A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African ancestry. We conducted a genome-wide association study (GWAS) for POAG in 11,275 individuals of African ancestry (6,003 cases; 5,272 controls). We detected 46 risk loci associated with POAG at genome-wide significance. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated two previously undescribed variants (rs1666698 mapping to DBF4P2; rs34957764 mapping to ROCK1P1) and one previously associated variant (rs11824032 mapping to ARHGEF12) as likely causal. For individuals of African ancestry, a polygenic risk score (PRS) for POAG from our mega-analysis (African ancestry individuals) outperformed a PRS from summary statistics of a much larger GWAS derived from European ancestry individuals. This study quantifies the genetic architecture similarities and differences between African and non-African ancestry populations for this blinding disease.

Manhattan Vision Screening and Follow-Up Study (NYC-SIGHT): optometric exam improves access and utilization of eye care services.

PURPOSE: To describe the benefits of optometric evaluation for detection of vision-affecting conditions in the context of community-based eye health screenings and identify factors associated with having a recent dilated eye exam. METHODS: Enrolled participants were age 40 and older, living independently in affordable housing developments in New York City. Eye health screening failure and criteria for seeing the on-site study optometrist were defined as visual acuity 20/40 or worse in either eye, intraocular pressure 23-29 mmHg, or an unreadable fundus image. The optometrist conducted a manifest refraction using loose lenses and used a portable slit lamp and ophthalmoscope to perform a non-dilated anterior and posterior segment ocular health evaluation. Demographics, social determinants of health, eye health screening results, and rates of suspected ophthalmic conditions were recorded. To determine factors associated with having a recent dilated eye exam, which was the main outcome for this statistical analysis, a stepwise multivariate logistic regression was performed. RESULTS: A total of 708 participants were screened, 308 attended the optometric exam; mean age 70.7 ± 11.7 [standard deviation (SD)] years. Among this subgroup, 70.1% identified as female, 54.9% self-identified as African American, 39% as Hispanic/Latino, and 26.6% Dominican ethnicity; 78.2% (241/308) had not undergone a dilated eye exam within the last year, 71.4% reported they did not have an eye care provider. Stepwise multivariate logistic regression analysis indicated that participants who self-reported having cataracts (odds ratio (OR) 2.15; 95% confidence interval (CI) 1.03-4.47; p = 0.041), self-reported having glaucoma/glaucoma suspect (OR 5.60; 95% CI 2.02-15.43; p = 0.001), or spoke Spanish as their primary language (OR 3.25; 95% CI 1.48-7.11; p = 0.003) had higher odds of having a recent dilated eye exam. CONCLUSIONS: This community-based screening initiative demonstrated the effectiveness of optometric exams in detecting vision-affecting conditions and identified factors associated with having a recent dilated eye exam. Optometrists play a vital role in increasing access to eye care for high-risk, underserved populations. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04271709).

Manhattan Vision Screening and Follow-Up Study: (NYC-SIGHT)Tele-Retinal Image Findings and Importance of Photography.

Purpose: To describe tele-retinal abnormality image findings from the Manhattan Vision Screening and Follow-up Study (NYC-SIGHT), which aims to investigate whether community-based eye health outreach strategies using telemedicine can improve visual outcomes among at-risk populations in Upper Manhattan. Methods: A 5-year prospective, cluster-randomized clinical trial was conducted. Eligible individuals aged 40 years and older were recruited from affordable housing developments and senior centers in New York City. Participants underwent on-site eye health screening (best-corrected visual acuity, intraocular pressure [IOP] measurements, and fundus photography). Fundus images were graded via telemedicine by a retina specialist. Multivariate logistic regression modeling was used to assess the factors associated with abnormal retinal findings requiring referral to ophthalmology. Results: Participants with a retinal abnormality on fundus photography (n = 157) were predominantly older adults, with a mean age of 68.4 ± 11.1 years, female (63.7%), African American (50.3%), and Hispanic (43.3%). A total of 32 participants in our study passed the vision and IOP screening but had an abnormal retinal image and ocular pathology that would have been missed without fundus photography. Individuals who self-identified as having preexisting glaucoma (odds ratio [OR] = 3.749, 95% confidence interval [CI] = 1.741-8.074, p = 0.0001) and had severe vision impairment (OR = 4.1034, 95% CI = 2.0740-8.1186, p = 0.000) at the screening had significantly higher odds of having an abnormal retinal image. Conclusion: This community-based study targeted populations at-risk for eye disease, improved access to eye care, detected a significant number of retinal image abnormalities requiring follow-up by using telemedicine, and provided evidence of the importance of fundus photography during eye health screenings. CTR number: NCT04271709.

