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Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach, we perform a systematic comparison of the distribution of VCDR and VDD and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI-based gradings increased estimates of heritability by ∼50% for VCDR and VDD. Our GWAS identified more than 200 loci associated with both VCDR and VDD (double the number of loci from previous studies) and uncovered dozens of biological pathways; many of the loci we discovered also confer risk for glaucoma. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWASs) require accurate cohort phenotyping, but expert labeling can be costly, time intensive, and variable. Here, we develop a machine learning (ML) model to predict glaucomatous optic nerve head features from color fundus photographs. We used the model to predict vertical cup-to-disc ratio (VCDR), a diagnostic parameter and cardinal endophenotype for glaucoma, in 65,680 Europeans in the UK Biobank (UKB). A GWAS of ML-based VCDR identified 299 independent genome-wide significant (GWS; p ≤ 5 × 10−8) hits in 156 loci. The ML-based GWAS replicated 62 of 65 GWS loci from a recent VCDR GWAS in the UKB for which two ophthalmologists manually labeled images for 67,040 Europeans. The ML-based GWAS also identified 93 novel loci, significantly expanding our understanding of the genetic etiologies of glaucoma and VCDR. Pathway analyses support the biological significance of the novel hits to VCDR: select loci near genes involved in neuronal and synaptic biology or harboring variants are known to cause severe Mendelian ophthalmic disease. Finally, the ML-based GWAS results significantly improve polygenic prediction of VCDR and primary open-angle glaucoma in the independent EPIC-Norfolk cohort. [ABSTRACT FROM AUTHOR]

Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-altering variant association analysis, we find a missense variant in ANGPTL7 in UK Biobank (rs28991009, p.Gln175His, MAF = 0.8%, genotyped in 82,253 individuals with measured IOP and an independent set of 4,238 glaucoma patients and 250,660 controls) that significantly lowers IOP (β = -0.53 and -0.67 mmHg for heterozygotes, -3.40 and -2.37 mmHg for homozygotes, P = 5.96 x 10−9 and 1.07 x 10−13 for corneal compensated and Goldman-correlated IOP, respectively) and is associated with 34% reduced risk of glaucoma (P = 0.0062). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.3%), which was genotyped in 6,537 glaucoma patients and 170,362 controls and is associated with a 29% lower glaucoma risk (P = 1.9 x 10−12 for all glaucoma types and also protection against its subtypes including exfoliation, primary open-angle, and primary angle-closure). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.0012 and 0.24 for Goldman-correlated and corneal compensated IOP, respectively), suggesting the protective mechanism likely resides in the loss of interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma. Author summary: Glaucoma is a common eye disease that damages the optic nerve. Using intraocular pressure, which is a known modifiable risk factor and predictive measure for glaucoma, genome-wide association studies have identified dozens of genetic variants likely affecting disease risk. However, the identification of potential therapeutic targets from those discoveries has been challenging because the functional consequences and the causal variants of the suggested common variant associations are typically unclear. Here, we present a strategy to scan for rare protein-altering variants, which provides direct insights into the functional consequence and the therapeutic effects, using more than 514,000 individuals with European ancestries in two population cohorts in the UK and Finland. We discover an allelic series of multiple rare ANGPTL7 missense and nonsense variants in UK Biobank that lower intraocular pressure and reduces the risk of glaucoma. We further identify an ANGPTL7 missense variant in FinnGen cohort with more than 50-fold enrichment in the Finnish population that provides protection against glaucoma and its subtypes. Our results highlight the benefits of multi-cohort analysis for the discovery of rare protein-altering variants in common diseases and indicate ANGPTL7 as a therapeutic target for glaucoma. [ABSTRACT FROM AUTHOR]

Purpose: In recent years, there has been widespread investment in imaging technologies by community optometrists in the UK, most notably optical coherence tomography (OCT). The aim of the current study was to determine the value of OCT in the diagnosis of posterior segment diseases in a representative sample of community optometrists using a clinical vignette methodology. Methods: A group of community optometrists (n = 50) initially completed a standardised training package on OCT interpretation followed by a computer‐based assessment featuring 52 clinical vignettes, containing images of healthy (n = 8) or glaucomatous (n = 18) discs or healthy (n = 8) or diseased (n = 18) fundi. Each vignette featured either a single fundus/disc photographic image, or a combination of a fundus/disc image with the corresponding OCT scan. An expert panel confirmed that the fundus images presented alone and those in combination with OCT data were of a similar level of difficulty and that the cases were typical of those seen in primary care. For each case, the optometrist selected their diagnosis from a pull‐down list and reported their confidence in their decision using a 10‐point Likert scale. Pairwise comparisons of the fundus image alone and fundus image/OCT combination were made for both diagnostic performance and confidence. Results: The mean percentage of correct diagnoses using fundus imaging alone was 62% (95% CI 59–64%) and for the combination of fundus image/OCT was 80% (95% CI 77–82%). The mean false negative rate with fundus alone was 27% reducing to 13% with the OCT combination. Median confidence scores for fundus imaging alone was 8.0 (IQR 7.0–8.0) and 8.3 (IQR 8.0–9.0) for the combination. Improvements in performance and confidence were statistically significant (p < 0.001). Conclusion: The results from this vignette study suggests that OCT improves optometrists' diagnostic performance compared to fundus observation alone. These initial results suggest that OCT provides valuable additional data that could augment case‐finding for glaucoma and retinal disease; however, further research is needed to assess its diagnostic performance in a routine clinical practice setting. [ABSTRACT FROM AUTHOR]

