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Age-related macular degeneration is an increasingly important public health issue due to ageing populations and increased longevity. Age-related macular degeneration affects individuals older than 55 years and threatens high-acuity central vision required for important tasks such as reading, driving, and recognising faces. Advances in retinal imaging have identified biomarkers of progression to late age-related macular degeneration. New treatments for neovascular age-related macular degeneration offer potentially longer-lasting effects, and progress is being made towards a treatment for atrophic late age-related macular degeneration. An effective intervention to slow progression in the earlier stages of disease, or to prevent late age-related macular degeneration development remains elusive, and our understanding of underlying mechanistic pathways continues to evolve. [ABSTRACT FROM AUTHOR]

Recent advancements in therapeutic options have provided hope for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Two intravitreal anti-complement factor treatments, Pegcetacoplan and Avacincaptad Pegol, have received FDA approval for use in the United States, with approvals in other jurisdictions expected to follow. The review article in Clinical and Experimental Ophthalmology provides a comprehensive summary of these approved treatments and other interventions currently being trialed. It is important for ophthalmologists to correctly identify patients with GA and consider the variables when counseling patients about treatment, as the decision to treat GA is more nuanced and individualized. Using a common nomenclature for AMD stages is crucial, and the term "dry AMD" should be used specifically for the late atrophic form of AMD that is now treatable. Various imaging techniques, such as fundus autofluorescence and optical coherence tomography, can aid in diagnosing and monitoring GA. Lesion characteristics, including size, location, and growth rate, should be considered when determining the threat to the fovea and the need for treatment. Longitudinal imaging data and the use of deep learning models can provide valuable information for predicting growth rates and guiding treatment decisions. It is important to manage patient expectations, as current treatments aim to slow the decline in visual function rather than reverse or stop visual loss. By utilizing multi-modal imaging and considering individual patient factors, ophthalmologists can make informed decisions [Extracted from the article]

The article discusses the use of optical coherence tomography (OCT) imaging to measure the thickness of different layers of the retina. These measurements are important in understanding eye diseases such as macular degeneration and glaucoma, as well as systemic diseases like diabetes and Alzheimer's. The article emphasizes the need for comprehensive understanding of normal values and how they change with age in order to interpret changes seen with disease. A longitudinal study presented in the article shows that age is a significant factor affecting macular thickness, with a decrease over 5 years, although not clinically significant. Other factors such as sex, refractive errors, and smoking were also found to be related to macular thickness changes. The article suggests that changes in retinal layer thickness with age could serve as biomarkers of the general aging process. [Extracted from the article]

The slowly progressive nature of age-related macular degeneration (AMD) means that establishing the efficacy of novel preventative treatments aiming to slow progression of disease, remains challenging, and where earlier endpoints are needed to improve their feasibility. This review examines whether the onset of atrophic AMD, as seen as anatomical signs on optical coherence tomography termed nascent geographic atrophy, could act as a useful surrogate endpoint for early intervention trials. [ABSTRACT FROM AUTHOR]

To describe the defining features of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA), a consensus term referring to the OCT-based anatomic changes often identified before the development of complete RPE and outer retinal atrophy (cRORA) in age-related macular degeneration (AMD). We provide descriptive OCT and histologic examples of disease progression. Consensus meeting. Panel of retina specialists, including retinal imaging experts, reading center leaders, and retinal histologists. As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analyzed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred before the development of atrophy secondary to AMD. New terms of iRORA and cRORA were defined. This report describes in detail the CAM consensus on iRORA. Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates. OCT was used in cases of early and intermediate AMD as the base imaging method 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, (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. An international consensus classification for OCT-defined anatomic 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 understand better the natural history of the 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 endeavors, acknowledging that the classification will be refined as new data are generated. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. The 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® laser, but they should not be extrapolated to other short-pulse lasers. [ABSTRACT FROM AUTHOR]

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 (T&E) 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 SRF >200 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 T&E protocol who tolerated some SRF achieved VA that is comparable, with fewer injections, with that achieved when treatment aimed to resolve all SRF completely. [ABSTRACT FROM AUTHOR]

Purpose To determine the histologic and cellular correlates in the retina and retinal pigment epithelium (RPE) with the presence of optical coherence tomography-defined reticular pseudodrusen (RPD). Design Observation case using immunocytochemistry of an exenterated eye with immediate fixation after removal. Participants Two patients, one with confirmed RPD and the other with mid-peripheral drusen, underwent multimethod imaging before exenteration and immediate fixation of the posterior eyecup for high-resolution immunocytochemical analysis. Methods Optical coherence tomography (OCT) was compared with high-resolution immunocytochemistry using a range of cellular markers to determine changes in the RPE, photoreceptors, and gliosis. Main Outcome Measures Correlations of the appearance of reticular pseudodrusen on OCT and immunocytochemical analysis. Results Reticular pseudodrusen were deposits juxtaposed to photoreceptor outer segments extending through the outer nuclear layer and even beyond the outer limiting membrane. Deposits were rich in vitronectin, photoreceptor-associated proteins, and Iba1-immunoreactive immune cells. In contrast to conventional drusen the lipid stain Oil Red O failed to stain RPD. Cellular analysis revealed that RPD were associated with photoreceptor disruption and loss and localized gliosis. In addition, anomalies in the RPE were observed. Conclusions Reticular pseudodrusen represent subretinal deposits that extend through the outer nuclear layer, affect photoreceptor integrity, and are associated with retinal gliosis and RPE damage. [ABSTRACT FROM AUTHOR]

Background/aims To determine the relationship between self-reported visual difficulties under low luminance conditions (night vision symptoms) and visual function measures in intermediate age-related macular degeneration (AMD). Methods One hundred participants with bilateral intermediate AMD were examined in a prospective crosssectional study with visual function measures including best-corrected visual acuity (BCVA), low luminance visual acuity (LLVA) and microperimetry in both eyes. A 10-item Night Vision Questionnaire (NVQ-10) was then used to determine the degree of self-reported night vision symptoms experienced by each participant. For analyses, low luminance deficit (LLD) was derived as the difference between LLVA and BCVA, and microperimetric mean sensitivity (MS; all points) and central sensitivity (CS; points within the central 1°) were determined. Rasch analysis was used to estimate the person measure of night vision symptoms, and its relationship with visual function parameters was determined. Results NVQ-10 person measures were significantly associated with LLD (β coefficient=0.067, 95% CI 0.005 to 0.130, p=0.034), but not BCVA, LLVA, microperimetric MS or CS (p≥0.090). Participants with the highest degree of self-reported night vision symptoms (fourth quartile of person measure) had significantly worse LLD than those with the least difficulty (first quartile of person measure; p=0.019). Conclusions In individuals with bilateral intermediate AMD, LLD was associated with self-reported night vision symptoms, suggesting that this measure may better capture the visual difficulties experienced by these individuals under low luminance conditions than the conventional measure of photopic visual acuity. [ABSTRACT FROM AUTHOR]

