Low-dose proton radiotherapy for pediatric choroidal hemangioma: A case series.

Management of pediatric choroidal hemangioma complicated by large exudative retinal detachment can be challenging, with few options available. Limited data have been published on outcomes following proton radiotherapy (PRT) for management of these patients. In this retrospective case series, nine patients were treated with a low-dose PRT regimen of 20 Gy(relative biological effectiveness [RBE]) in 10 fractions, and two were treated with 15 Gy(RBE) in four fractions. Visual acuity improved in seven patients (64%) and remained stable in the remaining four (36%). In patients with imaging follow-up (10 patients), subretinal fluid resolved in nine patients (90%) and tumor thickness decreased or remained stable in 10 (100%). Complications were observed in eight of 11 patients (73%). One patient developed grade 2 cataract; otherwise, no grade ≥2 complications were observed.

SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN COATS DISEASE.

PURPOSE: To evaluate microstructural retinal abnormalities on spectral domain optical coherence tomography (SD-OCT) imaging of eyes with Coats disease. METHODS: This is a multicenter, retrospective study in which SD-OCT images of patients with treatment-naive Coats disease were correlated with clinical examination and visual acuity and, when available, followed longitudinally over time. RESULTS: Macular SD-OCT of 27 eyes with Coats disease revealed intraretinal edema (59%), intraretinal exudates (67%), subretinal fluid (37%), subretinal exudate (48%), ellipsoid zone disruption (52%), external limiting membrane disruption (41%), and subfoveal nodule (26%). All these microstructural abnormalities correlated with worse baseline and final visual acuities (P < 0.05) on univariate analysis, except for intraretinal edema which exhibited a nonstatistically significant trend toward worse baseline visual acuity (P = 0.16). Within stage 2b eyes, external limiting membrane disruption and subretinal nodule on SD-OCT were associated with worse baseline visual acuity (P = 0.02 for both), and there was a trend toward worse final visual acuity with external limiting membrane disruption and subretinal nodule (P = 0.17 for both) and worse baseline (P = 0.08) and final (P = 0.13) visual acuities with ellipsoid zone disruption. No microstructural abnormalities were noted on OCT of fellow eyes. CONCLUSION: Spectral domain OCT can identify microstructural abnormalities in Coats disease that are associated on univariate analysis with worse baseline visual acuity and visual prognosis. Further larger studies are necessary.

miR-17~92 cooperates with RB pathway mutations to promote retinoblastoma.

The miR-17~92 cluster is a potent microRNA-encoding oncogene. Here, we show that miR-17~92 synergizes with loss of Rb family members to promote retinoblastoma. We observed miR-17~92 genomic amplifications in murine retinoblastoma and high expression of miR-17~92 in human retinoblastoma. While miR-17~92 was dispensable for mouse retinal development, miR-17~92 overexpression, together with deletion of Rb and p107, led to rapid emergence of retinoblastoma with frequent metastasis to the brain. miR-17~92 oncogenic function in retinoblastoma was not mediated by a miR-19/PTEN axis toward apoptosis suppression, as found in lymphoma/leukemia models. Instead, miR-17~92 increased the proliferative capacity of Rb/p107-deficient retinal cells. We found that deletion of Rb family members led to compensatory up-regulation of the cyclin-dependent kinase inhibitor p21Cip1. miR-17~92 overexpression counteracted p21Cip1 up-regulation, promoted proliferation, and drove retinoblastoma formation. These results demonstrate that the oncogenic determinants of miR-17~92 are context-specific and provide new insights into miR-17~92 function as an RB-collaborating gene in cancer.

Immediate Sequential Bilateral Pediatric Vitreoretinal Surgery: An International Multicenter Study.

