ANO2 Genetic Variants and Anti-VEGF Treatment Response in Neovascular AMD: A Pharmacogenetic Substudy of VIEW 1 and VIEW 2.

Purpose: This analysis investigated potential associations between gene variants and clinical end points in the VIEW 1 and 2 randomized clinical trials of intravitreal aflibercept and ranibizumab in neovascular age-related macular degeneration (AMD). Methods: A genome-wide association analysis was conducted in a subgroup of patients from VIEW 1 and 2 consenting to the optional pharmacogenetic analysis. Results: Data were pooled from 780 samples from patients representative of the overall VIEW 1 and 2 populations. After Bonferroni correction for multiplicity and statistical adjustment for baseline risk factors, no significant associations were found between previously identified prognostic AMD gene variants and treatment response according to key prespecified VIEW 1 and 2 end points. Genome-wide, there were no significant genetic associations in patients experiencing gains of ≥15 Early Treatment of Diabetic Retinopathy Study letters after 1 or 2 years of treatment. A cluster of variants in ANO2 (encoding anoctamin 2, a calcium-activated chloride channel expressed on photoreceptor cells) on chromosome 12 reached the level of significance for loss of ≥5 letters after 1 year of treatment (P < 5 × 10-8), with the ANO2 rs2110166 SNP demonstrating highly significant association (P = 1.99 × 10-8). Carriers of the ANO2 rs2110166 TT genotype showed a robust increase in visual acuity versus baseline compared with a small decrease in those with the TC genotype. Conclusions: None of the potential prognostic candidate genes were associated with the clinical end points for treated patients. Preliminary analyses suggest an association of ANO2 with retinal function, with a potential impact on vision of approximately one line over at least the first year. Further investigation of the function of ANO2 in retinal pathophysiology is merited.

Impact of residual retinal fluid on treatment outcomes in neovascular age-related macular degeneration.

Treatment decisions for neovascular age-related macular degeneration (nAMD) in the setting of individualised treatment regimens are adapted to disease activity. The main marker of disease activity and trigger for re-treatment with anti-vascular endothelial growth factor (anti-VEGF) agents is the presence of retinal fluid on optical coherence tomography (OCT). Recently, attention has focused on the impact of residual retinal fluid on nAMD management. Based on a literature review and the combined clinical experience of an international group of retinal specialists, this manuscript provides expert guidance on the treatment of nAMD according to fluid status and proposes an algorithm for determining when to administer anti-VEGF treatment according to residual fluid status. We explore the role of residual fluid in treatment decisions and outcomes in nAMD, taking into consideration fluid evaluation and, in particular, distinguishing between fluid in different anatomic compartments and at different stages during the treatment course. Current limitations to identifying and interpreting fluid on OCT, and the assumption that any residual retinal fluid reflects ongoing VEGF activity, are discussed.

Exploring the fragility of meta-analyses in ophthalmology: a systematic review.

OBJECTIVE: The fragility index (FI) of a meta-analysis evaluates the extent that the statistical significance can be changed by modifying the event status of individuals from included trials. Understanding the FI improves the interpretation of the results of meta-analyses and can help to inform changes to clinical practice. This review determined the fragility of ophthalmology-related meta-analyses. METHODS: Meta-analyses of randomized controlled trials with binary outcomes published in a journal classified as 'Ophthalmology' according to the Journal Citation Report or an Ophthalmology-related Cochrane Review were included. An iterative process determined the FI of each meta-analysis. Multivariable linear regression modeling evaluated the relationship between the FI and potential predictive factors in statistically significant and non-significant meta-analyses. RESULTS: 175 meta-analyses were included. The median FI was 6 (Q1-Q3: 3-12). This meant that moving 6 outcomes from one group to another would reverse the study's findings. The FI was 1 for 18 (10.2%) of the included meta-analyses and was ≤5 for 75 (42.4%) of the included meta-analyses. The number of events (p < 0.001) and the p-value (p < 0.001) were the best predictors of the FI in both significant and non-significant meta-analyses. CONCLUSION: The statistical significance of meta-analyses in ophthalmology often hinges on the outcome of a few patients. The number of events and the p-value are the most important factors in determining the fragility of the evidence. The FI is an easily interpretable measure that can supplement the reader's understanding of the strength of the evidence being presented. PROSPERO REGISTRATION: CRD42022377589.