Background A novel, ultra-low energy nanosecond laser (retinal rejuvenation therapy) has been developed with the aim to slow progression of early age-related macular degeneration ( AMD). The safety, changes in fundus characteristics and macular function in a cohort of participants with bilateral intermediate AMD are reported. Design Prospective non-randomised, pilot intervention study. Participants or Samples Subjects with bilateral intermediate AMD ( n = 50, aged 50-75 years). Methods Ultra-low energy laser pulses applied in 12 spots around the macula of one eye (0.15-0.45 mJ), using 400 μm diameter spot, 3 nanosecond pulse length, 532 nm wavelength and energy titrated to each patient. Main Outcome Measures Best corrected visual acuity, drusen area and macular sensitivity (flicker perimetry) at baseline and at 3, 6 and 12 months post-laser. Results Treatment was painless with no clinically visible lesions. No participant developed choroidal neovascularization, while two with thin central retinal thickness at baseline developed atrophy at 12-month follow up. Drusen area was reduced in 44% of treated eyes and 22% of untreated fellow eyes, with changes in drusen and function not being coincident. Improvement in flicker threshold within the central 3° was observed in both the treated and untreated fellow eyes at 3 months post-laser. Of the 11 eyes at greatest risk of progression (flicker defect >15 d B), seven improved sufficiently to be taken out of this high-risk category. Conclusions A single unilateral application of nanosecond laser to the macula produced bilateral improvements in macula appearance and function. The nanosecond retinal rejuvenation therapy laser warrants ongoing evaluation as an early intervention for AMD. [ABSTRACT FROM AUTHOR]

Purpose: To assess the impact of anti-vascular endothelial growth factor (VEGF) treatment in routine medical practice on vision-related quality of life (VRQoL) in neovascular age-related macular degeneration (AMD). Design: Prospective case series. Participants: A total of 169 patients with neovascular AMD undergoing anti-VEGF treatment. Methods: The VRQoL interviews at baseline (n = 169), 6 months (n = 138), and 12 months (n = 120), routine anti-VEGF treatment with up to monthly follow-ups, and re-treatment as indicated. The Impact of Vision Impairment (IVI) questionnaire was subjected to Rasch analysis to assess its measurement performance and generate interval-level estimates of VRQoL at all time points, anchoring the instrument to its baseline mea-surement characteristics. Factors associated with a change in reported VRQoL were assessed using generalized linear regression models. Main Outcome Measures: The VRQoL as measured by the IVI using its 3 subscales: Accessing Information, Mobility, and Emotional Well-being. Findings: The mean age was 70 years (±6 years standard deviation [SD]); 56% were female. Visual acuity (VA) improved by a mean of 8 letters (±17 SD), and mean retinal thickness decreased by 87 (±89.7) (im with an average of 6.5 (±2.6) injections over 12 months. Those who lost >2 lines (n = 13,11 %) reported worse VRQoL at 12 months on the Accessing Information and Mobility subscales (P = 0.007 and P = 0.050, respectively). Conversely, those who gained >2 lines (n = 29, 24%) reported better VRQoL on the Accessing Information and Emotional Well-being subscales (P = 0.009 and P = 0.008, respectively). Patients who did not experience a change in VA reported no change in their VRQoL. In multivariate analyses, only a change in VA but not whether the better or worse eye was treated predicted a change in VRQoL on the Accessing Information (P = 0.004) and the Emotional Well-being (P = 0.008) subscales. Conclusions: We confirmed that anti-VEGF treatment for neovascular AMD improves patients' VRQoL in those who gain vision and maintains VRQoL in those who maintain VA in their treated eye, irrespective of whether the worse or better eye is treated. Against this background, the best possible outcomes should be aimed for even if the worse eye is treated because a loss of VA in the worse eye will adversely affect patients' VRQoL. [ABSTRACT FROM AUTHOR]

Background: HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined. Methodology/Principal Findings: Objectives: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes. Design: A proof of concept double-masked randomized controlled study. Participants: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA≥20/60 in at least one eye, and a normal lipid profile. Intervention: Simvastatin 40 mg/day or placebo, allocated 1∶1. Main outcome measures: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18–0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27–3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07–0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02–0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected. Conclusion/Significance: Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted. Trial Registration: Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065 [ABSTRACT FROM AUTHOR]

Background Little quantitative information exists regarding the effect that retinitis pigmentosa ( RP) has on the choroid. The aim of this study was to determine choroidal thickness profiles in patients with RP. Design Prospective. Participants Forty-two RP and 22 control subjects participated in the study. RP patients had mild to severe disease, with a visual acuity range of logMAR 0.1 to no light perception. Methods Images of the retina and choroid were obtained using the enhanced depth-imaging method and optical coherence tomography ( OCT). Choroidal thickness measures were determined via manual segmentation of the OCT image. Main Outcome Measures The thickness profiles of the normal and RP groups were compared. The associations between choroidal thickness, visual acuity and duration of RP were determined. Results The choroid was thickest in the control eyes at the subfoveal location (336.60 ± 70.42 μm), and the thickness gradually decreased towards the peripheral retina (temporal 8° = 295.55 ± 60.52 μm; nasal 8° = 251.68 ± 49.93 μm). In RP, the mean thickness was also greater at the fovea (215.60 ± 94.91 μm) than the temporal (191.66 ± 72.42 μm) and nasal (149.91 ± 57.42 μm) retina, but all values were significantly lower than those of the controls ( P ≤ 0.001). Subfoveal choroidal thickness was significantly correlated with visual acuity (r = −0.46, P < 0.001) and duration of disease (r = −0.4, P = 0.001). Conclusions Patients with RP have a thinner choroid than controls. Patients with poorer visual acuity or longer duration of symptoms tended to have thinner choroids. Knowledge of choroidal thickness profile in RP is important for the field of restorative vision research and the development of suprachoroidal retinal prostheses. [ABSTRACT FROM AUTHOR]

