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Progression of geographic atrophy varies significantly based on individual and lesion characteristics. Much research has strived to understand prognostic indicators of lesion progression over time, yet integrating findings to date may pose a challenge to clinicians. This review strives to synthesize current knowledge on genetic, behavioral, structural, and functional factors that influence geographic atrophy across the lifetime. Further, it highlights how vision-related quality of life allows for a more holistic appraisal of the impact of geographic atrophy on everyday functioning. The ultimate aim of this paper is to aid clinicians in counseling patients on medical management as well as providing accurate disease prognostication tailored to the individual patient., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Purpose: As part of the prospective, non-interventional OCEAN study, the ORCA module evaluated physicians' spectral domain optical coherence tomography (SD-OCT) image interpretations in the treatment of diabetic macular oedema (DME) or macular oedema (ME) secondary to retinal vein occlusion (RVO)., Methods: Presence of intraretinal fluid (IRF) and/or subretinal fluid (SRF) was evaluated independently by physicians and reading centres (RCs) on 1612 SD-OCT scans of 133 patients diagnosed with either DME or ME secondary to RVO. Agreement between physicians and RCs was calculated for both cohorts individually and as a combined ME cohort. Physicians' treatment decisions were analysed related to the results of the OCT-evaluations., Results: For the combined ME cohort, presence of IRF/SRF was recorded by RCs in 792/1612 (49.1%) visits and by physicians in 852/1612 (52.9%) visits, with an agreement regarding presence or absence of foveal fluid in 70.4% of cases. In 64.4% (510/792) of visits with RC-detected foveal IRF and/or SRF no injection was given. In 30.3% of these visits with foveal fluid no reason was identified for a 'watch and wait' approach indicating possible undertreatment. BCVA deterioration was seen in a quarter of these eyes at the following visit., Conclusion: Despite good agreement between physicians and RCs to recognize SRF and IRF, our data indicate that omitting injections despite foveal involvement of fluid is frequent in routine clinical practice. This may put patients at risk of undertreatment, which may negatively impact real-life BCVA outcomes., Trial Registration: www., Clinicaltrials: gov , identifier NCT02194803., (© 2024. The Author(s).)

Purpose: The purpose of this study was to develop a deep learning algorithm for detecting and quantifying incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) and complete retinal pigment epithelium and outer retinal atrophy (cRORA) in optical coherence tomography (OCT) that generalizes well to data from different devices and to validate in an intermediate age-related macular degeneration (iAMD) cohort., Methods: The algorithm comprised a domain adaptation (DA) model, promoting generalization across devices, and a segmentation model for detecting granular biomarkers defining iRORA/cRORA, which are combined into iRORA/cRORA segmentations. Manual annotations of iRORA/cRORA in OCTs from different devices in the MACUSTAR study (168 patients with iAMD) were compared to the algorithm's output. Eye level classification metrics included sensitivity, specificity, and quadratic weighted Cohen's κ score (κw). Segmentation performance was assessed quantitatively using Bland-Altman plots and qualitatively., Results: For ZEISS OCTs, sensitivity and specificity for iRORA/cRORA classification were 38.5% and 93.1%, respectively, and 60.0% and 96.4% for cRORA. For Spectralis OCTs, these were 84.0% and 93.7% for iRORA/cRORA, and 62.5% and 97.4% for cRORA. The κw scores for 3-way classification (none, iRORA, and cRORA) were 0.37 and 0.73 for ZEISS and Spectralis, respectively. Removing DA reduced κw from 0.73 to 0.63 for Spectralis., Conclusions: The DA-enabled iRORA/cRORA segmentation algorithm showed superior consistency compared to human annotations, and good generalization across OCT devices., Translational Relevance: The application of this algorithm may help toward precise and automated tracking of iAMD-related lesion changes, which is crucial in clinical settings and multicenter longitudinal studies on iAMD.

