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PURPOSE: To evaluate the prevalence of retinal disease on fluorescein angiography (FA) in patients with incontinentia pigmenti (IP) and to compare the severity of retinal disease in those with and without known central nervous system (CNS) disease. DESIGN: Multi-institutional consecutive retrospective case series. SUBJECTS: New patients with a diagnosis of IP were seen at the Casey Eye Institute at the Oregon Health and Science University (OHSU), Moran Eye Center, University of Utah, or Bascom Palmer Eye Institute, University of Miami from December 2011 to September 2018. METHODS: Detailed ophthalmoscopic examination and FA were recommended for all new patients and performed on every patient who had parental consent. Ophthalmoscopic findings and FA images were graded for severity by 2 masked graders on a 3-point scale: 0 = no disease, 1 = vascular abnormalities without leakage, 2 = leakage or neovascularization, and 3 = retinal detachment. The presence of known CNS disease was documented. Additional cases were obtained from a pediatric retina listserv for examples of phenotypic variation. MAIN OUTCOME MEASURES: The proportion of eyes noted to have disease on ophthalmoscopy compared with FA and the severity of retinal disease in those with and without known CNS disease. RESULTS: Retinal pathology was detected in 18 of 35 patients (51%) by indirect ophthalmoscopy and 26 of 35 patients (74%) by FA (P = 0.048) in a predominantly pediatric population (median age, 9 months). Ten patients (29%) had known CNS disease at the time of the eye examination. A Wilcoxon rank-sum test indicated that the retinal severity scores for patients with CNS disease (median, 2) were significantly higher than the retinal severity scores for patients without CNS disease (median, 1), z = −2.12, P = 0.034. CONCLUSIONS: Retinal disease is present in the majority of patients with IP, and ophthalmoscopic examination is less sensitive than FA for detection of disease. There may be a correlation between the severity of retinal and CNS disease.

Visual field testing that is not frequent enough results in delayed identification of open-angle glaucoma (OAG) progression. Guidelines recommend at least annual testing. It is not known how frequently patients with OAG across the United States receive visual field testing and how patient characteristics and circumstances influence this frequency. If US patients with OAG do not receive visual field tests frequently enough, interventions to increase this frequency or to develop other forms of testing visual function may reduce unidentified OAG vision loss.Retrospective cohort study.The TruvenHealth MarketScan Commercial Claims Database (IBM) contains demographic and claims data for160 million individuals across the United States from 2008 to 2017. We identified enrollees in the database with a recorded diagnosis of OAG (International Classification of Diseases, Ninth Revision, Clinical Modification and International Classification of Diseases, Tenth Revision, Clinical Modification codes 356.1x and H40.1x, respectively). We excluded those aged40 years at the time of their first OAG diagnosis, those without at least 1 confirmatory OAG diagnosis at a subsequent visit, and those with4 years of follow-up data after OAG diagnosis.We calculated the number of visual field tests that each enrollee with OAG underwent per year and categorized the enrollees based on that number (0,0 to0.9, ≥ 0.9 to ≤ 1.1,1.1 to ≤ 2.1, and2.1). We used negative binomial regression to investigate the demographic or health variables that were associated with the frequency of visual field tests that enrollees with OAG received.Frequency of visual field testing among enrollees with OAG.Of the 380 029 enrollees included in the study, 33 267 (8.8%) did not receive a visual field test during the study period, 259 349 (68.2%) underwent0 to0.9 visual field tests per year, 42 129 (11.1%) underwent ≥ 0.9 to ≤ 1.1 visual field tests per year, 42 301 (11.1%) underwent1.1 to ≤ 2.1 visual field tests per year, and 2983 (0.8%) underwent ≥ 2.1 visual field tests per year. The median number of visual field tests per year was 0.63 (interquartile range, 0.33-0.88; mean, 0.65).More than 75% of enrollees with OAG received1 visual field test per year and, thus, did not receive guideline-adherent glaucoma monitoring.

