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Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. Monthly or as-needed (PRN) dosing strategies of intravitreal ranibizumab have been established as efficacious treatment options for neovascular AMD. More recently, the 'treat-and-extend' dosing regimen (TREX) is being adopted in clinical practice as it represents a patient-centric and economical option, reducing treatment burden by extending injection intervals when possible. However, the efficacy of TREX using ranibizumab monotherapy remains to be defined. Therefore, we performed a systematic review to assess the current evidence for TREX using ranibizumab by searching MEDLINE, Embase and PubMed. Of the 1733 articles identified, nine TREX studies were included in our analysis (n=748 eyes). Average patient age was 79.25 (range: 77.34-82.00; SD: 7.27). Baseline BCVA ranged from 48.5-68.9 ETDRS letters. BCVA improvement was 8.92 letters at 1 year (range: 6.5-11.5; SD: 7.54), as a weighted mean accounting for numbers of study eyes. The weighted mean number of injections at one year was 8.60 (range: 7.3-12.0; SD: 1.73). Previously, the landmark ANCHOR and MARINA trials reported gains of 11.3 and 7.2 letters, respectively, using monthly ranibizumab. Chin-Yee et al reported a gain of 3.5 ETDRS letters with 5.3 (S.D. 0.66) PRN ranibizumab injections as weighted means at 1 year in their recent systematic review. Our analysis suggests that TREX delivers visual outcomes superior to PRN and approaches similar efficacy to monthly injections. Further RCTs are needed to fully evaluate the efficacy and economy of TREX in the long-term.

Age-related macular degeneration (AMD) is a major cause of visual impairment that affects the central retina. Genome wide association studies and candidate gene screens have identified members of the complement pathway as contributing to the risk of AMD. In this review, we discuss the complement system, its importance in retinal development and normal physiology, how its dysregulation may contribute to disease, and how it might be targeted to prevent damage to the aging choriocapillaris in AMD., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The Retinal Pigment Epithelium (RPE) forms the primary site of pathology in several blinding retinopathies. RPE cultures are being continuously refined so that dynamic disease processes in this important monolayer can be faithfully studied outside the eye over longer periods. The RPE substrate, which mimics the supportive Bruch's membrane (BrM), plays a key role in determining how well in-vitro cultures recapitulate native RPE cells. Here, we evaluate how two different types of BrM substrates; (1) a commercially-available polyester transwell membrane, and (2) a novel electrospun scaffold developed in our laboratory, could support the generation of realistic RPE tissues in culture. Our findings reveal that both substrates were capable of supporting long-lasting RPE monolayers with structural and functional specialisations of in-situ RPE cells. These cultures were used to study autofluorescence and barrier formation, as well as activities such as outer-segment internalisation/trafficking and directional secretion of key proteins; the impairment of which underlies retinal disease. Hence, both substrates fulfilled important criteria for generating authentic in-vitro cultures and act as powerful tools to study RPE pathophysiology. However, RPE grown on electrospun scaffolds may be better suited to studying complex RPE-BrM interactions such as the formation of drusen-like deposits associated with early retinal disease., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We conducted a systematic review of the accuracy of fundus autofluorescence (FAF) imaging for diagnosing and monitoring retinal conditions. Searches in November 2014 identified English language references. Sources included MEDLINE, EMBASE, the Cochrane Library, Web of Science, and MEDION databases; reference lists of retrieved studies; and internet pages of relevant organisations, meetings, and trial registries. For inclusion, studies had to report FAF imaging accuracy quantitatively. Studies were critically appraised using QUADAS risk of bias criteria. Two reviewers conducted all review steps. From 2240 unique references identified, eight primary research studies met the inclusion criteria. These investigated diagnostic accuracy of FAF imaging for choroidal neovascularisation (one study), reticular pseudodrusen (three studies), cystoid macular oedema (two studies), and diabetic macular oedema (two studies). Diagnostic sensitivity of FAF imaging ranged from 32 to 100% and specificity from 34 to 100%. However, owing to methodological limitations, including high and/or unclear risks of bias, none of these studies provides conclusive evidence of the diagnostic accuracy of FAF imaging. Study heterogeneity precluded meta-analysis. In most studies, the patient spectrum was not reflective of those who would present in clinical practice and no studies adequately reported whether FAF images were interpreted consistently. No studies of monitoring accuracy were identified. An update in October 2016, based on MEDLINE and internet searches, identified four new studies but did not alter our conclusions. Robust quantitative evidence on the accuracy of FAF imaging and how FAF images are interpreted is lacking. We provide recommendations to address this.

PurposeTo investigate 1-year visual and anatomic outcomes of intravitreal aflibercept for neovascular age-related macular degeneration (nAMD) given at a fixed 8-weekly interval.MethodsRetrospective, single-practice data analysis from an electronic medical record system of 255 eyes (223 patients) with treatment-naïve nAMD receiving 8-weekly aflibercept.ResultsMean logarithm of the minimum angle of resolution best-corrected visual acuity (BCVA) improved from 0.66 at baseline to 0.50 at month 11 (P<0.0001). Mean central retinal thickness (CRT) decreased from 311 μm at baseline to 211 μm at month 11 (P<0.0001). Our mean VA gain of eight ETDRS letters was comparable to the VIEW 1 and VIEW 2 Trials' results at the end of year 1. After loading at month 5, mean BCVA was 0.48 (P<0.0001), and mean CRT was 235 μm. At month 5, 143 eyes (56%) were inactive defined by the absence of macular haemorrhage and intraretinal fluid (IRF) and subretinal fluid (SRF) on optical coherence tomography, and 112 eyes (44%) remained active. At month 11, 136 eyes (53%) were inactive, and 119 eyes (47%) remained active. At month 11, 77% of inactive eyes after loading remained inactive, and 77% of the active eyes after loading remained active. At month 11, mean BCVA of the inactive group was 0.51, and mean BCVA of the active group was 0.48 (P=0.54).ConclusionsAflibercept administered by fixed dosing over 1 year improved VA and macular morphology in treatment-naïve eyes. Active lesions at month 11 do not have worse VA outcomes compared with inactive lesions. The macular status after loading is a reliable indicator of disease activity at the end of year 1.

Age-related macular degeneration (AMD) causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer's-linked amyloid beta (Aβ) group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer's disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Aβ fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Aβ were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Aβ accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Aβ-mediated retinopathy. Furthermore, we discuss our findings revealing how Aβ behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Aβ as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for late-stage AMD., Competing Interests: Conflicts of interest: The authors report no conflicts on interests.

