An Updated Simplified Severity Scale for Age-Related Macular Degeneration, Incorporating Reticular Pseudodrusen: Age-Related Eye Disease Study Report No. 42.

PURPOSE: To update the Age-Related Eye Disease Study (AREDS) Simplified Severity Scale for risk of late age-related macular degeneration (AMD), including incorporation of reticular pseudodrusen (RPD), and to perform external validation on the AREDS2. DESIGN: Post hoc analysis of two clinical trial cohorts: AREDS and AREDS2. PARTICIPANTS: Participants with no late AMD in either eye at baseline in AREDS (n=2719) and AREDS2 (n=1472). METHODS: Five-year rates of progression to late AMD were calculated according to levels 0-4 on the Simplified Severity Scale, following two updates: (i) non-central GA considered part of the outcome rather than a risk feature, and (ii) scale separation according to RPD status (determined by validated deep learning grading of color fundus photographs). MAIN OUTCOME MEASURES: Five-year rate of progression to late AMD (defined as neovascular AMD or any GA). RESULTS: In the AREDS, following the first scale update, the five-year rates of progression to late AMD for levels 0-4 were 0.3%, 4.5%, 12.9%, 32.2%, and 55.6%, respectively. Following both updates, the proportion progressing to late AMD by five years was 8.4% in participants without RPD and 40.6% in those with RPD. As the final Simplified Severity Scale, the five-year progression rates for levels 0-4, respectively, were 0.3%, 4.3%, 11.6%, 26.7%, and 50.0%, for participants without RPD at baseline, and 2.8%, 8.0%, 29.0%, 58.7%, and 72.2%, for participants with RPD at baseline. In external validation on the AREDS2, for levels 2-4, the progression rates were similar, at 15.0%, 27.7%, and 45.7% (RPD absent) and 26.2%, 46.0%, and 73.0% (RPD present), respectively. CONCLUSIONS: The AREDS AMD Simplified Severity Scale has been modernized with two important updates. The new scale for individuals without RPD has five-year progression rates of ∼0.5%, 4%, 12%, ∼25%, and 50%, such that the rates on the original scale remain accurate. The new scale for individuals with RPD has five-year progression rates of 3%, 8%, ∼30%, ∼60%, and ∼70%, i.e., approximately double for most levels. This scale fits updated definitions of late AMD, has increased prognostic accuracy, appears generalizable to similar populations, but remains simple for broad risk categorization.

Phase 2 Trial Evaluating Minocycline for Geographic Atrophy in Age-Related Macular Degeneration: A Nonrandomized Controlled Trial.

Importance: Existing therapies to slow geographic atrophy (GA) enlargement in age-related macular degeneration (AMD) have relatively modest anatomic efficacy, require intravitreal administration, and increase the risk of neovascular AMD. Additional therapeutic approaches are desirable. Objective: To evaluate the safety and possible anatomic efficacy of oral minocycline, a microglial inhibitor, for the treatment of GA in AMD. Design, Setting, and Participants: This was a phase 2, prospective, single-arm, 45-month, nonrandomized controlled trial conducted from December 2016 to April 2023. Patients with GA from AMD in 1 or both eyes were recruited from the National Institutes of Health (Bethesda, Maryland) and Bristol Eye Hospital (Bristol, UK). Study data were analyzed from September 2022 to May 2023. Intervention: After a 9-month run-in phase, participants began oral minocycline, 100 mg, twice daily for 3 years. Main Outcomes and Measures: The primary outcome measure was the difference in rate of change of square root GA area on fundus autofluorescence between the 24-month treatment phase and 9-month run-in phase. Results: Of the 37 participants enrolled (mean [SD] age, 74.3 [7.6] years; 21 female [57%]), 36 initiated the treatment phase. Of these participants, 21 (58%) completed at least 33 months, whereas 15 discontinued treatment (8 by request, 6 for adverse events/illness, and 1 death). Mean (SE) square root GA enlargement rate in study eyes was 0.31 (0.03) mm per year during the run-in phase and 0.28 (0.02) mm per year during the treatment phase. The primary outcome measure of mean (SE) difference in enlargement rates between the 2 phases was -0.03 (0.03) mm per year (P = .39). Similarly, secondary outcome measures of GA enlargement rate showed no differences between the 2 phases. The secondary outcome measures of mean difference in rate of change between 2 phases were 0.2 letter score per month (95% CI, -0.4 to 0.9; P = .44) for visual acuity and 0.7 µm per month (-0.4 to 1.8; P = .20) for subfoveal retinal thickness. Of the 129 treatment-emergent adverse events among 32 participants, 49 (38%) were related to minocycline (with no severe or ocular events), including elevated thyrotropin level (15 participants) and skin hyperpigmentation/discoloration (8 participants). Conclusions and Relevance: In this phase 2 nonrandomized controlled trial, oral minocycline was not associated with a decrease in GA enlargement over 24 months, compared with the run-in phase. This observation was consistent across primary and secondary outcome measures. Oral minocycline at this dose is likely not associated with slower rate of enlargement of GA in AMD.

