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.

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.

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.

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.

Measurement Floors and Dynamic Ranges of OCT and OCT Angiography in Glaucoma.

PURPOSE: To determine if OCT angiography (OCTA)-derived vessel density measurements can extend the available dynamic range for detecting glaucoma compared with spectral-domain (SD) OCT-derived thickness measurements. DESIGN: Observational, cross-sectional study. PARTICIPANTS: A total of 509 eyes from 38 healthy participants, 63 glaucoma suspects, and 193 glaucoma patients enrolled in the Diagnostic Innovations in Glaucoma Study. METHODS: Relative vessel density and tissue thickness measurement floors of perifoveal vessel density (pfVD), circumpapillary capillary density (cpCD), circumpapillary retinal nerve fiber (cpRNFL) thickness, ganglion cell complex (GCC) thickness, and visual field (VF) mean deviation (MD) were investigated and compared with a previously reported linear change point model (CPM) and locally weighted scatterplot smoothing curves. MAIN OUTCOME MEASURES: Estimated vessel density and tissue thickness measurement floors and corresponding dynamic ranges. RESULTS: Visual field MD ranged from -30.1 to 2.8 decibels (dB). No measurement floor was found for pfVD, which continued to decrease constantly until very advanced disease. A true floor (i.e., slope of approximately 0 after observed CPM change point) was detected for cpRNFL thickness only. The post-CPM estimated floors were 49.5±2.6 µm for cpRNFL thickness, 70.7±1.0 µm for GCC thickness, and 31.2±1.1% for cpCD. Perifoveal vessel density reached the post-CPM estimated floor later in the disease (VF MD, -25.8±3.8 dB) than cpCD (VF MD, -19.3±2.4 dB), cpRNFL thickness (VF MD, -17.5±3.3 dB), and GCC thickness (VF MD, -13.9±1.8 dB; P < 0.001). The number of available measurement steps from normal values to the CPM estimated floor was greatest for cpRNFL thickness (8.9), followed by GCC thickness (7.4), cpCD (4.5), and pfVD (3.8). CONCLUSIONS: In late-stage glaucoma, particularly when VF MD is worse than -14 dB, OCTA-measured pfVD is a promising tool for monitoring progression because it does not have a detectable measurement floor. However, the number of steps within the dynamic range of a parameter also needs to be considered. Although thickness parameters reached the floor earlier than OCTA-measured pfVD, there are more such steps with thickness than OCTA parameters.

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.

Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.

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.

Peripapillary and Macular Vessel Density in Patients with Primary Open-Angle Glaucoma and Unilateral Visual Field Loss.

PURPOSE: To characterize OCT angiography (OCT-A) vessel density of patients with primary open-angle glaucoma (POAG) with unilateral visual field (VF) loss. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 33 patients with POAG with a VF defect in 1 eye (mean VF mean deviation [MD], -3.9±3.1 decibels [dB]) and normal VF in the other eye (mean VF MD, -0.2±0.9 dB) and 33 healthy eyes. METHODS: All subjects underwent OCT-A imaging, spectral-domain (SD)-OCT imaging, and VF testing. OCT-A retinal vascular measurements were summarized as whole image vessel density (wiVD), circumpapillary vessel density (cpVD), and parafoveal vessel density (pfVD). Inter-eye differences in vascular measures, as well as SD OCT retinal nerve fiber layer (RNFL), macular ganglion cell complex (mGCC) thickness, and rim area measurements in glaucoma and healthy eyes were compared. Areas under the receiver operating characteristic curves (AUROCs) were used to evaluate diagnostic accuracy for differentiating between unaffected eyes of patients with POAG and healthy eyes. MAIN OUTCOME MEASURES: Difference in OCT-A vessel density and SD OCT structural parameters between unaffected eyes of patients with POAG with the fellow affected eyes and healthy controls. RESULTS: Mean wiVD in unaffected eyes of patients with POAG (52.0%) was higher than in their fellow affected eyes (48.8%) but lower than in healthy eyes (55.9%; P < 0.001). Mean circumpapillary RNFL (cpRNFL) thickness, mGCC thickness, and rim area measurement in unaffected eyes of patients with POAG (87.5 µm, 87.7 µm, and 1.0 mm2) were also higher than those measurements in their fellow eyes (76.5 µm, 79.5 µm, and 0.8 mm2; P < 0.001) and lower than in healthy eyes (98.0 µm, 94.5 µm, and 1.4 mm2; P < 0.001). The AUROCs for differentiating unaffected eyes of patients with POAG from healthy eyes were highest for wiVD (0.84), followed by mGCC (0.78), cpRNFL (0.77), and pfVD (0.69). CONCLUSIONS: OCT-A measures detect changes in retinal microvasculature before VF damage is detectable in patients with POAG, and these changes may reflect damage to tissues relevant to the pathophysiology of glaucoma. Longitudinal studies are needed to determine whether OCT-A measures can improve the detection or prediction of the onset and progression of glaucoma.

