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Age-related macular degeneration (AMD) is a leading cause of irreversible, severe vision loss in Western countries. Recently, we identified a novel pathway involving P2X7 receptor scavenger function expressed on ocular immune cells as a risk factor for advanced AMD. In this study, we investigate the effect of loss of P2X7 receptor function on retinal structure and function during aging. P2X7-null and wild-type C57bl6J mice were investigated at 4, 12, and 18 months of age for macrophage phagocytosis activity, ocular histological changes, and retinal function. Phagocytosis activity of blood-borne macrophages decreased with age at 18 months in the wild-type mouse. Lack of P2X7 receptor function reduced phagocytosis at all ages compared to wild-type mice. At 12 months of age, P2X7-null mice had thickening of Bruchs membrane and retinal pigment epithelium dysfunction. By 18 months of age, P2X7-null mice displayed phenotypic characteristics consistent with early AMD, including Bruchs membrane thickening, retinal pigment epithelium cell loss, retinal functional deficits, and signs of subretinal inflammation. Our present study shows that loss of function of the P2X7 receptor in mice induces retinal changes representing characteristics of early AMD, providing a valuable model for investigating the role of scavenger receptor function and the immune system in the development of this age-related disease.

Purpose The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is an investigation of the safety and efficacy of subthreshold nanosecond laser treatment to slow the progression of intermediate age-related macular degeneration (AMD). This report presents the novel study design and baseline characteristics. Design Multicenter, double-masked, randomized controlled, medical device feasibility clinical trial. Participants Persons with bilateral drusen >125 μm within 1500 μm of the fovea, monocular best-corrected visual acuity (BCVA) ≥20/40, and microperimetric retinal sensitivity of Methods Participants were randomized to nanosecond or sham laser treatment. Twelve laser or sham spots are applied to the macular region of the study eye. Participants are reviewed in visits every 6 months with functional testing and MMI for 36 months and are re-treated at each visit (until 30 months) if an end point is not reached in the study eye. Main Outcome Measures Progression to late AMD or MMI-defined anatomic end points in the study eye. Results A total of 292 participants across 6 centers were enrolled, with 145 participants randomized to arm 1 and 147 participants randomized to arm 2. Population characteristics at baseline were as follows: median age 70 years, 73% female, 90% Anglo-Saxon, and 3% current smokers. Baseline ocular characteristics of the study eyes were BCVA of 83 letters (20/25); low luminance visual acuity (LLVA) of 68 letters (20/50); hyperpigmentation, 33%; reticular pseudodrusen, 23%; square root drusen area (SD-OCT), 0.77 mm; square root drusen area (color photographs), 0.92 mm; cube root drusen volume (SD-OCT), 0.26 mm; average retinal sensitivity, 26 dB; and worst point retinal sensitivity, 20 dB. Only lutein supplement use was significantly different between treatment arms. Conclusions The LEAD study uses novel inclusion/exclusion criteria and end points in an attempt to optimize our study design. Risk characteristics for progression to study end points are equally distributed between treatment arms.

PURPOSE: To summarize the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (AMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials. DESIGN: Systematic debate on the relevance of distinct imaging modalities held in 2 consensus meetings. PARTICIPANTS: A panel of retina specialists. METHODS: During the CAM, a consortium of international experts evaluated the advantages and disadvantages of various imaging modalities on the basis of the collective analysis of a large series of clinical cases. A systematic discussion on the role of each modality in future studies in non-neovascular and neovascular AMD was held. MAIN OUTCOME MEASURES: Advantages and disadvantages of current retinal imaging technologies and recommendations for their use in advanced AMD trials. RESULTS: Imaging protocols to detect, quantify, and monitor progression of atrophy should include color fundus photography (CFP), confocal fundus autofluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution optical coherence tomography volume scans. These images should be acquired at regular intervals throughout the study. In studies of non-neovascular AMD (without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indocyanine-green angiography (ICG-A) may be considered at baseline under certain conditions. For studies in patients with neovascular AMD, increased need for visualization of the vasculature must be taken into account. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain conditions. CONCLUSIONS: A multimodal imaging approach is recommended in clinical studies for the optimal detection and measurement of atrophy and its associated features. Specific validation studies will be necessary to determine the best combination of imaging modalities, and these recommendations will need to be updated as new imaging technologies become available in the future.

// Matthew Krilis 1, * , Miao Qi 2, * , Michele C. Madigan 1, 3 , Jason W. H. Wong 4 , Mahmoud Abdelatti 2 , Robyn H. Guymer 5 , John Whitelock 6 , Peter McCluskey 1 , Peng Zhang 2, 7 , Jian Qi 2 , Alex P. Hunyor 1 , Steven A. Krilis 2, * and Bill Giannakopoulos 2, 8, * 1 Save Sight Institute, University of Sydney and Sydney Eye Hospital, Sydney, NSW, Australia 2 Department of Infectious Diseases, Immunology and Sexual Health and Department of Medicine, St George Hospital, University of New South Wales, Sydney, NSW, Australia 3 School of Optometry and Vision Science, University of New South Wales, Sydney, NSW, Australia 4 Prince of Wales Clinical School, University of New South Wales, Lowy Cancer Research Centre, Sydney, NSW, Australia 5 Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia 6 Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW, Australia 7 Department of Cardiothoracic Surgery, Tianjin Medical University General Hospital, Tianjin, China 8 Department of Rheumatology, St George Hospital, Sydney, NSW, Australia * These authors have contributed equally to this work Correspondence to: Bill Giannakopoulos, email: bill.giannakopoulos@unsw.edu.au Keywords: macular degeneration, complement factor H, nitrosative stress, retina Received: November 11, 2016 Accepted: December 27, 2016 Published: February 01, 2017 ABSTRACT Nitrosative stress has been implicated in the pathogenesis of age related macular degeneration (AMD). Tyrosine nitration is a unique type of post translational modification that occurs in the setting of inflammation and nitrosative stress. To date, the significance and functional implications of tyrosine nitration of complement factor H (CFH), a key complement regulator in the eye has not been explored, and is examined in this study in the context of AMD pathogenesis. Sections of eyes from deceased individuals with AMD (n = 5) demonstrated the presence of immunoreactive nitrotyrosine CFH. We purified nitrated CFH from retinae from 2 AMD patients. Mass spectrometry of CFH isolated from AMD eyes revealed nitrated residues in domains critical for binding to heparan sulphate glycosaminoglycans (GAGs), lipid peroxidation by-products and complement (C) 3b. Functional studies revealed that nitrated CFH did not bind to lipid peroxidation products, nor to the GAG of perlecan nor to C3b. There was loss of cofactor activity for Factor I mediated cleavage of C3b with nitrated CFH compared to non-nitrated CFH. CFH inhibits, but nitrated CFH significantly potentiates, the secretion of the pro-inflammatory and angiogenic cytokine IL-8 from monocytes that have been stimulated with lipid peroxidation by-products. AMD patients (n = 30) and controls (n = 30) were used to measure plasma nitrated CFH using a novel ELISA. AMD patients had significantly elevated nitrated CFH levels compared to controls (p = 0.0117). These findings strongly suggest that nitrated CFH contributes to AMD progression, and is a target for therapeutic intervention.

Item does not contain fulltext PURPOSE: To better understand the association, in a white population, of physical activity and age-related macular degeneration (AMD)-the main cause of irreversible severe vision loss in developed countries-given the suggestion that a healthy lifestyle may assist in delaying the onset and progression of AMD. DESIGN: Systematic review and meta-analysis. METHODS: Medline, EMBASE, and Google Scholar were systematically searched for studies up to May 2015. Reference lists of published articles were hand searched and study authors were contacted to provide additional data. Those in the lowest category of activity in each study were compared with all other participants to assess the association between physical activity and both early and late AMD using random-effects meta-analysis. RESULTS: Nine studies (subject age range 30-97 years) were included in the meta-analysis. Physical activity was found to have a protective association with both early AMD (8 studies, n = 38 112, odds ratio (OR) 0.92, 95% confidence interval [CI] 0.86-0.98) and late AMD (7 studies, n = 28 854, OR 0.59, 95% CI 0.49-0.72). CONCLUSIONS: Physical activity is associated with lower odds of early and late AMD in white populations. These findings have important implications, reinforcing the public health message of staying active throughout life. However, further longitudinal studies are required to confirm and further characterize a protective effect of physical activity on the onset and/or progression of AMD.