Local and Global Associations of Reticular Pseudodrusen in Age-Related Macular Degeneration.

PURPOSE: To investigate the spatial distribution of reticular pseudodrusen (RPD) in eyes with age-related macular degeneration (AMD) and their correlation with functional measures, retinal thickness, and changes over time. DESIGN: Longitudinal, cohort study. PARTICIPANTS: Thirty-five participants with RPD and spectrum of AMD severity (including no AMD). METHODS: Multimodal imaging was graded by a reading center, including evaluation of color fundus imaging to assess AMD severity scores. Reticular pseudodrusen presence on OCT volumes was confirmed on en face imaging and the RPD extent was contoured on infrared images. One study eye per participant underwent rod-mediated dark adaptation, measuring rod intercept time (RIT) at 5° and/or 12° superior to the fovea. MAIN OUTCOME MEASURES: The primary outcome was RIT and OCT thickness measures which were correlated with RPD area. RESULTS: A total of 51 eyes had ≥ 1 visit with RPD detected (mean follow-up, 2.19 ± 2.04 years; range, 0-5 years), totaling 169 eye-based visits with RPD. Of the 51 eyes with RPD, 5 (9.8%) developed geographic atrophy and 17 (33.3%) progressed to neovascular AMD. Larger RPD areas were detected more frequently in AMD severity scores 6-7. Reticular pseudodrusen area within an eye generally increased over time. The lesion distribution showed a predilection for the superior retina, especially the outer superior subfield of the ETDRS grid, with the central subfield having least involvement. Reticular pseudodrusen area was inversely correlated with central subfield thickness and positively correlated with RIT at 5° (P = 0.001; r2 = 0.01) and 12° (P = 0.004; r2 = 0.01). Rod-mediated dark adaptation at 5° reached the test ceiling in > 85% of visits, irrespective of RPD lesion presence/absence at the test location. Retinal thickness decreased monotonically, with the central subfield demonstrating the greatest percentage change over 5 years (Δ = -5.47%). CONCLUSIONS: In AMD, RPD involve predominantly the superior retina but can involve all ETDRS subfields and evolve over time. Eyes with RPD exhibit structural and functional impairments that can be measured beyond the boundaries of the RPD lesions, suggesting changes associated with RPD are associated with both local changes and a more widespread process. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Critical Dependence on Area in Relationship between ARMS2/HTRA1 Genotype and Faster Geographic Atrophy Enlargement: Age-Related Eye Disease Study 2 Report Number 33.