A bstract Background: To describe the changes in retinal vascular calibre in response to intravitreal ranibizumab injections in patients with neovascular age-related macular degeneration. Design: Prospective interventional case series. Participants: Treatment naïve patients with neovascular age-related macular degeneration were recruited over a 1-year period. Methods: Each patient received three monthly intravitreal injections according to a 'loading dose'. Retinal arteriolar and venular calibre was measured from digital fundus photographs and summarized as central retinal artery equivalent and central retinal vein equivalent at baseline and 3 months. Main Outcome Measure: Central retinal artery equivalent and central retinal vein equivalent changes from baseline to 3 months. Results: Seventy-four eyes of 71 patients had good quality images for grading vessel calibre at baseline and at 3 months in treated (study) eyes and 51 eyes of 51 patients had good quality images in fellow (control) eyes. Over 3 months, in study eyes treated with ranibizumab, there was a significant increase in central retinal vein equivalent over baseline (+6.20 µm, P = 0.005), but no significant change in central retinal artery equivalent (+0.86 µm, P = 0.55). In control eyes, there was no change in central retinal vein equivalent (−0.82 µm, P = 0.70) or central retinal artery equivalent (0.34 µm, P = 0.75). Conclusion: Intravitreal ranibizumab has a significant vasodilational effect on retinal venular calibre in eyes treated for neovascular age-related macular degeneration. The reason for this change is unclear, but may relate to changes in blood flow or inflammatory changes within the retina. [ABSTRACT FROM AUTHOR]

The article discusses the benefit of genomic medicine in treating gene-related disease among patients in Australia. It states that the briard blind dog named Lancelot was treated with mutated gene therapy. It likewise notes that realizing the therapeutic potential of gene-based therapies will enhance the quality of medical care. Meanwhile, the author stresses the needs to educate health care professional. He also addresses the importance of risk profiling to identify the causes of the disease.

Abstract: This qualitative article describes the impact of age-related macular degeneration (ARMD) among 15 participants: how a person makes sense of ARMD, the effect of ARMD on the person's quality of life, the psychological disturbances associated with the limitations of ARMD, and the influence of ARMD on social interactions. Such in-depth appreciation of the impact of ARMD will assist in the design of specific and appropriate rehabilitation programs to minimize limitations and enhance participation in people with ARMD. [ABSTRACT FROM AUTHOR]

Abstract Age-related macular degeneration (AMD) is the leading cause of legal blindness in individuals 50 years and older in the developed world. Choroidal neovascularization (CNV) in exudative AMD is responsible for the majority of severe vision loss. Until recently, laser photocoagulation was the only well-established and widely accepted treatment for CNV. However, it is beneficial only for a small subset of patients, has a high rate of CNV persistence and recurrence and results in iatrogenic, collateral damage to the overlying retina. These issues make it difficult to recommend in the case of subfoveal lesions. Consequently, numerous experimental therapeutic interventions are under investigation with the common objective of destroying the CNV but leaving the foveal neurosensory retina intact. Treatment modalities can be grouped into five major categories: photodynamic therapy; radiotherapy; transpupillary thermotherapy; anti-angiogenic and angiostatic agents; and surgical intervention. The present review aims to explain the rationale behind these new treatments, analyse the evidence for their safety and efficacy, determine their stage of development and indicate in which patients they are potentially useful. [ABSTRACT FROM AUTHOR]

Abstract Background: A single base change within the EFEMP1 gene has been associated with malattia leventinese and Doyne honeycomb retinal dystrophy, two dominantly inherited macular diseases with early onset drusen. The aim of this study was to determine whether the same disease allele was also associated with other forms of early onset drusen or familial cases of age-related macular degeneration. Methods: Thirteen index cases of early onset drusen together with 15 other family members were examined. In addition, 54 familial cases of age-related macular degeneration were examined. Blood was taken for DNA analysis and screened for the Arg345Trp disease-associated allele of the EFEMP1 gene. Twenty-four cases of malattia leventinese or Doyne honeycomb retinal dystrophy were also screened as positive controls. Another 150 ethnicity- and age-matched individuals acted as controls. Results: The Arg345Trp disease-associated allele in the EFEMP1 gene was confirmed in individuals with malattia leventinese and Doyne honeycomb retinal dystrophy. However, involvement of this allele was not evident in either early onset drusen or familial age-related macular degeneration. Conclusions: The Arg345Trp disease-associated allele of the EFEMP1 gene does not appear to be associated with cases of early onset drusen that fall outside the diagnosis of malattia leventinese or Doyne honeycomb retinal dys­trophy, nor does it appear to play a role in familial age-related macular degeneration. These findings do not exclude the involvement of other alleles of the EFEMP1 gene in either phenotype. The genetic mechanisms involved in the hetero­geneous group of early onset drusen remain to be elucidated but should lead to insights into the genetic causes of macular diseases. [ABSTRACT FROM AUTHOR]

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

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

In recent years, there has been intense development of artificial intelligence (AI) techniques, which have the potential to improve the clinical management of age-related macular degeneration (AMD) and facilitate the prevention of irreversible vision loss from this condition. Such AI techniques could be used as clinical decision support tools to: (i) improve the detection of AMD by community eye health practitioners, (ii) enhance risk stratification to enable personalised monitoring strategies for those with the early stages of AMD, and (iii) enable early detection of signs indicative of possible choroidal neovascularisation allowing triaging of patients requiring urgent review. This review discusses the latest developments in AI techniques that show promise for these tasks, as well as how they may help in the management of patients being treated for choroidal neovascularisation and in accelerating the discovery of new treatments in AMD. [ABSTRACT FROM AUTHOR]

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

Background Methods Results Conclusions Nocturnal hypoxia is common, under‐diagnosed and is found in the same demographic at risk of age‐related macular degeneration (AMD). The objective of this study was to determine any association between nocturnal hypoxia and AMD, its severity, and the high‐risk sub‐phenotype of reticular pseudodrusen (RPD).This cross‐sectional study included participants aged ≥50 years with AMD, or normal controls, exclusive of those on treatment for obstructive sleep apnoea. All participants had at home, overnight (up to 3 nights) pulse oximetry recordings and multimodal imaging to classify AMD. Classification of Obstructive Sleep Apnea (OSA) was determined based on oxygen desaturation index [ODI] with mild having values of 5–15 and moderate‐to‐severe >15.A total of 225 participants were included with 76% having AMD, of which 42% had coexistent RPD. Of the AMD participants, 53% had early/intermediate AMD, 30% had geographic atrophy (GA) and 17% had neovascular AMD (nAMD). Overall, mild or moderate‐to‐severe OSAwas not associated with an increased odds of having AMD nor AMD with RPD (p ≥ 0.180). However, moderate‐to‐severe OSA was associated with increased odds of having nAMD (odds ratio = 6.35; 95% confidence interval = 1.18 to 34.28; p = 0.032), but not early/intermediate AMD or GA, compared to controls (p ≥ 0.130). Mild OSA was not associated with differences in odds of having AMD of any severity (p ≥ 0.277).There was an association between nocturnal hypoxia as measured by the ODI and nAMD. Hence, nocturnal hypoxia may be an under‐appreciated important modifiable risk factor for nAMD. [ABSTRACT FROM AUTHOR]