Robyn H. Guymer, Zhichao Wu, Fred K. Chen, Usha Chakravarthy, Jennifer J. Arnold ... Shane R.Durkin ... et al.

Purpose Nascent geographic atrophy (nGA) describes features on OCT imaging previously observed to precede the development of atrophy. This study sought to prospectively evaluate the predictive ability of nGA for the conventional clinical endpoint of geographic atrophy (GA) as defined on color fundus photography (CFP). Design Prospective, longitudinal, observational study. Participants A total of 284 eyes from 142 participants with bilateral large drusen and without nGA nor late age-related macular degeneration (AMD) at baseline were included. Methods OCT volume scans and CFP images were obtained from all participants at baseline and then at 6-month intervals for up to 36 months. OCT and CFP images were graded independently for the presence of nGA and GA, respectively. Eyes that developed neovascular AMD were censored at the day of its detection. Main Outcome Measures Time to development of GA. Results A total 12 eyes from 10 participants progressed to GA over 36 months of follow-up, and nGA was detected in 10 of these eyes (83%) at a preceding visit (median, 13 months prior; interquartile range, 6–25 months). A total of 40 eyes from 28 participants developed nGA or GA over 36 months of follow-up, and the probability of progression to nGA and GA after 36 months was 20% (95% confidence interval [CI], 14%–28%) and 9% (95% CI, 6%–13%), respectively. After the detection of nGA, the probability of progression to GA was 38% (95% CI, 15%–55%) after 24 months. The development of nGA was associated with a markedly increased risk of progression to GA compared with when it did not develop (adjusted hazard ratio, 78.1; 95% CI, 13.6–448.0; P Conclusions This study prospectively demonstrated that nGA was a strong predictor for the development of GA, providing supportive evidence of the potential value of nGA as a surrogate endpoint in future intervention trials for the early stages of AMD to improve their feasibility substantially.

PurposeTo investigate the progression characteristics of ellipsoid zone (EZ) loss in eyes with macular telangiectasia type 2 (MacTel) as reflected by area and linear measurements, and their relevance for visual acuity.MethodsParticipants were selected from the MacTel Study cohort. Linear and area measurements of EZ loss were performed in Spectral-Domain Optical Coherence Tomograph (SD-OCT) volume scans. Progression characteristics and correlations between linear and area measurements were analysed using linear mixed effects models.ResultsA total of 134 eyes of 70 patients were included (85 eyes with follow-up, mean 4.7years, range: 1.4-8years). Ellipsoid zone (EZ) loss significantly progressed at a mean annual increment of 0.057mm2 (p=0.005). The progression rate was non-linear and interacted significantly with initial EZ lesion size indicating an exponential growth before reaching a plateau. There was a strong heterogeneity in area sizes between fellow eyes. EZ break length had a significant linear effect on EZ break area (b=1.06, p&nbsp

Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously.Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant inTwo variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism.Elevated levels of atypical deoxysphingolipids, caused by variant

Purpose: To evaluate rod function longitudinally in intermediate age-related macular degeneration subjects with reticular pseudodrusen (RPD) and without RPD (AMD). Methods: Retinal sensitivities (505 and 625 nm) during dark adaptation, at 14 locations within the central 12° macula were obtained after photobleaching at baseline and 12-month visits. Pointwise sensitivity differences between both stimuli were used to assess static rod function, while rod intercept time (RIT) and rod recovery rate (RRR) were used to evaluate dynamic function. Changes in function over time were compared between groups. Results: A total of 23 controls, 12 AMD, and 13 RPD cases were followed-up. At baseline, the RPD group had significantly worst static and dynamic rod function compared to AMD and control groups. Static function in AMD was similar to controls. Static and dynamic function across the central 12° was consistent in controls; however, it was most impaired at 4° compared to 12° eccentricity in disease groups. Over 12 months, no AMD cases progressed clinically and static function in AMD improved (P ≤ 0.04), but remained unchanged in control and RPD groups (P ≥ 0.17). The RRR for control and RPD groups remained stable, while the AMD group deteriorated, but only at 12° (P = 0.02). The RIT was stable in AMD (P = 0.75) and RPD (P = 0.71) groups but improved in the control group (P = 0.002). Conclusions: A decrease in RRR was detected over 12 months at 12° eccentricity in the AMD group. Evaluating changes in rod function requires testing at multiple locations including the peripheral macula.

PURPOSE: To describe the defining features of “incomplete retinal pigment epithelial (RPE) and outer retinal atrophy” (iRORA), a consensus term referring to the optical coherence tomography (OCT) based anatomical changes often identified prior to the development of “complete RPE and outer retinal atrophy (cRORA)” in age-related macular degeneration (AMD). We provide descriptive OCT and histological examples of disease progression. DESIGN: Consensus meeting PARTICIPANTS: Panel of retina specialists, including retinal imaging experts, reading center leaders and retinal histologists. METHODS: As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analysed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred prior to the development of atrophy secondary to AMD. New terms of complete and incomplete RPE and outer retinal atrophy (iRORA and cRORA) were defined. This report describes in detail the CAM consensus on iRORA. MAIN OUTCOME MEASURES: Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates. RESULTS: OCT was used in cases of early and intermediate AMD as the base imaging modality to identify cases of iRORA. In the context of drusen, iRORA is defined on OCT as (1) a region of signal hypertransmission into the choroid and (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration. The term iRORA should not be used when there is an RPE tear. Longitudinal studies confirmed the concept of progression from iRORA to cRORA. CONCLUSIONS: An international consensus classification for OCT-defined anatomical features of iRORA, are described and examples of longitudinal progression to cRORA are provided. The ability to identify these OCT changes reproducibly, is essential to better understand the natural history of disease, to identify high risk signs of progression and to study early interventions. Longitudinal data are required to quantify the implied risk of vision loss associated with these terms. The CAM classification provides initial definitions to enable these future endeavours, acknowledging that the classification will be refined as new data are generated.

To investigate differences in the development of macular atrophy (MA) over 24 months between treat-and-extend (TE) ranibizumab and aflibercept in patients with neovascular age-related macular degeneration (nAMD).A phase 4 randomized, partially masked, multicenter study.Individuals 50 years of age or older diagnosed with active, treatment-naïve subfoveal choroidal neovascularization secondary to nAMD with baseline best-corrected visual acuity (BCVA) of 23 logarithm of minimum angle of resolution letters or more.Patients were randomized 1:1 to receive either intravitreal injections of ranibizumab 0.5 mg or aflibercept 2.0 mg and were treated according to the same reading center-guided TE regimen after 3 initial monthly injections.The primary outcome was mean change in square root area of MA from baseline to month 24. Key secondary outcomes included number of injections and mean change in BCVA from baseline to months 12 and 24.Two hundred seventy-eight patients were included in the analysis (ranibizumab 0.5 mg, n = 141; aflibercept 2.0 mg, n = 137). Mean change in square root area of MA from baseline to month 24 was +0.36 mm (95% confidence interval [CI], 0.27-0.45 mm) for ranibizumab and +0.28 mm (95% CI, 0.19-0.37 mm) for aflibercept (treatment difference, +0.08 mm [95% CI, -0.05 to 0.21 mm]; P = 0.24). The proportion of patients with MA increased from 7% (10/141) to 37% (43/117) for ranibizumab and from 6% (8/137) to 32% (35/108) for aflibercept from baseline to month 24. The average number of injections received per year was similar between both groups: 9.6 (95% CI, 9.2-10.0) for ranibizumab and 9.5 (95% CI, 9.1-9.9) for aflibercept. The mean change in BCVA from baseline to month 24 was +6.6 letters (95% CI,4.7-8.5 letters) for the ranibizumab group and +4.6 letters (95% CI, 2.7-6.6 letters) for the aflibercept group ( P = 0.15). Rates of adverse events (AEs) were similar between both groups.No significant differences in the rate of development or growth of MA over 24 months were observed between ranibizumab and aflibercept in nAMD patients treated using an identical TE regimen.