Juxtapapillary retinal capillary hemangiomas are sight-threatening hamartomas located on or adjacent to the optic nerve. Nonsurgical approaches including laser photocoagulation and cryotherapy have been shown to be effective to reduce exudation in peripheral hemangiomas. However, in juxtapapillary hemangiomas, the functional outcomes are limited due to associated potential damage of the retinal nerve fiber layer. We present an 18-year-old female patient with von Hippel–Lindau (VHL) disease who presented with a juxtapapillary retinal capillary hemangioma associated with a tractional epiretinal membrane (ERM) and secondary macular hole. After vitrectomy-assisted excision of the lesion and inner limiting membrane (ILM) peeling around the macular hole, visual acuity and macular anatomy were recovered at 10 months of follow-up. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:570–573.]

Retinopathy of prematurity (ROP) is a complex disease involving development of the neural retina, ocular circulations, and other organ systems of the premature infant. The external stresses of the ex utero environment also influence the pathophysiology of ROP through interactions among retinal neural, vascular, and glial cells. There is variability among individual infants and presentations of the disease throughout the world, making ROP challenging to study. The methods used include representative animal models, cell culture, and clinical studies. This article describes the impact of maternal–fetal interactions; stresses that the preterm infant experiences; and biologic pathways of interest, including growth factor effects and cell–cell interactions, on the complex pathophysiology of ROP phenotypes in developed and emerging countries. Expected final online publication date for the Annual Review of Vision Science, Volume 9 is September 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Background Recent clinical studies suggest that preeclampsia, characterized by uteroplacental insufficiency (UPI) and infant intrauterine growth restriction (IUGR), may be protective against retinopathy of prematurity (ROP) in preterm infants. Experimental models of UPI/IUGR have found an association of erythropoietin (EPO) with less severe oxygen-induced retinopathy (OIR); however, it is unclear if EPO/EPO receptor (EPOR) signaling was involved. We hypothesized that maternal UPI and resultant infant IUGR would protect against features of ROP through EPO/EPOR signaling. Methods We compared transgenic mice with hypoactive EPOR signaling (hWtEPOR) to littermate wild-type mice (mWtEpoR) in a novel combined model of IUGR and ROP. Thromboxane A2 (TXA2) was infused into pregnant C57Bl/6J dams to produce UPI/IUGR; postnatal pups and their foster dams were subjected to a murine OIR model. Results Following hyperoxia, hematocrits were similar between littermate wild-type (mWtEpoR) TXA2/OIR and vehicle/OIR pups. mWtEpoR TXA2/OIR had increased serum EPO, retinal EPO and VEGF, and decreased avascular retinal area (AVA) compared to vehicle/OIR pups. In comparison to the mWtEpoR TXA2/OIR pups, AVA was not reduced in hWtEPOR TXA2/OIR pups. Conclusion Our findings provide biologic evidence that UPI/OIR-induced endogenous EPOR signaling confers protection against hyperoxia-induced vascular damage that may be related to pathophysiology in ROP. Impact Maternal preeclampsia and infant growth restriction confer retinovascular protection against high oxygen-induced damage through endogenous erythropoietin signaling.