Background: Autosomal dominant cone-rod dystrophy 7 (CORD7) has been previously associated with the RIM1 c.2459G>A (Arg820His) mutation. Cystoid macular oedema (CMO) is a rare feature of CORD and has not been described in CORD7. We report a patient who was heterozygous for the RIM1 mutation with bilateral CMO and who manifested a retinitis pigmentosa phenotype., Materials and Methods: The patient's medical notes were retrospectively reviewed over an 18-month period. Genetic testing was performed by next generation sequencing for a panel of 176 genes associated with retinal dystrophy., Results: A 34-year-old man presented with a 5-year history of bilateral floaters and blurred vision. Visual acuity was 20/23 and 20/33 in the right and left eyes, respectively. Optical coherence tomography scans revealed bilateral CMO. Goldmann visual field tests detected mid-peripheral ring scotomas. Electrodiagnostic testing was overall consistent with a primary photoreceptor abnormality involving both rods and cones. Subsequent genetic testing identified heterozygosity for the RIM1 c.2459G>A (Arg820His) mutation. Various treatments for CMO were trialled unsuccessfully. However, at his latest clinic appointment the CMO had partially improved following topical brinzolamide therapy. Most recent visual acuity was 20/25 in the right eye and 20/24 in the left eye., Conclusions: This is the first reported case of bilateral CMO in association with the RIM1 mutation. Overall, our findings were more consistent with a phenotype of retinitis pigmentosa. This could imply that the RIM1 mutation causes diverse retinal dystrophies, or that the previously described CORD7 phenotype resulted from a different variant on the same haplotype.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: To describe associations of ocular and systemic factors with retinal pigment epithelium (RPE)-Bruch's membrane (BM) complex thickness as measured by spectral-domain (SD) optical coherence tomography (OCT)., Design: Multisite community-based study. This research has been conducted using the UK Biobank Resource., Participants: Sixty-seven thousand three hundred eighteen people 40 to 69 years old received questionnaires, physical examination, and eye examination, including macular SD OCT. Systematic selection process identified 34 652 eyes with high-quality SD OCT images from normal individuals for analysis., Methods: We included people with no self-reported ocular disease, diabetes, or neurologic disorders; visual acuity of ≥20/25; refraction between -6 diopters (D) to 6 D, and IOP of 6 to 21 mmHg. Only high-quality, well-centered SD OCT images with central, stable fixation were included. Descriptive statistics, t tests, and regression analyses were performed. Multivariate regression modeling was used to adjust for covariates and to identify relationships between RPE-BM thickness and ocular and systemic features., Main Outcome Measures: Retinal pigment epithelium-BM thickness, as measured by SD OCT segmentation using Topcon Advanced Boundary Segmentation at 9 Early Treatment of Diabetic Retinopathy Study subfields., Results: Mean RPE-BM thickness was 26.3 μm (standard deviation, 4.8 μm) at central subfield. Multivariate regression with age stratification showed that RPE thinning became apparent after age 45. Among those aged ≤45, RPE-BM was significantly thicker among those of black or mixed/other race (+3.61 and +1.77 μm vs. white, respectively; P < 0.001) and higher hyperopia (+0.4 μm/D; P < 0.001), but not for other variables considered. Among those age >45, RPE-BM was significantly thinner with older age (-0.10 μm/year; P < 0.001), Asian ethnicity (-0.45 μm vs. white; P = 0.02), taller height (-0.02 μm/cm; P < 0.001), higher IOP (-0.03 μm/mmHg; P < 0.001), and regular smoking (-0.27 μm vs. nonsmokers; P = 0.02). In contrast, RPE-BM was significantly thicker among black or mixed/other race (+3.29 μm and +0.81 μm vs. white, respectively; P < 0.001) and higher hyperopia (+0.28 μm/D; P < 0.001). There was no significant association with sex or Chinese ethnicity., Conclusions: We describe novel findings of RPE-BM thickness in normal individuals, a structure that varies with age, ethnicity, refraction, IOP, and smoking. The significant association with IOP is especially interesting and may have relevance for the etiology of glaucoma, while the association between age and smoking may have relevance for the etiology of age-related macular degeneration., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

PurposeTo study the usefulness of multicolor imaging (MC) photographs in addition to near infrared reflectance (NIR) and spectral domain optical coherence tomography (SD-OCT) in the detection and follow up of acute macular neuroretinopathy (AMN).Patients and methodsSix patients with a complaint of paracentral scotomas in at least one eye due to AMN were included. They underwent full ophthalmic examination and multimodal imaging including color fundus photographs, (SD-OCT), NIR, and MC at baseline and follow up.ResultsFour females and two males, aged 19-64 years, and eight eyes affected by AMN, were included. Acute phase SD-OCT in all patients confirmed the diagnosis of type 2 AMN with partial recovery of the outer retina in the convalescent phase. NIR and MC elicited in all cases hypo-reflective AMN lesions pointing toward the fovea. MC exhibited a higher contrast between the affected and the physiologic retina that slowly attenuated during the follow up showing a decrease in the hypo-reflectance of the lesions.ConclusionMC imaging was more detailed than fundus color photographs and as detailed as NIR in the detection of AMN. When available, MC imaging should complement SD-OCT and NIR in the diagnosis and follow up of this rare inflammatory condition that may be underdiagnosed.

Anti-vascular endothelial growth factor (VEGF) intravitreal agents are the only successful treatment for wet age-related macular degeneration (AMD). However, there are emerging signals that anti-VEGF treatment can potentially increase development of geographic atrophy (GA). Histopathologic, animal, and clinical studies support this hypothesis although direct proof of a relationship between GA and use of anti-VEGF agents in neovascular AMD is not yet established. This review presents current evidence supporting an association between anti-VEGF therapy and progression of geographic atrophy. The need of exploring alternative methods of treating AMD is indirectly but clearly emphasized.

