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Age-related macular degeneration (AMD) is a vision threatening disease in older adults. Anti-VEGF treatment is effective for the majority of neovascular AMD (nAMD) patients, although approximately 30% of nAMD patients have an incomplete response for unknown reasons. Here we assessed the contribution of single nucleotide polymorphisms (SNPs) in key angioinflammatory regulatory genes in nAMD patients with an incomplete response compared to those responsive to anti-VEGF treatment. A total of 25 responsive and 30 nAMD patients with an incomplete response to anti-vascular endothelial growth factor (anti-VEGF) treatment were examined for known SNPs that impact the structure and function of thromobospondin-1 (TSP1), Bcl-2-interacting mediator of cell death (BIM) and complement factor H (CFH). Plasma levels of C-C motif chemokine ligand 2 (CCL2/MCP1), TSP1 and VEGF were assessed by ELISA. Patients responsive to anti-VEGF treatment showed a significant increase in the TSP1 rs2228262 AA allele and a trend for the BIM (rs724710) CT allele. Consistent with previous reports, 42% of the patients responsive to anti-VEGF expressed the CC allele for CFH rs1061170. Although the CFH TT allele had similarly low prevalence in both groups, the TC allele tended to be more prevalent in patients with an incomplete response. Patients with an incomplete response also had increased plasma CCL2/MCP1 levels, consistent with the role increased inflammation has in the pathogenesis of nAMD. Our studies point to new tools to assess the potential responsiveness of nAMD patients to anti-VEGF treatment and suggest the potential use of anti-CCL2 for treatment of nAMD patients with an incomplete response to anti-VEGF., Competing Interests: The authors have declared no competing interests exist., (Copyright: © 2024 Sorenson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To gain an understanding of data labeling requirements to train deep learning models for measurement of geographic atrophy (GA) with fundus autofluorescence (FAF) images., Design: Evaluation of artificial intelligence (AI) algorithms., Subjects: The Age-Related Eye Disease Study 2 (AREDS2) images were used for training and cross-validation, and GA clinical trial images were used for testing., Methods: Training data consisted of 2 sets of FAF images; 1 with area measurements only and no indication of GA location (Weakly labeled) and the second with GA segmentation masks (Strongly labeled)., Main Outcome Measures: Bland-Altman plots and scatter plots were used to compare GA area measurement between ground truth and AI measurements. The Dice coefficient was used to compare accuracy of segmentation of the Strong model., Results: In the cross-validation AREDS2 data set (n = 601), the mean (standard deviation [SD]) area of GA measured by human grader, Weakly labeled AI model, and Strongly labeled AI model was 6.65 (6.3) mm 2 , 6.83 (6.29) mm 2 , and 6.58 (6.24) mm 2 , respectively. The mean difference between ground truth and AI was 0.18 mm 2 (95% confidence interval, [CI], -7.57 to 7.92) for the Weakly labeled model and -0.07 mm 2 (95% CI, -1.61 to 1.47) for the Strongly labeled model. With GlaxoSmithKline testing data (n = 156), the mean (SD) GA area was 9.79 (5.6) mm 2 , 8.82 (4.61) mm 2 , and 9.55 (5.66) mm 2 for human grader, Strongly labeled AI model, and Weakly labeled AI model, respectively. The mean difference between ground truth and AI for the 2 models was -0.97 mm 2 (95% CI, -4.36 to 2.41) and -0.24 mm 2 (95% CI, -4.98 to 4.49), respectively. The Dice coefficient was 0.99 for intergrader agreement, 0.89 for the cross-validation data, and 0.92 for the testing data., Conclusions: Deep learning models can achieve reasonable accuracy even with Weakly labeled data. Training methods that integrate large volumes of Weakly labeled images with small number of Strongly labeled images offer a promising solution to overcome the burden of cost and time for data labeling., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Purpose: To determine whether macular infarction measured as hyper-reflectivity of the middle and inner retinal layers predicts long-term visual acuity outcomes in participants with central retinal vein occlusion (CRVO) or hemi-retinal vein occlusion (HRVO)., Design: Clinical cohort study using post hoc secondary analysis of phase 3 clinical trial data., Methods: This post hoc secondary analysis of the phase 3 Study of COmparative Treatments for REtinal Vein Occlusions 2 (SCORE2) clinical trial included 310 of the 362 participants with macular edema secondary to CRVO/HRVO who were randomized to injections of aflibercept or bevacizumab. Month 01 (M01) optical coherence tomography (OCT) images were analyzed using the following grading scheme: no infarction (grade 0), only middle retinal infarction (grade 1), diffuse middle and patchy inner retinal infarction (grade 2), and diffuse middle and inner retinal infarction (grade 3). Visual acuity letter score (VALS), central subfield thickness (CST), and number of anti-vascular endothelial growth factor (anti-VEGF) injections were correlated with the infarction severity grade at month 01., Results: More severe macular infarction, with both middle and inner retinal layer hyper-reflectivity (ie, grades 2 and 3), was associated with worse M00 VALS and was predictive of VALS at M01 to M60 (P < .001). More severe infarction was associated with greater CST at presentation; however, after the first anti-VEGF injection, CST decreased and was similar across all grades at all time points (P > .05) with similar number of injections., Conclusions: Participants with more severe macular infarction at M01, as graded with OCT, exhibited worse visual outcomes despite significantly improved macular edema from month 6 to 5 years. This suggests that macular infarction may drive visual acuity after retinal fluid is treated with anti-VEGF., (Published by Elsevier Inc.)

