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Colin S Tan,1,2 Wei Kiong Ngo,1,2 Isaac W Chay,1,2 Dominic S Ting,1,2 SriniVas R Sadda3 1National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore; 2Fundus Image Reading Centre, National Healthcare Group Eye Institute, Singapore; 3Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, CA, USACorrespondence: SriniVas R Sadda, Doheny Image Reading Center, Doheny Eye Institute, 3623, 1450 San Pablo Street, Los Angeles, CA, 90033, USA, Email sadda@usc.eduAbstract: Neovascular age-related macular degeneration (nAMD) is a common world-wide cause of visual loss. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents are an effective means to treat nAMD and reduce its impact on vision compared to either sham treatment or photodynamic therapy. Currently, the approved anti-VEGF drugs include ranibizumab, aflibercept and brolucizumab. In addition, bevacizumab, used as an off-label drug, and has been shown to be effective in treating nAMD. While anti-VEGF agents are effective, its limitations include the requirement for frequent, often monthly injections, and the need for long-term treatment of nAMD. These present significant burdens on the healthcare system and on the patients. In addition, reviews of patients with nAMD treated with anti-VEGF have reported deterioration of vision over time with progression of geographic atrophy. These limitations are partly addressed by exploring different treatment regimens that reduce the frequency of treatments. Newer anti-VEGF drugs have been shown in Phase III clinical trials to have injection intervals as long as 12 or even 16 weeks for a proportion of patients. There is research on newer drugs that affect other pathways, such as the angiopoietin pathway, which may impact nAMD by extending the treatment interval and reducing the burden of treatment. Other measures include the use of sustained-release implants that release the drug regularly over a period of time, and can be refilled periodically, as well as hydrogel platforms that serve to release the drug. The use of biosimilars will also serve to reduce the cost of treatment for nAMD. A new frontier of gene therapy, primarily targeting genes involved in the transduction of retinal cells to produce anti-VEGF proteins intraocularly, also opens a new avenue of therapeutic approaches that can be used for treatment. This review paper will discuss both current treatment options and the newer treatments under development.Keywords: neovascular AMD, anti-VEGF, retina, gene therapy

Aditya Verma,1,2 Tommaso Bacci,3,4 David Sarraf,5 K Bailey Freund,3,4 SriniVas R Sadda1,2 1Doheny Eye Institute, Los Angeles, CA, USA; 2Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 3Vitreous Retina Macula Consultants of New York, New York, NY, USA; 4Department of Ophthalmology, New York University Grossman School of Medicine, New York, NY, USA; 5Stein Eye Institute, David Geffen School of Medicine at University of California, Los Angeles, CA, 90095, USACorrespondence: SriniVas R Sadda Email SSadda@doheny.orgAbstract: This review article summarizes the patho-anatomy of the vortex veins, the major drainage channels for the choroid, and describes the various pathways of diseases associated with vortex vein abnormalities. This report also details the technical advancements to image the vortex veins, such as ultra-widefield indocyanine green angiography, which are critical to elucidate the importance of the vortices in various retino-choroidal disorders. Future applications of these advanced imaging systems to better understand the role of the vortex veins in health and disease are also discussed.Keywords: choroid, optical coherence tomography angiography, pachychoroid disease, ultra-widefield imaging, vortex veins

Colin S Tan,1,2 SriniVas R Sadda3 1National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore; 2Fundus Image Reading Center, National Healthcare Group Eye Institute, Singapore; 3Doheny Eye Institute, University of California Los Angeles, CA, USA Abstract: Myopic choroidal neovascularization (CNV) is a sight-threatening condition which occurs in eyes with myopia, particularly in those with pathologic myopia. It is the most common cause of CNV among patients younger than 50 years. Hemorrhage and exudation from the CNV lesion may eventually result in scarring or chorioretinal atrophy. While myopic CNV was previously treated with focal laser photocoagulation or photodynamic therapy (PDT), the current treatment of choice is anti-vascular endothelial growth factor (VEGF) agents. Many studies have demonstrated the efficacy of intravitreal anti-VEGF agents in the treatment of myopic CNV. The RADIANCE study reported that intravitreal ranibizumab was superior to PDT in eyes with myopic CNV (at 3 months, both groups receiving intravitreal ranibizumab gained 10.5 and 10.6 letters vs 2.2 letters among patients receiving PDT). In addition, the study demonstrated similar visual outcomes in eyes treated on the basis of visual acuity stabilization or disease activity criteria. Other clinical studies have provided evidence for the efficacy of ranibizumab and aflibercept in the treatment of myopic CNV. This review addresses the epidemiology, pathophysiology, and imaging characteristics of myopic CNV, and discusses the evidence for the efficacy of anti-VEGF agents as compared to laser photocoagulation and PDT. Keywords: myopic choroidal neovascularization, ranibizumab, anti-vascular endothelial growth factor