PURPOSE: To determine the feasibility and safety of bilateral simultaneous vitreoretinal surgery in pediatric patients. DESIGN: International, multicenter, interventional, retrospective case series. PARTICIPANTS: Patients 17 years of age or younger from 24 centers worldwide who underwent immediate sequential bilateral vitreoretinal surgery (ISBVS)-defined as vitrectomy, scleral buckle, or lensectomy using the vitreous cutter-performed in both eyes sequentially during the same anesthesia session. METHODS: Clinical history, surgical details and indications, time under anesthesia, and intraoperative and postoperative ophthalmic and systemic adverse events were reviewed. MAIN OUTCOME MEASURES: Ocular and systemic adverse events. RESULTS: A total of 344 surgeries from 172 ISBVS procedures in 167 patients were included in the study. The mean age of the cohort was 1.3±2.6 years. Nonexclusive indications for ISBVS were rapidly progressive disease (74.6%), systemic morbidity placing the child at high anesthesia risk (76.0%), and residence remote from surgery location (30.2%). The most common diagnoses were retinopathy of prematurity (ROP; 72.7% [P < 0.01]; stage 3, 4.8%; stage 4A, 44.4%; stage 4B, 22.4%; stage 5, 26.4%), familial exudative vitreoretinopathy (7.0%), abusive head trauma (4.1%), persistent fetal vasculature (3.5%), congenital cataract (1.7%), posterior capsular opacification (1.7%), rhegmatogenous retinal detachment (1.7%), congenital X-linked retinoschisis (1.2%), Norrie disease (2.3%), and viral retinitis (1.2%). Mean surgical time was 143±59 minutes for both eyes. Higher ROP stage correlated with longer surgical time (P = 0.02). There were no reported intraoperative ocular complications. During the immediate postoperative period, 2 eyes from different patients demonstrated unilateral vitreous hemorrhage (0.6%). No cases of endophthalmitis, choroidal hemorrhage, or hypotony occurred. Mean total anesthesia time was 203±87 minutes. There were no cases of anesthesia-related death, malignant hyperthermia, anaphylaxis, or cardiac event. There was 1 case of reintubation (0.6%) and 1 case of prolonged oxygen desaturation (0.6%). Mean follow-up after surgery was 103 weeks, and anatomic success and globe salvage rates were 89.8% and 98.0%, respectively. CONCLUSIONS: This study found ISBVS to be a feasible and safe treatment paradigm for pediatric patients with bilateral vitreoretinal pathologic features when repeated general anesthesia is undesirable or impractical.

Vascular endothelial growth factor acts primarily via platelet-derived growth factor receptor α to promote proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) is a nonneovascular blinding disease and the leading cause for failure in surgical repair of rhegmatogenous retinal detachments. Once formed, PVR is difficult to treat. Hence, there is an acute interest in developing approaches to prevent PVR. Of the many growth factors and cytokines that accumulate in vitreous as PVR develops, neutralizing vascular endothelial growth factor (VEGF) A has recently been found to prevent PVR in at least one animal model. The goal of this study was to test if Food and Drug Administration-approved agents could protect the eye from PVR in multiple animal models and to further investigate the underlying mechanisms. Neutralizing VEGF with aflibercept (VEGF Trap-Eye) safely and effectively protected rabbits from PVR in multiple models of disease. Furthermore, aflibercept reduced the bioactivity of both experimental and clinical PVR vitreous. Finally, although VEGF could promote some PVR-associated cellular responses via VEGF receptors expressed on the retinal pigment epithelial cells that drive this disease, VEGF's major contribution to vitreal bioactivity occurred via platelet-derived growth factor receptor α. Thus, VEGF promotes PVR by a noncanonical ability to engage platelet-derived growth factor receptor α. These findings indicate that VEGF contributes to nonangiogenic diseases and that anti-VEGF-based therapies may be effective on a wider spectrum of diseases than previously appreciated.

Second nonocular tumors among survivors of retinoblastoma treated with contemporary photon and proton radiotherapy.

BACKGROUND: The leading cause of death among patients with hereditary retinoblastoma is second malignancy. Despite its high rate of efficacy, radiotherapy (RT) is often avoided due to fear of inducing a secondary tumor. Proton RT allows for significant sparing of nontarget tissue. The current study compared the risk of second malignancy in patients with retinoblastoma who were treated with photon and proton RT. METHODS: A retrospective review was performed of patients with retinoblastoma who were treated with proton RT at the Massachusetts General Hospital or photon RT at Boston Children's Hospital between 1986 and 2011. RESULTS: A total of 86 patients were identified, 55 of whom received proton RT and 31 of whom received photon RT. Patients were followed for a median of 6.9 years (range, 1.0 years-24.4 years) in the proton cohort and 13.1 years (range, 1.4 years-23.9 years) in the photon cohort. The 10-year cumulative incidence of RT-induced or in-field second malignancies was significantly different between radiation modalities (proton vs photon: 0% vs 14%; P = .015). The 10-year cumulative incidence of all second malignancies was also different, although with borderline significance (5% vs 14%; P = .120). CONCLUSIONS: Retinoblastoma is highly responsive to radiation. The central objection to the use of RT, the risk of second malignancy, is based on studies of patients treated with antiquated, relatively nonconformal techniques. The current study is, to the authors' knowledge, the first to present a series of patients treated with the most conformal of the currently available external-beam RT modalities. Although longer follow-up is necessary, the preliminary data from the current study suggest that proton RT significantly lowers the risk of RT-induced malignancy.

