EYEMATE-SC Trial: Twelve-Month Safety, Performance, and Accuracy of a Suprachoroidal Sensor for Telemetric Measurement of Intraocular Pressure.

PURPOSE: Measuring and controlling intraocular pressure (IOP) provide the foundation for glaucoma treatment. Self-tonometry has been proposed as an alternative to measure IOP throughout the entire day better. The novel EYEMATE-SC sensor (Implandata) is implanted in the suprachoroidal space to enable contactless continual IOP monitoring. The aim of the present study was to investigate the 1-year safety, performance, and accuracy of the EYEMATE-SC in patients with primary open-angle glaucoma undergoing simultaneous nonpenetrating glaucoma surgery (NPGS). DESIGN: Prospective, multicenter, open-label, single-arm, interventional clinical trial. PARTICIPANTS: Twenty-four eyes of 24 patients with primary open-angle glaucoma who were due to undergo NPGS (canaloplasty or deep sclerectomy). METHODS: An EYEMATE-SC sensor was implanted during NPGS. Goldmann applanation tonometry (GAT) measurements were compared with the sensors' IOP measurements at all postoperative visits through 12 months. MAIN OUTCOME MEASURES: Device position and adverse events. RESULTS: Fifteen eyes underwent canaloplasty, and 9 underwent deep sclerectomy. Successful implantation of the sensor was achieved in all eyes with no reported intraoperative difficulties. Through the 12-month follow-up, no device migration, dislocation, or serious device-related complications were recorded. A total of 536 EYEMATE-SC measurements were pairwise included in the IOP agreement analysis. The overall mean difference between GAT and EYEMATE-SC measurements was 0.8 mmHg (95% confidence interval [CI] of the limits of agreement [LoA], -5.1 to 6.7 mmHg). The agreement gradually improved, and from 3 months after surgery until the end of the follow-up, the mean difference was -0.2 mmHg (95% CI of LoA, -4.6 to 4.2 mmHg) over a total of 264 EYEMATE-SC measurements, and 100% of measurements were within ±5 mmHg of GAT. CONCLUSIONS: The EYEMATE-SC sensor was safe and well tolerated through 12 months. Moreover, it allowed accurate, continuous IOP monitoring. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Fast Progressors in Glaucoma: Prevalence Based on Global and Central Visual Field Loss.

PURPOSE: To determine the prevalence of fast global and central visual field (VF) progression in individuals with glaucoma under routine care. DESIGN: Observational study. PARTICIPANTS: Six hundred ninety-three eyes of 461 individuals with glaucoma followed up over a median of 4.5 years. METHODS: This study included (1) patients at a private ophthalmology clinic in Melbourne, Australia, and (2) individuals in 2 prospective longitudinal observational studies across 3 sites in the United States. All individuals had a diagnosis of glaucoma and were under routine care, and had performed 5 or more reliable 24-2 VF tests over a 1- to 5-year period. Ordinary least squares regression analyses were used to calculate the rate of global mean deviation (MD) change over time and the rate of the mean total deviation values of the 12 test locations within the central 10° region (MTD10) for each eye. MAIN OUTCOME MEASURES: Prevalence of progression based on the rate of MD and the MTD10 change across various fixed cutoffs and cutoffs based on the estimated normal distribution (from the positive slopes). RESULTS: Based on the MD and the MTD10, 12.5% and 11.7% of the eyes, respectively, exhibited a rate of change that was less than -1.0 dB/year (being a rate that typically is defined as "fast progression" for MD values), and 29.0% of the eyes showed a change of less than -0.5 dB/year on MTD10. Furthermore, 12.7% and 9.1% of the eyes exhibited a rate of change that exceeded the 1% cutoff of the estimated normal distribution MD and the MTD10 values, respectively. CONCLUSIONS: This study found that approximately 1 in 8 eyes with glaucoma receiving routine care showed fast progression based on global MD values (< -1.0 dB/year) and that nearly 1 in 3 eyes showed a < -0.5 dB/year decline centrally. These findings highlight the clinical importance of assessing progressive central VF loss and reinforce the need for new therapies to prevent functional disability in a notable proportion of individuals who continue to exhibit fast progression. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

High Myopia Normative Database of Peripapillary Retinal Nerve Fiber Layer Thickness to Detect Myopic Glaucoma in a Chinese Population.