Sequence of Morphological Changes Preceding Atrophy in Intermediate AMD Using Deep Learning.

Purpose: Investigating the sequence of morphological changes preceding outer plexiform layer (OPL) subsidence, a marker preceding geographic atrophy, in intermediate AMD (iAMD) using high-precision artificial intelligence (AI) quantifications on optical coherence tomography imaging. Methods: In this longitudinal observational study, individuals with bilateral iAMD participating in a multicenter clinical trial were screened for OPL subsidence and RPE and outer retinal atrophy. OPL subsidence was segmented on an A-scan basis in optical coherence tomography volumes, obtained 6-monthly with 36 months follow-up. AI-based quantification of photoreceptor (PR) and outer nuclear layer (ONL) thickness, drusen height and choroidal hypertransmission (HT) was performed. Changes were compared between topographic areas of OPL subsidence (AS), drusen (AD), and reference (AR). Results: Of 280 eyes of 140 individuals, OPL subsidence occurred in 53 eyes from 43 individuals. Thirty-six eyes developed RPE and outer retinal atrophy subsequently. In the cohort of 53 eyes showing OPL subsidence, PR and ONL thicknesses were significantly decreased in AS compared with AD and AR 12 and 18 months before OPL subsidence occurred, respectively (PR: 20 µm vs. 23 µm and 27 µm [P < 0.009]; ONL, 84 µm vs. 94 µm and 98 µm [P < 0.008]). Accelerated thinning of PR (0.6 µm/month; P < 0.001) and ONL (0.8 µm/month; P < 0.001) was observed in AS compared with AD and AR. Concomitant drusen regression and hypertransmission increase at the occurrence of OPL subsidence underline the atrophic progress in areas affected by OPL subsidence. Conclusions: PR and ONL thinning are early subclinical features associated with subsequent OPL subsidence, an indicator of progression toward geographic atrophy. AI algorithms are able to predict and quantify morphological precursors of iAMD conversion and allow personalized risk stratification.

Deep Neural Networks for Automated Outer Plexiform Layer Subsidence Detection on Retinal OCT of Patients With Intermediate AMD.

Purpose: The subsidence of the outer plexiform layer (OPL) is an important imaging biomarker on optical coherence tomography (OCT) associated with early outer retinal atrophy and a risk factor for progression to geographic atrophy in patients with intermediate age-related macular degeneration (AMD). Deep neural networks (DNNs) for OCT can support automated detection and localization of this biomarker. Methods: The method predicts potential OPL subsidence locations on retinal OCTs. A detection module (DM) infers bounding boxes around subsidences with a likelihood score, and a classification module (CM) assesses subsidence presence at the B-scan level. Overlapping boxes between B-scans are combined and scored by the product of the DM and CM predictions. The volume-wise score is the maximum prediction across all B-scans. One development and one independent external data set were used with 140 and 26 patients with AMD, respectively. Results: The system detected more than 85% of OPL subsidences with less than one false-positive (FP)/scan. The average area under the curve was 0.94 ± 0.03 for volume-level detection. Similar or better performance was achieved on the independent external data set. Conclusions: DNN systems can efficiently perform automated retinal layer subsidence detection in retinal OCT images. In particular, the proposed DNN system detects OPL subsidence with high sensitivity and a very limited number of FP detections. Translational Relevance: DNNs enable objective identification of early signs associated with high risk of progression to the atrophic late stage of AMD, ideally suited for screening and assessing the efficacy of the interventions aiming to slow disease progression.

Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration.

Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor-associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of IRAK3, which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD. Irak3-knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)-expressing human IRAK3 rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in Irak3-knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.

Gene and cell therapy for age-related macular degeneration: A review.

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss among the elderly in Western communities, with an estimated global prevalence of 10 - 20% in people older than 65 years. AMD leads to central vision loss due to degeneration of the photoreceptors, retinal pigment epithelium and the choriocapillaris. Beckman's classification for AMD, based upon color fundus photographs, divides the disease into early, intermediate, and late forms. The late, vision-threatening stage includes both neovascular AMD and geographic atrophy. Despite its high prevalence and impact on patients' quality of life, treatment options for AMD are limited. While neovascular AMD can be medically managed with anti-VEGF intravitreal injections, until very recently there has been no approved treatment options for atrophic AMD; however, in February 2023 the first treatment for geographic atrophy - pegcetacoplan - was approved by the US FDA. We describe the current landscape of potential gene and cell therapeutic strategies for late-stage AMD, with an emphasis on the therapeutic options that might become available in the next few years.

Clinical performance of predicting late age-related macular degeneration development using multimodal imaging.

BACKGROUND: To examine whether the clinical performance of predicting late age-related macular degeneration (AMD) development is improved through using multimodal imaging (MMI) compared to using colour fundus photography (CFP) alone, and how this compares with a basic prediction model using well-established AMD risk factors. METHODS: Individuals with AMD in this study underwent MMI, including optical coherence tomography (OCT), fundus autofluorescence, near-infrared reflectance and CFP at baseline, and then at 6-monthly intervals for 3-years to determine MMI-defined late AMD development. Four retinal specialists independently assessed the likelihood that each eye at baseline would progress to MMI-defined late AMD over 3-years with CFP, and then with MMI. Predictive performance with CFP and MMI were compared to each other, and to a basic prediction model using age, presence of pigmentary abnormalities, and OCT-based drusen volume. RESULTS: The predictive performance of the clinicians using CFP [AUC = 0.75; 95% confidence interval (CI) = 0.68-0.82] improved when using MMI (AUC = 0.79; 95% CI = 0.72-0.85; p = 0.034). However, a basic prediction model outperformed clinicians using either CFP or MMI (AUC = 0.85; 95% CI = 0.78-91; p ≤ 0.002). CONCLUSIONS: Clinical performance for predicting late AMD development was improved by using MMI compared to CFP. However, a basic prediction model using well-established AMD risk factors outperformed retinal specialists, suggesting that such a model could further improve personalised counselling and monitoring of individuals with the early stages of AMD in clinical practice.

Effect of Low-Dose Aspirin on the Course of Age-Related Macular Degeneration: A Secondary Analysis of the ASPREE Randomized Clinical Trial.

