Association of Retinal Thickness at Month 1 Post-Treatment with Later Thickness and Visual Acuity in Central Vein Occlusion.

PURPOSE: To investigate the association of retinal thickness 1 month post-randomization (1 month after first study injection with aflibercept or bevacizumab) with later retinal thickness, visual acuity, and number of treatments in eyes with central or hemiretinal vein occlusion enrolled in the SCORE2 trial. DESIGN: Cohort study using data from a randomized multicenter clinical trial. METHODS: Analysis included 350 SCORE2 participants through 2 years of follow-up. Main outcome measures are central subfield thickness (CST) on spectral domain optical coherence tomography, best-corrected visual acuity letter score (VALS), and number of treatments for macular edema. CST was classified as thin (≤216µm), medium (>216µm and ≤300µm), or thick (>300µm). RESULTS: At Month 1, 15% (51/350) of study eyes were in the thin CST class, 57% (199/350) in the medium CST class, and 29% (100/350) in the thick CST class. Of eyes with thin CST at Month 1, 89-96% were also thin during Months 2-12. Over all visits studied, the VALS of eyes in the medium Month 1 CST class was significantly greater than the Month 1 thin class. During Months 6-12 (p<0.001) and 12-24 (p <0.001), but not during Months 0-6 (p=0.36) when monthly treatment was protocol-specified, the mean number of treatments for macular edema per study eye was highest in the thick CST class and lowest in the thin CST class. The thin CST class is significantly more likely to have disorganization of the retinal inner layers inside the central subfield, more paracentral acute middle maculopathy at Month 1, and a history of anti-VEGF treatment prior to trial enrollment. CONCLUSIONS: Eyes with a thin CST at Month 1 were more likely to be in their Month 1 CST class during Months 2-12 than eyes in the thick or medium Month 1 CST classes. Eyes in the medium CST class had the best VALS, with fewest treatments in the thin class after Month 6. These findings suggest that having a post-treatment thin CST can be as detrimental to visual acuity as having a post-treatment thick CST.

Intensive Glycemic Management Is Associated With Reduced Retinal Structure Abnormalities on Ocular Coherence Tomography in the DCCT/EDIC Study.

OBJECTIVE: To investigate quantitative and qualitative changes in retinal structure using optical coherence tomography (OCT) and their associations with systemic or other risk factors in individuals with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, OCT images were obtained during study years 25-28 (2019-2022) in 937 participants; 54% and 46% were from the original intensive (INT) and conventional (CONV) glycemic management treatment groups, respectively. RESULTS: Average age for participants was 61 years old, diabetes duration 39 years, and HbA1c 7.6%. Participants originally in the CONV group were more likely to have disorganization of retinal inner layers (DRIL) (CONV 27.3% vs. INT 18.7%; P = 0.0003), intraretinal fluid (CONV 24.4% vs. INT 19.2%; P = 0.0222), and intraretinal cysts (CONV 20.8% vs. INT 16.6%; P = 0.0471). In multivariable models, sex, age, smoking, mean updated systolic blood pressure, and history of "clinically significant" macular edema (CSME) and of anti-VEGF treatment were independently associated with changes in central subfield thickness, while HbA1c, BMI, and history of CSME and of ocular surgery were associated with DRIL. Visual acuity (VA) decline was associated with significant thinning of all retinal subfields except for the central and inner nasal subfields. CONCLUSIONS: Early intensive glycemic management in T1D is associated with a decreased risk of DRIL. This important morphological abnormality was associated with a history of macular edema, a history of ocular surgery, and worse VA. This study reveals benefits of intensive glycemic management on the retina beyond features detected by fundus photographs and ophthalmoscopy.

Imaging Modalities for Assessing the Vascular Component of Diabetic Retinal Disease: Review and Consensus for an Updated Staging System.