Purpose: To investigate whether a nonlinear association between central subfield thickness (CST) on spectral-domain OCT and concurrent visual acuity letter score (VALS) exists in eyes treated initially with aflibercept or bevacizumab for macular edema associated with central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO) in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2)., Design: Long-term follow-up after a randomized clinical trial from 64 centers in the United States., Participants: Participants were followed up to 60 months and treated at investigator discretion after completing the 12-month treatment protocol., Methods: Two-segment linear regression models were compared with simple linear regression models of VALS on CST. Pearson correlation coefficients were calculated to assess strength of CST and VALS associations., Main Outcome Measures: Central subfield thickness was measured by OCT and VALS by the electronic Early Treatment Diabetic Retinopathy Study methodology., Results: Estimated inflection points, reflecting turning points at which the CST and VALS association changes from positive to negative, calculated at 7 postbaseline visits, range from 217 to 256 μm. A strongly positive correlation exists to the left of each estimated inflection point, ranging from 0.29 (P < 0.01 at month 60) to 0.50 (P < 0.01 at month 12), and a strongly negative correlation exists to the right of each estimated inflection point, ranging from -0.43 (P < 0.01 at month 1) to -0.74 (P < 0.01 at month 24). Randomization statistical tests showed that 2-segment models are favored over 1-segment models for all postbaseline months (P < 0.001 for all tests performed)., Conclusions: The relationship between CST and VALS in eyes with CRVO or HRVO after treatment with anti-vascular endothelial growth factor (VEGF) therapy is not simply linear. The usually modest correlations between OCT-measured CST and visual acuity belie strong left and right correlations present in 2-segment models. Post-treatment CST close to the estimated inflection points showed the best expected VALS. The SCORE2 participants with a post-treatment CST after treatment close to the estimated inflection points of 217 to 256 μm showed the best VALS. In patients treated with anti-VEGF for macular edema associated with CRVO or HRVO, a thinner retina is not always associated with better VALS., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: Determine prevalence, progression rates, and associations of newly detectable macular atrophy (MA) in patients with choroidal neovascularization (CNV) secondary to neovascular age-related macular degeneration (nAMD) with/without ranibizumab treatment., Design: Post hoc analysis of MA in patients with occult/minimally classic nAMD who received monthly intravitreal ranibizumab (0.3 or 0.5 mg) or sham injections for 24 months (M) in MARINA, a phase III trial in treatment-naive patients (NCT00056836)., Participants: Seven hundred six patients with nAMD: ranibizumab 0.3 mg, n = 236; 0.5 mg, n = 237; sham, n = 233., Methods: Macular atrophy, assessed by color fundus photographs/fluorescein angiography, was classified as "within," "adjacent," or "nonadjacent" to the original CNV lesion. Factors associated with MA were assessed by multivariate logistic regression., Main Outcome Measures: Prevalence/incidence of newly detectable MA over time, association with CNV area, MA progression rate, association of MA with visual acuity (VA), changes in CNV/leakage area, and factors predictive of new MA at 24M., Results: At 24M, new MA was detected in 36.8%, 40.4%, and 21.0% of eyes for ranibizumab 0.3 mg, 0.5 mg, and sham, respectively, most frequently within the area of the baseline CNV lesion (93.2%, 85.0%, and 69.0%). Rate of MA progression was similar across arms (∼ 0.3 to 0.4 mm/year). There was strong association between absence of fibrosis and detectable MA (odds ratio, 2.7; 95% confidence interval [CI], 1.29-5.56), whereas an association was not identified between detectable MA and baseline VA, baseline fellow eye atrophy, ranibizumab treatment, or change in leakage/CNV area at 24M. Ranibizumab-treated eyes gained VA with (0.3 mg: 5.3 letters [95% CI, -3.3, 13.8]; 0.5 mg: 9.8 [4.7-15.0]) or without new MA (0.3 mg: 6.4 [4.1-8.6]; 0.5 mg: 8.0 [5.3-10.6]), whereas VA in sham-treated eyes deteriorated with/without new MA (-14.7 [-23.6, -5.8] and -14.0 [-16.9, -11.1], respectively)., Conclusions: New MA was more frequently detected in ranibizumab-treated than sham-treated eyes. Macular atrophy progression was similar across arms. Multivariate analysis showed that absence of fibrosis was the only variable associated with increased MA. Regardless of MA presence/location at baseline or throughout the study, ranibizumab-treated eyes showed clinically significant improvements in VA, whereas VA in sham-treated eyes worsened., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Importance: Retinal vein occlusion is the second most common retinal vascular disease. Bevacizumab was demonstrated in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) to be noninferior to aflibercept with respect to visual acuity in study participants with macular edema due to central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO) following 6 months of therapy. In this study, the cost-utility of bevacizumab vs aflibercept for treatment of CRVO is evaluated., Objective: To investigate the relative cost-effectiveness of bevacizumab vs aflibercept for treatment of macular edema associated with CRVO or HRVO., Design, Setting, and Participants: This economic evaluation study used a microsimulation cohort of patients with clinical and demographic characteristics similar to those of SCORE2 participants and a Markov process. Parameters were estimated and validated using a split-sample approach of the SCORE2 population. The simulated cohort included 5000 patients who were evaluated 100 times, each with a different set of characteristics randomly selected based on the SCORE2 trial. SCORE2 data were collected from September 2014 October 2019, and data were analyzed from October 2019 to July 2021., Interventions: Bevacizumab (followed by aflibercept among patients with a protocol-defined poor or marginal response to bevacizumab at month 6) vs aflibercept (followed by a dexamethasone implant among patients with a protocol-defined poor or marginal response to aflibercept at month 6)., Main Outcomes and Measures: Incremental cost-utility ratio., Results: The simulation demonstrated that patients treated with aflibercept will have an expected cost $18 127 greater than those treated with bevacizumab in the year following initiation. When coupled with the lack of clinical superiority over bevacizumab (ie, patients treated with bevacizumab had a gain over aflibercept in visual acuity letter score of 4 in the treated eye and 2 in the fellow eye), these results demonstrate that first-line treatment with bevacizumab dominated aflibercept in the simulated cohort of SCORE2 participants. At current price levels, aflibercept would be considered the preferred cost-effective option only if treatment restored the patient to nearly perfect health., Conclusions and Relevance: While there will be some patients with CRVO-associated or HRVO-associated macular edema who will benefit from first-line treatment with aflibercept rather than bevacizumab, given the minimal differences in visual acuity outcomes and large cost differences for bevacizumab vs aflibercept, first-line treatment with bevacizumab is cost-effective for this condition.

Purpose: To assess the association of a novel spectral domain optical coherence tomography biomarker with 6-month visual acuity in in the Study of COmparative Treatments for REtinal Vein Occlusion 2., Methods: Spectral domain optical coherence tomography volume scans were evaluated for inner retinal hyperreflectivity, quantified by optical intensity ratio (OIR) and OIR variation. Baseline visual acuity letter score (VALS), baseline OCT biomarkers, and month 1 OIR were correlated with VALS at month 6. Regression trees, a machine learning technique yielding readily interpretable models, were used to assess for variable interaction., Results: Only baseline VALS correlated positively with month 6 VALS in multivariate regression. Regression trees detected a novel functional and anatomical interaction in a subgroup. Among patients with a baseline VALS worse than 43, those with an OIR variation at month 1 of more than 0.09 had a mean of 13 fewer letters of vision at 6 months compared with patients with an OIR variation of 0.09 or less., Conclusions: Baseline VALS was the strongest predictor of month 6 VALS. Regression tree analysis detected an interaction effect, in which higher OIR variation at month 1 predicted worse 6-month VALS in patients with low VALS at baseline. OIR variation may serve as a predictor for poor visual outcome despite treatment of macular edema secondary to retinal vein occlusion in patients with poor vision at baseline., Translational Relevance: Pixel heterogeneity in three-dimensional OCT data may serve as measure of disruption of the retinal laminations, and this factor may carry visually prognostic value.

