In one study, there were 26 adverse events in the phacoemulsification group: intraoperative corneal edema (n = 12), posterior capsular rupture (n = 1), intraoperative bleeding from iris root (n = 1), postoperative fibrinous anterior chamber reaction (n = 7), and visually significant posterior capsular opacification (n = 5), and no cases of suprachoroidal hemorrhage or endophthalmitis. There were four adverse events in the LPI group: closed iridotomy (n = 1) and small iridotomies that required supplementary laser (n = 3). In the other study, there was one adverse event in the phacoemulsification group (IOP > 30 mmHg on day 1 postoperatively (n = 1)), and no intraoperative complications. There were five adverse events in the LPI group: transient hemorrhage (n = 1), corneal burn (n = 1), and repeated LPI because of non-patency (n = 3).  Neither study reported health- or vision-related quality of life measures. AUTHORS' CONCLUSIONS: Low certainty evidence suggests that early lens extraction may produce more favorable outcomes compared to initial LPI in terms of IOP control. Evidence for other outcomes is less clear. Future high-quality and longer-term studies evaluating the effects of either intervention on the development of glaucomatous damage and visual field changes as well as health-related quality of life measures would be helpful.

Comparison of Perimetric Outcomes from a Tablet Perimeter, Smart Visual Function Analyzer, and Humphrey Field Analyzer.

PURPOSE: The tablet-based Melbourne Rapid Fields (MRF) visual field (VF) test and the IMOvifa Smart Visual Function Analyzer (SVFA) are portable perimeters that may allow for at-home monitoring and more frequent testing. We compared tablet and SVFA results with outputs from the Humphrey Field Analyzer (HFA) 24-2 Swedish Interactive Threshold Algorithm Standard program. DESIGN: Observational cross-sectional study. SUBJECTS: Adult participants with a diagnosis of glaucoma, suspected glaucoma, or ocular hypertension seen in the Massachusetts Eye and Ear glaucoma clinic were enrolled. All participants were reliable and experienced HFA testers. METHODS: Participants were tested with the SVFA and HFA. The study staff also trained participants on the MRF tablet with instructions to take weekly tests at home for 3 months. Visual field results from the 3 devices were compared. MAIN OUTCOME MEASURES: Mean deviation (MD), pattern standard deviation (PSD), reliability parameters, and point sensitivity. RESULTS: Overall, 79 participants (133 eyes) with a mean age of 61 ± 13 years (range, 26-79 years) were included; 59% of the participants were female, and the mean HFA MD was -2.7 ± 3.9 dB. The global indices of MD and PSD did not significantly vary between HFA and the 2 novel devices, except that the tablet VF reported a 0.6 dB higher PSD compared with HFA. However, tablet and SVFA sensitivities significantly differed from those of the HFA at 36 and 39 locations, respectively, out of 52 locations. Relative to HFA, the tablet overestimated light sensitivity in the nasal field while underestimating the temporal field. The SVFA generally underestimated light sensitivity, but its results were more similar to HFA results compared with the tablet. CONCLUSIONS: Although average MD values from the 2 novel devices suggest that they provide similar results to the HFA, point-by-point comparisons highlight notable deviations. Differences in specific point sensitivity values were significant, especially between the tablet and the other 2 devices. These differences may in part be explained by differences in the devices' normative databases as well as how MD is calculated. However, the tablet had substantial differences based on location, indicating that the tablet design itself may be responsible for differences in local sensitivities. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Cataract progression after Nd:YAG laser iridotomy in primary angle-closure suspect eyes.