Purpose: To review the evidence for imaging modalities in assessing the vascular component of diabetic retinal disease (DRD), to inform updates to the DRD staging system. Design: Standardized narrative review of the literature by an international expert workgroup, as part of the DRD Staging System Update Effort, a project of the Mary Tyler Moore Vision Initiative. Overall, there were 6 workgroups: Vascular Retina, Neural Retina, Systemic Health, Basic and Cellular Mechanisms, Visual Function, and Quality of Life. Participants: The Vascular Retina workgroup, including 16 participants from 4 countries. Methods: Literature review was conducted using standardized evidence grids for 5 modalities: standard color fundus photography (CFP), widefield color photography (WFCP), standard fluorescein angiography (FA), widefield FA (WFFA), and OCT angiography (OCTA). Summary levels of evidence were determined on a validated scale from I (highest) to V (lowest). Five virtual workshops were held for discussion and consensus. Main Outcome Measures: Level of evidence for each modality. Results: Levels of evidence for standard CFP, WFCP, standard FA, WFFA, and OCTA were I, II, I, I, and II respectively. Traditional vascular lesions on standard CFP should continue to be included in an updated staging system, but more studies are required before they can be used in posttreatment eyes. Widefield color photographs can be used for severity grading within the area covered by standard CFPs, although these gradings may not be directly interchangeable with each other. Evaluation of the peripheral retina on WFCP can be considered, but the method of grading needs to be clarified and validated. Standard FA and WFFA provide independent prognostic value, but the need for dye administration should be considered. OCT angiography has significant potential for inclusion in the DRD staging system, but various barriers need to be addressed first. Conclusions: This study provides evidence-based recommendations on the utility of various imaging modalities for assessment of the vascular component of DRD, which can inform future updates to the DRD staging system. Although new imaging modalities offer a wealth of information, there are still major gaps and unmet research needs that need to be addressed before this potential can be realized. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Thrombospondin-1, BIM and CFH polymorphisms and response to anti-VEGF treatment in neovascular age- related macular degeneration patients.

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.

Comparison of Standard 7-Field, Clarus, and Optos Ultrawidefield Imaging Systems for Diabetic Retinopathy (COCO Study).

Purpose: The purpose of this study was to compare diabetic retinopathy (DR) severity levels assessed from 7 standard-field stereoscopic color photographs on a 35° fundus camera to both Clarus and Optos ultrawidefield color images. Design: Cross-sectional, comparative imaging study. Participants: Participants with DR imaged at a single-center retina practice. Methods: Participants were imaged on 3 cameras at a single visit with the Topcon 35° fundus camera, Clarus, and Optos. The DR Severity Scale (DRSS) level was determined within the 7-field (7F) area of each image set using the ETDRS scale. An additional global DRSS was assigned for both Clarus and Optos images using the entire visible retina. Weighted kappa (wκ) measured the agreement between cameras. Main Outcome Measures: The primary outcome was a 3-way comparison of DRSS level within the 7F area imaged on the 3 cameras. Secondary outcomes included a comparison of the DRSS obtained with standard 7F imaging to the global DRSS of Clarus and Optos and a comparison of the global DRSS between Clarus and Optos only. Results: Ninety-seven eyes (50 participants) were evaluated. Agreement within 1-step of ETDRS levels between standard 7F imaging and Clarus 7F was 90.1% (wκ = 0.65), and with Optos 7F in 85.9%, (wκ = 0.58). Agreement within 1-step between standard 7F imaging and Clarus global was 88.9% of eyes (wκ = 0.63), and Optos global was 85.7%, (wκ = 0.54). Agreement between Clarus and Optos global DR level within 1-step was 89.1% (wκ = 0.68). Intergrader agreement for the 7F ETDRS level was 96% for standard 7F imaging, 98% for Clarus, and 95.5% for Optos. Conclusions: These findings suggest that when evaluating the 7F area on Clarus and Optos, DR severity grades are comparable to standard 7F imaging. However, it is important to understand the unique attributes and differences of each fundus camera when changing the type of system used in a clinical setting due to upgrading equipment. Additionally, if the facility has access to > 1 device, there should not be an exchange between cameras for the same patient. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Month 60 Imaging Findings and Relationship to Treatment Outcomes Following Anti-VEGF Therapy for Macular Edema Due to Central or Hemi-Retinal Vein Occlusion.

PURPOSE: To evaluate imaging findings from SCORE2 participants through 60 months, to describe the degree of resolution or progression of these variables, and to correlate changes in these imaging findings to treatment outcomes such as visual acuity and the number of treatments administered. METHODS: SCORE2 participants were followed for up to 60 months. Visual acuity, injection frequency and imaging tests color fundus photography (CFP), optical coherence tomography (OCT), and ultra-widefield fluorescein angiography [UWFA]) were performed throughout this period. RESULTS: Less than 6% of eyes had subretinal fluid at month 60. Disorganization of the retinal inner layers (DRIL) was the most likely finding to persist, present in 96% of eyes at baseline and unchanged at 95% at month 60. For UWFA, at baseline, there was a mean of 5.0% non-perfusion area (95% CI: 3.3%-6.8%) in the NETWORC grid with little change to month 60. For the Early Treatment Diabetic Retinopathy Study (ETDRS) grid, at baseline, there was a mean of 2.3% non-perfusion area (95% CI: 0.7%-3.9%) with little change to month 60. There was no correlation between any of the imaging variables at baseline and change in visual acuity to month 60 or in the number of injections following the variable treatment timeframe (month 12 to month 60). CONCLUSIONS: These analyses provide an anatomic explanation for persistent functional deficits many years following initial treatment. Clinical practice patterns should consider evaluation with these imaging tests to help explain persistent functional deficits in many eyes. Additionally, these 8 baseline imaging variables generally should not be relied on to predict visual acuity or intensity of treatment. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Visit Adherence and Visual Acuity in Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2).