Elias Reichel,1 Glenn J Jaffe,2 Srinivas R Sadda,3 Stefanie Schuman,2 Amir H Hariri,3 Keegan Skidmore,1 Jake Duker1 1Department of Ophthalmology, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, 2Duke Eye Center, Duke Reading Center, Durham, NC, 3Department of Ophthalmology, Doheny Eye Centers, University of California, Los Angeles, CA, USA Purpose: The aims of this study were to determine the prevalence of vitreomacular adhesion (VMA) in a random sample of clinical patients at three US retina clinics and to assess comorbid retinal conditions, ocular diseases, prior treatment history, and other medical histories. Patients and methods: This observational, retrospective cohort study was based on patients from the Doheny Eye Centers, Duke Eye Center, and Tufts Medical Center who received a bilateral spectral domain optical coherence tomography (SD-OCT) scan (one scan/eye) for clinical evaluation with available medical records. The study had three phases: 1) collection of retrospective patient data; 2) review of OCT scans at a reading center to assess VMA and associated conditions; and 3) analyses and reporting of data on the prevalence of VMA, patient demographics, and comorbid conditions. Data were obtained from electronic health records and OCT grading forms. Outcome measures from bilateral SD-OCT scans and medical records included OCT evaluation of VMA and retinal comorbid conditions. Results: In 719 patients with 1,483 reviewable OCT scans, the prevalence of VMA was estimated at 14.74% (90% CI, 12.58%–16.92%). The prevalence of unilateral VMA was estimated at 12.39%, while bilateral VMA was 2.36%. In patients with VMA, 34 out of 123 eyes with VMA (27.64%) also had fovea deformed by vitreomacular traction. Macular hole (MH) was significantly more prevalent in VMA-diagnosed eyes versus non-VMA-diagnosed eyes (6.5% versus 1.9%; P=0.02). There was a significantly higher incidence of full-thickness MH (P=0.008), operculum/flaps (P

Michael A Singer,1 Colin S Tan,2 Krishna R Surapaneni,3 Srinivas R Sadda4 1Medical Center Ophthalmology Associates, San Antonio, TX, USA; 2National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore; 3University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; 4Doheny Eye Institute, Los Angeles, CA, USA Introduction: Peripheral retinal ischemia not detectable by conventional fluorescein angiography has been proposed to be a driving force for rebound edema in retinal vein occlusions. In this report, we examine the treatment of peripheral retinal ischemia with targeted retinal photocoagulation (TRP) to manage a patient’s rebound edema.Methods: To assess the extent of peripheral nonperfusion, an Optos 200Tx device was used. To target the treatment to peripheral ischemia areas, a Navilas Panretinal Laser was used.Results: A 64-year-old male with a central retinal vein occlusion and a visual acuity 20/300, and central macular thickness 318 µm presented with rubeosis. Angiography revealed extensive peripheral nonperfusion. Despite TRP to areas of irreversible ischemia, after 2 months, he continued show rubeosis and rebound edema. Additional TRP laser was repeatedly added more posteriorly to areas of reversible nonperfusion, resulting in eventual resolution of rubeosis and edema.Conclusion: In this study, we demonstrate the use of widefield imaging with targeted photocoagulation of peripheral ischemia to treat rebound edema, while preserving most peripheral vision. In order to treat rebound edema, extensive TRP, across reversible and nonreversible areas of ischemia, had to be performed – not just in areas of nonreversible peripheral ischemia. These areas need to be mapped during episodes of rebound edema, when ischemia is at its maximum. In this way, by doing the most TRP possible, the cycle of rebound edema can be broken. Keywords: macular edema, retinal vein occlusion

Pearse A Keane1, Srinivas R Sadda21NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK; 2Doheny Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USAAbstract: Retinal vein occlusions (RVOs) constitute the second most common cause of retinal vascular disease after diabetic retinopathy, with a prevalence of between 1% and 2% in persons older than 40 years of age. Despite the existence of numerous potential therapeutic options, none is entirely satisfactory, and many patients with RVO suffer irreversible visual loss. Fortunately however, the recent introduction of antivascular endothelial growth factor (VEGF) agents, such as ranibizumab (Lucentis®, Genentech, South San Francisco, CA) and bevacizumab (Avastin®, Genentech), offers a potentially new treatment approach for clinicians managing this disorder. The results of the BRAVO and CRUISE trials have provided the first definitive evidence for the efficacy and safety of ranibizumab in the treatment of RVO. As a result, ranibizumab has recently been approved by the US Food and Drug Administration for the treatment of RVO-associated macular edema. In this review, we provide a critical evaluation of clinical trial data for the safety and efficacy of ranibizumab, and address unresolved issues in the management of this disorder. Keywords: ranibizumab, retinal vein occlusion, vascular endothelial growth factor, macular edema

The aim of this study was to determine whether retinal progenitor layer transplants form synaptic connections with the host and restore vision. Donor retinal sheets, isolated from embryonic day 19 rat fetuses expressing human placental alkaline phosphatase (hPAP), were transplanted to the subretinal space of 18 S334ter-3 rats with fast retinal degeneration at the age of 0.8-1.3 months. Recipients were killed at the age of 1.6-11.8 months. Frozen sections were analysed by confocal immunohistochemistry for the donor cell label hPAP and synaptic markers. Vibratome slices were stained for hPAP, and processed for electron microscopy. Visual responses were recorded by electrophysiology from the superior colliculus (SC) in 12 rats at the age of 5.3-11.8 months. All recorded transplanted rats had restored or preserved visual responses in the SC corresponding to the transplant location in the retina, with thresholds between -2.8 and -3.4 log cd/m(2). No such responses were found in age-matched S334ter-3 rats without transplants, or in those with sham surgery. Donor cells and processes were identified in the host by light and electron microscopy. Transplant processes penetrated the inner host retina in spite of occasional glial barriers between transplant and host. Labeled neuronal processes were found in the host inner plexiform layer, and formed apparent synapses with unlabeled cells, presumably of host origin. In conclusion, synaptic connections between graft and host cells, together with visual responses from corresponding locations in the brain, support the hypothesis that functional connections develop following transplantation of retinal layers into rodent models of retinal degeneration.