Purpose: To determine the interreader agreement for reticular pseudodrusen (RPD) assessment on combined infrared reflectance (IR) and OCT imaging in the early stages of age-related macular degeneration across a range of different criteria to define their presence., Design: Interreader agreement study., Participants: Twelve readers from 6 reading centers., Methods: All readers evaluated 100 eyes from individuals with bilateral large drusen for the following: (1) the presence of RPD across a range of different criteria and (2) the number of Stage 2 or 3 RPD lesions (from 0 to ≥ 5 lesions) on an entire OCT volume scan and on a selected OCT B-scan. Supportive information was available from the corresponding IR image., Main Outcome Measures: Interreader agreement, as assessed by Gwet's first-order agreement coefficient (AC 1 )., Results: When evaluating an entire OCT volume scan, there was substantial interreader agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions, and ≥ 5 definite lesions on en face IR images corresponding to Stage 2 or 3 lesions (AC 1  = 0.60-0.72). On selected OCT B-scans, there was also moderate-to-substantial agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions (AC 1  = 0.58-0.65) and increasing levels of agreement with increasing RPD stage (AC 1  = 0.08, 0.56, 0.78, and 0.99 for the presence of any Stage 1, 2, 3, and 4 lesions, respectively). There was substantial agreement regarding the number of Stage 2 or 3 lesions on an entire OCT volume scan (AC 1  = 0.68), but only fair agreement for this evaluation on selected B-scans (AC 1  = 0.30)., Conclusions: There was generally substantial or near-substantial-but not near-perfect-agreement for assessing the presence of RPD on entire OCT volume scans or selected B-scans across a range of differing RPD criteria. These findings underscore how interreader variability would likely contribute to the variability of findings related to the clinical associations of RPD. The low levels of agreement for assessing RPD number on OCT B-scans underscore the likely challenges of quantifying RPD extent with manual grading., Financial Disclosures: Proprietary or commercial disclosure may be found after the references., (© 2023 by the American Academy of Ophthalmology.)

Purpose: To investigate the relationship of anti-vascular endothelial growth factor (anti-VEGF) treatment discontinuation with baseline factors and outcomes in eyes treated initially with aflibercept or bevacizumab for macular edema from central or hemiretinal vein occlusion., Design: Long-term follow-up after a randomized clinical trial from 64 US centers., Methods: Analysis included 150 SCORE2 Month 60 completers classified into 3 groups: discontinued treatment early, treated intermittently, and treated continuously. Outcomes included visual acuity (VA) and central subfield thickness (CST)., Results: Patients who discontinued treatment early were younger (60.9 years, vs 66.7 and 70.5 for the treated intermittently and treated continuously groups; P = .001), and 17.4% were Black, compared to 19.5% and 4.7% for the treated intermittently and treated continuously groups (P = .006). At Month 60, the discontinued treatment early group had a higher proportion with complete resolution of macular edema (69.6%) than those treated intermittently (15.0%) and treated continuously (15.7%) (P < .001). Least-squares means analyses over follow-up demonstrated that the discontinued treatment early group had a lower mean CST (257 µm) than the treated intermittently (CST = 303 µm, P = .02) and treated continuously (CST = 300 µm, P = .01) groups., Conclusions: Compared to those treated continuously, those who discontinued treatment early were younger and more likely Black. The discontinued treatment early group had a higher proportion with complete resolution of macular edema at Month 60, and a lower mean CST over follow-up, but not better VA, than the treated continuously and treated intermittently groups. Results support the need for continued monitoring and individualized treatment for patients treated with anti-VEGF for macular edema from central or hemiretinal vein occlusion., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To investigate 5-year outcomes in eyes initially treated with aflibercept or bevacizumab for macular edema due to central retinal or hemiretinal vein occlusion., Methods: Long-term follow-up (LTF) after a randomized clinical trial from 64 centers in the United States. Participants were followed up to 60 months and treated at investigator discretion after completing the 12-month treatment protocol. Main outcomes were visual acuity letter score (VALS) and central subfield thickness (CST) on optical coherence tomography., Results: Seventy-five percent (248/330) of eligible participants completed at least 1 visit between months 24 and 60, and 45% completed the month 60 visit. Among participants completing month 60, overall mean VALS improvement over baseline was 13.5 (95% CI: 9.6, 17.5), less than the mean improvement of 20.6 (95% CI: 18.7, 22.4) observed at month 12, with no significant differences between originally assigned study groups. Further, 66% (99/150) had at least 1 treatment between months 48 and 60 with a mean (SD) of 3.41 (3.69) treatments over this period. Mean CST was 671 μm at baseline and 261 μm (95% CI: 241.2, 280.9) at month 60., Conclusions: Although VALS improved substantially when patients were treated per protocol through month 12, improvement lessened when treatment was at investigator discretion and fewer treatments were received although VALS remained markedly improved over baseline through year 5. Most patients continued to receive treatment in year 5. This suggests that continued monitoring and, if warranted, treatment with anti-VEGF therapy benefits patients with macular edema associated with central retinal or hemiretinal vein occlusion. Publication of this article is sponsored by the American Ophthalmological Society., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To evaluate changes in retinal thickness and morphology using OCT in youth with type 2 diabetes (T2D) and to identify systemic biomarkers correlating with these changes., Design: Retrospective subgroup analysis of a prospective study., Participants: Participants who underwent OCT imaging in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial and its follow-up study TODAY2., Methods: In 2010-2011 (TODAY) and 2017-2018 (TODAY2), 6 × 6-mm macular volume OCT scans were acquired, segmented, and analyzed to generate total retinal thickness, inner retinal thickness, and outer retinal thickness. The main retinal morphologies graded were intraretinal cystoid spaces, subretinal fluid, and posterior vitreous detachment (PVD)., Main Outcome Measures: Changes in total and individual retinal layer thickness and development of abnormal vitreomacular morphology between TODAY and TODAY2., Results: Participants had a mean age of 17.9 ± 2.4 years and glycated hemoglobin (HbA1c) of 8.2 ± 2.8% in TODAY and a mean age of 25.0 ± 2.4 years and mean HbA1c of 9.5 ± 2.8% in TODAY2. Longitudinally between assessments, there were overall decreases in outer retinal thickness from 167.2 ± 11.5 microns to 158.4 ± 12.8 microns ( P  < 0.001) and in photoreceptor thickness from 30.3 ± 2.9 microns to 29.8 ± 4.1 microns ( P  = 0.04) in the central subfield, while in the inner subfield, we noted a decrease in outer retinal thickness from 150.5 ± 10.1 microns to 144.9 ± 10.5 microns ( P  < 0.001) and an increase in inner retinal thickness from 136.9 ± 11.5 microns to 137.4 ± 12.6 microns ( P  = 0.01). Multivariate analysis showed that in the center subfield, HbA1c increases were associated with increases in total retinal thickness (r: 0.67, P  = 0.001), whereas fasting glucose was positively correlated with inner retinal thickness (r: 0.02, P  = 0.02). In the inner subfield, both systolic (r: -0.22, P  < 0.001) and diastolic (r: -0.22, P  = 0.003) blood pressures were negatively correlated with total retinal thickness. There was an increase in PVD (18.9%) and cystoid spaces (4.2%)., Conclusions: Youth with T2D develop retinal thickness changes on OCT, including increases in total retinal and inner retinal thickness in the center subfield that correlate with HbA1c and fasting glucose, respectively. Taken together with the increased prevalence of abnormal vitreomacular morphology in this cohort at risk, these findings emphasize the importance of controlling risk factors to prevent the development of sight-threatening retinal complications., (© 2022 by the American Academy of Ophthalmology.)