Introduction: Headaches, visual problems and tinnitus are symptoms of Idiopathic Intracranial Hypertension (IIH) which resolve with reduction of CSF pressure. Impaired cranial venous outflow has been implicated in the pathogenesis and there is evidence of good treatment results in IIH using venous sinus stenting. We are currently initiating a multi-centre randomised controlled trial, the VISION study (Venous Intervention versus Shunting in IIH for Optic Disc Swelling) comparing radiological (venous sinus stenting) to surgical intervention (CSF shunting). As part of the preparations for VISION we made a basic questionnaire available to members of the website IIH UK (www.iih.org.uk). Methods: 10-point questionnaire pertaining to IIH diagnosis, symptoms and management using www.surveymonkey.com. Results: 250 questionnaires were returned. 95.6% of respondents were female, mostly ≤40 years of age. 70% were diagnosed in the last 5 years, but only 35% were diagnosed less than a year after onset of symptoms. 59.4% of patients had not undergone any radiological/surgical intervention, 34.9% had had CSF diversion, 3.6% venous stenting and 2.0% had stent plus shunt. 16.8% indicated their lives were most affected by tinnitus and 18.1% by visual problems, but 49.6% said they were most affected by their headaches. 81% of patients indicated they would be happy to participate in a randomised trial comparing the two treatment options of venous stenting and CSF shunting. Conclusion: IIH patients want to be actively involved in their treatment and are favourably disposed towards clinical research. Variation exists in treatment modalities offered. There are individual differences regarding impact of symptoms. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is the most common intraocular malignancy in adults. Eye-preserving approaches like episcleral plaque brachytherapy are common but limited in patients (pts) with large tumors or those adjacent to the optic nerve. Proton therapy (PT) offers an alternative eye-preserving treatment option. We report a single-institution experience utilizing PT to treat UM. We hypothesized that PT would provide excellent local control (LC) and eye preservation (EP) with acceptable toxicity and visual outcomes across all patients, including those with large tumors in adverse locations. We reviewed the records of treatment-naive pts who received PT for non-metastatic UM between June 2012 and December 2020. All pts had ≥ 6 months of follow-up. Treatment planning was performed in EyePlan (Clatterbridge, UK) based on eye/tumor measurements and 3-4 implanted scleral fiducial markers, registered fundus photographs, and confirmed by CT/MRI. Pts were set-up in a seated position with gaze fixation and real-time image guidance using a single en face beam to a total 50-60 Gy RBE in 4-5 consecutive daily fractions. We estimated disease control and survival, including LC, EP, distant metastasis-free survival (DMFS), cause-specific survival (CSS), overall survival (OS), and grade 3+ toxicity as defined by CTCAEv5 using the cumulative incidence method. Regression of multiple variables simultaneously was accomplished with competing-risks Cox regression. 120 pts met inclusion criteria; 33 had a biopsy of their lesion; 9.2% were class 2. Moreover, 47.5% had COMS medium while 35.8% had large tumors. Median tumor thickness was 5.0 mm (0.5 – 13.0) and median basal dimension was 13.0 mm (4.0 – 25.0). Median distance to the fovea and optic disc was 3.5 mm. 38% had retinal detachment with 47% having significantly impaired visual acuity at baseline (worse than Snellen 20/40). 98.3% received 60 Gy RBE over 4 daily fractions. Median follow-up was 31 months (6 – 104). The 2-year estimates (95% CI) for LC, EP, DMFS, CSS, and OS were 94% (88-97%), 95% (90-98%), 88% (81-93%), 94% (88-97%), and 90% (83-95%), respectively. 9 pts underwent enucleation following PT (5 for recurrent/persistent disease). Retinopathy (5%), neovascular glaucoma (3.3%), and optic nerve disorder (2.5%) were the most common severe toxicities. 60% of toxicity resolved during follow-up. 38% had functional vision (20/40 or better) at last follow-up. Pretreatment visual acuity had a substantial impact on post-treatment vision. Tumor size was an independent prognostic factor for OS (p=0.01), CSS (p<0.01), EP (p=0.02), and DMFS (p<0.01). No prognostic factor was associated with LC. Our experience using PT for UM is consistent with previously reported outcomes demonstrating high rates of LC and EP with acceptable toxicity despite a significant percentage of patients with large tumors and/or adverse location near the optic nerve. [ABSTRACT FROM AUTHOR]