Macular and Optic Nerve Head Vessel Density and Progressive Retinal Nerve Fiber Layer Loss in Glaucoma.

PURPOSE: To investigate prospectively the relationship between macular and peripapillary vessel density and progressive retinal nerve fiber layer (RNFL) loss in patients with mild to moderate primary open-angle glaucoma. DESIGN: Prospective, observational study. PARTICIPANTS: One hundred thirty-two eyes of 83 patients with glaucoma followed up for at least 2 years (average: 27.3±3.36 months). METHODS: Measurements of macular whole image vessel density (m-wiVD) and optic nerve head whole image vessel density (onh-wiVD) were acquired at baseline using OCT angiography. RNFL, minimum rim width (MRW), and ganglion cell plus inner plexiform layer (GCIPL) thickness were obtained semiannually using spectral-domain OCT. Random-effects models were used to investigate the relationship between baseline vessel density parameters and rates of RNFL loss after adjusting for the following confounding factors: baseline visual field mean deviation, MRW, GCIPL thickness, central corneal thickness (CCT), and mean intraocular pressure during follow-up and disc hemorrhage, with or without including baseline RNFL. MAIN OUTCOME MEASURES: Effects of m-wiVD and onh-wiVD on rates of RNFL loss over time. RESULTS: Average baseline RNFL thickness was 79.5±14.8 µm, which declined with a mean slope of -1.07 µm/year (95% confidence interval, -1.28 to -0.85). In the univariate model, including only a predictive factor and time and their interaction, each 1% lower m-wiVD and onh-wiVD was associated with a 0.11-µm/year (P < 0.001) and 0.06-µm/year (P = 0.031) faster rate of RNFL decline, respectively. A similar relationship between low m-wiVD and onh-wiVD and faster rates of RNFL loss was found using different multivariate models. The association between vessel density measurements and rate of RNFL loss was weak (r2 = 0.125 and r2 = 0.033 for m-wiVD and onh-wiVD, respectively). Average CCT also was a predictor for faster RNFL decline in both the univariate (0.11 µm/year; P < 0.001) and multivariate models. CONCLUSIONS: Lower baseline macular and optic nerve head (ONH) vessel density are associated with a faster rate of RNFL progression in mild to moderate glaucoma. Assessment of ONH and macular vessel density may add significant information to the evaluation of the risk of glaucoma progression and prediction of rates of disease worsening.

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.

Peripapillary and Macular Vessel Density in Patients with Glaucoma and Single-Hemifield Visual Field Defect.

PURPOSE: To compare hemifield differences in the vessel density of the peripapillary and macula in open-angle glaucoma eyes with visual field (VF) defect confined to one hemifield using optical coherence tomography angiography (OCT-A). DESIGN: Cross-sectional study. PARTICIPANTS: A total of 58 eyes of 58 patients with glaucoma with VF loss confined to a single hemifield and 28 healthy eyes. METHODS: Retinal vasculature information was summarized as circumpapillary vessel density (cpVD) and perifoveal vessel density (pfVD). Circumpapillary retinal nerve fiber layer (cpRNFL) and macular ganglion cell complex (mGCC) thickness were calculated using spectral domain optical coherence tomography (SD OCT). Paired and unpaired t tests were used to evaluate differences between the perimetrically affected and intact hemiretinae and healthy hemiretinae. Linear regression analyses were performed to evaluate the associations between VF measures with vascular and structural measurements. MAIN OUTCOME MEASURES: Total and hemispheric cpVD, pfVD, cpRNFL, mGCC, and mean sensitivity (MS). RESULTS: Mean cpVD and pfVD in the intact hemiretinae of glaucoma eyes (59.0% and 51.1%, respectively) were higher than in the affected hemiretinae (54.7% and 48.3%, respectively; P < 0.001) but lower than in healthy eyes (62.4% and 53.8%, respectively; P < 0.001). Similar results were noted with cpRNFL and mGCC thickness measurements (P < 0.05 for both). The strongest associations between MS in the affected hemifields were found for cpVD (r = 0.707), followed by pfVD (r = 0.615), cpRNFL (r = 0.496), and mGCC (r = 0.482) in the corresponding hemiretinae (P < 0.001 for all). Moreover, the correlations in the intact hemifields between MS with cpVD and pfVD were higher (r = 0.450 and 0.403) than the correlations between MS and cpRNFL and mGCC thickness measurements (r = 0.340 and 0.290; P values <0.05 for all). CONCLUSIONS: Reduced peripapillary and macular vessel density was detectable in the perimetrically intact hemiretinae of glaucoma eyes with a single-hemifield defect. Vessel density attenuation in both affected and intact hemiretinae was associated with the extent of VF damage in the corresponding hemifields. Optical coherence tomography angiography potentially shows promise for identifying glaucomatous damage before focal VF defects are detectable.

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.