Importance: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in old age. There is no proven intervention to prevent AMD and, apart from lifestyle, nutritional, and supplement advice, there is no intervention to delay its progression. Objective: To determine the impact of long-term low-dose aspirin on the incidence and progression of AMD. Design, Setting and Participants: The Aspirin in Reducing Events in the Elderly-AMD (ASPREE-AMD) study was an Australian-based substudy of the ASPREE trial, a multicenter, international, randomized, double-masked, placebo-clinical trial investigating the efficacy of low-dose aspirin in prolonging disability-free survival among older individuals. Retinal photography was conducted at baseline from March 2010 to January 2015, then 3 and 5 years after randomization. AMD status was determined using color retinal images and treatment records. Australian participants in ASPREE aged 70 years and older without dementia, independence-limiting physical disability, cardiovascular disease, or chronic illness limiting 5-year survival and with gradable retinal images at baseline were included. Data were analyzed from December 2022 to December 2023. Interventions: Aspirin (100 mg daily, enteric coated) or placebo. Main Outcomes and Measures: Incidence of AMD and progression from early/intermediate to late AMD. Outcomes were analyzed by modified intention-to-treat analysis. Results: A total of 4993 participants were enrolled in this substudy. Baseline characteristics were similar between groups. At the time of sponsor-determined trial termination, retinal follow-up data were available for 3208 participants, 3171 of whom were analyzed for AMD incidence and progression, with a median (IQR) age of 73.5 (71.5-76.4) years and even sex distribution (1619 [51%] female). Median (IQR) follow-up time was 3.1 (3.0-3.5) years. Cumulative AMD incidence was 195 of 1004 (19.4%) in the aspirin group and 187 of 979 (19.1%) in the placebo group (relative risk [RR], 1.02; 95% CI, 0.85-1.22; P = .86). Cumulative progression from early/intermediate AMD to late AMD was observed in 14 of 615 (2.3%) participants in the aspirin group and 18 of 573 (3.1%) in the placebo group (RR, 0.72; 95% CI, 0.36-1.44; P = .36). Conclusions and Relevance: In this trial, low-dose aspirin administered for 3 years did not affect the incidence of AMD. The evidence was weaker for progression of AMD due to low number of progressed cases. Overall, these results do not support suggestion that low-dose daily aspirin prevents the development or progression of AMD. Trial Registration: anzctr.org Identifier: ACTRN12613000755730.

COMPLETE RETINAL PIGMENT EPITHELIAL AND OUTER RETINAL ATROPHY IN AGE-RELATED MACULAR DEGENERATION: A Longitudinal Evaluation.

PURPOSE: There is a need for robust earlier biomarkers of atrophic age-related macular degeneration that could act as surrogate endpoints for geographic atrophy (GA) in early interventional trials. This study sought to examine the risk of progression of complete retinal pigment epithelium and outer retinal atrophy (cRORA) to the traditional atrophic endpoint of GA on color fundus photography. This study also compared the risk of progression for cRORA to that associated with the specific optical coherence tomography features that define nascent GA (nGA), a strong predictor of GA development. METHODS: One hundred forty participants with bilateral large drusen at baseline underwent optical coherence tomography imaging and color fundus photography at 6-month intervals for up to 36 months. Optical coherence tomography volume scans were graded for the presence of cRORA and nGA, and color fundus photographs were graded for the presence of GA. The association and rate of progression to GA for cRORA and nGA were examined. RESULTS: Both cRORA and nGA were significantly associated with GA development (adjusted hazard ratio, 65.7 and 76.8 respectively; both P < 0.001). The probability of progression of cRORA to GA over 24 months (26%) was significantly lower than the probability of progression of nGA (38%; P = 0.039). CONCLUSION: This study confirmed that cRORA was a significant risk factor for developing GA, although its rate of progression was slightly lower compared with nGA. While requiring replication in future studies, these findings suggest that the specific features of photoreceptor degeneration used to define nGA appear important when assessing the risk of progression.

Inter-night variability of in-home, overnight pulse oximetry screening in an asymptomatic older adult population.

PURPOSE: Obstructive sleep apnoea (OSA) is common, yet often undiagnosed. Self-administered, overnight pulse oximetry (OPO) could screen for OSA in asymptomatic, older populations. However, the inter-night variability of OPO in an asymptomatic, older population is unknown. We determined the inter-night variability of home OPO parameters in an older population and correlated with sleep questionnaires. METHODS: Participants > 50 years without a diagnosis of OSA undertook home OPO for three consecutive nights and completed two sleep questionnaires (STOP-BANG (SBQ) and Epworth Sleepiness Score (ESS)). Analysis was performed with linear mixed models and Spearman's correlation coefficient. RESULTS: There was no difference in oxygen desaturation index (ODI), MeanSpO2, MinimumSpO2, and time spent with SpO2 < 90% (T90) across two or three nights (P ≥ 0.282). However, the variability of all parameters across nights increased with the magnitude of departure from normal values (P ≤ 0.002). All OPO parameters were associated with age (P ≤ 0.034) and body mass index (P ≤ 0.049). There was a weak correlation between three OPO parameters and SBQ (absolute ρ = 0.22 to 0.32; P ≤ 0.021), but not ESS (P ≥ 0.254). CONCLUSION: Inter-night variability of home OPO was minimal when values were near-normal in an older population. However, as values depart from normal, the inter-night variability increases, indicating the need for multiple night recordings. Low correlation to sleep questionnaires suggest the need for more robust OSA questionnaires in an asymptomatic population.