Purpose: Previous work has suggested that sensitivities measured on the iCare MAIA and Nidek MP‐1 microperimeters differ systematically, although it is unclear whether one or both devices are inaccurate. Here, we assess the discrepancy between these two instruments as well as with a rigorous reference standard. Methods: Fifteen healthy participants underwent visual field testing on the MAIA and MP‐1 microperimeters. Results were compared to a reference measure of increment thresholds on a laboratory‐based, calibrated computer monitor system using the same background luminance and target size. Discrepancies were assessed as a function of eccentricity along the vertical meridian. Differences in decibels (dB) due to differences in the maximum stimulus luminance between devices were accounted for mathematically. Results: The mean sensitivity measured with the MAIA was <1 dB lower than laboratory‐based measures, which was statistically significant but of limited clinical importance. In contrast, the mean sensitivity measured with the MP‐1 was >8 dB lower than the laboratory measures. The difference was greater for an eccentric superior retinal location, in contrast to what would be predicted if the discrepancy was due to a ceiling effect caused by the MP‐1's limited dynamic range. Conclusions: While MAIA measurements showed low bias compared with our rigorously determined reference standard, the MP‐1 showed large discrepancies that could not be explained purely by the limited dynamic range of the instrument. MAIA and MP‐1 sensitivity values cannot be compared directly, and caution is advised when assessing absolute sensitivities or eccentricity effects in the extensive MP‐1 literature. [ABSTRACT FROM AUTHOR]

Background: To examine the association between large choroidal signal hypertransmission ≥250 μm (LHyperT) on optical coherence tomography (OCT) with the risk of developing geographic atrophy (GA) and compare this risk with those associated with nascent geographic atrophy (nGA). Methods: Two hundred and eighty eyes from 140 participants with bilateral large drusen and without late age‐related macular degeneration (AMD) or nGA at baseline underwent OCT imaging and colour fundus photography (CFP) at 6‐monthly intervals up to 5 years. OCT scans were graded for the presence of LHyperT and nGA, and CFPs were graded for the presence of GA. Results: The five‐year incidence of LHyperT and nGA were 37% and 27% respectively (p = 0.003), and the two‐year probability of their progression to GA were 17% and 40%, respectively (p = 0.002). LHyperT and nGA explained 81% and 91% of the variance in the time to develop GA, respectively (p = 0.032), and they were both associated with a significantly higher rate of GA development compared to eyes without these lesions (adjusted hazard ratio = 110.8 and 183.2, respectively; p < 0.001 for both). Conclusions: LHyperT and nGA were both high‐risk features for GA development, but the latter showed a higher rate of GA progression and explained a significantly greater proportion of the variance in the time to develop GA. As such, nGA may be a more robust surrogate endpoint than LHyperT for the conventional clinical endpoint of CFP‐defined GA for intervention trials in the early stages of AMD. [ABSTRACT FROM AUTHOR]

With the introduction of therapies to treat geographic atrophy (GA), GA management in clinical practice is now possible. A living systematic review can provide access to timely and robust evidence synthesis. This review found that complement factor 3 and 5 (C3 and C5) inhibition compared to sham likely reduces change in square root GA area at 12 months and untransformed GA area at 24 months. There is likely little to no difference in the rate of systemic treatment-emergent adverse events compared to sham. C3 and C5 inhibition, however, likely does not improve best-corrected visual acuity (BCVA) at 12 months, and the evidence is uncertain regarding change in BCVA at 24 months. Higher rates of ocular treatment emergent adverse effects with complement inhibition occur at 12 months and likely at 24 months. Complement inhibition likely results in new onset neovascular age-related macular degeneration at 12 months. This living meta-analysis will continuously incorporate new evidence. [ABSTRACT FROM AUTHOR]

Purpose: Retinal non‐perfusion (RNP) is fundamental to disease onset and progression in diabetic retinopathy (DR). Whether anti‐vascular endothelial growth factor (anti‐VEGF) therapy can modify RNP progression is unclear. This investigation quantified the impact of anti‐VEGF therapy on RNP progression compared with laser or sham at 12 months. Methods: A systematic review and meta‐analysis of randomised controlled trials (RCTs) were performed; Ovid MEDLINE, EMBASE and CENTRAL were searched from inception to 4th March 2022. The change in any continuous measure of RNP at 12 months and 24 months was the primary and secondary outcomes, respectively. Outcomes were reported utilising standardised mean differences (SMD). The Cochrane Risk of Bias Tool version‐2 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines informed risk of bias and certainty of evidence assessments. Results: Six RCTs (1296 eyes) and three RCTs (1131 eyes) were included at 12 and 24 months, respectively. Meta‐analysis demonstrated that RNP progression may be slowed with anti‐VEGF therapy compared with laser/sham at 12 months (SMD: −0.17; 95% confidence interval [CI]: −0.29, −0.06; p = 0.003; I2 = 0; GRADE rating: LOW) and 24‐months (SMD: −0.21; 95% CI: −0.37, −0.05; p = 0.009; I2 = 28%; GRADE rating: LOW). The certainty of evidence was downgraded due to indirectness and due to imprecision. Conclusion: Anti‐VEGF treatment may slightly impact the pathophysiologic process of progressive RNP in DR. The dosing regimen and the absence of diabetic macular edema may impact this potential effect. Future trials are needed to increase the precision of the effect and inform the association between RNP progression and clinically important events. PROSPERO Registration: CRD42022314418. [ABSTRACT FROM AUTHOR]

Introduction: The specific impact from the patient's perspective of geographic atrophy (GA), an advanced form of age-related macular degeneration (AMD), is not well understood.Methods: An ethnographic study was conducted to understand the impact of bilateral GA secondary to AMD on daily functioning by observing regular activities performed at home and through semi-structured interviews. Eligible subjects had a definitive GA diagnosis, including presence of drusen, GA lesion size of at least one disc area in the better-seeing eye, and no other confounding ophthalmologic diagnosis. Data were collected via video recordings and field notes, and analyzed by coding video transcripts.Results: Functional impact domains affecting more than two of the 16 subjects from the United Kingdom, United States, or Germany were activities of daily living (difficulty reading, n = 16; driving, n = 12; and watching movies, television, or theater, n = 11), emotional (frustration, and fear of blindness, n = 7 each), social/leisure (interference with hobbies, n = 8, and diminished social activities, n = 4), physical (n = 4), and financial (n = 10). Subjects with a best-corrected visual acuity (BCVA) of 20/100 or better in the better-seeing eye (n = 10) reported similar functional impacts to those with a BCVA of worse than 20/100 in their better-seeing eye (n = 5).Conclusion: This study helps address gaps in patient-focused research into GA, which negatively impacts the day-to-day functioning of patients. Larger qualitative and quantitative studies are needed to quantify patient experiences and assess the correlation between BCVA score and impact of GA.Funding: F. Hoffmann-La Roche Ltd. [ABSTRACT FROM AUTHOR]

