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Lutein, zeaxanthin, and meso-zeaxanthin are three xanthophyll carotenoid pigments that selectively concentrate in the center of the retina. Humans cannot synthesize lutein and zeaxanthin, so these compounds must be obtained from the diet or supplements, with meso-zeaxanthin being converted from lutein in the macula. Xanthophylls are major components of macular pigments that protect the retina through the provision of oxidant defense and filtering of blue light. The accumulation of these three xanthophylls in the central macula can be quantified with non-invasive methods, such as macular pigment optical density (MPOD). MPOD serves as a useful tool for assessing risk for, and progression of, age-related macular degeneration, the third leading cause of blindness worldwide. Dietary surveys suggest that the dietary intakes of lutein and zeaxanthin are decreasing. In addition to low dietary intake, pregnancy and lactation may compromise the lutein and zeaxanthin status of both the mother and infant. Lutein is found in modest amounts in some orange- and yellow-colored vegetables, yellow corn products, and in egg yolks, but rich sources of zeaxanthin are not commonly consumed. Goji berries contain the highest known levels of zeaxanthin of any food, and regular intake of these bright red berries may help protect against the development of age-related macular degeneration through an increase in MPOD. The purpose of this review is to summarize the protective function of macular xanthophylls in the eye, speculate on the compounds’ role in maternal and infant health, suggest the establishment of recommended dietary values for lutein and zeaxanthin, and introduce goji berries as a rich food source of zeaxanthin.

To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.F Hoffmann-La Roche.

Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD).TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300).Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]).Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD.F Hoffmann-La Roche.

Neesurg Mehta,1 Rodney D Fong,1,2 Machelle Wilson,3 Kareem Moussa,1 Parisa Emami-Naeini,1,4 Ala Moshiri,1 Glenn Yiu,1 Susanna S Park1 1Department of Ophthalmology and Vision Science, University of California Davis Health, Sacramento, CA, USA; 2University of Nevada, Reno School of Medicine, Reno, NV, USA; 3Department of Public Health Sciences, Division of Biostatistics, University of California, Davis, CA, USA; 4Department of Ophthalmology, Veterans Administration Hospital, Mather, CA, USACorrespondence: Susanna S Park, Department of Ophthalmology & Vision Science, University of California Davis Health, Ernest E. Tschannen Eye Institute, 4860 Y St, Sacramento, CA, 95817, USA, Tel +1 916 734 6074, Fax +1 916 703 5076, Email sscpark@ucdavis.eduPurpose: To evaluate real-world experience using intravitreal brolucizumab (IVBr), alone or in combination with aflibercept, in eyes with neovascular age-related macular degeneration (nAMD) treated previously with other inhibitors of VEGF (anti-VEGF).Methods: This was a retrospective study of all eyes with nAMD treated with IVBr on a treat-and-extend protocol at a single center. Best-corrected visual acuity (BCVA), optical coherence tomography (OCT) at baseline and final visit, and drug-related adverse events were analyzed. Eyes with recurrent macular fluid on IVBr every 8 weeks were treated with a combination therapy alternating between IVBr and aflibercept every month.Results: Among 52 eyes (40 patients) on IVBr, all had been previously treated with other anti-VEGF therapy, with 73% having persistent macular fluid. After a mean follow-up of 46.2± 27.4 weeks on IVBr, the mean treatment interval for intravitreal therapy increased to 8.8± 2.1 weeks on IVBr from a baseline of 6.1± 3.1 weeks (p< 0.001). Macular fluid decreased and BCVA was stable/improved in 61.5% of eyes on IVBr. Ten eyes with increased macular fluid on IVBr monotherapy when extended to every 8 weeks were treated with combination therapy alternating between IVBr and aflibercept every 4 weeks. In these eyes, 80% had improved macular fluid on OCT and 70% stable or improved BCVA after a median follow-up of 53 weeks on combination therapy. Mild intraocular inflammation developed in four eyes, all occurring on IVBr monotherapy, and none had associated vision loss.Conclusion: In the real world, IVBr used to treat eyes with nAMD previously treated with other anti-VEGF therapies appears to be well tolerated and associated with an improvement in macular fluid, stabilization of BCVA, and/or increase in intravitreal treatment interval. Combination therapy alternating between IVBr and aflibercept monthly appears to be well tolerated and can be considered for eyes with macular fluid on IVBr every 8 weeks.Keywords: age-related macular degeneration, aflibercept, anti-VEGF, brolucizumab, intravitreal injection; optical coherence tomography