Age-related Macular Degeneration (AMD) is a common, irreversible blinding condition that leads to the loss of central vision. AMD has a complex aetiology with both genetic as well as environmental risks factors, and share many similarities with Alzheimer's disease. Recent findings have contributed significantly to unravelling its genetic architecture that is yet to be matched by molecular insights. Studies are made more challenging by observations that aged and AMD retinas accumulate the highly pathogenic Alzheimer's-related Amyloid beta (Aβ) group of peptides, for which there appears to be no clear genetic basis. Analyses of human donor and animal eyes have identified retinal Aβ aggregates in retinal ganglion cells (RGC), the inner nuclear layer, photoreceptors as well as the retinal pigment epithelium. Aβ is also a major drusen constituent; found correlated with elevated drusen-load and age, with a propensity to aggregate in retinas of advanced AMD. Despite this evidence, how such a potent driver of neurodegeneration might impair the neuroretina remains incompletely understood, and studies into this important aspect of retinopathy remains limited. In order to address this we exploited R28 rat retinal cells which due to its heterogeneous nature, offers diverse neuroretinal cell-types in which to study the molecular pathology of Aβ. R28 cells are also unaffected by problems associated with the commonly used RGC-5 immortalised cell-line, thus providing a well-established model in which to study dynamic Aβ effects at single-cell resolution. Our findings show that R28 cells express key neuronal markers calbindin, protein kinase C and the microtubule associated protein-2 (MAP-2) by confocal immunofluorescence which has not been shown before, but also calretinin which has not been reported previously. For the first time, we reveal that retinal neurons rapidly internalised Aβ 1-42 , the most cytotoxic and aggregate-prone amongst the Aβ family. Furthermore, exposure to physiological amounts of Aβ 1-42 for 24 h correlated with impairment to neuronal MAP-2, a cytoskeletal protein which regulates microtubule dynamics in axons and dendrites. Disruption to MAP-2 was transient, and had recovered by 48 h, although internalised Aβ persisted as discrete puncta for as long as 72 h. To assess whether Aβ could realistically localise to living retinas to mediate such effects, we subretinally injected nanomolar levels of oligomeric Aβ 1-42 into wildtype mice. Confocal microscopy revealed the presence of focal Aβ deposits in RGC, the inner nuclear and the outer plexiform layers 8 days later, recapitulating naturally-occurring patterns of Aβ aggregation in aged retinas. Our novel findings describe how retinal neurons internalise Aβ to transiently impair MAP-2 in a hitherto unreported manner. MAP-2 dysfunction is reported in AMD retinas, and is thought to be involved in remodelling and plasticity of post-mitotic neurons. Our insights suggest a molecular pathway by which this could occur in the senescent eye leading to complex diseases such as AMD., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: To determine real life clinical outcomes in poorly responsive and treatment-naïve neovascular age related macular degeneration (nvAMD) patients using bimonthly fixed dosing aflibercept regimen., Methods: This was a retrospective study of 165 eyes with nvAMD started on aflibercept at Southampton Eye Unit between June 2013 and June 2014. Patients were either switched from pro re nata (PRN) ranibizumab/bevacizumab due to poor response (107 eyes), or treatment-naïve (58 eyes). Patients initially received 3-monthly intravitreal aflibercept injections followed by 2-monthly fixed doses. Clinic visits were scheduled at month 0, 4, 10 and 12. Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline were assessed using the Wilcoxon signed-rank test. The proportion of patients maintaining BCVA (<15 letters loss) at 12mo was also evaluated., Results: Mean BCVA change at month 12 was +3.29 and +4.67 letters in the switched and naïve aflibercept groups respectively (P<0.01). BCVA was maintained in 95.3% of switched and 96.6% of naïve patients. CRT at month 12 showed a decrease of -6.16 µm in the switched group and -35.36 µm in the naïve group (P<0.01). Patients previously treated with ranibizumab/bevacizumab had on average received 7.4 ranibizumab/bevacizumab injections over 12.6mo, attending 10 clinic visits. The fixed dosing aflibercept regimen required an average of 7.1 injections (naïve group), 7.5 injections (switched group) and 4 clinic visits per year., Conclusion: Fixed bimonthly aflibercept is effective in both treatment-naïve and poorly responsive nvAMD patients. Adopting a fixed dosing regimen can reduce patient burden without compromising on outcomes.

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Purpose: Aflibercept has the potential advantage of reducing capacity problems by allowing 2 monthly visits for patients with neovascular macular degeneration (nAMD) compared with monthly pro re nata regimens that are the most commonly used in the United Kingdom. This study aimed to report the visual outcomes achieved in routine clinical practice using the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) protocol at 1 year and compare with trials data and other real-world reports., Design: Retrospective data analysis from an electronic medical record., Participants: Consecutive series of treatment-naïve patients initiated on aflibercept for nAMD at least 1 year before data extraction., Methods: Data were anonymized and remotely extracted from 16 centers in the United Kingdom that use the same electronic medical record (EMR) system (Medisoft Ophthalmology; Medisoft Limited, Leeds, UK)., Main Outcome Measures: The minimum data set defined before first data entry and mandated by the EMR included age, gender, visual acuity, injection episodes, and complications., Results: The mean age was 80.0 years (median, 81.0 years) and 63.7% were women. During the first year of treatment with aflibercept, 1840 treatment-naïve eyes of 1682 patients received a median of 8 (mean, 7.0) injections at a median of 8 (mean, 7.3) visits. The mean baseline visual acuity was 53.7 letters, improving to 58.8 letters (+5.1-letter gain) at 1 year. In first-treated eyes, the respective figures were 52.7 letters at baseline and 58.2 letters at 1 year, a gain of +5.5 letters. The proportion achieving 70 letters or more increased from 16.4% at baseline to 33.7% at 1 year, and 92% avoided moderate visual loss at 1 year., Conclusions: The visual acuity outcomes are comparable to randomized trials and better than many previous real-world data collections, with a mean +5.1-letter gain at 1 year compared with +8.4 letters in the integrated analysis of the VIEW 1 and VIEW 2 studies. Early visual gains were maintained through the year. Collection of outcomes beyond clinical trials can have limitations but better reflect the full pool of patients actually treated and are important to determine whether a particular treatment is performing as expected. Such data also have the potential to improve services by setting up a mechanism to compare sites., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

In the age-related macular degeneration (AMD) 'inflammation model', local inflammation plus complement activation contributes to the pathogenesis and progression of the disease. Multiple genetic associations have now been established correlating the risk of development or progression of AMD. Stratifying patients by their AMD genetic profile may facilitate future AMD therapeutic trials resulting in meaningful clinical trial end points with smaller sample sizes and study duration.

Background: Bevacizumab (Avastin®, Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis®, Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs., Objective: To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD., Design: Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed., Setting: Twenty-three ophthalmology departments in NHS hospitals., Participants: Patients ≥ 50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ≥ 25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter > 6000 µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required., Interventions: Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5 mg or bevacizumab 1.25 mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated., Main Outcome Measures: The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes., Results: Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p = 0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p = 0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p = 0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p = 0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p = 0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses., Conclusions: Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment., Trial Registration: Current Controlled Trials ISRCTN92166560., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 78. See the NIHR Journals Library website for further project information.

Age-related macular degeneration (AMD) is one of the most common causes of irreversible blindness affecting nearly 50 million individuals globally. The disease is characterised by progressive loss of central vision, which has significant implications for quality of life concerns in an increasingly ageing population. AMD pathology manifests in the macula, a specialised region of the retina, which is responsible for central vision and perception of fine details. The underlying pathology of this complex degenerative disease is incompletely understood but includes both genetic as well as epigenetic risk factors. The recent discovery that amyloid beta (Aβ), a highly toxic and aggregate-prone family of peptides, is elevated in the ageing retina and is associated with AMD has opened up new perspectives on the aetiology of this debilitating blinding disease. Multiple studies now link Aβ with key stages of AMD progression, which is both exciting and potentially insightful, as this identifies a well-established toxic agent that aggressively targets cells in degenerative brains. Here, we review the most recent findings supporting the hypothesis that Aβ may be a key factor in AMD pathology. We describe how multiple Aβ reservoirs, now reported in the ageing eye, may target the cellular physiology of the retina as well as associated layers, and propose a mechanistic pathway of Aβ-mediated degenerative change leading to AMD.