BACKGROUND/AIMS: Prophylactic laser peripheral iridotomy (LPI) is performed in primary angle-closure suspect (PACS) eyes to prevent acute angle-closure attacks. However, accelerated cataractogenesis is a potential risk of the procedure that may result in decreased visual acuity. We aimed to assess the long-term impact of LPI on cataract formation in Chinese PACS. METHODS: In the Zhongshan Angle Closure Prevention Trial, eligible bilateral PACS participants received LPI in one randomly selected eye, while the fellow eye remained untreated. Cataract was graded using the Lens Opacity Classification System III, and progression was defined as an increase in grade by at least two units in any category or cataract surgery. RESULTS: In total, 889 participants were randomly assigned to LPI in one eye only (mean age 59±5 years, 83% female). At 72 months, treated eyes had slightly higher average nuclear grades (p<0.001). However, there were no differences between eyes for predefined cataract progression (cumulative probability at 72 months: 21.2% in LPI vs 19.4% in control, p=0.401) or cataract surgery (1% for both). While LPI-treated eyes had a 10% higher risk of progression over 6 years (HR=1.10 (95% CI 0.88 to 1.36)), this was not statistically significant. Visual acuity at 72 months was similar in treated and untreated eyes (p=0.43). CONCLUSION: Although lenses were graded on average as slightly more opaque in laser-treated eyes, prophylactic neodymium:yttrium-aluminum-garnet LPI did not cause significant cataract progression. Our results suggest that LPI treatment of asymptomatic narrow angles does not increase the risk of developing clinically meaningful cataract worsening over time. TRIAL REGISTRATION NUMBER: ISRCTN45213099.

Predictors of long-term intraocular pressure control after lens extraction in primary angle closure glaucoma: results from the EAGLE trial.

BACKGROUND/AIMS: To assess baseline ocular parameters in the prediction of long-term intraocular pressure (IOP) control after clear lens extraction (CLE) or laser peripheral iridotomy (LPI) in patients with primary angle closure (PAC) disease using data from the Effectiveness of Early Lens Extraction for the treatment of primary angle-closure glaucoma (EAGLE) tria. METHODS: This study is a secondary analysis of EAGLE data where we define the primary outcome of 'good responders' as those with IOP<21 mm Hg without requiring additional surgery and 'optimal responders' as those who in addition were medication free, at 36-month follow-up. Primary analysis was conducted using a multivariate logistic regression model to assess how randomised interventions and ocular parameters predict treatment response. RESULTS: A total of 369 patients (182 in CLE arm and 187 in LPI arm) completed the 36-month follow-up examination. After CLE, 90% met our predefined 'good response' criterion compared with 67% in the LPI arm, and 66% met 'optimal response' criterion compared with 18% in the LPI arm, with significantly longer drops/surgery-free survival time (p<0.05 for all). Patients randomised to CLE (OR=10.1 (6.1 to 16.8)), Chinese (OR=2.3 (1.3 to 3.9)), and those who had not previously used glaucoma drops (OR=2.8 (1.6 to 4.8)) were more likely to maintain long-term optimal IOP response over 36 months. CONCLUSION: Patients with primary angle closure glaucoma/PAC are 10 times more likely to maintain drop-free good IOP control with initial CLE surgery than LPI. Non-Chinese ethnicity, higher baseline IOP and using glaucoma drops prior to randomisation are predictors of worse long-term IOP response.

Visual Field Prediction: Evaluating the Clinical Relevance of Deep Learning Models.

Purpose: Two novel deep learning methods using a convolutional neural network (CNN) and a recurrent neural network (RNN) have recently been developed to forecast future visual fields (VFs). Although the original evaluations of these models focused on overall accuracy, it was not assessed whether they can accurately identify patients with progressive glaucomatous vision loss to aid clinicians in preventing further decline. We evaluated these 2 prediction models for potential biases in overestimating or underestimating VF changes over time. Design: Retrospective observational cohort study. Participants: All available and reliable Swedish Interactive Thresholding Algorithm Standard 24-2 VFs from Massachusetts Eye and Ear Glaucoma Service collected between 1999 and 2020 were extracted. Because of the methods' respective needs, the CNN data set included 54 373 samples from 7472 patients, and the RNN data set included 24 430 samples from 1809 patients. Methods: The CNN and RNN methods were reimplemented. A fivefold cross-validation procedure was performed on each model, and pointwise mean absolute error (PMAE) was used to measure prediction accuracy. Test data were stratified into categories based on the severity of VF progression to investigate the models' performances on predicting worsening cases. The models were additionally compared with a no-change model that uses the baseline VF (for the CNN) and the last-observed VF (for the RNN) for its prediction. Main Outcome Measures: PMAE in predictions. Results: The overall PMAE 95% confidence intervals were 2.21 to 2.24 decibels (dB) for the CNN and 2.56 to 2.61 dB for the RNN, which were close to the original studies' reported values. However, both models exhibited large errors in identifying patients with worsening VFs and often failed to outperform the no-change model. Pointwise mean absolute error values were higher in patients with greater changes in mean sensitivity (for the CNN) and mean total deviation (for the RNN) between baseline and follow-up VFs. Conclusions: Although our evaluation confirms the low overall PMAEs reported in the original studies, our findings also reveal that both models severely underpredict worsening of VF loss. Because the accurate detection and projection of glaucomatous VF decline is crucial in ophthalmic clinical practice, we recommend that this consideration is explicitly taken into account when developing and evaluating future deep learning models.