Ranibizumab is a potential prophylaxis for proliferative vitreoretinopathy, a nonangiogenic blinding disease.

Proliferative vitreoretinopathy (PVR) exemplifies a disease that is difficult to predict, lacks effective treatment options, and substantially reduces the quality of life of an individual. Surgery to correct a rhegmatogenous retinal detachment fails primarily because of PVR. Likely mediators of PVR are growth factors in vitreous, which stimulate cells within and behind the retina as an inevitable consequence of a breached retina. Three classes of growth factors [vascular endothelial growth factor A (VEGF-A), platelet-derived growth factors (PDGFs), and non-PDGFs (growth factors outside of the PDGF family)] are relevant to PVR pathogenesis because they act on PDGF receptor α, which is required for experimental PVR and is associated with this disease in humans. We discovered that ranibizumab (a clinically approved agent that neutralizes VEGF-A) reduced the bioactivity of vitreous from patients and experimental animals with PVR, and protected rabbits from developing disease. The apparent mechanism of ranibizumab action involved derepressing PDGFs, which, at the concentrations present in PVR vitreous, inhibited non-PDGF-mediated activation of PDGF receptor α. These preclinical findings suggest that available approaches to neutralize VEGF-A are prophylactic for PVR, and that anti-VEGF-based therapies may be effective for managing more than angiogenesis- and edema-driven pathological conditions.

Longitudinal Characteristics of Choroidal Neovascular Membrane in Pediatric Patients.

PURPOSE: To report the clinical and imaging characteristics, including optical coherence tomography angiography (OCTA), and treatment outcomes of choroidal neovascular membranes (CNVMs) in children. DESIGN: Retrospective clinical cohort study. METHODS: Thirty eyes from 25 children (56% girls) with CNVM from 2 centers were examined from 2005 to 2022. Clinical features, imaging findings, treatment regimens, and outcomes are described. RESULTS: The most common causes of CNVM were idiopathic (48%) and inflammatory (20%). At diagnosis, most CNVMs were unilateral (80%), active (83.3%), and juxtafoveal (46.7%). Twenty-five eyes (83.3%) of 21 patients (84%) were treated. The most common first-line treatment was intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) (92%), with a retreatment rate of 52.2% at an average of 237 days. The average number of total injections per eye was 2.3. Injections were safely administered in the clinic (52.2%). A gain of 3 lines or 15 ETDRS (Early Treatment Diabetic Retinopathy Study) letters was observed at final visit. The average duration of follow-up was 56.46 ± 42.51 months. No ocular or systemic complication related to treatment was reported. Sixteen eyes (64%) had OCTA images at both presentation and final visit, which showed a decrease in CNVM vessel density and vessel-length density, and in the height of retinal pigment epithelium detachment (RPED). CONCLUSIONS: There are a variety of underlying etiologies for pediatric CNVMs, which are most often unilateral. Treatment with intravitreal anti-VEGF can be beneficial and does not often require frequent or chronic dosing. OCTA demonstrated a decrease in the CNVM vessel density and vessel-length density as well as in the height of RPED.

Coding and non-coding variants in the ciliopathy gene CFAP410 cause early-onset non-syndromic retinal degeneration.

Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. The implementation of next-generation sequencing in routine diagnostics, together with advanced clinical phenotyping including multimodal retinal imaging, have contributed to the increase of reports describing novel genotype-phenotype associations and phenotypic expansions. In this study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with syndromic recessive Jeune syndrome. The most common retinal phenotypes were cone-rod and rod-cone dystrophies, but the clinical presentations were unified by their early onset as well as the severe impact on central visual function. Twelve variants were detected (three pathogenic, seven likely pathogenic, two of uncertain significance), eight of which were novel. One deep intronic change, c.373+91A>G, led to the creation of a cryptic splice acceptor site in intron four, followed by the inclusion of a 200- base pair pseudoexon and subsequent premature stop codon formation. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Meta-analysis of all published and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.

A novel function of p53: a gatekeeper of retinal detachment.