Objective: The primary goal of this study was to determine how structural and functional parameters influence the vision-related quality of life (VRQoL) in patients suffering from geographic atrophy (GA) secondary to age-related macular degeneration., Design: This study was designed as a prospective, noninterventional, natural-history study (Directional Spread in Geographic-Atrophy study, NCT02051998)., Subjects: The research involved 82 patients with bilateral GA., Methods: The study examined parameters including GA location as assessed by the ETDRS grid, best-corrected visual acuity, low-luminance visual acuity (LLVA), reading acuity, and speed. These parameters were then correlated with VRQoL, which was gauged using the National Eye Institute Visual Function Questionnaire 25. The analysis method employed was the least absolute shrinkage and selection operator with linear mixed-effects models., Main Outcome Measures: The central parameters measured in this study encompassed GA area, VRQoL scores associated with different GA subfields, and the significance of LLVA for foveal-sparing patients., Results: On average, patients showed a total GA area of 2.9 ± 1.2 mm 2 in the better eye (BE) and 3.1 ± 1.3 mm 2 in the worse eye. The most significant associations with VRQoL scores for distance and near activities were observed in the inner lower and inner left subfields of the BE, respectively. For patients with foveal-sparing GA, the LLVA of the BE stood out as the most influential variable across all VRQoL scales., Conclusions: The study's findings point toward the pivotal role of GA location, especially the inner lower and inner left subfields of the BE, in relation to VRQoL in GA patients. The LLVA's importance becomes even more pronounced for foveal-sparing patients. These observations highlight the need for health care professionals to better understand the association between lesion location and patient-reported outcomes. This is critical for informing treatment decisions and refining the planning of interventional trials., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The first regulatory approval of treatment for geographic atrophy (GA) secondary to age-related macular degeneration in the USA constitutes an important milestone; however, due to the nature of GA as a non-acute, insidiously progressing pathology, the ophthalmologist faces specific challenges concerning risk stratification, making treatment decisions, monitoring of treatment and patient education. Innovative retinal imaging modalities, such as fundus autofluorescence (FAF) and optical coherence tomography (OCT) have enabled identification of typical morphological alterations in relation to GA, which are also suitable for the quantitative characterization of GA. Solutions based on artificial intelligence (AI) enable automated detection and quantification of GA-specific biomarkers on retinal imaging data, also retrospectively and over time. Moreover, AI solutions can be used for the diagnosis and segmentation of GA as well as the prediction of structure and function without and under GA treatment, thereby making a valuable contribution to treatment monitoring and the identification of high-risk patients and patient education. The integration of AI solutions into existing clinical processes and software systems enables the broad implementation of informed and personalized treatment of GA secondary to AMD., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose: To longitudinally assess the impact of high-risk structural biomarkers for natural disease progression in non-exudative age-related macular degeneration (AMD) on spatially resolved mesopic and scotopic fundus-controlled perimetry testing., Methods: Multimodal retinal imaging data and fundus-controlled perimetry stimuli points were semiautomatically registered according to landmark correspondences at each annual visit over a period of up to 4 years. The presence of sub-RPE drusen, subretinal drusenoid deposits, pigment epithelium detachments (PEDs), hyper-reflective foci (HRF), vitelliform lesions, refractile deposits, and incomplete RPE and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) were graded at each stimulus position and visit. Localized retinal layer thicknesses were extracted. Mixed-effect models were used for structure-function correlation., Results: Fifty-four eyes of 49 patients with non-exudative AMD (mean age, 70.7 ± 9.1 years) and 27 eyes of 27 healthy controls (mean age, 63.4 ± 8.9 years) were included. During study course, presence of PED had the highest functional impact with a mean estimated loss of -1.30 dB (P < 0.001) for mesopic and -1.23 dB (P < 0.001) for scotopic testing, followed by HRF with -0.89 dB (mesopic, P = 0.001) and -0.87 dB (scotopic, P = 0.005). Subretinal drusenoid deposits were associated with a stronger visual impairment (mesopic, -0.38 dB; P = 0.128; scotopic, -0.37 dB; P = 0.172) compared with sub-RPE drusen (-0.22 dB, P = 0.0004; -0.18 dB, P = 0.006). With development of c-RORA, scotopic retinal sensitivity further significantly decreased (-2.15 dB; P = 0.02). Thickening of the RPE-drusen-complex and thinning of the outer nuclear layer negatively impacted spatially resolved retinal sensitivity., Conclusions: The presence of PED and HRF had the greatest prognostic impact on progressive point-wise sensitivity losses. Higher predominant rod than cone-mediated localized retinal sensitivity losses with early signs of retinal atrophy development indicate photoreceptor preservation as a potential therapeutic target for future interventional AMD trials.

Importance: Age-related macular degeneration (AMD) affects approximately 20 million people in the US and 196 million people worldwide. AMD is a leading cause of severe vision impairment in older people and is expected to affect approximately 288 million people worldwide by 2040., Observations: Older age, genetic factors, and environmental factors, such as cigarette smoking, are associated with development of AMD. AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision. The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD. The annual incidence of AMD ranges from 0.3 per 1000 in people who are aged 55 to 59 years to 36.7 per 1000 in people aged 90 years or older. The estimated heritability of late-stage AMD is approximately 71% (95% CI, 18%-88%). Long-term prospective cohort studies show a significantly higher AMD incidence in people who smoke more than 20 cigarettes per day compared with people who never smoked. AMD is diagnosed primarily with clinical examination that includes a special lens that focuses light of the slit lamp through the pupil. Exudative neovascular AMD is best identified using angiography and by optical coherence tomography. Individuals with AMD who take nutritional supplements consisting of high-dose vitamin C, vitamin E, carotenoids, and zinc have a 20% probability to progress to late-stage AMD at 5 years vs a 28% probability for those taking a placebo. In exudative neovascular AMD, 94.6% of patients receiving monthly intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections experience less than a 15-letter visual acuity loss after 12 months compared with 62.2% receiving sham treatment., Conclusions and Relevance: The prevalence of AMD is anticipated to increase worldwide to 288 million individuals by 2040. Intravitreally administered anti-VEGF treatment is first-line therapy for exudative neovascular AMD.

Purpose: To describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in clinical practice. VOYAGER also aims to understand drivers of clinical practice treatment outcomes by gaining novel insight into the intersection of treatment regimens, decisions, anatomic outcomes, and vision., Design: Primary data collection, noninterventional, prospective, multinational, multicenter clinical practice study., Participants: At least 5000 patients initiating/continuing faricimab or PDS for nAMD/DME (500 sites, 31 countries)., Methods: Management will be per usual care, with no mandated scheduled visits/imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomic features, and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions., Main Outcome Measures: Primary end point: VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary end points: VA change over time and per treatment regimens (fixed, treat-and-extend, pro re nata, and other) and number. Exploratory end points: VA change in relation to presence/location of anatomic features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, and disorganization of retinal inner layers) and per treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety., Results: Recruitment commenced in November 2022 and will continue until late 2027, allowing for up to 5 years follow-up. Exploratory interim analyses are planned annually., Conclusions: VOYAGER is an innovative study of retinal diseases that will assess the effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2023 by the American Academy of Ophthalmology.)