Acute Angle-Closure Attacks Are Uncommon in Primary Angle-Closure Suspects after Pharmacologic Mydriasis: The Zhongshan Angle-Closure Prevention Trial.

PURPOSE: Angle-closure glaucoma is a major cause of blindness worldwide that carries an excessive risk of severe, bilateral visual impairment. A common concern among clinicians is the precipitation of acute angle-closure (AAC) attacks because of mydriasis. We evaluated the risk of AAC after pharmacologic dilation in Chinese individuals classified as having bilateral primary angle-closure suspects (PACSs). DESIGN: Randomized, interventional, controlled trial. PARTICIPANTS: A total of 889 patients with bilateral PACSs, aged between 50 and 70 years, were identified through community screening in Guangzhou, China, and enrolled in the study. METHODS: In the Zhongshan Angle-Closure Prevention Trial, bilateral PACSs were treated with laser peripheral iridotomy (LPI) in 1 randomly selected eye, with the fellow eye serving as an untreated control. Over 72 months of follow-up, the participants had their pupils pharmacologically dilated 6 times with 5% phenylephrine and 0.5% tropicamide. MAIN OUTCOME MEASURES: Incidence and risk of post-mydriasis AAC in LPI-treated and untreated, control eyes classified as PACSs. RESULTS: One bilateral AAC attack occurred after mydriasis at the 2-week post-LPI visit. No other AAC events occurred in the LPI-treated eyes. In the untreated eyes, 4 additional attacks occurred: 2 occurred after dilation (1 at 54 months and 1 at 72 months of follow-up) and 2 occurred spontaneously. The risk of post-mydriasis AAC in the untreated eyes was 1 attack in 1587 dilations. The risk of spontaneous AAC in the untreated eyes was 0.44 per 1000 eye-years (95% confidence interval, 0.11-1.77 per 1000 eye-years). CONCLUSIONS: The risk of incident AAC attacks in PACSs was extremely low, even in a higher-risk group that underwent repeated pharmacologic pupillary dilation over 6 years of follow-up. Prophylactic LPI reduced this small but real risk. This trial was registered at ISRCTN.com as ISRCTN45213099.

Deep Learning for Glaucoma Detection and Identification of Novel Diagnostic Areas in Diverse Real-World Datasets.