PurposeFoveoschisis involves the pathologic splitting of retinal layers at the fovea, which may occur congenitally in X-linked retinoschisis (XLRS) or as an acquired complication of myopia. XLRS is attributed to functional loss of the retinal adhesion protein retinoschisin 1 (RS1), but the pathophysiology of myopic foveoschisis is unclear due to the lack of animal models. Here, we characterized a novel nonhuman primate model of myopic foveoschisis through clinical examination and multimodal imaging followed by morphologic, cellular, and transcriptional profiling of retinal tissues and genetic analysis.MethodsWe identified a rhesus macaque with behavioral and anatomic features of myopic foveoschisis, and monitored disease progression over 14 months by fundus photography, fluorescein angiography, and optical coherence tomography (OCT). After necropsy, we evaluated anatomic and cellular changes by immunohistochemistry and transcriptomic changes using single-nuclei RNA-sequencing (snRNA-seq). Finally, we performed Sanger and whole exome sequencing with focus on the RS1 gene.ResultsAffected eyes demonstrated posterior hyaloid traction and progressive splitting of the outer plexiform layer on OCT. Immunohistochemistry showed increased GFAP expression in Müller glia and loss of ramified Iba-1+ microglia, suggesting macro- and microglial activation with minimal photoreceptor alterations. SnRNA-seq revealed gene expression changes predominantly in cones and retinal ganglion cells involving chromatin modification, suggestive of cellular stress at the fovea. No defects in the RS1 gene or its expression were detected.ConclusionsThis nonhuman primate model of foveoschisis reveals insights into how acquired myopic traction leads to phenotypically similar morphologic and cellular changes as congenital XLRS without alterations in RS1.

We analyzed OCT biomarkers of 65 eyes with treatment-naive RVO and ME. While none of the factors analyzed predicted successful treatment discontinuation, early improvements in vision and DRIL were associated with long-term visual outcomes.

BACKGROUND AND OBJECTIVE: To determine if age-related macular degeneration (AMD) status affects longitudinal retinal vessel changes. PATIENTS AND METHODS: Retrospective, cohort study of 125 eyes (75 patients) with AMD, following retinal vessel density (VD) and foveal avascular zone (FAZ) measurements using optical coherence tomography angiography (OCT-A) over 24 months. RESULTS: FAZ area ( P < .001) and perimeter ( P < .001) increased over 2 years, with no difference between nonexudative and exudative AMD ( P = .134–.976). Eyes with geographic atrophy (GA) showed greater progressive VD loss ( P = .023–.038), and greater increase in FAZ area ( P = .044) and perimeter ( P = .040) compared to eyes without GA. Neither baseline nor 2-year change in vascular parameters were associated with choroidal neovascularization (CNV) or GA incidence in nonexudative AMD, or anti-VEGF injection frequency in exudative AMD ( P = .070–.952). CONCLUSION: AMD eyes with GA undergo more rapid loss of retinal vessel density and FAZ enlargement over 2 years, suggesting a relationship between the retinal vasculature and AMD pathophysiology. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:529–536.]

To define the normal range of central corneal thickness (CCT) and corneal endothelial cell density (ECD) in rhesus macaques (Macaca mulatta) and the effects of age, body weight, sex, and intraocular pressure (IOP) on these parameters.Ophthalmic examinations were performed on 144 rhesus macaques without anterior segment pathology. The CCT was measured via ultrasound pachymetry (USP) and specular microscopy, and the ECD was semiautomatically and manually counted using specular microscopy. Rebound tonometry was used to measure IOP. Linear regression and mixed-effects linear regression models were used to evaluate the effects of age, body weight, sex, and IOP on CCT and ECD.We included 98 females and 46 males with an age range of 0.2 to 29.4 years. The mean CCT by USP and specular microscopy were 483 ± 39 and 463 ± 33 µm, respectively, and were statistically different (P0.001). The ECDs were 2717 ± 423 and 2747 ± 438 cells/mm2 by semiautomated and manual analysis, respectively. Corneal endothelial degeneration was identified in one aged rhesus macaque.The mean USP and specular microscopy CCT values differed significantly, whereas the semiautomatic and manual ECD did not. The CCT was associated with the IOP and sex, whereas the ECD was associated with body weight and age (P0.05). As in humans, corneal disease in rhesus macaques is uncommon.Establishing reference values is fundamental to use rhesus macaques as a model for corneal disease or to identify toxicity in studies of ocular drugs or devices.

This case report describes retinal telangiectatic vessels and aneurysms in a woman aged 23 years with a history of pathologic myopia.

