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Purpose: To apply methods for quantifying uncertainty of deep learning segmentation of geographic atrophy (GA). Design: Retrospective analysis of OCT images and model comparison. Participants: One hundred twenty-six eyes from 87 participants with GA in the SWAGGER cohort of the Nonexudative Age-Related Macular Degeneration Imaged with Swept-Source OCT (SS-OCT) study. Methods: The manual segmentations of GA lesions were conducted on structural subretinal pigment epithelium en face images from the SS-OCT images. Models were developed for 2 approximate Bayesian deep learning techniques, Monte Carlo dropout and ensemble, to assess the uncertainty of GA semantic segmentation and compared to a traditional deep learning model. Main Outcome Measures: Model performance (Dice score) was compared. Uncertainty was calculated using the formula for Shannon Entropy. Results: The output of both Bayesian technique models showed a greater number of pixels with high entropy than the standard model. Dice scores for the Monte Carlo dropout method (0.90, 95% confidence interval 0.87–0.93) and the ensemble method (0.88, 95% confidence interval 0.85–0.91) were significantly higher (P

Acquired retinal diseases such as age-related macular degeneration and diabetic retinopathy rank among the leading causes of blindness and visual loss worldwide. Effective treatments for these conditions are available, but often have a high treatment burden, and poor compliance can lead to disappointing real-world outcomes. Development of new treatment strategies that provide more durable treatment effects could help to address some of these unmet needs. Gene-based therapeutics, pioneered for the treatment of monogenic inherited retinal disease, are being actively investigated as new treatments for acquired retinal disease. There are significant advantages to the application of gene-based therapeutics in acquired retinal disease, including the presence of established therapeutic targets and common pathophysiologic pathways between diseases, the lack of genotype-specificity required, and the larger potential treatment population per therapy. Different gene-based therapeutic strategies have been attempted, including gene augmentation therapy to induce in vivo expression of therapeutic molecules, and gene editing to knock down genes encoding specific mediators in disease pathways. We highlight the opportunities and unmet clinical needs in acquired retinal disease, review the progress made thus far with current therapeutic strategies and surgical delivery techniques, and discuss limitations and future directions in the field. [ABSTRACT FROM AUTHOR]

Acquired retinal diseases such as age-related macular degeneration and diabetic retinopathy rank among the leading causes of blindness and visual loss worldwide. Effective treatments for these conditions are available, but often have a high treatment burden, and poor compliance can lead to disappointing real-world outcomes. Development of new treatment strategies that provide more durable treatment effects could help to address some of these unmet needs. Gene-based therapeutics, pioneered for the treatment of monogenic inherited retinal disease, are being actively investigated as new treatments for acquired retinal disease. There are significant advantages to the application of gene-based therapeutics in acquired retinal disease, including the presence of established therapeutic targets and common pathophysiologic pathways between diseases, the lack of genotype-specificity required, and the larger potential treatment population per therapy. Different gene-based therapeutic strategies have been attempted, including gene augmentation therapy to induce in vivo expression of therapeutic molecules, and gene editing to knock down genes encoding specific mediators in disease pathways. We highlight the opportunities and unmet clinical needs in acquired retinal disease, review the progress made thus far with current therapeutic strategies and surgical delivery techniques, and discuss limitations and future directions in the field.

