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Katie X Li,1 Nicholas Carducci,1 Omar Moinuddin,1 Yunshu Zhou,1 David C Musch,1,2 David N Zacks,1 Cagri G Besirli,1 Thomas J Wubben1 1Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA; 2Department of Epidemiology, University of Michigan, Ann Arbor, MI, USACorrespondence: Thomas J WubbenDepartment of Ophthalmology and Visual Sciences, University of Michigan Medical School, 1000 Wall St, Ann Arbor, MI, 48105, USATel +1 734 936 8072Email twubben@med.umich.eduPurpose: To investigate the clinical features and surgical outcomes of rhegmatogenous retinal detachment (RRD) associated with giant retinal tears (GRTs) at a tertiary referral center.Patients and Methods: A retrospective, non-consecutive interventional case series of GRT-associated RRDs that underwent primary surgical repair at the University of Michigan W.K. Kellogg Eye Center between January 1, 2011 and July 1, 2020. Clinical characteristics and preoperative, perioperative, and postoperative data were collected.Results: Forty-eight eyes of 47 patients with GRT-associated RRDs met inclusion criteria, including those that were children (under 12 years, N=4, 8.3%), associated with a history of trauma (N=20, 41.7%) or with grade C proliferative vitreoretinopathy (PVR-C) (N=7, 14.6%) at baseline. Median age was 46 years (interquartile range (IQR): 29 years, range: 4 to 72 years), median follow-up was 28 months (IQR: 43 months, range: 3– 124 months), and 83.3% (N=40) of subjects were male. Primary surgical repair for GRT-associated RRDs included pars plana vitrectomy (PPV) (N=40, 83.3%), scleral buckle (SB) (N=1, 2.1%), or combined PPV/SB (N=7, 14.6%). Surgical approach commonly involved the use of perfluorocarbon liquid (N=43, 90%) and gas tamponade (N=39, 81%). Single surgery anatomic success (SSAS) was 75% (95% CI: 60%, 85%) at 3 months and 65% (95 CI: 47%, 78%) at 2 years. Final anatomic success was achieved in all 48 eyes (100%). Median visual acuity improved from 20/250 preoperatively to 20/60 at final follow-up, with 44% (N=20) of eyes achieving postoperative visual acuity of 20/40 or better.Conclusion: In this series from a tertiary referral center, both complex and non-complex GRT-associated RRDs were most commonly managed with PPV alone, perfluorocarbon liquid, and gas tamponade with favorable final anatomic and visual outcomes comparable to other modern GRT series.Keywords: giant retinal tear, proliferative vitreoretinopathy, retinal detachment, scleral buckle, trauma, vitrectomy

Time-driven activity-based costing analysis of panretinal photocoagulation shows 47.8% of cases have a negative margin relative to maximum Medicare reimbursement, with large financial disincentives for bilateral cases, which may disincentivize high-value care for vulnerable patients., (Copyright © 2025. Published by Elsevier Inc.)