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.

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.

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.

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.

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.

The African Descent and Glaucoma Evaluation Study (ADAGES) III: Contribution of Genotype to Glaucoma Phenotype in African Americans: Study Design and Baseline Data.

PURPOSE: To describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III. DESIGN: Cross-sectional, case-control study. PARTICIPANTS: Three thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States. METHODS: Individuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review. MAIN OUTCOME MEASURES: Participant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded. RESULTS: The 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients. CONCLUSIONS: With its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES III genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.

Genetic Architecture of Primary Open-Angle Glaucoma in Individuals of African Descent: The African Descent and Glaucoma Evaluation Study III.

PURPOSE: To find genetic contributions to glaucoma in African Americans. DESIGN: Cross-sectional, case-control study. PARTICIPANTS: One thousand eight hundred seventy-five primary open-angle glaucoma (POAG) patients and 1709 controls, self-identified as being of African descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGES) III and Wake Forest School of Medicine. METHODS: MegaChip genotypes were imputed to Thousand Genomes data. Association of single nucleotide polymorphisms (SNPs) with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by receiver operator characteristic curves (ROC-AUCs). MAIN OUTCOME MEASURES: Primary open-angle glaucoma defined by visual field loss without other nonocular conditions (n = 1875). Advanced POAG was defined by age-based mean deviation of visual field (n = 946). RESULTS: Eighteen million two hundred eighty-one thousand nine hundred twenty SNPs met imputation quality of r2 > 0.7 and minor allele frequency > 0.005. Association of a novel locus, EN04, was observed for advanced POAG (rs185815146 ß, 0.36; standard error, 0.065; P < 3×10-8). For POAG, an AD signal was observed at the 9p21 European descent (ED) POAG signal (rs79721419; P < 6.5×10-5) independent of the previously observed 9p21 ED signal (rs2383204; P < 2.3×10-5) by conditional analyses. An association with POAG in FNDC3B (rs111698934; P < 3.9×10-5) was observed, not in linkage disequilibrium (LD) with the previously reported ED SNP. Additional previously identified loci associated with POAG in persons of AD were: 8q22, AFAP1, and TMC01. An AUC of 0.62 was observed with an unweighted genetic risk score comprising 11 SNPs in candidate genes. Two additional risk scores were studied by using a penalized matrix decomposition with cross-validation; risk scores of 50 and 400 SNPs were identified with ROC of AUC = 0.74 and AUC = 0.94, respectively. CONCLUSIONS: A novel association with advanced POAG in the EN04 locus was identified putatively in persons of AD. In addition to this finding, this genome-wide association study in POAG patients of AD contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine mapping of regions because of shorter average LD (FNDC3B). Although not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.

Oral Memantine for the Treatment of Glaucoma: Design and Results of 2 Randomized, Placebo-Controlled, Phase 3 Studies.

PURPOSE: To evaluate the effectiveness and safety of oral memantine as a potential neuroprotective agent in open-angle glaucoma (OAG) at risk for progression. DESIGN: Two randomized, double-masked, placebo-controlled, parallel-group, multicenter, 48-month studies identically designed, initiated 1 year apart, and completed in 2006. Protocol amendments included a 1-year extension (first study) and change in primary endpoint and analysis (second study). PARTICIPANTS: Patients (2298 total) with bilateral OAG; glaucomatous optic disc damage and visual field loss in 1 eye; glaucomatous optic disc damage and/or visual field loss in the contralateral eye (at screening), topically treated or untreated intraocular pressure (IOP) of 21 mmHg or less (at baseline); and at risk of glaucomatous progression (per prespecified criteria). METHODS: Patients were randomized 3:2:2 to receive memantine 20 mg, memantine 10 mg, or placebo tablets daily. Glaucomatous progression was assessed in the intent-to-treat population by full-threshold standard automated perimetry (SAP), frequency doubling technology (FDT), and stereoscopic optic disc photographs, standardized by quality control assessment at centralized reading centers. Safety evaluations included adverse events (AEs), best-corrected visual acuity, biomicroscopy, IOP, and ophthalmoscopy. Efficacy data from each study were analyzed per protocol. Pooled analyses of efficacy and safety data were also performed. MAIN OUTCOME MEASURES: The predefined primary efficacy measure was glaucomatous visual field progression, as measured by SAP. Additional efficacy measures included glaucomatous progression of visual field (FDT) and optic nerve damage (stereoscopic optic disc photographs). RESULTS: The proportion of patients who completed the studies was similar among groups (80%-83%). Compared with placebo, daily treatment with memantine 10 mg or 20 mg for 48 months did not delay glaucomatous progression significantly in the individual studies and pooled analyses. The pooled risk reduction ratio (95% confidence interval) assessed by SAP was -0.13 (-0.40, 0.09) and -0.17 (-0.46, 0.07) for memantine 10 mg and 20 mg, respectively. Results were similar per FDT and stereoscopic optic disc photographs. The most common AEs leading to treatment discontinuations were dizziness, headache, fatigue, and nausea. CONCLUSIONS: With technologies available when the studies were conducted, daily treatment with memantine over 48 months was not shown to prevent glaucomatous progression in this patient population.