Purpose: To apply methods for quantifying uncertainty of deep learning segmentation of geographic atrophy (GA)., Design: Retrospective analysis of OCT images and model comparison., Participants: One hundred twenty-six eyes from 87 participants with GA in the SWAGGER cohort of the Nonexudative Age-Related Macular Degeneration Imaged with Swept-Source OCT (SS-OCT) study., Methods: The manual segmentations of GA lesions were conducted on structural subretinal pigment epithelium en face images from the SS-OCT images. Models were developed for 2 approximate Bayesian deep learning techniques, Monte Carlo dropout and ensemble, to assess the uncertainty of GA semantic segmentation and compared to a traditional deep learning model., Main Outcome Measures: Model performance (Dice score) was compared. Uncertainty was calculated using the formula for Shannon Entropy., Results: The output of both Bayesian technique models showed a greater number of pixels with high entropy than the standard model. Dice scores for the Monte Carlo dropout method (0.90, 95% confidence interval 0.87-0.93) and the ensemble method (0.88, 95% confidence interval 0.85-0.91) were significantly higher ( P  < 0.001) than for the traditional model (0.82, 95% confidence interval 0.78-0.86)., Conclusions: Quantifying the uncertainty in a prediction of GA may improve trustworthiness of the models and aid clinicians in decision-making. The Bayesian deep learning techniques generated pixel-wise estimates of model uncertainty for segmentation, while also improving model performance compared with traditionally trained deep learning models., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Geographic atrophy (GA) remains a leading cause of central vision loss with no known cure. Until recently, there were no approved treatments for GA, often resulting in poor quality of life for affected patients. GA is characterized by atrophic lesions on the retina that may eventually threaten the fovea. Emerging treatments have demonstrated the ability to reduce the rate of lesion growth, potentially preserving visual function. Avacincaptad pegol (ACP; Astellas Pharma Inc), a complement component 5 inhibitor, is an FDA-approved treatment for GA that has been evaluated in numerous clinical trials. Here we review the current clinical trial landscape of ACP, including critical post hoc analyses that suggest ACP may reduce the risk of severe loss among patients with GA.

As the age of the population increases in many nations, age-related degenerative diseases pose significant socioeconomic challenges. One of the key degenerative diseases that compromise quality of life is age-related macular degeneration ( AMD). AMD is a multi-faceted condition that affects the central retina, which ultimately leads to blindness in millions of people worldwide. The pathophysiology and risk factors for AMD are complex, and the symptoms manifest in multiple related but distinct forms. The ability to develop effective treatments for AMD will depend on a thorough understanding of the underlying pathophysiology, risk factors, and driver molecular pathways, as well as the ability to develop useful animal models. This review provides an overview of the aforementioned aspects in AMD. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Age-related macular degeneration is the major cause of blindness in the elderly worldwide and the risk is influenced by both environmental and genetic risk factors. One important disease-associated region in humans is located on 10q26 and includes the two candidate genes ARMS2 and HTRA1. However, determination of the causative gene has not yet been possible and examining the situation in the rhesus monkey may help understand the situation in humans. In a recent paper, we characterized the rhesus monkey 10q26-orthologue region on chromosome 9 in detail and identified the drusen-associated HTRA1 promoter SNP rs196357513 as a putative risk factor. In this study, we predicted 9 binding sites for the vitamin D-dependent transcription factor vitamin D receptor in the rhesus HTRA1 promoter, one of which is destroyed by the rs196357513-risk allele. As patients with vitamin D deficit are at increased risk for age-related macular degeneration, a luciferase assay in transiently transfected ARPE19-cells was performed to evaluate the influence of the SNP rs196357513 and of 1,25-dihydroxyvitamin D on the rhesus monkey HTRA1 promoter activity. This revealed that the luciferase activity of the promoter construct containing the rs196357513 wild type allele was significantly reduced after vitamin D stimulation. An in silico analysis and literature search imply that this regulation could also play a role in human HTRA1 expression. Moreover, HTRA1 promoter activity of the construct containing the rs196357513 risk allele appeared diminished in comparison to the construct with the wild type allele, albeit this difference was not significant. The lower promoter activity due to the rhesus monkey rs196357513 risk allele apparently contradicts the common hypothesis for the human HTRA1 promoter risk allele of SNP rs11200638, for which a higher promoter activity has been observed. Our data point to a yet unexpected effect of decreased HTRA1 expression on drusen pathogenesis. Thus not only a higher HTRA1 expression, but an imbalance of HTRA1 might be disease-relevant. Both findings require closer analysis, but if relevance for humans proves true, it would impact current age-related macular degeneration research and treatment. [Copyright &y& Elsevier]