PurposeTo correlate the functional outcomes with histologic findings following transplantation of fetal retinal sheets in rd mice, and to investigate the mechanisms of visual function restoration.MethodsTwenty-one postnatal day 31-38 rd/rd (C3H/HeJ) mice were transplanted in one eye with retinal sheets (1.0 x 0.4 mm) obtained from embryonic day (E) 17 enhanced-green-fluorescent protein (eGFP) mice. Five mice underwent sham surgery without insertion of tissue. Four to five weeks after transplantation, visual responses to a light flash were recorded across the superior colliculus (SC) in seven eyes of seven transplanted mice that had clear corneas and lenses, and in all five sham surgery mice. Following the SC recording, the eyes were enucleated and processed for immunohistochemistry and examined using confocal microscopy.ResultsIn three out of the seven eyes (43%), positive responses were recorded in the SC in an area topographically corresponding to the placement of the transplant in the host retina. No responses were recorded in the untreated eyes of 5-week-old and 9-week-old rd/rd mice, and in the 9-week-old sham surgery mice. In contrast, visual responses were recorded over the entire SC in normal eyes. The response onset latencies of the 3 transplanted mice with responses were similar to those of normal control mice. The organization of the graft did not appear to correlate as expected with the electrophysiology results, as eyes with well-organized, laminated grafts showed no response whereas the three light-responsive eyes had rosetted or disorganized grafts. All three light-responsive eyes demonstrated much higher levels of recoverin immunoreactivity in the host retina overlying the graft compared with untreated age-matched rd/rd mice.ConclusionRestoration of the SC visual response does not appear to depend on a well-organized transplant in the rd mouse. Increased recoverin-staining in the host retina in light-responsive animals suggested that host cone rescue was the likely mechanism of vision restoration in this transplant model.

PurposeTo investigate different in vitro model systems for retinal progenitor cell (RPC) isolation and expansion.MethodsRPCs were isolated from embryonic day (E) 17 Long Evans rat retinas. Three different culture media: (1) modified serum free defined media (2) serum-containing media and (3) embryonic stem cell (ES)-conditioned media were used for RPC isolation and long term expansion. Expression of various cellular markers and cell morphologies were compared among the three culture systems at different passages by immunostaining and confocal microscopy.ResultsAll three culture systems could maintain RPCs as nestin-positive cells (78-87%) after long-term in vitro expansion. However, RPCs appeared to proliferate faster in the serum-free culture system. The ES-conditioned media provided the best RPC survival. Cells appeared smaller at early passages compared with later passages. This morphology change occurred at P9-P10 in the serum-free medium, and at P5-P6 in the other two culture systems.ConclusionsThe serum-free medium may be superior for preventing RPC differentiation during expansion.

Purpose: To report improvement in cystoid macular edema from central retinal vein occlusion with one injection of ranibizumab after failure with seven injections of bevacizumab. Methods: Case report. Results: A 74-year-old female developed persistent blurred vision for three months. Ocular examination revealed macular edema secondary to nonischemic central retinal vein occlusion. The patient was treated with intravitreal bevacizumab (1.25 mg in 0.05 mL). She received seven injections (every 5-6 weeks). Vision fluctuated between 20/30 and 20/60 with minimal variation in central foveal thickness (449-574 [mu]m). However, weeks after one injection of ranibizumab the patient's vision improved to 20/20 with near resolution of macular edema (CFT = 343 [mu]m). Conclusions: Patients with no response to bevacizumab injections can show a rapid and large improvement with ranibizumab. This underscores the important differences between these two medications. Further study is required to determine if these initial effects of ranibizumab can be maintained. [ABSTRACT FROM AUTHOR]