Objective: To analyze the ability to evaluate changes over time of individual lesions of incomplete or complete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA and cRORA, respectively) in patients with intermediate age-related macular degeneration (iAMD)., Design: OCT images from patients enrolled in Proxima B clinical trial (NCT02399072) were utilized., Participants: Patients enrolled in the Proxima B clinical trial, from the cohort with geographic atrophy (GA) in 1 eye and iAMD in the other eye at baseline, were included., Methods: Junior and senior readers analyzed OCT images for the qualitative presence of 9 distinct early atrophic features (presence of zone of choroidal hypertransmission, attenuation and/or disruption of RPE, disruption of ellipsoid zone [EZ] and external limiting membrane [ELM], outer nuclear layer [ONL] thinning, outer plexiform layer [OPL]/inner nuclear layer [INL] subsidence, and hyporeflective wedge-shaped band). If deemed "present," 7 features were quantified with a predefined tolerance level of 50 μm (diameter for the zone of choroidal hypertransmission, zone of attenuation and/or disruption of the RPE, outer retinal thickness left/right vertical diameter, outer retinal thickness thinnest vertical diameter, annotation of EZ, and ELM disruption)., Main Outcome Measures: Interreader agreements for qualitative assessments (κ-type statistics) and quantitative measurements (Bland-Altman statistics) were assessed. Progression of the lesion features over time was described., Results: Moderate agreement was found for presence of choroidal hypertransmission (κ = 0.54), followed by ELM disruption (κ = 0.58), OPL/INL subsidence (κ = 0.46), and a hyporeflective wedge-shaped band (κ = 0.47). Quantification measurements showed that choroidal hypertransmission had the highest agreement, whereas RPE attenuation/disruption had the lowest agreement. Longitudinal adjudicated changes for quantitative measurements of lesion progression showed that choroidal hypertransmission and ELM disruption showed significant progression, whereas EZ disruption and RPE attenuation/disruption did not., Conclusions: The ability to evaluate changes over time for specific features of iRORA and cRORA was explored. The most robust biomarker was found to be choroidal hypertransmission, followed by ELM disruption and the qualitative markers of OPL/INL subsidence, as well as a wedge-shaped band. Disease progression over time could be assessed by some, but not all, spectral-domain OCT features that were explored., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Geographic atrophy (GA) secondary to age-related macular degeneration is among the most common causes of irreversible vision loss in industrialized countries. Recently, two therapies have been approved by the US FDA. However, given the nature of their treatment effect, which primarily involves a relative decrease in disease progression, discerning the individual treatment response at the individual level may not be readily apparent. Thus, clinical decision-making may have to rely on the quantification of the slope of GA progression before and during treatment. A panel of imaging modalities and artificial intelligence (AI)-based algorithms are available for such quantifications. This article aims to provide a comprehensive overview of the fundamentals of GA imaging, the procedures for diagnosis and classification using these images, and the cutting-edge role of AI algorithms in automatically deriving diagnostic and prognostic insights from imaging data., (© 2023 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

This study aimed to determine the retest variability of quantitative fundus autofluorescence (QAF) in patients with and without age-related macular degeneration (AMD) and evaluate the predictive value of patient reliability indices on retest reliability. A total of 132 eyes from 68 patients were examined, including healthy individuals and those with various stages of AMD. Duplicate QAF imaging was conducted at baseline and 2 weeks later across six study sites. Intraclass correlation (ICC) analysis was used to evaluate the consistency of imaging, and mean opinion scores (MOS) of image quality were generated by two researchers. The contribution of MOS and other factors to retest variation was assessed using mixed-effect linear models. Additionally, a Random Forest Regressor was trained to evaluate the extent to which manual image grading of image quality could be replaced by automated assessment (inferred MOS). The results showed that ICC values were high for all QAF images, with slightly lower values in AMD-affected eyes. The average inter-day ICC was found to be 0.77 for QAF segments within the QAF8 ring and 0.74 for peripheral segments. Image quality was predicted with a mean absolute error of 0.27 on a 5-point scale, and of all evaluated reliability indices, MOS/inferred MOS proved most important. The findings suggest that QAF allows for reliable testing of autofluorescence levels at the posterior pole in patients with AMD in a multicenter, multioperator setting. Patient reliability indices could serve as eligibility criteria for clinical trials, helping identify patients with adequate retest reliability., (© 2023. Springer Nature Limited.)