Purpose To examine whether a microperimetry testing strategy based on quantifying the spatial extent of functional abnormalities (termed "defect-mapping" strategy) could improve the detection of progressive changes in deep scotomas compared to the conventional thresholding strategy. Methods A total of 30 healthy participants underwent two microperimetry examinations, each using the defect-mapping and thresholding strategies at the first visit to examine the test-retest variability of each method. Testing was performed using an isotropic stimulus pattern centered on the optic nerve head (ONH), which acted as a model of a deep scotoma. These tests were repeated at a second visit, except using a smaller stimulus pattern and thereby increasing the proportion of test locations falling within the ONH (to simulate the progressive enlargement of a deep scotoma). The extent of change detected between visits relative to measurement variability was compared between the two strategies. Results Relative to their effective dynamic ranges, the test-retest variability of the defect-mapping strategy (1.8%) was significantly lower compared to the thresholding strategy (3.3%; P < 0.001). The defect-mapping strategy also captured a significantly greater extent of change between visits relative to variability (-4.70 t-1) compared to the thresholding strategy (2.74 t-1; P < 0.001). Conclusions A defect-mapping microperimetry testing strategy shows promise for capturing the progressive enlargement of deep scotomas more effectively than the conventional thresholding strategy. Translational Relevance Microperimetry testing with the defect-mapping strategy could provide a more accurate clinical trial outcome measure for capturing progressive changes in deep scotomas in eyes with atrophic retinal diseases, warranting further investigations.

Importance Detection of early onset neovascular age-related macular degeneration (AMD) is critical to protecting vision. Background To describe the development and validation of a deep-learning algorithm (DLA) for the detection of neovascular age-related macular degeneration. Design Development and validation of a DLA using retrospective datasets. Participants We developed and trained the DLA using 56 113 retinal images and an additional 86 162 images from an independent dataset to externally validate the DLA. All images were non-stereoscopic and retrospectively collected. Methods The internal validation dataset was derived from real-world clinical settings in China. Gold standard grading was assigned when consensus was reached by three individual ophthalmologists. The DLA classified 31 247 images as gradable and 24 866 as ungradable (poor quality or poor field definition). These ungradable images were used to create a classification model for image quality. Efficiency and diagnostic accuracy were tested using 86 162 images derived from the Melbourne Collaborative Cohort Study. Neovascular AMD and/or ungradable outcome in one or both eyes was considered referable. Main outcome measures Area under the receiver operating characteristic curve (AUC), sensitivity and specificity. Results In the internal validation dataset, the AUC, sensitivity and specificity of the DLA for neovascular AMD was 0.995, 96.7%, 96.4%, respectively. Testing against the independent external dataset achieved an AUC, sensitivity and specificity of 0.967, 100% and 93.4%, respectively. More than 60% of false positive cases displayed other macular pathologies. Amongst the false negative cases (internal validation dataset only), over half (57.2%) proved to be undetected detachment of the neurosensory retina or RPE layer. Conclusions and relevance This DLA shows robust performance for the detection of neovascular AMD amongst retinal images from a multi-ethnic sample and under different imaging protocols. Further research is warranted to investigate where this technology could be best utilized within screening and research settings.

Geographic atrophy (GA) is a progressive, advanced form of age-related macular degeneration leading to visual function impairment and irreversible vision loss. Standard clinical tests to evaluate visual function in patients with GA provide poor anatomic-functional correlation, whereas fundus imaging does not assess the visual function deficit. Microperimetry is a psychophysical visual function test that spatially maps retinal sensitivity and allows for identification of correlation of anatomic features with visual function. In this review, we present an overview of mesopic microperimetry for GA, including commercially available microperimetry devices, strategies to capture a mesopic microperimetry test, and strategies to assess and interpret microperimetry data in patients with GA. We demonstrate the importance of microperimetry data for assessing GA progression and for evaluating visual function loss through anatomic-functional correlations. Although valuable, current microperimetry tests require an extensive time commitment from the patient and examiner, and the development of faster, more reproducible and accessible methods is important to enable broader use of microperimetry in both clinical and research settings.

International audience; PURPOSE:To explore various methods for assessing the early response to vascular endothelial growth factor (VEGF) inhibitors for neovascular age-related macular degeneration and investigate their association with 3-year visual acuity (VA) outcomes.DESIGN:Database study, prospectively designed.PARTICIPANTS:Treatment-naïve eyes in the Fight Retinal Blindness! registry that commenced anti-VEGF therapy between January 1, 2007, and March 1, 2014, that received 3 anti-VEGF injections within the first 3 months.METHODS:The early response was defined as occurring up until the fourth injection. Various early response metrics were explored: (1) achieving good VA (≥70 letters; Snellen equivalent, 20/40), (2) absolute change in VA from baseline, (3) time to first grading of the choroidal neovascular lesion as inactive, and (4) maximum rate of VA change between successive injections.MAIN OUTCOME MEASURES:Proportion of eyes achieving ≥70 letters 3 years.RESULTS:This study included 2051 treatment-naïve eyes from 1828 patients. Achieving good vision at 3 years was associated significantly with (1) having good vision by the fourth injection (VA ≥70 vs. VA 5 letters) early VA gains (vs. early VA loss: OR, 1.8; 95% CI, 1.2-2.6; P = 0.002; and OR, 1.8; 95% CI, 1.3-2.5; P < 0.001), (3) fewer injections until first grading of lesion inactivity (≤3 vs. >3 injections: OR, 1.6; 95% CI, 1.2-2.1; P < 0.001), (4) gradual change (between -4 and 4 letters) or rapid gains (≥5 letters) between successive injections (vs. rapid loss: OR, 1.7; 95% CI, 1.1-2.6; P = 0.015; and OR, 1.6; 95% CI, 1.1-2.3; P = 0.018). Eyes that achieved small or large early gains had similar vision at 3 years (65.0 and 64.7 letters, respectively) and had better vision than eyes with early VA loss (57.2 letters).CONCLUSIONS:Attainment of good vision by the fourth injection was associated strongly with 3-year visual outcomes, whereas other early response parameters showed a moderate association. The early response during the initial 3 monthly injections can be a useful guide for subsequent treatment decisions.

Analysis of time-to-event data, otherwise known as survival analysis, is a common investigative tool in ophthalmic research. For example, time-to-event data is useful when researchers are interested in investigating how long it takes for an ocular condition to worsen or whether treatment can delay the development of a potentially vision-threatening complication. Its implementation requires a different set of statistical tools compared to those required for analyses of other continuous and categorial outcomes. In this installment of the Focus on Data series, we present an overview of selected concepts relating to analysis of time-to-event data in eye research. We introduce censoring, model selection, consideration of model assumptions, and best practice for reporting. We also consider challenges that commonly arise when analyzing time-to-event data in ophthalmic research, including collection of data from two eyes per person and the presence of multiple outcomes of interest. The concepts are illustrated using data from the Laser Intervention in Early Stages of Age-Related Macular Degeneration study and statistical computing code for Stata is provided to demonstrate the application of the statistical methods to illustrative data.

