OBJECTIVE:To evaluate outcomes and complications of pars plana vitrectomy (PPV) for nonclearing vitreous hemorrhage (NCVH) secondary to proliferative diabetic retinopathy (DR) in the small-gauge, anti-VEGF era. DESIGN:Retrospective consecutive case series of patients seen at Cole Eye Institute from 2014 to 2022 SUBJECTS: Three hundred and six eyes undergoing PPV for NCVH. METHODS:Key inclusion criteria included PPV specifically indicated for NCVH without tractional retinal detachment secondary to the diagnosis of DR of any severity. Patients without preoperative documentation or 6- and 12-month follow-up visits were excluded. Pertinent data were then manually extracted from the electronic medical record. Descriptive statistics, univariate analysis, and propensity score-matched regression analysis were performed. MAIN OUTCOME MEASURES:Postoperative vitreous hemorrhage (POVH), repeated vitrectomy, and best-corrected visual acuity (BCVA) at 12 months. RESULTS:Anti-VEGF was used in 199 of 306 eyes (65.0%) preoperatively with an average number of 1.67 ± 0.8 injections before vitrectomy. At 12 months after surgery, 94.8% of patients gained or maintained their BCVA. Seventy-five of 306 patients (24.5%) had a POVH, with only 48 of 306 patients (15.6%) requiring a second vitrectomy. Preoperative anti-VEGF injections were not associated with reduced odds of recurrent vitreous hemorrhage, improved 12-month BCVA, nor did they protect against repeat vitrectomy. CONCLUSIONS:This study did not find evidence that preoperative anti-VEGF provided significant benefit in visual rehabilitation, reoperation, or overall POVH in NCVH cases without preoperative evidence of tractional detachment. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PURPOSE:Familial exudative vitreoretinopathy (FEVR) is a category of vitreoretinal diseases with a broad phenotypic spectrum ranging from subclinical peripheral vascular changes to total retinal detachments. We report the clinical and molecular genetic findings in a 43-year-old patient whose ocular findings were consistent with retinitis pigmentosa but genetic testing indicative of FEVR. METHODS:The patient underwent serial examinations over a 12-year period that included fluorescein angiography, electroretinophysiologic testing, and molecular genetic testing using a retinal dystrophy panel. RESULTS:Repeated examinations demonstrated retinal pigmentary changes, arteriolar narrowing, and waxy disc pallor consistent with retinitis pigmentosa. Fluorescein angiography demonstrated peripheral non-perfusion, staining, and window defects, while electroretinogram and electro-oculogram were within normal limits. Genetic testing identified a novel heterozygous likely pathogenic nonsense variant in TSPAN12 gene, c.315T > A, p. (Cys105*). CONCLUSIONS:This report highlights a novel TPSAN12 pathogenic variant causing atypical FEVR which manifests with a retinitis pigmentosa phenotype.

Background Choroidal neovascular membranes (CNVM) associated with optic nerve head drusen (ONHD) are rare but vision threatening. A variety of treatments, including laser photocoagulation, subretinal surgery, and anti-VEGF injections, are effective but pose risks, particularly in pediatric patients, underscoring the need for a comprehensive review. Methods A systematic review was conducted using PubMed, Embase, and Web of Science. Studies with treated pediatric cases of ONHD and CNVM were included. Age >18 years, non-English-language articles, minimal/irrelevant data, and duplicate studies were excluded. Data about patient characteristics, treatment details, and visual outcomes were extracted. Results Of 309 screened publications, 28 studies with 29 patients were included. Of the 19 pediatric patients (22 eyes) receiving anti-VEGF treatment, best-corrected visual acuity (BCVA) improved from 0.84 ± 0.60 logMAR to 0.13 ± 0.15 logMAR (P < 0.0001). In the surgical or laser treatment cohort of 10 patients (12 eyes), BCVA improved from 0.76 ± 0.43 logMAR to 0.18 ± 0.15 logMAR (P = 0.0025). Anti-VEGF treatment was equally effective as surgical or laser treatment. We found no significant difference in the number of injections needed among anti-VEGF agents utilized (ranibizumab, aflibercept, and bevacizumab). No cases developed systemic or extraocular complications with anti-VEGF treatments. One case (5%) had a recurrence of CNVM after treatment. Conclusions This study reinforces the equal efficacy of surgical, laser, and anti-VEGF treatments for CNVM associated with ONHD in pediatric patients. No adverse outcomes of anti-VEGF therapy were reported.