PURPOSE: To develop and validate the performance of a high myopia (HM)-specific normative database of peripapillary retinal nerve fiber layer (pRNFL) thickness in differentiating HM from highly myopic glaucoma (HMG). DESIGN: Cross-sectional multicenter study. PARTICIPANTS: A total of 1367 Chinese participants (2325 eyes) with nonpathologic HM or HMG were included from 4 centers. After quality control, 1108 eyes from 694 participants with HM were included in the normative database; 459 eyes from 408 participants (323 eyes with HM and 136 eyes with HMG) and 322 eyes from 197 participants (131 eyes with HM and 191 eyes with HMG) were included in the internal and external validation sets, respectively. Only HMG eyes with an intraocular pressure > 21 mmHg were included. METHODS: The pRNFL thickness was measured with swept-source (SS) OCT. Four strategies of pRNFL-specified values were examined, including global and quadrantic pRNFL thickness below the lowest fifth or the lowest first percentile of the normative database. MAIN OUTCOMES MEASURES: The accuracy, sensitivity, and specificity of the HM-specific normative database for detecting HMG. RESULTS: Setting the fifth percentile of the global pRNFL thickness as the threshold, using the HM-specific normative database, we achieved an accuracy of 0.93 (95% confidence interval [CI], 0.90-0.95) and 0.85 (95% CI, 0.81-0.89), and, using the first percentile as the threshold, we acheived an accuracy of 0.85 (95% CI, 0.81-0.88) and 0.70 (95% CI, 0.65-0.75) in detecting HMG in the internal and external validation sets, respectively. The fifth percentile of the global pRNFL thickness achieved high sensitivities of 0.75 (95% CI, 0.67-0.82) and 0.75 (95% CI, 0.68-0.81) and specificities of 1.00 (95% CI, 0.99-1.00) and 1.00 (95% CI, 0.97-1.00) in the internal and external validation datasets, respectively. Compared with the built-in database of the OCT device, the HM-specific normative database showed a higher sensitivity and specificity than the corresponding pRNFL thickness below the fifth or first percentile (P < 0.001 for all). CONCLUSIONS: The HM-specific normative database is more capable of detecting HMG eyes than the SS OCT built-in database, which may be an effective tool for differential diagnosis between HMG and HM. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma.

Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis.

Quality of life in glaucoma.

BACKGROUND: An essential goal of glaucoma management is to prevent a patient's visual impairment that compromises their health-related quality of life (QOL). The disease itself, in addition to the medical or surgical treatment, can have a large impact on one's life. We aim to briefly review and evaluate aspects of QOL in glaucoma. METHODS: The PubMed database was utilized for the literature examination of this review. Keywords that were searched included glaucoma, quality of life, vision-related QOL (VRQOL), quality of life questionnaire, and glaucoma therapy. RESULTS: The main topics identified and analyzed during the literature review stages include factors affecting VRQOL, the assessment of VRQOL using questionnaires, QOL in early and severe glaucoma, glaucoma and activities of daily living, glaucoma treatments, and new advances in clinically assessing QOL. The study findings indicate a relationship between the deterioration of visual field and the quality of life. The investigation shows that visual loss can result in a range of daily life challenges, which include compromised mental health status and difficulties with driving, reading, and recognizing people. CONCLUSION: Glaucoma-induced visual field loss can significantly impact different aspects of patients' life, and several methods exist for evaluating changes in quality of life. Quality of life assessments have their limitations as they are subjective. As potential future steps, we suggest exploring technological advancements such as virtual reality to improve patient care and outcomes.

Mental health and social support among glaucoma patients enrolled in the NIH All of Us COVID-19 Participant Experience (COPE) survey.

BACKGROUND: The COVID-19 pandemic created many challenges for our society. In this study, we explore how measures of mental health, coping strategies, and social support during the pandemic varied by glaucoma status. METHODS: A cohort of patients aged 40 and over enrolled in the NIH All of Us Research Program, a nationwide longitudinal cohort, who answered the COVID-19 Participant Experience (COPE) survey was obtained. We analyzed several measures of mental health, coping strategies, and social support used during the early stages of the COVID-19 pandemic. Surveys were recurring and answered from May 2020 to February 2021. Demographics and the most recently answered survey responses were obtained and stratified by glaucoma status. Pearson's Chi-squared tests and multivariable logistic regressions adjusting for age, gender, race, ethnicity, and income were used to generate p-values, odds ratios (ORs) and 95% confidence intervals (CIs) between outcome measures and glaucoma status. RESULTS: Of 42,484 patients who responded to All of Us COPE survey items, 2912 (6.9%) had a diagnosis of glaucoma. On Pearson's Chi-squared tests glaucoma patients were less likely to report drinking alcohol (P = 0.003), eating more food than usual (P = 0.004), and using marijuana (P = 0.006) to cope with social distancing than those without a diagnosis of glaucoma. Further, glaucoma patients had lower rates of probable mild, moderate, or severe depression as calculated by Patient Health Questionnaire-9 (PHQ-9) scores (P < 0.001) and had lower rates of reporting some or a lot of stress from social distancing (P < 0.001). However, glaucoma patients were less likely to report having someone to help prepare meals (P = 0.005) or help with daily chores (P = 0.003) if they became sick with COVID-19. In multivariable logistic regression analyses adjusting for confounding factors, no differences were found for measures of mental health or social support. CONCLUSIONS: Glaucoma patients did not fare worse on many measures of mental health and coping strategies during the early stages of the COVID-19 pandemic compared those without glaucoma. However, a substantial proportion of glaucoma patients still endorsed stress, social isolation, and probable depression, representing challenges for disease management.

Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons.

Axon injury is a hallmark of many neurodegenerative diseases, often resulting in neuronal cell death and functional impairment. Dual leucine zipper kinase (DLK) has emerged as a key mediator of this process. However, while DLK inhibition is robustly protective in a wide range of neurodegenerative disease models, it also inhibits axonal regeneration. Indeed, there are no genetic perturbations that are known to both improve long-term survival and promote regeneration. To identify such a neuroprotective target, we conducted a set of complementary high-throughput screens using a protein kinase inhibitor library in human stem cell-derived retinal ganglion cells (hRGCs). Overlapping compounds that promoted both neuroprotection and neurite outgrowth were bioinformatically deconvoluted to identify specific kinases that regulated neuronal death and axon regeneration. This work identified the role of germinal cell kinase four (GCK-IV) kinases in cell death and additionally revealed their unexpected activity in suppressing axon regeneration. Using an adeno-associated virus (AAV) approach, coupled with genome editing, we validated that GCK-IV kinase knockout improves neuronal survival, comparable to that of DLK knockout, while simultaneously promoting axon regeneration. Finally, we also found that GCK-IV kinase inhibition also prevented the attrition of RGCs in developing retinal organoid cultures without compromising axon outgrowth, addressing a major issue in the field of stem cell-derived retinas. Together, these results demonstrate a role for the GCK-IV kinases in dissociating the cell death and axonal outgrowth in neurons and their druggability provides for therapeutic options for neurodegenerative diseases.

Associations Between Thyroid Eye Disease and Glaucoma Among Those Enrolled in the National Institutes of Health All of Us Research Program.

PURPOSE: To assess the association between thyroid eye disease (TED) and glaucoma. METHODS: Patients 18 years of age and over enrolled in the NIH All of Us Research Program, a nationwide cohort, were extracted. Those with conditions relating to TED were identified and compared with 2020 US Census-matched controls without a diagnosis of TED in a 1:4 ratio. The authors used Pearson's χ 2 tests to study demographics by TED status, and logistic regression to generate odds ratios and 95% confidence intervals to evaluate the association between TED and glaucoma (any type, including glaucoma suspect), using those without TED as the reference group. Multivariable models were adjusted for age, gender, race/ethnicity, eye doctor visits, and smoking status. RESULTS: A total of 393 cases of TED and 1,572 US Census-matched controls were identified. The median age of the cohort was 63 years (interquartile range: 48-73 years). Age, gender, and race/ethnicity varied by TED status ( p < 0.001). Overall, 114 (29.0%) of TED cases had a diagnosis of glaucoma, compared with 94 (6.0%) of non-TED controls. On bivariate logistic regression models, those diagnosed with TED were significantly more likely to be diagnosed with glaucoma compared with controls (odds ratio: 6.42; 95% confidence interval: 4.76-8.70; p < 0.001). This trend persisted on multivariable logistic regression controlling for confounding factors (odds ratio: 3.37; 95% confidence interval: 1.85-6.20 p < 0.001). CONCLUSIONS: Individuals with TED were significantly more likely to be diagnosed with glaucoma. Clinicians caring for patients with TED should be aware of this elevated risk and arrange glaucoma evaluation, accordingly.

Impact of Smoking on Visual Field Progression in a Long-term Clinical Follow-up.

PURPOSE: To investigate the effect of smoking on rates of progressive visual field (VF) damage over time in glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Five hundred eleven eyes of 354 patients with glaucoma followed up from multicenter glaucoma registries. METHODS: In this longitudinal study, 354 patients with primary open-angle glaucoma with a minimum of 3 years of follow-up and 5 VF tests were enrolled from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. Univariate and multivariate linear mixed models were used to investigate the effects of smoking on rates of 24-2 VF mean deviation loss. Visual field progression was defined using pointwise linear and significant negative VF mean deviation loss. Logistic regression was used to identify baseline factors and whether different levels of smoking intensity were associated with VF progression. Kaplan-Meier survival analysis and the log-rank test were used to compare the cumulative risk ratio of progression between smoker and never smoker groups. MAIN OUTCOME MEASURES: Visual field progression. RESULTS: Five hundred eleven eyes of 354 patients were included over the median follow-up of 12.5 years. Median baseline age was 64.8 years. Of the 354 patients, 124 (35%) were Black, and 149 (42.1%) and 168 (59.8%) had reported a history of smoking or alcohol consumption, respectively. In a multivariate model, higher smoking intensity was associated with faster VF loss (coefficient, -0.05 decibels (dB)/year per 10 pack-years; 95% confidence interval [CI], -0.08 to -0.01 dB/year per 10 pack-years; P = 0.010). Developing VF progression in eyes of heavy smokers (≥ 20 pack-years) was 2.2 times more than in eyes of patients without smoking history (odds ratio, 2.21; 95% CI, 1.02-4.76; P = 0.044). Statistically significant differences were found between heavy smokers (≥ 20 pack-years) and never smokers by Kaplan-Meier analysis (P = 0.011, log-rank test). CONCLUSIONS: Heavy smokers are more likely to sustain VF loss in eyes with glaucoma. The prospective longitudinal design of this study supports the hypothesis that levels of smoking may be a significant predictor for glaucoma progression. Additionally, this information can be used for clinically relevant tobacco prevention and intervention messages.

