Search

Purpose: To evaluate functional and structural assessments as endpoints for clinical trials for USH2A-related retinal degeneration., Methods: People with biallelic disease-causing variants in USH2A, visual acuity ≥ 20/80, and visual field ≥ 10° diameter were enrolled in a 4-year, natural history study. Participants underwent static perimetry, microperimetry, visual acuity, fullfield stimulus testing (FST), and optical coherence tomography annually. Rates of change estimated from mixed-effects linear models and percentages of eyes with changes exceeding the coefficient of repeatability (CoR) or thresholds conforming with U.S. Food and Drug Administration (FDA) guidelines were evaluated., Results: Rates of change were generally more sensitive to change than proportions of eyes exceeding a threshold such as the CoR. Baseline ellipsoid zone area ≥ 3 mm2 was necessary to detect change. Mean sensitivity and volumetric hill of vision measures on static perimetry had similar properties and were the most sensitive to changes of the continuous measures. The highest 4-year proportions of eyes exceeding the CoR were from FST testing (47%) and microperimetry (32%). Specification of loci as functional transition points (FTPs) resulted in 45% (static perimetry) and 46% (microperimetry) at 4 years, meeting FDA guidelines for progression., Conclusions: Rate of change of mean sensitivity on static perimetry was a sensitive perimetric continuous measure. Percentages of within-eye change were largest with FST testing and microperimetry. FTPs appear to be particularly sensitive to change. These results affect clinical trial design for USH2A-related retinal degeneration., Translational Relevance: Analyses of natural history data from the Rate of Progression in USH2A-Related Retinal Degeneration (RUSH2A) study can inform eligibility criteria and endpoints for clinical trials.

Background/purpose: To define "strong" versus "weak" antivascular endothelial growth factor (anti-VEGF) treatment response in eyes with center-involved diabetic macular edema (CI-DME)., Methods: Exploratory analyses of three DRCR Retina Network randomized trials of eyes with CI-DME treated with aflibercept, bevacizumab, or ranibizumab. Thresholds of 5-, 10-, and 15-letter gain defined strong visual acuity (VA) response when baseline VA was 20/25-20/32, 20/40-20/63, or 20/80-20/320, respectively. Thresholds of 50, 100, or 200- µ m reduction defined strong anatomical response when baseline central subfield thickness (CST) was <75, ≥75 to <175, or ≥175- µ m above standard thresholds. Additional thresholds from regression equations were calculated., Results: At 24 weeks, outcomes for strong response were achieved by 476 of 958 eyes (50%) for VA and 505 eyes (53%) for CST. At 104 weeks among the 32% of eyes with strong VA and CST response at 24 weeks, 195 of 281 (69%) maintained strong VA and CST response, whereas 20 (7%) had neither strong VA nor strong CST response. Outcomes rates were similar across protocols and when defined using regression equations., Conclusion: These phenotypes are suitable for efforts to identify predictive biomarkers for response to anti-VEGF therapy for DME and might facilitate comparison of treatment response among diverse cohorts with DME.

Purpose: To identify the prevalence of extramacular drusen and their role in the progression of age-related macular degeneration (AMD)., Design: Retrospective analysis of a prospective cohort study., Participants: The study was conducted in 4168 eyes (2998 participants) with intermediate AMD in one or both eyes enrolled in the Age-Related Eye Disease Study 2 (AREDS2), a 5-year multicenter study of nutritional supplements., Methods: Baseline 3-field 30-degree color photographs were evaluated for drusen characteristics outside the macular grid, including size, area, and location. The characteristics of extramacular drusen were compared with those of drusen within the macula., Main Outcome Measures: Progression rates to late AMD., Results: Although extramacular drusen were observed in 3624 (86.9%) eyes, they represented a small area (< 0.5 mm 2 ) in 50.3% of eyes, with only 17.5% exhibiting an area of > 1 disc area. Eyes with extramacular drusen exhibited larger macular drusen size and area than eyes without extramacular drusen (P < 0.001). Extramacular drusen were not associated with progression to late AMD. The hazard ratio adjusted for baseline age, sex, smoking, AMD severity level, and reticular pseudodrusen for 4043 eyes at risk of developing late AMD over 5 years was 1.17 (95% confidence interval [CI], 0.88-1.54; P = 0.27) for geographic atrophy and 0.96 (95% CI, 0.76-1.2; P = 0.7) for neovascular AMD., Conclusions: Extramacular drusen are commonly observed in eyes with AMD and are more frequent with an increasing drusen burden within the macula. In eyes with intermediate AMD, extramacular drusen do not confer additional risk to previously identified risk factors in progression to late AMD., (Copyright © 2022 American Academy of Ophthalmology. All rights reserved.)

Background: In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear., Methods: At 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed., Results: A total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, -0.9 to 2.5; P = 0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group., Conclusions: In this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.)., (Copyright © 2022 Massachusetts Medical Society.)

Purpose: A training exercise was performed to study the ability of graders to reliably identify precursor lesions to geographic atrophy (GA), known as persistent choroidal hypertransmission defects (hyperTDs), using en face OCT images from eyes with nonexudative age-related macular degeneration (AMD)., Design: Intergrader agreement study., Participants: Eleven graders participated in this exercise., Methods: Formal training on how to identify persistent hyperTDs on en face OCT images was provided to the graders. A persistent hyperTD was defined as a bright lesion having a greatest linear dimension (GLD) of at least 250 μm. Training consisted of a tutorial session followed by the grading of 3 pretest exercises, each consisting of 3 cases. After all graders scored 100% on the pretest exercises, they performed a final exercise consisting of 30 en face OCT images from 29 eyes with nonexudative AMD containing 107 hyperTDs that each grader needed to evaluate. The cases contained a variety of AMD-related atrophic lesions., Main Outcome Measures: The sensitivity, positive predictive value (PPV), and modified accuracy were assessed for each grader., Results: A total of 1177 hyperTDs from 30 en face OCT images were reviewed by the graders. The mean sensitivity, PPV, and modified accuracy for all the graders were calculated to be 99.0%, 99.2%, and 98.2%, respectively. There was a 97% agreement observed between all the graders (first-order agreement coefficient [AC 1 ] = 0.97). Internal graders from the Bascom Palmer Eye Institute had a slightly higher agreement compared with the external graders (AC 1  = 0.98 vs. AC 1  = 0.96). The hyperTDs most often incorrectly identified included the following features: (1) hyperTDs containing hypotransmission defect cores, (2) single hyperTDs that were incorrectly graded as 2 separate lesions, and (3) hyperTDs with borderline GLDs that were close to 250 μm., Conclusions: The accurate detection of persistent hyperTDs on en face OCT images by graders demonstrates the feasibility of using this OCT biomarker to identify disease progression in eyes with nonexudative AMD, especially when used as a clinical trial end point in studies designed to test new therapies that may slow disease progression from intermediate AMD to GA., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Develop equations to convert Cirrus central subfield thickness (CST) to Spectralis CST equivalents and vice versa in eyes with diabetic macular edema (DME)., Methods: The DRCR Retina Network Protocol O data were split randomly to train (70% sample) and validate (30% sample) conversion equations. Data from an independent study (CADME) also validated the equations. Bland-Altman 95% limits of agreement between predicted and observed values evaluated the equations., Results: Protocol O included 374 CST scan pairs from 187 eyes (107 participants). The CADME study included 150 scan pairs of 37 eyes (37 participants). Proposed conversion equations are Spectralis = 40.78 + 0.95 × Cirrus and Cirrus = 1.82 + 0.94 × Spectralis regardless of age, sex, or CST. Predicted values were within 10% of observed values in 101 (90%) of Spectralis and 99 (88%) of Cirrus scans in the validation data; and in 136 (91%) of the Spectralis and 148 (99%) of the Cirrus scans in the CADME data. Adjusting for within-eye correlations, 95% of conversions are estimated to be within 17% (95% confidence interval, 14%-21%) of CST on Spectralis and within 22% (95% confidence interval, 18%-28%) of CST on Cirrus., Conclusions: Conversion equations developed in this study allow the harmonization of CST measurements for eyes with DME using a mix of current Cirrus and Spectralis device images., Translational Relevance: The CSTs measured on Cirrus and Spectralis devices are not directly comparable owing to outer boundary segmentation differences. Converting CST values across spectral domain optical coherence tomography instruments should benefit both clinical research and standard care efforts.

The Foundation Fighting Blindness, a 501(c)(3) nonprofit organization, established an international consortium of inherited retinal disease specialists in 2016, with a mission to accelerate the development of treatments for rare, inherited retinal degenerations, such as retinitis pigmentosa, Stargardt disease, Leber congenital amaurosis, Usher syndrome, choroideremia, and achromatopsia. The Consortium accomplishes its mission by evaluating novel outcome measures, sharing standardized study protocols and datasets, and disseminating findings. Having established research infrastructure in the first 3 years, including 39 global research sites, the network is now poised to expand its infrastructure for trials of new therapies in partnership with industry. This model represents an innovative approach to overcome challenges of therapeutic development for rare diseases.