The retina and the optic nerve are considered extensions of the central nervous system (CNS) and thus can serve as the window for evaluation of CNS disorders. Spectral domain optical coherence tomography (OCT) allows for detailed evaluation of the retina and the optic nerve. OCT can non-invasively document changes in single retina layer thickness and structure due to neuronal and retinal glial cells (RGC) modifications in systemic and local inflammatory and neurodegenerative diseases. These can include evaluation of retinal nerve fibre layer and ganglion cell complex, hyper-reflective retinal spots (HRS, sign of activated microglial cells in the retina), subfoveal neuroretinal detachment, disorganization of the inner retinal layers (DRIL), thickness and integrity of the outer retinal layers and choroidal thickness. This review paper will report the most recent data on the use of OCT as a non invasive imaging biomarker for evaluation of the most common systemic neuroinflammatory and neurodegenerative/neurocognitive disorders in the adults and in paediatric population. In the adult population the main focus will be on diabetes mellitus, multiple sclerosis, optic neuromyelitis, neuromyelitis optica spectrum disorders, longitudinal extensive transverse myelitis, Alzheimer and Parkinson diseases, Amyotrophic lateral sclerosis, Huntington's disease and schizophrenia. In the paediatric population, demyelinating diseases, lysosomal storage diseases, Nieman Pick type C disease, hypoxic ischaemic encephalopathy, human immunodeficiency virus, leukodystrophies spinocerebellar ataxia will be addressed.摘要: 视网膜和视神经是中枢神经系统 (CNS) 的延续, 因此可以作为评估CNS疾病的窗口。频域光学相干断层扫描 (SD-OCT) 可以对视网膜和视神经进行详细的评估。OCT可以无创性地记录系统性和局部炎症/神经退行性病变中, 由于神经元和视网膜胶质细胞 (RGC) 改变引起的视网膜单层厚度和结构的变化。OCT的观察的指征包括评估视网膜神经纤维层和神经节细胞复合体、视网膜高反射点 (HRS, 视网膜中小胶质细胞激活的征象) 、中心凹下神经视网膜脱离、视网膜内层结构紊乱 (DRIL) 、视网膜外层的厚度和完整性以及脉络膜厚度。本文将总结OCT作为无创成像生物标志物评估成人和儿童中最常见的系统性神经炎症和神经退行性病变/神经认知障碍的最新数据。在成人中, 我们最关注的疾病为糖尿病、多发性硬化症、视神经脊髓炎、视神经脊髓炎谱系障碍、纵向广泛横贯性脊髓炎、阿尔茨海默病和帕金森病、肌萎缩侧索硬化症、亨廷顿病和精神分裂症。在儿童中, 我们着重讨论的疾病有脱髓鞘疾病、溶酶体贮积病、尼曼-匹克病、缺氧缺血性脑病、人类免疫缺陷病毒、脑白质营养不良脊髓小脑性共济失调。.

Familial exudative vitreoretinopathy (FEVR) is a rare hereditary vitreoretinopathy resulting from mutations in the wnt signaling pathway leading to abnormalities in fetal retinal vasculogenesis, angiogenesis, and retinal vascular maintenance. Severe FEVR may result in congenital retinal detachment resembling Norrie disease. The authors report the first case of planned preterm delivery and treatment of a patient with severe FEVR from biallelic LRP5 mutations whose siblings had congenital tractional retinal detachments with light perception vision outcomes after conventional care. Early intervention allowed laser ablation of avascular retina and functional visual outcome despite a successfully repaired unilateral tractional retinal detachment. [ Ophthalmic Surg Lasers Imaging Retina . 2022;53(4):228–232.]

© 2023 Retina. All right 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 µm to 451.2 ± 184.3 µm in the intervention group, while it increased from 709.5 ± 344.2 µm to 791.0 ± 452.1 µm 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.

PurposePremature infants at risk of retinopathy of prematurity (ROP) miss placental transfer of carotenoids, lutein (L) and zeaxanthin (Z), during the third trimester. We previously demonstrated that prenatal L and Z supplementation raises carotenoid levels in infants at birth in theLutein andZeaxanthin inPregnancy (L-ZIP) study (NCT03750968). Based on their antioxidant effects and bioavailability, we hypothesized that prenatal maternal supplementation with macular carotenoids would reduce risk of ROP. To test this hypothesis, we utilized “macular pigment mice” genetically engineered to take up L and Z into the retina in a model of oxygen-induced retinopathy (OIR).MethodsPregnantBco2-/-mice were divided into nine experimental subgroups based on the type of supplementation (L, Z, or placebo) and on maternal supplementation start date corresponding to the three trimesters of human fetal development (E0, E11, and P1). Pups and nursing mothers were exposed to 75% O2for 5 days (P7-12) and returned to room air for 5 days (P12-17). Pups were sacrificed at P12 and P17, and their retinas were analyzed for vaso-obliteration (VO) and intravitreal neovascularization (INV).ResultsPups of pregnant mice supplemented with L or Z had significant reductions in VO and INV areas compared to placebo. Prenatal carotenoid supplementation starting at E0 or E11 was significantly more protective against OIR than postnatal supplementation starting at P1.ConclusionPrenatal supplementation with L and Z was beneficial in a mouse OIR model. We recommend testing prenatal L and Z supplementation in future human clinical trials to prevent ROP.