Proliferative vitreoretinopathy (PVR) is a blinding disease associated with rhegmatogenous retinal detachment, for which there is no satisfactory treatment. Surgery helps in many cases, but, to our knowledge, there are no pharmacological approaches to reduce PVR risk. We report that suppressing expression of p53 was a required event in two assays of PVR (namely, platelet-derived growth factor receptor α-mediated contraction of cells in a collagen gel and retinal detachment in an animal model of PVR). Furthermore, preventing the decline in the level of p53 with agents such as Nutlin-3 protected from retinal detachment, which is the most vision-compromising component of PVR. Finally, Nutlin-3 may be effective in the clinical setting because it prevented human PVR vitreous-induced contraction of cells isolated from a patient PVR membrane. These studies identify Nutlin-3 as a potential PVR prophylaxis.

Refractory Choroidal Neovascularization in a Patient With Pseudoxanthoma Elasticum and Cowden Syndrome.

Purpose: To describe a patient with concurrent pseudoxanthoma elasticum (PXE) and Cowden syndrome who developed choroidal neovascularization (CNV) secondary to angioid streaks. The CNV presented at a young age and was relatively refractory to intravitreal antivascular endothelial growth factor (anti-VEGF) therapy. Methods: A retrospective chart review was performed. Results: A 32-year-old man was treated for bilateral sequential CNV over 11 years. Good visual acuity was maintained with 53 anti-VEGF injections in the right eye and 82 injections in the left eye. On average, 1 injection was administered every 1.7 months in each eye to control the exudation. A skin biopsy and genetic testing confirmed a diagnosis of PXE. He was also found to harbor a PTEN mutation consistent with Cowden syndrome. Conclusions: The concurrent PTEN mutation lends a possible explanation for the relative resistance of CNV to anti-VEGF therapy in this patient with PXE. Phosphatase and tensin homolog is a tumor suppressor that negatively regulates the VEGF pathway.

An ultralow-cost portable centrifuge from discarded materials for medical applications.

Reliable centrifugation for medical applications has historically required access to expensive, bulky, and electricity-dependent commercial devices, which are generally unavailable in resource-poor settings. Although several portable, low-cost, non-electric centrifuges have been described, these solutions have predominately been designed for diagnostic applications requiring sedimentation of relatively small volumes. Moreover, construction of these devices frequently requires access to specialized materials and tools that are often unavailable in underserved areas. Herein, we describe the design, assembly, and experimental validation of the CentREUSE-an ultralow-cost, portable, discarded material-based, human-powered centrifuge for use in therapeutic applications. The CentREUSE demonstrated a mean centrifugal force of 10.5 relative centrifugal force (RCF) ± 1.3. Sedimentation of 1.0 mL triamcinolone acetonide suspension for intravitreal use after 3 min of CentREUSE centrifugation was comparable to that achieved after 12 h of gravity-mediated sedimentation (0.41 mL ± 0.04 vs. 0.38 mL ± 0.03, p = 0.14). Sediment compactness after 5 min and 10 min of CentREUSE centrifugation was similar to that observed after centrifugation with a commercial device for 5 min at 10 RCF (0.31 mL ± 0.02 vs. 0.32 mL ± 0.03, p = 0.20) and 50 RCF (0.20 mL ± 0.02 vs. 0.19 mL ± 0.01, p = 0.15), respectively. Templates and instructions for construction of the CentREUSE are included as part of this open-source publication.

Combined X-linked familial exudative vitreoretinopathy and retinopathy of prematurity phenotype in an infant with mosaic turner syndrome with ring X chromosome.

BACKGROUND: Retinopathy of prematurity (ROP) and familial exudative vitreoretinopathy (FEVR) are two distinct pathologies of retinal angiogenesis with overlapping clinical features. METHODS: Examination, multimodal imaging, and genetic testing were used to guide diagnosis and treatment. RESULTS: We report a combined phenotype of X-linked FEVR and ROP in a 4-month-old girl with mosaic Turner syndrome with ring X chromosome born at 26 weeks gestational age. She was initially diagnosed with atypical ROP with a vitreous band causing a localized traction retinal detachment, inferotemporal to the macula in the right eye, vessels to posterior zone 2 with no clear ridge temporally in the left eye, and fluorescein leakage in both eyes. Due to the suspicion of concurrent FEVR, genetic testing using a vitreoretinopathy panel was performed which revealed a mosaic Turner syndrome associated with 45,X/46,X,r(X), subsequently confirmed by chromosome analysis. The deleted region in the ring X chromosome included the NDP and RS1 genes. The patient was treated with laser photocoagulation of the peripheral avascular retina and sub-Tenon's triamcinolone injection in both eyes, intravitreal injection of bevacizumab in the left eye, and pars plicata vitrectomy in the right eye. CONCLUSIONS: In premature neonates with atypical ROP, a clinical suspicion of concurrent FEVR or similar vasculopathy is important and genetic testing may elucidate a genetic etiology, which could influence management and prognosis. Turner syndrome can be connected with co-occurring Mendelian gene disorders, particularly in individuals with mosaicism. The concurrence of FEVR and ROP appears to result in atypical and possibly more severe phenotypes.