Purpose: To evaluate the clinical outcomes and prognostic factors in unilateral Coats disease in the era of anti-VEGF therapy., Design: Global, multicenter, retrospective case series., Subjects: 656 eyes of 656 subjects with Coats disease were included in this study. Exclusion criteria were Coats disease secondary to retinitis pigmentosa as well as bilateral cases., Methods: Clinical data from patients with Coats disease were collected from 20 ophthalmic practices around the world. We compared early-stage (stage 1-2) and advanced-stage (stage 3-5) Coats disease in terms of clinical characteristics and treatment modalities., Main Outcome Meaures: Functional outcomes include achieving visual acuity (VA) of 0.3 logMAR or better and VA improvement or stability. Anatomical failure was defined as the development of phthisis, chronic retinal detachment, massive fibrosis, or the requirement for enucleation., Results: Subjects with early-stage disease were significantly older, with a mean age of 17.4 ± 17.8 years, compared to 7.1 ± 7.1 years in the advanced-stage group (p < 0.001). There was a male predominance in both early and advanced stages (84.7%). Advanced disease was associated with a higher incidence of strabismus (20.2% vs. 6.7%, p < 0.001) and leukocoria (12.3% vs. 3.2%, p < 0.001). More subjects with early-stage disease received laser photocoagulation as monotherapy (44.7% vs. 21.1%, p < 0.001). Additionally, early-stage disease received more sessions of intravitreal anti-VEGF injections as adjunct therapy (4.4 ± 6.2 vs. 2.7 ± 2.1, p = 0.005). Factors associated with poorer functional outcomes included worse presenting visual acuity, advanced disease stage, and the presence of a foveal nodule. Worse presenting visual acuity and advanced disease stage was associated with lower likelihood of anatomical success while combination therapy increased the odds of anatomical success., Conclusion: Unilateral Coats disease predominantly affects males, regardless of disease stage. Identifying a foveal nodule is crucial for visual prognosis. Laser photocoagulation remains the primary treatment. While anti-VEGF may prevent enucleation, its role in early-stage disease requires further clarification., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To assess the safety and efficacy of AAV5-hRKp.RPGR in participants with retinitis pigmentosa GTPase regulator (RPGR)-associated X-linked retinitis pigmentosa (XLRP)., Design: Open-label, phase 1/2 dose escalation/expansion study (ClinicalTrials.gov Identifier: NCT03252847)., Methods: Males (≥5 years old) with XLRP-RPGR were evaluated. In the dose escalation phase, subretinal AAV5-hRKp.RPGR (low: 1.0 × 10 11 vg/ml; intermediate: 2.0 × 10 11 vg/ml; high: 4.0 × 10 11 vg/ml) was administered to the poorer-seeing eye (n = 10). Dose confirmation (intermediate dose) was carried out in 3 pediatric participants. In the dose expansion phase, 36 participants were randomized 1:1:1 to immediate (low or intermediate dose) or deferred (control) treatment. The primary outcome was safety. Secondary efficacy outcomes included static perimetry, microperimetry, vision-guided mobility, best corrected visual acuity, and contrast sensitivity. Safety and efficacy outcomes were assessed for 52 weeks for immediate treatment participants and 26 weeks for control participants., Results: AAV5-hRKp.RPGR was safe and well tolerated, with no reported dose-limiting events. Most adverse events (AEs) were transient and related to the surgical procedure, resolving without intervention. Two serious AEs were reported with immediate treatment (retinal detachment, uveitis). A third serious AE (increased intraocular pressure) was reported outside the reporting period. All ocular inflammation-related AEs responded to corticosteroids. Treatment with AAV5-hRKp.RPGR resulted in improvements in retinal sensitivity and functional vision compared with the deferred group at Week 26; similar trends were observed at Week 52., Conclusions: AAV5-hRKp.RPGR demonstrated an anticipated and manageable AE profile through 52 weeks. Safety and efficacy findings support investigation in a phase 3 trial., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: This study compared two imaging grading techniques to assess the utility of longitudinal image-based analysis in retinopathy of prematurity (ROP) screening: (1) time-limited without image comparison (a proxy for bedside indirect ophthalmoscopy, termed sBIO) and time-unlimited with image comparison (for telemedicine grading, termed TELE) screening. We tested two hypotheses: (1) H1: TELE was superior to sBIO for the detection of change (Tempo)-same, better, or worse and (2) H2: granular data of change (e.g., at the image and feature level) is integrated by graders to achieve the Tempo assessment., Design: Prospective reliability analysis., Methods: Gold standard reference (GS) was a published curated ROP image database consisting of both Tempo and granular level changes (image and components) from 40 patients in 2 sets. Graders were divided into 2 cohorts. There were two screening techniques: (1) sBIO with time limited review of 10 minutes/patient, access to prior notes and drawings and (2) TELE with unlimited review time, access to prior weeks' images, notes and schematics. Graders switched techniques and sets after 6 weeks. H1 outcome was comparison of graders' weekly Tempo scores to GS-Gestalt and for H2 was Tempo score compared to GS-View and GS-Component., Results: H1 demonstrated no difference-accuracy of sBIO and TELE compared to GS was 51.7% and 51.9% respectively (P = .95). Highest agreement occurred when all exams exhibited no change (91.5% sBIO vs 93.5% TELE, P = .46) and worst agreement was when exams always demonstrated worsening (46.5% sBIO vs 47.1% TELE, P = .93). Both sets of graders did worse in weeks 7-12, irrespective of technique. H2 demonstrated that Tempo assessment did not correlate with granular data changes in the GS for View level and Component level assessments-overall agreement dropped to 31.4% for Tempo vs GS-VIEW (31.2% for sBIO, 31.5% for TELE) and 4.6% for Tempo vs GS-COMPONENT (4.9% for sBIO, 4.3% for TELE)., Conclusions: Detection of ROP Tempo was independent of screening technique by expert pediatric retina graders. Both groups did significantly better in the first half of the study, indicative of a fatigue factor. This is the first study in ROP history to demonstrate that graders integrate image and retinal features in various ways that can be in contradiction of their assessment of overall disease progression., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To perform a time-driven, activity-based cost analysis of retinal detachment (RD) surgery and compare it with reimbursement rates. Methods: This economic analysis at a single academic institution used time-driven, activity-based costing methodology to determine the cost of rhegmatogenous RD repair with primary pars plana vitrectomy. A process flow map was created to highlight each surgical case's operative episodes, including clinical follow-ups. Time logs were obtained from the electronic health record for each operative phase and clinical follow-up. The overhead and anesthesia costs were collected from the institution's cost accounting system. The direct material and personnel costs were obtained from internal financial data. Results: Seventy-six cases that met the inclusion criteria were included in the cost analysis study. The time-driven, activity-based cost of RD was $6247.17, and the reimbursement was $5442.91. Therefore, each procedure had a net negative loss of $804.26. To break even, the average operation time would need to be reduced from the determined average of 90.49 minutes to 64.90 minutes. Conclusions: This study found that Medicare underestimates the true cost of RD surgery. Changes in referral patterns may be motivated by reimbursement rates lower than the cost of the procedure, which could ultimately affect patient access to care., Competing Interests: The authors declared no potential conflicts of interests with respect to research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Our previous study discussed crystallin family induction in an experimental rat model of retinal detachment. Therefore, we attempted to evaluate the role of α-crystallin in photoreceptor survival in an experimental model of retinal detachment, as well as its association with the intrinsically neuroprotective protein Fas-apoptotic inhibitory molecule 2 (FAIM2). Separation of retina and RPE was induced in rat and mouse eyes by subretinal injection of hyaluronic acid. Retinas were subsequently analyzed for the presence αA-crystallin (HSPB4) and αB-crystallin (HSPB5) proteins using immunohistochemistry and immunoblotting. Photoreceptor death was analyzed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining and cell counts. The 661W cells subjected to FasL were used as a cell model of photoreceptor degeneration to assess the mechanisms of the protective effect of αA-crystallin and its dependence on its phosphorylation on T148. We further evaluated the interaction between FAIM2 and αA-crystallin using a co-immunoprecipitation assay. Our results showed that α-crystallin protein levels were rapidly induced in response to retinal detachment, with αA-crystallin playing a particularly important role in protecting photoreceptors during retinal detachment. Our data also show that the photoreceptor intrinsically neuroprotective protein FAIM2 is induced and interacts with α-crystallins following retinal detachment. Mechanistically, our work also demonstrated that the phosphorylation of αA-crystallin is important for the interaction of αA-crystallin with FAIM2 and their neuroprotective effect. Thus, αA-crystallin is involved in the regulation of photoreceptor survival during retinal detachment, playing a key role in the stabilization of FAIM2, serving as an important modulator of photoreceptor cell survival under chronic stress conditions.

Photoreceptor loss results in vision loss in many blinding diseases, and metabolic dysfunction underlies photoreceptor degeneration. So, exploiting photoreceptor metabolism is an attractive strategy to prevent vision loss. Yet, the metabolic pathways that maintain photoreceptor health remain largely unknown. Here, we investigated the dependence of photoreceptors on Gln catabolism. Gln is converted to glutamate via glutaminase (GLS), so mice lacking GLS in rod photoreceptors were generated to inhibit Gln catabolism. Loss of GLS produced rapid rod photoreceptor degeneration. In vivo metabolomic methodologies and metabolic supplementation identified Gln catabolism as critical for glutamate and aspartate biosynthesis. Concordant with this amino acid deprivation, the integrated stress response (ISR) was activated with protein synthesis attenuation, and inhibiting the ISR delayed photoreceptor loss. Furthermore, supplementing asparagine, which is synthesized from aspartate, delayed photoreceptor degeneration. Hence, Gln catabolism is integral to photoreceptor health, and these data reveal a novel metabolic axis in these metabolically-demanding neurons., Competing Interests: Declaration of Interests Moloy T. Goswami declares no competing interests. Eric Weh declares no completing interests. Shubha Subramanya declares no competing interests. Katherine M. Weh declares no competing interests. Hima Bindu Durumutla declares no competing interests. Heather Hager declares no competing interests. Nicholas Miller declares no competing interests. Sraboni Chaudhury declares no competing interests. Anthony Andren declares no competing interests. Peter Sajjakulnukit declares no competing interests. Li Zhang declares no competing interests. Cagri G. Besirli owns Johnson & Johnson stock and has equity interest in Ocutheia and iRenix Medical. Costas A. Lyssiotis has consulted for Astellas Pharmaceuticals, Odyssey Therapeutics, Third Rock Ventures, and T-Knife Therapeutics. C.A.L. is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-ME1 pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015). Thomas J. Wubben has equity interest in Ocutheia.

