Purpose: To investigate the effect of intravitreal (IVT) aflibercept injection monotherapy on retinal ischemia in eyes with severe proliferative diabetic retinopathy (PDR) that underwent pars plana vitrectomy (PPV) without panretinal photocoagulation (PRP) for vitreous hemorrhage. Methods: Thirty-one eyes with PDR-related vitreous hemorrhage underwent PPV without endolaser PRP and received 1 preoperative and 1 intraoperative IVT aflibercept injection before being randomized postoperatively to receive an IVT aflibercept injection once every 8 weeks (q8-week) or once every 16 weeks (q16-week). Ultra-widefield fluorescein angiography (FA) was performed 4 weeks post-PPV (baseline) and quarterly for 3 years. Images were independently graded at the Wisconsin Reading Center for the nonperfusion index, which is the proportion of assessable retinal area demonstrating capillary nonperfusion on ultra-widefield FA. Results: The IVT aflibercept q16-week group showed a significant increase in nonperfusion index of 0.096 by week 152 (P < .0001), whereas the q8-week group showed no significant progression. The q8-week group received more total injections and reached therapeutic saturation earlier, whereas the q16-week group showed a significant increase in unscheduled rescue injections across successive intervals (weeks 52-104, P = .017; weeks 104-152, P = .045) and still demonstrated worsening ischemia. In the q16-week group, higher cumulative injection counts correlated positively with nonperfusion index burden (P = .016), a relationship not observed in the q8-week group (P = .82). Conclusions: In eyes with PDR that underwent PPV without PRP, more frequent aflibercept dosing (q8-week) mitigated progression of retinal nonperfusion compared with extended-interval (q16-week) aflibercept therapy, suggesting that tighter antivascular endothelial growth factor treatment intervals may slow retinal ischemic progression.

Purpose:Ellipsoid zone (EZ) loss is an emerging end point in geographic atrophy (GA) clinical trials. Standardized ground truth is important to train artificial intelligence models in this biomarker. This study compares segmentation and edge detection methods for quantifying EZ and retinal pigment epithelium (RPE) loss on optical coherence tomography (OCT). Methods:OCT images from 50 eyes with GA were analyzed using segmentation (OCT Explorer) and edge detection (3D Slicer). With segmentation, the EZ and RPE borders were traced to generate thickness maps. For edge detection, graders marked regions of complete EZ or RPE loss on each B-scan. En face maps were generated from both methods and compared. Longitudinal progression was evaluated in 15 eyes with 1 year of follow-up. Results:The mean EZ loss area was 11.09 ± 5.40 mm2 by segmentation and 9.98 ± 5.01 mm2 by edge detection (P < 0.001). The mean RPE loss area was 7.66 ± 4.40 mm2 and 7.48 ± 4.23 mm2, respectively (P = 0.53) The EZ/RPE ratio was larger with segmentation (1.59 vs. 1.42; P < 0.001). Longitudinally, the mean EZ loss change was 1.71 mm²/year vs. 1.45 mm²/year (P = 0.43), and the RPE loss change was 1.74 vs. 1.60 mm²/year (P = 0.23). Conclusions:Segmentation and edge detection showed high agreement for EZ and RPE loss, but systematic differences were observed in EZ measurement. Segmentation yielded larger EZ areas by including attenuation over drusen, while edge detection provided more conservative boundaries restricted to GA only. Translational Relevance:Measurement method influences ellipsoid zone quantification, with implications for trial design and artificial intelligence ground truth development.