A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) thwarts the repair of rhegmatogenous retinal detachments. Currently, there is no effective prevention for PVR. Platelet-derived growth factor receptor α (PDGFRα) is associated with PVR in humans and strongly promotes experimental PVR driven by multiple vitreal growth factors outside the PDGF family. We sought to identify vitreal factors required for experimental PVR and to establish a potential approach to prevent PVR. Vitreous was obtained from normal rabbits or those in which PVR was either developing or stabilized. Normal vitreous contained substantial levels of growth factors and cytokines, which changed quantitatively and/or qualitatively as PVR progressed and stabilized. Neutralizing a subset of these agents in rabbit vitreous eliminated their ability to induce PVR-relevant signaling and cellular responses. A single intravitreal injection of neutralizing reagents for this subset prevented experimental PVR. To identify growth factors and cytokines likely driving PVR in humans, we subjected vitreous from patients with or without PVR to a similar series of analyses. This analysis accurately identified those agents required for vitreous-induced contraction of cells from a patient PVR membrane. We conclude that combination therapy encompassing a subset of vitreal growth factors and cytokines is a potential approach to prevent PVR.

SARS-CoV-2 RNA Detected in Vitreous Samples Obtained at Autopsy.

Purpose: This work aims to examine the vitreous of autopsy patients with COVID-19 for the presence of SARS-CoV-2 RNA. Methods: Four deceased patients with COVID-19 had an autopsy at Massachusetts General Hospital. Two control specimens were obtained from patients undergoing retinal detachment repair with negative preoperative polymerase chain reaction (PCR) testing for SARS-CoV-2 RNA. Vitreous specimens were obtained from autopsy patients with COVID-19 after povidone was placed on the ocular surface to decrease the risk of contamination of the vitreous specimen. SARS-CoV-2 RNA for gene N (nucleocapsid) was tested using reverse transcription-PCR. Results: SARS-CoV-2 RNA was detected in the vitreous of 2 of 4 autopsy patients who died from complications of COVID-19. Conclusions: SARS-CoV-2 RNA can penetrate into the vitreous of systemically infected patients, which might present risks to operating room personnel during ophthalmic surgical procedures.

Two pediatric cases of reticular corneal epithelial edema associated with netarsudil.

Purpose: To report two pediatric cases of reticular corneal epithelial edema associated with the use of netarsudil ophthalmic solution 0.02%. Observations: In Case 1, a six-year-old male with glaucoma following cataract surgery was treated with netarsudil for thirteen months and developed diffuse reticular corneal epithelial edema on post-operative day one after undergoing transscleral diode cyclophotocoagulation for persistently elevated intraocular pressures. In Case 2, a three-month-old male with bilateral ocular hypertension developed unilateral inferior reticular corneal epithelial edema five weeks after initiation of netarsudil, which had been discontinued in the fellow eye two weeks prior. In both cases, the reticular epithelial edema resolved following cessation of netarsudil. Conclusions and Importance: Netarsudil-associated reticular corneal epithelial edema can occur in infants and young children.

Restoration of Vision in Severe, Cicatricial, Ocular Surface Disease With the Boston Keratoprosthesis Type II.

PURPOSE: To assess clinical outcomes of patients with severe, cicatricial ocular surface disease (OSD) implanted with the currently marketed design of the Boston keratoprosthesis type II (BK2). DESIGN: Retrospective cohort study. METHODS: Records of consecutive patients undergoing BK2 implantation from June 2009 to March 2021 were assessed for postoperative visual acuity, postoperative complications, device replacement, and additional surgeries. RESULTS: Fifty-six eyes of 53 patients with a mean follow-up of 45.8 months (range, 0.2-134.7 months) were included. Stevens-Johnson syndrome/toxic epidermal necrolysis was the most common indication (49.1%), followed by mucous membrane pemphigoid (39.6%) and other OSD (11.3%). Visual acuity improved from logMAR 2.2 ± 0.5 preoperatively to 1.5 ± 1.2 at final follow-up. Of 56 eyes, 50 saw ≥20/200 at some point postoperatively. Of the eyes with a follow-up of more than 5 years, 50.0% retained a visual acuity of ≥20/200 at their final follow-up. The most common complications over the entire postoperative course (mean ∼4 years) were de novo or worsening glaucoma (41.1%), choroidal effusions (30.3%), retinal detachment (25.0%), and end-stage glaucoma (25.0%). In a univariate analysis, patients who experienced irreversible loss of ≥20/200 visual acuity were more likely to have been previously implanted with an older design of BK2, less likely to be on preoperative systemic immunosuppressive therapy, and less likely to have undergone concurrent glaucoma tube implantation, compared to patients who retained ≥20/200 acuity (P < .04 for all). CONCLUSIONS: Advances in device design and postoperative care have made implantation of BK2 a viable option for corneal blindness in the setting of severe cicatricial OSD.