Purpose: To report baseline visual fields in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) study., Design: Cross-sectional study within a natural history study., Methods: Setting: multicenter, international., Study Population: Usher syndrome type 2 (USH2) (n = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP) (n = 47) associated with biallelic disease-causing sequence variants in USH2A., Observation Procedures: Repeatability of full-field static perimetry (SP) and between-eye symmetry of kinetic perimetry (KP) were evaluated with intraclass correlation coefficients (ICCs). The association of demographic and clinical characteristics with total hill of vision (V TOT ) was assessed with general linear models. Associations between V TOT and other functional and morphologic measures were assessed using Spearman correlation coefficients and t tests., Main Outcome Measures: V TOT (SP) and III4e isopter area (KP)., Results: USH2 participants had more severe visual field loss than ARRP participants (P < .001, adjusting for disease duration, age of enrollment). Mean V TOT measures among 3 repeat tests were 32.7 ± 24.1, 31.2 ± 23.4, and 31.7 ± 23.9 decibel-steradians (intraclass correlation coefficient [ICC] = 0.96). Better VA, greater photopic ERG 30-Hz flicker amplitudes, higher mean microperimetry sensitivity, higher central subfield thickness, absence of macular cysts, and higher III4e seeing area were associated with higher V TOT (all r > .48; P < .05). Mean III4e isopter areas for left (4561 ± 4426 squared degrees) and right eyes (4215 ± 4300 squared degrees) were concordant (ICC = 0.94)., Conclusions: USH2 participants had more visual field loss than participants with USH2A-related ARRP, adjusting for duration of disease and age of enrollment. V TOT was repeatable and correlated with other functional and structural metrics, suggesting it may be a good summary measure of disease severity in patients with USH2A-related retinal degeneration., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to evaluate baseline best corrected visual acuity (BCVA), full-field electroretinography (ERG), full-field stimulus thresholds (FST), and their relationship with baseline demographic and clinical characteristics in the Rate of Progression in Usher syndrome type 2 ( USH2A )-related Retinal Degeneration (RUSH2A) multicenter study., Methods: Participants had Usher syndrome type 2 (USH2, N = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP, N  = 47) associated with biallelic variants in the USH2A gene. Associations of demographic and clinical characteristics with BCVA, ERG, and FST were assessed with regression models., Results: In comparison to ARRP, USH2 had worse BCVA (median 79 vs. 82 letters; P < 0.001 adjusted for age), lower rod-mediated ERG b-wave amplitudes (median 0.0 vs. 6.6 µV; P < 0.001) and 30 Hz flicker cone-mediated ERG amplitudes (median 1.5 vs. 3.1 µV; P  = 0.001), and higher (white, blue, and red) FST thresholds (means [-26, -31, -23 dB] vs. [-39, -45, -28 dB]; P < 0.001 for all stimuli). After adjusting for age, gender, and duration of vision loss, the difference in BCVA between diagnosis groups was attenuated ( P  = 0.09). Only diagnosis was associated with rod- and cone-mediated ERG parameters, whereas both genders ( P  = 0.04) and duration of visual loss ( P < 0.001) also were associated with FST white stimulus., Conclusions: USH2 participants had worse BCVA, ERG, and FST than ARRP participants. FST was strongly associated with duration of disease; it remains to be determined whether it will be a sensitive measure of progression., Translational Relevance: Using standardized research protocols in RUSH2A, measures have been identified to monitor disease progression and treatment response and differentiate features of prognostic relevance between USH2 and ARRP participants with USH2A mutations., Competing Interests: Disclosure: D.G. Birch, Biogen/Nightstarx (F), Acucela (C), ProQR (F, C), Nacuity (C), AGTC (F, C), Editas (C), 4D Therapeutics (F, C); P. Cheng None; J.L. Duncan, 4D Therapeutics (C), Acucela (F), AGTC (C), DTx Pharma, Inc. (C), Editas (C), Eloxx (C), Gyroscope (C), Biogen/Nightstarx (F, C), ProQR (C), Spark (C), SparingVision (S), Vedere Bio (S), Horama (C); A.R. Ayala None; M.G. Maguire Genentech/Roche (C), Regenera (C); I. Audo Novartis (C), SparingVision (C); J.K. Cheetham, AbbVie (I); T.A. Durham None; A.T. Fahim None; F.L. Ferris III, Bausch and Lomb (P, R), Janssen Research & Development, LLC (C) Viewpoint Therapeutics, Inc (C), Genetech (C), Norvo Nordisk (C), Apellis (C), Roche (C), SemaThera PTC Therapeutics (C), Regenera (C), Novartis (C), Eyevensys (C), Kodiak (C), 4D Molecular (C), Clear Side Biomedical (C); E. Heon None; R.M. Huckfeldt, AGTC (F), Spark (F), Biogen (F), ProQR (F), MeiraGTx (F); A. Iannaccone, Alia Therapeutics (S), ClearView Healthcare Partners (C), Teladoc Health (C), GLG Group (C), Guidepoint (C), Astellas Institute for Regenerative Medicine (C), Roivant Pharma (C), Editas (C), Rhythm Pharmaceuticals (C), IQVIA (C), Gyroscope (C), Ocugen (C), AGTC (F), AbbVie (F), Acucela (F), ProQR (F), Retinagenix (F), 4D Molecular Therapeutics (F), BridgeBio Pharma/Retinagenix (F); N.W. Khan None; E.M. Lad, Biogen/Nightstarx (C) and Novartis (C); M. Michaelides, MeiraGTx (F), Stargazer Pharma (F), Acucela (F), Astellas (F), ProQR (F), 2CTech (F); M.E. Pennesi, AbbVie/Editas (C), Spark Therapeutics (C), Wave Biosciences (C), Astellas Pharmaceuticals (C), RegenexBio (C), Iveric (C), Biogen (C), Novartis (C), Adverum (C), Gensight (F), ProQR (F), Horama (F), Eyevensys (F), Nayan (F) (I), Nacuity (F, I), Ocugen (F, I), Vedere Bio (F, I), SparingVision (F, I), AGTC (C), Sanofi (C); K. Stingl, ProQR (F); A. Vincent, ADVERUM Biotechnologies INC (C); C.Y. Weng, Allergan/AbbVie, Inc. (C), Alcon (C), Alimera Sciences (C), Regeneron (C), Novartis (C), Dutch Ophthalmic Research Center (C), (Copyright 2020 The Authors.)

Objective: To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment., Design: Multicenter, randomized clinical trial., Participants: Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial., Interventions: At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment., Main Outcome Measures: Mean change in visual acuity., Results: Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF)., Conclusions: Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: To determine the prevalence of reticular pseudodrusen (RPD) in eyes with age-related macular degeneration (AMD), assess the role of RPD as an independent risk factor for late AMD development, and evaluate genetic association with RPD., Design: Prospective cohort study., Participants: Participants with intermediate AMD in 1 or both eyes enrolled in the Age-Related Eye Disease Study 2 (AREDS2), a 5-year multicenter study of nutritional supplement., Methods: Fundus autofluorescence (FAF) images from a subset of AREDS2 participants were evaluated at annual visits for presence of RPD. Six single nucleotide polymorphisms-rs10490924 (ARMS2), rs1061170 (CFH), rs2230199 (C3), rs116503776 and rs114254831 (C2/CFB), and rs943080 (VEGF-A)-and the genetic risk score (GRS) were assessed for association with RPD. Development of late AMD, defined as geographic atrophy (GA) or neovascular AMD (NVAMD), was identified., Main Outcome Measures: Prevalence of RPD, odds ratio (OR) of late AMD development, and genetic associations of RPD., Results: The FAF images were evaluated for 5021 eyes (2516 participants). Reticular pseudodrusen were seen in 1186 eyes (24% of eyes, 29% of participants). Prevalence of RPD varied with baseline AREDS AMD severity level: 6% in early AMD (n = 458), 26% in intermediate AMD (n = 2606), 36% in GA (n = 682), and 19% in NVAMD (n = 1246). Mean age of participants with RPD was 79 years (standard deviation [SD], 7) and 75 years (SD, 8) in those without RPD (P < 0.0001). Reticular pseudodrusen were more frequent in female participants (65% RPD vs. 53% no RPD). Odds ratio adjusted for baseline age, gender, race, educational status, smoking, and AMD severity level for 1710 eyes at risk of developing late AMD at the next annual visit was 2.42 (95% confidence interval [CI], 1.80-3.24; P < 0.001) for GA and 1.21 (95% CI, 0.87-1.7; P = 0.26) for NVAMD. Presence of RPD was significantly associated with higher GRS (P < 0.0001) and ARMS2 risk alleles (P < 0.0001) and, at a nominal level, with C3 risk alleles (P = 0.04) and CFH risk alleles (P = 0.048 for homozygotes)., Conclusions: Participants with RPD have an increased risk of progression to GA but not NVAMD. ARMS2 risk alleles and higher GRS were associated with the presence of RPD. This study suggests that RPD are an important risk marker and should be included in classification systems used for patient prognosis., (Copyright © 2019 American Academy of Ophthalmology. All rights reserved.)