Background: Early vitrectomy for postsurgical endophthalmitis may improve visual acuity outcomes. Silicone oil as a tamponade has some potential benefits in the management of endophthalmitis. This study aims to evaluate the use of a silicone oil tamponade in the surgical management of endophthalmitis. Material and Methods: All patients with a pars plana vitrectomy with silicone oil tamponade for postsurgical endophthalmitis at the Department of Ophthalmology, University of Bonn, Germany, between 2017 and 2021 were retrospectively reviewed. We included all preoperative data, including BCVA at diagnosis, clinical findings, and symptoms. For every follow-up visit, we looked at BCVA and complications. Results: In total, 82 patients were included in this study. The mean follow-up was 13.1 months (range 1-58 months). An intravitreal injection was the cause in 42 patients (51.2%) and cataract surgery in 29 patients (35.4%). The mean interval between the causing event and the date of onset was 8.8 days (range, 1-59 days). The most prevalent pathogen was Staphylococcus epidermidis in 16 patients (19.5%). In 47 patients (57.3%), no pathogen was found. The initial best-corrected visual acuity was 2.1 logMAR and improved significantly to 1.0 logMAR after six months ( p < 0.001) and 1.1 logMAR after 1 year ( p < 0.001). In a multivariate analysis, a low BCVA at diagnosis ( p = 0.041) was a significant predictor for poor visual acuity outcomes. A total of 17 patients (20.1%) developed postoperative complications. Five patients (6.1%) needed an anterior chamber washout with repeated injections of antibiotics. Two patients (2.4%) had persistent fibrin and were treated with YAG-laser treatment. Three patients (6.7%) developed a retinal detachment. Two patients (2.4%) had persistent corneal decompensation with endothelial cell loss and received perforating keratoplasty. We performed a matched-pair analysis ( n = 30, each group n = 15) to compare a silicone oil tamponade with BSS at the end of surgery. The visual acuity outcome showed no significant differences (BCVA after one year: 1.17 logMAR in eyes with silicone oil and 0.90 logMAR in eyes with BSS; p = 0.684). Conclusions: In our study, a vitrectomy with silicone oil tamponade in the surgical management of postoperative endophthalmitis led to a significant improvement in visual acuity and had a low complication rate. Low BCVA at diagnosis was significantly associated with poor visual acuity outcomes. A comparison of silicone oil and BSS at the end of surgery showed similar results.

Purpose: To examine deep learning (DL)-based methods for accurate segmentation of geographic atrophy (GA) lesions using fundus autofluorescence (FAF) and near-infrared (NIR) images., Methods: This retrospective analysis utilized imaging data from study eyes of patients enrolled in Proxima A and B (NCT02479386; NCT02399072) natural history studies of GA. Two multimodal DL networks (UNet and YNet) were used to automatically segment GA lesions on FAF; segmentation accuracy was compared with annotations by experienced graders. The training data set comprised 940 image pairs (FAF and NIR) from 183 patients in Proxima B; the test data set comprised 497 image pairs from 154 patients in Proxima A. Dice coefficient scores, Bland-Altman plots, and Pearson correlation coefficient (r) were used to assess performance., Results: On the test set, Dice scores for the DL network to grader comparison ranged from 0.89 to 0.92 for screening visit; Dice score between graders was 0.94. GA lesion area correlations (r) for YNet versus grader, UNet versus grader, and between graders were 0.981, 0.959, and 0.995, respectively. Longitudinal GA lesion area enlargement correlations (r) for screening to 12 months (n = 53) were lower (0.741, 0.622, and 0.890, respectively) compared with the cross-sectional results at screening. Longitudinal correlations (r) from screening to 6 months (n = 77) were even lower (0.294, 0.248, and 0.686, respectively)., Conclusions: Multimodal DL networks to segment GA lesions can produce accurate results comparable with expert graders., Translational Relevance: DL-based tools may support efficient and individualized assessment of patients with GA in clinical research and practice.

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

Background: Pigment epithelial detachments (PEDs) occur in association with various chorioretinal diseases. With respect to the broad clinical spectrum of PEDs we describe fundus autofluorescence (FAF) characteristics of PEDs., Methods: Ninety-three eyes of 66 patients (mean age 71.9 ± 11.1) with uni- or bilateral PED ( ≥ 350 µm) were included in a retrospective cross-sectional study. PEDs were secondary to age-related macular degeneration (n = 79), central serous chorioretinopathy (n = 7), polypoidal choroidal vasculopathy (n = 2), pattern dystrophy (n = 3) or idiopathic PED (n = 2). FAF images were recorded using confocal scanning laser ophthalmoscopy (488 nm excitation wavelength, detection of emission >500 nm). Diagnosis of PED was confirmed using spectral-domain optical coherence tomography. A qualitative FAF grading system was established, and grading was performed by two independent readers., Results: PEDs showed highly variable characteristics on FAF imaging. FAF within the area of PED was found to be irregular/granular (n = 59, 63.4%), increased (n = 28, 30.1%), decreased (n = 3, 3.2 %), or normal (n = 3, 3.2%). Accompanying FAF changes included condensation of macular pigment (n = 67, 72.0%), focally increased FAF at the PED apex (n = 14, 15.1%) or elsewhere (n = 52, 55.9%), focally decreased FAF (n = 23, 24.7%), a cartwheel-like pattern (n = 10, 10.8%), a doughnut sign (n = 6, 6.5%), and a halo of decreased FAF encircling the PED (completely n = 20, 21.5% or incompletely n = 20, 21.5%)., Conclusions: PEDs show a variety of abnormal patterns on FAF imaging. These changes in FAF signals may be secondary to morphological and metabolic alterations within corresponding retinal layers and do not necessarily correspond with the underlying PED subtype or a specific pathology., (© 2022. The Author(s).)