Frequent injections of anti-vascular endothelial growth factor (anti-VEGF) agents are a clinical burden for patients with neovascular age-related macular degeneration (AMD). Genomic disruption of VEGF-A using adeno-associated viral (AAV) delivery of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 has the potential to permanently suppress aberrant angiogenesis, but the factors that determine the optimal efficacy are unknown. Here, we investigate two widely used Cas9 endonucleases, SpCas9 and SaCas9, and evaluate the relative contribution of AAV-delivery efficiency and genome-editing rates invivo to determine the mechanisms that drive successful CRISPR-based suppression of VEGF-A, using a mouse model of laser-induced choroidal neovascularization (CNV). We found that SpCas9 demonstrated higher genome-editing rates, greater VEGF reduction, and more effective CNV suppression than SaCas9, despite similar AAV transduction efficiency between a dual-vector approach for SpCas9 and single-vector system for SaCas9 to deliver the Cas9 orthologs and single guide RNAs (gRNAs). Our results suggest that successful VEGF knockdown using AAV-mediated CRISPR systems may be determined more by the efficiency of genome editing rather than viral transduction and that SpCas9 may be more effective than SaCas9 as a potential therapeutic strategy for CRISPR-based treatment of CNV in neovascular AMD.

PurposeAlthough the choroid contributes to the pathogenesis of age-related macular degeneration (AMD), the role of retinal perfusion is unclear. We sought to compare retinal vascular measurements between eyes with nonexudative and exudative AMD using optical coherence tomography angiography (OCT-A).DesignRetrospective, cross-sectional study.MethodsOCT-A images were analyzed from 310 eyes of 182 patients (mean age ± standard deviation [SD], 78.8 ± 8.8 years) with nonexudative (54.2%) and exudative (45.8%) AMD to measure retinal vessel density (VD) from the superficial capillary plexus in the foveal, parafoveal, and full macular regions and foveal avascular zone (FAZ) area, perimeter, and circularity. Multivariate regressions were used to compare nonexudative and exudative AMD eyes and the impact of anti-vascular endothelial growth factor (anti-VEGF) treatments or geographic atrophy (GA).ResultsIn eyes with AMD, VD decreases with age in the foveal (β=-0.211, P < .001), parafoveal (β=-0.305, P < .001), and full macular regions (β=-0.295, P < .001). Eyes with exudative AMD demonstrated lower VD, especially in the parafoveal (29.8% ± 6.3% vs 33.0% ± 5.7%, P < .001) and full regions (27.9% ± 6.2% vs 31.2% ± 5.5%, P < .001) compared with nonexudative AMD. There were no differences in FAZ area, perimeter, or circularity between the 2 groups (P= .503-.907). In eyes with exudative AMD, previous anti-VEGF treatments did not impact retinal vascular measurements (P= .324-.986). Nonexudative AMD severity and presence of central GA also impacted retinal VD and FAZ morphology.ConclusionsRetinal VD is decreased in eyes with exudative AMD compared with nonexudative AMD but is unaffected by anti-VEGF treatments, suggesting a retinal vascular contribution to the pathogenesis of AMD.

Retinal gene therapy using adeno-associated viruses (AAVs) is constrained by the mode of viral vector delivery. Intravitreal AAV injections are impeded by the internal limiting membrane barrier, while subretinal injections require invasive surgery and produce a limited region of therapeutic effect. In this study, we introduce a novel mode of ocular gene delivery in rhesus macaques using transscleral microneedles to inject AAV8 into the subretinal or suprachoroidal space, a potential space between the choroid and scleral wall of the eye. Using in vivo imaging, we found that suprachoroidal AAV8 produces diffuse, peripheral expression in retinal pigment epithelial (RPE) cells, but it elicited local infiltration of inflammatory cells. Transscleral subretinal injection of AAV8 using microneedles leads to focal gene expression with transduction of RPE and photoreceptors, and minimal intraocular inflammation. In comparison, intravitreal AAV8 shows minimal transduction of retinal cells, but elicits greater systemic humoral immune responses. Our study introduces a novel mode of transscleral viral delivery that can be performed without vitreoretinal surgery, with focal or diffuse transgene expression patterns suitable for different applications. The decoupling of local and systemic immune responses reveals important insights into the immunological consequences of AAV delivery to different ocular compartments surrounding the blood-retinal barrier. Keywords: retinal gene therapy, suprachoroidal delivery, retina, AAV, rhesus macaques, nonhuman primate, gene therapy, suprachoroidal, microneedles