Purpose: To identify the most suitable model for assessing the rate of growth of total geographic atrophy (GA) by analysis of model structure uncertainty. Methods: Model structure uncertainty refers to unexplained variability arising from the choice of mathematical model and represents an example of epistemic uncertainty. In this study, we quantified this uncertainty to help identify a model most representative of GA progression. Fundus autofluorescence (FAF) images and GA progression data (i.e., total GA area estimation at each presentation) were acquired using Spectralis HRA+OCT instrumentation and RegionFinder software. Six regression models were evaluated. Models were compared using various statistical tests, [i.e., coefficient of determination (r2), uncertainty metric (U), and test of significance for the correlation coefficient, r], as well as adherence to expected physical and clinical assumptions of GA growth. Results: Analysis was carried out for 81 GA-affected eyes, 531 FAF images (range: 3-17 images per eye), over median of 57 months (IQR: 42, 74), with a mean baseline lesion size of 2.62 ± 4.49 mm2 (range: 0.11-20.69 mm2). The linear model proved to be the most representative of total GA growth, with lowest average uncertainty (original scale: U = 0.025, square root scale: U = 0.014), high average r2 (original scale: 0.92, square root scale: 0.93), and applicability of the model was supported by a high correlation coefficient, r, with statistical significance (P = 0.01). Conclusions: Statistical analysis of uncertainty suggests that the linear model provides an effective and practical representation of the rate and progression of total GA growth based on data from patient presentations in clinical settings. Translational Relevance: Identification of correct model structure to characterize rate of growth of total GA in the retina using FAF images provides an objective metric for comparing interventions and charting GA progression in clinical presentations.

IMPORTANCE: Age-related macular degeneration (AMD), the leading cause of irreversible blindness in older adults, appears to have no effective preventive measures. The common antidiabetic drug metformin has been shown to have protective outcomes in multiple age-associated diseases and may have the potential to protect against the development of AMD. OBJECTIVE: To determine whether metformin use is associated with reduced odds of developing AMD. DESIGN, SETTING, AND PARTICIPANTS: This case-control study of patients from a nationwide health insurance claims database included a population-based sample of patients. Those aged 55 years and older with newly diagnosed AMD from January 2008 to December 2017 were defined as cases and matched with control participants. Data analyses were completed from June 2019 to February 2020. EXPOSURES: Dosage of metformin and exposure to other prescribed medications, as identified from outpatient drug claims. MAIN OUTCOMES AND MEASURES: Risk of developing AMD. RESULTS: A total of 312 404 affected individuals were included (181 817 women [58.2%]). After matching, 312 376 control participants were included (172 459 women [55.2%]; age range, 55 to 107 years). The case group had a slightly higher percentage of participants with diabetes (81 262 participants [26.0%]) compared with the control group (79 497 participants [25.5%]). Metformin use was associated with reduced odds of developing AMD (odds ratio [OR], 0.94 [95% CI, 0.92-0.96]). This association was dose dependent, with low to moderate doses of metformin showing the greatest potential benefit (dosages over 2 years: 1-270 g, OR, 0.91 [95% CI, 0.88-0.94]; 271-600 g, OR, 0.90 [95% CI, 0.87-0.93]; 601-1080 g, OR, 0.95 [95% CI, 0.92-0.98]). Doses of more than 1080 g of metformin over 2 years did not have reduced odds of developing AMD. Both the reduction in odds ratio and the dose-dependent response were preserved in a cohort consisting only of patients with diabetes. Metformin use was associated with a decreased OR of AMD in patients with diabetes without coexisting diabetic retinopathy (OR, 0.93 [95% CI, 0.91-0.95]) but was a risk factor in patients with diabetic retinopathy (OR, 1.07 [95% CI, 1.01-1.15]). CONCLUSION AND RELEVANCE: In this study, metformin use was associated with reduced odds of developing AMD. This association was dose dependent, with the greatest benefit at low to moderate doses. When looking only at patients with diabetes, we saw a preservation of the dose-dependent decrease in the odds of patients developing AMD. Metformin does not appear to be protective in patients with diabetes and coexisting diabetic retinopathy. This study suggests that metformin may be useful as a preventive therapy for AMD and provides the basis for potential prospective clinical trials.

The disease-initiating molecular events for age-related macular degeneration (AMD), a multifactorial retinal disease affecting many millions of elderly individuals worldwide, are still unknown. Of the over 30 risk and protective loci so far associated with AMD through whole genome-wide association studies (GWAS), the Age-Related Maculopathy Susceptibility 2 (ARMS2) gene locus represents one of the most highly associated risk regions for AMD. A unique insertion/deletion (in/del) sequence located immediately upstream of the High Temperature Requirement A1 (HTRA1) gene in this region confers high risk for AMD. Using electrophoretic mobility shift assay (EMSA), we identified that two Gtf2i-β/δ transcription factor isoforms bind to the cis-element 5'- ATTAATAACC-3' contained in this in/del sequence. The binding of these transcription factors leads to enhanced upregulation of transcription of the secretory serine protease HTRA1 in transfected cells and AMD patient-derived induced pluripotent stem cells (iPSCs). Overexpression of Htra1 in mice using a CAG-promoter demonstrated increased blood concentration of Htra1 protein, caused upregulation of vascular endothelial growth factor (VEGF), and produced a choroidal neovascularization (CNV)-like phenotype. Finally, a comparison of 478 AMD patients to 481 healthy, age-matched controls from Japan, India, Australia, and the USA showed a statistically increased level of secreted HTRA1 blood concentration in AMD patients compared with age-matched controls. Taken together, these results suggest a common mechanism across ethnicities whereby increased systemic blood circulation of secreted serine protease HTRA1 leads to subsequent degradation of Bruch's membrane and eventual CNV in AMD.

Background Late neovascular age-related macular degeneration (nvAMD) is very common and causes irreversible severe visual loss unless treated swiftly with vascular endothelial growth factor (VEGF) inhibitors. Although publicly subsidized access to treatment may be inequitable, which is why we assessed treatment provision across Australia. Design Secondary analysis of Australian data Participants All Pharmaceutical Benefits Scheme (incl. Repatriation PBS) beneficiaries Methods Treatment and incidence data were obtained from Medicare Australia, the Royal Australian and New Zealand College of Ophthalmologists, Optometry Australia, the Blue Mountains Eye Study, and the Australian Bureau of Statistics. Data were mapped using geographical information software, and factors associated with treatment provision assessed using multiple linear regression models. Main Outcome Measure Unmet need (%) for anti-VEGF treatment for nvAMD Results On average we estimated 7,316 incident cases of nvAMD not to be treated per year from 2010 to 2014 (50.1% of total). Number of ophthalmologists and optometrists (per 1,000, β = -0.024; 95% confidence interval (CI) -0.041, -0.007) and being located in remote regions (β = 0.186; 95% CI 0.110, 0.262) were associated with percentage of untreated cases. A higher proportion of the population speaking a language other than English at home was associated in univariate analyses only (β = 0.0015; 95% CI -0.0004, 0.0027; p = 0.007). Conclusion A large proportion of incident nvAMD is not treated with anti-VEGF. Not receiving treatment is more likely in regional or remote areas and areas with fewer service providers. Not speaking English at home may further limit access. Service delivery models for more equitable service provision are needed.