Purpose: Determine rates of progression of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) to complete retinal pigment epithelium and outer retinal atrophy (cRORA) and rates of progression of drusen to iRORA/cRORA in eyes with geographic atrophy (GA) treated with avacincaptad pegol (ACP)., Methods: Post hoc analysis of the GATHER1 prospective, randomized, double-masked Phase II/III study that evaluated ACP 2 mg vs. sham. Optical coherence tomography (OCT) data from GATHER1 were transferred to the Doheny Image Reading and Research Lab for masked analysis by readers experienced with Classification of Atrophy Meeting (CAM) grading features. Regions of OCT volume scans more than 500 µm from the border of GA lesions were evaluated at baseline and at months 6, 12, and 18. Participants with iRORA and/or drusen (≥ 40 µm height on OCT) at baseline were included in the analysis., Results: The proportion of eyes progressing from iRORA to cRORA in the ACP 2 mg group was 5.0%, 15.0%, and 20.0% at months 6, 12, and 18 respectively, as compared with 11.8%, 30.2%, and 41.8% of eyes in the sham group. The proportion of ACP 2 mg-treated eyes progressing from drusen to iRORA or cRORA was 3.8%, 7.6%, and 7.6% at months 6, 12, and 18 compared with 15.9%, 18.1%, and 27.2% of sham-treated eyes., Conclusions: Rates of progression from iRORA to cRORA and drusen to iRORA/cRORA were reduced in eyes treated with ACP 2 mg vs. sham, with increasing separation between groups over time, suggesting early intervention may slow disease progression., Trial Registration: ClinicalTrials.gov identifier: NCT02686658. Date of registration: February 16, 2016., Key Messages: What is known Geographic atrophy is an advanced form of age-related macular degeneration (AMD) that leads to irreversible vision loss, presenting a significant public health unmet need. The Classification of Atrophy Meeting (CAM) group recommended a new nomenclature for advanced AMD lesions, based on the affected anatomical layers on optical coherence tomography. Accordingly, the terms incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) and complete retinal pigment epithelium and outer retinal atrophy (cRORA) were introduced (Guymer et al., Ophthalmology 127:394-409, 2020; Sadda et al., Ophthalmology 125:537-548, 2018). What is new GATHER1 post hoc analysis shows that treatment with avacincaptad pegol (ACP) 2 mg decreases the proportion of eyes that progress from iRORA to cRORA, and from drusen to iRORA or cRORA, compared with sham, over 6, 12, and 18 months. These findings suggest a potential role for ACP in delaying the progression of existing pre-atrophic AMD lesions., Competing Interests: Declarations Ethics approval The GATHER1 trial was performed in accordance with the tenets of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines [13]. The appropriate ethics committee or institutional review board at each study center involved in the study (80 centers) approved the protocol [13]. Consent to participate Written informed consent was obtained from all participants [13]. Disclosure statement SriniVas R Sadda- although the author is the editor of the journal, there was no involvement with the peer review process for this article. Competing interests GC has received lecture fees from Nidek. AK, SS, SL, SBV, FC, YA, and MGN have no financial disclosures. SR Sadda has consulted/advised for: Apellis Pharmaceuticals, Inc.; Amgen Inc.; AbbVie/Allergan, Inc.; Samsung Bioepis; Biogen; Boehringer Ingelheim; Iveric Bio; Novartis; Roche/Genentech; Bayer Healthcare Pharmaceuticals; Regeneron Pharmaceuticals, Inc.; Pfizer Inc.; Astellas; Nanoscope Therapeutics; Janssen Pharmaceuticals, Inc.; CenterVue, Inc.; Optos, Inc.; and Heidelberg Engineering; has received lecture fees/speakers bureau fees from: Heidelberg Engineering; Roche/Genentech; Novartis; and Optos, Inc.; and has received research equipment from: CenterVue, Inc.; Optos, Inc.; Carl Zeiss Meditec; Topcon Medical Systems, Inc.; Heidelberg Engineering; and Nidek Inc. SR Sadda, the corresponding author, is an editor of the journal; however, there was no involvement with the peer review process for this article. DD and LZ are former employees of Astellas, and DA is an employee of Astellas., (© 2024. The Author(s).)

Purpose: To study intravitreal brolucizumab in the management of persistent macular fluid in chronic central serous chorioretinopathy (CSCR) without choroidal neovascular membrane (CNVM)., Methods: Retrospective case series which included eyes with chronic CSCR with persistent macular fluid for ≥ 3 months without CNVM. Intravitreal brolucizumab was administered in all eyes. Primary outcome measure was the resolution of intraretinal (IRF) and/or subretinal fluid (SRF) on OCT., Results: Five eyes (four patients) with chronic CSCR were included. All eyes showed complete resolution of SRF 1 month following injection. Minimal residual IRF was present in two eyes. Best corrected visual acuity (BCVA) was stable in three eyes, and two eyes showed improvement. Central macular thickness (CMT) and subfoveal choroidal thickness (SFCT) showed reduction., Conclusion: Intravitreal brolucizumab is effective in the rapid reduction of persistent macular fluid in chronic CSCR without CNVM. Long-term follow-up data are required to study recurrence and adverse effect profile.

Background/Objectives : To evaluate the clinical performance of two optical coherence tomography angiography (OCTA) devices, including a semi-automated device, with respect to image quality and pathology detection, with fluorescein angiography (FA) and indocyanine green angiography (ICGA) serving as the reference standards. Methods : In this prospective cross-sectional study, normal eyes and those with various retinal and choroidal pathologies were enrolled and underwent OCTA scanning using semi-automated 3D OCT-1 Maestro2 and Cirrus™ HD-OCT 5000 devices, as well as FA/ICGA imaging. OCTA scans and FA/ICGA images were independently graded for image quality and the visibility of prespecified anatomic vascular features, along with the presence or absence of pathology on the OCTA scans and the FA/ICGA images (within regions corresponding to the OCTA scan areas). Positive percent agreement (PPA), defined as the proportion of eyes in which the OCTA demonstrated pathology when the corresponding FA/ICGA showed pathology, and negative percent agreement (NPA), defined as the proportion of eyes in which the OCTA showed no pathology when the FA/ICGA also showed no pathology, were calculated. Results : In total, 38 normal eyes and 86 pathologic eyes were enrolled in the study. The majority of images for both devices were considered clinically useful. The PPA and NPA were high for both devices, indicating a good ability to identify disease when present and to rule it out when not present. Conclusions : The findings of this study suggest that the semi-automated Maestro2 and Cirrus have comparably good clinical performance, particularly with regard to accuracy when identifying vascular pathologies.

Background/objectives: To characterise morphological changes in neovascular age-related macular degeneration (nAMD) during anti-angiogenic therapy and explore relationships with best-corrected visual acuity (BCVA) and development of macular atrophy (MA)., Subjects/methods: Post-hoc analysis of the phase III HARBOR trial. SD-OCT scans from 1097 treatment-naïve nAMD eyes were analysed. Volumes of intraretinal cystoid fluid (ICF), subretinal hyperreflective material (SHRM), subretinal fluid (SRF), pigment epithelial detachment (PED) and cyst-free retinal volume (CFRV) were measured by deep-learning model. Volumes were analysed by treatment regimen, macular neovascularisation (MNV) subtypes and topographic location. Associations of volumetric features with BCVA and MA development were quantified at month 12/24., Results: Differences in feature volume changes by treatment regimens and MNV subtypes were observed. Each additional 100 nanolitre unit (AHNU) of residual ICF, SHRM and CFRV at month 1 in the fovea was associated with deficits of 10.3, 7.3 and 12.2 letters at month 12. Baseline AHNUs of ICF, CFRV and PED were associated with increased odds of MA development at month 12 by 10%, 4% and 3%. While that of SRF was associated with a decrease in odds of 5%. Associations at month 24 were similar to those at month 12., Conclusion: Eyes with different MNV subtypes showed distinct trajectories of feature volume response to treatment. Higher baseline volumes of ICF or PED and lower baseline volume of SRF were associated with higher likelihoods of MA development over 24 months. Residual intraretinal fluid, including ICF and CFRV, along with SHRM were predictors of poor visual outcomes., (© 2024. The Author(s).)