Predictive Performance of an Updated Polygenic Risk Score for Age-Related Macular Degeneration.

PURPOSE: A recent genome-wide association study of age-related macular degeneration (AMD) identified new AMD-associated risk variants. These variants now can be incorporated into an updated polygenic risk score (PRS). This study aimed to assess the performance of an updated PRS, PRS2023, in an independent cohort of older individuals with retinal imaging data and to compare performance with an older PRS, PRS2016. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 4175 participants of European ancestry, 70 years of age or older, with genotype and retinal imaging data. METHODS: We used logistic regression models and area under the receiver operating characteristic curve (AUC) to assess the performance of PRS2023 compared with PRS2016. AMD status and severity were graded using color fundus photography. MAIN OUTCOME MEASURES: Association of PRS2023 and PRS2016 with AMD risk at baseline. RESULTS: At enrollment among 4175 participants, 2605 participants (62.4%) had no AMD and 853 participants (20.4%), 671 participants (16.1%), and 46 participants (1.1%) had early, intermediate, and late-stage AMD, respectively. More than 27% of the participants with a high PRS2023 (top quartile) had intermediate or late-stage AMD, compared with < 15% for those in the middle 2 quartiles and less than 13% for those in the lowest quartile. Both PRS2023 and PRS2016 were associated significantly with AMD after adjustment for age, sex, smoking status, and lipid levels, with increasing odds ratios (ORs) for worsening AMD grades. PRS2023 outperformed PRS2016 (P = 0.03 for all AMD and P = 0.03 for late AMD, DeLong test comparing AUC). PRS2023 was associated with late-stage AMD with an adjusted OR of 5.05 (95% confidence interval [CI], 3.41-7.47) per standard deviation. The AUC of a model containing conventional or nongenetic risk factors and PRS2023 was 91% (95% CI, 87%-95%) for predicting late-stage AMD, which improved 12% over the model without the PRS (AUC, 79%; P < 0.001 for difference). CONCLUSIONS: A new PRS, PRS2023, for AMD outperforms a previous PRS and predicts increasing risk for late-stage AMD (with stronger association for more severe imaging-confirmed AMD grades). Our findings have clinical implications for the improved prediction and risk stratification of AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

TENAYA and LUCERNE: Two-Year Results from the Phase 3 Neovascular Age-Related Macular Degeneration Trials of Faricimab with Treat-and-Extend Dosing in Year 2.