Assess the correlation between optical coherence tomography findings and change in vision for patients receiving "treat and extend" protocol ranibizumab for neovascular age-related macular degeneration.Optical coherence tomography analysis and best-corrected visual acuity (BCVA) change: mild = 5 to 9 letters, moderate = 10 to 14 letters, and severe ≥15 letters.A total of 103 eyes (99 patients, 63% female, 65-91 years) followed for 20.8 ± 4.9 months. By 12 months, there were 1.38 ± 0.59 instances of intraretinal fluid (IRF)/subretinal fluid recurrence on optical coherence tomography and 1.25 ± 1.00 instances of BCVA loss (≥5 letters) per patient. When BCVA was lost, IRF/subretinal fluid was present in 37.3% of cases. Occurrences of severe BCVA loss were less likely to recover vision than when BCVA loss was mild (5.9% vs. 75.6%, P = 0.001). New occurrence of IRF (33.9%) or subretinal fluid (29.6%) was more likely to lead to BCVA loss, compared with dry (16.6%) or persistent IRF (11.9%) or persistent subretinal fluid (14%, P0.001). With persistent fluid, any new loss of vision had a lower chance of recovery than when fluid was new in onset (64.3% vs. 85.3%, P = 0.04).During ranibizumab treatment, vision can decrease without signs of fluid. When fluid is present, IRF is associated with poorer vision. New occurrence of any fluid on optical coherence tomography is likely to lead to vision loss, but small amounts of persistent fluid can be tolerated without compromising vision.

Since the 1950s, vision researchers have been working towards the ambitious goal of restoring a functional level of vision to the blind via electrical stimulation of the visual pathways. Groups based in Australia, USA, Germany, France and Japan report progress in the translation of retinal visual prosthetics from the experimental to clinical domains, with two retinal visual prostheses having recently received regulatory approval for clinical use. Regulatory approval for cortical visual prostheses is yet to be obtained; however, several groups report plans to conduct clinical trials in the near future, building upon the seminal clinical studies of Brindley and Dobelle. In this review, we discuss the general principles of visual prostheses employing electrical stimulation of the visual pathways, focusing on the retina and visual cortex as the two most extensively studied stimulation sites. We also discuss the surgical and functional outcomes reported to date for retinal and cortical prostheses, concluding with a brief discussion of novel developments in this field and an outlook for the future.

Purpose To determine the prevalence of reticular pseudodrusen (RPD) and its association with age-related macular degeneration (AMD) and AMD risk factors in a large sample. Design Community-based cohort study in Melbourne, Victoria, Australia. Participants A total of 21130 participants 48 to 86 years of age available for ophthalmic assessment at follow-up from 2003 through 2007. Methods Lifestyle, diet, and anthropometric measurements were obtained at baseline and follow-up. At follow-up, digital macular color photographs were graded for early, intermediate, and late AMD as well as the presence of RPD. Data were analyzed using multinomial logistic regression controlling for age, gender, smoking, country of birth, and diet. Main Outcome Measures Detection of RPD based on color fundus photographs. Results Prevalence of RPD was 0.41% (87 of 21130 participants), with 51% having bilateral RPD. Patients with RPD were older compared with patients with large drusen (>125 μm; 76±4 vs. 68±9 years; P 125 μm) were associated with a higher prevalence of RPD. Presence of geographic atrophy (GA) was associated with the highest odds of having RPD (odds ratio [OR], 153; 95% confidence interval [CI], 53–442), followed by choroidal neovascularization (CNV; OR, 90; 95% CI, 26–310), intermediate AMD (OR, 33; 95% CI, 14–77), and early AMD (OR, 12; 95% CI, 5–31) compared with those with no AMD. The ARMS2 single nucleotide polymorphism (SNP) rs10490924, HTRA1 SNPs rs11200638 and rs3793917, and CFH SNPs rs393955, rs1061170, and rs2274700 were associated with increased prevalence of RPD (all P Conclusions Reticular pseudodrusen are highly concurrent with AMD and have similar associations with known AMD risk factors such as age, gender, smoking, and genetic risk factors. Reticular pseudodrusen are associated more strongly with GA than with CNV. Although RPD are not specific to AMD, they are likely to be a strong risk factor for progression to late-stage AMD, similar to focal pigmentary abnormalities and large drusen.

Aims To examine 12-month outcomes of eyes switching from intravitreal ranibizumab to aflibercept for neovascular age-related macular degeneration (nAMD). Methods Database observational study of eyes with nAMD tracked by the Fight Retinal Blindness outcome registry that received ranibizumab for at least 12 months before switching to aflibercept and followed for at least 12 months after the switch. Visual acuity (VA) recorded at 12 months after the switch was analysed using locally weighted scatterplot smoothing curves. Lesion activity was graded according to a prospectively identified definition. Main outcomes were change in VA and treatment intervals 12 months after the treatment switch. Secondary outcomes included change in activity grading, effect of duration of treatment before switching and analysis of eyes that switched back. Results A total of 384 eyes switched from ranibizumab to aflibercept after a mean duration of 39.8 months on the original treatment. The mean VA did not change from the time of switching treatment (63.4, SD 15.9 logarithm of the minimum angle of resolution letters) to 12 months later (63.3, SD 16.7). While 10% of eyes gained 10 or more letters 12 months after the switch, 13% lost the same amount. The mean number of injections decreased by around one injection in the 12 months after switching (p

Emergence of the high-resolution optical coherence tomography has allowed better delineation of retinal layers, and many of the anatomical correlations of these layers have now been agreed upon. However, some anatomical correlates still remain contentious, such as the second hyper-reflective band, which is now termed ellipsoid zone. Despite the lack of consensus of the actual origin of the ellipsoid zone, there has been much interest in evaluating its integrity and intensity in different disease processes. This review paper aims to provide an overview of the ellipsoid zone and its clinical and research applications.

The Independent Mobility Questionnaire (IMQ) assesses participants' perceived ability for independent mobility. However, it has not been validated in a severely visually impaired population. The aim of this study was to explore the IMQ's psychometric properties in participants with severe visual impairment.This was a cross-sectional study of 40 participants with retinitis pigmentosa (better eye visual acuity20/200 and/or visual field10%). The key psychometric properties of the IMQ were examined using Rasch analysis, including precision, targeting, and item fit. Construct validity was assessed by testing the correlation between the IMQ and the Mobility and Independence subscale of the Impact of Vision Impairment questionnaire (Pearson correlation coefficient, r). Criterion validity was also assessed.The IMQ had excellent precision (Person Separation Index, 3.01) with the capacity to distinguish at least four strata of participant ability, and item difficulty was well targeted to participant ability (difference between mean person and item measures, -0.21). Items 34, 35, 21, and 14 displayed misfit (infit MnSq1.4); however, given our sample size restrictions, these items were not removed from the analysis. The IMQ had good construct validity (moderate correlation with the Impact of Vision Impairment Mobility subscale, r = 0.595, p0.05) but did not demonstrate criterion validity.The psychometric properties of the IMQ were promising. Our findings are useful for researchers evaluating the effectiveness of novel treatment technologies on mobility in a severely visually impaired population from the participant's perspective. However, further validation studies in larger samples are required to confirm our results.

Age-related macular degeneration (AMD) affects the region of the retina that is responsible for high-resolution vision. It is a major cause of blindness in the aging population. This is the first study that examines the association of redox-modified, cysteine-based, post-translational forms of beta 2-glycoprotein I (β2GPI) in the plasma of individuals with early and late stages of patients with AMD compared with controls. Exploration is also undertaken to assess whether the free thiol form of β2GPI versus the oxidized disulfide form have distinct functional properties in the setting of hydrogen peroxide (H(2)O(2))-mediated cell death of an immortalized human retinal pigment epithelium (RPE) cell line. We demonstrate β2GPI in the retina and choroid of patients with AMD. Free thiol β2GPI is shown to protect the immortalized human RPE cell line against H(2)O(2)-induced cell death, whereas the oxidized form of β2GPI and free thiol bovine serum albumin were not protective. Free thiol β2GPI levels were significantly decreased in patients with late AMD compared with early AMD and healthy controls. Our observations lead to the hypothesis that free thiol β2GPI may protect against oxidative stress injury to RPE cells in the early stages of AMD.