The application of machine learning to tasks involving volumetric biomedical imaging is constrained by the limited availability of annotated datasets of three-dimensional (3D) scans for model training. Here we report a deep-learning model pre-trained on 2D scans (for which annotated data are relatively abundant) that accurately predicts disease-risk factors from 3D medical-scan modalities. The model, which we named SLIViT (for 'slice integration by vision transformer'), preprocesses a given volumetric scan into 2D images, extracts their feature map and integrates it into a single prediction. We evaluated the model in eight different learning tasks, including classification and regression for six datasets involving four volumetric imaging modalities (computed tomography, magnetic resonance imaging, optical coherence tomography and ultrasound). SLIViT consistently outperformed domain-specific state-of-the-art models and was typically as accurate as clinical specialists who had spent considerable time manually annotating the analysed scans. Automating diagnosis tasks involving volumetric scans may save valuable clinician hours, reduce data acquisition costs and duration, and help expedite medical research and clinical applications., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: The goal of this study was to evaluate and compare the intermodality and interreader agreement of manual and semiautomated geographic atrophy (GA) area measurements in eyes with GA due to age-related macular degeneration (AMD) using conventional blue-light fundus autofluorescence (FAF) and ultrawidefield (UWF) green-light FAF systems., Design: Prospective Cohort Study., Subjects: Seventy-two eyes of 50 patients with a diagnosis of advanced nonneovascular AMD with GA., Methods: Fundus autofluorescence images of eyes with GA were obtained during a single visit using both the Spectralis HRA + OCT2 device and the Optos California device. The area of the GA lesion(s) was segmented and quantified (mm 2 ) with a fully manual approach where the lesions were outlined using Optos Advance and Heidelberg Eye Explorer (HEYEX) software. In addition, for the Heidelberg blue FAF images, GA lesions were also measured using the instrument's semiautomated software (Region Finder 2.6.4). For comparison between modalities/grading method, the mean values of the 2 graders were used. Intraclass correlation coefficients were computed to judge the agreement between graders., Results: Seventy-two eyes of 50 patients were included in this study. There was nearly perfect agreement between graders for the measurement of GA area for all 3 modalities (intraclass correlation coefficient: 0.996 for manual Optos Advance, 0.996 for manual Heidelberg HEYEX, and 0.995 for Heidelberg Region Finder). The measurement of GA area was strongly correlated between modalities, with Spearman correlation coefficients of 0.985 (P < 0.001) between manual Heidelberg and manual Optos, 0.991 (P < 0.001) for Region Finder versus manual Heidelberg, and 0.985 (P < 0.001) for Region Finder versus manual Optos. The absolute mean area differences between the Heidelberg manual versus Region Finder, manual Optos versus Region Finder, and manual Optos versus manual Heidelberg were 1.61 mm 2 (P < 0.001), 0.90 mm 2 (P < 0.006), and 0.71 mm 2 (P < 0.001), respectively., Conclusions: We observed excellent interreader agreement for measurement of GA using either 30-degree blue-light FAF or UWF green-light FAF, establishing the reliability of UWF imaging for macular GA assessment. Although the absolute measurements between devices were strongly correlated, they differed significantly, highlighting the importance of using the same device for a given patient for the duration of a study., 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.)

Modern mediation analysis techniques supplement the primary intention-to-treat analysis with the aim to shed light onto the treatment mechanism. We investigate to what extent the anatomic marker vitreomacular adhesion resolution (VMAR) mediates vision benefits, comparing ocriplasmin vs. a sham regimen. A causal mediation analysis is applied to randomized trial data including 218 participants with vitreomacular traction. Logistic regression models are used to estimate the total treatment effect (TTE) on binary outcomes. Outcomes, assessed at month 24, included visual acuity improvement (VA-I): ≥2-line increase in VA; visual function questionnaire improvement (VFQ-I): ≥5-point increase in the 25-item visual function questionnaire composite score (VFQ-25cs); visual function improvement (VF-I): defined as either a VA-I or a clinically meaningful improvement in the VFQ-25cs. Quantity of interest is the breakdown of TTE into an indirect (through VMAR) and direct effect to estimate the extent to which the TTE is transmitted through the mediating variable (VMAR) vs. other pathways. Causal effects are expressed as risk differences. Indirect effects for VFQ-I, VA-I, and VF-I are 5.7%, 11.8%, and 5.2%, respectively, representing the increase in the probability of a vision improvement if VMAR status were changed for each participant to the extent that it is affected by ocriplasmin. The direct effects are 8.3%, 12.1%, and 24.1% respectively, capturing the effect of treatment on the probability of a vision improvement if ocriplasmin left each participant's VMAR status unchanged. The relative treatment effect of ocriplasmin on the functional outcome VA-I is to a large extent the result of its effect on VMAR, while an improvement in the patient-reported outcomes VFQ-I or VF-I was only partially mediated by VMAR., Competing Interests: Conflicts of InterestThe authors declare the following conflicts of interest: BL reports the following: Consultant: Oxurion; Regenxbio. SV reports the following: Consultant: Janssen Pharmaceuticals; Novo Nordisk. Lecture Fees/Speakers Bureau: Janssen Pharmaceuticals; Grants/contracts: GSK. TLJ reports the following: Consultant: DORC, Alcon, iLumen, Opthea, Outlook Therapeutics, 2CTech; Expert testimony: Allan & Overy; Meetings and/or travel support: Roche: Equipment, drugs: LKC, Zeiss, Bayer. Research contracts: Oxurion; Misc commercial retinal trials. SVS reports the following: Consultant/Advisor: 4DMT, Alexion, Allergan, Inc., Alnylam Pharmaceuticals, Amgen Inc., Apellis Pharmaceuticals, Inc., Astellas, Bayer Healthcare Pharmaceuticals, Biogen, Boerhinger Ingelheim, Carl Zeiss Meditec, Catalyst Pharmaceuticals Inc, Centervue, Inc., GENENTECH; Gyroscope Therapeutics, Heidelberg Engineering, Iveric Bio, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Nanoscope, Novartis Pharma AG, Optos, Inc., Oxurion/ Thrombogenics, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Samsung Bioepis, Vertex Pharmaceuticals Inc.; Lecture Fees/Speakers Bureau: Carl Zeiss Meditec, Heidelberg Engineering, Nidek Inc., Novartis Pharma AG, Topcon Medical Systems Inc.; Grant Support: Carl Zeiss Meditec, Heidelberg Engineering. LD reports the following: Consultant: Oxurion. Oxurion provided the individual-participant-level data. The sponsor had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (© 2024 by the authors.)