PURPOSE: To evaluate 2-year efficacy, durability, and safety of the bispecific antibody faricimab, which inhibits both angiopoietin-2 and VEGF-A. DESIGN: TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) were identically designed, randomized, double-masked, active comparator-controlled phase 3 noninferiority trials. PARTICIPANTS: Treatment-naive patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older. METHODS: Patients were randomized (1:1) to intravitreal faricimab 6.0 mg up to every 16 weeks (Q16W) or aflibercept 2.0 mg every 8 weeks (Q8W). Faricimab fixed dosing based on protocol-defined disease activity at weeks 20 and 24 up to week 60, followed up to week 108 by a treat-and-extend personalized treatment interval regimen. MAIN OUTCOME MEASURES: Efficacy analyses included change in best-corrected visual acuity (BCVA) from baseline at 2 years (averaged over weeks 104, 108, and 112) and proportion of patients receiving Q16W, every 12 weeks (Q12W), and Q8W dosing at week 112 in the intention-to-treat population. Safety analyses included ocular adverse events (AEs) in the study eye through study end at week 112. RESULTS: Of 1326 patients treated across TENAYA/LUCERNE, 1113 (83.9%) completed treatment (n = 555 faricimab; n = 558 aflibercept). The BCVA change from baseline at 2 years was comparable between faricimab and aflibercept groups in TENAYA (adjusted mean change, +3.7 letters [95% confidence interval (CI), +2.1 to +5.4] and +3.3 letters [95% CI, +1.7 to +4.9], respectively; mean difference, +0.4 letters [95% CI, -1.9 to +2.8]) and LUCERNE (adjusted mean change, +5.0 letters [95% CI, +3.4 to +6.6] and +5.2 letters [95% CI, +3.6 to +6.8], respectively; mean difference, -0.2 letters [95% CI, -2.4 to +2.1]). At week 112 in TENAYA and LUCERNE, 59.0% and 66.9%, respectively, achieved Q16W faricimab dosing, increasing from year 1, and 74.1% and 81.2%, achieved Q12W or longer dosing. Ocular AEs in the study eye were comparable between faricimab and aflibercept groups in TENAYA (55.0% and 56.5% of patients, respectively) and LUCERNE (52.9% and 47.5% of patients, respectively) through week 112. CONCLUSIONS: Treat-and-extend faricimab treatment based on nAMD disease activity maintained vision gains through year 2, with most patients achieving extended dosing intervals. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Rationale and Design of VOYAGER: Long-term Outcomes of Faricimab and Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema in Clinical Practice.

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.

Visual Sensitivity Loss in Geographic Atrophy: Structure-Function Evaluation Using Defect-Mapping Microperimetry.

Purpose: To examine the structure-function relationship in eyes with geographic atrophy (GA) using defect-mapping microperimetry, a testing strategy optimized to quantify the spatial extent of deep visual sensitivity losses. Methods: Fifty participants with GA underwent defect-mapping microperimetry testing of the central 8°-radius region (208 locations tested once with a 10-decibel stimuli) and fundus autofluorescence imaging in one eye. The GA extent in the corresponding central 8°-radius was derived by manual annotations and image co-registration to examine the global structure-function relationship. The distance of each test location from the GA margin was also derived, and regions defined, to examine the local structure-function relationship. Results: GA extent in the central 8° explained a substantial proportion of variance in the percentage of locations missed (nonresponse) on microperimetry at the global level (R2 = 0.90). At a local level, the probability of missing stimuli at the outer junctional zone (0-500 µm outside the GA margin) and GA margin (probability = 7% and 34%, respectively) was higher than at the outer nonlesional zone (>500 µm outside the GA margin; probability = 2%; P < 0.001 for both). The probability of missing stimuli at the inner junctional zone (0-250 µm inside the GA margin) was also lower than at the inner lesional zone (>250 µm inside the GA margin; probability = 64% and 88%; P < 0.001). Conclusions: This study confirms the expected functional relevance of the region with GA on fundus autofluorescence imaging and underscores the potential effectiveness of defect-mapping microperimetry testing for capturing visual function changes when evaluating new GA treatments.

Functional Evaluation of Retinal Pigment Epithelium and Outer Retinal Atrophy by High-Density Targeted Microperimetry Testing.