Purpose: To evaluate macular thickness fluctuations and their association with visual acuity outcome in eyes with macular edema (ME) secondary to central (CRVO) or hemiretinal vein occlusion (HRVO) treated initially with intravitreal aflibercept or bevacizumab., Methods: Post hoc analysis of 362 patients with ME secondary to CRVO or HRVO initially randomized to six monthly intravitreal injections of aflibercept or bevacizumab. Three spectral domain optical coherence tomography (SD-OCT) central subfield thickness (CST) fluctuation measures were investigated over Months 1-12: standard deviation (SD), number of turning points (T) for each participant, and a measure denoted as Zigzag reflecting the magnitude of alternating ups and downs in a participant's CST. Main outcome measure is Month 12 visual acuity letter score (VALS)., Results: More fluctuations occurred in eyes randomized to bevacizumab than aflibercept: SD (59.98 vs 32.12; p < 0.0001), T (4.03 vs 3.53; p = 0.02) and Zigzag (24.91 vs 11.60; p = 0.0003). Month 12 VALS is significantly lower for the 4th (highest) quartile of the CST fluctuation measure than for the 1st (lowest) quartile for both SD (mean difference in VALS of 7.87; 95% confidence interval: 3.03, 12.70) and Zigzag (mean difference in VALS of 5.11; 95% confidence interval: 0.29, 9.93). SD and Zigzag quartiles were no longer significantly different after Month 1 VALS was added to the regression analysis., Conclusions: Greater CST fluctuation as assessed by SD and Zigzag was negatively associated with Month 12 VALS. However, early post-treatment VALS is a stronger predictor of VALS outcomes than the CST fluctuation measures., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Intravitreal anti-vascular endothelial growth factor (VEGF) injections are commonly used to treat eyes with macular edema secondary to hemiretinal vein occlusion (HRVO) or central retinal vein occlusion (CRVO). Information on whether differences exist in outcomes after anti-VEGF therapy can help guide treatment for each of the different disease types., Objective: To compare baseline characteristics, treatment burden, and outcomes of macular edema treatment in participants with HRVO with those of participants with CRVO., Design, Setting, and Participants: This post hoc outcome analysis from the Study of Comparative Treatments for Retinal Vein Occlusion 2 randomized clinical trial included 362 participants with macular edema caused by HRVO or CRVO treated at 66 US sites. Randomization began in September 2014, and the last month 24 follow-up visit occurred in February 2018. Data were analyzed from April 2020 to May 2021., Interventions: Eyes were initially randomized to 6 monthly intravitreal injections of aflibercept or bevacizumab and were treated according to protocol between months 6 to 12 depending on 6-month outcome. After month 12, patients were treated per investigator discretion and observed through month 60., Main Outcomes and Measures: Mean visual acuity letter score (VALS)., Results: Of 362 included patients, 157 (43.4%) were female, and the mean (SD) age was 68.9 (12.0) years. Outcome data were analyzed up to month 24 owing to substantial missing data at later visits. A significantly greater proportion of participants with HRVO than those with CRVO were Black (37% vs 11%). Treatment rates between months 12 to 23 were 0.36 (95% CI, 0.32-0.40) injections per month for patients with CRVO and 0.28 (95% CI, 0.19-0.36) for patients with HRVO (P = .11). The mean VALS from months 1 to 24 of an HRVO study eye exceeded that of a CRVO study eye by 5.5 (95% CI, 1.5-9.5; P = .01), consistent with the magnitude of the VALS difference between eyes with CRVO and HRVO at baseline. Eyes with CRVO presented at baseline with more macular edema than eyes with HRVO (difference in central subfield thickness [CST], 86 μm; 95% CI, 48-124; P < .001), with no difference in CST between the groups throughout months 1 to 24., Conclusions and Relevance: Black race was more prevalent among participants with HRVO than CRVO, and no differences were observed in the frequency of treatments for macular edema between eyes with CRVO and HRVO. Although eyes with CRVO presented with worse visual acuity and more macular edema on average than did eyes with HRVO, the magnitude of VALS improvement, central retinal thickness in response to anti-VEGF therapy, and treatment burden were similar between the groups.

Purpose: To identify anatomic endpoints altered by intravitreal ranibizumab in central retinal vein occlusion (CRVO) to determine any potential underlying disease modification that occurs with anti-vascular endothelial growth factor (anti-VEGF) therapy beyond best-corrected visual acuity and central optical coherence tomography outcomes., Methods: A post hoc analysis of a double-masked, multicenter, randomized clinical trial was performed. A total of 392 patients with macular edema after CRVO were randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections. Central reading center-read data were reviewed to explore potential anatomic endpoints altered by therapy., Results: At 6 months, there was a reduction in the ranibizumab groups compared with sham groups with respect to total area of retinal hemorrhage (median change from baseline in disc areas: - 1.17 [sham], - 2.37 [ranibizumab 0.3 mg], - 1.64 [ranibizumab 0.5 mg]), development of disc neovascularization (prevalence: 3% [sham], 0% [ranibizumab 0.3 mg], 0% [ranibizumab 0.5 mg]), and presence of papillary swelling (prevalence: 22.9% [sham], 8.0% [ranibizumab 0.3 mg], 8.3% [ranibizumab 0.5 mg], p < 0.01). There was no difference between groups in collateral vessel formation. Analysis of vitreous and preretinal hemorrhage could not be performed due to low frequency of events in both treated and sham groups., Conclusions: Ranibizumab for CRVO resulted in beneficial disease-modifying effects through a reduction in retinal hemorrhage, neovascularization, and papillary swelling. These findings may form the basis for future work in the development of a treatment response or severity scale for eyes with CRVO., (© 2021. The Author(s).)