Objectives: To determine the associations between the presence of various-sized hypertransmission defects (hyperTDs) and progression to incomplete retinal pigment epithelial (RPE) and outer retinal atrophy (iRORA) and complete RORA (cRORA) in eyes with intermediate age-related macular degeneration (iAMD)., Methods: Optical coherence tomography (OCT) data from consecutive iAMD patients, were retrospectively reviewed. All of iAMD eyes with or without iRORA (but not cRORA) at baseline were included. Graders evaluated the presence of hyperTDs at baseline (small: 63-124 µm; medium: 125-249 µm; large: ≥ 250 µm in diameter on choroidal en face OCT) and the progression two years later., Results: Of the 145 eyes that not developed neovascular AMD at two years, the eyes that progressed to or developed iRORA or cRORA included 13 eyes (10.7%), 5 eyes (83.3%), 9 eyes (81.8%), and 6 eyes (85.7%) in the groups with no, small, medium, and large hyperTDs at baseline, respectively (P-value < 0.001). The odds ratios (95% CI) for progression were 41.6 (4.5-383.6), 37.4 (7.3-192.0), and 49.9 (5.6-447.1) in the small, medium, and large hyperTDs groups, compared to no hyperTDs (P-value ≤ 0.001). Eyes with ≥ 2 hyperTDs also showed more frequent progression than eyes with one or no hyperTDs (100% vs. 16.4%; P-value < 0.001)., Conclusions: While most iAMD eyes with no hyperTDs remained stable on OCT over two years, eyes with hyperTDs of any size appeared to be at a higher risk for progression. HyperTDs may provide an important OCT biomarker for identifying high-risk iAMD patients., (© 2024. The Author(s).)

Purpose: This study aims to define the characteristics of acquired vitelliform lesions (AVLs) in patients with intermediate age-related macular degeneration (iAMD)., Design: Retrospective, observational, cross sectional study., Subjects: This study included 217 eyes with AVLs associated with iAMD, and an equivalent number of control patients., Methods: OCT scans were evaluated for qualitative and quantitative parameters at both the eye and lesion level. Eye-level parameters included the presence of: hyporeflective core drusen, intraretinal hyperreflective foci (IHRF), subretinal drusenoid deposits, macular pachyvessels, central retinal thickness, and central choroidal thickness. Lesion-level qualitative parameters included the presence of ellipsoid zone (EZ) and external limiting membrane disruption overlying the AVL, IHRF overlying the AVL, AVL overlying drusen, pachyvessels under the AVL, a solid core within AVL, and AVL location. Lesion-level quantitative characteristics included AVL height and width, AVL distance from the fovea, and sub-AVL choroidal thickness., Main Outcome Measures: The primary outcomes assessed included the frequency of IHRF, the presence of macular pachyvessels, central choroidal thickness, and the dimensions (both height and width) of AVLs., Results: Comparing the AVL and control groups, the frequency of IHRF (AVL: 49.3% vs. control: 26.3%) and macular pachyvessels (37.3% vs. 6.9%) was significantly higher in the AVL case group, and the central choroidal thickness (256.8 ± 88 μm vs. 207.1± 45 μm) was thicker in the AVL group. Acquired vitelliform lesions located over drusen, with overlying IHRF, or situated subfoveally, and AVL lesions with EZ disruption were found to have a greater lesion height and width compared with AVL lesions lacking these characteristics (P value < 0.001 for all). Additionally, a significant negative correlation was observed between the distance from the fovea and AVL height (Spearman rho: -0.19, P = 0.002) and width (Spearman rho: -0.30, P = 0.001)., Conclusions: This study represents the largest reported cohort of AVL lesions associated with iAMD. Novel findings include the higher frequency of pachyvessels in addition to the presence of a thicker choroid in these eyes, as well as the greater height and width of AVL closer to the foveal center. These findings may offer insights into pathophysiologic mechanisms underlying the development of AVL., 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.)