We reviewed the use of patient-reported outcome measures (PROMs) in the treatment of ophthalmologic conditions as recommended by the Clinical Practice Guidelines (CPGs) published by the American Academy of Ophthalmology (AAO). Patient-reported outcome measures are standardized instruments that provide information regarding a patient's health status or health-related quality of life. Patient-reported outcome measures are increasingly used to inform study end points in ophthalmology studies. However, the extent to which PROMs are ultimately informing patient management recommendations in ophthalmology as part of CPGs remains an area of evidence gap. We included all CPGs published by the AAO from inception to June 2022. We also included all primary studies and systematic reviews cited in the treatment sections of the CPGs evaluating treatment of an ophthalmic condition. The primary outcome was the frequency of PROMs discussed in CPGs and in cited studies evaluating treatment. Secondary outcomes included frequency of minimal important difference (MID) use to contextualize PROM results and percentage of strong and discretionary recommendations supported by PROMs. We published a study protocol a priori on PROSPERO (CRD42022307427). Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. We assessed risk of bias using the Appraisal of Guidelines, Research and Evaluation II (AGREE II) instrument. We identified 24 eligible CPGs, providing 2458 cited studies (2191 primary, 267 secondary) evaluating treatment of eye conditions. Ten CPGs (41.7%) reported consideration of PROMs. Of these, 31 of 94 (33%) recommendations were informed by studies evaluating a PROM as an outcome. Across all studies cited in the development of CPGs, 221 (9.0%) used PROMs as a primary or secondary outcome, of which 4 PROM results (1.8%) were interpreted using an empirically determined MID. Overall, the risk of bias was low for all CPGs. Overall, outcomes of PROMs are seldom used in ophthalmology CPGs published by the AAO and in cited primary and secondary research on treatments. When PROMs were considered, their interpretation was seldom based on an MID. To improve patient care, guideline developers may consider incorporating PROMs and applicable MIDs to inform key outcomes when formulating treatment recommendations. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Geographic atrophy is a leading cause of progressive, irreversible vision loss. The objectives of OAKS and DERBY were to assess the efficacy and safety of pegcetacoplan compared with sham treatment in patients with geographic atrophy. OAKS and DERBY were two 24-month, multicentre, randomised, double-masked, sham-controlled, phase 3 studies, in which patients aged 60 years and older with geographic atrophy secondary to age-related macular degeneration were enrolled at 110 clinical sites and 122 clinical sites worldwide, respectively. Patients were randomly assigned (2:2:1:1) by central web-based randomisation system to intravitreal 15 mg per 0·1 mL pegcetacoplan monthly or every other month, or sham monthly or every other month using stratified permuted block randomisation (stratified by geographic atrophy lesion area at screening, history or presence of active choroidal neovascularisation in the eye not under assessment, and block size of six). Study site staff, patients, reading centre personnel, evaluating physicians, and the funder were masked to group assignment. Sham groups were pooled for the analyses. The primary endpoint was the change from baseline to month 12 in the total area of geographic atrophy lesions in the study eye based on fundus autofluorescence imaging, in the modified intention-to-treat population (ie, all patients who received one or more injections of pegcetacoplan or sham and had a baseline and at least one post-baseline value of lesion area). Key secondary endpoints (measured at 24 months) were change in monocular maximum reading speed of the study eye, change from baseline in mean functional reading independence index score, change from baseline in normal luminance best-corrected visual acuity score, and change from baseline in the mean threshold sensitivity of all points in the study eye by mesopic microperimetry (OAKS only). Safety analyses included patients who were randomly assigned and received at least one injection of pegcetacoplan or sham. The now completed studies are registered with ClinicalTrials.gov , NCT03525613 (OAKS) and NCT03525600 (DERBY). Between Aug 30, 2018, and July 3, 2020, 1258 patients were enrolled in OAKS and DERBY. The modified intention-to-treat populations comprised 614 (96%) of 637 patients in OAKS (202 receiving pegcetacoplan monthly, 205 pegcetacoplan every other month, and 207 sham) and 597 (96%) of 621 patients in DERBY (201 receiving pegcetacoplan monthly, 201 pegcetacoplan every other month, and 195 sham). In OAKS, pegcetacoplan monthly and pegcetacoplan every other month significantly slowed geographic atrophy lesion growth by 21% (absolute difference in least-squares mean –0·41 mm2, 95% CI –0·64 to –0·18; p=0·0004) and 16% (–0·32 mm2, –0·54 to –0·09; p=0·0055), respectively, compared with sham at 12 months. In DERBY, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth, although it did not reach significance, by 12% (–0·23 mm2, –0·47 to 0·01; p=0·062) and 11% (–0·21 mm2, –0·44 to 0·03; p=0·085), respectively, compared with sham at 12 months. At 24 months, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth by 22% (–0·90 mm2, –1·30 to –0·50; p<0·0001) and 18% (–0·74 mm2, –1·13 to –0·36; p=0·0002) in OAKS, and by 19% (–0·75 mm2, –1·15 to –0·34; p=0·0004) and 16% (–0·63 mm2, –1·05 to –0·22; p=0·0030) in DERBY, respectively, compared with sham. There were no differences in key secondary visual function endpoints at 24 months. Serious ocular treatment-emergent adverse events were reported in five (2%) of 213, four (2%) of 212, and one (<1%) of 211 patients in OAKS, and in four (2%) of 206, two (1%) of 208, and two (1%) of 206 patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. New-onset exudative age-related macular degeneration was reported in 24 (11%), 16 (8%), and four (2%) patients in OAKS, and in 27 (13%), 12 (6%), and nine (4%) patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. Pegcetacoplan, the first treatment approved by the US Food and Drug Administration for geographic atrophy, slowed geographic atrophy lesion growth with an acceptable safety profile. Apellis Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Abstract: Importance: Identifying variables that influence presenting visual acuity (VA) in patients with neovascular age‐related macular degeneration (nAMD) is important because it is a strong predictor of long‐term outcomes. Background: To assess the clinical and social characteristics associated with low presenting VA in nAMD patients. Design: The present study is a cross‐sectional analysis from a prospective, observational database. Participants: We identified 3242 treatment‐naïve patients from 54 Australian practices in the Fight Retinal Blindness! registry. Methods: Age, gender, ethnicity and VA were recorded at the baseline visit. Socio‐economic status was determined using the Australian Bureau of Statistics socio‐economic indexes for areas. Main Outcome Measures: Association between clinical and socio‐economic characteristics with presenting VA was identified. Results: Poor VA (≤35 letters) in the presenting eye was associated with older age (adjusted odds ratio [AOR]: 1.33 for patients aged ≥80 years vs. <80 years [95% confidence interval, CI: 1.04, 1.71]), treatment at a public practice (AOR: 1.91 for public vs. private practices [95% CI: 1.46, 2.50]) and intermediate (36–69 letters) VA in the fellow eye (AOR: 0.67 [95% CI: 0.47, 0.95] and 0.64 [95% CI: 0.48, 0.85] for poor [≤35 letters] and good [≥70 letters] VA vs. intermediate VA in the fellow eye). Gender, ethnicity and socio‐economic status were not independently associated with VA at presentation. Conclusions and Relevance: Poor presenting vision is detrimental to the long‐term outcomes of nAMD. Poor presentation of nAMD in Australia may not be related to socio‐economic circumstances, but due to systems of care. Further research is warranted to determine why patients at public practices present with worse vision compared with private practices in Australia. [ABSTRACT FROM AUTHOR]