Classification of Visual Field Abnormalities in Highly Myopic Eyes without Pathologic Change.

PURPOSE: To develop a classification system of visual field (VF) abnormalities in highly myopic eyes with and without glaucoma. DESIGN: Secondary analysis of VF data from a longitudinal cohort study. PARTICIPANTS: One thousand eight hundred ninety-three VF tests from 1302 eyes (825 individuals). METHODS: All participants underwent VF testing (Humphrey 24-2 Swedish interactive threshold algorithm standard program; Carl Zeiss Meditec) and detailed ophthalmic examination. A comprehensive set of VF defect patterns was defined via observation of the 1893 VF reports, literature review, and consensus meetings. The classification system comprised 4 major types of VF patterns, including normal type, glaucoma-like defects (paracentral defect, nasal step, partial arcuate defect, arcuate defect), high myopia-related defects (enlarged blind spot, vertical step, partial peripheral rim, nonspecific defect), and combined defects (nasal step with enlarged blind spot). A subset (n = 1000) of the VFs was used to evaluate the interobserver and intraobserver agreement and weighted κ values of the classification system by 2 trained readers. The prevalence of various VF patterns and their associated factors were determined. MAIN OUTCOME MEASURES: The classification of VF in highly myopic eyes and its associated risk factors. RESULTS: We found that normal type, glaucoma-like defects, high myopia-related defects, and combined defects accounted for 74.1%, 10.8%, 15.0%, and 0.1% of all unique VF tests, respectively. The interobserver and intraobserver agreements were > 89%, and the corresponding κ values were 0.86 or more between readers. Both glaucoma-like and high myopia-related VF defects were associated with older age (odds ratios [ORs], 1.07 [95% confidence interval (CI), 1.04-1.10; P < 0.001] and 1.06 [95% CI, 1.04-1.10; P < 0.001]) and longer axial length (ORs, 1.65 [95% CI, 1.32-2.07; P < 0.001] and 1.37 [95% CI, 1.11-1.68; P = 0.003]). Longer axial length showed a stronger effect on the prevalence of glaucoma-like VF defects than on the prevalence of high myopia-related VF defects (P = 0.036). CONCLUSIONS: We propose a new and reproducible classification system of VF abnormalities for nonpathologic high myopia. Applying a comprehensive classification system will facilitate communication and comparison of findings among studies.

Short-Term and Long-Term Variability of Intraocular Pressure Measured with an Intraocular Telemetry Sensor in Patients with Glaucoma.

PURPOSE: To evaluate the short-term and long-term variability of intraocular pressure (IOP) in eyes with primary open-angle glaucoma. DESIGN: Prospective study. PARTICIPANTS: Twenty-two patients previously implanted with a sulcus-based IOP sensor (EyeMate, Implandata GmbH, Germany). METHODS: Twenty-two patients previously implanted with the EyeMate were requested to obtain at least 4 IOP measurements daily. Data were grouped according to the eye and the medication so that an eye treated with a particular medication was considered as one group, and the same eye treated with a different medication during the observation period was considered as a different group. A day was divided into 7 periods: night, midnight to 5:59 am; early, 6 am to 7:59 am; morning, 8 am to 10:59 am; noon, 11 am to 1:59 pm; afternoon, 2 pm to 5:59 pm; evening, 6 pm to 8:59 pm; and late, 9 pm to 11:59 pm. Short-term variability during a particular period was defined as the variability in IOP measurements obtained during that period on different days within 3 months of each other. Long-term variability was defined as the variability in IOP measurements obtained during a particular period on different days over a period of 1 year or more. Variability was assessed using intraclass correlation coefficients (ICCs). RESULTS: The mean age of study participants was 67.8 ± 6.8 years and 36.4% were women. The mean follow-up duration of patients was 19.2 ± 21.3 months (median, 9 months; range, 1-58 months). Overall, 92 860 IOP measurements over 15 811 measurement days were obtained and analyzed during the study period. The number of measurements obtained from each eye ranged from 1 daily to 277 daily. Intraclass correlation coefficients for short-term variability among the 7 periods during the day ranged from 0.52 (morning) to 0.66 (early). Long-term ICCs ranged from 0.29 (night) to 0.51 (late). CONCLUSIONS: Continual IOP monitoring showed that IOP has moderate short-term and high long-term variability in glaucoma patients. These findings demonstrate that single IOP measurements do not characterize day-to-day variations in IOP. Moreover, they show the importance of continual IOP monitoring in glaucoma patients.