PURPOSE: To analyze ARMS2/HTRA1 as a risk factor for faster geographic atrophy (GA) enlargement according to (1) GA area and (2) contiguous enlargement versus progression to multifocality. DESIGN: Age-Related Eye Disease Study 2 (AREDS2) cohort analysis. PARTICIPANTS: Eyes with GA: 546 eyes of 406 participants. METHODS: Geographic atrophy area was measured from color fundus photographs at annual visits. Mixed-model regression of square root of GA area and proportional hazards regression of progression to multifocality were analyzed by ARMS2 genotype. MAIN OUTCOME MEASURES: Change in square root GA area and progression to multifocality. RESULTS: Geographic atrophy enlargement was significantly faster with ARMS2 risk alleles (P < 0.0001) at 0.224 mm/year (95% CI, 0.195-0.252 mm/year), 0.298 mm/year (95% CI, 0.271-0.324 mm/year), and 0.317 mm/year (95% CI, 0.279-0.355 mm/year), for 0 to 2 risk alleles, respectively. However, a significant interaction (P = 0.011) was observed between genotype and baseline area. In eyes with very small area (< 1.9 mm2), enlargement was significantly faster with ARMS2 risk alleles (P < 0.0001) at 0.193 mm/year (95% CI, 0.162-0.225 mm/year) versus 0.304 mm/year (95% CI, 0.280-0.329 mm/year) for 0 versus 1 to 2 risk alleles, respectively. With moderately small (1.9-3.8 mm2) or medium to large (≥ 3.8 mm2) area, enlargement was not significantly faster with ARMS2 risk alleles (P = 0.66 and P = 0.70, respectively). In nonmultifocal GA, enlargement was significantly faster with ARMS2 risk alleles (P = 0.001) at 0.175 mm/year (95% CI, 0.142-0.209 mm/year), 0.226 mm/year (95% CI, 0.193-0.259 mm/year), and 0.287 mm/year (95% CI, 0.237-0.337 mm/year) with 0 to 2 risk alleles, respectively. ARMS2 genotype was not associated significantly with progression to multifocal GA. CONCLUSIONS: The relationship between ARMS2/HTRA1 genotype and faster GA enlargement depends critically on GA area: risk alleles represent a strong risk factor for faster enlargement only in eyes with very small area. They increase the growth rate more through contiguous enlargement than progression to multifocality. ARMS2/HTRA1 genotype is more important in increasing risk of progression to GA and initial GA enlargement (contiguously) than in subsequent enlargement or progression to multifocality. These findings may explain some discrepancies between previous studies and have implications for both research and clinical practice. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A deep network DeepOpacityNet for detection of cataracts from color fundus photographs.

BACKGROUND: Cataract diagnosis typically requires in-person evaluation by an ophthalmologist. However, color fundus photography (CFP) is widely performed outside ophthalmology clinics, which could be exploited to increase the accessibility of cataract screening by automated detection. METHODS: DeepOpacityNet was developed to detect cataracts from CFP and highlight the most relevant CFP features associated with cataracts. We used 17,514 CFPs from 2573 AREDS2 participants curated from the Age-Related Eye Diseases Study 2 (AREDS2) dataset, of which 8681 CFPs were labeled with cataracts. The ground truth labels were transferred from slit-lamp examination of nuclear cataracts and reading center grading of anterior segment photographs for cortical and posterior subcapsular cataracts. DeepOpacityNet was internally validated on an independent test set (20%), compared to three ophthalmologists on a subset of the test set (100 CFPs), externally validated on three datasets obtained from the Singapore Epidemiology of Eye Diseases study (SEED), and visualized to highlight important features. RESULTS: Internally, DeepOpacityNet achieved a superior accuracy of 0.66 (95% confidence interval (CI): 0.64-0.68) and an area under the curve (AUC) of 0.72 (95% CI: 0.70-0.74), compared to that of other state-of-the-art methods. DeepOpacityNet achieved an accuracy of 0.75, compared to an accuracy of 0.67 for the ophthalmologist with the highest performance. Externally, DeepOpacityNet achieved AUC scores of 0.86, 0.88, and 0.89 on SEED datasets, demonstrating the generalizability of our proposed method. Visualizations show that the visibility of blood vessels could be characteristic of cataract absence while blurred regions could be characteristic of cataract presence. CONCLUSIONS: DeepOpacityNet could detect cataracts from CFPs in AREDS2 with performance superior to that of ophthalmologists and generate interpretable results. The code and models are available at https://github.com/ncbi/DeepOpacityNet ( https://doi.org/10.5281/zenodo.10127002 ).

Cataracts are cloudy areas in the eye that impact sight. Diagnosis typically requires in-person evaluation by an ophthalmologist. In this study, a computer program was developed that can identify cataracts from specialist photographs of the eye. The computer program successfully identified cataracts and was better able to identify these than ophthalmologists. This computer program could be introduced to improve the diagnosis of cataracts in eye clinics.

Artificial intelligence for home monitoring devices.