The retinal pigment epithelium (RPE) is a single layer of cells that supports the light-sensitive photoreceptor cells that are essential for retinal function. Age-related macular degeneration (AMD) is a leading cause of visual impairment, and the primary pathogenic mechanism is thought to arise in the RPE layer. RPE cell structure and function are well understood, the cells are readily sustainable in laboratory culture and, unlike other cell types within the retina, RPE cells do not require synaptic connections to perform their role. These factors, together with the relative ease of outer retinal imaging, make RPE cells an attractive target for cell transplantation compared with other cell types in the retina or central nervous system. Seminal experiments in rats with an inherited RPE dystrophy have demonstrated that RPE transplantation can prevent photoreceptor loss and maintain visual function. This review provides an update on the progress made so far on RPE transplantation in human eyes, outlines potential sources of donor cells, and describes the technical and surgical challenges faced by the transplanting surgeon. Recent advances in the understanding of pluripotent stem cells, combined with novel surgical instrumentation, hold considerable promise, and support the concept of RPE transplantation as a regenerative strategy in AMD.

The Ranibizumab for the Treatment of Choroidal Neovascularisation (CNV) Secondary to Pathological Myopia (PM): an Individualized Regimen (REPAIR) trial was a prospective study exploring the efficacy and safety of intravitreal ranibizumab 0.5 mg using an individualized treatment regimen over 12 months. The current study investigated the impact of treatment with ranibizumab as needed (pro re nata [PRN]) on individuals with myopic choroidal neovascularization (mCNV) in the REPAIR study, using patient-reported outcome measures (PROMs) for treatment satisfaction and well-being. This study included 65 adults with mCNV and a best-corrected visual acuity (BCVA) letter score of 24-78 in the study eye. Patients completed the Macular Disease Treatment Satisfaction Questionnaire (MacTSQ) at months 1, 6 and 12, and the 12-item Well-Being Questionnaire (W-BQ12) at baseline and months 1, 6 and 12. Subgroup analyses investigated the relationship between PROM scores and treatment in the better- or worse-seeing eye (BSE/WSE), number of injections received, baseline BCVA, BCVA improvement and age. Pearson correlations between change in BCVA, MacTSQ scores and W-BQ12 scores were calculated. The main outcome measures were treatment satisfaction measured with the MacTSQ (score 0-72) and well-being measured with the W-BQ12 (score 0-36). Treatment satisfaction significantly increased over the study period (p = 0.0001). Mean MacTSQ scores increased by 9.7 and 10.0 in patients treated in their WSE and BSE, respectively. Treatment satisfaction was highest in individuals receiving only one injection at month 1; however, by month 12, scores were similar across injection subgroups. Patients aged 68 years or older had the highest MacTSQ scores. Well-being scores also significantly increased over the study period (p = 0.03). Mean W-BQ12 scores increased by 1.7 in patients treated in their WSE and by 2.1 in patients treated in their BSE. Individuals aged 40 years or younger had the greatest increases in general well-being. Patients who experienced stable or improved BCVA at month 12 had greater increases in W-BQ12 scores than those who experienced a decrease. Correlations between BCVA, MacTSQ scores and W-BQ12 scores were largely non-significant. In conclusion, treatment satisfaction and well-being increased during treatment with ranibizumab PRN. Although directly comparable data are limited for the MacTSQ and W-BQ12 in mCNV, these results complement PROM outcomes reported in related studies.

Background: The intravitreal anti-vascular endothelial growth factor treatments ranibizumab and aflibercept have proven efficacy in clinical trials, but their real world usage in central retinal vein occlusion (CRVO) has not been assessed. We therefore evaluated the treatment patterns of both drugs in a US claims database., Methods: The IMS Integrated Data Warehouse was used to identify the patients with CRVO in the USA with claims for ranibizumab or aflibercept between 24 September 2012 and 31 March 2014 with at least 12 months follow-up. Patients were required to have had no anti-VEGF treatment code for 6 months before index ('treatment-naive'). Mean numbers of injections and non-injection visits to a treating physician were compared with patients receiving these treatments., Results: Patient characteristics were similar for patients receiving ranibizumab (n=206) or aflibercept (n=79) at index. The mean (±SD) numbers of injections received by patients treated with ranibizumab or aflibercept were 4.4±2.8 and 4.7±2.9 (P=0.38), respectively; the total number of patient visits to their treating physician was 7.3±3.7 and 7.0±2.9 (P=0.52), respectively. For patients receiving one or more injections (n=238), the mean interval between injections was 55.1 days (ranibizumab) and 54.2 days (aflibercept; P=0.44)., Conclusions: Our results suggest that, in routine clinical practice, patients receive a comparable number of injections in the first year of treatment with ranibizumab or aflibercept. This may have implications for commissioning and service development of CRVO care pathways.

It is becoming increasingly evident that epigenetic mechanisms influence gene expression and can explain how interactions between genetics and the environment result in particular phenotypes during development. The extent to which this epigenetic effect contributes to phenotype heritability in age-related macular degeneration (AMD) is currently ill defined. However, emerging evidence suggests that epigenetic changes are relevant to AMD and as such provide an exciting new avenue of research for AMD. This review addresses information on the impact of posttranslational modification of the genome on the pathogenesis of AMD, such as DNA methylation changes affecting antioxidant gene expression, hypoxia-regulated alterations in chromatin structure, and histone acetylation status in relation to angiogenesis and inflammation. It also contains information on the role of non-coding RNA-mediated gene regulation in AMD at a posttranscriptional (before translation) level. Our aim was to review the epigenetic mechanisms that cause heritable changes in gene activity without changing the DNA sequence. We also describe some long-term alterations in the transcriptional potential of a cell, which are not necessarily heritable but remains to be defined in the future. Increasing understanding of the significance of common and rare genetic variants and their relationship to epigenetics and environmental influences may help in establishing methods to assess the risk of AMD. This in turn may allow new therapeutic interventions for the leading cause of central vision impairment in patients over the age of 50 years in developed countries. Search strategy We searched the MEDLINE/PubMed database following MeSH suggestions for articles including the terms: 'ocular epigenetic mechanisms', 'human disease epigenetics', and 'age-related macular degeneration genetics'. The headline used to locate related articles in PubMed was 'epigenetics in ocular disease', and to restrict search, we used the headlines 'DNA methylation in age related macular degeneration', 'altered gene expression in AMD pathogenesis'. A manual search was also based on references from these articles as well as review articles.