Purpose: To develop a three-dimensional (3D) deep learning algorithm to detect glaucoma using spectral-domain optical coherence tomography (SD-OCT) optic nerve head (ONH) cube scans and validate its performance on ethnically diverse real-world datasets and on cropped ONH scans. Methods: In total, 2461 Cirrus SD-OCT ONH scans of 1012 eyes were obtained from the Glaucoma Clinic Imaging Database at the Byers Eye Institute, Stanford University, from March 2010 to December 2017. A 3D deep neural network was trained and tested on this unique raw OCT cube dataset to identify a multimodal definition of glaucoma excluding other concomitant retinal disease and optic neuropathies. A total of 1022 scans of 363 glaucomatous eyes (207 patients) and 542 scans of 291 normal eyes (167 patients) from Stanford were included in training, and 142 scans of 48 glaucomatous eyes (27 patients) and 61 scans of 39 normal eyes (23 patients) were included in the validation set. A total of 3371 scans (Cirrus SD-OCT) from four different countries were used for evaluation of the model: the non overlapping test dataset from Stanford (USA) consisted of 694 scans: 241 scans from 113 normal eyes of 66 patients and 453 scans of 157 glaucomatous eyes of 89 patients. The datasets from Hong Kong (total of 1625 scans; 666 OCT scans from 196 normal eyes of 99 patients and 959 scans of 277 glaucomatous eyes of 155 patients), India (total of 672 scans; 211 scans from 147 normal eyes of 98 patients and 461 scans from 171 glaucomatous eyes of 101 patients), and Nepal (total of 380 scans; 158 scans from 143 normal eyes of 89 patients and 222 scans from 174 glaucomatous eyes of 109 patients) were used for external evaluation. The performance of the model was then evaluated on manually cropped scans from Stanford using a new algorithm called DiagFind. The ONH region was cropped by identifying the appropriate zone of the image in the expected location relative to Bruch's Membrane Opening (BMO) using a commercially available imaging software. Subgroup analyses were performed in groups stratified by eyes, myopia severity of glaucoma, and on a set of glaucoma cases without field defects. Saliency maps were generated to highlight the areas the model used to make a prediction. The model's performance was compared to that of a glaucoma specialist using all available information on a subset of cases. Results: The 3D deep learning system achieved area under the curve (AUC) values of 0.91 (95% CI, 0.90-0.92), 0.80 (95% CI, 0.78-0.82), 0.94 (95% CI, 0.93-0.96), and 0.87 (95% CI, 0.85-0.90) on Stanford, Hong Kong, India, and Nepal datasets, respectively, to detect perimetric glaucoma and AUC values of 0.99 (95% CI, 0.97-1.00), 0.96 (95% CI, 0.93-1.00), and 0.92 (95% CI, 0.89-0.95) on severe, moderate, and mild myopia cases, respectively, and an AUC of 0.77 on cropped scans. The model achieved an AUC value of 0.92 (95% CI, 0.90-0.93) versus that of the human grader with an AUC value of 0.91 on the same subset of scans (\(P=0.99\)). The performance of the model in terms of recall on glaucoma cases without field defects was found to be 0.76 (0.68-0.85). Saliency maps highlighted the lamina cribrosa in glaucomatous eyes versus superficial retina in normal eyes as the regions associated with classification. Conclusions: A 3D convolutional neural network (CNN) trained on SD-OCT ONH cubes can distinguish glaucoma from normal cases in diverse datasets obtained from four different countries. The model trained on additional random cropping data augmentation performed reasonably on manually cropped scans, indicating the importance of lamina cribrosa in glaucoma detection. Translational Relevance: A 3D CNN trained on SD-OCT ONH cubes was developed to detect glaucoma in diverse datasets obtained from four different countries and on cropped scans. The model identified lamina cribrosa as the region associated with glaucoma detection.

Baseline vision results from the Baltimore Reading and Eye Disease Study.

OBJECTIVE: We describe the Baltimore Reading and Eye Disease Study, report baseline ocular findings, and explore the feasibility of eye examinations in the school setting. DESIGN: Prospective, school-based cohort study. PARTICIPANTS: Students in second and third grades. METHODS: Baseline eye examinations, including near and distance presenting visual acuity (VA), stereopsis, ocular alignment, dilated retinal examination, and cycloplegic refraction, were performed in 12 Baltimore public schools during the 2014-15 school year. MAIN OUTCOME MEASURES: Presenting VA, prevalence of refractive error, and other ocular findings. RESULTS: Among the 1054 eligible students, 321 participated. There were 271 (84.4%) African American and 186 (57.9%) female students; mean age was 7.9 ± 0.8 years. Cycloplegia was achieved in 308. The mean presenting distance and near VA was 0.1 ± 0.2 logMAR (range -0.1 to 1.5) and 0.1 ± 0.2 logMAR (range 0.0-1.6) in the better-seeing eye, respectively. The most common ocular findings were +1.00 diopter (D) or greater hyperopia (34.7%), -0.50 D or greater myopia (29.5%), 1.00 D or greater astigmatism (23.4%), and convergence insufficiency (7.2%). Thirty-seven (11.5%) children needed referral to an eye care provider; 10% of students required glasses full-time. CONCLUSIONS: Whereas the majority of second and third grade students in this study have good VA and minimal refractive error, 1 in 9 have an ocular finding necessitating further evaluation. It was feasible to conduct cycloplegic eye examinations in the school setting.

A 3D Deep Learning System for Detecting Referable Glaucoma Using Full OCT Macular Cube Scans.