PurposeTo evaluate spectral-domain (SD)-OCT features associated with baseline vision and visual outcomes in the prospective, multicenter Study Evaluating Dosing Regimens for Treatment with Intravitreal Ranibizumab Injections in Subjects with Macular Edema following Retinal Vein Occlusion (SHORE).DesignPost hoc analysis of prospective clinical trial data.ParticipantsTwo hundred two participants in the 15-month, phase 4 SHORE study comparing monthly versus pro re nata ranibizumab after 7 monthly doses in eyes with retinal vein occlusion (RVO) with macular edema.MethodsBaseline SD-OCT images were assessed for (1) central subfield thickness (CST); (2) presence of vitreomacular adhesion, vitreomacular traction, or epiretinal membrane; (3) presence, location, and amount of intraretinal fluid or subretinal fluid (SRF); (4) presence, location, and amount of hyperreflective foci (HF); (5) disorganization of retinal inner layers (DRIL); and (6) disruption of external limiting membrane (ELM), ellipsoid zone (EZ), and interdigitation zone (IZ). Univariate and multivariate regression analyses were performed to evaluate the association of these features with baseline best-corrected visual acuity (BCVA) and change in BCVA after 7 monthly ranibizumab injections.Main outcome measuresAssociation of SD-OCT features with baseline BCVA and change in BCVA after 7 monthly ranibizumab injections.ResultsBefore therapy, worse baseline BCVA was associated with ERM presence (P= 0.0045), thicker SRF (P= 0.0006), larger intraretinal cysts (P= 0.0015), and higher percentage of DRIL (P < 0.0001), percentage of ELM disruption (P < 0.0001), percentage of EZ disruption (P= 0.0003), and percentage of IZ disruption (P= 0.0018). In multivariate models, only percentage of ELM disruption independently impacted baseline BCVA (P < 0.0001). After 7 monthly ranibizumab injections, mean BCVA improved by 18.3±12.6 Early Treatment Diabetic Retinopathy Study letters in treated eyes. The only factors independently associated with BCVA gain after 7 monthly ranibizumab treatments were younger age (P < 0.0001) and worse baseline BCVA (P < 0.0001).ConclusionsAlthough SD-OCT features may be associated with presenting vision in eyes with macular edema and RVO, most eyes treated with ranibizumab achieve substantial vision gains, and only older age and better baseline BCVA limited visual improvements.

Gene therapies aim to deliver a therapeutic payload to specified tissues with underlying protein deficiency. Since the 1990s, gene therapies have been explored as potential treatments for chronic conditions requiring lifetime care and medical management. Ocular gene therapies target a range of ocular disorders, but retinal diseases are of particular importance due to the prevalence of retinal disease and the current treatment burden of such diseases on affected patients, as well as the challenge of properly delivering these therapies to the target tissue. The purpose of this review is to provide an update on the most current data available for five different retinal gene therapies currently undergoing clinical trials for use against age-related macular degeneration (AMD) and the development of novel delivery routes for the administration of such therapies. Research has been performed and compiled from PubMed and the select authors of this manuscript on the treatment and effectiveness of five current retinal gene therapies: Luxturna, ADVM-022, RGX-314, GT-005, and HMR59. We present the available data of current clinical trials for the treatment of neovascular and dry age-related macular degeneration with different AAV-based gene therapies. We also present current research on the progress of developing novel routes of administration for ocular gene therapies. Retinal gene therapies offer the potential for life-changing treatment for chronic conditions like age-related macular degeneration with a single administration. In doing so, gene therapies change the landscape of treatment options for these chronic conditions for both patient and provider.摘要: 基因治疗的目的是将具备治疗作用的载体运输至有潜在蛋白缺乏的特定组织。自二十世纪九十年代以来, 基因治疗作为有潜力的一种治疗方法而被研究, 用于需要终生治疗和管理的慢性疾病。眼基因治疗可以靶向治疗一系列眼病, 但由于目前视网膜疾病的患病率高、病人治疗的负担大以及将治疗载体送至特定靶组织挑战性大的特点, 基因治疗在视网膜疾病中的作用尤为重要。这篇综述旨在更新与视网膜疾病基因治疗相关的最新数据, 包括正在进行的临床试验、用于年龄相关性黄斑变性 (AMD) 的5种不同治疗方法及基因治疗的新型给药途径等。通过检索PubMed, 本文作者围绕Luxturna、ADVM-022、RGX-314、GT-005和HMR59这五种视网膜基因的治疗方法和治疗有效性进行了研究和汇编。我们提供了目前临床试验的可用数据, 这些试验以不同AAV基因治疗为基础, 用于治疗新生血管和干性年龄相关性黄斑变性。针对眼基因治疗, 我们还介绍了近期新型给药途径的研究进展。视网膜基因治疗为需要终生治疗的慢性疾病 (如年龄相关性黄斑变性) 提供了单次给药的可能性。在此过程中, 基因治疗同时改变了患者和医生对这些慢性疾病的治疗选择。.