Unlabelled: The purpose is to study the diagnostic performance of optical coherence tomography (OCT) and alternative diagnostic tests for neovascular age-related macular degeneration (nAMD). Methods employed are as follows:systematic review and meta-analysis;, Index Test: OCT including time-domain (TD-OCT) and the most recently developed spectral domain (SD-OCT); comparator tests: visual acuity, clinical evaluation (slit lamp), Amsler chart, colour fundus photographs, infra-red reflectance, red-free images/blue reflectance, fundus autofluorescence imaging (FAF), indocyanine green angiography (ICGA), preferential hyperacuity perimetry (PHP), and microperimetry; reference standard: fundus fluorescein angiography. Databases searched included MEDLINE, MEDLINE In Process, EMBASE, Biosis, SCI, the Cochrane Library, DARE, MEDION, and HTA database. Last literature searches: March 2013. Risk of bias assessed using QUADAS-2. Meta-analysis models were fitted using hierarchical summary receiver operating characteristic (HSROC) curves. Twenty-two studies (2 abstracts and 20 articles) enrolling 2124 participants were identified, reporting TD-OCT (12 studies), SD-OCT (1 study), ICGA (8 studies), PHP (3 studies), Amsler grid, colour fundus photography and FAF (1 study each). Most studies were considered to have a high risk of bias in the patient selection (55%, 11/20), and flow and timing (40%, 8/20) domains. In a meta-analysis of TD-OCT studies, sensitivity and specificity (95% CI) were 88% (46-98%) and 78% (64-88%), respectively. There was insufficient information to undertake meta-analysis for other tests. TD-OCT is a sensitive test for detecting nAMD, although specificity was only moderate. Data on SD-OCT are sparse. Diagnosis of nAMD should not rely solely on OCT.

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

Purpose: The complement system has been implicated in the pathogenesis of age-related macular degeneration (AMD). Complement factor I (CFI) is a serum protease that inhibits all complement pathways. A previous multicenter study identified a single missense CFI mutation (p.Gly119Arg) in 20/3,567 (0.56%) of AMD cases versus 1/3,937 (0.025%) of controls, thus suggesting that this mutation confers a high risk of AMD. A second CFI mutation, p.Gly188Ala, was identified in one patient with AMD., Methods: We screened 521 unrelated AMD cases and 627 controls for the p.Gly119Arg and p.Gly188Ala variants. All participants were Caucasian and >55 years, and recruited through Southampton Eye Unit or research clinics in Guernsey. All participants underwent dilated fundal examination by an experienced retinal specialist. SNP assays were performed using KASP™ biochemistry., Results: The p.Gly119Arg mutation was identified in 7/521 AMD cases compared to 1/627 age-matched controls (odds ratio [OR] = 8.47, confidence interval [CI] = 1.04-69.00, p = 0.027). There was a varied phenotype among the seven cases with the mutation, which was present in 4/254 (1.6%) cases with active or end-stage wet AMD and 3/267 dry AMD cases (1.1%). The p.Gly188Ala substitution was identified in 1/521 cases and 1/627 controls., Conclusions: Our results identified a much higher frequency of heterozygosity for p.Gly119Arg in both cases and controls than in previous studies. Of note is that our sub-cohort from Guernsey had a particularly high frequency of p.Gly119Arg heterozygosity in affected individuals (4%) compared to our sub-cohort from the mainland (0.71%). Although these data support the conclusions of van de Ven et al. that the p.Gly119Arg substitution confers a high risk of AMD, our data suggest that this missense mutation is not as rare or as highly penetrant as previously reported. There was no difference in frequency for a second CFI variant, p.Gly188Ala, between the cases and the controls.

Purpose: Central serous chorioretinopathy (CSCR) is an idiopathic disorder characterised by detachment of the neurosensory retina due to serous fluid accumulation between the photoreceptor outer segments and the retinal pigment epithelium. There are currently no set guidelines or protocols on its treatment. This study was undertaken to assess the current literature on the the efficacy and safety of photodynamic therapy (PDT) as a treatment option for CSCR., Methods: Seven databases (PubMed, CENTRAL, MEDLINE, Web of Science, Embase, Scopus, and The Cochrane Database of Systematic Reviews) were searched without restrictions on time or location. We followed PRISMA guidelines and evaluated quality according to STROBE criteria. In total, 117 citations were identified and 31 studies describing 787 eyes were included for review. Data on indications for PDT in CSCR, dosing regimens of verteprofin PDT (which includes treatment dose of vertoporfin, treatment time, fluence, and spot size), number of treatment sessions, response to treatment, mean length of follow-up, and complications were extracted and analysed., Results: Since the introduction of PDT for the treatment of CSCR in 2003, there have been three randomised controlled trials (RCTs), one for acute and two chronic CSCR and 28 further studies that met the STROBE criteria that compared the use of PDT with other treatment options. All studies showed short-term efficacy of PDT in CSCR. The studies were of small sample size and lacked sufficient follow-up to draw conclusions on long-term efficacy and safety., Conclusions: There is sufficient scientific evidence to suggest that PDT may be a useful treatment option for chronic CSCR in the short-term. The review identifies a need for robust RCTs with longer follow-up to ascertain the role of PDT as a useful treatment option for CSCR.