Purpose: This study assesses the repeatability of quantitative autofluorescence (qAF) in a multicenter setting and evaluates qAF as the end point for clinical trials in recessive Stargardt disease 1 (STGD1)., Methods: A total of 102 patients with STGD1 underwent qAF imaging as part of the Stargardt Remofuscin Treatment Trial (STARTT; EudraCT No. 2018-001496-20). For 166 eyes, we obtained qAF imaging at 2 visits, with 2 recordings per visit. The qAF8 values were independently determined by the study site and a central reading center. Intra- and inter-visit reproducibility, as well as interobserver (study site versus reading center) reproducibility were obtained using intraclass correlation (ICC), one-sample t-test, and Bland-Altman coefficient of repeatability., Results: The qAF repeatability was ± 26.1% for intra-visit, ± 40.5% for inter-visit, and ± 20.2% for the interobserver reproducibility measures. Intra-visit repeatability was good to excellent for all sites (ICC of 0.88-0.96). Variability between visits was higher with an overall ICC of 0.76 (0.69-0.81). We observed no significant difference in qAF values across sites between visits (7.06 ± 93.33, P = 0.238)., Conclusions: Real-life test-retest variability of qAF is higher in this set of data than previously reported in single center settings. With improved operator training and by selecting the better of two recordings for evaluation, qAF serves as a useful method for assessing changes in autofluorescence signal., Translational Relevance: The qAF can be adopted as a clinical trial end point, but steps to counterbalance variability should be considered.

Drusen are hallmarks of early and intermediate age-related macular degeneration (AMD) but their quantification remains a challenge. We compared automated drusen volume measurements between different OCT devices. We included 380 eyes from 200 individuals with bilateral intermediate (iAMD, n = 126), early (eAMD, n = 25) or no AMD (n = 49) from the MACUSTAR study. We assessed OCT scans from Cirrus (200 × 200 macular cube, 6 × 6 mm; Zeiss Meditec, CA) and Spectralis (20° × 20°, 25 B-scans; 30° × 25°, 241 B-scans; Heidelberg Engineering, Germany) devices. Sensitivity and specificity for drusen detection and differences between modalities were assessed with intra-class correlation coefficients (ICCs) and mean difference in a 5 mm diameter fovea-centered circle. Specificity was > 90% in the three modalities. In eAMD, we observed highest sensitivity in the denser Spectralis scan (68.1). The two different Spectralis modalities showed a significantly higher agreement in quantifying drusen volume in iAMD (ICC 0.993 [0.991-0.994]) than the dense Spectralis with Cirrus scan (ICC 0.807 [0.757-0.847]). Formulae for drusen volume conversion in iAMD between the two devices are provided. Automated drusen volume measures are not interchangeable between devices and softwares and need to be interpreted with the used imaging devices and software in mind. Accounting for systematic difference between methods increases comparability and conversion formulae are provided. Less dense scans did not affect drusen volume measurements in iAMD but decreased sensitivity for medium drusen in eAMD.Trial registration: ClinicalTrials.gov NCT03349801. Registered on 22 November 2017., (© 2022. The Author(s).)

Preservation of photoreceptors beyond areas of retinal pigment epithelium atrophy is a critical treatment goal in eyes with geographic atrophy (GA) to prevent vision loss. Thus, we assessed the association of treatment with the complement C3 inhibitor pegcetacoplan with optical coherence tomography (OCT)-based photoreceptor laminae thicknesses in this post hoc analysis of the FILLY trial (NCT02503332). Retinal layers in OCT were segmented using a deep-learning-based pipeline and extracted along evenly spaced contour-lines surrounding areas of GA. The primary outcome measure was change from baseline in (standardized) outer nuclear layer (ONL) thickness at the 5.16°-contour-line at month 12. Participants treated with pegcetacoplan monthly had a thicker ONL along the 5.16° contour-line compared to the pooled sham arm (mean difference [95% CI] + 0.29 z-score units [0.16, 0.42], P < 0.001). The same was evident for eyes treated with pegcetacoplan every other month (+ 0.26 z-score units [0.13, 0.4], P < 0.001). Additionally, eyes treated with pegcetacoplan exhibited a thicker photoreceptor inner segment layer along the 5.16°-contour-line at month 12. These findings suggest that pegcetacoplan could slow GA progression and lead to reduced thinning of photoreceptor layers beyond the GA boundary. Future trials in earlier disease stages, i.e., intermediate AMD, aiming to slow photoreceptor degeneration warrant consideration., (© 2022. The Author(s).)