Purpose: To investigate the natural history of dark adaptation (DA) function as measured by the change in rod intercept time (RIT) over 4 years and to correlate RIT change with age-related macular degeneration (AMD) severity., Design: Longitudinal, single-center, observational study., Participants: A total of 77 participants aged ≥50 years with a range of AMD severities., Methods: Participants each contributing a single study eye to the analysis were assigned into person-based AMD severity groups based on fundus characteristics (drusen, pigmentary changes, late AMD, and subretinal drusenoid deposits [SDDs]). The DA function was assessed in study eyes at baseline and 3, 6, 12, 18, 24, 36, and 48 months. Mean change in DA function over time was calculated using the slope of linear regression fits of longitudinal RIT data. Patient-reported responses on a Low Luminance Questionnaire (LLQ) were obtained at baseline and yearly. Nonparametric statistical testing was performed on all comparisons., Main Outcome Measure: The RIT, defined as the time taken after a photobleach for visual sensitivity to recover detection of a 5×10 -3 cd/m 2 stimulus (a decrease of 3 log units), was monitored in study eyes over 4 years, and the mean rate of change was computed., Results: Longitudinal analysis of 65 study eyes followed on the standard testing protocol (mean age, 71±9.3 years; 49% were female) revealed that higher rates of RIT prolongation were correlated with AMD severity group assignment at baseline (P = 0.026) and with severity group assignments at year 4 (P = 0.0011). Study eyes that developed SDD during follow-up demonstrated higher rates of RIT prolongation relative to those that did not (P < 0.0001). Overall, higher rates of RIT prolongation were significantly correlated with greater 4-year decreases in LLQ scores (total mean score, P = 0.0032)., Conclusions: Longitudinal decline in DA function, which correlated with patient-reported functional deficits, was accelerated in eyes with greater AMD severity and especially in eyes with SDD both at baseline and at 4 years. The RIT prolongation as a measure of changing DA function may be a functional outcome measure in AMD clinical studies., (Published by Elsevier Inc.)

Importance: Previous studies of the role of dietary and supplementary calcium in age-related macular degeneration (AMD) have produced mixed results, suggesting that supplementation and decreased dietary intake are both harmful., Objective: To evaluate the association of baseline dietary and supplementary calcium intake with progression of AMD., Design, Setting, and Participants: This study involved secondary analyses of participants enrolled in the Age-Related Eye Disease Study (AREDS). The AREDS study (1992-2001) enrolled patients from academic and community-based retinal practices in the United States. Men and women with varying severity of AMD were included. Data analysis for this article occurred from September 2015 to December 2018., Exposures: Baseline self-reported dietary or supplementary calcium intake., Main Outcomes and Measures: Development of late AMD, geographic atrophy (central or noncentral), or neovascular AMD detected on centrally graded baseline and annual fundus photographs., Results: A total of 4751 participants were included (mean [SD] age, 69.4 [5.1] years); 4543 (95.6%) were white, and 2655 (55.9%) were female. Compared with those who were in the lowest quintile, the participants in the highest quintile of dietary calcium intake had a lower risk of developing late AMD (hazard ratio [HR], 0.73 [95% CI, 0.59-0.90]), central geographic atrophy (HR, 0.64 [95% CI, 0.48-0.86]), and any geographic atrophy (HR, 0.80 [95% CI, 0.64-1.00]). The participants in the highest tertile of supplementary calcium intake had a lower risk of developing neovascular AMD (HR, 0.70 [95% CI, 0.50-0.97]) compared with those who did not take calcium supplements. When stratified by sex, women in the highest quintile of dietary calcium intake had a lower risk of developing late AMD (HR, 0.73 [95% CI, 0.56-0.97]) compared with those in the lowest quintile. Women in the highest tertile of calcium supplementation had a lower risk of progression to neovascular AMD (HR, 0.67 [95% CI, 0.48-0.94]) compared with those who did not take calcium supplements. Similar findings were found in men for dietary calcium. Too few men took calcium supplements to allow for analyses., Conclusions and Relevance: In this secondary analysis, higher levels of dietary and supplementary calcium intake were associated with lower incidence of progression to late AMD in AREDS participants. The results may be owing to uncontrolled confounding or chance and should be considered hypothesis development requiring additional study.

The Progression of Atrophy Secondary to Stargardt Disease (ProgStar) studies were designed to measure the progression of Stargardt disease through the use of fundus autofluorescence imaging, optical coherence tomography, and microperimetry. The overarching objectives of the studies were to document the natural course of Stargardt disease and identify the most appropriate clinical outcome measures for clinical trials assessing the efficacy and safety of upcoming treatments for Stargardt disease. A workshop organized by the Foundation Fighting Blindness Clinical Research Institute was held on June 11, 2018, in Baltimore, MD, USA. Invited speakers discussed spectral-domain optical coherence tomography, fundus autofluorescence, and microperimetry methods and findings in the ProgStar prospective study. The workshop concluded with a panel discussion of optimal endpoints for measuring treatment efficacy in Stargardt disease. We summarize the workshop presentations in light of the most current literature on Stargardt disease and discuss potential clinical outcome measures and endpoints for future treatment trials.

Purpose: To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement., Design: Prospective cohort study within a controlled clinical trial., Participants: Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50-85 years., Methods: Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype., Main Outcome Measures: (1) Presence or development of GA; (2) change in the square root of GA area over time., Results: At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27-0.30) and incident GA (0.28 mm/year; 0.27-0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P < 0.0001 for interaction in each case) but not with AREDS2 treatment assignment (P = 0.33) or smoking status (P = 0.05). Enlargement was significantly faster with ARMS2 risk (P < 0.0001), C3 non-risk (P = 0.0002), and APOE non-risk (P = 0.001) genotypes., Conclusions: Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning., (Published by Elsevier Inc.)

Importance: Ranibizumab is a viable treatment option for eyes with proliferative diabetic retinopathy (PDR) through 2 years. However, longer-term results are needed., Objective: To evaluate efficacy and safety of 0.5-mg intravitreous ranibizumab vs panretinal photocoagulation (PRP) over 5 years for PDR., Design, Setting, and Participants: Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial evaluated 394 study eyes with PDR enrolled February through December 2012. Analysis began in January 2018., Interventions: Eyes were randomly assigned to receive intravitreous ranibizumab (n = 191) or PRP (n = 203). Frequency of ranibizumab was based on a protocol-specified retreatment algorithm. Diabetic macular edema could be managed with ranibizumab in either group., Main Outcomes and Measures: Mean change in visual acuity (intention-to-treat analysis) was the main outcome. Secondary outcomes included peripheral visual field loss, development of vision-impairing diabetic macular edema, and ocular and systemic safety., Results: The 5-year visit was completed by 184 of 277 participants (66% excluding deaths). Of 305 enrolled participants, the mean (SD) age was 52 (12) years, 135 (44%) were women, and 160 (52%) were white. For the ranibizumab and PRP groups, the mean (SD) number of injections over 5 years was 19.2 (10.9) and 5.4 (7.9), respectively; the mean (SD) change in visual acuity letter score was 3.1 (14.3) and 3.0 (10.5) letters, respectively (adjusted difference, 0.6; 95% CI, -2.3 to 3.5; P = .68); the mean visual acuity was 20/25 (approximate Snellen equivalent) in both groups at 5 years. The mean (SD) change in cumulative visual field total point score was -330 (645) vs -527 (635) dB in the ranibizumab (n = 41) and PRP (n = 38) groups, respectively (adjusted difference, 208 dB; 95% CI, 9-408). Vision-impairing diabetic macular edema developed in 27 and 53 eyes in the ranibizumab and PRP groups, respectively (cumulative probabilities: 22% vs 38%; hazard ratio, 0.4; 95% CI, 0.3-0.7). No statistically significant differences between groups in major systemic adverse event rates were identified., Conclusions and Relevance: Although loss to follow-up was relatively high, visual acuity in most study eyes that completed follow-up was very good at 5 years and was similar in both groups. Severe vision loss or serious PDR complications were uncommon with PRP or ranibizumab; however, the ranibizumab group had lower rates of developing vision-impairing diabetic macular edema and less visual field loss. Patient-specific factors, including anticipated visit compliance, cost, and frequency of visits, should be considered when choosing treatment for patients with PDR. These findings support either anti-vascular endothelial growth factor therapy or PRP as viable treatments for patients with PDR., Trial Registration: ClinicalTrials.gov Identifier: NCT01489189.