PURPOSE OF REVIEW: Home monitoring in ophthalmology is appropriate for disease stages requiring frequent monitoring or rapid intervention, for example, neovascular age-related macular degeneration (AMD) and glaucoma, where the balance between frequent hospital attendance versus risk of late detection is a constant challenge. Artificial intelligence approaches are well suited to address some challenges of home monitoring. RECENT FINDINGS: Ophthalmic data collected at home have included functional (e.g. perimetry), biometric (e.g. intraocular pressure), and imaging [e.g. optical coherence tomography (OCT)] data. Potential advantages include early detection/intervention, convenience, cost, and visual outcomes. Artificial intelligence can assist with home monitoring workflows by handling large data volumes from frequent testing, compensating for test quality, and extracting useful metrics from complex data. Important use cases include machine learning applied to hyperacuity self-testing for detecting neovascular AMD and deep learning applied to OCT data for quantifying retinal fluid. SUMMARY: Home monitoring of health conditions is useful for chronic diseases requiring rapid intervention or frequent data sampling to decrease risk of irreversible vision loss. Artificial intelligence may facilitate accurate, frequent, large-scale home monitoring, if algorithms are integrated safely into workflows. Clinical trials and economic evaluations are important to demonstrate the value of artificial intelligence-based home monitoring, towards improved visual outcomes.

Deep-GA-Net for Accurate and Explainable Detection of Geographic Atrophy on OCT Scans.

Objective: To propose Deep-GA-Net, a 3-dimensional (3D) deep learning network with 3D attention layer, for the detection of geographic atrophy (GA) on spectral domain OCT (SD-OCT) scans, explain its decision making, and compare it with existing methods. Design: Deep learning model development. Participants: Three hundred eleven participants from the Age-Related Eye Disease Study 2 Ancillary SD-OCT Study. Methods: A dataset of 1284 SD-OCT scans from 311 participants was used to develop Deep-GA-Net. Cross-validation was used to evaluate Deep-GA-Net, where each testing set contained no participant from the corresponding training set. En face heatmaps and important regions at the B-scan level were used to visualize the outputs of Deep-GA-Net, and 3 ophthalmologists graded the presence or absence of GA in them to assess the explainability (i.e., understandability and interpretability) of its detections. Main Outcome Measures: Accuracy, area under receiver operating characteristic curve (AUC), area under precision-recall curve (APR). Results: Compared with other networks, Deep-GA-Net achieved the best metrics, with accuracy of 0.93, AUC of 0.94, and APR of 0.91, and received the best gradings of 0.98 and 0.68 on the en face heatmap and B-scan grading tasks, respectively. Conclusions: Deep-GA-Net was able to detect GA accurately from SD-OCT scans. The visualizations of Deep-GA-Net were more explainable, as suggested by 3 ophthalmologists. The code and pretrained models are publicly available at https://github.com/ncbi/Deep-GA-Net. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Geographic Atrophy in Age-Related Macular Degeneration: A Tale of Two Stages.

Purpose: To examine disease progression in age-related macular degeneration (AMD) at 2 distinct stages, progression to geographic atrophy (GA) versus GA expansion, by comparison of the risk and protective factors at each stage. Design: Perspective. Subjects: Individuals at risk of GA or with GA. Main Outcome Measures: Progression to GA and GA expansion rate. Methods: Critical synthesis of the literature on risk and protective factors, both environmental and genetic, for progression to GA versus GA expansion in AMD. Results: Comparison of the risk and protective factors demonstrates partially overlapping but partially distinct risk and protective factors for progression to GA versus GA expansion. Some factors are shared (i.e., operating in the same direction at both stages), others are not shared, and others seem to operate in different directions at each stage. Risk variants at ARMS2/HTRA1 increase both risk of progression to GA and GA expansion rate, presumably through the same mechanism. By contrast, risk and protective variants at CFH/CFHR alter risk of GA but not GA expansion rate. A risk variant at C3 increases risk of GA but is associated with slower GA expansion. In environmental factors, cigarette smoking is associated with increased risk of GA and faster GA expansion, whereas increased age is associated with the former but not the latter. The Mediterranean diet is associated with decreased progression at both stages, although the food components with the largest contributions seem to differ between the 2 stages. Some phenotypic features, such as reticular pseudodrusen and hyperreflective foci, are associated with increased progression at both stages. Conclusions: Analysis of the risk and protective factors for progression to GA and GA expansion demonstrates partially overlapping but partially distinct elements at each stage: some are shared, some are relevant to 1 stage only, and some even seem active in opposite directions at each stage. Aside from ARMS2/HTRA1, the overlap between the genetic risk factors for the 2 stages is minimal. This suggests that the biologic mechanisms differ at least partially between the 2 disease stages. This has implications for therapeutic approaches and suggests that treatment aimed at the underlying disease processes may need to be tailored by stage. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Dietary nutrient intake and cognitive function in the Age-Related Eye Disease Studies 1 and 2.

