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.

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.

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.

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.

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.

Detection of retinal microvascular changes in von Hippel-Lindau disease using optical coherence tomography angiography.

PURPOSE: Von Hippel-Lindau (VHL) disease is a hereditary disorder that can lead to ophthalmic manifestations, including retinal capillary hemangioma (RCH). The diagnosis of RCH is often guided by wide-field fluorescein angiography. In some cases, optical coherence tomography angiography (OCT-A) serves as a non-invasive alternative to FA. Herein, we used OCT-A to examine the macular microvasculature in patients with VHL disease. SUBJECTS: Subjects were selected from patients with a diagnosis of VHL. The control group included eyes without retinal diagnosis from patients with an episode of unilateral retinal detachment or trauma and age ≤ 50 years old. METHODS: Subjects were scanned on the Optovue RTVue-XR device to acquire 3mm x 3mm OCT-A images of the superficial (SCP) and deep capillary plexus (DCP). SCP and DCP vessel density (VD) were calculated after the images were binarized. Furthermore, for subjects with RCH, each OCT-A image was divided equally into four quadrants. SCP and DCP VD of quadrants with RCH were compared to those without RCH. T-tests were performed for statistical analysis. RESULTS: 67 eyes with a history of VHL disease were included as study subjects, while 16 eyes were included as controls. Significant increases in VD were found in patients with VHL disease for both the SCP (p = 0.0441) and DCP (p = 0.0344). When comparing quadrants with associated RCH development to those without, we found no significant difference in SCP VD (p = 0.160) or DCP VD (p = 0.484). CONCLUSIONS: OCT-A can detect changes in the retinal microvasculature in the macula of patients with VHL disease. OCT-A imaging may be an additional tool for screening and early detection of patients at risk of developing ocular complications of VHL disease. Future studies should explore subtle progression on OCT-A associated with the pathogenesis and development of RCH, particularly with larger scan patterns.

PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.

Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110δ, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform δ is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110δ inactivation was found to attenuate pathological retinal angiogenesis. p110δ inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110δ constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.

Efficacy of Retinal Lesion Screening in Von Hippel-Lindau Patients With Widefield Color Fundus Imaging Versus Widefield FA.

BACKGROUND AND OBJECTIVE: Retinal hemangioblastoma is a retinal tumor in patients with Von Hippel-Lindau (VHL). The authors' objective was to determine whether widefield fluorescein angiography (FA) improves lesion detection. PATIENTS AND METHODS: Retrospective case series of VHL patients who underwent widefield fundus imaging and FA. Masked retina specialists graded fundus images as having: 1) definite retinal hemangioblastoma; 2) possible lesion; 3) no lesion. The number of lesions on FA was compared to widefield color imaging. RESULTS: One hundred six eyes of 55 patients were evaluated. A total of 94 lesions were identified on FA in 61.8% patients. Forty-three lesions (45.7%) were not identified on fundus images. Small lesion detection was significantly higher with FA compared to color imaging (P = .013). CONCLUSIONS: This study reports on improved detection of retinal hemangioblastomas with widefield FA compared to widefield fundus images. The authors recommend VHL monitoring guidelines to include periodic widefield FA to adequately screen for smaller lesions. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e260-e265.].

Autonomous early detection of eye disease in childhood photographs.

The "red reflex test" is used to screen children for leukocoria ("white eye") in a standard pediatric examination, but is ineffective at detecting many eye disorders. Leukocoria also presents in casual photographs. The clinical utility of screening photographs for leukocoria is unreported. Here, a free smartphone application (CRADLE: ComputeR-Assisted Detector of LEukocoria) was engineered to detect photographic leukocoria and is available for download under the name "White Eye Detector." This study determined the sensitivity, specificity, and accuracy of CRADLE by retrospectively analyzing 52,982 longitudinal photographs of children, collected by parents before enrollment in this study. The cohort included 20 children with retinoblastoma, Coats' disease, cataract, amblyopia, or hyperopia and 20 control children. For 80% of children with eye disorders, the application detected leukocoria in photographs taken before diagnosis by 1.3 years (95% confidence interval, 0.4 to 2.3 years). The CRADLE application allows parents to augment clinical leukocoria screening with photography.

Characterization of Epiretinal Proliferation in Full-Thickness Macular Holes and Effects on Surgical Outcomes.