Purpose: To describe risk factors for scar formation and changes to fibrotic scar through 5 years in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)., Design: Multicenter, prospective cohort study., Participants: A total of 1061 subjects in CATT., Methods: Color photographic and fluorescein angiographic images from baseline and 1, 2, and 5 years were evaluated. Incidence of scar formation was estimated with Kaplan-Meier curves. Risk factors were assessed with Cox regression models., Main Outcome Measures: Scar formation, fibrotic scar area, and macular atrophy associated with fibrotic scar ("atrophy")., Results: Cumulative proportion of eyes with scar was 32%, 46%, and 56% at years 1, 2, and 5, respectively. Baseline factors associated with increased risk (adjusted hazards ratio [aHR] and 95% confidence interval [CI]) were classic choroidal neovascularization (CNV) (aHR, 4.49; 95% CI, 3.34-6.04) versus occult, hemorrhage >1 disc area (DA) (aHR, 2.28; 95% CI, 1.49-3.47) versus no hemorrhage, retinal thickness >212 μm (aHR, 2.58; 95% CI, 1.69-3.94) versus <120 μm, subretinal tissue complex thickness >275 μm (aHR, 2.64; 95% CI, 1.81-3.84) versus ≤75 μm, subretinal fluid thickness >25 μm (aHR, 1.31; 95% CI, 0.97-1.75) versus no fluid, visual acuity (VA) in fellow eye 20/20 (aHR, 1.72; 95% CI, 1.25-2.36) versus 20/50 or worse, retinal pigment epithelium elevation absence (aHR, 1.71; 95% CI, 1.21-2.41), and subretinal hyperreflective material (aHR, 1.72; 95% CI, 1.25-2.36). Among 68 eyes that developed fibrotic scar at year 1, VA decreased by a mean of additional 13 letters between years 1 and 5. Mean scar area was 1.2, 1.2, and 1.9 DA at 1, 2, and 5 years, respectively. Atrophy was present in 18%, 24%, and 54% of these eyes at years 1, 2, and 5, respectively; the mean areas were 1.6, 2.0, and 3.1 DA, respectively. Atrophy replaced fibrotic scar in 8 eyes at year 5. There was no significant correlation between scar growth and atrophy growth. The rate of growth for both was similar between the clinical trial and observation periods., Conclusions: Several morphologic features, including classic CNV and large hemorrhage, are associated with scar formation. Rate of new scar formation declined after 2 years. Most fibrotic scars and accompanying macular atrophy expanded over time, reducing VA., (Copyright © 2018 American Academy of Ophthalmology. All rights reserved.)

Purpose: We investigate whether responses on a Low Luminance Questionnaire (LLQ) in patients with a range of age-related macular degeneration (AMD) severity are associated with their performance on focal dark adaptation (DA) testing and with choroidal thickness., Design: Cross-sectional, single-center, observational study., Participants: A total of 113 participants older than 50 years of age with a range of AMD severity., Methods: Participants answered the LLQ on the same day they underwent DA testing using a focal dark adaptometer measuring rod intercept time (RIT). We performed univariable and multivariable analyses of the LLQ scores and age, RIT, AMD severity, subfoveal choroidal thickness [SFCT], phakic status, and best-corrected visual acuity., Main Outcome Measures: The primary outcome of this study was the score on the 32-question LLQ. Each item in the LLQ is designated to 1 of 6 subscales describing functional problems in low luminance: driving, emotional distress, mobility, extreme lighting, peripheral vision, and general dim lighting. Scores were computed for each subscale, in addition to a weighted total mean score., Results: Responses from 113 participants (mean age, 76.2±9.3 years; 58.4% were female) and 113 study eyes were analyzed. Univariable analysis demonstrated that lower scores on all LLQ subscales were correlated with prolonged DA testing (longer RIT) and decreased choroidal thickness. All associations were statistically significant except for the association of choroidal thickness and "peripheral vision." The strongest association was the LLQ subscale of driving with RIT (r =-0.97, P < 0.001). Multivariable analysis for each of the LLQ subscale outcomes, adjusted for age, included RIT, with total LLQ score, "driving," "extreme lighting," and "mobility" also including choroidal thickness. In all multivariable analyses, RIT had a stronger association than choroidal thickness., Conclusions: This cross-sectional analysis demonstrates associations of patient-reported functional deficits, as assessed on the LLQ, with both reduced DA and reduced choroidal thickness, in a population of older adults with varying degrees of AMD severity and good visual acuity in at least 1 eye. These analyses suggest that local functional measurements of DA testing (RIT) and choroidal thickness are associated with patient-reported functional deficits., (Published by Elsevier Inc.)

Purpose: We determine whether the automated segmentation software, Duke Optical Coherence Tomography Retinal Analysis Program (DOCTRAP), can measure, in a platform-independent manner, retinal thickness on Cirrus and Spectralis spectral domain optical coherence tomography (SD-OCT) images in eyes with diabetic macular edema (DME) under treatment in a clinical trial., Methods: Automatic segmentation software was used to segment the internal limiting membrane (ILM), inner retinal pigment epithelium (RPE), and Bruch's membrane (BM) in SD-OCT images acquired by Cirrus and Spectralis commercial systems, from the same eye, on the same day during a clinical interventional DME trial. Mean retinal thickness differences were compared across commercial and DOCTRAP platforms using intraclass correlation (ICC) and Bland-Altman plots., Results: The mean 1 mm central subfield thickness difference (standard error [SE]) comparing segmentation of Spectralis images with DOCTRAP versus HEYEX was 0.7 (0.3) μm (0.2 pixels). The corresponding values comparing segmentation of Cirrus images with DOCTRAP versus Cirrus software was 2.2 (0.7) μm. The mean 1 mm central subfield thickness difference (SE) comparing segmentation of Cirrus and Spectralis scan pairs with DOCTRAP using BM as the outer retinal boundary was -2.3 (0.9) μm compared to 2.8 (0.9) μm with inner RPE as the outer boundary., Conclusions: DOCTRAP segmentation of Cirrus and Spectralis images produces validated thickness measurements that are very similar to each other, and very similar to the values generated by the corresponding commercial software in eyes with treated DME., Translational Relevance: This software enables automatic total retinal thickness measurements across two OCT platforms, a process that is impractical to perform manually.

Importance: When a patient with neovascular age-related macular degeneration or diabetic macular edema does not respond to an initial anti-vascular endothelial growth factor agent, usually after several injections, ophthalmologists may switch to another anti-vascular endothelial growth factor agent. Authors of case series have suggested beneficial effects from switching. However, to our knowledge, there are no studies with an appropriate control group to evaluate how such patients would do without switching agents., Objective: To assess outcomes in patients who have a poor initial response but continue treatment without switching agents., Design, Setting, and Participants: We obtained data from 2 multicenter clinical trials, the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and the Diabetic Retinopathy Clinical Research Network (DRCR.net). Based on typical clinical reasons for switching agents, we developed "switching rules" at both 3 and 6 months after initiation of treatment. Using these switching rules, we identified a 3-month and a 6-month cohort of "treatment failures" from both CATT and DRCR.net studies., Interventions: Although the cohorts from each study met criteria for switching, they were treated with the initial agent throughout the study (bevacizumab or ranibizumab in CATT and ranibizumab in DRCR.net)., Main Outcomes and Measures: Primary outcomes were change in visual acuity and change in central retinal thickness on optical coherence tomography from the 3- or 6-month visit at which switching rules were met., Results: The 126 patients from CATT and the 59 patients from DRCR.net who were selected for the switching analysis were similar in age, sex and race/ethnicity to the overall study populations. Among the participants who met the criteria for switching, the CATT participants were a mean (SD) of 79.7 (7.8) years of age, 65.9% women, and 97.6% white, while the DRCR.net participants were a mean (SD) of 65.5 (9.3) years of age, 44.1% women, and 76.3% white In all 4 cohorts, there was a 3- to 5-letter improvement in mean visual acuity over the 3 months after the switching rules were met, although all patients continued on their originally assigned treatment. Mean central retinal thickness also improved by 40 to 70 μM., Conclusions and Relevance: These results demonstrate the importance of having a comparison group to evaluate the effect of switching anti-vascular endothelial growth factor agents for treatment of neovascular age-related macular degeneration or diabetic macular edema. Without a comparison group, it is impossible to know whether any improvement observed after switching was related to the new treatment or was related to regression to the mean and time effects as observed in the 4 cohorts presented here. Randomization to switching or not switching drugs would provide a basis for valid conclusions about the effects of switching.