Purpose: To determine the functional characteristics of color fundus photograph (CFP)- and fundus autofluorescence (FAF)-defined geographic atrophy (GA) lesions by evaluating the prevalence of repeatable deep visual sensitivity defects. Design: Reader study. Participants: One hundred seventy-one pairs of CFP and FAF images from 60 eyes of 53 individuals. Methods: High-density, targeted microperimetry testing (with Goldmann Size III stimuli) was performed twice per visit in a 3.5° (approximately 1000 μm) diameter region of interest with retinal pigment epithelium and outer retinal atrophy on OCT imaging. Twelve readers from 6 established reading centers assessed CFP and FAF images within these regions sampled on microperimetry for GA, and performed annotations where GA was deemed to be present. Geographic atrophy on CFP was defined as a well-demarcated, roughly round or oval region of hypopigmentation, separately with and without requiring increased visibility of the underlying choroidal vessels (referred to as CFP-defined GA1 and GA2, respectively). GA on FAF was defined as a region of definite decreased autofluorescence. Main Outcome Measures: Prevalence of a repeatable ≤10 dB defect for CFP- and FAF-defined GA ≥175 μm, and the minimum lesion size showing a ≥90% prevalence of a repeatable ≤10 dB defect (deemed characteristic of regions with a truly nonresponding test location on microperimetry). Results: Color fundus photograph-defined GA1 and GA2 and FAF-defined GA ≥175 μm were graded as present in 13%, 31%, and 41% of images, respectively, and 77%, 67%, and 62% lesions, respectively, had a repeatable ≤10 dB defect. Only CFP-defined GA1 ≥625 μm, CFP-defined GA2 ≥650 μm, and FAF-defined ≥675 μm had a ≥90% prevalence of a repeatable ≤10 dB defect. Conclusions: Color fundus photograph and FAF-defined GA lesions ≥175 μm do not show the same functional characteristics as regions with a truly nonresponding test location, and only much larger lesions (approximately ≥650 μm) showed such similar functional characteristics. These findings provide crucial insights when considering CFP- and FAF-defined atrophic endpoints for clinical studies. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose:To investigate the natural history of macular tissue preservation in geographic atrophy (GA) by evaluating the relationship between the macular tissue integrity index (MTII) and best-corrected visual acuity (BCVA) over time. Design:Post hoc analysis of Age-Related Eye Disease Study 2 (AREDS2), a multi-center, randomized clinical trial. Participants:Participants from the AREDS2 fundus autofluorescence ancillary study with nonsubfoveal GA. Methods:Areas of GA were segmented by a deep learning algorithm and verified by expert graders. Macular tissue integrity index was defined as the percentage of the macula without GA within the central 1-mm and 3-mm circles. Baseline associations with BCVA were assessed, and longitudinal analyses evaluated GA progression, MTII loss, and BCVA decline over time. Main Outcome Measures:Geographic atrophy area, MTII, and BCVA. Results:Two hundred forty-three eyes (194 participants) were included. The median follow-up was 2 years. At baseline, the mean GA area was 1.8 mm2 (standard deviation 2.7), and the growth rate was 1.3 mm2/year. Baseline mean MTII in the 1-mm zone was 95.2% (standard deviation 9.1) with a decrease of 5.4%/year, and 87.3% (standard deviation 14.5) in the 3-mm zone with a decrease of 6.7%/year. Baseline mean BCVA was 76.4 letters (standard deviation 11.8; Snellen equivalent 20/30) with a 1.5-letter loss/year. Baseline MTII showed significant correlations with BCVA (1 mm: r = 0.17, P = 0.01; 3 mm: r = 0.14, P = 0.03), while GA area was not significantly associated with BCVA (r = -0.02, P = 0.71). Multivariable analysis showed that MTII in the 1-mm and 3-mm zones was associated with visual loss (both P < 0.0001). When eyes were stratified by MTII decline rate (stable/moderate/rapid), those in the rapid group showed numerically greater vision loss and GA growth. Conclusions:This study characterizes the natural history of central macular preservation in GA using MTII. Results show moderate but significant associations with BCVA cross-sectionally and longitudinally. These findings suggest that MTII may offer complementary functional context for evaluating disease progression in GA, warranting further validation in clinical trial settings. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose To investigate the natural history of macular tissue preservation in geographic atrophy (GA) by evaluating the relationship between the macular tissue integrity index (MTII) and best-corrected visual acuity (BCVA) over time. Methods Post-hoc analysis was performed on Age-Related Eye Disease Study 2 (AREDS2) fundus autofluorescence (FAF) ancillary study participants with non-subfoveal GA. Areas of GA were segmented by a deep learning algorithm and verified by expert graders. MTII was defined as the percentage of the macula without GA within the central 1 mm and 3 mm circles. Baseline associations with BCVA were assessed, and longitudinal analyses evaluated GA progression, MTII loss, and BCVA decline over time. Results 243 eyes (194 participants) were included. Median follow-up was 2 years.At baseline, the mean GA area was 1.8 mm2 (SD 2.7), and the growth rate was 1.3 mm2/year. Baseline mean MTII in the 1 mm zone was 95.2% (SD 9.1) with a decrease of 5.4%/year, and 87.3% (SD 14.5) in the 3 mm zone with a decrease of 6.7%/year. Baseline mean BCVA was 76.4 letters (SD 11.8; Snellen equivalent 20/30) with a 1.5-letter loss/year.Baseline MTII showed significant correlations with BCVA (1 mm: r = 0.17, p = 0.01; 3 mm: r = 0.14, p = 0.03), while GA area was not significantly associated with BCVA (r = -0.02, p = 0.71). Multivariable analysis showed that MTII in the 1 mm and 3 mm zones was associated with visual loss (both p<0.0001). When eyes were stratified by MTII decline rate (stable/moderate/rapid), those in the rapid group showed numerically greater vision loss and GA growth. Conclusion This study characterizes the natural history of central macular preservation in GA using MTII. Results show moderate but significant associations with BCVA cross-sectionally and longitudinally. These findings suggest that MTII may offer complementary functional context for evaluating disease progression in GA, warranting further validation in clinical trial settings.