Purpose: Classify the appearance and quantify the growth rate of chorioretinal atrophy in patients who received voretigene neparvovec-rzyl (VN) for RPE65-mediated retinal degeneration., Design: Multicenter retrospective analysis., Subjects: Patients who underwent subretinal VN injection at 5 institutions and demonstrated posterior-pole chorioretinal atrophy., Methods: Ultrawidefield scanning laser ophthalmoscopy or color fundus photos were assessed before and after subretinal VN. Atrophy was defined as regions with ≥ 2 of the following: (1) partial or complete retinal pigment epithelial depigmentation; (2) round shape; (3) sharp margins; and (4) increased visibility of choroidal vessels. Atrophy was qualitatively classified into different subtypes. All atrophy was manually segmented. Linear mixed-effects models with random slopes and intercepts were fit using atrophy area and square root of atrophy area., Main Outcome Measures: Number of eyes with each atrophy pattern, and slopes of linear mixed-effects models., Results: Twenty-seven eyes from 14 patients across 5 centers developed chorioretinal atrophy after subretinal VN. A mean of 5.8 ± 2.7 images per eye obtained over 2.2 ± 0.8 years were reviewed, and atrophy was categorized into touchdown (14 eyes), nummular (15 eyes), and perifoveal (12 eyes) subtypes. Fifteen eyes demonstrated > 1 type of atrophy. Thirteen of 14 patients demonstrated bilateral atrophy. The slopes of the mixed-effects models of atrophy area and square root of atrophy area (estimate ± standard error) were 1.7 ± 1.3 mm 2 /year and 0.6 ± 0.2 mm/year for touchdown atrophy, 5.5 ± 1.3 mm 2 /year and 1.2 ± 0.2 mm/year for nummular atrophy, and 16.7 ± 1.8 mm 2 /year and 2.3 ± 0.2 mm/year for perifoveal atrophy. The slopes for each type of atrophy were significantly different in the square root of atrophy model, which best fit the data (P < 0.05)., Conclusions: Chorioretinal atrophy after subretinal VN for RPE65-mediated retinal degeneration developed according to a touchdown, nummular, and/or perifoveal pattern. Perifoveal atrophy grew the most rapidly, while touchdown atrophy grew the least rapidly. Understanding the causes of these findings, which are present in a minority of patients, merits further investigation., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with CNGB3-associated achromatopsia (ACHM)., Design: Prospective, phase 1/2 (NCT03001310), open-label, nonrandomized clinical trial., Methods: The study enrolled 23 adults and children with CNGB3-associated ACHM. In the dose-escalation phase, adult participants were administered 1 of 3 AAV8-hCARp.hCNGB3 dose levels in the worse-seeing eye (up to 0.5 mL). After a maximum tolerated dose was established in adults, an expansion phase was conducted in children ≥3 years old. All participants received topical and oral corticosteroids. Safety and efficacy parameters, including treatment-related adverse events and visual acuity, retinal sensitivity, color vision, and light sensitivity, were assessed for 6 months., Results: AAV8-hCARp.hCNGB3 (11 adults, 12 children) was safe and generally well tolerated. Intraocular inflammation occurred in 9 of 23 participants and was mainly mild or moderate in severity. Severe cases occurred primarily at the highest dose. Two events were considered serious and dose limiting. All intraocular inflammation resolved following topical and systemic steroids. There was no consistent pattern of change from baseline to week 24 for any efficacy assessment. However, favorable changes were observed for individual participants across several assessments, including color vision (n = 6/23), photoaversion (n = 11/20), and vision-related quality-of-life questionnaires (n = 21/23)., Conclusions: AAV8-hCARp.hCNGB3 for CNGB3-associated ACHM demonstrated an acceptable safety and tolerability profile. Improvements in several efficacy parameters indicate that AAV8-hCARp.hCNGB3 gene therapy may provide benefit. These findings, with the development of additional sensitive and quantitative end points, support continued investigation., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

HK2 and PKM2 are two main regulators of aerobic glycolysis. Photoreceptors (PRs) use aerobic glycolysis to produce the biomass necessary for the daily renewal of their outer segments. Previous work has shown that HK2 and PKM2 are important for the normal function and long-term survival of PRs but are dispensable for PR maturation, and their individual loss has opposing effects on PR survival during acute nutrient deprivation. We generated double conditional (dcKO) mice lacking HK2 and PKM2 expression in rod PRs. Western blotting, immunofluorescence, optical coherence tomography, and electroretinography were used to characterize the phenotype of dcKO animals. Targeted and stable isotope tracing metabolomics, qRT-PCR, and retinal oxygen consumption were performed. We show that dcKO animals displayed early shortening of PR inner/outer segments, followed by loss of PRs with aging, much more rapidly than either knockout alone without functional loss as measured by ERG. Significant alterations to central glucose metabolism were observed without any apparent changes to mitochondrial function, prior to PR degeneration. Finally, PR survival following experimental retinal detachment was unchanged in dcKO animals as compared to wild-type animals. These data suggest that HK2 and PKM2 have differing roles in promoting PR neuroprotection and identifying them has important implications for developing therapeutic options for combating PR loss during retinal disease.

Retinal cell death is the major cause of vision loss in many forms of blinding retinal disease. A plethora of research is focused on understanding the mechanisms of retinal cell death to identify potential neuroprotective strategies that prevent vision loss in these diseases. Traditionally, histological techniques have been used to determine the type and extent of cell death in the retina. These techniques, such as TUNEL labeling and immunohistochemistry, are laborious and time consuming, resulting in low throughput and variable results depending on the experimenter. To increase throughput and reduce variability, we developed several flow cytometry-based assays to detect and quantify retinal cell death. The methods and accompanying data presented demonstrate that flow cytometry can readily detect both retinal cell death and oxidative stress and importantly, the efficacy of neuroprotective agents. These methods will be of interest to investigators looking to increase throughput and efficiency without compromising sensitivity as the methods herein reduce analysis time from several months to less than a week. As such, the flow cytometry methods presented have the potential to expedite research efforts focused on developing novel strategies for retinal cell neuroprotection., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Purpose: To study the effect of the pandemic-related lockdown (physical distance measures and movement restrictions) on the characteristics and management of retinopathy of prematurity (ROP)., Methods: In this controlled, multicenter cohort study, the medical records of patients born prematurely and screened for ROP in the neonatal intensive care unit during four time periods were reviewed retrospectively: (1) November 1, 2018, to March 15, 2019; (2) March 16, 2019, to August 2, 2019 (lockdown control period); (3) November 1, 2019, to March 15, 2020; and (4) March 16, 2020-August 2, 2020., Results: A total of 1,645 patients met inclusion criteria. Among the 1,633 patients with complete data, mean gestational age (GA) at birth was 28.2, 28.4, 28.0, and 28.3 weeks across time periods 1 to 4, respectively (P = 0.16). The mean birth weight of all patients was 1079.1 ± 378.60 g, with no significant variation across time periods (P = 0.08). There were fewer patients screened during the lockdown period (n = 411) compared with the period immediately before (n = 491) and the same period in the prior year (n = 533). Significantly more patients were screened using indirect ophthalmoscopy, compared to digital imaging (telemedicine), during the lockdown (P < 0.01). There were 11.7%, 7.7%, 9.0%, and 8.8% of patients requiring treatment in each time period, respectively (P = 0.42), with a median postmenstrual age at initial treatment of 37.2, 36.45, 37.1, and 36.3 weeks, respectively (P = 0.32)., Conclusions: We recorded a decrease in the number of infants meeting criteria for ROP screening during the lockdown. The GA at birth and birth weight did not differ. Significantly more infants were screened with indirect ophthalmoscopy, compared to digital imaging, during the lockdown., (Copyright © 2023 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Treatment options are lacking to prevent photoreceptor death and subsequent vision loss. Previously, we demonstrated that reprogramming metabolism via the pharmacologic activation of PKM2 is a novel photoreceptor neuroprotective strategy. However, the features of the tool compound used in those studies, ML-265, preclude its advancement as an intraocular, clinical candidate. This study sought to develop the next generation of small-molecule PKM2 activators, aimed specifically for delivery into the eye. Compounds were developed that replaced the thienopyrrolopyridazinone core of ML-265 and modified the aniline and methyl sulfoxide functional groups. Compound 2 demonstrated that structural changes to the ML-265 scaffold are tolerated from a potency and efficacy standpoint, allow for a similar binding mode to the target, and circumvent apoptosis in models of outer retinal stress. To overcome the low solubility and problematic functional groups of ML-265, compound 2 's efficacious and versatile core structure for the incorporation of diverse functional groups was then utilized to develop novel PKM2 activators with improved solubility, lack of structural alerts, and retained potency. No other molecules are in the pharmaceutical pipeline for the metabolic reprogramming of photoreceptors. Thus, this study is the first to cultivate the next generation of novel, structurally diverse, small-molecule PKM2 activators for delivery into the eye.