PURPOSE: We quantify the association between visit adherence and visual acuity (VA) in retinal vein occlusions (CRVO). METHODS: The SCORE2 protocol included a visit every 4 weeks (every 28-35 days) during the first year. Visit adherence was measured as follows: number of missed visits, average and longest (avg and max days) visit interval, and average and longest (avg and max missed days) and unintended visit interval. Avg and max missed days were categorized as on time (0 days), late (>0-60 days), and very late (>60 days). The primary outcome was a change in the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity letter score (VALS) between baseline study visit and last attended visit during Year 1, using multivariate linear regression models controlling for numerous demographic and clinical factors. RESULTS: After adjustment, for each visit missed, patients lost 3.0 letters (95% CI: -6.2, 0.2) of vision (p = .07). On average, the 48 patients who missed at least 1 visit lost 9.4 letters (95% CI: -14.4, -4.3, p < .001) of vision after adjustment. Average days and maximal intervals between visits were not associated with changes in VALS (p > .22) for both comparisons. However, when a visit was missed, the average missed days between missed visits and the max missed interval were both associated with loss of VALS (both variables: 0 days missed as reference, late [1-60 days] -10.8 letters [95% CI: -16.9, -4.7], very late [>60 days] -7.3 letters [95% CI: -14.5, -0.2]; p = .003 for both). CONCLUSIONS: Visit adherence is associated with VALS outcomes in CRVO patients.

Intraocular Pressure in Eyes With Retinal Vein Occlusion Compared With Fellow Eyes: Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) Report 27.

This cohort study investigates intraocular pressure (IOP) in eyes with retinal vein occlusion (RVO) compared with fellow, unaffected eyes.

OCT Grading System of Macular Infarction Predicts Vision in Participants With Central Retinal or Hemiretinal Vein Occlusion: A Secondary Analysis of SCORE2.

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.

Reticular Pseudodrusen: Interreader Agreement of Evaluation on OCT Imaging in Age-Related Macular Degeneration.

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 (AC1). 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 (AC1 = 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 (AC1 = 0.58-0.65) and increasing levels of agreement with increasing RPD stage (AC1 = 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 (AC1 = 0.68), but only fair agreement for this evaluation on selected B-scans (AC1 = 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.

High Variation in Inner Retinal Reflectivity Predicts Poor Visual Outcome in Patients With Central Retinal Vein Occlusion: SCORE2 Report 21.

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.

Cost-Utility Comparison of Bevacizumab and Aflibercept in the Treatment of Central or Hemiretinal Vein Occlusion in the SCORE2 Trial.

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.

SCORE2 Report 24: Nonlinear Relationship of Retinal Thickness and Visual Acuity in Central Retinal and Hemiretinal Vein Occlusion.

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.

Prevalence of Macular Atrophy in the MARINA Study of Ranibizumab versus Sham for Neovascular Age-Related Macular Degeneration.

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.

SCORE2 Report 20: Relationship of Treatment Discontinuation With Visual Acuity and Central Subfield Thickness Outcomes.

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.

Implementation of a Large-Scale Image Curation Workflow Using Deep Learning Framework.

Purpose: The curation of images using human resources is time intensive but an essential step for developing artificial intelligence (AI) algorithms. Our goal was to develop and implement an AI algorithm for image curation in a high-volume setting. We also explored AI tools that will assist in deploying a tiered approach, in which the AI model labels images and flags potential mislabels for human review. Design: Implementation of an AI algorithm. Participants: Seven-field stereoscopic images from multiple clinical trials. Methods: The 7-field stereoscopic image protocol includes 7 pairs of images from various parts of the central retina along with images of the anterior part of the eye. All images were labeled for field number by reading center graders. The model output included classification of the retinal images into 8 field numbers. Probability scores (0-1) were generated to identify misclassified images, with 1 indicating a high probability of a correct label. Main Outcome Measures: Agreement of AI prediction with grader classification of field number and the use of probability scores to identify mislabeled images. Results: The AI model was trained and validated on 17 529 images and tested on 3004 images. The pooled agreement of field numbers between grader classification and the AI model was 88.3% (kappa, 0.87). The pooled mean probability score was 0.97 (standard deviation [SD], 0.08) for images for which the graders agreed with the AI-generated labels and 0.77 (SD, 0.19) for images for which the graders disagreed with the AI-generated labels (P < 0.0001). Using receiver operating characteristic curves, a probability score of 0.99 was identified as a cutoff for distinguishing mislabeled images. A tiered workflow using a probability score of < 0.99 as a cutoff would include 27.6% of the 3004 images for human review and reduce the error rate from 11.7% to 1.5%. Conclusions: The implementation of AI algorithms requires measures in addition to model validation. Tools to flag potential errors in the labels generated by AI models will reduce inaccuracies, increase trust in the system, and provide data for continuous model development.