Purpose: The purpose of this study was to develop a 3D deep learning system from spectral domain optical coherence tomography (SD-OCT) macular cubes to differentiate between referable and nonreferable cases for glaucoma applied to real-world datasets to understand how this would affect the performance. Methods: There were 2805 Cirrus optical coherence tomography (OCT) macula volumes (Macula protocol 512 × 128) of 1095 eyes from 586 patients at a single site that were used to train a fully 3D convolutional neural network (CNN). Referable glaucoma included true glaucoma, pre-perimetric glaucoma, and high-risk suspects, based on qualitative fundus photographs, visual fields, OCT reports, and clinical examinations, including intraocular pressure (IOP) and treatment history as the binary (two class) ground truth. The curated real-world dataset did not include eyes with retinal disease or nonglaucomatous optic neuropathies. The cubes were first homogenized using layer segmentation with the Orion Software (Voxeleron) to achieve standardization. The algorithm was tested on two separate external validation sets from different glaucoma studies, comprised of Cirrus macular cube scans of 505 and 336 eyes, respectively. Results: The area under the receiver operating characteristic (AUROC) curve for the development dataset for distinguishing referable glaucoma was 0.88 for our CNN using homogenization, 0.82 without homogenization, and 0.81 for a CNN architecture from the existing literature. For the external validation datasets, which had different glaucoma definitions, the AUCs were 0.78 and 0.95, respectively. The performance of the model across myopia severity distribution has been assessed in the dataset from the United States and was found to have an AUC of 0.85, 0.92, and 0.95 in the severe, moderate, and mild myopia, respectively. Conclusions: A 3D deep learning algorithm trained on macular OCT volumes without retinal disease to detect referable glaucoma performs better with retinal segmentation preprocessing and performs reasonably well across all levels of myopia. Translational Relevance: Interpretation of OCT macula volumes based on normative data color distributions is highly influenced by population demographics and characteristics, such as refractive error, as well as the size of the normative database. Referable glaucoma, in this study, was chosen to include cases that should be seen by a specialist. This study is unique because it uses multimodal patient data for the glaucoma definition, and includes all severities of myopia as well as validates the algorithm with international data to understand generalizability potential.

Laser peripheral iridotomy for the prevention of angle closure: a single-centre, randomised controlled trial.

BACKGROUND: Primary angle-closure glaucoma affects 20 million people worldwide. People classified as primary angle closure suspects have a higher but poorly quantified risk of developing glaucoma. We aimed to assess efficacy and safety of laser peripheral iridotomy prophylaxis against primary angle-closure glaucoma in Chinese people classified as primary angle closure suspects. METHODS: In this randomised controlled trial, bilateral primary angle closure suspects aged 50-70 years were enrolled at the Zhongshan Ophthalmic Center, a tertiary specialised hospital in Guangzhou, China. Eligible patients received laser peripheral iridotomy in one randomly selected eye, with the other remaining untreated. The primary outcome was incident primary angle closure disease as a composite endpoint of elevation of intraocular pressure, peripheral anterior synechiae, or acute angle-closure during 72 months of follow-up in an intention-to-treat analysis between treated eyes and contralateral controls. This trial is registered with the ISRCTN registry, number ISRCTN45213099. FINDINGS: Of 11 991 screened individuals, 889 individuals were randomly assigned from June 19, 2008 (889 treated and 889 untreated eyes). Incidence of the primary outcome was 4·19 per 1000 eye-years in treated eyes compared with 7·97 per 1000 eye-years in untreated eyes (hazard ratio 0·53; 95% CI 0·30-0·92; p=0·024). A primary outcome event occurred in 19 treated eyes and 36 untreated eyes with a statistically significant difference using pair-wise analysis (p=0·0041). No serious adverse events were observed during follow-up. INTERPRETATION: Incidence of angle-closure disease was very low among individuals classified as primary angle closure suspects identified through community-based screening. Laser peripheral iridotomy had a modest, albeit significant, prophylactic effect. In view of the low incidence rate of outcomes that have no immediate threat to vision, the benefit of prophylactic laser peripheral iridotomy is limited; therefore, widespread prophylactic laser peripheral iridotomy for primary angle-closure suspects is not recommended. FUNDING: Fight for Sight, the Sun Yat-Sen University 5010 Project Fund, Moorfields Eye Charity, and the National Natural Science Foundation of China.

Darkroom prone provocative testing in primary angle closure suspects and those with open angles.

