Sagnik Sen

Purpose: To quantify spectral-domain optical coherence tomography (SD-OCT) images cross-sectionally and longitudinally in a large cohort of molecularly characterized patients with inherited retinal disease (IRDs) from the UK. Design: Retrospective study of imaging data. Participants: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone macular SD-OCT imaging at Moorfields Eye Hospital (MEH) between 2011 and 2019. We retrospectively identified 4,240 IRD patients from the MEH database (198 distinct IRD genes), including 69,664 SD-OCT macular volumes. Methods: Eight features of interest were defined: retina, fovea, intraretinal cystic spaces (ICS), subretinal fluid (SRF), subretinal hyper-reflective material (SHRM), pigment epithelium detachment (PED), ellipsoid zone loss (EZ-loss) and retinal pigment epithelium loss (RPE-loss). Manual annotations of five b-scans per SD-OCT volume was performed for the retinal features by four graders based on a defined grading protocol. A total of 1,749 b-scans from 360 SD-OCT volumes across 275 patients were annotated for the eight retinal features for training and testing of a neural-network-based segmentation model, AIRDetect-OCT, which was then applied to the entire imaging dataset. Main Outcome Measures: Performance of AIRDetect-OCT, comparing to inter-grader agreement was evaluated using Dice score on a held-out dataset. Feature prevalence, volume and area were analysed cross-sectionally and longitudinally. Results: The inter-grader Dice score for manual segmentation was ≥90% for retina, ICS, SRF, SHRM and PED, >77% for both EZ-loss and RPE-loss. Model-grader agreement was >80% for segmentation of retina, ICS, SRF, SHRM, and PED, and >68% for both EZ-loss and RPE-loss. Automatic segmentation was applied to 272,168 b-scans across 7,405 SD-OCT volumes from 3,534 patients encompassing 176 unique genes. Accounting for age, male patients exhibited significantly more EZ-loss (19.6mm ² vs 17.9mm ² , p-4 ) and RPE-loss (7.79mm ² vs 6.15mm ² , p-6 ) than females. RPE-loss was significantly higher in Asian patients than other ethnicities (9.37mm ² vs 7.29mm ² , pRS1 (0.47mm ³ ) and NR2E3 (0.25mm ³ ), SRF in BEST1 (0.21mm ³ ) and PED in EFEMP1 (0.34mm ³ ). BEST1 and PROM1 showed significantly different patterns of EZ-loss (p-4 ) and RPE-loss (pRHO (Δ=-0.414 mm ² , p=0.036) and EYS (Δ=-0.908 mm ² , p=1.5×10 ^-4 ). In ABCA4 retinopathy, more severe genotypes (group A) were associated with faster progression of EZ-loss (2.80±0.62 mm ² /yr), whilst the p.(Gly1961Glu) variant (group D) was associated with slower progression (0.56 ±0.18 mm ² /yr). There were also sex differences within groups with males in group A experiencing significantly faster rates of progression of RPE-loss (2.48 ±1.40 mm ² /yr vs 0.87 ±0.62 mm ² /yr, p=0.047), but lower rates in groups B, C, and D. Conclusions: AIRDetect-OCT, a novel deep learning algorithm, enables large-scale OCT feature quantification in IRD patients uncovering cross-sectional and longitudinal phenotype correlations with demographic and genotypic parameters.

Rare eye diseases such as inherited retinal diseases (IRDs) are challenging to diagnose genetically. IRDs are typically monogenic disorders and represent a leading cause of blindness in children and working-age adults worldwide. A growing number are now being targeted in clinical trials, with approved treatments increasingly available. However, access requires a genetic diagnosis to be established sufficiently early. Critically, the timely identification of a genetic cause remains challenging. We demonstrate that a deep learning algorithm, Eye2Gene, trained on a large multimodal imaging dataset of individuals with IRDs (n = 2,451) and externally validated on data provided by five different clinical centres, provides better-than-expert-level top-five accuracy of 83.9% for supporting genetic diagnosis for the 63 most common genetic causes. We demonstrate that Eye2Gene’s next-generation phenotyping can increase diagnostic yield by improving screening for IRDs, phenotype-driven variant prioritization and automatic similarity matching in phenotypic space to identify new genes. Eye2Gene is accessible online (app.eye2gene.com) for research purposes.