Purpose: Relative ellipsoid zone reflectivity (rEZR) represents a potential biomarker of photoreceptor health on spectral-domain optical coherence tomography (SD-OCT). Because manual quantification of rEZR is laborious and lacks of spatial resolution, automated quantification of the rEZR would be beneficial. The purpose of this study was to evaluate the reliability and reproducibility of an automated rEZR quantification method. Methods: The rEZR was acquired using a manual and an automated approach in eyes with age-related macular degeneration (AMD) and healthy controls. The rEZR obtained from both methods was compared and the agreement between the methods and their reproducibility assessed. Results: Forty eyes of 40 participants with a mean (± standard deviation) age of 65.2 ± 7.8 years were included. Both the manual and automated method showed that control eyes exhibit a greater rEZR than AMD eyes (P < 0.001). Overall, the limits of agreement between the manual and automated method were -7.5 to 7.3 arbitrary units (AU) and 95% of the data points had a difference in the rEZR between the methods of ±8.2%. An expected perfect reproducibility was observed for the automated method, whereas the manual method had a coefficient of repeatability of 6.3 arbitrary units. Conclusions: The automated quantification of rEZR method is reliable and reproducible. Further studies of the rEZR as a novel biomarker for AMD severity and progression are warranted. Translational Relevance: Automated quantification of SD-OCT-based rEZR allows for its comprehensive and longitudinal characterization evaluating its relevance as an in vivo biomarker of photoreceptor function and its prognostic value for AMD progression.

Purpose We determine the feasibility of using a home-based tablet device to monitor retinal sensitivity (RS) in intermediate age-related macular degeneration (iAMD), the benefits of weekly reminders, and the comparison with clinic-based results. Methods A customized test for tablets was designed to measure RS (within central 2°) in individuals with iAMD at weekly intervals in their home, with remote data collection. Half of the participants were randomized to receive weekly test reminders. Clinic-based microperimetric macular sensitivity results were compared to tablet results. Participation rates were analyzed at 2 months. Results Of 38 participants (mean age, 70.3 years) with iAMD enrolled in the study, 21 (55%) were using the tablet-based test at 2 months. Common reasons for inactivity were noncompatible devices (41.1%) or other technology access issues (35.3%). Participants with weekly reminders completed tests more regularly (6.6 ± 3.9 vs. 8.7 ± 4.1 days, P = 0.01), but weekly reminders showed no effect on participation rates (P = 0.69). Mean RS from the tablet device (25.03 ± 2.41 dB) was not significantly different from the clinic-based microperimetry performance (25.21 ± 2.20 dB; P = 0.58). Conclusions Regular monitoring of retinal function on a tablet device in a home setting in individuals with iAMD is feasible with results comparable to those of clinic-based microperimetry. Weekly reminders resulted in more frequent testing. Seamless ability to access technology will be important for higher participation rates. Translational relevance The use of home-monitoring on a tablet-device is promising, but adequate support for an older cohort to take up technology is required if such a tool is to be useful for long-term home monitoring.

To test the hypothesis that tolerating some subretinal fluid (SRF) in patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab using a treat-and-extend (TE) regimen can achieve similar visual acuity (VA) outcomes as treatment aimed at resolving all SRF.Multicenter, randomized, 24-month, phase 4, single-masked, noninferiority clinical trial.Participants with treatment-naïve active subfoveal choroidal neovascularization (CNV).Participants were randomized to receive ranibizumab 0.5 mg monthly until either complete resolution of SRF and intraretinal fluid (IRF; intensive arm: SRF intolerant) or resolution of all IRF only (relaxed arm: SRF tolerant except for SRF200 μm at the foveal center) before extending treatment intervals. A 5-letter noninferiority margin was applied to the primary outcome.Mean change in best-corrected VA (BCVA), and central subfield thickness and number of injections from baseline to month 24.Of the 349 participants randomized (intensive arm, n = 174; relaxed arm, n = 175), 279 (79.9%) completed the month 24. The mean change in BCVA from baseline to month 24 was 3.0 letters (standard deviation, 16.3 letters) in the intensive group and 2.6 letters (standard deviation, 16.3 letters) in the relaxed group, demonstrating noninferiority of the relaxed compared with the intensive treatment (P = 0.99). Similar proportions of both groups achieved 20/40 or better VA (53.5% and 56.6%, respectively; P = 0.92) and 20/200 or worse VA (8.7% and 8.1%, respectively; P = 0.52). Participants in the relaxed group received fewer ranibizumab injections over 24 months (mean, 15.8 [standard deviation, 5.9]) than those in the intensive group (mean, 17 [standard deviation, 6.5]; P = 0.001). Significantly more participants in the intensive group never extended beyond 4-week treatment intervals (13.5%) than in the relaxed group (2.8%; P = 0.003), and significantly more participants in the relaxed group extended to and maintained 12-week treatment intervals (29.6%) than the intensive group (15.0%; P = 0.005).Patients treated with a ranibizumab TE protocol who tolerated some SRF achieved VA that is comparable, with fewer injections, with that achieved when treatment aimed to resolve all SRF completely.

There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD.The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial.Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy.Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RTThe primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events.Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant.In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT

Purpose To report the presence of drusen in infancy, in a patient with Type 1 retinopathy of prematurity and a rare congenital sodium diarrhea secondary to a sporadic GUCY2C mutation. Methods A case report generated by review of clinical course, with imaging of 1 patient and literature review. Results A 1.075-kg infant born at gestation age 27 weeks was admitted to our institution with respiratory distress and secretory diarrhea. During screening for retinopathy of prematurity, peripheral drusen-like subretinal deposits were identified. There were no similar findings in either parent or family history of ocular pathologies. Their distribution is atypical for that seen in other causes of early onset drusen such as autosomal dominant drusen or Sorsby fundus dystrophy. Retinopathy of prematurity was identified, which progressed to Type 1, and was treated with bilateral indirect peripheral retinal photocoagulation at gestational age of 40 weeks. Fluorescein angiography was performed and was consistent with peripheral drusen. Optical coherence tomography of the central macula and an awake electroretinogram at 6 months were normal. Serial examinations confirmed no progression in the drusen-like deposits or in retinopathy of prematurity, with clinically appropriate visual development observed during close follow-up. Conclusion We identify a unique ocular phenotype of retinal drusen-like deposits in an infant with a rare, sporadic GUCY2C mutation.

Complement Factor H (CFH) is an important inhibitor of the alternate complement pathway in Bruch's membrane (BM), located between the choriocapillaris and the retinal pigment epithelium. Furthermore dysfunction of its activity as occurs with certain polymorphisms is associated with an increased risk of age related macular degeneration (AMD). The retina is a site of high generation of reactive oxygen species (ROS) and dysfunction of redox homeostasis in this milieu also contributes to AMD pathogenesis. In this study we wanted to explore if CFH exists in distinct redox forms and whether these species have unique protective biological functions. CFH can be reduced by the naturally occurring thioredoxin - 1 in CFH domains 1-4, 17-20. We found a duality of function between the oxidised and reduced forms of CFH. The oxidised form was more efficient in binding to C3b and lipid peroxidation by-products that are known to accumulate in the retinae and activate the alternate complement pathway. Oxidised CFH enhances Factor I mediated cleavage of C3 and C3b whereas the reduced form loses this activity. In the setting of oxidative stress (hydrogen peroxide)-mediated death of human retinal pigment epithelial cells as can occur in AMD, the free thiol form of CFH offers a protective function compared to the oxidised form. We found for the first time using a novel ELISA system we have developed for free thiol CFH, that both redox forms of CFH are found in the human plasma. Furthermore there is a distinct ratio of these redox forms in plasma depending if an individual has early or late AMD, with individuals with early AMD having higher levels of the free thiol form compared to late AMD.