Stickler Syndrome is typically characterized by ophthalmic manifestations including vitreous degeneration and axial lengthening that predispose to retinal detachment. Systemic findings consist of micrognathia, cleft palate, sensorineural hearing loss, and joint abnormalities. COL2A1 mutations are the most common, however, there is a lack of genotype-phenotype correlations. Retrospective, single-center case series of a three-generation family. Clinical features, surgical requirements, systemic manifestations, and genetic evaluations were collected. Eight individuals clinically displayed Stickler Syndrome, seven of whom had genetic confirmation, and two different COL2A1 mutations (c.3641delC and c.3853G>T) were identified. Both mutations affect exon 51, but display distinct phenotypes. The c.3641delC frameshift mutation resulted in high myopia and associated vitreous and retinal findings. Individuals with the c.3853G>T missense mutation exhibited joint abnormalities, but mild ocular manifestations. One individual in the third generation was biallelic heterozygous for both COL2A1 mutations and showed ocular and joint findings in addition to autism and severe developmental delay. These COL2A1 mutations exhibited distinct eye vs. joint manifestations. The molecular basis for these phenotypic differences remains unknown and demonstrates the need for deep phenotyping in patients with Stickler syndrome to correlate COL2A1 gene function and expression with ocular and systemic findings.

Purpose: To determine whether vascular endothelial growth factor (VEGF), angiopoeitin-1 (Ang-1), angiopoetin-2 (Ang-2), and matrix metalloproteinase-9 (MMP-9) can be reliably collected and analyzed from infant tears to aid in the diagnosis of retinopathy of prematurity (ROP) and enhance the ability to objectively monitor its clinical course., Methods: In this nonrandomized controlled investigation, tear and saliva samples collected from 20 premature infants during serial ophthalmic examination were analyzed using enzyme-linked immunoassay with results analyzed as a function of disease stage and need for treatment., Results: Tear volume was directly correlated with corrected gestational age (P < 0.001). Tear VEGF levels from samples corresponding to stage 3 ROP were 47.9% lower (P = 0.006) than in samples corresponding to stage 0-1 and 49.1% lower (P = 0.01) than in samples corresponding to stage 2 ROP. There were no between-group differences after normalizing tear VEGF by saliva VEGF levels. Tear/saliva ratio for Ang-1 was 200% greater (P = 0.042) and tear/saliva ratio for Ang-2 was 165% greater (P = 0.035) in samples corresponding to stage 2 versus stage 0-1 ROP disease. Ang-1/Ang-2 ratio was lower in samples from infants who developed stage 2 or worse ROP than in samples from infants who never developed worse than stage 1 ROP (P = 0.031)., Conclusions: In this study cohort, cytokines involved in the pathophysiology of ROP could be reliably identified in and analyzed from infant tears, and showed variation with ROP severity., (Copyright © 2023 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Purpose: To report outcomes of pediatric patients with combined hamartoma of the retina and the retina pigment epithelium followed up conservatively or after pars plana vitrectomy., Methods: This retrospective multicenter study included 62 eyes of 59 pediatric patients with combined hamartoma of the retina and the retina pigment epithelium from 13 different international centers with an average age of 7.7 ± 4.7 (0.3-17) years at the time of the diagnosis and having undergone pars plana vitrectomy or followed conservatively. At baseline and each visit, visual acuity values, optical coherence tomography for features and central foveal thickness, and tumor location were noted. Lesions were called as Zone 1, if it involves the macular and peripapillary areas, and the others were called as Zone 2 lesions., Results: Twenty-one eyes of 20 patients in the intervention group and 41 eyes of 39 patients in the conservative group were followed for a mean of 36.2 ± 40.4 (6-182) months. Best-corrected visual acuity improved in 11 (68.8%) of 16 eyes in the intervention group and 4 (12.9%) of 31 eyes in the conservative group ( P < 0.001). The mean central foveal thickness decreased from 602.0 ± 164.9 µ m to 451.2 ± 184.3 µ m in the intervention group, while it increased from 709.5 ± 344.2 µ m to 791.0 ± 452.1 µ m in Zone 1 eyes of the conservative group. Posterior location of tumor, irregular configuration of the foveal contour and ellipsoid Zone defect in optical coherence tomography, subretinal exudate and prominent vascular tortuosity were associated with poor visual acuity., Conclusion: Vitreoretinal surgery is safe and effective in improving vision and reducing retinal distortion in Zone 1 combined hamartoma of the retina and the retina pigment epithelium in children., Competing Interests: It is to specifically state “No Competing interests are at stake and there is No Conflict of Interest” with other people or organizations that could inappropriately influence or bias the content of the paper.