Background: We aimed to describe the self‐reported level of eyesight amongst a cohort of relatively healthy older Australian adults, and to investigate associations between poorer self‐rated eyesight and demographic, health, and functional characteristics Methods: The ASPirin in Reducing Events in the Elderly (ASPREE) Longitudinal Study of Older Persons (ALSOP) study was embedded in a multisite trial which recruited independently living Australians from general practices (2010–2014). Self‐rated eyesight was recorded on a paper‐based questionnaire as Excellent, Good, Fair, Poor, Very poor, or Completely blind at the baseline study wave Results: Data from 14 592 participants (aged 70–95 years, 54.61% female) were included in this cross‐sectional analysis. Eighty percent of participants reported excellent or good eyesight (n = 11 677). People with complete blindness were precluded from enrolling but 299 participants (2.0%) reported poor or very poor eyesight, and 2616 rated their eyesight as fair (17.9%). Lower levels of eyesight were associated with being older, female, fewer years of formal education, a primary language other than English, smoking, and self‐reported macular degeneration, glaucoma, retinopathy, cataracts, and hearing problems (each p ≤ 0.021). People with lower levels of eyesight had a higher number of falls, frailty characteristics, and depressive symptoms, and lower mental and physical health functioning scores (each p < 0.001) Conclusions: Whilst most of these healthy older Australians reported good or excellent eyesight, a notable minority reported poor or very poor eyesight, and this was associated with a range of poorer health measures. These findings support the need for additional resources to prevent vision loss and associated sequelae [ABSTRACT FROM AUTHOR]

To examine the association between incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) on OCT imaging and the subsequent risk of developing geographic atrophy (GA) defined on conventional color fundus photography (CFP) and to compare this with the specific features that define nascent GA (nGA). Retrospective analysis of data from a longitudinal study. A total of 280 eyes from 140 participants with bilateral large drusen without specific nGA-defining features or late age-related macular degeneration (AMD) at baseline. OCT imaging and CFP were performed at baseline and then at 6-month intervals for up to 36 months. Eyes that developed neovascular AMD were censored on the day it was detected. OCT volume scans were graded for the presence of iRORA and nGA separately, and CFP images were graded for the presence of GA. Association with and variance explained in time to GA development. A total of 58 eyes (21%) from 46 participants (33%) had iRORA at baseline, and a further 87 eyes (31%) developed iRORA over the follow-up period. Time-to-event analyses demonstrated that prevalent or incident iRORA was associated with an increased rate of GA development (adjusted hazard ratio [HR], 12.1; P = 0.021), as was incident nGA (adjusted HR, 78.6; P < 0.001). However, only the specific nGA features (adjusted P < 0.001), and not iRORA (adjusted P = 0.520), were associated with an increased rate of GA development when both features were included in the same multivariable model. The proportion of variance explained in the time to GA development by iRORA itself (R 2 = 43%) was significantly lower than explained by nGA alone (R 2 = 91%; P = 0.010). In this cohort, iRORA is a significant risk factor for GA development, but its association with GA development appears to be accounted for by the development of the specific features that define nGA. Although requiring replication, these findings provide useful guidance on the relative utility of nGA and iRORA as risk factors for GA and as potential surrogate end points for future interventional studies in the early stages of AMD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

: Retinal visual prostheses (“bionic eyes”) have the potential to restore vision to blind or profoundly vision-impaired patients. The medical bionic technology used to design, manufacture and implant such prostheses is still in its relative infancy, with various technologies and surgical approaches being evaluated. We hypothesised that a suprachoroidal implant location (between the sclera and choroid of the eye) would provide significant surgical and safety benefits for patients, allowing them to maintain preoperative residual vision as well as gaining prosthetic vision input from the device. This report details the first-in-human Phase 1 trial to investigate the use of retinal implants in the suprachoroidal space in three human subjects with end-stage retinitis pigmentosa. The success of the suprachoroidal surgical approach and its associated safety benefits, coupled with twelve-month post-operative efficacy data, holds promise for the field of vision restoration. Trial Registration: Clinicaltrials.gov [ABSTRACT FROM AUTHOR]

To determine the prognostic significance and impact on visual function of the cuticular drusen phenotype in a cohort with intermediate age-related macular degeneration (AMD). Longitudinal, observational study. Participants aged 50 years or older, with bilateral large conventional drusen, without late AMD. Multimodal imaging (MMI) and microperimetry were performed at baseline and then every 6 months for up to 3 years. Eyes were graded for the MMI-based presence of cuticular drusen at baseline. Color fundus photographs were used to grade for the presence of pigmentary abnormalities. OCT scans were used to calculate drusen volume. The associations between cuticular drusen and progression to MMI-defined late AMD (including OCT signs of atrophy) and the impact on visual sensitivity were examined with and without adjustment for the confounders of baseline age, pigmentary abnormalities, and drusen volume. Time to develop MMI-defined late AMD and change in mean visual sensitivity. A total of 280 eyes from 140 participants were included, with 70 eyes from 35 individuals (25%) having cuticular drusen at baseline. Cuticular drusen were not significantly associated with an increased rate of progression to late AMD with and without adjustment for confounders (P ≥ 0.784 for both). In an adjusted model, cuticular drusen were not associated with lower baseline visual sensitivity (P = 0.758) or a faster rate of visual sensitivity decline (P = 0.196). In a cohort with bilateral large conventional drusen, individuals with the cuticular drusen phenotype had neither a higher nor lower risk of developing late AMD over 3 years and were not associated with a difference in rate of visual sensitivity decline compared with those without this phenotype. As such, individuals with this phenotype currently warrant similar monitoring strategies as those with conventional drusen. [ABSTRACT FROM AUTHOR]