PURPOSE: To describe the results of darkroom prone provocative testing (DRPPT) in primary angle closure suspects (PACS) and to compare the findings to controls with open angles. METHODS: 889 subjects with PACS in the Zhongshan Angle Closure Prevention Trial (a randomised controlled trial to compare prophylactic laser iridotomy to no treatment in PACS) and 89 with open angles in the 5-year follow-up of Liwan Eye Study were placed in a darkroom face down for 15 min. Intraocular pressure (IOP) was measured immediately before and after DRPPT. RESULTS: PACS participants were of similar age than controls (59.3 vs 60.5), more often female (82.9% vs 58.4%) and had lower IOP (14.3 vs 15.2 mm Hg). The average IOP increases after DRPPT was 4.3±3 mm Hg in PACS and 5.2±2.8 in controls (p<0.05). 20.5% of controls and 13.9 % of those with PACS developed an IOP spike ≥8 mm Hg after DRPPT (p<0.05). Among PACS, 15.8 % of those with all four quadrants closed had an IOP elevation of ≥ 8 mm Hg as opposed to 10.0%-12.4 % with two or three closed quadrants (p<0.05). DRPPT failed to predict who would reach a clinical trial endpoint over 6-year follow-up of those with PACS. CONCLUSIONS: A modified DRPPT failed to separate PACS from those with open angle. Although the test resulted in greater IOP elevation among those PACS participants with all four quadrants closed than in those with two or three closed quadrants, it did not offer any insight into the risk of developing acute or chronic angle closure disease over 6-year follow-up.

The Relationship Between Quantitative Pupillometry and Estimated Ganglion Cell Counts in Patients With Glaucoma.

PURPOSE: To assess the relationship between pupillary light reflex and estimated retinal ganglion cell (RGC) counts in patients with glaucoma. METHODS: We recorded and analyzed pupil responses using an automated binocular pupillometer in 148 patients with glaucoma (mean age 67±11, 49% female) and 71 controls (age 60±9.6, 69% female) as part of a prospective clinical study. The amplitude of pupil constriction was calculated as the percentage change in pupil diameter between constriction onset and peak constriction in response to controlled stimuli. The magnitude of a relative afferent pupillary defect (RAPD) was defined as the log of the ratio of the amplitude between 2 eyes multiplied by 10. RGC counts were estimated using empirical formulas that combine estimates from both functional (eccentricity and sensitivity measured by standard automated perimetry) and structural (retinal nerve fiber layer thickness) tests. For analyses performed at the level of individual eyes, we used multilevel modeling to account for between-eye correlations within individuals. RESULTS: Eyes with higher estimated RGC counts had a larger pupil response amplitude (z-score=8.24, P<0.001), shorter latency (z=-3.17, P=0.002), faster constriction velocity (z=6.64, P<0.001), shorter time to maximum constriction (z=-1.96, P=0.049), and longer time to maximum dilation (z=6.66, P<0.001). For every 0.3 log unit difference in RAPD score, there was an average decrease in estimated RGC count of 37,817 (P<0.001). CONCLUSIONS: There is a statistically significant association between estimated RGC count and pupillary response to stimuli. Quantitative pupillography may be useful in diagnosis and monitoring of optic neuropathies.

Results From a Modified Bleb Needling Procedure With Continuous Infusion Performed in the Operating Room.