Photoreceptor cell death is the cause of vision loss in many forms of retinal disease. Metabolic dysfunction within the outer retina has been shown to be an underlying factor contributing to photoreceptor loss. Therefore, a comprehensive understanding of the metabolic pathways essential to photoreceptor health and function is key to identifying novel neuroprotective strategies. Glutamic-oxaloacetic transaminase 1 ( Got1 ) encodes for a cytosolic aspartate aminotransferase that reversibly catalyzes the transfer of an amino group between glutamate and aspartate and is an important aspect of the malate-aspartate shuttle (MAS), which transfers reducing equivalents from the cytosol to the mitochondrial matrix. Previous work has demonstrated that the activity of this enzyme is highest in photoreceptor inner segments. Furthermore, ex vivo studies have demonstrated that the retina relies on aspartate aminotransferase for amino acid metabolism. Importantly, aspartate aminotransferase has been suggested to be an early biomarker of retinal degeneration in retinitis pigmentosa and a possible target for neuroprotection. In the present study, we characterized the effect of Got1 deletion on photoreceptor metabolism, function, and survival in vivo by using a rod photoreceptor-specific, Got1 knockout mouse model. Loss of the GOT1 enzyme from rod photoreceptors resulted in age-related photoreceptor degeneration with an accumulation of retinal aspartate and NADH and alterations in the expression of genes involved in the MAS, the tricarboxylic acid (TCA) cycle, and redox balance. Hence, GOT1 is critical to in vivo photoreceptor metabolism, function, and survival., Competing Interests: Conflict of interest In the past three years, CL has consulted for Astellas Pharmaceuticals, Odyssey Therapeutics, Third Rock Ventures, and T-Knife Therapeutics, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-ME1 pathway as a therapeutic approach US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015. CB is an employee of Janssen R&D. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Purpose: To investigate late vitreoretinal complications and visual outcomes in patients with regressed retinopathy of prematurity (ROP) with or without prior treatment., Design: International, multicenter, noncomparative retrospective case series., Participants: We analyzed 264 eyes of 238 patients from 13 centers worldwide who developed vitreoretinal complications (retinal detachment [RD], vitreous hemorrhage [VH], or retinal break) ≥ 2 years after resolution of acute ROP., Methods: Each participant was assigned to 1 of 3 groups (the RD, VH, and retinal break groups) according to their primary diagnosis. The average age at presentation, visual acuities, refractive error, axial length, gestational age, birth weight, acute ROP classification, prior treatments for acute ROP, postoperative visual acuity (VA), and concomitant eye conditions in the 3 groups were documented and compared., Main Outcome Measures: Clinical features and visual outcomes of late vitreoretinal complications in patients with regressed ROP., Results: A total of 264 eyes of 238 patients were included. The prior acute ROP status was comparable among the 3 groups, except that the VH group had a higher proportion of patients with type 1 ROP (P = 0.03) and prior treatment (P < 0.001) than the other groups. The average age at presentation was earlier in the RD (20.3 ± 15.5 years) and VH (21.4 ± 18.9 years) groups than in the retinal break group (31.9 ± 18.2 years; P < 0.001). The retinal break group had the best presenting best-corrected VA, followed by the RD and VH groups (P < 0.001). Surgical intervention improved VA in both the RD and VH groups (both P < 0.05). The overall trend of VA was the most favorable in the retinal break group, followed by that in the VH and RD groups. Cicatricial changes in the fellow retina were observed in > 90% of patients with unilateral involvement., Conclusions: Infants with acute ROP remain at a high risk of vision-threatening complications throughout childhood and adulthood. Continual follow-up of patients with ROP is important. When severe complications, such as RD or VH, are detected, timely surgical intervention is necessary to ensure favorable visual outcomes in these patients., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To highlight the financial incentive to the physician of choosing an intravitreal anti-vascular endothelial growth factor (VEGF)-based strategy for treating non-proliferative and proliferative diabetic retinopathy, and its possible risks to the patient and costs to the health care system., Design: Perspective with retrospective cost and profit analysis., Methods: Review and synthesis of selected literature on the treatment of diabetic retinopathy, with interpretation of activity-based and time-based costing of an intravitreal aflibercept strategy for diabetic retinopathy. Data from the DRCR Retina Network Protocols W and AB and PANORAMA trial were used to illustrate the potential financial incentive underlying such a treatment strategy., Results: Physician treatment algorithms for diabetic vitreous hemorrhage and non-proliferative diabetic retinopathy may be influenced by the substantial financial incentives that intravitreal aflibercept strategies present, despite functional equivalence with alternative and less profitable strategies. For example, pursuing an intravitreal aflibercept-based strategy for diabetic vitreous hemorrhage presents a 76% increased profit over pars plana vitrectomy with laser, with equivalent functional outcomes. For non-proliferative diabetic retinopathy, preventative aflibercept injections represent a potential 414% increase in profit over observation and an increased cost of $12,164 to $17,542 over 2 years per patient, with no improvement in visual function. These findings demonstrate that there may be misaligned financial incentives in the management of diabetic retinopathy., Conclusions: While anti-VEGF therapy is a useful tool in the management of proliferative diabetic retinopathy and diabetic macular edema, it is believed that physicians should avoid overreliance on anti-VEGF injections in the treatment of diabetic retinopathy. Retinal specialists should be cognizant of the limitations, costs, and risks of anti-VEGF monotherapy and prophylactic therapy, and of the imperative to avoid bias towards financially remunerative practice patterns when equally effective alternatives exist., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Synthetic high-density lipoprotein (sHDL) and rapamycin (Rap) have both been shown to be potential treatments for age-related macular degeneration (AMD). The low aqueous solubility of Rap, however, limits its therapeutic utility. Here we used an Apolipoprotein A-I mimetic peptide and phospholipid-based sHDL for the intravitreal delivery of Rap. By incorporation of Rap in sHDL nanoparticles (sHDL-Rap), we achieve 125-fold increase in drug aqueous concentration. When applied in vitro to retinal pigment epithelium cells, sHDL-Rap exhibited the abilities to efflux cholesterol, neutralize endotoxin, and suppress NF-κB activation. As an mTOR inhibitor, Rap induced autophagy and inhibited NF-κB-mediated pro-inflammatory signaling. Additionally, a greater reduction in lipofuscin accumulation and increased anti-inflammatory effects were achieved by sHDL-Rap relative to free drug or sHDL alone. In vivo studies demonstrated that sHDL reached the target retina pigment epithelium (RPE) layer following intravitreal administration in rats. These results suggest that sHDL-Rap holds potential as a treatment for AMD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Prcis: In children, Baerveldt implants showed 84% success at 1 year, but decreased to 32% at 8 years. Age, race, and glaucoma type were not risk factors for failure. Concurrent intraocular surgery was associated with complications., Purpose: Evaluate success and risk factors for failure and complications of Baerveldt glaucoma implants in children., Methods: Retrospective case series of children who underwent Baerveldt implant placement (2012-2019 by single surgeon) with ≥1 year follow-up. Ocular examination and surgical details were collected. Failure defined as intraocular pressure (IOP) <5 mm Hg or >21 mm Hg for 2 consecutive visits, need for IOP related surgery, or visually significant complication., Results: One hundred-six eyes of 76 patients underwent 110 Baerveldt placement at median 6.4 years. Baerveldt placement was combined with additional procedures in 49% with vitrectomy most common (30%). Success of first Baerveldt (per patient) was 64% at final follow-up (median 4.7 y). One-, 5-, and 8-year survival rates were 84%, 60%, and 32%, respectively. There was no difference (P=0.97) in survival between first Baerveldt and all Baerveldt surgeries. Failure of first Baerveldt was not associated with sex, age, ethnicity, prior IOP-lowering surgery, concurrent intraocular surgery, or glaucoma type. Complications occurred in 14% and were associated with concurrent surgery. Twenty-six percent required additional IOP-lowering surgery. At final follow-up, IOP and glaucoma medications were significantly decreased (P<0.0001). Eyes underwent an average of 3.8±2.3 ocular surgeries and 3.0±2.0 glaucoma surgeries., Conclusions: Baerveldt implants showed good success initially, but survival rates declined over time. No risk factors for failure of first implanted Baerveldt were identified. Concurrent surgery was associated with complications. Majority of eyes required multiple surgeries to achieve IOP control and preserve vision., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To report a 4-year-old boy with a large, macula-involving combined hamartoma of the retina and retinal pigment epithelium (CHRRPE) lesion with an associated choroidal neovascular membrane involving the fovea, characterized with multimodal imaging., Methods: Case report., Results: Given the low likelihood of visual improvement with intervention, observation was recommended and the CHRRPE remained stable on follow-up 4 months after presentation., Conclusion: CHRRPE is a rare congenital retinal lesion that is variably pigmented. Awareness of rare complications, such as CNVM, as seen in this pediatric case is paramount., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Purpose: To investigate real-world safety and efficacy of voretigene neparvovec gene therapy administration in pediatric patients with biallelic RPE65 disease-causing variants., Methods: A retrospective study of 27 eyes of 14 patients with RPE65-associated Leber congenital amaurosis examined postoperative complications and longitudinal changes in photoreceptor function following treatment with subretinal injection of voretigene neparvovec. Full-field stimulus threshold testing (FST), Goldmann visual fields (GVF), best-corrected visual acuity (BCVA), and central subfield thickness (CST) on optical coherence tomography (OCT) scans were collected preoperatively and up to 12 months posttreatment., Results: Baseline through 6-12 month follow-up FST and GVF data were obtained for 13 eyes of 7 patients. FST improved for each eye after treatment with a mean improvement of 2.1 log-units (P < 0.001) and GVF improved for each eye with a mean improvement of 221 sum degrees (P < 0.001). BCVA improved from logMAR 0.98 at baseline to logMAR 0.83 at last follow-up (P < 0.001). Across 19 eyes of 10 patients included in CST analysis, there was a small but statistically significant 9-μ decrease in mean CST from baseline to last follow-up (P < 0.001). The most common postoperative issues included elevation in intraocular pressure (59%), persistent intraocular inflammation (15%), and vitreous opacities (26%) that resolved over a period of months., Conclusions: This report provides some of the earliest longitudinal real-world evidence of the pediatric safety and efficacy of voretigene neparvovec using multiple functional and structural measures of the retina. Outcomes demonstrate significant improvements in visual function consistent with clinical trial results., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To describe eight patients with toxoplasma retinochoroiditis following exposure to wild game., Methods: Retrospective, multicenter case series., Results: Eight men, aged 29 to 71 (mean, 56 years), developed toxoplasmic retinochoroiditis after hunting and/or consuming wild game in the United States, including seven deer and one bear. Five patients developed the disease after eating undercooked game meat, while three developed ocular findings after cleaning hunted animals. Seven patients were healthy prior to exposure. LogMAR visual acuity at presentation was 0.697 ± 0.745, improving to 0.256 ± 0.335 by last follow-up. Disease complications developed in five (62.5%) patients, of which recurrence of retinochoroiditis was the most common., Conclusions: Contact with wild game is a potential source of primary ocular toxoplasmosis in immunocompetent adults. Hunters and consumers of rare game are at risk of serious ocular disease and appropriate contact precautions and cooking may reduce this complication.