Purpose: In this study, we identify risk factors that predict the progression of acquired vitelliform lesions (AVLs) over time., Design: Retrospective cohort study., Subjects: One hundred sixty-three eyes of 132 patients with a diagnosis of intermediate age-related macular degeneration (iAMD) with AVL., Methods: This retrospective study evaluated consecutive eyes with AMD from a retina clinic population and included 1181 patients and 2362 eyes. After excluding cases with associated geographic atrophy, macular neovascularization (MNV), vitreomacular traction, and those with <2 years of follow-up data, the final analysis cohort consisted of 163 eyes (132 patients) with ≥1 AVL. The first available visit in which an AVL was evident was considered the baseline visit, and follow-up data were collected from a visit 2 years (± 3 months) later. Progression outcomes at the follow-up visit were classified into 6 categories: resorbed, collapsed, MNV, stable, increasing, and decreasing. Subsequently, we analyzed the baseline characteristics for each category and calculated odds ratios (ORs) to predict these various outcomes., Main Outcome Measures: The study focused on identifying predictive factors influencing the evolution of AVL in iAMD eyes., Results: In total, 163 eyes with AVL had follow-up data at 2 years. The collapsed group demonstrated a significantly greater baseline AVL height and width compared with other groups (P < 0.001). With regard to qualitative parameters, subretinal drusenoid deposits (SDDs) and intraretinal hyperreflective foci (IHRF) at the eye level, AVL located over drusen, and IHRF and external limiting membrane disruption over AVL were significantly more prevalent in the collapsed group compared with other groups (P < 0.05 for all comparisons). Odds ratios for progressing to atrophy after 2 years of follow-up, compared with the resorbed group, were significant for SDD (OR, 2.82; P = 0.048) and AVL height (OR, 1.016; P = 0.006)., Conclusions: The presence of SDDs and greater AVL height significantly increases the risk of developing atrophy at the location of AVL after 2 years of follow-up. These findings may be of value in risk prognostication and defining patient populations for inclusion in future early intervention trials aimed at preventing progression to atrophy., Financial Disclosures: 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.)

Purpose: To compare the ganglion cell complex (GCC) thickness in eyes with age-related macular degeneration (AMD) vs healthy controls in an elderly Amish population., Design: Prospective cross-sectional study., Methods: This is a post hoc analysis of the family-based prospective study of Amish subjects. Study subjects underwent imaging with the Cirrus HD-OCT (Carl Zeiss Meditec Inc) using a macular cube protocol of 512 × 128 scans (128 horizontal B-scans, each comprising 512 A-scans) over a 6 mm × 6 mm region centered on the fovea. The ganglion cell analysis algorithm calculated the GCC thickness by segmenting the outer boundaries of the retinal nerve fiber layer (RNFL) and inner plexiform layer (IPL) in all B-scans of the volume, with the region between these boundaries representing the combined thickness of the ganglion cell layer (GCL) and the IPL. A number of parameters were used to evaluate the GCC thickness: the average GCC thickness, minimum (lowest GCC thickness at a single meridian crossing the elliptical annulus), and sectoral (within each of 6 sectoral areas: superior, superotemporal, superonasal, inferior, inferonasal, and inferotemporal). The stage of AMD was graded on color fundus photographs in accordance with the Beckman Initiative for Macular Research classification system., Results: Of 1339 subjects enrolled in the Amish eye study, a total of 1294 eyes of 1294 subjects had all required imaging studies of sufficient quality and were included in the final analysis. Of these, 798 (62%) were female. Following age adjustment, the average GCC thickness was significantly (P < .001) thinner in AMD subjects (73.71 ± SD; 13.77 µm) compared to normals (77.97 ± 10.42 µm). An independent t test showed that the early AMD (75.03 ± 12.45 µm) and late AMD (61.64 ± 21.18 µm) groups (among which eyes with geographic atrophy [GA] had the lowest thickness, of 58.10 ± 20.27 µm) had a statistically significant lower GCC thickness compared to eyes without AMD. There was no significant differences in average GCC thickness between early AMD and intermediate AMD (76.36 ± 9.25 µm) eyes., Conclusions: The GCC thickness in AMD eyes is reduced compared to normal eyes; however, the relationship is complex, with the greatest reduction in late AMD eyes (particularly eyes with GA) but no difference between early and intermediate AMD eyes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To describe the outcomes from treatment of macular neovascularization in an eye affected by late-onset retinal degeneration., Methods: A 72-year-old female patient presented with a history of decreased vision since several years. The patient was previously diagnosed with age-related macular degeneration and treated with anti-vascular endothelial growth factors., Results: Clinical examination of the retina and ultra-widefield color fundus photographs showed extensive atrophy in both eyes. The left eye showed macular neovascularization on fluorescein angiography, subretinal fluid on optical coherence tomography, and correspondent hemorrhages on the color fundus photography. Aflibercept anti-vascular endothelial factor treatment was used to treat the macular neovascularization in the left eye., Conclusion: We report a case of genetically confirmed late-onset retinal degeneration (heterozygous pathogenic mutation p.Ser163Arg in one C1QTN5 allele) with advanced degeneration of the retina complicated by macular neovascularization, which responded well to treatment with a single aflibercept injection.