Purpose: The current study aims to assess incidence of postoperative macular edema (PME), risk factors behind PME and outcomes after cataract surgery in eyes with retinal vein occlusion (RVO). Methods: This retrospective study included 162 eyes of 162 RVO patients, who underwent cataract surgery between 1 January 2015 and 31 December 2019. Eyes with RVO which did not have cystoid macular edema (CME) on optical coherence tomography (OCT) within the immediate 1 month prior to surgery were included. Results: Patients were followed up for an average duration of 13 ± 10.9 months after cataract surgery (range, 6–60 months). The mean time to PME development was 1.87 ± 1.7 months. Postoperative macular edema developed within 3 months after surgery in 40.1% of all eyes, 21% eyes with no previous CME, 57.3% of eyes with previous CME, and in 50% of eyes of patients with diabetes. Significant risk factors of PME identified were diabetes (OR = 2.1) and previous CME (OR = 4.62) requiring treatment with anti-VEGF (OR = 4.83). The visual acuity (VA) of operated eyes significantly improved from 0.85 ± 0.55 logMAR at baseline to 0.365 ± 0.39 logMAR ( P P < 0.0001); however, eyes with PME had a higher chance of poorer vision gain (worse than 6/18). Poor prognostic factors for vision were presence of PME, previous CME and treatment history with injections, central RVO and poor VA at baseline. Conclusion: The study demonstrates that RVO eyes with previous CME requiring intravitreal treatment are at significant risk of postoperative macular edema after uneventful cataract surgery, and this risk increases in people with diabetes. The incidence is not affected by the type of RVO. Considering almost 2/3 ^rd of PME developed within the 1 ^st month of surgery, we recommend a routine OCT scan as a part of postoperative assessment at the 1 ^st visit after surgery, in eyes at risk. Eyes developing PME may have poorer visual outcomes, especially eyes with CRVO; hence, patients need to be counseled carefully regarding outcomes of cataract surgery. The outcomes might depend on the previous treatment course they have received, and they may need to undergo a repeat cycle of treatment due to a risk of return of macular edema.

Diabetic macular edema (DME) is a vision-threatening complication of diabetic retinopathy and causes significant morbidity in patients. Anti-vascular endothelial growth factor (VEGF) agents are the mainstay of treatment for DME, with steroid implants being used for the treatment of anti-VEGF resistant eyes. Over the years, several classification systems have been devised to describe the patterns of DME using optical coherence tomography (OCT). With the advent of effective treatments, it has become imperative that imaging cues are not merely used for classifying the disease but also as biomarkers for prognostication of disease activity and treatment response. In this aspect, newer imaging findings such as hyperreflective dots, photoreceptor integrity, and disorganization of retinal inner layers have been characterized in detail by several authors. Macular perfusion analysis using OCT angiography is the latest in the armamentarium for imaging DME. In this narrative review, we have summarized all relevant literature related to the ultrastructural imaging-based biomarkers of DME and their correlation to treatment.

Stem cell-based therapy has gained importance over the past decades due to huge advances in science and technology behind the generation and directed differentiation of pluripotent cells from embryos and adult cells. Preclinical proof-of-concept studies have been followed by clinical trials showing efficacy and safety of transplantation of stem cell-based therapy, which are beginning to establish this as a modality of treatment. Disease candidates of interest are primarily conditions that may benefit from replacing dead or dying cells, including advanced inherited retinal dystrophies and age-related macular degeneration, and predominantly seek to transplant either RPE or photoreceptors, although neurotrophic approaches have also been trialed. Whilst a consensus has yet to be reached about the best stage/type of cells for transplantation (stem cells, progenitor cells, differentiated RPE and photoreceptors) and the methods of implantation (sheet, suspension), several CTs have shown safety. There remain potential concerns regarding tumorigenicity and immune rejection; however, with ongoing improvements in cell generation, selection, and delivery, these can be minimized. Earlier studies showed efficacy with immunosuppressive drugs to prevent rejection, and recent donor-matched transplants have avoided the need for immunosuppression. Retinal regenerative medicine is a challenging field and is in a nascent stage but holds tremendous promise. This narrative review delves into the current understanding of stem cells and the latest clinical trials of retinal cell transplantation.

Purpose: To report real-world clinical evidence of brolucizumab in treating neovascular age-related macular degeneration (nAMD). Methods: This study included 37 eyes with nAMD treated with intravitreal injections of brolucizumab. The main outcomes were best corrected visual acuity (BCVA) changes, central retinal thickness (CRT), and serious ocular adverse events. Intraretinal fluid (IRF) and subretinal fluid (SRF), subretinal hyperreflective material (SHRM), pigment epithelial detachments (PEDs), hyperreflective foci, macular atrophy, and retinal pigment epithelial tears were evaluated. Results: The mean BCVA of all patients showed a post-treatment value of 0.47 ± 0.33 log of minimum angle of resolution (LogMAR), compared to a baseline measure of 0.50 ± 0.28 LogMAR ( P = 0.372). For treatment-naïve patients, a non-statistically significant improvement in BCVA was observed ( P = 0.116). Both treatment-naive patients and the entire patient cohort exhibited a statistically significant improvement in the mean CRT after injections. Majority of patients exhibited improvements in optical coherence tomography findings, specifically in the resolution of IRF, SRF, SHRM, and PEDs. Four eyes experienced ocular adverse events in the form of intraocular inflammation. Conclusion: Brolucizumab did not yield a substantial improvement in BCVA, but it exhibited efficacy in reducing CRT in the entire study population and treatment-naive patients with nAMD. Our study identified intraocular inflammation as a significant adverse event with brolucizumab. Thus, precise patient selection, education, and vigilant inflammation monitoring are crucial for patients undergoing this treatment.