Retinopathy of prematurity (ROP) blinds severely premature infants and is caused by oxygen supplementation. Hypoxia-inducible factor (HIF) stabilization during hyperoxia can prevent oxygen-induced retinopathy (OIR), the experimental correlate of ROP. Stabilization of hepatic HIF-1 alone can prevent OIR while contemporaneously protecting other organ systems, such as the lung and brain, from oxygen toxicity. However, HIF stabilization in central nervous system (CNS) oligodendrocytes reduces myelination. Here, we report the synthesis of small molecules specifically designed to not cross the blood-brain barrier based on a prodrug structure susceptible to hepatic carboxylesterases that release active drug. Twenty compounds were synthesized and rank ordered by Western blot, hypoxia response element binding, and reporter gene analysis. The lead compound prevented OIR, maintained normal CNS myelination, preserved the electroretinogram b-wave, and protected astrocytes. Strategies such as this might be broadly applicable to target specific hepatic functions while limiting off-target effects in other organs.

Hereditary vitreoretinopathies (HVRs), also known as hereditary vitreoretinal degenerations comprise a heterogeneous group of inherited disorders of the retina and vitreous, collectively and variably characterised by vitreal abnormalities, such as fibrillary condensations, liquefaction or membranes, as well as peripheral retinal abnormalities, vascular changes in some, an increased risk of retinal detachment and early-onset cataract formation. The pathology often involves the vitreoretinal interface in some, while the major underlying abnormality is vascular in others. Recent advances in molecular diagnosis and identification of the responsible genes and have improved our understanding of the pathogenesis, risks and management of the HVRs. Clinically, HVRs can be classified according to the presence or absence of skeletal or other systemic abnormalities, retinal dysfunction or retinal vascular abnormalities [2]. There are some discrepancies in the literature regarding which diseases are included under the overarching term 'hereditary vitreoretinopathies'. Conditions such as Stickler syndrome, Wagner syndrome and familial exudative vitreoretinopathy are generally included, while others such as autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) and autosomal dominant vitreoretinochoroidapathy (ADVIRC) may not. In this review, we will discuss some historical aspects, the molecular pathogenesis, clinical features and management of diseases and syndromes commonly considered as HVRs.