INTRODUCTION: The objective was to analyze associations between dietary intake of multiple nutrients and altered cognitive function and/or decline. METHODS: Observational analyses of participants (n = 6334) in two randomized trials of nutritional supplements for age-related macular degeneration: Age-Related Eye Disease Study (AREDS) and AREDS2. RESULTS: In AREDS, for 4 of 38 nutrients examined, higher intake quintiles were significantly associated with decreased risk of cognitive impairment on the Modified Mini-Mental State test (<80): ß-carotene, copper, docosahexaenoic acid, and insoluble fiber. In AREDS2, for 13 of 44 nutrients, higher intake quintiles were associated with decreased risk on the Telephone Interview Cognitive Status-Modified (<30). Rate of cognitive decline over up to 10 years was not significantly different with higher intake of any nutrient. DISCUSSION: Higher dietary intake of multiple nutrients, including specific vitamins, minerals, carotenoids, fatty acids, and fiber, was associated with lower risk of cognitive impairment but not slower decline in cognitive function.

Hyperreflective Foci in Age-Related Macular Degeneration are Associated with Disease Severity and Functional Impairment.

PURPOSE: To analyze presence of hyperreflective foci (HRF) across different age-related macular degeneration (AMD) severities and examine its correlation with other structural and functional AMD features. DESIGN: Longitudinal, single-center, case-control study. PARTICIPANTS: One hundred and fifty-eight participants aged > 50 years old with varying AMD severities (including no AMD). METHODS: Color fundus imaging was used to assess AMD severity and hyperpigmentation (PGM) presence. Subretinal drusenoid deposits (SDD) and HRF were detected on OCT volumes. The correlations of HRF with additional AMD features were evaluated using linear and logistic mixed-effects models. One study eye per participant underwent dark adaptation (DA) testing to measure rod intercept time (RIT) for structure function associations. Eyes were followed longitudinally and changes in AMD severity and RIT were measured relative to HRF presence. MAIN OUTCOME MEASURES: The primary outcome was presence of HRF, which was compared with presence of other AMD features and DA impairment. RESULTS: One hundred and fifty-eight participants (median baseline age of 73.1 [interquartile range (IQR) = 66-79] years) contributing 1277 eye visits were included. Hyperreflective foci (HRF) were detected more frequently in higher AMD severities. Hyperreflective-foci presence was significantly associated with PGM presence (odds ratio 832.9, P < 0.001) and SDD presence (odds ratio 9.42, P = 0.017). Eyes with HRF demonstrated significantly longer DA (median 27.1 [IQR = 16-40] minutes) than those without HRF (13.5 [10-22] minutes) but less than eyes with SDD only (40 [28-40] minutes). Highest RIT values were found in eyes with both HRF and SDD (40.0 [40-40] minutes). Age and HRF explained a similar proportion of RIT variability as age and SDD. Eyes that developed HRF demonstrated baseline RITs closer to eyes with HRF at baseline, compared with eyes that never developed HRF (29.1 [16-40], 38.5 [22-40] versus 13.1 [10-22] minutes; Kruskal-Wallis P < 0.001). CONCLUSIONS: The progressively increased presence of HRF in higher AMD severities, and its correlation with previously associated AMD biomarkers, suggests HRF is an important OCT feature adding to the understanding of disease progression. Hyperreflective foci presence was associated with delays in DA, indicating HRF is a marker for visual cycle impairment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Association of Dietary Nitrate and a Mediterranean Diet With Age-Related Macular Degeneration Among US Adults: The Age-Related Eye Disease Study (AREDS) and AREDS2.