Purpose: To compare baseline characteristics, visual acuity (VA) and morphological outcomes between eyes with baseline hard exudates (HE) and all other eyes among patients with neovascular age-related macular degeneration (NVAMD) treated with anti-vascular endothelial growth factors (anti-VEGF)., Design: Prospective cohort study within the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Participants: Patients with NVAMD., Methods: Readers evaluated baseline and follow-up morphology on digital color images, fluorescein angiography (FA), and optical coherence tomography (OCT) in eyes with NVAMD that were randomly assigned to treatment with either ranibizumab or bevacizumab. Ophthalmologists identified HE on color images in the study eye., Main Outcome Measures: VA; scar; geographic atrophy; retinal thickness, fluid; and number of anti-VEGF injections., Results: HE was present in 128 of 1185 (11%) study eyes at baseline, 77% within 1 disc diameter of the foveal center. Patients with study eye HE were more likely female (81% vs 60%; p<0.001) and non-smokers (53% vs 42%; p=0.004). Both groups had similar proportions of hypercholesterolemia and hypertriglyceridemia. At baseline, eyes with HE had worse VA (mean 57 vs 61 letters; p=0.003), larger total lesion size (3.3 vs 2.4 DA; p <0.001), greater total foveal thickness (522µm vs 452µm; p<0.001), more retinal angiomatous proliferation (18% vs 10%; p=0.009) and sub-RPE fluid (65% vs 47%; p<0.001). At 1 year, VA was similar in both groups; more eyes with baseline HE had no fluid (45% vs 29%; p<0.001) and greater reduction in total foveal thickness (-266µm vs -158u; p<0.001). VA at year 2 was similar but retinas of eyes with baseline HE were thinner (267µm vs 299µm; p=0.03) and fewer eyes had sub-retinal fluid (23% vs 36%; p=0.008). HE was present in 19% of eyes at 1 year and 5% of eyes at 2 years. LIPC promoter SNP rs10468017 was not associated with NVAMD HE., Conclusion: Eyes with HE have larger CNV lesions and more RAP. Their initially thicker retina rapidly becomes thinner on anti-VEGF treatment. HE is not significantly associated with hyperlipidemia. HE at baseline does not significantly influence VA, scar and GA outcomes in eyes with NVAMD treated with anti-VEGF. Few eyes have HE at year 2.

Importance: To test potential treatments for age-related macular degeneration (AMD), clinical trials need standardized outcome measures that are valid for predicting AMD progression in different study populations., Objective: To evaluate the validity of the Age-Related Eye Disease Study (AREDS) detailed and simple AMD severity scales by comparing rates of development of late AMD (neovascular AMD and/or central geographic atrophy) between AREDS and AREDS2 participants., Design, Setting, and Participants: Both AREDS (1992-2001) and AREDS2 (2006-2012) enrolled patients from academic and community-based retinal practices across the United States. In AREDS (n = 4519), participants with varying severity of AMD-from no AMD to late AMD in 1 eye-were enrolled. In AREDS2 (n = 4203), participants with bilateral large drusen or large drusen in the study eye and late AMD in the fellow eye were enrolled., Main Outcomes and Measures: Five-year incidence of late AMD, assessed by annual masked centralized fundus photograph grading., Results: In AREDS, the mean (SD) age of the patients was 69.3 (5.7) years, and 2519 (55.7%) were female. In AREDS2, the mean (SD) age of the patients was 73.1 (7.7) years, and 2388 (56.8%) were female. The 5-year rates of late AMD did not differ between AREDS2 and AREDS participants within nearly all baseline AMD detailed severity scale levels: levels 1 to 3: 2.4% vs 0.5% (difference, 1.9%; 95% CI, -0.2% to 4.0%; P < .001); level 4: 6.5% vs 4.9% (difference, 1.6%; 95% CI, -1.7% to 4.8%; P = .34); level 5: 8.0% vs 5.6% (difference, 2.4%; 95% CI, -1.2% to 5.9%; P = .22); level 6: 12.8% vs 13.7% (difference, -0.9%; 95% CI, -4.8% to 3.1%; P = .66); level 7: 26.2% vs 27.8% (difference, -1.5%; 95% CI, -6.6% to 3.5%; P = .54); and level 8: 46.4% vs 44.7% (difference, 1.7%; 95% CI, -7.5% to 10.9%; P = .72). Within simple scale levels, AREDS2 and AREDS 5-year rates did not differ significantly except for level 1 (9.4% vs 3.1%, P = .02; level 2: 12.8% vs 11.8%, P = .65; level 3: 26.3% vs 25.9%, P = .90; and level 4: 45.6% vs 47.3%, P = .57)., Conclusions and Relevance: The AREDS detailed and simple AMD severity scales were useful measures for assessing the risk of developing late AMD in the AREDS2 population; these data suggest that they should be useful tools for clinical trials of AMD treatments.

Purpose: To describe outcomes 5 years after initiating treatment with bevacizumab or ranibizumab for neovascular age-related macular degeneration (AMD)., Design: Cohort study., Participants: Patients enrolled in the Comparison of AMD Treatments Trials., Methods: Patients were assigned randomly to ranibizumab or bevacizumab and to 1 of 3 dosing regimens. After 2 years, patients were released from the clinical trial protocol. At 5 years, patients were recalled for examination., Main Outcome Measures: Visual acuity (VA) and morphologic retinal features., Results: Visual acuity was obtained for 647 of 914 (71%) living patients with average follow-up of 5.5 years. The mean number of examinations for AMD care after the clinical trial ended was 25.3, and the mean number of treatments was 15.4. Most patients (60%) were treated 1 time or more with a drug other than their assigned drug. At the 5-year visit, 50% of eyes had VA of 20/40 or better and 20% had VA of 20/200 or worse. Mean change in VA was -3 letters from baseline and -11 letters from 2 years. Among 467 eyes with fluorescein angiography, mean total lesion area was 12.9 mm(2), a mean of 4.8 mm(2) larger than at 2 years. Geographic atrophy was present in 213 of 515 (41%) gradable eyes and was subfoveal in 85 eyes (17%). Among 555 eyes with spectral-domain optical coherence tomography, 83% had fluid (61% intraretinal, 38% subretinal, and 36% sub-retinal pigment epithelium). Mean foveal total thickness was 278 μm, a decrease of 182 μm from baseline and 20 μm from 2 years. The retina was abnormally thin (<120 μm) in 36% of eyes. Between 2 and 5 years, the group originally assigned to ranibizumab for 2 years lost more VA than the bevacizumab group (-4 letters; P = 0.008). Otherwise, there were no statistically significant differences in VA or morphologic outcomes between drug or regimen groups., Conclusions: Vision gains during the first 2 years were not maintained at 5 years. However, 50% of eyes had VA of 20/40 or better, confirming anti-vascular endothelial growth factor therapy as a major long-term therapeutic advance for neovascular AMD., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Importance: New methods are needed to quantify the change in the outer retinal structures in retinitis pigmentosa (RP)., Objective: To implement an alternate method for tracking ellipsoid zone (EZ) changes in RP by quantifying the EZ area on en face spectral domain-optical coherence tomographic (SD-OCT) images., Design, Setting, and Participants: Data for this observational case study were collected at the Department of Ophthalmology, University of California, Los Angeles, from May 1 to July 30, 2015, and included SD-OCT images of a subset of patients from the Trial of Oral Valproic Acid for Retinitis Pigmentosa. To be eligible for the en face OCT subanalysis, the preserved EZ area was required to be limited to the SD-OCT scanning field. Cases in which the EZ band extended to the margins of any B-scan or the most superior or inferior B-scan were excluded. The SD-OCT images of all included cases were imported into the manufacturer's software to generate en face images at the level of the EZ. Two certified SD-OCT graders independently delineated the boundaries of the preserved EZ on the en face images., Main Outcomes and Measures: Comparison of the 2 masked gradings of the generated en face images of patients with RP for agreement between the graders and the validity of the method., Results: Of the 43 available patients with volume SD-OCT data, 45 eyes of 24 patients met the eligibility criteria and were included in this subanalysis. Every patient had 2 visits that were 1 year apart, which included a total of 90 en face OCT images that were graded. The mean (SD) absolute difference and percentage difference between the 2 independent graders for each visit were 0.08 (0.10) mm2 and 4.5% (5.9%), respectively. The EZ area determined by the 2 graders showed excellent agreement with an intraclass correlation coefficient of 0.996 (95% CI, 0.995-0.997; P < .001)., Conclusions and Relevance: Quantification of the preserved EZ area on en face SD-OCT images of patients with RP is a valid and reproducible method. En face SD-OCT quantification may be a useful tool for monitoring the EZ changes of patients with advanced RP and a useful outcome measurement variable in therapeutic trials.