Aims: The aim of this study is to assess baseline characteristics of drusen preceding the development of intraretinal hyper-reflective foci (IHRF) in eyes with intermediate age-related macular degeneration (AMD)., Methods: In this retrospective case-control study, longitudinal optical coherence tomography (OCT) volume data from eyes with intermediate AMD in a retina clinic population were screened. All drusen that developed overlying IHRF were marked. A random number generator was used to select for further grading three drusen that did not develop IHRF., Results: Ninety eyes (from 72 patients), including 140 drusen with overlying IHRF and 270 IHRF- drusen, were analysed. Greater drusen height, basal drusen width and overlying ellipsoid zone (EZ) and external limiting membrane disruption were associated with a significantly greater risk for IHRF development (p≤0.001). Regression analysis revealed EZ disruption increased these odds by 4.1 (p≤0.001). Each 10-µm increase in drusen height and width increased the odds by 34% (p≤0.001) and 3% (p: 0.005), respectively. Each 100-µm increase in distance from the fovea decreased the odds by 10% (p: 0.013)., Conclusions: The presence of overlying EZ disruption and a greater drusen height substantially increased the risk for IHRF development, whereas drusen further from the fovea indicated reduced risk. Given the importance of IHRF as a biomarker for AMD progression, these findings may be of value in defining patient populations for future early intervention trials., Competing Interests: Competing interests: SriniVas R. Sadda receives support from 4DMT, Alexion, Allergan, Alnylam Pharmaceuticals, Amgen Inc Apellis Pharmaceuticals, Astellas, Bayer Healthcare Pharmaceuticals, Carl Zeiss Meditec, Catalyst Pharmaceuticals, Centervue, GENENTECH, Gyroscope Therapeutics, Heidelberg Engineering, Iveric Bio, Janssen Pharmaceuticals, Merck & Co., Nanoscope, Nidek Incorporated, Novartis Pharma AG, Optos, Oxurion/ Thrombogenics, Pfizer, Regeneron Pharmaceuticals, Samsung Bioepis, Topcon Medical Systems, Vertex Pharmaceuticals Incorporated. David Sarraf receives support from Amgen, Bayer, Endogena Therapeutics, Genentech, Iveric Bio, Novartis and Optovue/Visionix and receives research grants from Amgen, Boehringer, Genentech, Heidelberg, Optovue/Visionix, Regeneron, and Topcon. Charles C. Wykoff receives support from 4DMT, AbbVie, Adverum, Aerie, AGTC, Alcon, Alimera, Allergan, Allgenesis, Alnylam, Annexon, Apellis, Arrowhead, Bausch + Lomb, Bayer, Bionic Vision, Boehringer Ingelheim, Chengdu Kanghong, Cholgene, Clearside, Curacle, EyePoint, Foresite, Frontera, Genentech, Gyroscope, IACTA, IVERIC Bio, Janssen, Kato, Kiora, Kodiak, Kriya, Merck, Nanoscope, NGM, Notal Vision, Novartis, OccuRx, Ocular Therapeutix, Ocuterra, OliX, ONL, Opthea, Palatin, PerceiveBio, Perfuse, PolyPhotonix, Ray, RecensMedical, Regeneron, RegenXBio, Resonance, Roche, SciNeuro, Stealth, Surrozen, THEA, TissueGen, Valo, Verana, Vitranu. Grants from ongoing relationships as a Principal Investigator with: 4DMT, Adverum, Aerie, AffaMed, Aldeyra, Alexion, Alimera, Alkahest, Allergan, Allgenesis, Amgen, Annexin, Annexon, Apellis, Asclepix, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Curacle, EyePoint, Gemini, Genentech, Graybug Vision, Gyroscope, IONIS, iRENIX, IVERIC bio, Kodiak, LMRI, Nanoscope, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, Opthea, Oxurion, Oxular, Oyster Point, Perceive Biotherapeutics, RecensMedical, Regeneron, RegenXBio, Roche, SamChunDang Pharm, Sandoz, Taiwan Liposome Company, UNITY, Verily, Xbrane. Stock Options (not owner) from ongoing relationships as a Consultant from Private Companies: ONL, PolyPhotonix, RecensMedical, TissueGen, Visgenx, Vitranu. Giulia Corradetti receives support from Nidek. Muneeswar Gupta Nittala receives support from Eyenuk., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The purpose of this study was to quantitatively analyze and compare OCT characteristics of intraretinal hyper-reflective foci (IHRF) in eyes with diabetic retinopathy (DR) versus age-related macular degeneration (AMD)., Design: a retrospective observational study., Participants: 54 treatment-naïve eyes (27 DR and 27 AMD)., Methods: The IHRF lesions in OCT B-scan were semi-automatically segmented. Mean reflectivity (MR), maximum diameter, circularity index (Cir), area, and the angle between the greatest linear dimension (GLD) and the horizontal were computed for each IHRF lesion. The presence and absence of a posterior shadow and the axial location were assessed. The MR was normalized using the vitreous and nerve fiber layer reflectance as dark and bright reference standards, respectively., Results: A total of 1149 IHRF (1051 in DR and 98 in the AMD group) were identified, with a mean of 39 ± 36 lesions in DR eyes compared to only 4 ± 4 in AMD eyes (p < 0.001). The mean area of individual IHRF lesions was greater in DR eyes (1305 ± 1647 μm² vs 1031 ± 750 μm²; p = 0.016), but IHRF in AMD eyes had higher reflectivity (1.17 ± 0.14 vs 1.03 ± 0.17; p < 0.001). The angle of the GLD relative to the horizontal was greater in AMD eyes, indicating that IHRF in AMD eyes were more horizontally oriented. In AMD eyes, 88.8% of IHRF were located beneath the inner border of the outer nuclear layer (ONL), while in DR eyes, 56.9% were located there (p < 0.001)., Conclusions: IHRF lesions in eyes with DR and AMD demonstrate significant differences, with IHRF in DR eyes tending to be larger and less hyper-reflective compared to AMD eyes., (Copyright © 2024 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)