Purpose: To compare Early Treatment Diabetic Retinopathy Study (ETDRS) severity levels between two digital fundus imaging protocols for research studies of diabetic retinopathy: the gold standard 7-field (7F) imaging and the more recent 4-widefield (4W) imaging., Methods: Two hundred twenty-two participants enrolled in the Diabetes Prevention Program Outcomes Study underwent concurrent 7F and 4W imaging. The ETDRS levels from 220 paired gradable images were determined by masked graders. Each image was graded by two independent graders with adjudication by a senior grader, if necessary. Percent agreement between graders and between imaging protocols was evaluated with kappa statistics and weighted kappa statistics., Results: Of 220 gradable eyes, diabetic retinopathy was seen in 11.8%; this was mild in 10.4% and more than mild in 1.4% using 7F imaging. The ETDRS levels showed exact agreement of 95% between 7F and 4W imaging (weighted kappa 0.86). Intergrader agreement for each modality had exact agreement of 89% (weighted kappa of 0.73) for 7F and 91% (weighted kappa 0.77) for 4W., Conclusions: There is substantial agreement in the ETDRS severity level between the 7F and 4W digital imaging protocols, demonstrating that the two imaging protocols are interchangeable. Both 4W and 7F digital imaging protocols can be used for assessing ETDRS levels, even in populations with minimal diabetic retinopathy., Translational Relevance: The 4W protocol requires fewer images than the 7F, is more comfortable for the patients, is easier for photographic capture, and provides diabetic retinopathy data that is equivalent to the 7F imaging protocol.

Purpose: To determine the interreader agreement for incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) and their related features in age-related macular degeneration (AMD)., Design: Interreader agreement study., Participants: Twelve readers from 6 reading centers., Methods: After formal training, readers qualitatively assessed 60 OCT B-scans from 60 eyes with AMD for 9 individual features associated with early atrophy and performed 7 different annotations to quantify the spatial extent of OCT features within regions of interest. The qualitative and quantitative features were used to derive the presence of iRORA and cRORA and also in an exploratory analysis to examine if agreement could be improved using different combinations of features to define OCT atrophy., Main Outcome Measures: Interreader agreement based on Gwet's first-order agreement coefficient (AC 1 ) for qualitatively graded OCT features and classification of iRORA and cRORA, and smallest real difference (SRD) for quantitatively graded OCT features., Results: Substantial or better interreader agreement was observed for all qualitatively graded OCT features associated with atrophy (AC 1  = 0.63-0.87), except for RPE attenuation (AC 1  = 0.46) and disruption (AC 1  = 0.26). The lowest SRD for the quantitatively graded horizontal features was observed for the zone of choroidal hypertransmission (± 190.8 μm). Moderate agreement was found for a 3-category classification of no atrophy, iRORA, and cRORA (AC 1  = 0.53). Exploratory analyses suggested a significantly higher level of agreement for a 3-category classification using (1) no atrophy; (2) presence of inner nuclear layer and outer plexiform layer subsidence, or a hyporeflective wedge-shaped band, as a less severe atrophic grade; and (3) the latter plus an additional requirement of choroidal hypertransmission of 250 μm or more for a more severe atrophic grade (AC 1  = 0.68; P = 0.013)., Conclusions: Assessment of iRORA and cRORA, and most of their associated features, can be performed relatively consistently and robustly. A refined combination of features to define early atrophy could further improve interreader agreement., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the prevalence and morphologic features of reticular pseudodrusen (RPD) and their association with participant demographics and age-related macular degeneration (AMD) status in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2) sample, an ancillary study of the Women's Health Initiative Observational Study., Design: Cross-sectional, multicenter, natural history study., Participants: Nine hundred and twenty-seven eyes from 466 postmenopausal women 69 to 101 years of age., Methods: Multimodal imaging, including spectral-domain (SD) OCT and infrared reflectance (IR), were used to identify RPD characteristics, including location (within or outside the 6-mm diameter circle centered at the macula), presence of peripapillary RPD, pattern of RPD, and RPD area. Age-related macular degeneration features from SD OCT, IR, and color photographs also were assessed and AMD severity was categorized., Main Outcome Measures: Reticular pseudodrusen prevalence using SD OCT and IR imaging and AMD status., Results: Reticular pseudodrusen were present in 130 eyes (14% of eyes, 16% of participants), with increasing prevalence with age: 7% in those younger than 78 years, 14% in those 78 to 83 years of age, and 30% in those older than 83 years. Using clinical classification of AMD with color photography, RPD were seen in 2.4% of eyes with no AMD or aging changes, 11.5% in early AMD, 25.1% in intermediate AMD, and 51.1% in late AMD. Mean RPD area was 17.4 mm 2 (standard deviation, 14.7 mm 2 ). Ribbon morphologic RPD (53%) was more common than dot morphologic RPD (36%). Reticular pseudodrusen mostly were located both within and outside the 6-mm circle with primarily superior retinal distribution. Reticular pseudodrusen were visualized with corresponding color fundus photography in only 38 eyes (4% of total eyes). Participants with and without RPD had a visual acuity±standard error of 77.9 ± 1.4 letters and 81.3 ± 0.4 letters, respectively (P = 0.02)., Conclusions: The prevalence of RPD in CAREDS2 increased with age and was associated with AMD severity. Reticular pseudodrusen were detected in eyes without other features of AMD and could represent an earlier disease state. Multimodal imaging with SD OCT and IR has significantly greater sensitivity for visualizing RPD than color fundus photography., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the association between ellipsoid zone (EZ) on spectral domain optical coherence tomography (SD-OCT) and visual acuity letter score (VALS) in participants with retinal vein occlusion in the Study of Comparative Treatments for Retinal Vein Occlusion 2., Methods: SD-OCT scans of 362 participants were qualitatively assessed at baseline and months 1, 6, 12, and 24 for EZ status as normal, patchy, or absent. The thickness of EZ layer in the central subfield was also obtained using machine learning., Results: EZ assessments were not possible at baseline due to signal blockage in >75% of eyes. At month 1, EZ was normal in 37.6%, patchy in 48.1%, and absent in 14.3%. EZ was measurable in 48.7% with a mean area of 0.07 ± 0.16 mm2. Mean VALS was better in eyes without an EZ defect compared to eyes with an EZ defect (P < 0.0001 at all visits). EZ defect at month 1 was associated with poorer VALS at all follow-up visits (P < 0.0001)., Conclusions: Both qualitative and quantitative assessments of EZ status strongly correlated with VALS. Absence of EZ was associated with poorer VALS at both corresponding and future visits, with larger areas of EZ loss associated with worse VALS., Translational Relevance: Assessment of EZ can be used to identify patients with potentially poor response in eyes with retinal vein occlusion.