Background: This report describes the study design and baseline characteristics of patients with Stargardt disease (STGD1) enrolled in the STArgardt Remofuscin Treatment Trial (STARTT). Methods: In total, 87 patients with genetically confirmed STGD1 were randomized in a double-masked, placebo-controlled proof of concept trial to evaluate the safety and efficacy of 20 milligram oral remofuscin for 24 months. The primary outcome measure is change in mean quantitative autofluorescence value of an 8-segment ring centred on the fovea (qAF 8 ). Secondary efficacy variables are best corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), mesopic microperimetry (mMP),  spectral domain optical coherence tomography (SD-OCT), reading speed on Radner reading charts, and patient-reported visual function as assessed by the National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) and Functional Reading Independence (FRI) Index. Results: Mean age of participants was 35±11 years with 49 (56%) female. Median qAF 8 value was 438 Units (range 210-729). Median BCVA and LLVA in decimal units were 0.50 (range 0.13-0.80) and 0.20 (range 0.06-0.63), respectively. The median of the mean retinal sensitivity with mMP was 20.4 dB (range 0.0-28.8). SD-OCT showed median central subfield retinal thickness of 142 µm (range 72-265) and median macular volume of 1.65 mm 3 (range 1.13-2.19). Compared to persons without vision impairment, both reading performance and patient-reported visual function were significantly lower (p<0.001, one sample t-test). Mean reading speed was 108±39 words/minute with logRAD-score of 0.45±0.28. Mean VFQ-25 composite score was 72±13. Mean FRI Index score 2.8±0.6. Conclusions: This trial design may serve as reference for future clinical trials as it explores the utility of qAF 8 as primary outcome measure. The baseline data represent the largest, multi-national, STGD1 cohort to date that underwent standardized qAF imaging, reading speed assessment and vision-related quality of life measures which all contribute to the characterization of STGD1. EudraCT registration: 2018-001496-20 (09/05/2019)., Competing Interests: Competing interests: Wolfgang Klein: financial support, personal financial interest, and consultant for Katairo GmbH. Mario G Fsadni: paid consultant to Katairo GmbH, outsourced from International Pharm-Med Ltd in United Kingdom. Oliver Jungmann: commercial relationships via employment Smerud Medical Research Hans Müller: commercial relationships via employment Smerud Medical Research Philipp T. Möller, Frank G. Holz and Steffen Schmitz-Valckenberg: contracted research for reading center services by Katairo GmbH All other authors: no relevant competing interests disclosed., (Copyright: © 2022 Dhooge PPA et al.)

Quantification of the relative ellipsoid zone reflectivity (rEZR) might be a structural surrogate parameter for an early disease progression in the context of age-related macular degeneration (AMD). Within the European multicenter, cross-sectional MACUSTAR study, we have devised an automatic approach to determine the mean rEZR [arbitrary units, AU] at two independent visits in SD-OCT volume scans in study participants. Linear mixed-effects models were applied to analyze the association of AMD stage and AMD associated high-risk features including presence of pigmentary abnormalities, reticular pseudodrusen (RPD), volume of the retinal-pigment-epithelial-drusenoid-complex (RPEDC) with the rEZR. Intra-class correlation coefficients (ICC) were determined for rEZR reliability analysis. Within the overall study cohort (301 participants), we could observe decreased rEZR values (coefficient estimate ± standard error) of - 8.05 ± 2.44 AU (p = 0.0011) in the intermediate and of - 22.35 ± 3.28 AU (p &lt; 0.0001) in the late AMD group. RPD presence was significantly associated with the rEZR in iAMD eyes (- 6.49 ± 3.14 AU; p = 0.0403), while there was a good ICC of 0.846 (95% confidence interval: 0.809; 0.876) in the overall study cohort. This study showed an association of rEZR with increasing disease severity and the presence of iAMD high-risk features. Further studies are necessary to evaluate the rEZR's value as a novel biomarker for AMD and disease progression., (© 2022. The Author(s).)

Background: Treatment initiation with brolucizumab, a new potent anti-vascular endothelial growth factor (VEGF) agent, is typically performed with three monthly injections (loading dose) and has been well studied in treatment-naïve patients. However, no clinical data are available yet on whether or not anti-VEGF pretreated patients also benefit from a loading dose. In the clinical setting, different heterogeneous treatment patterns are used as no clinical trial has addressed this so far in a head-to-head comparison. Therefore, the FALCON study is investigating whether patients with unsatisfactory response to previous anti-VEGF treatments benefit from a loading dose at the switch to brolucizumab treatment., Methods: FALCON is a 52-week, two-arm, randomized, open-label, multicenter, multinational study in patients with residually active neovascular age-related macular degeneration (nAMD) who will be randomized 1:1 and started with brolucizumab 6 mg loading (three monthly loading doses) or brolucizumab 6 mg non-loading (one initial injection) and consecutive treatment every 12 weeks, respectively. The primary objective is to demonstrate non-inferiority of the non-loading vs. loading arm in mean change of best-corrected visual acuity (BCVA) from baseline to the mean value at week 40 to week 52. Secondary objectives include the assessment of anatomical outcomes, treatment intervals, safety and tolerability., Results: FALCON will be the first study to assess treatment initiation with an anti-VEGF agent in a switch situation with or without loading dose in patients with nAMD., Conclusions: The results will support the optimization of treatment of patients with previous unsatisfactory anti-VEGF response. Therefore, we expect to see an impact on current clinical practice which has been established for more than a decade., Trial Registration: Clinicaltrials.gov: NCT04679935, date of registration-22-Dec 2020; EUDRACT number: 2019-004763-53, date of registration-03 Dec 2019., (© 2022. The Author(s).)

Purpose: To analyze the intersession repeatability of structural biomarkers in eyes with early and intermediate age-related macular degeneration (iAMD) within the cross-sectional part of the observational multicenter MACUSTAR study., Methods: Certified site personnel obtained multimodal imaging data at two visits (38 ± 20 [mean ± standard deviation] days apart), including spectral-domain optical coherence tomography (SD-OCT). One junior reader performed systematic and blinded grading at the central reading center, followed by senior reader review. Structural biomarkers included maximum drusen size classification (>63 to ≤125 µm vs. >125 µm), presence of large pigment epithelium detachments (PEDs), reticular pseudodrusen (RPD), vitelliform lesions, and refractile deposits. Intrasession variability was assessed using Cohen's κ statistics., Results: At the first visit, 202 study eyes of 202 participants were graded as manifesting with either early (n = 34) or intermediate (n = 168) AMD. Grading of imaging data between visits revealed perfect agreement for the maximum drusen size classification (κ = 0.817; 95% confidence interval, 0.70-0.94). In iAMD eyes, perfect to substantial agreement was determined for the presence of large PEDs (0.87; 0.69-1.00) and RPD (0.752; 0.63-0.87), while intersession agreement was lower for the presence of vitelliform lesions (0.649; 0.39-0.65) and refractile deposits (0.342; -0.029-0.713), respectively., Conclusions: Multimodal retinal imaging analysis between sessions showed a higher repeatability for structural biomarkers with predefined cutoff values than purely qualitative defined parameters., Translational Relevance: A high repeatability of retinal imaging biomarkers will be important to implement automatic grading approaches and to establish robust and meaningful structural clinical endpoints for future interventional clinical trials in patients with iAMD.