Deep Learning Estimation of 10-2 and 24-2 Visual Field Metrics Based on Thickness Maps from Macula OCT.

PURPOSE: To develop deep learning (DL) systems estimating visual function from macula-centered spectral-domain (SD) OCT images. DESIGN: Evaluation of a diagnostic technology. PARTICIPANTS: A total of 2408 10-2 visual field (VF) SD OCT pairs and 2999 24-2 VF SD OCT pairs collected from 645 healthy and glaucoma subjects (1222 eyes). METHODS: Deep learning models were trained on thickness maps from Spectralis macula SD OCT to estimate 10-2 and 24-2 VF mean deviation (MD) and pattern standard deviation (PSD). Individual and combined DL models were trained using thickness data from 6 layers (retinal nerve fiber layer [RNFL], ganglion cell layer [GCL], inner plexiform layer [IPL], ganglion cell-IPL [GCIPL], ganglion cell complex [GCC] and retina). Linear regression of mean layer thicknesses were used for comparison. MAIN OUTCOME MEASURES: Deep learning models were evaluated using R2 and mean absolute error (MAE) compared with 10-2 and 24-2 VF measurements. RESULTS: Combined DL models estimating 10-2 achieved R2 of 0.82 (95% confidence interval [CI], 0.68-0.89) for MD and 0.69 (95% CI, 0.55-0.81) for PSD and MAEs of 1.9 dB (95% CI, 1.6-2.4 dB) for MD and 1.5 dB (95% CI, 1.2-1.9 dB) for PSD. This was significantly better than mean thickness estimates for 10-2 MD (0.61 [95% CI, 0.47-0.71] and 3.0 dB [95% CI, 2.5-3.5 dB]) and 10-2 PSD (0.46 [95% CI, 0.31-0.60] and 2.3 dB [95% CI, 1.8-2.7 dB]). Combined DL models estimating 24-2 achieved R2 of 0.79 (95% CI, 0.72-0.84) for MD and 0.68 (95% CI, 0.53-0.79) for PSD and MAEs of 2.1 dB (95% CI, 1.8-2.5 dB) for MD and 1.5 dB (95% CI, 1.3-1.9 dB) for PSD. This was significantly better than mean thickness estimates for 24-2 MD (0.41 [95% CI, 0.26-0.57] and 3.4 dB [95% CI, 2.7-4.5 dB]) and 24-2 PSD (0.38 [95% CI, 0.20-0.57] and 2.4 dB [95% CI, 2.0-2.8 dB]). The GCIPL (R2 = 0.79) and GCC (R2 = 0.75) had the highest performance estimating 10-2 and 24-2 MD, respectively. CONCLUSIONS: Deep learning models improved estimates of functional loss from SD OCT imaging. Accurate estimates can help clinicians to individualize VF testing to patients.

OCT Angiography Artifacts in Glaucoma.

PURPOSE: To determine the prevalence of different types of artifacts seen in OCT angiography (OCTA) images of healthy and glaucoma eyes and evaluate the characteristics associated with poor-quality images. DESIGN: Retrospective study. PARTICIPANTS: A total of 649 eyes of 368 healthy, glaucoma suspect, and glaucoma patients. METHODS: Angiovue (Optovue Inc) high-density (HD) and non-HD optic nerve head and macula OCTA images of participants were evaluated by 4 expert reviewers for the presence of different artifacts, including eye movement, defocus, shadow, decentration, segmentation error, blink, and Z offset in the superficial vascular layer. Each OCTA scan was designated to have good or poor quality based on the presence of artifacts. The association of demographic and ocular characteristics with the likelihood of obtaining poor-quality OCTA images was evaluated. MAIN OUTCOME MEASURES: The prevalence of OCTA artifacts and the factors associated with increased likelihood of capturing poor-quality OCTA images. RESULTS: A total of 5263 OCTA images were evaluated. Overall, 33.9% of the OCTA images had poor quality. The majority of images with acceptable quality scores (QS ≥ 4) had no artifacts (76.6%). Other images had 1 (13.6%) or 2 or more artifacts (9.8%). Older age (P < 0.001), male gender (P = 0.045), worse visual field mean deviation (P < 0.001), absence of eye tracking (P < 0.001), and macular scan area (P < 0.001) were associated with a higher likelihood of obtaining poor-quality images. In images with acceptable QS, the commercially available quality measures including QS and signal strength index had the area under the receiver operating characteristic curves of 0.65 (95% confidence interval [CI], 0.62-0.69) and 0.70 (95% CI, 0.68-0.73) to detect good-quality images, respectively. CONCLUSIONS: OCTA artifacts associated with poor-quality images are frequent, and their prevalence is affected by ocular and patient characteristics. One should not rely solely on the quantitative assessments that are provided automatically by OCTA instruments. A systematic scan review should be conducted to ensure appropriate interpretation of OCTA images. Given the high prevalence of poor-quality OCTA images, the images should be reacquired whenever an apparent and correctable artifact is present on a captured image.