Age-related macular degeneration (AMD) is a degenerative disease of the retina and the leading cause of blindness in industrialized countries. AMD is a complex disease caused by the combination of genetic predisposition and environmental factors. The prevalence of AMD increases with age. The adverse effect of smoking is well established. Genetic predisposition has been demonstrated by familial aggregation studies and twin studies. Using genome linkage scan and association studies, multiple potentially causative genes have been identified. The chromosomes most commonly implicated are 1q25-31 and 10q26. In particular, variants in the gene for the complement factor H (CFH) and the genes PLEKHA1/LOC387715/HTRA1, Factor B (BF) and complement component 2 (C2) have been implicated as major risk or protective factors for the development of AMD. There have been some advances in the treatment of this condition; however, a complete cure remains remote but hopeful. Understanding the causative environmental and genetic interactions will facilitate the development of future preventive methods and treatments. [ABSTRACT FROM AUTHOR]

Background: Changes in choroidal vascularity index (CVI) are associated with multiple choroid-related ocular diseases. CVI is calculated as the area/volume ratio of vessels in the choroid, which could be affected by alterations in regional signal intensities due to hypo-transmission defects (hypoTDs) caused by drusen and retinal pigment epithelium (RPE) detachments, and hyper-transmission defects (hyperTDs) caused by the absence of RPE. To develop a simulation model to verify the CVI assessments in eyes with hyper/hypoTDs and demonstrate that accurate CVIs can be achieved after attenuation correction on swept-source optical coherence tomography (SS-OCT)., Methods: A simulation model was developed on 6×6 mm macular scans from normal subjects. Signal intensity in a cylindrical region below RPE was altered to mimic hyper/hypoTDs. CVIs were compared inside and outside the simulated regions before and after attenuation correction. CVI assessments of OCT scans from patients with hyperTDs due to geographic atrophy (GA) and from patients with hypoTDs due to drusen that subsequently resolved with the disappearance of the hypoTDs were compared with and without attenuation correction., Results: Ten normal eyes were recruited to generate the hyper/hypoTD simulation model. In eyes with hypoTDs, CVIs were overestimated, and in eyes with hyperTDs, the CVIs were underestimated (P<0.001). After attenuation correction, the uneven distribution of signal intensity was eliminated and the resulting CVI showed no significant difference compared with the 'ground truth', which is measured from the original scans. Attenuation correction successfully eliminated the influence of hyperTDs caused by GA on CVI measurements (n=38). Quantitatively, no significant difference was found in the CVIs of eyes before and after drusen collapse with attenuation correction (n=8)., Conclusions: The simulation model could reveal the impact of hypo/hyperTDs on CVI quantification in eyes with choroid-involved ocular diseases. The importance of attenuation correction to ensure accuracy in choroidal vessel segmentation was demonstrated by analyzing eyes with GA or drusen., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-21-1093/coif). RKW serves as an unpaid Deputy Editor of Quantitative Imaging in Medicine and Surgery. RKW discloses intellectual property owned by the Oregon Health and Science University and the University of Washington, and receives research support from Moptim Inc., Colgate Palmolive Company, and Carl Zeiss Meditec, Inc.; GG receives research support from Carl Zeiss Meditec, Inc. GG and the University of Miami co-own a patent that is licensed to Carl Zeiss Meditec, Inc. PJR receives research support from Carl Zeiss Meditec, Inc. and Stealth BioTherapeutics. He is a consultant for Apellis, Boehringer-Ingelheim, Carl Zeiss Meditec, Chengdu Kanghong Biotech, Ocunexus/InflammX Therapeutics, Ocudyne, Regeneron, and Unity Biotechnology. And he has equity interest in Apellis, Ocudyne, Ocunexus/InflammX, and Verana Health. He is a consultant to Carl Zeiss Meditec. The other authors have no conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