Objective: To compare the effectiveness of low-luminance visual acuity (LLVA) and microperimetry as functional measures in early stages of age-related macular degeneration (AMD). Design: Prospective cross-sectional study. Participants: One hundred seventy-nine participants with a clinical spectrum of non-neovascular AMD and 26 control participants. Methods: Best-corrected visual acuity (BVCA), LLVA, and microperimetric retinal sensitivity were measured on 1 eye of all participants. Low-luminance deficit (LLD) was calculated as the difference between LLVA and BCVA. The functional parameters were compared between 6 clinical severity groups (from controls to non-foveal geographic atrophy [GA]), and the relationships and magnitude of these parameters were determined and compared. Main Outcome Measures: Visual acuity parameters (BCVA, LLVA, and LLD) and central retinal sensitivity. Results: Best-corrected visual acuity, LLVA, and central retinal sensitivity were reduced significantly for all AMD clinical severity groups when compared with control participants (P ≤ 0.002), except for those with drusen between 63 and 125 µm (P ≥ 0.107). However, LLD was not significantly different from control participants in all groups (P ≥ 0.073), except in the non-foveal GA group (P = 0.008). A significant positive relationship between central retinal sensitivity and LLD (R = 0.613; P < 0.001), but not BCVA, suggests that there is a trend for LLVA to detect a greater extent of functional deficit than BCVA in eyes with increasingly poorer retinal sensitivity. However, the results of the linear regression models estimated central retinal sensitivity to be 6.1, 3.7, and 5.1 standard deviations (SDs) less than normal by the time BCVA, LLVA, and LLD, respectively, were 2 SDs less than normal. Conclusions: In early stages of AMD, LLVA did not detect a greater extent of functional deficit than BCVA when compared with control participants. Although there was a trend for LLVA to be more effective at detecting foveal deficits than BCVA in eyes with increasingly poorer retinal sensitivity, both visual acuity measures were much less sensitive compared with microperimetry. [ABSTRACT FROM AUTHOR]

Reticular pseudodrusen (RPD) are subretinal deposits that, when observed with age-related macular degeneration (AMD), form a distinct phenotype, often associated with late-stage disease. To date, RPD genetic risk associations overlap six well-established AMD-risk regions. Determining RPD-specific underlying genetic causes by using adequate imaging methods should improve our understanding of the pathophysiology of RPD. [ABSTRACT FROM AUTHOR]

A bstract The last decade has produced pivotal change in our understanding of the molecular mechanisms underlying age-related macular degeneration (AMD), a leading cause of global blindness. In this time, the complement system has featured as a unifying theme for several elements of new evidence: initially, the discovery of complement proteins within drusen and subsequently, the association between AMD and mutations in various complement pathway genes, most notably complement factor H. Increasingly, a wealth of data are pointing towards a role for chronic local inflammation and complement activation in the patho-aetiology of AMD. These findings have paved the way for the exploration of a new paradigm of therapy in AMD management; targeting of specific molecular constituents in the complement pathway thus producing dampening or inhibition of the inflammatory response. Such an approach has the potential to intervene earlier in the disease process and ideally before vision is compromised. In this review we discuss the role of the complement system in AMD, novel therapies in preclinical evaluation and clinical trial, and whether these have a part to play in reducing the burden of disease. [ABSTRACT FROM AUTHOR]

Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. It has been proposed that the polymorphism encoding Y402H (T1277C) in the complement factor H gene (CFH) is one of the main determinants of disease. We genotyped the polymorphism at a number of loci in the region encompassing the Regulators of Complement Activation (RCA) on chromosome 1, including T1277C SNP, in 187 patients and 146 controls. Haplotypes have been classified as protective (P) or susceptible (S) with respect to AMD. This included the identification of an S haplotype with a T at 1277. The results show that no single locus should be assumed to be directly responsible for AMD, but rather argue for the existence of RCA haplotypes, which can be assigned meaningful predictive values for AMD. We conclude that the critical sequences are within a region 450kb centromeric to 128kb telomeric of CFH. [Copyright &y& Elsevier]

It can be argued that age-related macular degeneration is one of the best characterized complex trait diseases. Extensive information related to genetic and environmental risk factors exists, and a number of different biological pathways are strongly implicated in its aetiology. Along with recent improvements in high throughput and relatively inexpensive genetic technologies, we are now in a position to consider developing a presymptomatic, personalized approach towards the assessment, management and treatment of this disease. We explore the applicability and challenges of this approach if it is to become commonplace for guiding treatment decisions for individuals with pre-existing disease or for those at high risk of developing it. [ABSTRACT FROM AUTHOR]

Objective: To examine the relationship of retinal vascular caliber to macular telangiectasia (MT) type 2. Design: Case-control study. Participants: Patients with MT aged 18 years and older were identified from Australian sites of the multicenter Macular Telangiectasia Project. Three controls per case were selected from participants of the Australian Diabetes, Obesity and Lifestyle study, matched according to age and diabetes status. Methods: Baseline ophthalmic examinations of cases included assessment of best corrected visual acuity, fluorescein angiography, autofluorescence imaging, optical coherence tomography, and retinal photography. Retinal vascular caliber of cases and controls were measured from optic disc-centered digital retinal images by a computer-assisted method. Main Outcome Measures: MT, central retinal arteriolar, and venular caliber. Results: There were 55 cases and 170 controls. After controlling for diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglycerides, hypertension, fasting plasma glucose, and glycosylated hemoglobin, each standard deviation (SD) increase in retinal arteriolar caliber was associated with a 2-fold higher odds of MT (odds ratio [OR] 2.18; 95% confidence interval [CI], 1.50–3.18). Similarly, each SD increase in retinal venular caliber was associated with increased odds of having MT (OR 1.87; 95% CI, 1.31–2.67). Conclusions: This study shows that MT is associated with wider arteriolar and venular caliber, measured outside of the foveal area. Generalized changes in retinal vascular caliber may reflect underlying dysfunction in retinal pericytes or glial cells, and may provide a means to monitor progression of disease. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [Copyright &y& Elsevier]

Background: Tobacco smoking is a risk factor for age-related macular degeneration, but studies of ex-smokers suggest quitting can reduce the risk. Methods: We fitted a function predicting the decline in risk of macular degeneration after quitting to data from 7 studies involving 1,488 patients. We assessed the cost -effectiveness of smoking cessation in terms of its impact on macular degeneration-related outcomes for 1,000 randomly selected U.S. smokers. We used a computer simulation model to predict the incidence of macular degeneration and blindness, the number of quality-adjusted life-years (QALYs), and direct costs (in 2004 U.S. dollars) until age 85 years. Cost-effectiveness ratios were based on the cost of the Massachusetts Tobacco Control Program. Costs and QALYs were discounted at 3% per year. Results: If 1,000 smokers quit, our model predicted 48 fewer cases of macular degeneration, 12 fewer cases of blindness, and a gain of 1,600 QALYs. Macular degeneration -related costs would decrease by $2.5 million if the costs of caregivers for people with vision loss were included, or by $1.1 million if caregiver costs were excluded. At a cost of $1,400 per quitter, smoking cessation was cost-saving when caregiver costs were included, and cost about $200 per QALY gained when caregiver costs were excluded. Sensitivity analyses had a negligible impact. The cost per quitter would have to exceed $77,000 for the cost per QALY for smoking cessation to reach $50,000, a threshold above which interventions are sometimes viewed as not cost-effective. Conclusion: Smoking cessation is unequivocally cost-effective in terms of its impact on age-related macular degeneration outcomes alone. [ABSTRACT FROM AUTHOR]