Ganglion Cell Complex Thickness and Macular Vessel Density Loss in Primary Open-Angle Glaucoma.

PURPOSE: To characterize the change rate of ganglion cell complex (GCC) thickness and macular vessel density in healthy, preperimetric glaucoma and primary open-angle glaucoma (POAG) eyes. DESIGN: Prospective, longitudinal study. PARTICIPANTS: One hundred thirty-nine eyes (23 healthy eyes, 36 preperimetric glaucoma eyes, and 80 POAG eyes) of 94 patients who had at least 3 visits were included from the Diagnostic Innovations in Glaucoma Study. The mean follow-up was 2.0 years for healthy eyes, 2.6 years for preperimetric glaucoma eyes, and 2.6 years for POAG eyes. METHODS: OCT angiography (OCTA)-based vessel density and OCT-based structural thickness of the same 3×3-mm2 GCC scan slab were evaluated. The dynamic range-based normalized rates of vessel density and thickness change were calculated and compared within each diagnostic group. The association between the rates of thickness and vessel density change and potential factors were evaluated. MAIN OUTCOME MEASURES: The rates of GCC thinning and macular vessel density loss. RESULTS: Significant rates of GCC thinning and macular vessel density decrease were detectable in all diagnostic groups (all P < 0.05). In healthy eyes and preperimetric glaucoma eyes, the normalized rates of GCC thinning and macular vessel density decrease were comparable (all P > 0.1). In contrast, the normalized rate (mean, 95% confidence interval) of macular vessel density decrease in the POAG eyes (-7.12 [-8.36, -5.88]%/year) was significantly faster than GCC thinning (-2.13 [-3.35, -0.90]%/year; P < 0.001). In the POAG group, more than two thirds of the eyes showed faster macular vessel density decrease than GCC thinning; faster macular vessel density decrease rate was associated significantly with worse glaucoma severity (P = 0.037). The association between GCC thinning rate and glaucoma severity was not significant (P = 0.586). Intraocular pressure during follow-up significantly affected the rate of GCC thinning in all groups (all P < 0.05) but showed no association with the rate of macular vessel density decrease. CONCLUSIONS: Both GCC thinning and macular vessel density decrease were detectable over time in all diagnostic groups. In POAG eyes, macular vessel density decrease was faster than GCC thinning and was associated with severity of disease. Macular vessel density is useful for evaluating glaucoma progression, particularly in more advanced disease.

Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1).

PURPOSE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10- and 15-µg bimatoprost implant in subjects with open-angle glaucoma (OAG) and ocular hypertension (OHT) after initial and repeated administrations. DESIGN: Randomized, 20-month, multicenter, subject- and efficacy evaluator-masked, parallel-group, phase 3 clinical study. PARTICIPANTS: Adults with OAG or OHT in each eye, open iridocorneal angle inferiorly in the study eye, and study eye baseline IOP (hour 0; 8 am) of 22-32 mmHg after washout. METHODS: Study eyes received bimatoprost implant 10 µg (n = 198) or 15 µg (n = 198) on day 1 with readministration at weeks 16 and 32, or twice-daily topical timolol maleate 0.5% (n = 198). Intraocular pressure was measured at hours 0 and 2 at each visit. MAIN OUTCOME MEASURES: Primary end points were IOP and change from baseline IOP through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). RESULTS: Both dose strengths of bimatoprost implant were noninferior to timolol in IOP lowering after each administration. Mean diurnal IOP was 24.0, 24.2, and 23.9 mmHg at baseline and from 16.5-17.2, 16.5-17.0, and 17.1-17.5 mmHg through week 12 in the 10-µg implant, 15-µg implant, and timolol groups, respectively. The incidence of corneal and inflammatory TEAEs of interest (e.g., corneal endothelial cell loss, iritis) was higher with bimatoprost implant than timolol and highest with the 15-µg dose strength. Incidence of corneal TEAEs increased after repeated treatment; with 3 administrations at fixed 16-week intervals, incidence of ≥20% CECD loss was 10.2% (10-µg implant) and 21.8% (15-µg implant). Mean best-corrected visual acuity (BCVA) was stable; 3 implant-treated subjects with corneal TEAEs had >2-line BCVA loss at their last visit. CONCLUSIONS: Both dose strengths of bimatoprost implant met the primary end point of noninferiority to timolol through week 12. One year after 3 administrations, IOP was controlled in most subjects without additional treatment. The risk-benefit assessment favored the 10-µg implant over the 15-µg implant. Ongoing studies are evaluating other administration regimens to reduce the potential for CECD loss. The bimatoprost implant has potential to improve adherence and reduce treatment burden in glaucoma.