Purpose: To investigate the comparative efficacy of bevacizumab (Avastin) and ranibizumab (Lucentis; both Genentech, Inc, South San Francisco, CA) for diabetic macular edema (DME) using a crossover study design., Design: Randomized, double-masked, 36-week, 3-period crossover clinical trial., Participants: Fifty-six subjects with DME involving the center of the macula in one or both eyes., Methods: Monthly intravitreous injections of bevacizumab (1.25 mg) or ranibizumab (0.3 mg)., Main Outcome Measures: Comparison of mean changes in visual acuity and central retinal thickness, tested using a linear mixed-effects model., Results: Based on the linear mixed-effects model, the 3-month estimated mean improvement in visual acuity was 5.3 letters for bevacizumab and 6.6 letters for ranibizumab (difference, 1.3 letters; P = 0.039). Estimated change in optical coherence tomography (OCT) central subfield mean thickness (CSMT) was -89 μm for bevacizumab and -137 μm for ranibizumab (difference, 48 μm; P < 0.001). Incorporating cumulative treatment benefit, the model yielded a predicted 36-week (9-month) average improvement in visual acuity of 7.1 letters (95% confidence interval [CI], 5.0-9.2) for bevacizumab and 8.4 letters (95% CI, 6.3-10.5) for ranibizumab, and a change in OCT CSMT of -128 μm (95% CI, -155 to -100) for bevacizumab and -176 μm (95% CI, -202 to -149) for ranibizumab. There was no significant treatment-by-period interaction (i.e., treatment difference was constant in all 3 periods), nor was there a significant differential carryover effect from one period to the next., Conclusions: This trial demonstrated a statistically significant but small relative clinical benefit of ranibizumab compared with bevacizumab for treatment of DME, using a markedly reduced sample size relative to a full comparative efficacy study. The effects on visual acuity and central retinal thickness for the 2 drugs are consistent with those reported at 1 year for the concurrent parallel-group trial by the Diabetic Retinopathy Clinical Research Network testing bevacizumab, ranibizumab, and aflibercept for DME. The 3-period crossover design allowed for meaningful and efficient comparison, suggesting that this approach may be useful for future comparative efficacy studies of anti-vascular endothelial growth factor drugs for DME., (Published by Elsevier Inc.)

Importance: The prevalence of persistent diabetic macular edema (DME) after months of anti-vascular endothelial growth factor therapy and its effect on visual acuity are unknown., Objective: To assess subsequent outcomes of eyes with DME persisting for 24 weeks after initiating treatment with 0.5 mg of ranibizumab., Design, Setting, and Participants: We performed post hoc, exploratory analyses of a randomized clinical trial from March 20, 2007, through January 29, 2014, from 117 of 296 eyes (39.5%) randomly assigned to receive ranibizumab with persistent DME (central subfield thickness ≥250 μm on time domain optical coherence tomography) through the 24-week visit., Interventions: Four monthly intravitreous injections of ranibizumab and then as needed per protocol., Main Outcomes and Measures: Cumulative 3-year probabilities of chronic persistent DME (failure to achieve a central subfield thickness <250 μm and at least a 10% reduction from the 24-week visit on at least 2 consecutive study visits) determined by life-table analyses, and at least 10 letter (≥2 line) gain or loss of visual acuity among those eyes., Results: The probability of chronic persistent DME among eyes with persistent DME at the 24-week visit decreased from 100% at the 32-week visit to 81.1% (99% CI, 69.6%-88.6%), 55.8% (99% CI, 42.9%-66.9%), and 40.1% (99% CI, 27.4%-52.4%) at the 1-, 2-, and 3-year visits, respectively. At 3 years, visual acuity improved in eyes with and without chronic persistent DME through the follow-up period, respectively, by a mean of 7 letters and 13 letters from baseline. Among 40 eyes with chronic persistent edema through 3 years, 17 (42.5%) (99% CI, 23.1%-63.7%) gained 10 letters or more from baseline, whereas 5 (12.5%) (99% CI, 2.8%-31.5%) lost 10 letters or more from baseline., Conclusions and Relevance: These data suggest less than half of eyes treated for DME with intravitreous ranibizumab have persistent central-involved DME through 24 weeks after initiating treatment. Among the 40% that then have chronic persistent central-involved DME through 3 years, longer-term visual acuity outcomes appear to be slightly worse than in the 60% in which DME does not persist. Nevertheless, when following the treatment protocol used in this trial among eyes with vision impairment from DME, long-term improvement in visual acuity from baseline is typical and substantial (≥2-line) loss of visual acuity is likely uncommon through 3 years, even when central-involved DME chronically persists.

Purpose: To conduct a longitudinal study on age-related nuclear cataracts using dynamic light scattering (DLS) to determine if cataract progression is associated with loss of the unbound form of the lens molecular chaperone protein, α-crystallin., Design: Natural history and cohort study., Participants: Patients 30 years of age or older of either gender seeking treatment at the Wilmer Eye Institute Cornea-Cataract Department., Methods: All patients underwent a comprehensive dilated eye examination every 6 months, including slit-lamp grading of their lenses using the Age-Related Eye Disease Study (AREDS) clinical lens grading system and obtaining an estimate of unbound α-crystallin level in the nucleus, the α-crystallin index (ACI), using the National Aeronautics and Space Administration-National Eye Institute DLS device. We used a random effects statistical model to examine the relationship of lens opacity changes over time with ACI changes., Main Outcome Measures: α-Crystallin Index (ACI) and AREDS nuclear cataract grade., Results: Forty-five patients (66 eyes) 34 to 79 years of age with AREDS nuclear lens grades of 0 to 3.0 were followed up every 6 months for a mean of 19 months (range, 6-36 months). We found that lenses with the lowest baseline levels of ACI had the most rapid progression of cataracts, whereas lenses with higher ACI at baseline had no or slower cataract progression. Lenses that lost α-crystallin at the highest rates during the study also had faster progression of nuclear cataracts than lenses with a slower rate of ACI loss. Kaplan-Meier survival curves showed that lenses with the lowest initial ACI had the highest risk of undergoing cataract surgery., Conclusions: This longitudinal study corroborates our previous cross-sectional study finding that higher levels of unbound α-crystallin as assessed by ACI are associated with lower risk of cataract formation and that loss of ACI over time is associated with cataract formation and progression. This study suggested that assessment of ACI with the DLS device could be used as a surrogate for lens opacity risk in clinical studies, and for assessing nuclear cataract events in studies where cataract development may be a side effect of a drug or device., (Published by Elsevier Inc.)

Purpose: To evaluate the association of statin use with progression of age-related macular degeneration (AMD)., Design: Preplanned, prospective cohort study within a controlled clinical trial of oral supplementation for age-related eye diseases., Participants: Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50 to 85 years., Methods: Factors, including age, gender, smoking status, aspirin use, and history of diabetes, hypertension, heart disease, angina, and stroke-all known to be associated with statin use-were included in a logistic regression model to estimate propensity scores for each participant. Age-adjusted proportional hazards regression models, with and without propensity score matching, were performed to evaluate the association of statin use with progression to late AMD. Analyses adjusting for the competing risk of death were also performed., Main Outcome Measures: Baseline and annual stereoscopic fundus photographs were assessed centrally by masked graders for the development of late AMD, either neovascular AMD or geographic atrophy (GA)., Results: Of the 3791 participants (2462 with bilateral large drusen and 1329 with unilateral late AMD at baseline), 1659 (43.8%) were statin users. The overall analysis, with no matching of propensity scores and no adjustment for death as a competing risk, showed that statin use was not associated with progression to late AMD (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.83-1.41; P = 0.56). When matched for propensity scores and adjusted for death as a competing risk, the result was not statistically significant (HR, 0.81; 95% CI, 0.55-1.20; P = 0.29). Furthermore, subgroup analyses of persons with or without late AMD at baseline and the various components of late AMD (neovascular AMD, central GA, or any GA) also showed no statistically significant association of statin use with progression to AMD., Conclusions: Statin use was not statistically significantly associated with progression to late AMD in the AREDS2 participants, and these findings are consistent with findings in the majority of previous studies. Statins have been demonstrated to reduce the risk of cardiovascular disease, but our data do not provide evidence of a beneficial effect on slowing AMD progression., (Published by Elsevier Inc.)

Importance: Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME)., Objective: To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy., Design, Setting, and Participants: Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015., Interventions: Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME., Main Outcomes and Measures: The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization., Results: Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified., Conclusions and Relevance: Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy., Trial Registration: clinicaltrials.gov Identifier: NCT01489189.