This report describes the clinical and histological findings, genetic study, and treatment in a 1.3-year-old rhesus macaque with bilateral cataracts and unilateral secondary glaucoma. Intravitreal injection of gentamicin decreased the intraocular pressure from 56 to

PURPOSE To identify clinical and anatomic factor-associated vision loss in eyes with treatment-naive diabetic macular edema and good initial visual acuity. METHODS Retrospective cohort study after long-term history of eyes with untreated center-involving diabetic macular edema and baseline visual acuity ≥ 20/25 seen at the University of California, Davis Eye Center between March 2007 and March 2018. We collected characteristics including diabetes type, hemoglobin A1c, presence of visual symptoms, visual acuity, and diabetic retinopathy severity; and spectral-domain optical coherence tomography biomarkers including central subfield thickness, intraretinal cyst size, intraretinal hyperreflective foci, disorganization of retinal inner layers, and outer layer disruptions to determine factors associated with vision loss as defined by DRCR Protocol V as threshold for initiating aflibercept therapy. RESULTS Fifty-six eyes (48 patients) with untreated diabetic macular edema and mean baseline visual acuity of logMAR 0.05 ± 0.05 (Snellen 20/22) were followed for an average of 5.1 ± 3.3 years, with a median time to vision loss of 465 days (15 months). Older age (hazard ratio [HR] 1.04/year, P = 0.0195) and eyes with severe NPDR (HR 3.0, P = 0.0353) or proliferative diabetic retinopathy (HR 7.7, P = 0.0008) had a higher risk of a vision loss event. None of the spectral-domain optical coherence tomography biomarkers were associated with vision loss except central subfield thickness (HR 0.98, P = 0.0470) and cyst diameter (HR 1.0, P = 0.0094). CONCLUSION In eyes with diabetic macular edema and good initial vision, those with older age and worse diabetic retinopathy severity should be monitored closely for prompt treatment initiation when vision loss occurs.

BACKGROUND Retinal structure and vascular changes are used as biomarkers for preclinical Alzheimer disease. We conducted a cohort study to evaluate the feasibility of obtaining these data in patients with low-grade gliomas (LGGs) who completed chemoradiation therapy with and without self or family reported cognitive concerns. METHODS Optical coherence tomography (OCT) and angiography (OCTA, OptoVue, Inc.) images were obtained from 6 LGG patients and 2 healthy controls using 4.5 x 4.5 mm peripapillary and 6x6 mm macular scan patterns. We measured OCTA parameters including radial peripapillary capillary density for the peri-optic disc region, whole macular density, and foveal avascular zone (FAZ). RESULTS We analyzed two eyes of two control subjects, an LGG patient with normal cognition, and 5 LGG patients with cognitive impairment (mean age 45 years, range of 3 months to 10 years after chemoradiation). Both controls had normal eye exams. Average retinal nerve fiber layer thickness was thinner in patients with and without cognitive dysfunction (104 um and 106 um, respectively) than controls (123 um). A similar pattern was seen in macula thickness (283 um and 290 um vs. 325 um). The average peripapillary vessel densities were lower in patients with and without cognitive dysfunction (47.7% and 48.3%, respectively) than controls (51.9%). The whole macular vessel densities were similar in three groups (46.7 %, 48.0%, and 48.0 %). Average FAZs were larger in patients with cognitive dysfunction (0.254 mm2) than the patient with normal cognition (0.204 mm2) and controls (0.226 mm2). CONCLUSIONS Retinal architecture and microvascular changes measured by OCT/OCTA is feasible in LGG patients after chemoradiation. A larger prospective study is needed to investigate the role of OCT/OCTA in detecting peripapillary and perifoveal changes in brain tumor patients with treatment-associated cognitive dysfunction.

According to a national claims database, remote retinal imaging utilization in the U.S. increased rapidly from 2011 to 2020, but insurance coverage declined, with disproportionate impact on vulnerable populations including older, Black, and lower-income patients.

PurposeTo assess age-related changes in the rhesus macaque eye and evaluate them to corresponding human age-related eye disease.MethodsData from eye exams and imaging tests including intraocular pressure (IOP), lens thickness, axial length, and retinal optical coherence tomography (OCT) images were evaluated from 142 individuals and statistically analyzed for age-related changes. Quantitative autofluorescence (qAF) was measured as was the presence of macular lesions as related to age.ResultsAges of the 142 rhesus macaques ranged from 0.7 to 29 years (mean=16.4 years, stdev=7.5 years). Anterior segment measurements such as IOP, lens thickness, and axial length were acquired. Advanced retinal imaging in the form of optical coherence tomography and qAF were obtained. Quantitative assessments were made and variations by age groups were analyzed to compare with established age-related changes in human eyes. Quantitative analysis of data revealed age-related increase in intraocular pressure (0.165mm Hg per increase in year of age), ocular biometry (lens thickness 7.2μm per increase in year of age; and axial length 52.8μm per increase in year of age), and presence of macular lesions. Age-related changes in thicknesses of retinal layers on OCT were observed and quantified, showing decreased thickness of the retinal ganglion cell layer and inner nuclear layer, and increased thickness of photoreceptor outer segment and choroidal layers. Age was correlated with increased qAF by 1.021 autofluorescence units per increase in year of age.ConclusionsThe rhesus macaque has age-related ocular changes similar to humans. IOP increases with age while retinal ganglion cell layer thickness decreases. Macular lesions develop in some aged animals. Our findings support the concept that rhesus macaques may be useful for the study of important age-related diseases such as glaucoma, macular diseases, and cone disorders, and for development of therapies for these diseases.