Optic Nerve Head Drusen Prevalence and Associated Factors in Clinically Normal Subjects Measured Using Optical Coherence Tomography.

OBJECTIVE: To investigate the prevalence of optic nerve head drusen (ONHD) in clinically normal subjects using enhanced depth imaging (EDI) optical coherence tomography (OCT) and to evaluate associated factors. DESIGN: Prospective, cross-sectional, observational study. PARTICIPANTS: Total of 130 clinically normal subjects. METHODS: Serial horizontal and vertical EDI OCT B-scans (interval between scans, ∼30 µm) of the optic nerve head (ONH) were obtained in both eyes of clinically normal subjects. Signs of ONHD were defined as horizontal hyperreflective bands perpendicular to the OCT beam with or without a signal-poor core. The minimum length of isolated hyperreflective bands was determined based on analysis of 34 eyes with clinically definite ONHD. Age, gender, ONH diameter, and axial length were obtained from participants. MAIN OUTCOME MEASURES: Prevalence of ONHD in clinically normal subjects and its association with age, gender, ONH diameter, and axial length. RESULTS: Based on the measurements of 94 isolated hyperreflective bands in the 34 eyes with clinically definite ONHD, the minimum length of isolated hyperreflective ONHD bands in clinically normal subjects was set as 45 µm (mean minus 2 standard deviations). Among 260 clinically normal eyes (130 subjects; 68 women; mean age, 40±17 years), EDI OCT was positive for horizontal hyperreflective ONHD bands in 28 eyes (10.8%) of 19 subjects (14.6%). Of these 28 eyes, 25 eyes (9.6% of total 260 eyes) of 16 subjects (12.3% of total 130 subjects) showed isolated hyperreflective bands with no signal-poor core, and 3 eyes (1.2% of total 260 eyes) of 3 subjects (2.3% of total 130 subjects) showed a signal-poor core surrounded by hyperreflective bands. No significant differences were found in mean age (44 vs. 39 years; P = 0.121) or gender distribution (56% vs. 52% female; P = 0.766) between clinically normal subjects with hyperreflective ONHD bands and those without. Logistic regression analysis showed that a decrease in ONH diameter by 100 µm and axial length by 1 mm increased the odds of ONHD presence by 1.5-fold (odds ratio [OR] = 1.56 [confidence interval (CI), 1.22-2.00]; P < 0.001) and 2-fold (OR = 2.00 [CI, 1.15-3.49]; P = 0.015), respectively. CONCLUSIONS: Subclinical ONHD may be more prevalent than previously believed. Significant associations of subclinical ONHD with smaller ONH and shorter axial length were found.

Rates of Local Retinal Nerve Fiber Layer Thinning before and after Disc Hemorrhage in Glaucoma.