Purpose: Although impairment of rod function in the early stages of age-related macular degeneration (AMD) has been well recognized, data on longitudinal changes in rod function at multiple retinal locations remain limited. This study investigated the longitudinal changes in retinotopic rod function in eyes with intermediate AMD (iAMD). Methods: Complete ophthalmic examination, multimodal imaging, and scotopic perimetry were performed at baseline and at 12-month follow-up. Perimetric scotopic retinal sensitivities for the 505-nm stimulus were repeatedly measured for 20 minutes after exposing to a single photobleach (∼30%). The rod intercept time (RIT) and retinal sensitivity at seven retinal loci within the central 12° were ascertained. Using the 95% limit of measurement variability derived from the control eyes as a reference, the proportion of test points with a significant change in retinal sensitivity or RIT at follow-up was determined. Results: Twenty iAMD and 6 control eyes were included. Decline in rod function was detected at 12-month follow-up in eyes with iAMD, but not in control eyes. Approximately 25% of test points in iAMD eyes showed a significant increase in RIT compared to 6% of test points with a decrease in RIT over the 12-month period (P < 0.001). Similarly, 40% of test points demonstrated a reduction in retinal sensitivity compared to the 7% of test points with an increase in retinal sensitivity at follow-up (P < 0.001). Conclusions: There are detectable retinotopic changes in rod function over 12 months in iAMD eyes, indicating an ongoing disease progression in rod impairment or loss with time.

Structural variation and single-nucleotide variation of the complement factor H (CFH) gene family underlie several complex genetic diseases, including age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (AHUS). To understand its diversity and evolution, we performed high-quality sequencing of this ∼360-kbp locus in six primate lineages, including multiple human haplotypes. Comparative sequence analyses reveal two distinct periods of gene duplication leading to the emergence of four CFH-related (CFHR) gene paralogs (CFHR2 and CFHR4 ∼25-35 Mya and CFHR1 and CFHR3 ∼7-13 Mya). Remarkably, all evolutionary breakpoints share a common ∼4.8-kbp segment corresponding to an ancestral CFHR gene promoter that has expanded independently throughout primate evolution. This segment is recurrently reused and juxtaposed with a donor duplication containing exons 8 and 9 from ancestral CFH, creating four CFHR fusion genes that include lineage-specific members of the gene family. Combined analysis of >5,000 AMD cases and controls identifies a significant burden of a rare missense mutation that clusters at the N terminus of CFH [P = 5.81 × 10-8, odds ratio (OR) = 9.8 (3.67-Infinity)]. A bipolar clustering pattern of rare nonsynonymous mutations in patients with AMD (P 2,400 individuals reveals five recurrent rearrangement breakpoints that show variable frequency among AMD cases and controls. These data suggest a dynamic and recurrent pattern of mutation critical to the emergence of new CFHR genes but also in the predisposition to complex human genetic disease phenotypes.

IMPORTANCE: Reticular pseudodrusen (RPD) is strongly associated with late age-related macular degeneration (AMD) but their aetiology remains unknown. RPD have been associated with reduced choroidal thickness (ChT) but most studies are limited by small sample size and varying severity of AMD. BACKGROUND: To investigate the relationship between choroidal thickness and RPD in eyes with intermediate AMD (iAMD), controlling for variables known to influence ChT. DESIGN: Retrospective cohort study. PARTICIPANTS: Participants were recruited from Centre for Eye Research Australia. METHODS: Colour fundus photographs, fundus auto fluorescence, near-infrared and spectral-domain ocular coherence tomography (OCT) were graded for RPD. ChT was measured from enhanced-depth imaging OCT scans at the centre of fovea, 1500 and 3000 μm nasal, temporal, superior and inferior from centre of fovea. MAIN OUTCOME MEASURES: ChT between RPD and non-RPD group. RESULTS: A total of 297 eyes from 152 subjects were included. A total of 84 (28%) had RPD and were older than non-RPD group (75.1 ± 5.4 years and 68.7 ± 6.9 years, respectively; P < 0.001). In unadjusted analysis, the RPD group was significantly associated with thinner choroids across all measured locations (P ≤ 0.022). After adjustment for variables, the presence of RPD was no longer associated with ChT (P ≥ 0.132 for all locations) but age (P < 0.001) and refractive error (P = 0.002) remained significantly associated with ChT. CONCLUSIONS AND RELEVANCE: Age and refractive error, rather than RPD, was significantly associated with reduced ChT in eyes with iAMD. Choroidal insufficiency may be a less important variable in RPD aetiology than previously considered.

Reticular pseudodrusen (RPD), also known as subretinal drusenoid deposits, represent a morphological change to the retina distinct from other subtypes of drusen by being located above the level of the retinal pigment epithelium. Although they can infrequently appear in individuals with no other apparent pathology, their highest rates of occurrence are in association with age-related macular degeneration (AMD), for which they hold clinical significance by being highly correlated with end-stage disease sub-types, choroidal neovascularisation and geographic atrophy. Reticular pseudodrusen are also found in other diseases, most notably Sorsby's fundus dystrophy, pseudoxanthoma elasticum and acquired vitelliform lesions. They are found more frequently in females, with increased age and more commonly bilaterally than unilaterally. Increased risk of RPD formation is conveyed by genetic variants known to increase risk of AMD development, including complement factor H, age-related maculopathy susceptibility 2, and high-temperature requirement A serine peptidase 1; however, to date, no genetic factor has been found to predispose to RPD independent of those that carry risks for AMD. They have typical features visible on multimodal imaging, identifiable either as single lesions or more commonly in yellowish-white net-like patterns on colour fundus photography and are particularly distinguishable using spectral domain optical coherence tomography, fundus auto-fluorescence, and near infrared reflectance imaging. On histological examination, RPD have been shown to have distinct compositions in comparison to typical drusen, suggesting different pathways of pathogenesis. Although their aetiology remains unclear, presence of opsin within lesions, a high topographic association with areas of highest rod-photoreceptor concentration and functional deficits most pronounced within the scotopic range, has implicated rod photoreceptor dysfunction as a component of RPD.

To assess outcomes of the treat-and-extend (TE) injection regimen for neovascular age-related macular degeneration (AMD) as compared to either a monthly or a pro re nata (PRN) treatment strategy.Systematic review and meta-analysis.Studies that compared the TE regimen with either monthly or PRN dosing for treatment-naïve AMD were included. Trial eligibility, data extraction, and risk of bias were assessed according to Cochrane review methods. Estimates were pooled using random-effects meta-analysis.Four eligible studies were identified, all using ranibizumab (total N = 940 eyes), including 2 randomized controlled trials comparing TE to monthly and 2 retrospective reviews comparing TE to PRN. No studies evaluating aflibercept were identified. Improvements in vision and central retinal thickness were similar between TE and monthly at 12 months, with a mean difference of -1.79 letters (95% confidence interval [CI]: 3.70, 0.13) and 3.76 μm (95% CI: -13.78, 21.30) in favor of monthly injections. In contrast, visual gains were higher in the TE compared to the PRN group (difference of +6.18 letters, 95% CI: 3.28, 9.08). Fewer injections were required using the TE regimen when compared to monthly (mean of -1.6 and -6.9 injections at 12 and 24 months, respectively). A mean of 1.44 more injections was required for the TE compared to PRN regimen at 12 months; however, this was achieved with fewer visits.Despite the growing preference for the TE regimen, there is limited head-to-head evidence comparing dosing strategies. The evidence available, however, suggests that at 12 months, TE is comparable to monthly and superior to PRN dosing for both efficacy and safety outcomes when using ranibizumab.