The suprachoroid is a potential space located between the sclera and choroid of the eye, which provides a novel route for ocular drug or viral vector delivery. Suprachoroidal injection of adeno-associated virus (AAV)8 using transscleral microneedles enables widespread transgene expression in eyes of nonhuman primates, but may cause intraocular inflammation. We characterized the host humoral and cellular immune responses after suprachoroidal delivery of AAV8 expressing green fluorescent protein (GFP) in rhesus macaques, and found that it can induce mild chorioretinitis that resolves after systemic corticosteroid administration, with recovery of photoreceptor morphology, but persistent immune cell infiltration after 3 months, corresponding to a loss of GFP expression from retinal pigment epithelial cells, but persistent expression in scleral fibroblasts. Suprachoroidal AAV8 triggered B cell and T cell responses against GFP, but only mild antibody responses to the viral capsid compared to intravitreal injections of the same vector and dose. Systemic biodistribution studies showed lower AAV8 levels in liver and spleen after suprachoroidal injection compared with intravitreal delivery. Our findings suggest that suprachoroidal AAV8 primarily triggers host immune responses to GFP, likely due to sustained transgene expression in scleral fibroblasts outside the blood-retinal barrier, but elicits less humoral immune reactivity to the viral capsid than intravitreal delivery due to lower egress into systemic circulation. As GFP is not native to primates and not a clinically relevant transgene, suprachoroidal AAV delivery of human transgenes may have significant translational potential for retinal gene therapy.

Upon completion of this activity, participants will be able to: In support of improving patient care, this activity has been planned and implemented by Medscape, LLC and Springer Nature. Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at www.medscape.org/journal/eye; (4) view/print certificate. 1.0 Release date: 19 April 2019 Expiration date: 19 April 2020 Post-test link: https://medscape.org/eye/posttest909693 S.S. has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Allergan, Inc.; Bayer AG; Boehringer Ingelheim Pharmaceuticals, Inc.; Heidelberg Pharma GmbH; Novartis Pharmaceuticals Corporation; Optos; Roche. Served as a speaker or a member of a speakers bureau for: Allergan, Inc.; Bayer AG; Novartis Pharmaceuticals Corporation; Optos. Received grants for clinical research from: Allergan, Inc.; Bayer AG; Boehringer Ingelheim Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Optos. L.S.M. has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Genentech, Inc.; IRIDEX Corporation. Served as a speaker or a member of a speakers bureau for: Genentech, Inc.; IRIDEX Corporation. Received grants for clinical research from: Genentech, Inc. S.S.P. has disclosed the following relevant financial relationships: Received grants for clinical research from: Allergan, Inc.; Roche/Novartis Pharmaceuticals Corporation. G.Y. has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Alimera Sciences; Allergan, Inc.; Carl Zeiss Meditec; IRIDEX Corporation. Received grants for clinical research from: Alcon Laboratories, Inc.; IRIDEX Corporation. K-Y.L., T.K., A.Y., L.M., B.P.D-J., A.M. have disclosed no relevant financial relationships. Laurie Barclay has disclosed no relevant financial relationships. To evaluate the long-term progression of idiopathic epiretinal membranes (iERMs) with good baseline visual acuity, and to identify predictors of visual decline. Retrospective case series We reviewed records of 145 eyes with iERM and best-corrected visual acuity (BCVA) of 20/40 or greater at presentation, including BCVA, lens status, and central macular thickness (CMT) at yearly visits; as well as anatomic biomarkers including vitreomacular adhesion, pseudohole, lamellar hole, intraretinal cysts, disorganization of the inner retinal layers (DRIL), and disruption of outer retinal layers. Linear mixed effects and mixed-effects Cox proportional hazards models were used to identify clinical and anatomic predictors of vision change and time to surgery. At presentation, mean BCVA was 0.17 ± 0.10 logMAR units (Snellen 20/30) and mean CMT was 353.3 ± 75.4 μm. After a median follow-up of 3.7 years (range 1–7 years), BCVA declined slowly at 0.012 ± 0.003 logMAR units/year, with phakic eyes declining more rapidly than pseudophakic eyes (0.019 ± 0.003 vs. 0.010 ± 0.004 logMAR units/year). Metamorphopsia, phakic lens status, lamellar hole, and inner nuclear layer cysts were associated with faster visual decline. Cumulative rates of progression to surgery were 2.9, 5.6, 12.2, and 21.1% at years 1–4. Visual symptoms, metamorphopsia, greater CMT, and disruption of outer retinal layers were associated with greater hazard for surgery. Eyes with iERM and visual acuity ≥ 20/40 experience slow visual decline, with 21% of eyes requiring surgery after 4 years. Clinical and anatomic predictors of vision loss may be distinct from factors associated with earlier surgical intervention.