Objective: To assess the incremental cost and cost-effectiveness of continuous and discontinuous regimens of bevacizumab (Avastin) and ranibizumab (Lucentis) for neovascular age-related macular degeneration (nAMD) from a UK National Health Service (NHS) perspective., Design: A within-trial cost-utility analysis with a 2-year time horizon, based on a multicentre factorial, non-inferiority randomised controlled trial., Setting: 23 hospital ophthalmology clinics., Participants: 610 patients aged ≥50 years with untreated nAMD in the study eye., Interventions: 0.5 mg ranibizumab or 1.25 mg bevacizumab given continuously (monthly) or discontinuously (as-needed) for 2 years., Main Outcome Measures: Quality-adjusted life-years (QALYs)., Results: Total 2-year costs ranged from £3002/patient ($4700; 95% CI £2601 to £3403) for discontinuous bevacizumab to £18 590/patient ($29 106; 95% CI £18 258 to £18 922) for continuous ranibizumab. Ranibizumab was significantly more costly than bevacizumab for both continuous (+£14 989/patient ($23 468); 95% CI £14 522 to £15 456; p<0.001) and discontinuous treatment (+£8498 ($13 305); 95% CI £7700 to £9295; p<0.001), with negligible difference in QALYs. Continuous ranibizumab would only be cost-effective compared with continuous bevacizumab if the NHS were willing to pay £3.5 million ($5.5 million) per additional QALY gained. Patients receiving continuous bevacizumab accrued higher total costs (+£599 ($938); 95% CI £91 to £1107; p=0.021) than those receiving discontinuous bevacizumab, but also accrued non-significantly more QALYs (+0.020; 95% CI -0.032 to 0.071; p=0.452). Continuous bevacizumab therefore cost £30 220 ($47 316) per QALY gained versus discontinuous bevacizumab. However, bootstrapping demonstrated that if the NHS is willing to pay £20 000/QALY gained, there is a 37% chance that continuous bevacizumab is cost-effective versus discontinuous bevacizumab., Conclusions: Ranibizumab is not cost-effective compared with bevacizumab, being substantially more costly and producing little or no QALY gain. Discontinuous bevacizumab is likely to be the most cost-effective of the four treatment strategies evaluated in this UK trial, although there is a 37% chance that continuous bevacizumab is cost-effective., Trial Registration Number: ISRCTN92166560., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Importance: Normal-tension glaucoma (NTG) is a common cause of vision loss., Objective: To investigate the role of TANK binding kinase 1 (TBK1) gene duplications in NTG to gain insights into the causes of glaucoma that occurs at low intraocular pressure (IOP)., Design, Setting, and Participants: In this multicenter case-control study, we investigated patients who met the criteria for NTG, including glaucomatous optic neuropathy, visual field defects, and maximum recorded untreated IOP of 21 mm Hg or less, and matched controls. Participants (N = 755) were recruited from Southampton, United Kingdom (180 patients and 178 controls), Rochester, Minnesota (65 patients and 12 controls), New York, New York (96 patients and 16 controls), and Iowa City, Iowa (208 controls)., Main Outcomes and Measures: Detection of TBK1 gene duplications and comparison of the extent of the identified DNA that is duplicated with prior TBK1 copy number variations associated with NTG., Results: A TBK1 gene duplication was detected in 1 of 96 patients (1.0%) from New York and none of the controls. Analysis of duplication borders with comparative genome hybridization demonstrated that this patient has a novel duplication that has not been previously reported. No gene duplications were detected in any of the other cohorts of patients or controls., Conclusions and Relevance: Duplication of the TBK1 gene is a rare cause of NTG. The identification of another case of NTG attributed to TBK1 gene duplication strengthens the case that this mutation causes glaucoma.

Purpose: Role of intravitreal injection of dexamethasone implant (Ozurdex) for refractory macular thickening., Methods: A case report of a 13-year-old boy with Rhodopsin-positive, CRB1-negative retinitis pigmentosa presenting with Coat's-like exudative vitreoretinopathy and treatment-resistant cystoid macular oedema., Results: A reduction in the macular thickening following a single injection of Ozurdex., Conclusion: We present our experience in successful treatment of refractory macular oedema with intravitreal injection of dexamethasone implant resulting in clinically significant resolution of macular thickening.

Background: Choroideremia is an X-linked recessive disease that leads to blindness due to mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1). We assessed the effects of retinal gene therapy with an adeno-associated viral (AAV) vector encoding REP1 (AAV.REP1) in patients with this disease., Methods: In a multicentre clinical trial, six male patients (aged 35-63 years) with choroideremia were administered AAV.REP1 (0·6-1·0×10(10) genome particles, subfoveal injection). Visual function tests included best corrected visual acuity, microperimetry, and retinal sensitivity tests for comparison of baseline values with 6 months after surgery. This study is registered with ClinicalTrials.gov, number NCT01461213., Findings: Despite undergoing retinal detachment, which normally reduces vision, two patients with advanced choroideremia who had low baseline best corrected visual acuity gained 21 letters and 11 letters (more than two and four lines of vision). Four other patients with near normal best corrected visual acuity at baseline recovered to within one to three letters. Mean gain in visual acuity overall was 3·8 letters (SE 4·1). Maximal sensitivity measured with dark-adapted microperimetry increased in the treated eyes from 23·0 dB (SE 1·1) at baseline to 25·3 dB (1·3) after treatment (increase 2·3 dB [95% CI 0·8-3·8]). In all patients, over the 6 months, the increase in retinal sensitivity in the treated eyes (mean 1·7 [SE 1·0]) was correlated with the vector dose administered per mm(2) of surviving retina (r=0·82, p=0·04). By contrast, small non-significant reductions (p>0·05) were noted in the control eyes in both maximal sensitivity (-0·8 dB [1·5]) and mean sensitivity (-1·6 dB [0·9]). One patient in whom the vector was not administered to the fovea re-established variable eccentric fixation that included the ectopic island of surviving retinal pigment epithelium that had been exposed to vector., Interpretation: The initial results of this retinal gene therapy trial are consistent with improved rod and cone function that overcome any negative effects of retinal detachment. These findings lend support to further assessment of gene therapy in the treatment of choroideremia and other diseases, such as age-related macular degeneration, for which intervention should ideally be applied before the onset of retinal thinning., Funding: UK Department of Health and Wellcome Trust., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Several lines of evidence suggest the involvement of antibodies and immune complex inflammation in AMD, a blinding disease with a strong inflammatory component. To examine this further, we developed a novel experimental mouse model of retinal inflammation and evaluated whether inflammation associated with immune complex formation was present in eyes of AMD donors., Methods: A localized immune complex-mediated reaction was induced in the retina of wild-type (WT), Fc receptor γ chain-deficient (γ(-/-)), and C1q-deficient (C1q(-/-)) mice, and donor eyes were obtained after death from donors with early or wet AMD and from healthy control subjects. The presence of immune complexes, Fcγ receptors (FcγRs), and markers of macrophage/microglia activation was investigated by immunohistochemistry., Results: In WT and C1q(-/-) mice, immune complex deposition in the retina led to a robust inflammatory response with activation of microglia, recruitment of myeloid cells, and increased expression of FcγRI through FcγRIV and major histocompatibility complex class II. This response was not observed in γ(-/-) mice lacking activating FcγRs. We found that early AMD was associated with deposition of IgG, C1q, and membrane attack complex in the choriocapillaris and with increased numbers of CD45+ cells expressing FcγRIIa and FcγRIIb. Furthermore, FcγRIIa and FcγRIIb were observed in eyes of donors with wet AMD., Conclusions: Our studies suggest that immune complexes may contribute to AMD pathogenesis through interaction of IgG with FcγRs and might inform about possible adverse effects associated with therapeutic antibodies.

Electrospun fibrous matrices prepared from methacrylate-based copolymers are investigated as a tool for retinal pigment epithelium (RPE) transplantation in the treatment of degenerative retinal diseases. Human RPE cells were used to probe the cell-surface interactions on these copolymer matrices. For the first time, simple changes in chemical functionality have been found to induce gel formation of these methacrylate backbone copolymers in vitro. This effect is shown to significantly improve RPE cell adhesion and survival.