Purpose:To investigate whether consensus can be reached on the acceptability of end-stage atrophy onset as a clinical end point in early intervention trials of age-related macular degeneration (AMD), and the criteria for defining such an end point. Design:A modified Delphi study. Participants:International panel of experts in AMD, retinal imaging, and histopathology that are part of the Classification of Atrophy Meetings group. Methods:A modified Delphi study was undertaken to determine if there is consensus on the acceptability of the onset of end-stage atrophic AMD as a clinical end point to evaluate early interventions and the criteria for defining such an end point. Two initial rounds of online surveys were conducted. Aggregate results and anonymized comments were provided after each round, followed by a face-to-face meeting before a final survey round was completed. Main Outcome Measures:Statements where consensus was reached, defined as ≥80% of responses within the 3-point bracket for agreement or disagreement based on a 9-point Likert rating scale, from a total of 33 statements included in the final round of the survey. Results:Consensus was reached for the statement that the onset of end-stage atrophic AMD was an appropriate clinical end point to evaluate early interventions (82% responses in agreement). Consensus was also reached for the statement that such an end point should be defined based on anatomical changes that have been previously shown in clinical studies to be associated with marked, but not necessarily complete, functional loss (95% responses in agreement). Consensus was nearly reached for the specific criterion that ≥90% of such atrophic AMD lesions should have ≥1 test location that was ≤10 decibels on 2 microperimetry tests (77% responses in agreement). Conclusions:There was expert group consensus that the onset of end-stage atrophy is an appropriate clinical end point to evaluate early interventions in AMD, and that such an end point should show evidence of marked functional loss in prior clinical studies. We believe these findings will help to define incident clinical end points that are acceptable to regulatory authorities. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose: To identify combination(s) of OCT changes that define atrophic age-related macular degeneration (AMD) lesions associated with repeatable deep visual sensitivity defects. Design: Reader study. Participants: One hundred seventy-one OCT scans from 60 eyes of 53 participants. Methods: Participants underwent 2 high-density targeted microperimetry tests (Macular Integrity Assessment device with Goldmann Size III stimuli) per visit of a 3.5° (approximately 1000 μm) diameter region-of-interest that had evidence of at least incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA). OCT B-scans within the region sampled on microperimetry were annotated by 12 readers from 6 established reading centers for 7 different features related to RPE and outer retinal atrophy. The prevalence of the presence of a repeatable ≤10 decibel (dB) defect on microperimetry for lesions categorized by 18 different combinations of such features, or criteria, was determined. Main Outcome Measures: The criteria for OCT-defined atrophic changes showing a ≥90% prevalence of a repeatable ≤10 dB defect, which has previously shown to be characteristic of regions with a truly nonresponding test location on microperimetry. Results: Sixty percent of complete RPE and outer retinal atrophy (cRORA) lesions—based on the presence of hypertransmission and RPE abnormalities ≥250 μm in width, with evidence of overlying photoreceptor (PR) degeneration, on an OCT B-scan—had a repeatable ≤10 dB defect. However, between 92% and 98% of lesions with both hypertransmission and complete RPE loss ≥500 μm, and with evidence of any size of any feature of overlying PR degeneration, had a repeatable ≤10 dB defect, depending on the criteria considered. Between 92% and 95% of lesions with hypertransmission ≥500 μm and either overlying external limiting membrane disruption, or outer plexiform layer and inner nuclear layer subsidence, and/or hyporeflective wedge-shaped band(s) ≥500 μm, with or without RPE abnormalities, had a repeatable ≤10 dB defect. Conclusions: This study identified various criteria for OCT-defined atrophic AMD lesions with functional characteristics that can be expected of regions with a truly nonresponding test location on high-density targeted microperimetry testing (i.e., having a ≥90% prevalence of a repeatable ≤10 dB defect). Such OCT-defined lesions could thus serve as functionally relevant clinical endpoints of end-stage atrophic AMD to facilitate preventative treatment trials. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

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. RESEARCH DESIGN AND METHODS In the Epidemiology of Diabetes Interventions and Complications 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) treatment groups, respectively. RESULTS Participants were on average 61 years old with diabetes duration of 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 SBP, and history of CSME and of anti-VEGF treatment were independently associated with changes in central subfield thickness, while HbA1c, BMI, history of CSME and of ocular surgery were associated with DRIL. Visual acuity decline was associated with significant thinning of all retinal subfields except for the central and inner nasal subfields. CONCLUSIONS Early intensive glycemic management in type 1 diabetes 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 visual acuity. This study reveals benefits of intensive glycemic management on the retina beyond features detected by fundus photographs and ophthalmoscopy.