Purpose: We investigate whether ocular and person-based characteristics were associated with dark adaptation (DA)., Design: Cross-sectional, single-center, observational study., Participants: One hundred sixteen participants older than 50 years of age with a range of age-related macular degeneration (AMD) severity., Methods: Participants underwent best-corrected visual acuity (BCVA) testing, ophthalmoscopic examination, and multimodal imaging. Presence of reticular pseudodrusen (RPD) was assessed by masked grading of fundus images and was confirmed with optical coherence tomography. Eyes also were graded for AMD features (drusen, pigmentary changes, late AMD) to generate person-based AMD severity groups. One eye was designated the study eye for DA testing. Nonparametric statistical testing was performed on all comparisons., Main Outcome Measures: The primary outcome of this study was the rod intercept time (RIT), which is defined as the time for a participant's visual sensitivity to recover to a stimulus intensity of 5×10(-3) cd/m(2) (a decrease of 3 log units), or until a maximum test duration of 40 minutes was reached., Results: A total of 116 study eyes from 116 participants (mean age, 75.4±9.4 years; 58% female) were analyzed. Increased RIT was associated significantly with increasing AMD severity, increasing age (r = 0.34; P = 0.0002), decreasing BCVA (r = -0.54; P < 0.0001), pseudophakia (P = 0.03), and decreasing subfoveal choroidal thickness (r = -0.27; P = 0.003). Study eyes with RPD (15/116 [13%]) had a significantly greater mean RIT compared with eyes without RPD in any AMD severity group (P < 0.02 for all comparisons), with 80% reaching the DA test ceiling., Conclusions: Impairments in DA increased with age, worse visual acuity, presence of RPD, AMD severity, and decreased subfoveal choroidal thickness. Analysis of covariance found the multivariate model that best fit the data included age, AMD group, and presence of RPD (R(2) = 0.56), with the presence of RPD conferring the largest parameter estimate., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate whether dietary intake of luteiin/zeaxanthin and B vitamins is associated with cataract prevalence and incidence., Design: Clinic-based, baseline cross-sectional and prospective cohort study designs., Participants: Three thousand one hundred fifteen patients (6129 eyes) enrolled in the Age-Related Eye Disease Study 55 to 80 years of age followed up for mean of 9.6 years., Methods: Participants completed baseline food frequency questionnaires. Baseline and annual lens photographs were graded centrally. Multivariate models controlling for previously identified risk factors for cataracts tested for the association of cataracts with reported dietary intake, using the lowest quintile as reference., Main Outcome Measures: Cataract surgery, cataract status (type and severity) at baseline, and development of cataracts., Results: At baseline, increased dietary riboflavin and B12 were associated inversely with nuclear and cortical lens opacities. In comparisons of persons with and without cataract, persons with the highest riboflavin intake versus those with the lowest intake had the following associations: mild nuclear cataract: odds ratio (OR), 0.78; 95% confidence interval (CI), 0.63-0.97; moderate nuclear cataract: OR, 0.62; 95% CI, 0.43-0.90; and mild cortical cataract: OR, 0.80; 95% CI, 0.65-0.99. For B12, the results were: mild nuclear cataract: OR, 0.78; 95% CI, 0.63-0.96; moderate nuclear cataract: OR, 0.62; 95% CI, 0.43-0.88; and mild cortical cataract: OR, 0.77; 95% CI, 0.63-0.95. Highest dietary B6 intake was associated with a decreased risk of moderate nuclear lens opacity developing compared with the lowest quintile (OR, 0.67; 95% CI, 0.45-0.99). Highest dietary intake levels of niacin and B12 were associated with a decreased risk of development of mild nuclear or mild cortical cataracts in participants not taking Centrum (Pfizer, New York, NY) multivitamins. For participants taking multivitamins during the study, the highest intake of dietary folate was associated with an increased risk of mild posterior subcapsular lens opacity development. No statistically significant associations were found between lutein plus zeaxanthin intake and presence at baseline or development of nuclear or cortical lens opacity outcomes., Conclusions: These findings are consistent with earlier studies suggesting that dietary intake of B vitamins may affect the occurrence of age-related lens opacities. Further investigations are warranted., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate whether the 2-year change in lens opacity severity on the Age-Related Eye Disease Study (AREDS) lens grading scale predicts progression to cataract surgery or loss of visual acuity by 5 years., Design: Prospective cohort study within a randomized clinical trial of oral supplements., Participants: The AREDS participants whose eyes were phakic at baseline and free of late age-related macular degeneration throughout the study., Methods: Baseline and annual lens photographs of AREDS participants (n = 3466/4757; 73%) were graded for severity of cataracts using the AREDS system for classifying cataracts from photographs. Clinical examinations conducted semiannually collected data on cataract surgery and visual acuity. Association of the change in lens opacities at 2 years with these outcomes at 5 years was analyzed with adjusted Cox proportional hazard models., Main Outcome Measurements: Progression of lens opacities on stereoscopic lens photographs at 2 years, cataract surgery, and visual acuity loss of 2 lines or more at 5 years., Results: The adjusted hazard ratios (HRs) for association of progression to cataract surgery at 5 years were: nuclear cataract increase of 1.0 unit or more compared with less than 1.0-unit change at 2 years, 2.77 (95% confidence interval [CI], 2.07-3.70; P < 0.001); cortical cataract increase of 5% or more in lens opacity in the central 5 mm of the lens compared with less than 5% increase at 2 years, 1.91 (95% CI, 1.27-2.87; P = 0.002); and posterior subcapsular cataract increase of 5% or more versus less than 5% in the central 5 mm of the lens, 8.25 (95% CI, 5.55-12.29; P < 0.001). Similarly, HRs of vision loss of 2 lines or more at 5 years for this degree of lens changes at 2 years were the following: nuclear, 1.83 (95% CI, 1.49-2.25; P < 0.001); cortical, 1.13 (95% CI, 0.78-1.65; P = 0.519); and posterior subcapsular cataract, 3.05 (95% CI, 1.79-5.19; P < 0.001)., Conclusions: Two-year changes in severity of lens opacities on the AREDS lens grading scale are predictive of long-term clinically relevant outcomes, making them potential surrogate end points in follow-up studies., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To compare baseline characteristics, treatment frequency, visual acuity (VA), and morphologic outcomes of eyes with >50% of the lesion composed of blood (B50 group) versus all other eyes (Other group) enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Design: Prospective cohort study within a multicenter randomized clinical trial., Participants: CATT patients with neovascular age-related macular degeneration (AMD)., Methods: Treatment for the study eye was assigned randomly to either ranibizumab or bevacizumab and to 3 different dosing regimens over a 2-year period. Reading center graders evaluated baseline and follow-up morphology in color fundus photographs, fluorescein angiography (FA), and optical coherence tomography (OCT). Masked examiners tested VA., Main Outcome Measures: Morphologic features and VA at 1 and 2 years., Results: The B50 group consisted of 84 of 1185 (7.1%) patients enrolled in CATT. Baseline lesion characteristics differed between groups. In the B50 group, choroidal neovascularization size was smaller (0.73 vs 1.83 disc areas [DA]; P < 0.001), total lesion size was greater (4.55 vs 2.31 DA; P <0.001), total retinal thickness was greater (524 vs 455 μm; P = 0.02), and mean VA was worse (56.0 vs 60.9 letters; P = 0.002). Increases in mean VA were similar in the B50 and Other groups at 1 year (+9.3 vs +7.2 letters; P = 0.22) and at 2 years (9.0 vs 6.1 letters; P = 0.17). Eyes treated PRN received a similar number of injections in the 2 groups (12.2 vs 13.4; P = 0.27). Mean lesion size in the B50 group decreased by 1.2 DA at both 1 and 2 years (primarily owing to resolution of hemorrhage) and increased in the Other group by 0.33 DA at 1 year and 0.91 DA at 2 years (P < 0.001). Leakage on FA and fluid on OCT were similar between groups at 1 and 2 years., Conclusions: In CATT, the B50 group had a visual prognosis similar to the Other group. Lesion size decreased markedly through 2 years. Eyes like those enrolled in CATT with neovascular AMD lesions composed of >50% blood can be managed similarly to those with less or no blood., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To compare subjective and objective clinical tests used in the screening for hydroxychloroquine retinal toxicity to multifocal electroretinography (mfERG) reference testing., Design: Prospective, single-center, case control study., Participants: Fifty-seven patients with a previous or current history of hydroxychloroquine treatment of more than 5 years' duration., Methods: Participants were evaluated with a detailed medical history, dilated ophthalmologic examination, color fundus photography, fundus autofluorescence (FAF) imaging, spectral-domain (SD) optical coherence tomography (OCT), automated visual field testing (10-2 visual field mean deviation [VFMD]), and mfERG testing. We used mfERG test parameters as a gold standard to divide participants into 2 groups: those affected by hydroxychloroquine-induced retinal toxicity and those unaffected., Main Outcome Measures: We assessed the association of various imaging and psychophysical variables in the affected versus the unaffected group., Results: Fifty-seven study participants (91.2% female; mean age, 55.7±10.4 years; mean duration of hydroxychloroquine treatment, 15.0±7.5 years) were divided into affected (n = 19) and unaffected (n = 38) groups based on mfERG criteria. Mean age and duration of hydroxychloroquine treatment did not differ statistically between groups. Mean OCT retinal thickness measurements in all 9 macular subfields were significantly lower (<40 μm) in the affected group (P < 0.01 for all comparisons) compared with those in the unaffected group. Mean VFMD was 11 dB lower in the affected group (P < 0.0001). Clinical features indicative of retinal toxicity were scored for the 2 groups and were detected in 68.4% versus 0.0% using color fundus photographs, 73.3% versus 9.1% using FAF images, and 84.2% versus 0.0% on the scoring for the perifoveal loss of the photoreceptor ellipsoid zone on SD-OCT for affected and unaffected participants, respectively. Using a polynomial modeling approach, OCT inner ring retinal thickness measurements and Humphrey 10-2 VFMD were identified as the variables associated most strongly with the presence of hydroxychloroquine as defined by mfERG testing., Conclusions: Optical coherence tomography retinal thickness and 10-2 VFMD are objective measures demonstrating clinically useful sensitivity and specificity for the detection of hydroxychloroquine toxicity as identified by mfERG, and thus may be suitable surrogate tests., (Published by Elsevier Inc.)