Inherited retinal diseases (IRDs) are a collection of rare genetic conditions, which can lead to complete blindness. A large number of causative genes have been identified for IRDs and while some success has been achieved with gene therapies, they are limited in scope to each individual gene and/or the specific mutation harbored by each patient with an IRD. Multiple studies are underway to elucidate common underlying mechanisms contributing to photoreceptor (PR) loss and to design gene-agnostic, pan-disease therapeutics. The rd10 mouse, which recapitulates slow degeneration of PRs, is an in vivo IRD model used commonly by vision researchers. Light deprivation by rearing animals in complete darkness significantly delays PR death in rd10 mice, subsequently increasing the time window for in vivo studies investigating neuroprotective strategies. Longitudinal in vivo retinal imaging following the same rd10 mice over time is a potential solution for reducing the number of animals required to complete a study. We describe a previously unreported phenotype in the dark-reared rd10 model that is characterized by dramatic PR degeneration following brief exposure to low-intensity light. This exquisite light sensitivity precludes the use of longitudinal studies employing in vivo imaging or other functional assessment requiring room light in rd10 mice and highlights the importance of closely following animal models of IRD to determine any deviations from the expected degeneration curve during routine experimentation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To assess whether metformin is associated with dry age-related macular degeneration (dAMD) development., Methods: In this retrospective cohort study, patients enrolled in a nationwide U.S. medical insurance claims database from 2002 to 2016 were included if they had diabetes mellitus, were ⩾55 years old, and were enrolled for ⩾2 years without a prior AMD diagnosis. The primary exposure was metformin use analyzed as either active or prior use or cumulative metformin dosage over the study period. A time updating Cox proportional hazard regression was used to estimate the hazard ratio of dAMD incidence with metformin exposure., Results: Among 1,007,226 diabetic enrollees, 53.3% were female and 66.4% were white with a mean hemoglobin A1c of 6.8%. Of eligible enrollees, 166,115 (16.5%) were taking metformin at the index date. Over the study period, 29,818 (3.0%) participants developed dAMD. In the active versus prior use of metformin model, active use conferred an increased hazard of developing dAMD (HR, 1.08; 95% CI, 1.04-1.12) while prior use had a decreased hazard (HR, 0.95; 95% CI 0.92-0.98). The cumulative metformin dosage model showed a significant trend toward increased hazard of dAMD incidence with increasing cumulative dosage ( p  < 0.001), with the lowest dosage quartile having decreased hazard of dAMD incidence (HR, 0.95; 95% CI, 0.91-0.99) and the highest having increased hazard (HR, 1.07; 95% CI, 1.01-1.13)., Conclusions: Small, conflicting associations between metformin exposure and development of dAMD were observed depending on cumulative dosage and whether drug use was active, suggesting metformin did not substantially affect the development of dAMD.