Retinal Thickness and Morphology Changes on OCT in Youth with Type 2 Diabetes: Findings from the TODAY Study.

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.

Risk Factors for the Development of Retinopathy in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Experience.

OBJECTIVE: To determine glycemic and nonglycemic risk factors that contribute to the presence of diabetic retinopathy (DR) before and after the onset of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: During the Diabetes Prevention Program (DPP) and DPP Outcome Study (DPPOS), we performed fundus photography over time in adults at high risk for developing T2D, including after they developed diabetes. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading system, with DR defined as typical lesions of DR (microaneurysms, exudates, hemorrhage, or worse) in either eye. RESULTS: By DPPOS year 16 (∼20 years after random assignment into DPP), 24% of 1,614 participants who had developed T2D and 14% of 885 who remained without diabetes had DR. In univariate analyses, using results from across the entire duration of follow-up, American Indian race was associated with less frequent DR compared with non-Hispanic White (NHW) race, and higher HbA1c, fasting and 2-h plasma glucose levels during an oral glucose tolerance test, weight, and history of hypertension, dyslipidemia, and smoking, but not treatment group assignment, were associated with more frequent DR. On multivariate analysis, American Indian race was associated with less DR compared with NHW (odds ratio [OR] 0.36, 95% CI 0.20-0.66), and average HbA1c was associated with more DR (OR 1.92, 95% CI 1.46-1.74 per SD [0.7%] increase in HbA1c). CONCLUSIONS: DR may occur in adults with prediabetes and early in the course of T2D. HbA1c was an important risk factor for the development of DR across the entire glycemic range from prediabetes to T2D.

Anatomic Biomarkers of Macular Edema Associated with Retinal Vein Occlusion.

PURPOSE: To assess the relationship between best-corrected visual acuity (BCVA) and anatomic features in patients with macular edema (ME) related to retinal vein occlusion (RVO). DESIGN: Post hoc analysis of 3 clinical trials, which included verified diagnoses, protocol refractions, and the assessment of OCT and fluorescein angiography (FA) images at a masked reading center. PARTICIPANTS: Patients diagnosed with RVO-ME. METHODS: Correlation analyses were performed to determine the correlation between BCVA and macular anatomy at baseline and at 12 and 24 weeks and between changes from baseline to 12 and 24 weeks. MAIN OUTCOME MEASURES: The correlations between BCVA and central subfield thickness (CST), ellipsoid zone (EZ) integrity, intraretinal fluid (IRF), subretinal fluid, central leakage, and ischemia were assessed. RESULTS: In a total of 828 eyes with RVO-ME, the mean age, BCVA, and CST at baseline was 64.7 years, 51.1 letters, and 656.9 µm, respectively. At baseline, a moderate negative correlation was observed between BCVA and CST (r = - 0.56, P < 0.001). At weeks 12 and 24, the mean BCVA of eyes with definitely abnormal (absent) EZ was statistically significantly worse than that of eyes with normal EZ. At week 12, a moderate negative correlation was observed between changes in BCVA and changes in CST (r = - 0.35, P < 0.001), with a similar degree of association noted at week 24 (r = - 0.35, P < 0.001). At weeks 12 and 24, eyes that showed any improvement in central IRF showed a greater improvement in BCVA than eyes that showed no improvement worsening (week 12: 463 eyes, 18.3 letters vs. 177 eyes, 13.0 letters, respectively, P < 0.001) and (week 24: 332 eyes, 20.2 letters vs. 131 eyes, 13.3 letters, respectively, P < 0.001). With respect to the correlation between baseline BCVA and fluorescein leakage or capillary nonperfusion, the Pearson correlation coefficients were - 0.41 (P < 0.001) and - 0.16 (P = 0.060), respectively. CONCLUSIONS: In addition to CST, there are important clinically relevant relationships between BCVA and both OCT and FA anatomic features in patients with RVO-ME.