Purpose: To minimize the risk of medical error in the diagnosis and choice of treatment of ROP by improving the quality and analysis of modeled wide‐field images on the Key to Diagnosis I platform. Methods: 1278 RetCam images of ROP 272(544 eyes) were divided into 5 groups 1‐I stage 152(304 eyes), 2‐II stage 45(90 eyes), 3‐III stage 8(12 eyes), 4‐posterior aggressive ROP 7(14 eyes), 5‐retinal immaturity 60(120 eyes); A standard clinical examination, analysis of wide‐field retinal images, macula localization and traction index of the macular region (Tm) calculation were performed. Tm is a leght‐to‐width attitude of ellipse goes through the center of optic nerve head and arcades. Results: Platform modules have been developed for automatic modeling of wide‐field retinal images and localization of the macula, which is a reference point for centering wide‐field images and assessing the extent of pathological changes. In the ROP group, a significant inverse correlation was observed between the values of Tm, 1A‐0.8 ± 0.03, 1B‐0.75 ± 0.04, 1B‐0.74 ± 0.13, 1D‐0.99 ± 0.01, 1D‐0.91 ± 0.09. Discussion: The macular area can be described by ellipse, which form correlate with refraction [1]. The influence of the traction component on the macular zone connected with decrease in refractive pathology in the treatment Anti‐vascular endothelial growth factor [2]. Conclusions: At ROP Tm reflects the severity of traction processes at the retina periphery and marks the severity of pathology in case of diagnostic defects. The macula localization determines the stable points: the optic nerve disc physiological excavation center, temporal arcades and the macula circumference for photogrammetry of 3D eye model. Hill D. Retinal characteristics of myopic eyes in a semi‐rural UK population. Diss. Aston University, 2019.Sankar M. J., Sankar J., Chandra P. Anti‐vascular endothelial growth factor drugs for treatment of retinopathy of prematurity. Cochrane Database of Systematic Reviews. 2018; 1. [ABSTRACT FROM AUTHOR]

Aims: To report visual acuity (VA) outcomes following chemotherapy for optic pathway glioma (OPG) in children with or without neurofibromatosis type-1 (NF1) and to analyse associated risk factors., Methods: A prospective, multicentre, cohort study involving 155 children treated between September 2004 and December 2012. Initial and final VA was used for per-eye and per-subject analysis. Correlation tests were performed to determine whether initial VA predicted final VA. Logistic regression was used to determine whether age and tumour location were associated risk factors., Results: 90 children had complete ophthalmological data. At initiation of chemotherapy, 26% and 49% of eyes with NF1-OPG and sporadic OPG, respectively, had VA of ≥0.7 log of the minimum angle of resolution (logMAR). At final visit, per eye, 49% had ≤0.2, 23% had 0.30-0.60 and 28% had VA≥0.70 logMAR in the NF1-OPG group. In the sporadic OPG group, per eye, 32% had ≤0.2, 11% had VA 0.30-0.60 and 57% had ≥0.70 logMAR. Children with sporadic OPG, per eye, were significantly less likely to have VA outcomes ≤0.60 logMAR compared with children with NF1-OPG (OR=0.30; 95% CI 0.16 to 0.56; P<0.0001). Per subject, VA improved in 24%, remained stable in 35% and worsened in 41% of children with NF1-OPG and improved in 18%, remained stable in 43% and worsened in 39% of children with sporadic OPG., Conclusions: Children with and without NF1 demonstrated the same rate of VA improvement, stabilisation or worsening; however, children with sporadic OPG had a poorer VA outcome. Better initial VA, older age, absence of postchiasm tumour and presence of NF1 were associated with improved or stable VA outcomes., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose To assess the impact of vessel segment length when analysing retinal vessel responses to flicker light provocation in healthy individuals. Methods 12 healthy individuals (mean age 30±6) underwent digital sphygmomanometry (UA‐767, A&D Instruments, UK), non‐contact tonometry (Keeler Pulsair, UK) and dynamic retinal diameter assessment using the retinal vessel analyser (Imedos Systems, Germany) in order to evaluate the influence of segment length on flicker light induced dilation of retinal arterioles and venules. Up to seven segments of each superior artery and vein, were extracted off‐line from video recordings of each subject within a minimum distance of 1 disc diameter (DD) from the rim of the optic nerve head and up to a maximum of 4 DD away from the rim. Results Retinal arteriolar and venular dilation amplitude were independent of segment length, blood pressure and intraocular pressure. Conclusion Independence of segment length is essential as retinal vessel anatomy is highly variable, some individuals having numerous vessel crossings and bifurcations making it difficult to measure long vessel segments. [ABSTRACT FROM AUTHOR]

The article offers information on a study which investigated the efficacy of weight loss in reducing intracranial pressure and treating patients with idiopathic intracranial hypertension. The study subjects, who were recruited in two hospitals in Great Britain, were 25 women with chronic active idiopathic and intracranial pressure. Outcome measures studied were reduction in intracranial pressure after the diet and papilloedema as measured by ultrasonography of the optic disc elevation and nerve sheath diameter. The research findings are presented.