PURPOSE: To investigate longitudinal temporal and spatial associations between disc hemorrhage (DH) and rates of local retinal nerve fiber layer (RNFL) thinning before and after DHs. DESIGN: Longitudinal, observational cohort study. PARTICIPANTS: Forty eyes of 37 participants (23 with glaucoma and 17 with suspect glaucoma at baseline) with DH episodes during follow-up from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. METHODS: All subjects underwent optic disc photography annually and spectral-domain optical coherence tomography (OCT) RNFL thickness measurements every 6 months. The rates of RNFL thinning were calculated using multivariate linear mixed-effects models before and after DH. MAIN OUTCOME MEASURES: Rates of global and local RNFL thinning. RESULTS: Thirty-six eyes of 33 participants with inferior or superior DHs were analyzed. The rates of RNFL thinning were significantly faster in DH quadrants than in non-DH quadrants after DH (-2.25 and -0.69 µm/year; P < 0.001). In the 18 eyes with intensified treatment after DH, the mean rate of RNFL thinning significantly slowed after treatment compared with before treatment in the non-DH quadrants (-2.89 and -0.31 µm/year; P < 0.001), but not in the DH quadrants (-2.64 and -2.12 µm/year; P = 0.19). In 18 eyes with unchanged treatment, the rate of RNFL thinning in the DH quadrant was faster after DH than before DH (P = 0.008). Moreover, compared with eyes without a treatment change, intensification of glaucoma treatment after DH significantly reduced the global, non-DH quadrants, and DH quadrant rates of RNFL thinning after DH compared with before DH (global, P = 0.004; non-DH quadrant, P < 0.001; DH quadrant, P = 0.005). In the multiple linear regression analysis, treatment intensification (ß, 1.007; P = 0.005), visual field mean deviation (ß, 0.066; P = 0.049), and difference in intraocular pressure before and after DH (ß, -0.176; P = 0.034) were associated significantly with the difference of global RNFL slope values before and after DH. CONCLUSIONS: Although the rate of RNFL thinning worsened in a DH quadrant after DH, glaucoma treatment intensification may have a beneficial effect in reducing this rate of thinning.

24-2 Visual Fields Miss Central Defects Shown on 10-2 Tests in Glaucoma Suspects, Ocular Hypertensives, and Early Glaucoma.

PURPOSE: To investigate the prevalence of visual field defects in glaucomatous eyes, glaucoma suspects, and ocular hypertensives with 24-2 and 10-2 visual fields. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Patients with or suspected glaucoma tested with 24-2 and 10-2. Patients were classified into 3 groups on the basis of the presence of glaucomatous optic neuropathy (GON) and 24-2 visual field abnormalities: early glaucoma (GON and abnormal visual field, mean deviation >-6 decibels [dB]), glaucoma suspects (GON and normal visual field), and ocular hypertensives (normal disc, normal visual field, and intraocular pressure >22 mmHg). For the classification of visual field abnormalities, 24-2 and 10-2 tests performed on the same visit were analyzed. MAIN OUTCOME MEASURES: Comparison of the prevalence of abnormal 24-2 versus 10-2 visual field results based on cluster criteria in each diagnostic group. RESULTS: A total of 775 eyes (497 patients) were evaluated. A total of 364 eyes had early glaucoma, 303 eyes were glaucoma suspects, and 108 eyes were ocular hypertensives. In the glaucoma group, 16 of the 26 eyes (61.5%) classified as normal based on cluster criteria on 24-2 tests were classified as abnormal on 10-2 visual fields. In eyes with suspected glaucoma, 79 of the 200 eyes (39.5%) classified as normal on the 24-2 test were classified as abnormal on 10-2 visual fields. In ocular hypertensive eyes, 28 of the 79 eyes (35.4%) classified as normal on the 24-2 were classified as abnormal on the 10-2. Patients of African descent were more likely to have an abnormal 10-2 result (67.3 vs. 56.8%, P = 0.009). CONCLUSIONS: Central visual field damage seen on the 10-2 test is often missed with the 24-2 strategy in all groups. This finding has implications for the diagnosis of glaucoma and classification of severity.

Latanoprostene Bunod 0.024% versus Timolol Maleate 0.5% in Subjects with Open-Angle Glaucoma or Ocular Hypertension: The APOLLO Study.