Purpose: To report an anatomic change following subretinal injection of voretigene neparvovec-rzyl (VN) for RPE65-mediated Leber congenital amaurosis., Design: Multicenter, retrospective chart review., Participants: Patients who underwent subretinal VN injection at each of 4 participating institutions., Methods: Patients were identified as having perifoveal chorioretinal atrophy if (1) the areas of atrophy were not directly related to the touch-down site of the subretinal cannula; and (2) the area of atrophy progressively enlarged over time. Demographic data, visual acuity, refractive error, fundus photographs, OCT, visual fields, and full-field stimulus threshold (FST) were analyzed., Main Outcome Measures: Outcome measures included change in visual acuity, FST, visual fields, and location of atrophy relative to subretinal bleb position., Results: A total of 18 eyes of 10 patients who underwent subretinal injection of VN were identified as having developed perifoveal chorioretinal atrophy. Eight of 10 patients (80%) developed bilateral atrophy. The mean age was 11.6 years (range, 5-20 years), and 6 patients (60%) were male. Baseline mean logarithm of the minimum angle of resolution visual acuity and FST were 0.82 (standard deviation [SD], 0.51) and -1.3 log cd.s/m 2 (SD, 0.44), respectively. The mean spherical equivalent was -5.7 diopters (D) (range, -11.50 to +1.75 D). Atrophy was identifiable at an average of 4.7 months (SD, 4.3) after surgery and progressively enlarged in all cases up to a mean follow-up period of 11.3 months (range, 4-18 months). Atrophy developed within and outside the area of the subretinal bleb in 10 eyes (55.5%), exclusively within the area of the bleb in 7 eyes (38.9%), and exclusively outside the bleb in 1 eye (5.5%). There was no significant change in visual acuity (P = 0.45). There was a consistent improvement in FST with a mean improvement of -3.21 log cd.s/m 2 (P < 0.0001). Additionally, all 13 eyes with reliable Goldmann visual fields demonstrated improvement, but 3 eyes (23.1%) demonstrated paracentral scotomas related to the atrophy., Conclusions: A subset of patients undergoing subretinal VN injection developed progressive perifoveal chorioretinal atrophy after surgery. Further study is necessary to determine what ocular, surgical delivery, and vector-related factors predispose to this complication., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background and Objective: To investigate the effect of the coronavirus disease 2019 (COVID-19) lockdown on the presentation and management of acute, primary rhegmatogenous retinal detachment (RRD)., Patients and Methods: This was a single-center, consecutive case series with historic controls, examining patients during the COVID-19 "stay-at-home" order (March 24 to June 1, 2020), the subsequent reopening phase (June 1 to July 31, 2020), and corresponding preceding intervals (March 24 to July 31, 2016 to 2019)., Results: Despite a significant increase in patients presenting with macula-off RRD during the COVID-19 lockdown compared to the 2016 to 2019 timeframe ( P = .03), the rate of single surgery anatomical success was similar between all groups ( P = .66), as was final visual acuity ( P = .61). No delays between presentation and surgical intervention were observed during the lockdown ( P = .49)., Conclusions: Despite the limitations of the COVID-19 lockdown, patients underwent surgery in a timely manner and achieved comparable visual outcomes to controls before COVID-19. [ Ophthalmic Surg Lasers Imaging Retina . 2021;52:593-600.] .

Purpose: To clarify the histologic basis of bacillary layer detachment (BALAD) through a review of the current literature and an analysis of retinal imaging., Methods: The literature for previous reports of BALAD were reviewed. An analysis of retinal images was performed to support anatomical conclusions., Results: A total of 164 unique patients with BALAD on optical coherence tomography (OCT) were identified from the published literature. Twenty-two underlying etiologies, all associated with subretinal exudation, were identified. Forty-one different OCT terminologies were found. The defining OCT feature of BALAD was a split at the level of the photoreceptor inner segment myoid creating a distinctive intraretinal cavity. Resolution of BALAD was followed by a rapid restoration of the ellipsoid zone. Histology of age-related macular degeneration eyes suggests that individual photoreceptors can shed inner segments. Furthermore, detachment of the entire layer of inner segments is a common postmortem artifact. It is proposed that BALAD occurs when outwardly directed forces promoting attachment of photoreceptor outer segments to the retinal pigment epithelium exceed the tensile strength of the photoreceptor inner segment myoid., Conclusion: This review serves to strengthen the OCT nomenclature "bacillary layer detachment," based on specific reflectance information obtained by OCT and previously published histologic observations.

Purpose of Review: Frontotemporal dementia (FTD) is often misdiagnosed or recognized late. Clinical heterogeneity and overlap with other dementias impede accurate diagnosis. FTD biomarkers are limited, expensive, and invasive. We present a narrative review of the current literature focused on optical coherence tomography (OCT) to identify retinal biomarkers of dementia, discuss OCT findings in FTD, and explore the implications of an FTD-specific ocular biomarker for research and patient care., Recent Findings: Recent studies suggest that outer retinal thinning detected via OCT may function as a novel ocular biomarker of FTD. The degree and rate of inner retinal thinning may correlate with disease severity and progression. In Alzheimer disease (AD), OCT demonstrates thinning of the inner retina, which may differentiate this condition from FTD. We conducted a comprehensive search of the literature and reviewed published OCT findings in FTD, AD, and mild cognitive impairment, as well as reports on biomarkers of FTD and AD used in the research and patient care settings. Three of the authors (O.M., N.S.K., and K.Z.Y.) independently conducted literature searches using PubMed to identify studies published before May 1, 2020, using the following search terminology: "Alzheimer's disease," "Alzheimer's dementia," "frontotemporal dementia," "FTD," "mild cognitive impairment," "dementia biomarkers," and "neurodegeneration biomarkers." Search results were then refined using one or more of the following keywords: "optical coherence tomography," "optical coherence tomography angiography," "retinal imaging," and "retinal thinning." The selection of published works for inclusion in this narrative review was then limited to full-text articles written in English based on consensus agreement of the authors., Summary: FTD diagnosis is imprecise, emphasizing the need for improved state and trait biomarkers. OCT imaging of the retina holds considerable potential for establishing effective ocular biomarkers for FTD., (© 2021 American Academy of Neurology.)

Purpose/Aim : To assess whether ocular antihypertensives are associated with the development and progression of age-related macular degeneration (AMD). Materials and Methods : This retrospective, observational cohort study using healthcare claims data from a U.S. nationwide managed-care network between January 1, 2006 and December 31, 2016, included enrollees ≥40 years old with primary open-angle glaucoma with or without a diagnosis of nonexudative AMD at the index date. Hazard ratios (HR) for developing AMD or progressing from nonexudative to exudative AMD with exposure to ocular antihypertensive medications were analyzed. Results : Of 132 963 eligible enrollees, 118 174 (87.5%) had no diagnosis of AMD at baseline while 14 789 (12.5%) had adiagnosis of nonexudative AMD. Prostaglandin analog exposure had adecreased hazard of developing AMD among individuals without baseline disease (HR, 0.90; 95% CI, 0.87-0.94; p < .0001), while topical alpha 2 -agonist exposure demonstrated an increased hazard of AMD development (HR, 1.08; 95% CI, 1.03-1.14; p = .004). Among patients with baseline nonexudative AMD, topical carbonic anhydrase inhibitor exposure was associated with adecreased hazard of progressing to exudative disease (HR, 0.84; 95% CI, 0.71-0.99; p = .04) while topical alpha 2 -agonists had increased hazard (HR, 1.17; 95% CI, 1.01-1.36; p = .04). Conclusions : Certain ocular antihypertensive medications may be associated with development or progression of AMD. Their role in AMD pathogenesis should be better understood as they are considered for therapeutics in this disease.

Concentric macular rings (CMRs) of Henle's fiber layer (HFL) are an uncommon imaging phenomenon previously associated with foveal hypoplasia and epiretinal membrane. Here, we present a case of a 15-year-old boy with bilateral CMRs, normal visual function, and no ocular pathology. These bilateral findings in the absence of vitreomacular traction, foveal hypoplasia, or any other ocular abnormality suggest that macular rings may occur as a normal but rare variant of HFL architecture. [ Ophthalmic Surg Lasers Imaging Retina . 2021;52:353-355.] .