Importance: Low dietary nitrate intake has previously been suggested to be a risk factor for age-related macular degeneration (AMD) progression; however, this finding has not been replicated in other cohorts or adjusted for dietary patterns. Objective: To determine whether there is an association between dietary nitrate intake and AMD progression. Design, Setting, and Participants: This cohort study analyzed data from the prospective Age-Related Eye Disease Study (AREDS) and AREDS2 randomized clinical trial cohorts and their extended follow-up studies, which were conducted in multicenter outpatient retinal practices. Participants in both trials had non-late AMD in at least 1 eye. Data were analyzed from March 1, 2020, to September 30, 2022. Exposure: Dietary nitrate intake. Main Outcomes and Measures: Association between dietary nitrate intake and development of late AMD (neovascular AMD [nAMD] or geographic atrophy [GA]) or large drusen. The interactions of dietary patterns, with common at-risk single-nucleotide polymorphisms, were also assessed. Results: In the combined AREDS/AREDS2 cohort of 7788 participants (4288 AREDS participants and 3610 AREDS2 participants [110 of whom participated in both studies]), there were 13 511 eligible eyes. The combined cohort comprised 4396 women (56%) and 3392 men (44%), and the combined mean (SD) age was 71.1 (6.6) years. Dietary nitrate intake was associated with a decreased risk of progression to late AMD in the combined AREDS/AREDS2 cohort (hazard ratio [HR], 0.77 [95% CI, 0.69-0.86] for quartile 4 vs quartile 1 of intake) and a decreased risk of GA (HR, 0.71 [95% CI, 0.61-0.83]) and nAMD (HR, 0.85 [95% CI, 0.73-0.99]). In AREDS, increased nitrate intake (quartile 4 vs quartile 1) was associated with a decreased risk of late AMD (HR, 0.77 [95% CI, 0.65-0.91]) and GA (HR, 0.80 [95% CI, 0.65-0.97]) but not nAMD; in AREDS2, there was no association between nitrate intake (quartile 4 vs quartile 1) and late AMD (HR, 0.90 [95% CI, 0.80-1.02]) or nAMD (HR, 0.93 [95% CI, 0.78-1.11]). There was a correlation between Mediterranean dietary patterns and dietary nitrate intake (r = 0.52, P < .001). Conclusions and Relevance: The findings of this cohort study suggest that dietary nitrate intake was associated with lower AMD risk. However, this association disappeared after adjusting for Mediterranean dietary patterns. These results are subject to potential bias and are hypothesis-generating in nature; therefore, they are insufficient to support new clinical recommendations. Previously described associations between dietary nitrate intake and AMD may in fact represent overall dietary patterns. Further research is needed before dietary nitrate intake can be recommended as a therapy for AMD.

Reticular Pseudodrusen Status, ARMS2/HTRA1 Genotype, and Geographic Atrophy Enlargement: Age-Related Eye Disease Study 2 Report 32.