Purpose To evaluate the outcomes of patients undergoing pneumatic retinopexy (PR) performed by vitreoretinal fellows at 6 academic centers in the United States. Design Retrospective, multicenter, consecutive case series. Participants Four hundred eighty-three patients with primary retinal detachments who underwent PR by 49 vitreoretinal fellows from 6 United States training sites between 2002 and 2016. Methods We reviewed medical records of patients and recorded baseline clinical characteristics (age, gender, baseline visual acuity, lens status, presence of lattice degeneration, presence of vitreous hemorrhage, location of retinal breaks, macular status, and size of detachment), visual and anatomic outcomes at 3 months after PR, as well as training level and PR experience of the fellow at the time of the procedure. Main Outcome Measures Single-procedure anatomic success and visual acuity at 3 months of follow-up and association with clinical and training-related factors. Results Vitreoretinal fellows performed a variable number of PR procedures, with a median of 7 per fellow (range, 1–24). Single-procedure anatomic success was 66.8%, and mean visual outcome was 0.43 logarithm of the minimum angle of resolution (Snellen equivalent, 20/54) at 3 months. Factors that were associated independently with single-procedure success included phakic lens status (P = 0.01), smaller size of retinal detachment (P = 0.02), and the fellow’s procedure experience (P = 0.01). The only factor associated with worse visual outcome was baseline visual acuity (P Conclusions Vitreoretinal fellows perform variably few PR procedures but have outcomes comparable with those reported by experienced specialists. Procedure experience of individual fellows may impact anatomic outcomes.

Inherited retinal degenerations are a common cause of untreatable blindness worldwide, with retinitis pigmentosa and cone dystrophy affecting approximately 1 in 3500 and 1 in 10,000 individuals, respectively. A major limitation to the development of effective therapies is the lack of availability of animal models that fully replicate the human condition. Particularly for cone disorders, rodent, canine, and feline models with no true macula have substantive limitations. By contrast, the cone-rich macula of a nonhuman primate (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders that are predictive of human conditions, are necessary to more efficiently advance new therapies for patients. We have identified 4 related NHPs at the California National Primate Research Center with visual impairment and findings from clinical ophthalmic examination, advanced retinal imaging, and electrophysiology consistent with achromatopsia. Genetic sequencing confirmed a homozygous R565Q missense mutation in the catalytic domain of PDE6C, a cone-specific phototransduction enzyme associated with achromatopsia in humans. Biochemical studies demonstrate that the mutant mRNA is translated into a stable protein that displays normal cellular localization but is unable to hydrolyze cyclic GMP (cGMP). This NHP model of a cone disorder will not only serve as a therapeutic testing ground for achromatopsia gene replacement, but also for optimization of gene editing in the macula and of cone cell replacement in general.

To evaluate the anatomical and visual outcomes of patients who underwent pneumatic retinopexy by vitreoretinal fellows.We included 198 eyes (198 patients) that underwent pneumatic retinopexy by vitreoretinal fellows at a single academic institution between November 2002 and June 2016. Main outcomes were single-operation success and final anatomical success in retinal reattachment, as well as visual acuity at 3 months and 6 months after treatment.Single-operation success rate was 63.6% at 3 months and 59.5% at 6 months. Final anatomical reattachment was achieved in 92.9% (n = 184) and 96.6% (n = 143) at 3 months and 6 months, respectively. Logarithm of the minimum angle of resolution visual acuity improved from 0.72 ± 0.1 (∼20/100 Snellen) at baseline to 0.36 ± 0.06 (∼20/40 Snellen) at 6 months (P0.001). There was no statistical difference in anatomical success rates or visual outcomes between cases performed by first- or second-year fellows (P0.50). Single-operation success was associated only with size of detachment (P = 0.01). Visual outcome was associated with macula status at baseline (P = 0.032) and number of reoperations (P0.001).Anatomical and visual outcomes of fellow-performed pneumatic retinopexy are comparable with those reported in the previous literature.