• Processing of series of fundus images for monitoring dry AMD, which had not yet been done. • The images of the series are processed jointly to correct illumination distortion. • The inter-image normalization allows the longitudinal study of atrophy progression. • Experiments on a dataset of 18 series manually segmented by a medical expert, to demonstrate the benefits of the proposed method. • Computation of colored maps highlighting the disease progression, of high interest for clinical interpretation. Age-related macular degeneration (ARMD) is a degenerative disease that affects the retina, and the leading cause of visual loss. In its dry form, the pathology is characterized by the progressive, centrifugal expansion of retinal lesions, called geographic atrophy (GA). In infrared eye fundus images, the GA appears as localized bright areas and its growth can be observed in series of images acquired at regular time intervals. However, illumination distortions between the images make impossible the direct comparison of intensities in order to study the GA progress. Here, we propose a new method to compensate for illumination distortion between images. We process all images of the series so that any two images have comparable gray levels. Our approach relies on an illumination/reflectance model. We first estimate the pixel-wise illumination ratio between any two images of the series, in a recursive way; then we correct each image against all the others, based on those estimates. The algorithm is applied on a sliding temporal window to cope with large changes in reflectance. We also propose morphological processing to suppress illumination artefacts. The corrected illumination function is homogeneous in the series, enabling the direct comparison of grey-levels intensities in each pixel, and so the detection of the GA growth between any two images. To demonstrate that, we present numerous experiments performed on a dataset of 18 series (328 images), manually segmented by an ophthalmologist. First, we show that the normalization preprocessing dramatically increases the contrast of the GA growth areas. Secondly, we apply segmentation algorithms derived from Otsu's thresholding to detect automatically the GA total growth and the GA progress between consecutive images. We demonstrate qualitatively and quantitatively that these algorithms, although fully automatic, unsupervised and basic, already lead to interesting segmentation results when applied to the normalized images. Colored maps representing the GA evolution can be derived from the segmentations. To our knowledge, the proposed method is the first one which corrects automatically and jointly the illumination inhomogeneity in a series of fundus images, regardless of the number of images, the size, shape and progression of lesion areas. This algorithm greatly facilitates the visual interpretation by the medical expert. It opens up the possibility of treating automatically each series as a whole (not just in pairs of images) to model the GA growth. [ABSTRACT FROM AUTHOR]

Background: To determine whether patients with severe vision impairment due to advanced age-related macular degeneration (AMD) benefit from bilateral cataract surgery in terms of vision-related quality of life (QoL)., Methods: A prospective interventional single-center study. Ten patients with severe vision impairment due to advanced bilateral AMD were included. The preoperative corrected distance visual acuity (CDVA) was ≥1.0/≥1.0 LogMAR units on Snellen chart and <20/<20 points on Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Patients were not on active treatment for wet AMD as the treatment was expected to have no effect or benefit. The patients were scheduled for immediate sequential bilateral cataract surgery, with target refraction emmetropia (SN60WF, Alcon). Vision-related QoL was measured with National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) preoperatively, at 3 months and 1 year., Results: The mean age of the patients was 82.5±6.2 years. The mean NEI VFQ-25 overall composite score changed from 44.0±7.1 preoperatively to 54.9±13.7 at 3 months and to 56.9±15.6 at 1 year (P=0.045, Friedman test). During the 1-year follow-up, there was an improvement in the subscale scores indicating difficulty with peripheral vision, mental health symptoms, and role difficulties due to vision (P<0.05 for all, Wilcoxon sign-rank test)., Conclusions: Cataract surgery may improve the vision-related QoL in patients with severe vision impairment due to bilateral advanced AMD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-2020-965). The series “Recent developments in cataract surgery” was commissioned by the editorial office without any funding or sponsorship. AG served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)