Purpose: To evaluate the relationship of retinal layer thickness with age and age-related macular degeneration (AMD) in the Carotenoids in Age-Related Eye Disease Study 2., Methods: Total retinal thickness within the macular area, and individual layer thickness was determined for CAREDS2 participants (n = 906 eyes, 473 women) from the Women's Health Initiative using Heidelberg optical coherence tomography (OCT). Mean measurements within the OCT grid were compared across age tertiles (69-78, 78-83, and 83-101 years) and AMD outcomes., Results: Mean retinal thickness in the central circle, inner ring, and outer ring were 277 ± 34 µm, 326 ± 20 µm, and 282 ± 15 µm, respectively. Thickness did not vary by age in the central circle, but decreased with age in the inner and outer circles (P ≤ 0.004). Specifically, ganglion cell (GCL), inner plexiform, and outer nuclear (ONL) layer thickness decreased with age (P ≤ 0.003). Age-adjusted retinal thickness in all three circles did not vary by AMD outcomes (486 without AMD and 413 with AMD). However, individual layers showed changes with GCL and photoreceptor thinning and retinal pigment epithelial thicknening in eyes with late AMD. After controlling for age and AMD, higher ONL thickness was associated with better visual acuity., Conclusions: In this cohort of older women, a decrease in perifoveal thickness was associated with increasing age, particularly in the inner retinal layers. Variabilty in thickness in AMD eyes was primarily due to outer retinal layers. Among all retinal layers, the ONL plays an important role in preserving visual acuity., Translational Relevance: The study provides a deeper understanding of age related changes to the retinal layers and their effect on visual loss.

Purpose: To investigate the relationship between intraretinal macular hemorrhage and visual acuity outcomes in eyes with central retinal vein occlusion or hemiretinal vein occlusion managed with aflibercept, bevacizumab, or observation., Design: Retrospective analysis of data from 2 randomized clinical trials., Methods: A total of 362 participants were randomized in the Study of Comparative Treatments for Retinal Vein Occlusion 2, and 88 participants randomized to observation in the Standard Care vs Corticosteroid in Retinal Vein Occlusion Study. Participants received monthly intravitreal aflibercept or bevacizumab through month 6 or observation through month 8. The main outcome was visual acuity letter score (VALS)., Results: Reduced area of hemorrhage by month 6 was observed in 70.7% (116 of 164) of aflibercept-treated eyes, 63.8% (104 of 163) of bevacizumab-treated eyes, and 42.2% (27 of 64) of observation eyes by month 8 (P < .01). Relative to eyes with hemorrhage during follow-up, aflibercept-treated eyes without hemorrhage at month 6 had a mean VALS improvement of 8.0 (99% confidence interval [CI]: 1.9, 14.2); bevacizumab-treated eyes without hemorrhage at month 6 had a mean VALS improvement of 3.2 (99% CI: -4.6, 11.0); and observation eyes without hemorrhage at month 8 had a mean VALS improvement of 13.5 (99% CI: 0.4, 26.5). At month 6, the presence of hemorrhage and the change in central subfield thickness (CST) were significantly associated with the change in VALS; however, CST was a more important predictor., Conclusion: Improvement in hemorrhage during follow-up was associated with visual acuity improvements and predicted visual acuity changes beyond what was explained by CST. These findings suggest that intraretinal macular hemorrhage is an important indicator of disease severity in retinal vein occlusion., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To compare geographic atrophy (GA) area and enlargement rate measured with spectral domain OCT (SD-OCT) with fundus autofluorescence (FAF), color fundus photography (CFP), and infrared reflectance (IR) imaging., Design: Retrospective, multicenter, natural history case series., Participants: A total of 70 eyes with GA from 48 participants were included., Methods: Participants underwent SD-OCT, FAF, CFP, and IR imaging at baseline and 12 months in the study eye. Spectral domain OCT images were graded for GA area using 2 distinct criteria: (1) complete retinal pigment epithelium and outer retinal atrophy (cRORA) and (2) hypertransmission through Bruch's membrane. Areas were measured with SD-OCT using a custom-developed tool that allows for mapping areas of retinal layer loss on SD-OCT cross-sectional scans with co-registered IR images. Circularity index was calculated from area and perimeter. Spectral domain OCT images were also assessed for presence of reticular pseudodrusen, outer-retinal tubules, and hyporeflective wedge-shaped bands. Area of GA was measured in millimeters squared from FAF, CFP, and IR images., Main Outcome Measures: Geographic atrophy mean baseline area and enlargement rate measured with 2 SD-OCT criteria, FAF, CFP, and IR., Results: At baseline, the mean GA area was 6.9 (standard deviation [SD], 4.7) mm 2 using the SD-OCT cRORA criteria and 7.3 (SD, 4.7) mm 2 using the SD-OCT hypertransmission criteria. The mean annual enlargement rate of GA was 1.6 (SD, 1.1) mm 2 using the SD-OCT cRORA criteria and 1.5 (SD, 1.0) mm 2 using the SD-OCT hypertransmission criteria. When comparing both SD-OCT grading criteria with FAF, CFP, and IR, there were no statistically significant differences in baseline area or annual enlargement rate of GA. Circularity index was identified as the risk factor for increased annual enlargement rate., Conclusions: Measuring GA using retinal layer morphology provides a novel means of obtaining area measurements. Area measurements tend to vary based on criteria used and are comparable to other imaging modalities., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Diabetic retinopathy is the most common microvascular complication of diabetes and is a major cause of blindness, but an understanding of the pathogenesis of the disease has been hampered by a lack of accurate animal models. Here, we explore the dynamics of retinal cellular changes in the Nile rat (Arvicanthis niloticus), a carbohydrate-sensitive model for type 2 diabetes. The early retinal changes in diabetic Nile rats included increased acellular capillaries and loss of pericytes that correlated linearly with the duration of diabetes. These vascular changes occurred in the presence of microglial infiltration but in the absence of retinal ganglion cell loss. After a prolonged duration of diabetes, the Nile rat also exhibits a spectrum of retinal lesions commonly seen in the human condition including vascular leakage, capillary non-perfusion, and neovascularization. Our longitudinal study documents a range and progression of retinal lesions in the diabetic Nile rat remarkably similar to those observed in human diabetic retinopathy, and suggests that this model will be valuable in identifying new therapeutic strategies.

Purpose: Repackaged bevacizumab in single-dose, prefilled syringes for intravitreal injection is available, but with shelf life limited from 60 days to 90 days. For the Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2), 2-mL sterile glass vials were used rather than prefilled syringes to provide a longer shelf life for study supplies., Methods: Repackaged bevacizumab in glass vials was tested at release and, for 1 lot, after 1, 3, 6, and 12 months for physical stability, including concentration, purity and appearance, and for sterility and endotoxins. Vials from 2 lots were tested at release and after 20 months and 21 months, respectively. One lot was tested at 21 months for anti-VEGF bioactivity compared with a fresh supply of commercial bevacizumab., Results: Repackaged bevacizumab in 2-mL glass vials continued to meet all quality release specifications and remain sterile for up to 21 months. In addition, no degradation in anti-VEGF bioactivity was observed at 21 months compared with a fresh bevacizumab control., Conclusion: Bevacizumab can be repackaged into small, single-dose glass vials for intravitreal injection and the qualities of the commercial product maintained, including anti-VEGF bioactivity, for up to 21 months in refrigerated storage. Consideration should be given to repackaging bevacizumab for ophthalmic use in small glass vials as opposed to plastic syringes.