Purpose: With therapeutic advances, central nervous system (CNS) involvement in leukemia has become more common. Leukemic optic disc infiltration, often a clinical diagnosis, can present as an isolated finding in primary or relapsed CNS disease and therefore requires early recognition. Not previously well appreciated, we report here signs of intraocular inflammation accompanying leukemic optic disc infiltration, suggesting infectious or non-infectious uveitis as an alternative diagnosis. We describe a novel optical coherence tomography (OCT) sign favoring leukemic infiltration., Methods: Retrospective consecutive case series of all leukemic patients with disc edema (5 patients, 6 eyes) presenting to the University of Michigan's Ocular Oncology Clinic between October 2019 and March 2020., Results: We report five leukemic patients (6 eyes) who were evaluated for disc edema and vitritis and eventually diagnosed with leukemic papillopathy. All five patients initially had a bland lumbar puncture (LP), and all four patients who underwent magnetic resonance imaging (MRI) had no retrobulbar nerve involvement. Clinical findings included preserved visual acuity (n = 5 eyes, 83%), anterior chamber (AC) cell (n = 3 eyes, 50%), vitreous cell (n = 6 eyes, 100%), and retinal whitening (n = 4 eyes, 66%). In five eyes (83%), a diagnosis of infectious or non-infectious uveitis was initially considered. The OCT finding of inner retinal thickening and loss of inner retinal lamination with largely preserved outer retinal architecture helped point towards a leukemic infiltrative process emanating from the disc and spreading retrograde through the nerve fiber layer., Conclusions: These cases highlight the difficulty of distinguishing intraocular inflammation associated with leukemic papillopathy from infectious or non-infectious uveitis, especially considering bland LP and negative retrobulbar MRI signal in all our patients. We propose juxtapapillary inner retinal infiltration with the loss of inner retinal lamination and relative preservation of outer retinal architecture on OCT imaging as a finding that supports the diagnosis of leukemic papillopathy.

We present a pediatric case to highlight the clinical appearance and management of choroidal neovascularization in the setting of active toxoplasma retinochoroiditis (TRC). A 17-year-old female presented with 2 days of blurry vision in her left eye. Retinal examination demonstrated a pigmented chorioretinal lesion with associated subretinal fluid, vessel sheathing, and adjacent intraretinal hemorrhage. She was diagnosed with active choroidal neovascularization and successful treatment with bevacizumab revealed an underlying active toxoplasmosis lesion. Choroidal neovascularization may rarely present during an acute case of TRC. Dual therapy with anti-vascular endothelial growth factor antibody and anti-parasitic agents leads to improved visual outcomes., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

We report a finding of a pigmented chorioretinal scar with acute retinal necrosis (ARN) caused by herpes simplex virus 2 (HSV-2) infection rather than toxoplasma, creating an initial diagnostic dilemma. A 53-year-old functionally monocular male presented with painless floaters and blurry vision in his seeing eye over a period of 4 days. An exam demonstrated anterior chamber (AC) reaction, vitritis, multifocal patches of whitening, and an occlusive retinal vasculitis. A superior pigmented chorioretinal scar with overlying contracted vitreous was noted in the periphery with no adjacent retinal whitening. The patient was treated for both ARN and toxoplasma chorioretinitis until PCR study of the vitreous and AC returned positive for HSV-2 and negative for toxoplasmosis. Management consisted of a dual therapy regimen of both oral and intravitreal antiviral agents as well as oral corticosteroids. The patient's clinical course was complicated by rhegmatogenous retinal detachment within 2 weeks after symptom onset, requiring pars plana vitrectomy with silicone oil and intraoperative intraocular incubation with foscarnet. We review emerging evidence for pigmented chorioretinal scars in ARN specifically caused by HSV-2, as well as diagnostic and treatment dilemmas in the management of ARN and ARN detachments., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

We assess the effect of autophagy inhibition on photoreceptor (PR) survival during experimental retinal detachment (RD) and examine the and examine the relationship between autophagy and the expression of glycolytic enzymes HK2 and PKM2 in the retina. We find that inhibiting autophagy by genetic knock out of the autophagy activator Atg5 in rod PRs resulted in increased apoptotic and necroptotic cell death during RD, demonstrated by elevated terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, caspase 8 activity, transcript levels of Fas receptor and RIPK3 as compared to controls. The absence of autophagy in rods resulted in downregulation of hexokinase 2 and pyruvate kinase muscle isozyme 2 levels. More than 460 proteins were identified by mass spectroscopy in autophagosomes isolated from detached retinas compared with less than 150 proteins identified in autophagosomes from attached retinas. Among various cellular compartments, proteins from cytoskeleton, cytoplasm and intracellular organelles constituted a large portion of increased autophagosome contents. These proteins represent numerous biological processes, including phototransduction, cell-cell signaling, metabolism and inflammation. Our findings suggest that competent autophagy machinery is necessary for PR homeostasis and improving PR survival during periods of nutrient deprivation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To report anatomic and visual outcomes of pars plana vitrectomy (PPV), as well as scleral buckling (SB) and PPV/SB as surgical treatments for the management of primary, non-complex rhegmatogenous retinal detachment (RRD)., Methods and Analysis: Data from 751 eyes that underwent PPV, SB or combined PPV/SB as a surgical treatment for primary non-complex RRD with at least 3 months of follow-up were analysed to determine rates of single surgery anatomic success (SSAS) and final anatomic success (FAS). Patients or the public were not involved in the design, conduct or reporting of this research., Results: PPV accounted for 89.0% (n=668), PPV/SB for 6.8% (n=51) and SB for 4.2% (n=32) cases. Overall SSAS (91.2% PPV, 84.3% PPV/SB, 93.8% SB; p=0.267) and FAS (96.7% PPV, 94.1% PPV/SB and 100.0% SB; p=0.221) were reported for the three surgical groups. SSAS and FAS were similar for lens status, macular detachment status and the presence or absence of inferior retinal breaks for each of the PPV, PPV/SB and SB groups., Conclusions: In this large, single institution, retrospective case series, we report surgical outcomes for patients with primary non-complex RRD managed with PPV, SB or PPV/SB in the modern era of small-gauge vitrectomy. We demonstrate that primary PPV without adjunct SB provides excellent anatomic and visual outcomes irrespective of lens status, macular involvement or pathology location., Competing Interests: Competing interests: ‘Yes, there are competing interests for one or more authors and I have provided a Competing Interests statement in my manuscript and in the box below’, (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Acquired and inherited retinal disorders are responsible for vision loss in an increasing proportion of individuals worldwide. Photoreceptor (PR) death is central to the vision loss individuals experience in these various retinal diseases. Unfortunately, there is a lack of treatment options to prevent PR loss, so an urgent unmet need exists for therapies that improve PR survival and ultimately, vision. The retina is one of the most energy demanding tissues in the body, and this is driven in large part by the metabolic needs of PRs. Recent studies suggest that disruption of nutrient availability and regulation of cell metabolism may be a unifying mechanism in PR death. Understanding retinal cell metabolism and how it is altered in disease has been identified as a priority area of research. The focus of this review is on the recent advances in the understanding of PR metabolism and how it is critical to reduction-oxidation (redox) balance, the outer retinal metabolic ecosystem, and retinal disease. The importance of these metabolic processes is just beginning to be realized and unraveling the metabolic and redox pathways integral to PR health may identify novel targets for neuroprotective strategies that prevent blindness in the heterogenous group of retinal disorders.