Purpose Subthreshold, nanosecond pulsed laser treatment shows promise as a treatment for age-related macular degeneration (AMD); however, the safety profile needs to be robustly examined. The aim of this study was to investigate the effects of laser treatment in humans and mice. Methods Patients with AMD were treated with nanosecond pulsed laser at subthreshold (no visible retinal effect) energy doses (0.15-0.45 mJ) and retinal sensitivity was assessed with microperimetry. Adult C57BL6J mice were treated at subthreshold (0.065 mJ) and suprathreshold (photoreceptor loss, 0.5 mJ) energy settings. The retinal and vascular responses were analyzed by fundus imaging, histologic assessment, and quantitative PCR. Results Microperimetry analysis showed laser treatment had no effect on retinal sensitivity under treated areas in patients 6 months to 7 years after treatment. In mice, subthreshold laser treatment induced RPE loss at 5 hours, and by 7 days the RPE had retiled. Fundus imaging showed reduced RPE pigmentation but no change in retinal thickness up to 3 months. Electron microscopy revealed changes in melanosomes in the RPE, but Bruch's membrane was intact across the laser regions. Histologic analysis showed normal vasculature and no neovascularization. Suprathreshold laser treatment did not induce changes in angiogenic genes associated with neovascularization. Instead pigment epithelium-derived factor, an antiangiogenic factor, was upregulated. Conclusions In humans, low-energy, nanosecond pulsed laser treatment is not damaging to local retinal sensitivity. In mice, treatment does not damage Bruch's membrane or induce neovascularization, highlighting a reduced side effect profile of this nanosecond laser when used in a subthreshold manner.

IMPORTANCE: Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD. OBJECTIVE: To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD. DESIGN, SETTING, AND PARTICIPANTS:: In this multicenter genome-wide association study, 678 patients with nAMD with genome-wide genotyping data were included in the discovery phase; 1380 additional patients with nAMD were genotyped for selected common variants in the replication phase. All participants received 3 monthly injections of bevacizumab or ranibizumab. Clinical data were evaluated for inclusion/exclusion criteria from October 2014 to October 2015, followed by data analysis from October 2015 to February 2016. For replication cohort genotyping, clinical data collection and analysis (including meta-analysis) was performed from March 2016 to April 2017. MAIN OUTCOMES AND MEASURES: Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline. RESULTS: Of the 2058 included patients, 1210 (58.8%) were women, and the mean (SD) age across all cohorts was 78 (7.4) years. Patients included in the discovery cohort and most of the patients in the replication cohorts were of European descent. The mean (SD) baseline VA was 51.3 (20.3) Early Treatment Diabetic Retinopathy Study (ETDRS) score letters, and the mean (SD) change in VA after the loading dose of 3 monthly injections was a gain of 5.1 (13.9) ETDRS score letters (ie, 1-line gain). Genome-wide single-variant analyses of common variants revealed 5 independent loci that reached a P value less than 10 × 10−5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; P = 1.38 × 10−5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10−7) and UNC93B1 (P = 6.09 × 10−7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 genes lost a mean (SD) VA of 30.6 (17.4) ETDRS: score letters (ie, loss of 6.09 lines) and 26.5 (13.8) ETDRS score letters (ie, loss of 5.29 lines), respectively, after 3 months of anti-VEGF treatment. CONCLUSIONS AND RELEVANCE: We propose that there is a limited contribution of common genetic variants to variability in nAMD treatment response. Our results suggest that rare protein-altering variants in the C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.

International audience; PURPOSE:To report 24-month outcomes of a treat and extend (T&E) regimen using aflibercept in eyes with neovascular age-related macular degeneration.METHODS:This was a database observational study that included treatment-naive eyes with neovascular age-related macular degeneration tracked by the Fight Retinal Blindness! outcome registry completing 24 months of sole monotherapy with aflibercept treatment under a T&E regimen between November 1, 2012 and January 31, 2014. Locally weighted scatterplot smoothing curves were used to display visual acuity outcomes. Main outcome measures were change in visual acuity at 24 months and number of injections and visits during the study period.RESULTS:The study population, identified by reviewing the database, consisted of 136 eyes from 123 patients completing 24 months of follow-up on aflibercept. Mean (SD) age was 77.2 (7.0) years, 59% were female. Mean visual acuity increased from 61.4 (∼20/60; SD 17.4) letters at baseline to 67.4 (∼20/45; SD 17.7) letters at 24 months (+6.0 letters [95% confidence interval: 3.3-8.5]; P < 0.001). From baseline to 24 months, the proportion of eyes with visual acuity ≥70 letters (20/40) increased (40%-58%, P < 0.001) and the proportion of eyes with visual acuity ≤35 letters (20/200) remained the same (10%; P = 0.547). Ninety-eight per cent of eyes starting with visual acuity ≥70 letters (20/40) were able to maintain this up to 24 months. From the first to the second year of treatment, the mean number of injections (7.8 [2.1] vs. 5.7 [2.6]; P < 0.001) and visits (8.7 [1.7] vs. 6.5 [2.4]; P < 0.001) decreased for eyes completing 24 months of treatment. When data from 60 eligible eyes that did not complete 2 years follow-up, along with 14 eyes that switched to ranibizumab, were included using last observation carried forward, the mean change in visual acuity from baseline was +5.6 letters (95% confidence interval: 3.3-7.7).CONCLUSION:These data indicate that eyes treated with aflibercept, as a sole therapy, in routine clinical practice with a T&E regimen can achieve good visual outcomes while decreasing the burden of treatments and clinic visits.

Purpose To analyze the long-term outcomes of eyes with neovascular age-related macular degeneration (AMD) starting treatment with vascular endothelial growth factor (VEGF) inhibitors at least 5 years earlier. Design Database observational study. Participants Treatment-naive eyes with neovascular AMD tracked by the Fight Retinal Blindness outcome registry that received at least 1 anti-VEGF injection. Methods Locally weighted scatterplot smoothing curves were used to display visual acuity (VA) results. Main Outcome Measures Change in mean VA and number of injections and visits from baseline up to 7 years after initiating treatment. Results The mean follow-up time of all 1212 identified eyes was 53.5 months, and 549 (45%) continued attending after 60 months. Mean VA improved from 55.1 to 61.4 letters after 6 months and remained above the mean presenting VA for approximately 6 years. After 7 years, mean VA was 2.6 letters lower than baseline for the 131 eyes still being followed; 40% had VA ≥70 (20/40) letters, and 18% had VA ≤35 letters (20/200). Of those with 20/40 VA before treatment, 40% had lost it after 7 years. Geographic atrophy affecting the fovea was thought to be the cause of a ≥10-letter loss after 6.5 years in 37% of a subset of such eyes that were retrospectively analyzed. A median of 6 injections and 9 visits were recorded over the first 12 months, and then 5 treatments and 7 to 9 visits per annum thereafter through 7 years. Treatment was discontinued for 663 eyes (53%) within the first 5 years. Despite initial gains in vision, the mean VA of these eyes had deteriorated to baseline or worse around the time treatment was discontinued. The rate of serious adverse events was low. Conclusions Good long-term outcomes of VEGF inhibition for neovascular AMD were found in this study. These results may be better than other reports because more injections were given to our patients, possibly associated with a greater incentive for the physician to treat. Further studies to determine how to maximize the proportion of eyes that retain the initial VA gains of anti-VEGF are warranted.

Age-related macular degeneration (AMD) is a progressive, degenerative disease of the retina that occurs with increasing incidence with age and ranks third among the global causes of visual impairment. VEGF has been implicated in the development and progression of neovascular AMD. Drugs that block VEGF, leading to regression of the abnormal blood vessels, are the mainstay of treatment of neovascular AMD, particularly for subfoveal neovascular lesions. Anti-VEGF agents currently in use in neovascular AMD are pegaptanib (Macugen(®)), ranibizumab (Lucentis(®)), bevacizumab (Avastin(®)) and a soluble VEGF receptor decoy aflibercept (Eylea(®)). Recently, China Food and Drug Administration have approved conbercept for the treatment of neovascular AMD in China. Conbercept appears to offer yet another anti-VEGF drug for use in neovascular AMD. However, there is still a need for large, well-designed, randomized clinical trials to ensure its safety and efficacy.