Importance: The Standard of Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study showed that intravitreal triamcinolone acetonide (IVTA) is effective at reducing macular edema and improving visual acuity in participants with retinal vein occlusion. Secondary analysis of the incidence, risk factors, and timing of intraocular pressure (IOP) elevation occurring after IVTA provides guidance for clinical decision making and management of patients treated with IVTA., Objective: To investigate the incidence, risk factors, and time course of IOP elevation in participants in the SCORE Study., Design, Setting, and Participants: Secondary analysis conducted from August through December 2014 of a prospective, randomized clinical trial featuring an evaluable population conducted at 75 clinical sites. Six hundred eighty-two patients with macular edema secondary to retinal vein occlusion were enrolled in the study. The SCORE Study enrollment period ran from November 4, 2004, to February 29, 2008, with participant follow-up ending February 28, 2009., Interventions: Study participants were randomized to standard of care, 1 mg of IVTA, or 4 mg of IVTA therapy and followed up for a mean (SD) of 24.7 (10.3) months., Main Outcomes and Measures: Intraocular pressure elevation greater than 10 mm Hg from baseline., Results: Kaplan-Meier incidences of IOP elevation greater than 10 mm Hg from baseline at 36 months were 0.02 (95% CI, 0.01-0.06), 0.09 (95% CI, 0.05-0.14), and 0.45 (95% CI, 0.38-0.53) in the standard of care, 1-mg IVTA, and 4-mg IVTA groups, respectively. The rates of IOP-related events were higher for the 4-mg IVTA group compared with the other groups (P ≤ .001 for main outcome measure). Younger age, 4-mg IVTA vs 1-mg IVTA treatment, and higher baseline IOP were found to confer greater risk for IOP-related events (P < .05 for all). The median number of days from time of first injection to IOP elevation greater than 10 mm Hg from baseline was 34.0 and 52.5 days in participants treated with 1-mg and 4-mg IVTA, respectively., Conclusions and Relevance: Intravitreal triamcinolone acetonide injection therapy, in particular the 4-mg dose, is associated with an increased risk for IOP elevation. The risk factors for an IOP-related event include higher treatment dose, younger age, and higher baseline IOP. Intraocular pressure-related events may take several months from the time of first IVTA injection to occur. Clinicians should be mindful of these risk factors when assessing the risks and benefits of IVTA therapy and also of the need for long-term follow-up of participants at risk for this complication., Trial Registration: clinicaltrials.gov Identifier: NCT00105027.

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.

Importance: Age-related cataract is a leading cause of visual impairment in the United States. The prevalence of age-related cataract is increasing, with an estimated 30.1 million Americans likely to be affected by 2020., Objective: To determine whether daily oral supplementation with lutein/zeaxanthin affects the risk for cataract surgery., Design, Setting, and Patients: The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, double-masked clinical trial, enrolled 4203 participants, aged 50 to 85 years, at risk for progression to advanced age-related macular degeneration., Interventions: Participants were randomly assigned to daily placebo; lutein/zeaxanthin, 10mg/2mg; omega-3 long-chain polyunsaturated fatty acids, 1 g; or a combination to evaluate the effects on the primary outcome of progression to advanced age-related macular degeneration., Main Outcomes and Measures: Cataract surgery was documented at annual study examination with the presence of pseudophakia or aphakia, or reported during telephone calls at 6-month intervals between study visits. Annual best-corrected visual acuity testing was performed. A secondary outcome of AREDS2 was to evaluate the effects of lutein/zeaxanthin on the subsequent need for cataract surgery., Results: A total of 3159 AREDS2 participants were phakic in at least 1 eye and 1389 of 6027 study eyes underwent cataract surgery during the study, with median follow-up of 4.7 years. The 5-year probability of progression to cataract surgery in the no lutein/zeaxanthin group was 24%. For lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratios for progression to cataract surgery was 0.96 (95% CI, 0.84-1.10; P = .54). For participants in the lowest quintile of dietary intake of lutein/zeaxanthin, the hazard ratio comparing lutein/zeaxanthin vs no lutein/zeaxanthin for progression to cataract surgery was 0.68 (95% CI, 0.48-0.96; P = .03). The hazard ratio for 3 or more lines of vision loss was 1.03 (95% CI, 0.93-1.13; P = .61 for lutein/zeaxanthin vs no lutein/zeaxanthin)., Conclusions and Relevance: Daily supplementation with lutein/zeaxanthin had no statistically significant overall effect on rates of cataract surgery or vision loss., Trial Registration: clinicaltrials.gov Identifier: NCT00345176.

Purpose: To examine the prevalence of macular telangiectasia type 2 and lesions characterizing it., Design: Population-based cohort study., Methods: setting: City and township of Beaver Dam, 1988-1990. study population: A total of 4790 people 43-86 years of age. observation procedure(s): Grading from stereoscopic fundus photographs to measure macular telangiectasia type 2. main outcome measure: Prevalent macular telangiectasia type 2., Results: Macular telangiectasia type 2 was present at baseline in 0.1% of the population (95% confidence interval [CI] 0.09, 0.1). The frequencies of loss of retinal transparency, crystals in the inner retinal layers, blunted retinal vessels, localized intraretinal pigment migration in the juxtafoveolar region, and presence of yellow deposits and lamellar holes in the foveal area in those without macular telangiectasia type 2 varied from 0.06% for retinal telangiectatic vessels to 1.2% for lamellar holes. Smoking was associated with pigment clumping (odds ratio [OR] per pack year 1.02; 95% CI 1.00, 1.03; P = .02), retinal pigment epithelial (RPE) depigmentation (OR 1.02 per pack year; 95%CI 1.00, 1.04; P = .02), loss of transparency (OR 1.02 per pack year; 95% CI 1.00, 1.03; P = .008), and the presence of a yellow spot in the fovea (OR 2.24 current vs past or never smoker; 95% CI 1.29, 3.89; P = .004), but not with presence of macular telangiectasia type 2 (OR 2.72; 95% CI 0.45, 16.28; P = .27)., Conclusions: The prevalence of macular telangiectasia type 2 (0.1%) is higher than previously thought. These data are useful in estimating the burden of this condition in the population. The role of smoking in the development of macular telangiectasia type 2 requires further study., (2010 Elsevier Inc. All rights reserved.)