PURPOSE: To determine whether reticular pseudodrusen (RPD) status, ARMS2/HTRA1 genotype, or both are associated with altered geographic atrophy (GA) enlargement rate and to analyze potential mediation of genetic effects by RPD status. DESIGN: Post hoc analysis of an Age-Related Eye Disease Study 2 cohort. PARTICIPANTS: Eyes with GA: n = 771 from 563 participants. METHODS: Geographic atrophy area was measured from fundus photographs at annual visits. Reticular pseudodrusen presence was graded from fundus autofluorescence images. Mixed-model regression of square root of GA area was performed by RPD status, ARMS2 genotype, or both. MAIN OUTCOME MEASURES: Change in square root of GA area. RESULTS: Geographic atrophy enlargement was significantly faster in eyes with RPD (P < 0.0001): 0.379 mm/year (95% confidence interval [CI], 0.329-0.430 mm/year) versus 0.273 mm/year (95% CI, 0.256-0.289 mm/year). Enlargement was also significantly faster in individuals carrying ARMS2 risk alleles (P < 0.0001): 0.224 mm/year (95% CI, 0.198-0.250 mm/year), 0.287 mm/year (95% CI, 0.263-0.310 mm/year), and 0.307 mm/year (95% CI, 0.273-0.341 mm/year) for 0, 1, and 2, respectively. In mediation analysis, the direct effect of ARMS2 genotype was 0.074 mm/year (95% CI, 0.009-0.139 mm/year), whereas the indirect effect of ARMS2 genotype via RPD status was 0.002 mm/year (95% CI, -0.006 to 0.009 mm/year). In eyes with incident GA, RPD presence was not associated with an altered likelihood of central involvement (P = 0.29) or multifocality (P = 0.16) at incidence. In eyes with incident noncentral GA, RPD presence was associated with faster GA progression to the central macula (P = 0.009): 157 µm/year (95% CI, 126-188 µm/year) versus 111 µm/year (95% CI, 97-125 µm/year). Similar findings were observed in the Age-Related Eye Disease Study. CONCLUSIONS: Geographic atrophy enlargement is faster in eyes with RPD and in individuals carrying ARMS2/HTRA1 risk alleles. However, RPD status does not mediate the association between ARMS2/HTRA1 genotype and faster enlargement. Reticular pseudodrusen presence and ARMS2/HTRA1 genotype are relatively independent risk factors, operating by distinct mechanisms. Reticular pseudodrusen presence does not predict central involvement or multifocality at GA incidence but is associated with faster progression toward the central macula. Reticular pseudodrusen status should be considered for improved predictions of enlargement rate. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Characterising treatment outcomes of patients achieving quarterly aflibercept dosing for neovascular age-related macular degeneration: real-world clinical outcomes from a large tertiary care centre.

BACKGROUND AND OBJECTIVE: To evaluate the proportion of patients achieving a 12-week (q12) aflibercept dosing interval in patients with neovascular age-related macular degeneration (nAMD). PATIENTS AND METHODS: Retrospective, comparative, non-randomised electronic medical record (EMR) database study of the Moorfields database of treatment-naïve nAMD eyes. Extraction criteria included at least 7 aflibercept injections in first year of treatment, AMD in the diagnosis field of EMR, and minimum of 1 year follow-up data. RESULTS: There were 2416 eyes of 2163 patients started on anti-vascular endothelial growth factor (anti-VEGF) between 01-11-2013 & 14-02-2020 who had received at least 7 aflibercept intravitreal injections (electronic database accessed March 2021). Of these, 1674 (68%) eyes of 1537 patients had at least one q12 dosing interval (>=84 and < =98 days between injections) during the first 2 years of treatment. This included 926 (61.8%) female patients and 856 (right eyes age at 1st injection), 936 (62.4%) Caucasian, and 32 (2.1%) Afro-Caribbean patients. The median time to the first q12 injection (95% confidence interval) was 1.76 years (1.70-1.86) with mean (±SD) of 11.8 (±6.0) injections. Visual acuity (ETDRS letters) of the eyes without q12 injection and eyes with a q12 injection was 57.9 ± 14.7 and 56.7 ± 14.8 respectively at baseline, 61.4 ± 18.1 and 63.0 ± 15.9 respectively at 12 months and 61.2 ± 20.1 and 61.1 ± 17.8 respectively at 24 months. CONCLUSION: 68% of eyes were able to achieve a q12 injection dose within the first 2 years of treatment. Eyes achieving a q12 injection in the first 2 years achieved a similar visual acuity outcome at both 1 and 2-year follow-up to those unable to do so, with a fewer number of total injections.

Investigations of Renal Function and Age-Related Macular Degeneration Phenotypes.