Wagner disease is a rare, nonsyndromic vitreoretinopathy caused by autosomal dominant variants in the versican (VCAN) gene. It is associated with abnormalities of the vitreoretinal interface that can lead to peripheral traction and retinal detachments, which also occur in other vitreoretinopathies such as X-linked retinoschisis (XLRS), familial exudative vitreoretinopathy (FEVR) and Stickler syndrome. There is variability in the clinical phenotype in Wagner disease potentially due to variants in VCAN gene variants. In this article, we report a family harboring the VCAN c.9265+1G>C variant and describe the clinical and retinal findings in two members. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:639–643.]

Retinopathy of prematurity (ROP) is a devastating neurovascular disease of the retina in newborn infants that can lead to vision deficits or even blindness. In this concise review we discuss our current knowledge about diagnosis, etiology, pathogenesis, intervention, and outcomes of the disease. Major advancements have been made both in categorizing the disease in the new International Classification of Retinopathy of Prematurity, Third Edition classification and in treating severe ROP with anti-vascular endothelial growth factor (VEGF) agents. New development always creates new questions and opens up new areas of research. We will discuss in this review both the benefits and downsides of the new anti-VEGF treatment approaches in ROP, especially in light of our improved understanding of the underlying ROP pathophysiology. We also offer pointers to areas where more research is needed.

The pathophysiology of retinopathy of prematurity (ROP) is postulated to first involve delayed intraretinal vascularization, followed by intravitreal neovascularization (IVNV). Although intravitreal agents that reduce the bioactivity of vascular endothelial growth factor (VEGF) are used to treat IVNV, concerns exist regarding their effects on intraretinal vascularization. In an experimental ROP model, VEGF receptor 2 (VEGFR2) knockdown in retinal endothelial cells reduced IVNV and promoted intraretinal vascularization, whereas knockdown of a downstream effector, signal transducer and activator of transcription 3 (STAT3) in retinal endothelial cells only reduced IVNV. In this study, we tested the hypothesis that the different pathways involved in VEGF-triggered VEGFR2 signaling and VEGF-triggered STAT3 signaling in retinal endothelial cells would allow us to delineate signaling pathways involved in IVNV from those involved in intraretinal vascularization in ROP. To address our hypothesis, we used RNA-sequencing and pathway enrichment analysis to determine changes in the transcriptome of cultured human retinal microvascular endothelial cells (HRMECs). Of the enriched pathways, inactivation of oncostatin M signaling was predicted by either KDR or STAT3 knockdown in the presence of VEGF. Activation of kinetochore metaphase signaling was predicted by KDR knockdown, whereas inactivation was predicted by STAT3 knockdown in the presence of VEGF. Inactivation of signaling by the Rho family of GTPases was predicted by KDR knockdown, but activation was predicted by STAT3 knockdown in the presence of VEGF. Taken together, our data identified unique signaling pathway differences between VEGF-triggered VEGFR2 and VEGF-triggered STAT3 in HRMECs that might have implications in ROP.