Objective: To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with observation for eyes with vision loss associated with macular edema secondary to perfused central retinal vein occlusion (CRVO)., Methods: Multicenter, randomized, clinical trial of 271 participants., Main Outcome Measure: Gain in visual acuity letter score of 15 or more from baseline to month 12., Results: Seven percent, 27%, and 26% of participants achieved the primary outcome in the observation, 1-mg, and 4-mg groups, respectively. The odds of achieving the primary outcome were 5.0 times greater in the 1-mg group than the observation group (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.8-14.1; P = .001) and 5.0 times greater in 4-mg group than the observation group (OR, 5.0; 95% CI, 1.8-14.4; P = .001); there was no difference identified between the 1-mg and 4-mg groups (OR, 1.0; 95% CI, 0.5-2.1; P = .97). The rates of elevated intraocular pressure and cataract were similar for the observation and 1-mg groups, but higher in the 4-mg group., Conclusions: Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema secondary to CRVO in patients who have characteristics similar to those in the SCORE-CRVO trial. The 1-mg dose has a safety profile superior to that of the 4-mg dose. Application to Clinical Practice Intravitreal triamcinolone in a 1-mg dose, following the retreatment criteria applied in the SCORE Study, should be considered for up to 1 year, and possibly 2 years, for patients with characteristics similar to those in the SCORE-CRVO trial. Trial Registration clinicaltrials.gov Identifier: NCT00105027.

Objective: To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with standard care (grid photocoagulation in eyes without dense macular hemorrhage and deferral of photocoagulation until hemorrhage clears in eyes with dense macular hemorrhage) for eyes with vision loss associated with macular edema secondary to branch retinal vein occlusion (BRVO)., Methods: Multicenter, randomized clinical trial of 411 participants. Main Outcome Measure Gain in visual acuity letter score of 15 or more from baseline to month 12., Results: Twenty-nine percent, 26%, and 27% of participants achieved the primary outcome in the standard care, 1-mg, and 4-mg groups, respectively. None of the pairwise comparisons between the 3 groups was statistically significant at month 12. The rates of elevated intraocular pressure and cataract were similar for the standard care and 1-mg groups, but higher in the 4-mg group., Conclusions: There was no difference identified in visual acuity at 12 months for the standard care group compared with the triamcinolone groups; however, rates of adverse events (particularly elevated intraocular pressure and cataract) were highest in the 4-mg group. Application to Clinical Practice Grid photocoagulation as applied in the SCORE Study remains the standard care for patients with vision loss associated with macular edema secondary to BRVO who have characteristics similar to participants in the SCORE-BRVO trial. Grid photocoagulation should remain the benchmark against which other treatments are compared in clinical trials for eyes with vision loss associated with macular edema secondary to BRVO. Trial Registration clinicaltrials.gov Identifier: NCT00105027.

Objective: To evaluate interobserver agreement between investigator and Reading Center classification of retinal vein occlusion., Design: The Standard Care versus COrticosteroid in REtinal Vein Occlusion (SCORE) Study includes 2 multicenter phase 3 randomized clinical trials evaluating the efficacy and safety of intravitreal triamcinolone: one involves participants with central retinal vein occlusion (CRVO) and one for participants with branch retinal vein occlusion (BRVO). Eyes with hemiretinal vein occlusion (HRVO) were classified as BRVO., Participants: A total of 682 SCORE Study participants, including 271 with CRVO and 411 with BRVO., Methods: Participants were enrolled in each trial on the basis of investigator classification of retinal vein occlusion. Definitions of CRVO, BRVO, and HRVO based on clinical findings were specified in the study protocol. At baseline, 7-field color stereoscopic fundus photographs of the study eye of each participant were forwarded to the University of Wisconsin Fundus Photograph Reading Center (Reading Center) for evaluation., Main Outcome Measures: Percent agreement and kappa statistics comparing investigator and Reading Center classification of retinal vein occlusion type., Results: With HRVO categorized as BRVO (consistent with the SCORE Study design), there was 98.0% agreement between investigator and Reading Center classification (641/654 eyes; kappa = 0.96; 95% confidence interval, 0.94-0.98). Disagreements were fairly evenly divided between classification of an eye as CRVO by the investigator and as BRVO by the Reading Center (7/13 disagreements) and vice versa (6 disagreements). When all 3 disease categories (CRVO, BRVO, and HRVO) were compared, there was 92.2% agreement (603/654; unweighted kappa = 0.86; 95% confidence interval, 0.83-0.90). Most disagreements (38/51, or 74.5%) were between BRVO and HRVO, with 9 between CRVO and BRVO, and 4 between HRVO and CRVO. In univariate analyses, baseline factors significantly associated with disagreement include larger area of capillary loss and black race; black race was the only significant factor in a multivariate analysis., Conclusions: Investigator and Reading Center agreement was excellent in the SCORE Study; disease classification would have been altered in only 13 eyes (2.0%) had Reading Center eligibility been required. Interobserver agreement was least for classification between BRVO and HRVO.

Objective: To evaluate associations between nuclear cataract (determined from slitlamp photographs between May 2001 and January 2004) and lutein and zeaxanthin in the diet and serum in patients between 1994 and 1998 and macula between 2001 and 2004., Design: A total of 1802 women aged 50 to 79 years in Iowa, Wisconsin, and Oregon with intakes of lutein and zeaxanthin above the 78th (high) and below the 28th (low) percentiles in the Women's Health Initiative Observational Study (1994-1998) were recruited 4 to 7 years later (2001-2004) into the Carotenoids in Age-Related Eye Disease Study., Results: Women in the group with high dietary levels of lutein and zeaxanthin had a 23% lower prevalence of nuclear cataract (age-adjusted odds ratio, 0.77; 95% confidence interval, 0.62-0.96) compared with those with low levels. Multivariable adjustment slightly attenuated the association (odds ratio, 0.81; 95% confidence interval, 0.65-1.01). Women in the highest quintile category of diet or serum levels of lutein and zeaxanthin as compared with those in the lowest quintile category were 32% less likely to have nuclear cataract (multivariable-adjusted odds ratio, 0.68; 95% confidence interval, 0.48-0.97; P for trend = .04; and multivariable-adjusted odds ratio, 0.68; 95% confidence interval, 0.47-0.98; P for trend = .01, respectively). Cross-sectional associations with macular pigment density were inverse but not statistically significant., Conclusions: Diets rich in lutein and zeaxanthin are moderately associated with decreased prevalence of nuclear cataract in older women. However, other protective aspects of such diets may in part explain these relationships.

The benefit of the AREDS study and of nutritional supplements in reducing the onset or progression of end-stage AMD in those known to be at risk is a step forward in our understanding of what can be a blinding and debilitating disease. Nutritional supplements are not without risks, and their effects must be diligently and accurately monitored. However, they pose a viable complement in the venue of treating ocular disease and conditions.