PURPOSE: To compare the diurnal intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) ophthalmic solution 0.024% every evening (qpm) with timolol maleate 0.5% twice daily (BID) in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). DESIGN: Phase 3, randomized, controlled, multicenter, double-masked, parallel-group clinical study. PARTICIPANTS: Subjects aged ≥18 years with a diagnosis of OAG or OHT in 1 or both eyes. METHODS: Subjects were randomized (2:1) to a 3-month regimen of LBN 0.024% qpm or timolol 0.5% 1 drop BID. Intraocular pressure was measured at 8 am, 12 pm, and 4 pm of each postrandomization visit (week 2, week 6, and month 3). Adverse events were recorded throughout the study. MAIN OUTCOME MEASURES: The primary efficacy end point was IOP in the study eye measured at each of the 9 assessment time points. Secondary efficacy end points included the proportion of subjects with IOP ≤18 mmHg consistently at all 9 time points and the proportion of subjects with IOP reduction ≥25% consistently at all 9 time points. RESULTS: Of 420 subjects randomized, 387 completed the study (LBN 0.024%, n = 264; timolol 0.5%, n = 123). At all 9 time points, the mean IOP in the study eye was significantly lower in the LBN 0.024% group than in the timolol 0.5% group (P ≤ 0.002). At all 9 time points, the percentage of subjects with mean IOP ≤18 mmHg and the percentage with IOP reduction ≥25% were significantly higher in the LBN 0.024% group versus the timolol 0.5% group (mean IOP ≤18 mmHg: 22.9% vs. 11.3%, P = 0.005; IOP reduction ≥25%: 34.9% vs. 19.5%, P = 0.001). Adverse events were similar in both treatment groups. CONCLUSIONS: In this phase 3 study, LBN 0.024% qpm demonstrated significantly greater IOP lowering than timolol 0.5% BID throughout the day over 3 months of treatment. Latanoprostene bunod 0.024% was effective and safe in these adults with OAG or OHT.

Visual Field Change and 24-Hour IOP-Related Profile with a Contact Lens Sensor in Treated Glaucoma Patients.

PURPOSE: To test the hypothesis that a 24-hour recording of intraocular pressure (IOP)-related measurements derived from a contact lens sensor (CLS) correlates to the rate of visual field progression in treated glaucomatous eyes. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Forty treated glaucomatous patients with 8 or more 24-2 visual field tests. METHODS: Twenty-four-hour recording with a CLS that provides IOP-related measurements. MAIN OUTCOME MEASURES: Rates of visual field mean deviation (MD) change before and at the time of CLS recording and CLS parameters, namely number of large peaks, mean peak ratio, wake-to-sleep slope, amplitude and area under the cosine curve, and variability from the mean. RESULTS: When comparing the rate of MD change before and at the time of CLS recording of all patients, the average slope was -0.05 dB/year faster in the beginning compared with the end (P = 0.087), suggesting a deceleration of progression by the time of CLS recording. The number of long peaks and the mean peak ratio when patients were awake were the best predictors of faster progression. The combination of CLS parameters provided better measures of goodness of fit than Goldmann IOP parameters (mean, peak, and fluctuation) in the same period. CONCLUSIONS: Intraocular pressure-related parameters obtained with 24-hour recording with a CLS were associated with the rate of visual field progression in treated glaucomatous eyes. This technology may be useful in detecting eyes at higher risk of glaucoma progression while receiving treatment.

Efficacy of the Amsler Grid Test in Evaluating Glaucomatous Central Visual Field Defects.

PURPOSE: To investigate the efficacy of the Amsler grid test in detecting central visual field (VF) defects in glaucoma. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Patients with glaucoma with reliable Humphrey 10-2 Swedish Interactive Threshold Algorithm standard VF on the date of enrollment or within the previous 3 months. METHODS: Amsler grid tests were performed for each eye and were considered "abnormal" if there was any perceived scotoma with missing or blurry grid lines within the central 10 degrees ("Amsler grid scotoma"). An abnormal 10-2 VF was defined as ≥3 adjacent points at P < 0.01 with at least 1 point at P < 0.005 in the same hemifield on the pattern deviation plot. Sensitivity, specificity, and positive and negative predictive values of the Amsler grid scotoma area were calculated with the 10-2 VF as the clinical reference standard. Among eyes with an abnormal 10-2 VF, regression analyses were performed between the Amsler grid scotoma area and the 10-2 VF parameters (mean deviation [MD], scotoma extent [number of test points with P < 0.01 in total deviation map] and scotoma mean depth [mean sensitivity of test points with P < 0.01 in total deviation map]). MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values of the Amsler grid scotoma area. RESULTS: A total of 106 eyes (53 patients) were included (mean ± standard deviation age, 24-2 MD and 10-2 MD = 66±12 years, -9.61±8.64 decibels [dB] and -9.75±9.00 dB, respectively). Sensitivity, specificity, and positive and negative predictive values of the Amsler grid test were 68%, 92%, 97%, and 46%, respectively. Sensitivity was 40% in eyes with 10-2 MD better than -6 dB, 58% in eyes with 10-2 MD between -12 and -6 dB, and 92% in eyes with 10-2 MD worse than -12 dB. The area under the receiver operating characteristic curve of the Amsler grid scotoma area was 0.810 (95% confidence interval, 0.723-0.880, P < 0.001). The Amsler grid scotoma area had the strongest relationship with 10-2 MD (quadratic R(2)=0.681), followed by 10-2 scotoma extent (quadratic R(2)=0.611) and 10-2 scotoma mean depth (quadratic R(2)=0.299) (all P < 0.001). CONCLUSIONS: The Amsler grid can be used to screen for moderate to severe central vision loss from glaucoma.