Purpose: To investigate potential associations between renal function and age-related macular degeneration (AMD) features as assessed with multimodal retinal imaging. Methods: A subset of participants included in a dark adaptation study with varying AMD severities had estimated glomerular filtration rate (eGFR) values (mL/min/1.73 m2) obtained from renal function laboratory testing of serum creatinine and cystatin C. Multimodal imaging from visit dates associated with serum samples was graded by the Wisconsin Reading Center for AMD features. Associations of eGFR with AMD features and severity grades, age, smoker status and rod-intercept time were investigated. Simple univariate analyses, age-corrected multivariate analyses, and a feature-selecting least absolute shrinkage and selection operator regression were performed for eGFR as a continuous dependent variable. Results: A total of 110 patients (mean age, 75.1 ± 9.4 years; mean eGFR, 70.7 ± 18.2 mL/min/1.73 m2) were included. In univariate analyses age (estimate, -1.16 units/year; 95% confidence interval [CI], -1.46 to -0.87; P < 0.0001), rod-intercept time (estimate, -0.54 units/minute; 95% CI, -0.81 to -0.27; P < 0.001) and subretinal drusenoid deposits (-11.12 units for subretinal drusenoid deposit presence in either eye; 95% CI, -20.23 to -2.01; P = 0.017) were associated with decreased renal function. However, in age-corrected multivariate models, age was the only significant variable associated with renal function, confirmed by least absolute shrinkage and selection operator regression. Conclusions: Accounting for age, renal function parameters did not show an association with AMD features. Translational Relevance: Bruch's membrane of the eye and the glomerular basement membrane of the kidney share physiologic similarities such that decreased renal function may demonstrate associations with AMD phenotypes.

Assessment of Retinal Changes Following Intravitreal Aflibercept in 2 Patients With Von Hippel-Lindau Disease-Related Retinal Capillary Hemangioblastoma.

This case report of 2 patients describes peripheral Von Hippel-Lindau disease associated with a series of aflibercept injections.

Deep Learning-Based Modeling of the Dark Adaptation Curve for Robust Parameter Estimation.

Purpose: This study investigates deep-learning (DL) sequence modeling techniques to reliably fit dark adaptation (DA) curves and estimate their key parameters in patients with age-related macular degeneration (AMD) to improve robustness and curve predictions. Methods: A long-short-term memory autoencoder was used as the DL method to model the DA curve. The performance was compared against the classical nonlinear regression method using goodness-of-fit and repeatability metrics. Experiments were performed to predict the latter portion of the curve using data from early measurements. The prediction accuracy was quantified as the rod intercept time (RIT) prediction error between predicted and actual curves. Results: The two models had comparable goodness-of-fit measures, with root mean squared error (RMSE; SD) = 0.11 (0.04) log-units (LU) for the classical model and RMSE = 0.13 (0.06) LU for the DL model. Repeatability of the curve fits evaluated after introduction of random perturbations, and after performing repeated testing, demonstrated superiority of the DL method, especially among parameters related to cone decay. The DL method exhibited superior ability to predict the curve and RIT using points prior to -2 LU, with 3.1 ± 3.1 minutes RIT prediction error, compared to 19.1 ± 18.6 minutes RIT error for the classical method. Conclusions: The parameters obtained from the DL method demonstrated superior robustness as well as predictability of the curve. These could provide important advances in using multiple DA curve parameters to characterize AMD severity. Translational Relevance: Dark adaptation is an important functional measure in studies of AMD and curve modeling using DL methods can lead to improved clinical trial end points.

Longitudinal characterization and treatment response of retinal arterial macroaneurysms in adult-onset coats disease.

Purpose: To perform longitudinal analysis of retinal arterial macroaneurysms in 3 patients with adult-onset Coats disease. Observations: Three eyes of three patients with adult-onset Coats disease were followed longitudinally for 4-15 years. Ultra-widefield images and montage color fundus photographs of affected eyes were analyzed. Size, retinal location, and grading for predominant characteristic (hemorrhagic, exudative, or quiescent) of each individual macroaneurysm were followed longitudinally from the time of onset. Fifty-one individual retinal arterial macroaneurysms were identified. The distance of any lesion-associated hemorrhage or exudation present from the foveal center was measured. Macroaneurysms were located in all quadrants of the retina, with the majority (37/51) graded as hemorrhagic at lesion onset. Hemorrhagic and exudative macroaneurysms that entered the quiescent phase remained quiescent for an average of 26 months. Seven macroaneurysms were found to have hemorrhage or exudation that came within 125 µm of the fovea and all three eyes followed demonstrated a longitudinal decrease in visual acuity despite laser and intravitreal injection therapy. At the initial visit, visual acuities ranged from 20/40 to 20/200, but decreased to 20/80 to 20/320 by the last follow-up visit. Conclusion and Importance: There are many challenges in treating patients with adult-onset Coats disease. Long-term loss of visual acuity often results from sequelae of hemorrhage and exudation affecting the macula.