Importance: Age-related macular degeneration (AMD) is a common cause of irreversible vision loss among individuals older than 50 years. Although considerable advances have been made in our understanding of AMD genetics, the differential effects of major associated loci on disease manifestation and progression may not be well characterized., Objective: To elucidate the specific associations of the 2 most common genetic risk loci for AMD, the CFH-CFHR5 locus on chromosome 1q32 (Chr1) and the ARMS2/HTRA1 locus on chromosome 10q26 (Chr10)-independent of one another and in combination-with time to conversion to late-stage disease and to visual acuity loss., Design, Setting, and Participants: This case series study included 502 individuals who were homozygous for risk variants at both Chr1 and Chr10 (termed Chr1&10-risk) or at either Chr1 (Chr1-risk) or Chr10 (Chr10-risk) and who had enrolled in Genetic and Molecular Studies of Eye Diseases at the Sharon Eccles Steele Center for Translational Medicine between September 2009 and March 2020. Multimodal imaging data were reviewed for AMD staging, including grading of incomplete and complete retinal pigment epithelium and outer retinal atrophy., Main Outcomes and Measures: Hazard ratios and survival times for conversion to any late-stage AMD, atrophic or neovascular, and associated vision loss of 2 or more lines., Results: In total, 317 participants in the Chr1-risk group (median [IQR] age at first visit, 75.6 [69.5-81.7] years; 193 women [60.9%]), 93 participants in the Chr10-risk group (median [IQR] age at first visit, 77.5 [72.2-84.2] years; 62 women [66.7%]), and 92 participants in the Chr1&10-risk group (median [IQR] age at first visit, 71.7 [68.0-76.3] years; 62 women [67.4%]) were included in the analyses. After adjusting for age and AMD grade at first visit, compared with 257 participants in the Chr1-risk group, 56 participants in the Chr1&10-risk group (factor of 3.3 [95% CI, 1.6-6.8]; P < .001) and 58 participants in the Chr10-risk group (factor of 2.6 [95% CI, 1.3-5.2]; P = .007) were more likely to convert to a late-stage phenotype during follow-up. This difference was mostly associated with conversion to macular neovascularization, which occurred earlier in participants with Chr1&10-risk and Chr10-risk. Eyes in the Chr1&10-risk group (median [IQR] survival, 5.7 [2.1-11.1] years) were 2.1 (95% CI, 1.1-3.9; P = .03) times as likely and eyes in the Chr10-risk group (median [IQR] survival, 6.3 [2.7-11.3] years) were 1.8 (95% CI, 1.0-3.1; P = .05) times as likely to experience a visual acuity loss of 2 or more lines compared with eyes of the Chr1-risk group (median [IQR] survival, 9.4 [4.1-* (asterisk indicates event rate did not reach 75%)] years)., Conclusions and Relevance: These findings suggest differential associations of the 2 major AMD-related risk loci with structural and functional disease progression and suggest distinct underlying biological mechanisms associated with these 2 loci. These genotype-phenotype associations may warrant consideration when designing and interpreting AMD research studies and clinical trials.

Aims: The aim of the study was to evaluate the feasibility of ultra-widefield (UWF) imaging to identify ocular pathologies amongst in- and out-patients in a tertiary university hospital., Methods: We followed a prospective double-blinded multicenter clinical study. In total, 634 patients from a university hospital with pulmonary, cardiovascular, and endocrine diseases were examined by two teams by conventional slit-lamp biomicroscopy (CBM). UWF images with Optos Tx200 were taken and subsequently graded independently by two retina specialists and graders from two reading centers for the presence of pre-defined pathologies. Interrater reliability was calculated using Fleiss statistical software. An independent, trained and certified ophthalmologist with retinal subspecialty (BL) classified all UWF images with retinal hemorrhages by severity and interrater agreement., Results: Complete data were available for 502 patients. The Moorfields Eye Hospital Reading Center, London, UK (RM), reported the highest number of cases with retinal pathologies (378), and the Reading Center GRADE Bonn, Germany (RB), did so for cases with optic disc cupping (466). Two retinal consultants (R1 and R2) from the Department of Ophthalmology, University Hospital Giessen and Marburg GmbH, Campus Giessen, Germany, noted optic disc pathologies. R1 reported 151 cases with optic disc pallor, while R2 reported only 39 disc pathologies. Both for clinical and for image readers, the early changes had equally low interrater reliability. The presence of at least 3 retinal hemorrhages had the highest interrater reliability (0.59)., Conclusions: UWF imaging is convenient to identify overt retinal pathologies in patients at risk of ocular complications of their systemic disease who are attending hospital clinics. Imaging the eye allows for remote retinal assessment and for placing the patient into the appropriate clinical pathway for ophthalmology., Precis: UWF-imaging in a population of in- and out-patients at a university hospital who are at risk of retinal complications is effective to detect overt retinal pathologies and allows for tele-ophthalmology approaches to be enabled for placing the patients into the appropriate clinical pathways., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