Importance: Providing long-term follow-up of the natural history of age-related macular degeneration (AMD) and associated risk factors will facilitate future epidemiologic studies and clinical trials., Objective: To describe 10-year progression rates to intermediate or advanced AMD., Design, Setting, and Participants: We observed the Age-Related Eye Disease Study (AREDS) participants for an additional 5 years after a randomized clinical trial of antioxidant vitamins and minerals was completed. Observation occurred at 11 clinical sites of medical retinal practices from academic institutions and community medical centers. Participants aged 55 to 80 years with no AMD or AMD of varying severity (n = 4757) were followed up in the AREDS trial for a median duration of 6.5 years. When the trial ended, 3549 of the 4203 surviving participants were followed for 5 additional years., Exposure: Treatment with antioxidant vitamins and minerals., Main Outcomes and Measures: Development of varying stages of AMD and changes in visual acuity. The rates of progression to large drusen and advanced AMD (neovascular AMD or central geographic atrophy) were evaluated using annual fundus photographs assessed centrally. Best-corrected visual acuity was measured at annual study visits., Results: The risk of progression to advanced AMD increased with increasing age (P = .01) and severity of drusen. Women (P = .005) and current smokers (P < .001) were at increased risk of neovascular AMD. In the oldest participants with the most severe AMD status at baseline, the risks of developing neovascular AMD and central geographic atrophy by 10 years were 48.1% and 26.0%, respectively. Similarly, rates of progression to large drusen increased with increasing severity of drusen at baseline, with 70.9% of participants with bilateral medium drusen progressing to large drusen and 13.8% to advanced AMD in 10 years. Median visual acuity at 10 years in eyes that had large drusen at baseline but never developed advanced AMD was 20/25; eyes that developed advanced AMD had a median visual acuity of 20/200., Conclusions and Relevance: The natural history of AMD demonstrates relentless loss of vision in persons who developed advanced AMD. These progression data and the risk factor analyses may be helpful to investigators conducting research in clinic populations.

Importance: The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina., Objective: To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD., Design, Setting, Participants: The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye., Interventions: In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination., Main Outcomes and Measure: S Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy., Conclusion and Relevance: The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements., Trial Registration: clinicaltrials.gov Identifier: NCT00345176.

Purpose: Explore differences in green compared with yellow focal/grid laser treatment on functional and anatomical endpoints in eyes with diabetic macular edema., Methods: Data from two randomized clinical trials were evaluated for differences in visual acuity and optical coherence tomography parameters for eyes assigned to sham injection + prompt laser, ranibizumab + prompt laser, or prompt laser only: among subgroups of eyes treated exclusively and electively with either green or yellow laser., Results: In the sham injection + prompt laser group, the mean visual acuity letter score change for eyes receiving green and yellow laser treatment, respectively, was +2.4 ± 14 and +5.1 ± 13 at the 52-week visit (P = 0.06) and +2.4 ± 15 and +6.0 ± 13 at the 104-week visit (P = 0.13), with no corresponding evidence of differences in optical coherence tomography thickness. When comparing wavelength groups in the ranibizumab + prompt laser and prompt laser-only groups, meaningful differences in visual acuity and optical coherence tomography thickness were not detected at 1 year or 2 years., Conclusion: A trend toward improved vision outcome with yellow laser observed in one trial was not corroborated by anatomical outcomes or by the other trial. In this study, without random assignment to different wavelengths controlling for bias and confounding, it is not possible to determine whether one wavelength is better than the other.

Purpose: We described the system for grading lens opacities using stereoscopic digital fundus reflex photographs in the Age-Related Eye Disease Study 2 (AREDS2) and compared reproducibility with the AREDS lens grading system, which used retroillumination film images., Methods: Stereoscopic fundus reflex photographs were acquired in a standardized fashion at baseline and annually. Images were enhanced and evaluated in the red channel at a central reading center. Percentage involvement of cortical and posterior subcapsular (PSC) lens opacities within the central 5 mm diameter zone of a modified AREDS lens grid was estimated. Reproducibility was assessed for contemporaneous variability (ongoing, monthly regrade on 5% of submissions, n = 777 eyes) and temporal drift (regrading a subset of baseline photographs annually, n = 88)., Results: In the contemporaneous exercise, the agreement for presence of cortical opacities was 93% (κ = 0.86) and for PSC opacities it was 97% (κ = 0.83). Intraclass correlation (ICC) for area of central zone involvement was 0.95 for cortical and 0.99 for PSC opacities. Historic data for contemporaneous regrading of film-based images in AREDS showed an ICC of 0.94 for cortical and 0.82 for PSC. The final annual temporal drift exercise had a reproducibility of 95% for cortical and PSC opacities., Conclusions: Digital grading using fundus reflex images with image enhancing tools has reproducibility comparable to film-based retroillumination images, and may be useful for centralized objective lens opacity assessment in clinical trials using widely available fundus cameras. Red reflex images limit evaluation to cortical and PSC opacities, and do not permit assessment of nuclear opacities. (ClinicalTrials.gov number, NCT00345176.).

Purpose: To establish continuity with the grading procedures and outcomes from the historical data of the Age-Related Eye Disease Study (AREDS), color photographic imaging and evaluation procedures for the assessment of age-related macular degeneration (AMD) were modified for digital imaging in the AREDS2. The reproducibility of the grading of index AMD lesion components and for the AREDS severity scale was tested at the AREDS2 reading center., Methods: Digital color stereoscopic fundus photographs from 4203 AREDS2 subjects collected at baseline and annual follow-up visits were optimized for tonal balance and graded according to a standard protocol slightly modified from AREDS. The reproducibility of digital grading of AREDS2 images was assessed by reproducibility exercises, temporal drift (regrading a subset of baseline annually, n = 88), and contemporaneous masked regrading (ongoing, monthly regrade on 5% of submissions, n = 1335 eyes)., Results: In AREDS2, 91% and 96% of images received replicate grades within two steps of the baseline value on the AREDS severity scale for temporal drift and contemporaneous assessment, respectively (weighted Kappa of 0.73 and 0.76). Historical data for temporal drift in replicate gradings on the AREDS film-based images were 88% within two steps (weighted Kappa = 0.88). There was no difference in AREDS2-AREDS concordance for temporal drift (exact P = 0.57)., Conclusions: Digital color grading has nearly the same reproducibility as historical film grading. There is substantial agreement for testing the predictive utility of the AREDS severity scale in AREDS2 as a clinical trial outcome. (ClinicalTrials.gov number, NCT00345176.)

Purpose: To investigate the long-term incidence of age-related cataract and cataract surgery in the Age-Related Eye Disease Study (AREDS) cohort., Methods: Baseline and annual lens photographs of participants, aged 55-80 years, were graded centrally for nuclear, cortical, and posterior subcapsular (PSC) lens opacities using the AREDS System for Classifying Cataracts. Progression from a baseline status of no or mild lens opacity to at least moderate severity was analyzed and cumulative incidence estimated rates were calculated for each lens opacity type and cataract surgery stratified by age, sex, race, age-related macular degeneration category, multivitamin (Centrum) use and history of diabetes., Results: The ten-year cumulative incidence was 43.6% for any cataract, 23.1% for nuclear cataract, 22.0% for cortical cataract, 13.1% for PSC cataract, and 26.8% for cataract surgery. The 5- and 10-year incidence rates of all cataract types and cataract surgery were significantly higher with increasing age. Females had a higher incidence of any, nuclear and cortical cataract and cataract surgery (p = 0.02-0.05). Incidence of cortical cataract was higher in non-white participants (p = 0.001)., Conclusions: These results are largely consistent with the results of previous observational studies. Long-term incidence rates of type-specific cataract can be useful in designing clinical studies of age-related cataract.