Purpose: To determine if prespecified genetic polymorphisms influence responsiveness to vascular endothelial growth factor (VEGF) inhibition in neovascular age-related macular degeneration (nAMD). The objectives were to replicate 3 reported pharmacogenetic associations of response in nAMD and to test for novel associations., Design: Cohort study, combining information about patients' genotypes with information from a randomized controlled trial about responsiveness to anti-VEGF therapy for nAMD., Participants: Five hundred nine participants with nAMD, enrolled in the Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) trial., Methods: Participants were classified as responders or nonresponders to VEGF inhibition based on the optical coherence tomography (OCT) metric of total retinal thickness (TRT). We computed the change in TRT from baseline to the latest time point for which OCT data were available (3, 6, 9, or 12 months). Eyes with changes in TRT greater than or equal to the 75th percentile or more were classified as responders, and those with changes less than or equal to the 25th percentile or lower were classified as non-responders. Three previously reported associations of response to VEGF inhibition in nAMD involving single nucleotide polymorphisms (SNPs) at the CFH, FZD4, and HTRA1/ARMS2 loci were tested for replication. An additional 482 SNPs also were tested using a candidate gene approach. Associations were estimated as odds ratios (ORs) with confidence intervals (CIs)., Main Outcome Measures: The primary outcome was evidence of a genetic association with response to VEGF inhibition as measured by change in TRT., Results: One hundred twenty-six participants were classified as responders and 128 were classified as nonresponders. The SNP rs10490924 in HTRA1/ARMS2 showed a borderline association with responsiveness after Bonferroni correction (OR, 1.53; CI, 0.99-2.36; P = 0.055, Bonferroni correction). None of the other 484 additional SNPs tested for association was significant after Bonferroni correction for multiple testing. The smallest corrected P value was 0.84 (P = 0.002, uncorrected) for rs9679290 in the EPAS1 (HIF2A) gene on chromosome 2. Four of the 10 most significant results were in this gene., Conclusions: We estimated pharmacogenetic associations using high-quality phenotype data from a randomized controlled clinical trial of nAMD. No significant association or replication of previous associations were observed. Further investigation of the EPAS1 (HIF2A) gene, however, may, be merited., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate phenotypic variability in terms of best-corrected visual acuity (BCVA) in patients with Stargardt disease (STGD) and confirmed ABCA4 mutations., Methods: Entire coding region analysis of the ABCA4 gene by direct sequencing of seven patients with clinical findings of STGD seen in the Retina Clinics of Southampton Eye Unit between 2002 and 2011.Phenotypic variables recorded were BCVA, fluorescein angiographic appearance, electrophysiology, and visual fields., Results: All patients had heterozygous amino acid-changing variants (missense mutations) in the ABCA4 gene. A splice sequence change was found in a 30-year-old patient with severly affected vision. Two novel sequence changes were identified: a missense mutation in a mildly affected 44-year-old patient and a frameshift mutation in a severly affected 34-year-old patient., Conclusion: The identified ABCA4 mutations were compatible with the resulting phenotypes in terms of BCVA. Higher BCVAs were recorded in patients with missense mutations. Sequence changes, predicted to have more deleterious effect on protein function, resulted in a more severe phenotype. This case series of STGD patients demonstrates novel genotype/phenotype correlations, which may be useful to counselling of patients. This information may prove useful in selection of candidates for clinical trials in ABCA4 disease.

Background: Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint., Methods: In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560., Findings: Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference -1·37 letters, 95% CI -3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1·63 letters, -4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 [6%] of 314 participants) and bevacizumab (12 [4%] of 296; odds ratio [OR] 1·69, 95% CI 0·80-3·57; p=0·16), or those given continuous (12 [4%] of 308) and discontinuous treatment (20 [7%] of 302; 0·56, 0·27-1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22-1·03; p=0·05), but did not differ by drug group (0·96, 0·46-2·02; p=0·91)., Interpretation: Ranibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought., Funding: UK National Institute for Health Research Health Technology Assessment programme., (Copyright © 2013 Chakravarthy et al. Open Access article distributed under the terms of CC BY-NC-SA. Published by Elsevier Ltd. All rights reserved.)

Posterior vitreous detachment (PVD) is a common phenomenon in the aging eye. However, this may be complicated by persistent symptomatic vitreomacular adhesions that exert tractional forces on the macula (vitreomacular traction; VMT). VMT itself may be associated with epiretinal membrane formation and the development of idiopathic macular holes (IMH). Such pathologies may cause visual disturbances, including metamorphopsia, photopsia, blurred vision, and decreased visual acuity, which impact an individual's quality of life. Technologies such as optical coherence tomography allow an increasingly more accurate visualisation of the macular anatomy, including quantification of macular hole characteristics, and this facilitates treatment decision-making. Pars plana vitrectomy remains the primary treatment option for many patients with VMT or IMH; for the latter, peeling of the inner limiting membrane (ILM) of the retina has shown improved outcomes when compared with no ILM peeling. The development of narrow-gauge transconjunctival vitrectomy systems has improved the rate of visual recovery following surgery. Ocriplasmin, by degrading laminin and fibronectin at the vitreoretinal interface, may allow induction of PVD in a non-invasive manner. Indeed, clinical studies have supported its use as an alternative to surgery in certain patient populations. However, further research is still needed with respect to greater understanding of the pathophysiology underlying the development of VMT and IMH.