Diagnostic Accuracy of the Spectralis and Cirrus Reference Databases in Differentiating between Healthy and Early Glaucoma Eyes.

PURPOSE: To evaluate and compare the diagnostic accuracy of global and sector analyses for detection of early visual field (VF) damage using the retinal nerve fiber layer (RNFL) reference databases of the Spectralis (Heidelberg Engineering, Heidelberg, Germany) and Cirrus (Carl Zeiss Meditec, Dublin, CA) spectral-domain optical coherence tomography (SD OCT) devices. METHODS: Healthy subjects and glaucoma suspects from the Diagnostic Innovations in Glaucoma Study (DIGS) and African Descent and Glaucoma Evaluation Study (ADAGES) with at least 2 years of follow-up were included. Global and sectoral RNFL measures were classified as within normal limits, borderline (BL), and outside normal limits (ONL) on the basis of the device reference databases. The sensitivity of ONL classification was estimated in glaucoma suspect eyes that developed repeatable VF damage. RESULTS: A total of 353 glaucoma suspect eyes and 279 healthy eyes were included. A total of 34 (9.6%) of the glaucoma suspect eyes developed VF damage. In glaucoma suspect eyes, Spectralis and Cirrus ONL classification was present in 47 eyes (13.3%) and 24 eyes (6.8%), respectively. The sensitivity of the global RNFL ONL classification among eyes that developed VF damage was 23.5% for Cirrus and 32.4% for Spectralis. The specificity of within-normal-limits global classification in healthy eyes was 100% for Cirrus and 99.6% for Spectralis. There was moderate to substantial agreement between Cirrus and Spectralis classification as ONL. CONCLUSIONS: The Spectralis and Cirrus reference databases have a high specificity for identifying healthy eyes and good agreement for detection of eyes with early glaucoma damage.

Association between Intraocular Pressure and Rates of Retinal Nerve Fiber Layer Loss Measured by Optical Coherence Tomography.

PURPOSE: To evaluate the relationship between intraocular pressure (IOP) and rates of retinal nerve fiber layer (RNFL) thickness change over time measured by spectral-domain (SD) optical coherence tomography (OCT). DESIGN: Observational cohort study. PARTICIPANTS: The study involved 547 eyes of 339 patients followed up for an average of 3.9±0.9 years. Three hundred eight (56.3%) had a diagnosis of glaucoma and 239 (43.7%) were considered glaucoma suspects. METHODS: All eyes underwent imaging using the Spectralis SD OCT (Heidelberg Engineering GmbH, Heidelberg, Germany), along with IOP measurements and standard automated perimetry (SAP). Glaucoma progression was defined as a result of "Likely Progression" from the Guided Progression Analysis software for SAP. Linear mixed models were used to investigate the relationship between average IOP during follow-up and rates of RNFL thickness change, while taking into account potential confounding factors such as age, race, corneal thickness, and baseline disease severity. MAIN OUTCOME MEASURES: The association between IOP and rates of global and sectorial RNFL thickness loss measured by SD OCT. RESULTS: Forty-six eyes (8.4%) showed progression on SAP during follow-up. Rates of global RNFL thickness change in eyes that progressed by SAP were faster than in those that did not progress (-1.02 vs. -0.61 µm/year, respectively; P = 0.002). For progressing eyes, each 1-mmHg higher average in IOP during follow-up was associated with an additional average loss of 0.20 µm/year (95% confidence interval [CI]: 0.08 to 0.31 µm/year; P < 0.001) of global RNFL thickness versus only 0.04 µm/year (95% CI: 0.01 to 0.07 µm/year; P = 0.015) for nonprogressing eyes. The largest associations between IOP and rates of RNFL change were seen for measurements from the temporal superior and temporal inferior sectors, whereas the smallest association was seen for measurements from the nasal sector. CONCLUSIONS: Higher levels of IOP during follow-up were associated with faster rates of RNFL loss over time measured by SD OCT. These findings support the use of SD OCT RNFL thickness measurements as biomarkers for the evaluation of the efficacy of IOP-lowering therapies to slow down the rate of disease progression.