The Effect of Sample Medication Use on Subsequent Anti-VEGF Agent Selection for Neovascular Age-Related Macular Degeneration.

PURPOSE: Medication samples of anti-VEGF agents can represent a good option for retina specialists to provide timely treatment for newly converted neovascular age-related macular degeneration (nvAMD) while prior-authorizations (PA) are pending. Our study examines the effect of medication sample use (ranibizumab or aflibercept) on future anti-vascular endothelial growth factor (VEGF) agent selection in nvAMD. DESIGN: Retrospective cohort study. PARTICIPANTS: nvAMD patients who underwent an initial anti-VEGF injection with a sample medication were compared to nvAMD control patients who never received a medication sample. METHODS: Charts from 2017 through 2020 were reviewed for data regarding demographics, anti-VEGF agent selection, and visual acuity outcomes for both groups. The utilization of different anti-VEGF agents in each group was compared at various time points using chi-square tests for independence of proportions. MAIN OUTCOME MEASURES: Anti-VEGF agent selection for the first four injections and at one year were examined. RESULTS: Adherence to the initial agent was high between first and subsequent injections (2nd, 3rd, 4th injection, and 1 year) in sample (96.2%, 95.9%, 91.9%, 93.4%, respectively), and control groups (98.1%, 94.2%, 94.9%, 87.8%, respectively). Bevacizumab usage was significantly lower among eyes receiving samples relative to controls at the second (1.9% vs. 38.7%, p < .001), third (3.1% vs. 41.3%, p < .001), fourth injections (4.7% vs. 40.4%, p < .001), and at 1 year (0% vs. 33.8%, p < .001). Aflibercept usage was significantly higher in sample eyes relative to controls at the second (78.3% vs. 43.4%, p < .001), third (76.3% vs. 41.5%, p < .001), and fourth injections (76.7% vs. 43.4%, p < .001), and at 1 year (77.0% vs. 52.7%, p < .001). CONCLUSIONS: Sample medications in nvAMD may be initiated for many reasons, including awaiting PA approval. Our study found that eyes receiving a sample anti-VEGF agent (ranibizumab or aflibercept) for their initial injection were less likely to receive bevacizumab at future visits relative to eyes that did not receive an anti-VEGF sample, even after one year of treatment. Given the persistent use of more expensive medications at subsequent injections for patients who were initiated on samples, insurance payors may consider waiving PA requirements for bevacizumab to avoid a paradoxical increase in health-care costs.

The Prevalence of Retinal Disease and Associated CNS Disease in Young Patients with Incontinentia Pigmenti.

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.

Bilateral anterior segment dysgenesis and peripheral avascular retina with tractional retinal detachment in an infant with multiple congenital anomalies-hypotony-seizures syndrome 3.

Background: Multiple congenital anomalies-hypotony-seizures syndrome 3 (MCAHS3) is a rare autosomal recessive disorder caused by mutations in the PIGT gene. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, which plays a crucial role in protein anchoring to cell membranes. The clinical presentation of MCAHS3 is variable in expression and severity, but can be characterized by developmental delay, seizures, hypotonia, facial dysmorphism, and other abnormalities.Materials and Methods: Case report.Results: We report unusual ocular findings including bilateral anterior segment dysgenesis, avascular retinal periphery, and tractional retinal detachment in a 1-month-old male infant with compound heterozygous PIGT mutations consistent with MCAHS3. Whole-exome sequencing did not detect any other genetic abnormalities.Conclusions: This case expands the clinical spectrum of MCAHS3 to include anomalies in ocular anterior segment and retinal vascular development. Given the rarity and the genetic heterogeneity of MCAHS3, giving rise to varied non-ocular phenotypes, it is possible that milder intraocular phenotypes could have gone unrecognized in the past.