PURPOSE: Needling of a scarred trabeculectomy bleb is often performed in the office using a slit-lamp microscope as an alternative to additional surgery to lower intraocular pressure (IOP). However, the success rate in an office setting is highly variable, with reported success rates as low as 13%. We report a retrospective assessment of an intraoperative needling technique for reviving failed blebs. DESIGN: A retrospective chart review. PARTICIPANTS: Patients undergoing the intraoperative modified bleb revision technique in the setting of a failed trabeculectomy due to scarring at the Wilmer Eye Institute, Johns Hopkins Hospital between August 16, 2010 and August 29, 2012. METHODS: Patients with uncontrolled IOP were operated on using a modified bleb needling technique. In this technique, a 25-G infusion cannula is placed in the anterior chamber and fibrotic adhesions within the bleb are lysed with a 25-G needle. The continuous infusion of balanced salt solution from the anterior chamber causes bleb elevation, which helps to guide the endpoint of lysis for the procedure. A subconjunctival injection of 5-fluorouracil is given at the conclusion of each case. MAIN OUTCOME MEASURES: IOP reduction and number of glaucoma medications at postoperative day 1, week 1, month 1, month 3, month 6, and month 12. RESULTS: A total of 33 eyes of 30 patients were included. At the visit before the procedure, the mean (±SD) IOP was 22.1±9.2 (range, 11 to 58) and subjects were using an average of 2.3±1.4 (range, 0 to 4) glaucoma medications. The mean IOP reduction was 8.7 mm Hg [95% confidence interval (CI), 5.6-11.8] at postoperative day 1, 8.1 mm Hg (95% CI, 4.0-12.3) at week 1, 8.9 mm Hg (95% CI, 5.3-12.5) at month 1, 8.1 mm Hg (95% CI, 4.2-12.0) at month 3, 8.2 mm Hg (95% CI, 3.9-12.5) at month 6, and 6.2 mm Hg (95% CI, 3.6-8.7) at month 12. IOP was reduced about 30% to 40% compared with baseline at each time point (P<0.05). The average reduction in medications used was 1.7 at day 1, 1.0 at month 1, 1.2 at month 3, 1.5 at month 6, and 0.5 at month 12. Seven patients underwent repeat needling. Overall, 64% of subjects maintained IOP at or below their target after 12 months. CONCLUSIONS: A modified bleb needling procedure performed in the operating room can successfully lower IOP in the setting of a previous trabeculectomy in over 60% of subjects a year after the procedure.

The Association between Near Work Activities and Myopia in Children-A Systematic Review and Meta-Analysis.

Myopia has a multifactorial etiology, although environmental factors are predominant in determining its current patterns. Currently, associations between near work activities and myopia have not been consistently observed. Therefore, we performed a systematic review to quantify the effect of near work activities on myopia in children. Relevant articles published between 1989 and 2014 were identified in MEDLINE, Embase, and the Cochrane Library, and the citation lists were reviewed. Twelve cohort studies and 15 cross-sectional studies were included (25,025 children aged between 6 and 18 years). The I2 statistic was used to assess heterogeneity. Study-level data were pooled using a random-effects model or a fixed-effects model (when less than 5 studies were included). We found that more time spent on near work activities was associated with higher odds of myopia (odds ratio [OR] = 1.14; 95% confidence interval [CI] = 1.08-1.20) and that the odds of myopia increased by 2% (OR:1.02; 95% CI = 1.01-1.03) for every one diopter-hour (hr) more of near work per week. Therefore, the development of a strategy to reduce the impact of near work on myopia would be important for preventing myopia in children.

Electronic monitoring to assess adherence with once-daily glaucoma medications and risk factors for nonadherence: the automated dosing reminder study.

IMPORTANCE: Adherence with topical glaucoma medications is low in some patients. To identify these patients, we need more information on risk factors for nonadherence. OBJECTIVE: To assess adherence with once-daily glaucoma medication. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study involving patients who were recruited from a university-based glaucoma clinic and treated with once-daily prostaglandin eyedrops. Baseline characteristics were recorded, and each patient was provided a medication bottle to hold his or her eyedrop bottle throughout the study. An electronic cap recorded each time the larger bottle holding the eyedrops was opened. Participants were administered standardized tests of depression and mental status and answered questions about their health and their attitudes toward medication adherence. They used the electronic monitors for 3 months, during which their adherence with medications was assessed. MAIN OUTCOMES AND MEASURES: Adherence with daily glaucoma medication and factors associated with poor adherence. RESULTS: Of the 491 participants enrolled, 407 (82.9%) successfully completed the 3-month adherence assessment. Of this group, 337 (82.8%) took their medication correctly on at least 75% of days and were deemed adherent. Compared with this adherent group, the 70 participants (17.2%) who were nonadherent were slightly younger, were more likely to be of African descent, took medications for a shorter time, had a lower level of educational attainment, and had worse scores on mental status and depression scales (P < .05 for all). Nonadherent participants were less likely to be able to name their glaucoma medications, reported a lower estimate of adherence, and were more likely to admit some missed doses over the past 2 weeks or in general (P < .05 for all). Those who were nonadherent were also less likely to agree that remembering their eyedrops is easy, more likely to strongly agree with the statement that eyedrops can cause problems, and less likely to agree that they followed physicians' orders. CONCLUSIONS AND RELEVANCE: Electronic monitoring of patient adherence documented that a sizable number of patients with glaucoma do not take their medications as prescribed. Factors were identified that may prove useful in targeting those nonadherent patients for interventions.