Deep Learning Approaches Predict Glaucomatous Visual Field Damage from OCT Optic Nerve Head En Face Images and Retinal Nerve Fiber Layer Thickness Maps.

PURPOSE: To develop and evaluate a deep learning system for differentiating between eyes with and without glaucomatous visual field damage (GVFD) and predicting the severity of GFVD from spectral domain OCT (SD OCT) optic nerve head images. DESIGN: Evaluation of a diagnostic technology. PARTICIPANTS: A total of 9765 visual field (VF) SD OCT pairs collected from 1194 participants with and without GVFD (1909 eyes). METHODS: Deep learning models were trained to use SD OCT retinal nerve fiber layer (RNFL) thickness maps, RNFL en face images, and confocal scanning laser ophthalmoscopy (CSLO) images to identify eyes with GVFD and predict quantitative VF mean deviation (MD), pattern standard deviation (PSD), and mean VF sectoral pattern deviation (PD) from SD OCT data. MAIN OUTCOME MEASURES: Deep learning models were compared with mean RNFL thickness for identifying GVFD using area under the curve (AUC), sensitivity, and specificity. For predicting MD, PSD, and mean sectoral PD, models were evaluated using R2 and mean absolute error (MAE). RESULTS: In the independent test dataset, the deep learning models based on RNFL en face images achieved an AUC of 0.88 for identifying eyes with GVFD and 0.82 for detecting mild GVFD significantly (P < 0.001) better than using mean RNFL thickness measurements (AUC = 0.82 and 0.73, respectively). Deep learning models outperformed standard RNFL thickness measurements in predicting all quantitative VF metrics. In predicting MD, deep learning models based on RNFL en face images achieved an R2 of 0.70 and MAE of 2.5 decibels (dB) compared with 0.45 and 3.7 dB for RNFL thickness measurements. In predicting mean VF sectoral PD, deep learning models achieved high accuracy in the inferior nasal (R2 = 0.60) and superior nasal (R2 = 0.67) sectors, moderate accuracy in inferior (R2 = 0.26) and superior (R2 = 0.35) sectors, and lower accuracy in the central (R2 = 0.15) and temporal (R2 = 0.12) sectors. CONCLUSIONS: Deep learning models had high accuracy in identifying eyes with GFVD and predicting the severity of functional loss from SD OCT images. Accurately predicting the severity of GFVD from SD OCT imaging can help clinicians more effectively individualize the frequency of VF testing to the individual patient.

Segmental differences found in aqueous angiographic-determined high - and low-flow regions of human trabecular meshwork.

This work sought to compare aqueous angiographic segmental patterns with bead-based methods which directly visualize segmental trabecular meshwork (TM) tracer trapping. Additionally, segmental protein expression differences between aqueous angiographic-derived low- and high-outflow human TM regions were evaluated. Post-mortem human eyes (One Legacy and San Diego eye banks; n = 15) were perfused with fluorescent tracers (fluorescein [2.5%], indocyanine green [0.4%], and/or fluorescent microspheres). After angiographic imaging (Spectralis HRA+OCT; Heidelberg Engineering), peri-limbal low- and high-angiographic flow regions were marked. Aqueous angiographic segmental outflow patterns were similar to fluorescent microsphere TM trapping segmental patterns. TM was dissected from low- and high-flow areas and processed for immunofluorescence or Western blot and compared. Versican expression was relatively elevated in low-flow regions while MMP3 and collagen VI were relatively elevated in high-flow regions. TGF-ß2, thrombospondin-1, TGF-ß receptor1, and TGF-ß downstream proteins such as α-smooth muscle actin were relatively elevated in low-flow regions. Additionally, fibronectin (FN) levels were unchanged, but the EDA isoform (FN-EDA) that is associated with fibrosis was relatively elevated in low-flow regions. These results show that segmental aqueous angiographic patterns are reflective of underlying TM molecular characteristics and demonstrate increased pro-fibrotic activation in low-flow regions. Thus, we provide evidence that aqueous angiography outflow visualization, the only tracer outflow imaging method available to clinicians, is in part representative of TM biology.

Smart Electronic Eyedrop Bottle for Unobtrusive Monitoring of Glaucoma Medication Adherence.

Glaucoma, the leading cause of irreversible blindness, affects >70 million people worldwide. Lowering intraocular pressure via topical administration of eye drops is the most common first-line therapy for glaucoma. This treatment paradigm has notoriously high non-adherence rates: ranging from 30% to 80%. The advent of smart phone enabled technologies creates promise for improving eyedrop adherence. However, previous eyedrop electronic monitoring solutions had awkward medication bottle adjuncts and crude software for monitoring the administration of a drop that adversely affected their ability to foster sustainable improvements in adherence. The current work begins to address this unmet need for wireless technology by creating a "smart drop" bottle. This medication bottle is instrumented with sensing electronics that enable detection of each eyedrop administered while maintaining the shape and size of the bottle. This is achieved by a thin electronic force sensor wrapped around the bottle and underneath the label, interfaced with a thin electronic circuit underneath the bottle that allows for detection and wireless transmission to a smart-phone application. We demonstrate 100% success rate of wireless communication over 75 feet with <1% false positive and false negative rates of single drop deliveries, thus providing a viable solution for eyedrop monitoring for glaucoma patients.