PURPOSE:To evaluate the short-term outcomes of patients with exudative neovascular age-related macular degeneration (nAMD) treated with high-dose aflibercept (HDA) 8.0 mg, focusing on anatomical and functional changes, as well as the feasibility of extending treatment intervals in a clinical practice setting. DESIGN:Retrospective, noncomparative cohort study. SUBJECTS:Two hundred nineteen eyes from 184 patients with nAMD who received ≥3 HDAs between August 2023 and October 2024. METHODS:Patients included in this study were either treatment-naïve or had been previously treated with other anti-VEGF agents. Clinical outcomes, including best-corrected visual acuity (BCVA) and macular OCT parameters, were evaluated at baseline and after each HDA. MAIN OUTCOME MEASURES:The primary outcome was the proportion of eyes able to sustain an 8 ± 1-week or longer treatment interval without anatomical deterioration. The secondary outcomes included anatomical and functional changes. RESULTS:The average follow-up time was 22.9 ± 4.9 weeks; 209 eyes (95.4%) were previously treated, and 10 eyes (4.6%) were treatment-naïve. After the first 3 injections, 206 eyes (94.1%) received a fourth HDA, and 70 eyes (31.9%) received a fifth HDA. One hundred two eyes (46.6%) of the total cohort with an interval shorter than 8 weeks after 3 initial injections had persistent macular fluid; 24 eyes (11.0%) were switched to another anti-VEGF agent. Overall, the mean BCVA was 61.9 ± 21.7 ETDRS letters at baseline and 61.7 ± 22.6 at the final visit, with no statistically significant difference observed (P = 0.934). Central subfield thickness and pigment epithelial detachment height remained stable. Significant reductions were observed in subretinal (54.3%-41.1%, P = 0.006) and intraretinal fluid (53.9%-39.3%, P = 0.002). Among previously treated eyes, the mean preswitch treatment interval was 5.8 ± 2.5 weeks and increased to 7.4 ± 2.2 weeks after the 3 initial injections (P < 0.0001). CONCLUSIONS:High-dose aflibercept demonstrated stable BCVA and significant reductions in macular fluid during the follow-up period. A considerable proportion of patients were unable to extend treatment intervals to ≥8 weeks due to persistent macular fluid. These findings suggest that HDA maintains functional stability while improving anatomic outcomes, though challenges in managing chronic nAMD in a clinical-practice setting may limit the ability to extend treatment intervals. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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:Six hundred fifty-six 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 MEASURES:Functional outcomes include achieving visual acuity (VA) of 0.3 logarithm of the minimum angle of resolution 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 with 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 VA, advanced disease stage, and the presence of a foveal nodule. Worse presenting VA and advanced disease stage were associated with lower likelihood of anatomical success, whereas combination therapy increased the odds of anatomical success. CONCLUSIONS: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. Although anti-VEGF may prevent enucleation, its role in early-stage disease requires further clarification. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose To investigate the demographics, eye surgeries, and social determinants of health in pediatric patients with low vision in one or both eyes. Methods This is a cross-sectional study of children 3-18 years of age examined at an academic eye center from 2014 to 2019. Low vision was present if one eye had a distance best-corrected visual acuity (BCVA) of <20/70. ZIP code was used to estimate patient income via a public third-party database. Results Of 47,571 children examined during the study period, 882 had at least one eye with low vision. Of the 882, 88 (10%) had BCVA of <20/400 in at least one eye, and 228 patients (26%) had bilateral low vision. The most common cause of low vision was refractive/strabismic amblyopia (n = 304). The severest forms of vision loss (BCVA<20/200) were predominantly due to retinal dystrophies or detachment (n = 91). Three hundred patients (34%) had undergone at least one ophthalmic surgery—predominantly extraocular muscle procedures in eyes with mild visual loss and vitreoretinal surgeries in those with more severe loss. The severity of vision loss was significantly associated with a higher likelihood and number of surgeries (P < 0.0001). Income and insurance coverage did not have a significant association with BCVA or the likelihood of surgery. Conclusions Refractive and strabismic amblyopia are the predominant causes of reduced worse-eye vision in children, and retinal diseases commonly caused severe vision loss. The type and number of surgeries correlate with the severity of vision loss. We did not find any association of income and insurance type with studied outcomes.

PURPOSE:To evaluate whether providing clinicians with an artificial intelligence (AI)-based vascular severity score (VSS) improves consistency in the diagnosis of plus disease in retinopathy of prematurity (ROP). DESIGN:Multireader diagnostic accuracy imaging study. PARTICIPANTS:Eleven ROP experts, 9 of whom had been in practice for 10 years or more. METHODS:RetCam (Natus Medical Incorporated) fundus images were obtained from premature infants during routine ROP screening as part of the Imaging and Informatics in ROP study between January 2012 and July 2020. From all available examinations, a subset of 150 eye examinations from 110 infants were selected for grading. An AI-based VSS was assigned to each set of images using the i-ROP DL system (Siloam Vision). The clinicians were asked to diagnose plus disease for each examination and to assign an estimated VSS (range, 1-9) at baseline, and then again 1 month later with AI-based VSS assistance. A reference standard diagnosis (RSD) was assigned to each eye examination from the Imaging and Informatics in ROP study based on 3 masked expert labels and the ophthalmoscopic diagnosis. MAIN OUTCOME MEASURES:Mean linearly weighted κ value for plus disease diagnosis compared with RSD. Area under the receiver operating characteristic curve (AUC) and area under the precision-recall curve (AUPR) for labels 1 through 9 compared with RSD for plus disease. RESULTS:Expert agreement improved significantly, from substantial (κ value, 0.69 [0.59, 0.75]) to near perfect (κ value, 0.81 [0.71, 0.86]), when AI-based VSS was integrated. Additionally, a significant improvement in plus disease discrimination was achieved as measured by mean AUC (from 0.94 [95% confidence interval (CI), 0.92-0.96] to 0.98 [95% CI, 0.96-0.99]; difference, 0.04 [95% CI, 0.01-0.06]) and AUPR (from 0.86 [95% CI, 0.81-0.90] to 0.95 [95% CI, 0.91-0.97]; difference, 0.09 [95% CI, 0.03-0.14]). CONCLUSIONS:Providing ROP clinicians with an AI-based measurement of vascular severity in ROP was associated with both improved plus disease diagnosis and improved continuous severity labeling as compared with an RSD for plus disease. If implemented in practice, AI-based VSS could reduce interobserver variability and could standardize treatment for infants with ROP. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