Background: Intravitreal ranibizumab prevents vision loss and improves visual acuity in patients with neovascular age-related macular degeneration, but it is expensive, and efficacy beyond 2 years is uncertain. Methods: We assessed the cost-effectiveness of ranibizumab compared with no ranibizumab over 10 years, using randomized trial efficacy data for the first 2 years, post-trial efficacy assumptions, and ranibizumab acquisition costs ranging from the wholesale price ($1,950 per dose) to the price of bevazicumab ($50), a similar molecule which may be equally efficacious. We used a computer simulation model to estimate the probability of blindness, the number of quality-adjusted life-years (QALYs), direct costs (in 2004 U.S. dollars), and cost-effectiveness ratios for a 67-year old woman. Costs and QALYs were discounted at 3% per year. Results: The probability of blindness over 10 years was reduced from 56% to 34% if ranibizumab was efficacious for only 2 years, 27% if efficacy was maintained for a further 2 years only (base-case scenario), and 17% if visual acuity at 4 years was then sustained. It was cost-saving under all price assumptions, when caregiver costs were included. When caregiver costs were excluded, the cost per QALY for the base-case ranged from $5,600, assuming the bevazicumab price, to $91,900 assuming the wholesale ranibizumab price. The cost per QALY was < $50,000 when the cost of ranibizumab was less than $1000. Conclusion: From a societal perspective, ranibizumab was cost-saving. From a health care funder's perspective, ranibizumab was an efficient treatment when it cost less than $1000 per dose. [ABSTRACT FROM AUTHOR]

Cardiovascular disease and age-related macular degeneration (AMD) may share common risk factors in their causal pathways. Decades of research from the cardiovascular sciences on fats have led investigators to focus on specific types of fats rather than total fat as a whole. They have established that saturated and trans-unsaturated fats ( trans fats) are damaging to cardiovascular health while polyunsaturated fats, particularly the marine omega 3 fatty acids appear protective. This has led to a number of studies investigating the associations of fat and AMD. Though the causal relationship between fats and AMD remain unproven, some studies suggest that an association may be present. To be able to understand and interpret the study results and their implications, an understanding of the fats in the diet is important. This review aims to give an overview of fatty acids, particularly the trans-unsaturated fatty acids, and the relevant food groups. [ABSTRACT FROM AUTHOR]

Background: Subthreshold nanosecond laser (SNL) treatment has been studied as a potential intervention in intermediate age-related macular degeneration (iAMD). This study investigated the effect of 100 SNL treatment spots on retinal structure and function. Methods: A prospective single-arm interventional pilot study. SNL treatment was delivered as 100 spots around the retinal vascular arcades of the study eye (worst visual acuity) in a single session in subjects with iAMD. Multimodal retinal imaging and dark-adapted chromatic perimetry were performed at baseline and at 0.5, 3, 6 and 12 months post treatment. Post treatment changes in best corrected visual acuity (BCVA), retinal thickness, relative ellipsoid zone reflectivity (rEZR) and rod-mediated functional parameters were compared to baseline. Results: Twenty-one subjects with iAMD were recruited. SNL treatment was associated with an increase in retinal thickness (p = 0.008) and decrease in rEZR (p < 0.001) at 2 weeks post laser. Recovery of retinal thickness and rEZR was observed at the 3-month post laser visit. A gradual improvement in BCVA was observed after laser treatment. The mean change in BCVA between baseline and 12-month visit was +1.9 ± 3.3 letters for the SNL treated eyes, compared to -0.4 ± 3.0 letters for the fellow eyes (p = 0.027). Rod-mediated function improved at 3 months post laser (p < 0.001) and returned to the baseline levels at 12 months post treatment. Conclusions: A single treatment with 100 SNL spots causes a short-term change in retinal structure and improvement in retinal function that are apparent at 3 months post treatment. [ABSTRACT FROM AUTHOR]

Purpose: Age‐related macular degeneration (AMD) is a major cause of vision loss. This study investigated whether performing clinical audit and receiving analytical performance feedback altered documentation of the AMD care provided by optometrists. Methods: Australian optometrists were recruited and completed a survey about their demographics and confidence in AMD care, and a three‐month audit of their practice records using an AMD audit tool (termed the pre‐audit evaluation). After receiving analytical feedback, participants identified areas for improvement and re‐audited their practices after three months to analyse changes in performance (termed the post‐audit evaluation). Paired t‐tests and Wilcoxon signed‐rank tests, as appropriate, were used to compare pre‐ and post‐audit data. Results: Twenty optometrists, most practising in Victoria, Australia, completed the study. Participants primarily worked in corporate practice and/or rural settings and had a range of optometric experience (2–40 years). At baseline, participants felt confident in their: knowledge of AMD risk factors (65%), advice to patients about these factors (55%) and management of earlier stages of AMD (55%). Each clinician completed (median [IQR]): 15 [IQR: 10–19] and 12 [IQR: 8–16] audits of unique patient records, pre‐ and post‐audit, respectively. Post‐audit, average record documentation (per optometrist) improved for asking about: AMD family history (94% to 100%, p = 0.03), smoking status (21% to 58%, p < 0.01), diet (11% to 29%, p < 0.01) and nutritional supplementation (20% to 51%, p < 0.01). For clinical examination, compliance with documenting pinhole visual acuity, performing an in‐office Amsler grid (upon indication) and using optical coherence tomography improved post‐audit (p < 0.05). Accuracy of severity documentation improved for earlier stages of AMD (p < 0.05). For earlier stages of AMD, documentation of counselling about modifiable risk factors significantly improved post‐audit (p < 0.05). Aspects well‐performed pre‐audit that did not change included documenting: medical histories (100% at both time points, p = 0.06) and retinal imaging (77% at both time points, p = 0.97). Conclusions: Self‐audit with analytical feedback improved clinical record documentation of: AMD risk factors, clinical examination, AMD severity classification and management advice. These findings support a role for audit to improve optometric clinical care of AMD, as evidenced by improved documentation of the AMD care delivered. [ABSTRACT FROM AUTHOR]

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-ß/d transcription factor isoforms bind to the cis-element 50-ATTAATAACC-30 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. [ABSTRACT FROM AUTHOR]