Purpose: To investigate whether modification of liver complement factor H (CFH) production, by alteration of liver CFH Y402H genotype through liver transplantation (LT), influences the development of age-related macular degeneration (AMD)., Design: Multicenter, cross-sectional study., Participants: We recruited 223 Western European patients ≥ 55 years old who had undergone LT ≥ 5 years previously., Methods: We determined AMD status using a standard grading system. Recipient CFH Y402H genotype was obtained from DNA extracted from recipient blood samples. Donor CFH Y402H genotype was inferred from recipient plasma CFH Y402H protein allotype, measured using enzyme-linked immunosorbent assays. This approach was verified by genotyping donor tissue from a subgroup of patients. Systemic complement activity was ascertained by measuring levels of plasma complement proteins using an enzyme-linked immunosorbent assay, including substrates (C3, C4), activation products (C3a, C4a, and terminal complement complex), and regulators (total CFH, C1 inhibitor)., Main Outcome Measures: We evaluated AMD status and recipient and donor CFH Y402H genotype., Results: In LT patients, AMD was associated with recipient CFH Y402H genotype (P = 0.036; odds ratio [OR], 1.6; 95% confidence interval [CI], 1.0-2.4) but not with donor CFH Y402H genotype (P = 0.626), after controlling for age, sex, smoking status, and body mass index. Recipient plasma CFH Y402H protein allotype predicted donor CFH Y402H genotype with 100% accuracy (n = 49). Plasma complement protein or activation product levels were similar in LT patients with and without AMD. Compared with previously reported prevalence figures (Rotterdam Study), LT patients demonstrated a high prevalence of both AMD (64.6% vs 37.1%; OR, 3.09; P<0.001) and the CFH Y402H sequence variation (41.9% vs 36.2%; OR, 1.27; P = 0.014)., Conclusions: Presence of AMD is not associated with modification of hepatic CFH production. In addition, AMD is not associated with systemic complement activity in LT patients. These findings suggest that local intraocular complement activity is of greater importance in AMD pathogenesis. The high AMD prevalence observed in LT patients may be associated with the increased frequency of the CFH Y402H sequence variation., Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Aims: To evaluate the efficacy and safety of intravitreal ranibizumab in patients with choroidal neovascularisation secondary to pathological myopia (myopic CNV). Data are from a pre-planned, 6-month interim analysis., Methods: Phase II, open-label, single arm, multicentre, 12-month study, recruiting patients (aged ≥18 years) with active primary or recurrent subfoveal or juxtafoveal myopic CNV, with a best-corrected visual acuity (BCVA) score of 24-78 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the study eye and a diagnosis of high myopia of at least -6 dioptres. Patients received 0.5 mg ranibizumab administered intravitreally to the study eye, followed by monthly injections given as needed (based on a predefined algorithm) for up to 11 months., Results: At 6 months, mean BCVA improved from baseline by 12.2 letters, as did central macular thickness (in this interim analysis defined as a measure of either central subfield macular thickness or centre point macular thickness) from baseline by 108 μm in the 48 study eyes of 48 patients. Fewer patients had centre-involving intraretinal oedema (13.0% vs 91.5%), intraretinal cysts (10.9% vs 57.4%), or subretinal fluid (13.0% vs 66.0%) at 6 months than at baseline. Patients received a mean of 1.9 retreatments, were satisfied with ranibizumab treatment, and well being was maintained. No new safety signals were identified., Conclusions: Results from the planned interim analysis support the role of ranibizumab in the treatment of myopic CNV, with excellent efficacy achieved with a low number of injections and few serious adverse events.

Objectives: (1) To investigate and integrate the tomographic, angiographic and electrodiagnostic findings in pattern dystrophy. (2) To correlate visual acuity (VA) with central macular thickness (CMT), the electrooculogram (EOG) and pattern electroretinogram (PERG)., Design: A retrospective study of patients with pattern dystrophy. 52 eyes of 26 patients were examined., Results: Thirty-three eyes had adult-onset foveomacular vitelliform dystrophy, 8 had multifocal pattern dystrophy, 6 had butterfly pattern dystrophy and 2 had reticular pattern dystrophy. SD-OCT demonstrated hyperreflectivity between the retinal pigment epithelium (RPE)/ Bruch's complex, and the junction of the inner and outer segments (IS/OS) of the photoreceptors. Disruption of the IS/OS was observed in 20, and disruption of the end tips of photoreceptors was clearly visible in eight eyes. 11 eyes showed abnormal focal hyper-reflectivity originating from the RPE towards the outer nuclear layer (ONL), and in two eyes this appeared to originate from the junction of the IS/OS towards the ONL. EDTs revealed borderline or a reduced EOG in 25 (51%) and a degraded PERG in 41eyes (83.6%) with the P50 component reduced in 23 and N95 in 18. CMT and Arden ratio did not show any significant correlation with VA., Conclusions: We observed relatively consistent features between different types of pattern dystrophies. In addition we observed novel findings on 3D-OCT. We also report 3D-OCT features of reticular, multifocal and butterfly pattern dystrophies. The degraded PERG results observed in our study indicate that the disease process in this condition is not limited to the RPE.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

Purpose: To describe two cases of retinal angiomatous proliferation (RAP)-like lesion following radiation therapy for primary tumor., Patients and Methods: Retrospective evaluation of two patients with previous irradiation treatment for a pleomorphic adenoma of the lacrimal gland and a vocal cord carcinoma, respectively. Visual acuity (VA), fluorescein angiography and optical coherence tomography were performed and demonstrated a RAP-like lesion in both cases. Treatment with intravitreal injections of Ranibizumab was performed with a follow-up of 19 and 10 months, respectively., Results: Both the patients had a positive response to the treatment with improvement in VA and reduction of intraretinal fluid., Conclusion: RAP-like lesions can develop following radiation treatment for a primary tumor. In patients presenting with idiopathic RAP, a history of prior radiotherapy should be considered.

Purpose: To describe the results of photodynamic therapy (PDT) for juxtapapillary and peripheral retinal capillary hemangioma (RCH)., Patients and Methods: Interventional case series of four eyes (four patients) with juxtapapillary RCH and one eye (one patient) with peripheral RCH. Two eyes with juxtapapillary RCH had received two sessions of full-fluence, double-duration PDT; whereas other two eyes had received single session of half-fluence, single-duration PDT. The peripheral RCH was treated with a single session of full-fluence, single-duration PDT., Results: Two patients had von Hippel-Lindau disease. Follow-up duration ranged from 4 months to 1 year. Pre-PDT visual acuity (VA) ranged from 20/200 to HM (juxtapapillary RCH) and 20/100 (peripheral RCH). Among the eyes with juxtapapillary RCH, tumor regression with partial resolution of macular edema was noted in two eyes (one eye each with half-fluence and full-fluence PDT), whereas two eyes had no change in tumor size with persistent macular edema. VA remained stable in three eyes and declined in one eye. In an eye with peripheral RCH, regression of tumor and macular edema with VA improvement was noted. Post-PDT complications included epiretinal membrane (one eye) and transient exudative retinal detachment (one eye)., Conclusion: PDT can be effective in reducing macular edema associated with RCH but this does not always correspond with an improvement in VA especially for juxtapapillary tumors.

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10(-8)). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4-1.88, P = 2.7 × 10(-10), and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29-1.68, P = 4.9 × 10(-9)). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10(-4); tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD.

Age-related macular degeneration (AMD) is the most common cause of blindness in the developed world. There is currently no treatment for the cellular loss, which is characteristic of AMD. Transplantation of retinal pigment epithelium (RPE) cells represents a potential therapy. Because of AMD-related pathology in the native support, Bruch's membrane, transplanted RPE cells require a scaffold to reside on. We present here the development of an electrospun fibrous scaffold derived from methyl methacrylate and poly(ethylene glycol) (PEG) methacrylate for novel application as an RPE scaffold. Scaffolds were chemically modified to improve cell adhesion by functionalization not previously reported for this type of copolymer system. A human RPE cell line was used to investigate cell-scaffold interactions for up to two weeks in vitro. Scanning electron microscopy was used to characterize the fibrous scaffolds and confirm cell attachment. By day 15, cell area was significantly (p < 0.001) enhanced on scaffolds with chemical modification of the PEG chain terminus. In addition, significantly, less-apoptotic cell death was demonstrable on these modified surfaces., (Copyright © 2012 Wiley Periodicals, Inc.)