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

Purpose: This trial was conducted to investigate the clinical equivalence of the proposed biosimilar FYB201 and reference ranibizumab in patients with treatment-naive, subfoveal choroidal neovascularization caused by neovascular age-related macular degeneration (nAMD)., Design: This was a prospective, multicenter, evaluation-masked, parallel-group, 48-week, phase III randomized study., Participants: A total of 477 patients were randomly assigned to receive FYB201 (n = 238) or reference ranibizumab (n = 239)., Methods: Patients received FYB201 or reference ranibizumab 0.5 mg by intravitreal (IVT) injection in the study eye every 4 weeks., Main Outcome Measures: The primary end point was change from baseline in best-corrected visual acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 8 weeks before the third monthly IVT injection. Biosimilarity of FYB201 to its originator was assessed via a 2-sided equivalence test, with an equivalence margin in BCVA of 3 ETDRS letters., Results: The BCVA improved in both groups, with a mean improvement of +5.1 (FYB201) and +5.6 (reference ranibizumab) ETDRS letters at week 8. The analysis of covariance (ANCOVA) least squares mean difference for the change from baseline between FYB201 and reference ranibizumab was -0.4 ETDRS letters with a 90% confidence interval (CI) of -1.6 to 0.9. Primary end point was met as the 90% CI was within the predefined equivalence margin. Adverse events were comparable between treatment groups., Conclusions: FYB201 is biosimilar to reference ranibizumab in terms of clinical efficacy and ocular and systemic safety in the treatment of patients with nAMD., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: Pathological angiogenesis is a hallmark of various diseases characterized by local hypoxia and inflammation. These disorders can be treated with inhibitors of angiogenesis, but current compounds display a variety of side effects and lose efficacy over time. This makes the identification of novel signaling pathways and pharmacological targets involved in angiogenesis a top priority. Approach and Results: Here, we show that inactivation of FAAH (fatty acid amide hydrolase), the enzyme responsible for degradation of the endocannabinoid anandamide, strongly impairs angiogenesis in vitro and in vivo. Both, the pharmacological FAAH inhibitor URB597 and anandamide induce downregulation of gene sets for cell cycle progression and DNA replication in endothelial cells. This is underscored by cell biological experiments, in which both compounds inhibit proliferation and migration and evoke cell cycle exit of endothelial cells. This prominent antiangiogenic effect is also of pathophysiological relevance in vivo, as laser-induced choroidal neovascularization in the eye of FAAH -/- mice is strongly reduced., Conclusions: Thus, elevation of endogenous anandamide levels by FAAH inhibition represents a novel antiangiogenic mechanism.

Importance: As a disabling and frequent disease, geographic atrophy secondary to age-related macular degeneration (AMD) constitutes an important study subject. Emerging clinical trials require suitable end points. The characterization and validation of reading performance as a functional outcome parameter is warranted., Objective: To prospectively evaluate reading performance in geographic atrophy and to assess its association with established visual function assessments and structural biomarkers., Design, Setting, and Participants: The noninterventional, prospective natural history Directional Spread in Geographic Atrophy study included patients with geographic atrophy secondary to AMD who were recruited at the University Hospital in Bonn, Germany. Participants were enrolled from June 2013 to June 2016. Analysis began December 2019 and ended January 2021., Main Outcomes and Measures: Reading acuity and reading speed were assessed using Radner charts. Longitudinal fundus autofluorescence and infrared reflectance images were semiautomatically annotated for geographic atrophy, followed by extraction of shape-descriptive variables. Linear mixed-effects models were applied to investigate the association of those variables with reading performance., Results: A total of 150 eyes of 85 participants were included in this study (median [IQR] age, 77.9 [72.4-82.1] years; 51 women [60%]; 34 men [40%]). Reading performance was impaired with a median (IQR) monocular reading acuity of 0.9 (0.4-1.3) logarithm of the reading acuity determination and a reading speed of 52.8 (0-123) words per minute. In the multivariable cross-sectional analysis, best-corrected visual acuity, area of geographic atrophy in the central Early Treatment Diabetic Retinopathy Study (ETDRS) subfield, classification of noncenter vs center-involving geographic atrophy, and area of geographic atrophy in the inner-right ETDRS subfield showed strongest associations with reading acuity (cross-validated R2for reading acuity = 0.69). Regarding reading speed, the most relevant variables were best-corrected visual acuity, low-luminance visual acuity, area of geographic atrophy in the central ETDRS subfield, in the inner-right ETDRS subfield, and in the inner-upper ETDRS subfield (R2 for reading speed = 0.67). In the longitudinal analysis, a similar prediction accuracy for reading performance was determined (R2 for reading acuity = 0.73; R2 for reading speed = 0.70). Prediction accuracy did not improve when follow-up time was added as an independent variable. Binocular reading performance did not differ from reading performance in the better-seeing eye., Conclusions and Relevance: The association of reading acuity and speed with visual functional and structural biomarkers supports the validity of reading performance as a meaningful end point in clinical trials. These findings suggest that measures in clinical and low-vision care for patients with geographic atrophy should focus primarily on the better-seeing eye.