IMPORTANCE: Intravitreal bevacizumab effectively treats severe retinopathy of prematurity (ROP), but it enters the bloodstream and may reduce serum vascular endothelial growth factor (VEGF), potentially causing detrimental effects on developing organs in the premature infant. OBJECTIVE: To evaluate the association of intravitreal bevacizumab with plasma bevacizumab and VEGF concentrations at 2 and 4 weeks after predefined, de-escalating doses of intravitreal bevacizumab were administered to infants with severe ROP. DESIGN, SETTING, AND PARTICIPANTS: This phase 1 dose de-escalation case series study was conducted at 10 US hospitals of ophthalmology institutions from May 21, 2015, to May 7, 2019. Blood samples were collected 2 and 4 weeks after intravitreal bevacizumab injection. Participants included 83 premature infants with type 1 ROP in 1 or both eyes and no previous ROP treatment. Data were analyzed from April 2017 to August 2021. INTERVENTIONS: Study eyes received a single bevacizumab injection of 0.250 mg, 0.125 mg, 0.063 mg, 0.031 mg, 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg. When the fellow eye required treatment, one dose higher was administered. Total dose administered at baseline was defined as the sum of doses given to each eye within 3 days of initial study-eye injection. MAIN OUTCOMES AND MEASURES: Plasma bevacizumab concentration at 2 and 4 weeks after injection and the percentage change in plasma VEGF concentrations from pretreatment levels. RESULTS: A total of 83 infants (mean [SD] age, 25 [2] weeks; 48 boys [58%]) were included in this study. Higher doses of bevacizumab administered at baseline were associated with higher plasma bevacizumab concentrations at 2 weeks (ρ, 0.53; 95% CI, 0.31-0.70) and 4 weeks (ρ, 0.44; 95% CI, 0.18-0.64). Plasma VEGF concentrations decreased by 50% or more from pretreatment levels in 40 of 66 infants (61%) at 2 weeks and 31 of 61 infants (51%) at 4 weeks, but no association was observed between the total dose of bevacizumab administered at baseline and percentage change in plasma VEGF concentrations 2 weeks (ρ, −0.04; 95% CI, −0.28 to 0.20) or 4 weeks (ρ, −0.17; 95% CI, −0.41 to 0.08) after injection. CONCLUSIONS AND RELEVANCE: Results of this phase 1 dose de-escalation case series study revealed that bevacizumab doses as low as 0.002 mg were associated with reduced plasma VEGF levels for most infants at 2 and 4 weeks after intravitreal administration; however, no association was observed between total bevacizumab dose administered and reductions in plasma VEGF levels from preinjection to 2 weeks or 4 weeks. Additional studies are needed to evaluate the long-term effects of low-dose bevacizumab on neurodevelopment and retinal structure.

Vitreous collagen structure plays an important role in ocular mechanics, but capturing this structure with existing vitreous imaging methods is hindered by loss of sample position and orientation, low resolution, or small field of view. The objective of this study was to evaluate confocal reflectance microscopy as a solution to these limitations. The use of intrinsic reflectance avoids staining and optical sectioning eliminates the requirement for thin sectioning, minimizing processing for optimal preservation of natural structure. We developed a sample preparation and imaging strategy usingex vivogrossly sectioned porcine eyes. Imaging revealed a network of uniform diameter crossing fibers (1.1 ± 0.3 μm for a typical image) with generally poor alignment (alignment coefficient = 0.40 ± 0.21 for a typical image). To test the utility of our approach for detecting differences in fiber spatial distribution, we imaged eyes every 1 mm along an anterior-posterior axis originating at the limbus and quantified the number of fibers in each image. Fiber density was higher anteriorly near the vitreous base, regardless of imaging plane. These data demonstrate that confocal reflectance microscopy addresses the previously unmet need for a robust, micron-scale technique to map features of collagen networksin situacross the vitreous.

In central serous chorioretinopathy (CSC), the macula is detached because of fluid leakage at the level of the retinal pigment epithelium. The fluid appears to originate from choroidal vascular hyperpermeability, but the etiology for the fluid is controversial. The choroidal vascular findings as elucidated by recent optical coherence tomography (OCT) and wide-field indocyanine green (ICG) angiographic evaluation show eyes with CSC have many of the same venous patterns that are found in eyes following occlusion of the vortex veins or carotid cavernous sinus fistulas (CCSF). The eyes show delayed choroidal filling, dilated veins, intervortex venous anastomoses, and choroidal vascular hyperpermeability. While patients with occlusion of the vortex veins or CCSF have extraocular abnormalities accounting for the venous outflow problems, eyes with CSC appear to have venous outflow abnormalities as an intrinsic phenomenon. Control of venous outflow from the eye involves a Starling resistor effect, which appears to be abnormal in CSC. Similar choroidal vascular abnormalities have been found in peripapillary pachychoroid syndrome. However, peripapillary pachychoroid syndrome has intervortex venous anastomoses located in the peripapillary region while in CSC these are seen to be located in the macular region. Spaceflight associated neuro-ocular syndrome appears to share many of the pathophysiologic problems of abnormal venous outflow from the choroid along with a host of associated abnormalities. These diseases vary according to their underlying etiologies but are linked by the venous decompensation in the choroid that leads to significant vision loss. Choroidal venous overload provides a unifying concept and theory for an improved understanding of the pathophysiology and classification of a group of diseases to a greater extent than previous proposals.