Association of severity of primary open-angle glaucoma with serum vitamin D levels in patients of African descent.

Purpose: To study the relationship between primary open-angle glaucoma (POAG) in a cohort of patients of African descent (AD) and serum vitamin D levels. Methods: A subset of the AD and glaucoma evaluation study III (ADAGES III) cohort, consisting of 357 patients with a diagnosis of POAG and 178 normal controls of self-reported AD, were included in this analysis. Demographic information, family history, and blood samples were collected from all the participants. All the subjects underwent clinical evaluation, including visual field (VF) mean deviation (MD), central cornea thickness (CCT), intraocular pressure (IOP), and height and weight measurements. POAG patients were classified into early and advanced phenotypes based on the severity of their visual field damage, and they were matched for age, gender, and history of hypertension and diabetes. Serum 25-Hydroxy (25-OH) vitamin D levels were measured by enzyme-linked immunosorbent assay (ELISA). The association of serum vitamin D levels with the development and severity of POAG was tested by analysis of variance (ANOVA) and the paired t-test. Results: The 178 early POAG subjects had a visual field MD of better than -4.0 dB, and the 179 advanced glaucoma subjects had a visual field MD of worse than -10 dB. The mean (95% confidence interval [CI]) levels of vitamin D of the subjects in the control (8.02 ± 6.19 pg/ml) and early phenotype (7.56 ± 5.74 pg/ml) groups were significantly or marginally significantly different from the levels observed in subjects with the advanced phenotype (6.35 ± 4.76 pg/ml; p = 0.0117 and 0.0543, respectively). In contrast, the mean serum vitamin D level in controls was not significantly different from that of the subjects with the early glaucoma phenotype (p = 0.8508). Conclusions: In this AD cohort, patients with advanced glaucoma had lower serum levels of vitamin D compared with early glaucoma and normal subjects.

24-Hour Intraocular Pressure Control with Fixed-dose Combination Brinzolamide 1%/Brimonidine 0.2%: A Multicenter, Randomized Trial.

PURPOSE: To determine the intraocular pressure (IOP)-lowering effect of fixed-combination brinzolamide 1%/brimonidine 0.2% (BBFC) over a 24-hour period. DESIGN: Prospective, multicenter, double-masked, parallel-group clinical trial conducted at 16 academic and nonacademic sites in the United States. PARTICIPANTS: Subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT) aged ≥18 years with mean baseline IOP measurements in at least 1 eye of ≥21 and <28 mmHg. METHODS: Duplicate mean pneumatonometer IOP measurements were collected every 2 hours over a 24-hour period in controlled light conditions in overnight facilities. Daytime (8 am-8 pm) and nocturnal (10 pm-6 am) IOP measurements were collected in a sitting or supine position, respectively. Baseline 24-hour IOP was measured in untreated subjects after a washout (up to 4 weeks) and eligibility phase. After the baseline visit, participants were randomized 1:1 to receive masked BBFC or vehicle, 1 drop 3 times daily (8 am, 3 pm, and 10 pm) for 4 weeks. At week 4, IOP measurements were repeated in both groups under the same conditions. MAIN OUTCOME MEASURE: Mean change from baseline in 24-hour IOP at week 4. RESULTS: Of 125 participants randomized, 123 (98%; BBFC, n = 62; vehicle, n = 61) completed the study. No subjects randomized to BBFC discontinued the study. At week 4, BBFC-treated eyes had significantly reduced mean 24-hour IOP vs. vehicle (least squares mean difference [95% confidence interval]: -2.5 [-3.3, -1.7]; P < 0.001); daytime (-3.4 [-4.3, -2.6]; P < 0.001) and nocturnal (-1.2 [-2.3, 0.0]; P = 0.053) reductions were observed. Mean change from baseline was significantly different between BBFC- and vehicle-treated eyes at all daytime points and 3 of 5 nocturnal time points (10 pm, 12 am, and 6 am; secondary end point). The frequency of adverse events was similar between treatment groups; in the BBFC arm, ocular hyperemia, corneal abrasion, and dysgeusia were the most frequently reported, consistent with events described in the drug label. CONCLUSIONS: This large, multicenter study of 24-hour IOP control with BBFC met its primary end point; BBFC demonstrated significantly superior 24-hour IOP-lowering efficacy versus vehicle after 4 weeks of 3-times-daily treatment in subjects with OAG or OHT.