Purpose: Complete retinal pigment epithelium (RPE) and outer retinal atrophy (cRORA) on OCT imaging has recently been proposed to describe end-stage atrophy in age-related macular degeneration (AMD) by international consensus and expected to be associated with a dense scotoma, but such functional evidence is lacking. This study sought to examine the visual sensitivity defects associated with cRORA and to determine OCT features associated with deep defects. Design: Observational study. Participants: Sixty eyes from 53 participants, including 342 microperimetry tests over 171 study visits. Methods: Participants underwent targeted high-density threshold-based microperimetry testing of atrophic lesions (with at least incomplete RPE and outer retinal atrophy [iRORA]) with a 3.5° diameter grid. The maximum extent of signs of atrophy for all lesions was graded on OCT imaging. Main Outcome Measures: Number of deep visual sensitivity defects (threshold ≤ 10 decibels [dB]). Results: Presence of choroidal signal hypertransmission ≥ 500 µm, complete RPE loss ≥250 µm, and inner nuclear layer and outer plexiform layer subsidence, and hyporeflective wedge-shaped band (defined as nascent geographic atrophy [nGA]) ≥ 500 µm (P ≤ 0.020), but not RPE attenuation or disruption (P ≥ 0.192), were all independently associated with a significant increase in the number of deep visual sensitivity defects ≤ 10 dB. Only cRORA lesions with hypertransmission ≥ 500 µm or complete RPE loss ≥ 250 µm, or with both of these features (P < 0.001), but not lesions with only hypertransmission 250-499 µm (P = 0.303), had significantly more deep visual sensitivity defects ≤ 10 dB compared with iRORA lesions. Lesions with nGA ≥ 500 µm, irrespective of the presence of hypertransmission ≥ 500 µm and/or complete RPE loss ≥ 250 µm, also showed a higher number of deep visual sensitivity defects ≤ 10 dB compared with lesions without nGA ≥ 500 µm (P ≤ 0.011). Conclusions: Not all cRORA lesions show a difference in the number of deep visual sensitivity defects compared with iRORA. Instead, hypertransmission ≥ 500 µm, complete RPE loss ≥ 250 µm, and nGA ≥ 500 µm are all OCT features independently associated with deep visual sensitivity detects that could help inform the definition of end-stage atrophy on OCT imaging. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Targeted High-Density Microperimetry Testing of Nascent Geographic Atrophy in Age-Related Macular Degeneration.

Purpose: To examine the effectiveness of a targeted high-density microperimetry testing strategy for detecting visual sensitivity abnormalities in eyes with nascent geographic atrophy (nGA) when compared with standard central microperimetry testing. Design: Observational study. Participants: Three-hundred and twenty-one eyes from 176 individuals with nonneovascular age-related macular degeneration (AMD). Methods: Thirty-five eyes from 33 participants underwent targeted high-density microperimetry testing of atrophic lesions (either nGA or geographic atrophy [GA]) within a 1.75° radius (or approximately 1000 µm diameter) region. Another cohort of 286 eyes from 143 participants with bilateral large drusen at baseline underwent standard microperimetry testing of the central 6° radius region at 6-monthly intervals for up to 36 months and thus included eyes that developed nGA and GA over the follow-up. All eyes underwent 2 tests at each visit to evaluate intrasession measurement repeatability. Main Outcome Measures: Magnitude of visual sensitivity abnormalities based on mean sensitivity (MS), pointwise sensitivity standard deviation (PSD), and the number of test locations with a threshold of ≤ 10 decibels (dB; or deep defects) in eyes with nGA, compared between eyes that underwent targeted high-density microperimetry testing and standard central microperimetry testing. Results: The magnitude of visual sensitivity abnormalities based on MS, PSD and the number of deep defects were all significantly greater in eyes with nGA using targeted, high-density microperimetry testing compared with eyes with nGA using standard central microperimetry testing (all P < 0.001) and were all significantly less than eyes with GA using targeted, high-density microperimetry testing (all P ≤ 0.004). The intrasession coefficient of repeatability, where 95% of the test-retest differences are expected to occur, for MS in eyes with atrophic changes was 0.9 dB with the targeted, high-density microperimetry testing, and 1.8 dB with standard central microperimetry testing. Conclusions: Targeted, high-density microperimetry testing enabled the detection of a significantly greater magnitude of visual sensitivity abnormalities in eyes with nGA than standard microperimetry testing. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.