Author(s): Zhang, Tingwei; Kho, Aaron M; Yiu, Glenn; Srinivasan, Vivek J | Abstract: PurposeTo use visible light optical coherence tomography (OCT) to investigate subcellular reflectivity contributions to the outermost (4th) of the retinal hyperreflective bands visualized by current clinical near-infrared (NIR) OCT.MethodsVisible light OCT, with 1.0 µm axial resolution, was performed in 28 eyes of 19 human subjects (21-57 years old) without history of ocular pathology. Two foveal and three extrafoveal hyperreflective zones were consistently depicted within band 4 in all eyes. The two outermost hyperreflective bands, occasionally visualized by NIR OCT, were presumed to be the retinal pigment epithelium (RPE) and Bruch's membrane (BM). RPE thickness, BM thickness, and RPE interior reflectivity were quantified topographically across the macula.ResultsA method for correcting RPE multiple scattering tails was found to both improve the Gaussian goodness-of-fit for the BM intensity profile and reduce the coefficient of variation of BM thickness in vivo. No major topographical differences in macular BM thickness were noted. RPE thickness decreased with increasing eccentricity. Visible light OCT signal intensity in the RPE was weighted to the apical side and attenuated more across the RPE in the fovea than peripherally.ConclusionsMorphometry of the presumed RPE and BM bands is consistent with known anatomy. Weighting of RPE reflectivity toward the apical side suggests that melanosomes are the predominant contributors to RPE backscattering and signal attenuation in young eyes.Translational relevanceBy enabling morphometric analysis of the RPE and BM, visible light OCT deciphers the main reflectivity contributions to outer retinal band 4, commonly visualized by commercial OCT systems.

Bruch’s membrane (BM) is a pentalaminar structure that mediates transport between the retinal pigment epithelium (RPE) and choriocapillaris. With near-infrared Optical Coherence Tomography (OCT), it has been challenging to visualize, let alone quantify, BM non-invasively in non-pathologic eyes. First, we show that shorter wavelength visible light OCT consistently delineates BM better than longer wavelength visible light OCT in pigmented human subjects, independent of axial resolution. Second, we develop a physical model of RPE and BM reflectivity to explain this finding. Third, we employ this model to devise a morphometric algorithm to more accurately map BM thickness in the normal macula.

Objective Diseases such as age-related macular degeneration (AMD) are classified based on human rubrics that are prone to bias. Supervised neural networks trained using human-generated labels require labor-intensive annotations and are restricted to specific trained tasks. Here, we trained a self-supervised deep learning network using unlabeled fundus images, enabling data-driven feature classification of AMD severity and discovery of ocular phenotypes. Design Development of a self-supervised training pipeline to evaluate fundus photographs from the Age-Related Eye Disease Study (AREDS). Participants One hundred thousand eight hundred forty-eight human-graded fundus images from 4757 AREDS participants between 55 and 80 years of age. Methods We trained a deep neural network with self-supervised Non-Parametric Instance Discrimination (NPID) using AREDS fundus images without labels then evaluated its performance in grading AMD severity using 2-step, 4-step, and 9-step classification schemes using a supervised classifier. We compared balanced and unbalanced accuracies of NPID against supervised-trained networks and ophthalmologists, explored network behavior using hierarchical learning of image subsets and spherical k-means clustering of feature vectors, then searched for ocular features that can be identified without labels. Main Outcome Measures Accuracy and kappa statistics. Results NPID demonstrated versatility across different AMD classification schemes without re-training and achieved balanced accuracies comparable with those of supervised-trained networks or human ophthalmologists in classifying advanced AMD (82% vs. 81–92% or 89%), referable AMD (87% vs. 90–92% or 96%), or on the 4-step AMD severity scale (65% vs. 63–75% or 67%), despite never directly using these labels during self-supervised feature learning. Drusen area drove network predictions on the 4-step scale, while depigmentation and geographic atrophy (GA) areas correlated with advanced AMD classes. Self-supervised learning revealed grader-mislabeled images and susceptibility of some classes within more granular AMD scales to misclassification by both ophthalmologists and neural networks. Importantly, self-supervised learning enabled data-driven discovery of AMD features such as GA and other ocular phenotypes of the choroid (e.g., tessellated or blonde fundi), vitreous (e.g., asteroid hyalosis), and lens (e.g., nuclear cataracts) that were not predefined by human labels. Conclusions Self-supervised learning enables AMD severity grading comparable with that of ophthalmologists and supervised networks, reveals biases of human-defined AMD classification systems, and allows unbiased, data-driven discovery of AMD and non-AMD ocular phenotypes.