We asked whether hyperoxia might induce hypomyelination of the corpus callosum, clinically described as periventricular leukomalacia (PVL) of the severely preterm infant. Mouse pups and their nursing dams were placed in 80% oxygen from P4-P8, then removed to room air until P11. Corpus callosal sections were probed myelin immunofluorescence, tested for myelin basic protein concentration by Western blot, and both glial fibrillary acidic protein levels and apoptosis quantified. Density of corpus callosal capillaries were measured after lectin staining and hypoxia measured by Hypoxyprobe. Numbers of oligodendrocytes were quantified by immunohistochemistry. We next used hypoxiamimesis as a surrogate to hypoxia by comparing cerebral hypoxia inducible factor (HIF) stabilization to hepatic HIF stabilization. Hyperoxia induced hypomyelination and a reduction of corpus callosal capillaries. Hyperoxia decreased numbers of oligodendrocytes with an increase in corpus callosal fibrosis and apoptosis. Cerebral hypoxiamimesis induced hypomyelination whereas hepatic hypoxiamimesis alone increased myelination, oligodendrocyte numbers, and corpus callosal capillary density. Hepatic HIF-1 dependence on myelination was confirmed using the cre/lox hepatic HIF-1 knockout. These findings suggest that hyperoxia can induce hypomyelination through vasoobliteration and subsequent ischemia, adding a potential oxygen induced mechanism to the diverse causes of periventricular leukomalacia of the severely preterm infant. Targeting hepatic HIF-1 alone led to increased myelination.

BACKGROUND:We investigated the role of postnatal steroids on the severity of retinopathy of prematurity (ROP) and its impact on peripheral avascular retina (PAR). METHODS:A retrospective cohort study of infants born at ≤32 weeks gestation and/or birth weight ≤1500 g. Demographics, the dose and duration of steroid treatment, and age when full retinal vascularization occurred were collected. The primary outcomes were the severity of ROP and time to full vascularization of the retina. RESULTS:A total of 1695 patients were enrolled, 67% of whom received steroid therapy. Their birth weight was 1142 ± 396 g and gestational age was 28.6 ± 2.7 weeks. The total hydrocortisone-equivalent dose prescribed was 28.5 ± 74.3 mg/kg. The total days of steroid treatment were 8.9 ± 35.1 days. After correction for major demographic differences, infants who received a higher cumulative dose of steroids for a longer duration had a significantly increased incidence of severe ROP and PAR (P < 0.001). For each day of steroid treatment, there was a 3.2% increase in the hazard of the severe form of ROP (95% CI: 1.022-1.043) along with 5.7% delay in achieving full retinal vascularization (95% CI: 1.04-1.08) (P < 0.001). CONCLUSION:Cumulative dose and duration of postnatal steroid use were independently associated with the severity of ROP and PAR. Thus, postnatal steroids should be used very prudently. IMPACT:We report ROP outcomes in a large cohort of infants from two major healthcare systems where we have studied the impact of postnatal steroids on the severity of ROP, growth, and development of retinal vessels. After correcting our data for three major outcome measures, we show that high-dose postnatal steroids used for a prolonged duration of time are independently associated with severe ROP and delay in retinal vascularization. Postnatal steroids impact the visual outcomes of VLBW infants significantly, so their clinical use needs to be moderated.