PURPOSE: Epiretinal proliferation is a distinct clinical entity from epiretinal membrane that classically is associated with lamellar macular holes, but its prevalence and association with full-thickness macular holes (FTMH) have not been well described. We characterized macular hole-associated epiretinal proliferation (MHEP) and its effects on long-term surgical outcomes. DESIGN: Multicenter, interventional, retrospective case-control study. PARTICIPANTS: Consecutive eyes that underwent surgery for FTMH with a minimum of 12 months follow-up. METHODS: All eyes underwent pars plana vitrectomy, removal of any epiretinal membranes, and gas tamponade, with or without internal limiting membrane (ILM) peeling. Spectral-domain OCT imaging was obtained before and after surgery. MAIN OUTCOME MEASURES: Improvement in visual acuity and single-surgery hole closure rates in eyes with, versus without, MHEP at 12 months. RESULTS: Seven hundred twenty-five charts were analyzed, and 113 patients met inclusion criteria. Of 113 eyes with FTMH, 30 (26.5%) showed MHEP. Patients with FTMH and MHEP were older (P < 0.002) and more often men (P = 0.001), and showed more advanced macular hole stages than those without MHEP (P = 0.010). A full posterior vitreous detachment was more common in eyes with MHEP (P < 0.004). Twelve months after surgery, FTMH with MHEP patients showed significantly less improvement in visual acuity (P = 0.019) with higher rates of ellipsoid and external limiting membrane defects (P < 0.05) and with a higher rate of failure to close with 1 surgery compared to FTMH without MHEP (26.7% vs. 4.8%; P = 0.002]). Peeling the ILM was associated with improved rates of hole closure in FTMH with MHEP (P < 0.001). Multivariate testing confirmed that the presence of MHEP was an independent risk factor for less visual improvement (P = 0.031) and for single-surgery nonclosure (P = 0.009) and that ILM peeling improved single-surgery closure rates (P = 0.026). CONCLUSIONS: We found that FTMH with MHEP showed poorer anatomic and visual outcomes after vitrectomy compared with FTMH without MHEP. Internal limiting membrane peeling was associated with improved closure rates and should be considered when MHEP is detected before surgery.

Longitudinal Examination of Fellow-Eye Vascular Anomalies in Coats' Disease With Widefield Fluorescein Angiography: A Multicenter Study.

BACKGROUND AND OBJECTIVE: Retinovascular anomalies in the fellow eyes of patients with Coats' disease have been described, but the clinical significance is unknown, as well as whether these lesions progress over time. PATIENTS AND METHODS: This is an international, multicenter, retrospective, observational cohort study of fellow-eye abnormalities on widefield fluorescein angiography in patients with Coats' disease. RESULTS: Three hundred fifty eyes of 175 patients with Coats' disease were analyzed. A total of 33 patients (18.8%) demonstrated abnormal fellow-eye findings: 14 (42.4%) telangiectasias, 18 (54.5%) aneurysms, six (18.2%) segmental non-perfusion, six (18.2%) leakage, and two (6.0%) vascular tortuosity. All eyes were asymptomatic, and none of the lesions progressed over time. There was no association between fellow-eye findings with severity of Coats' disease (P = .16), patient age (P = .16), or presence of systemic vascular disease (P = .16). CONCLUSIONS: The vascular abnormalities in fellow eyes of patients with Coats' disease did not progress over time. Observation is a reasonable initial management strategy. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:221-227.].

Early Neuroblastic and Astrocytic Differentiation Demonstrated Immunohistochemically in a Small Intraocular Medulloepithelioma.

PURPOSE: To investigate the source of fibrous astrocytes and neuroblasts in a small ciliary body medulloepithelioma appearing as a leukocoria in a 3-week-old baby girl. METHODS: Histopathologic and immunohistochemical studies included Alcian blue, periodic acid-Schiff, and antisera for the detection of S100 protein, CD99, glial fibrillary acidic protein (GFAP), CRX, NeuN, neurofilaments, synaptophysin, desmin, and myogenin. RESULTS: A small, nonteratoid ciliary body medulloepithelioma with collections of Alcian blue+ mucoplysaccharides was present in the enucleated globe. The retinal mass displayed multilaminar dysplastic rosettes that were CRX+, NeuN-, and synaptophysin-. Intraretinal neurofilaments and scattered NeuN+ neurocytes were also identified. At the base of the retinal mass ribbons and pseudopapillae of CRX+, NeuN- medullary epithelium were found. The latter developed from an S100+ and weakly CD99+ monolayer of premedullary epithelium. GFAP+ fibrous astrocytes and NeuN- neuroblasts streamed from the medullary epithelium. CONCLUSIONS: A multilaminar medullary epithelium and a precursor monolayer of premedullary epithelium were both identified. Neuroblasts and fibrous astrocytes were determined to arise separately from the medullary epithelium. The early stage of tumorigenesis afforded by a small tumor provided the opportunity to discover morphologic and immunohistochemical evidence for these differentiations.

Introduction of the MDM2 T309G Mutation in Primary Human Retinal Epithelial Cells Enhances Experimental Proliferative Vitreoretinopathy.

Purpose: The murine double minute (MDM)2 is a critical negative regulator of the p53 tumor suppressor, and MDM2 SNP309G is associated with a higher risk of proliferative vitreoretinopathy (PVR); in addition, the MDM2 T309G created using clustered regularly interspaced short palindromic repeats (CRISPR)/associated endonuclease (Cas)9 enhances normal rabbit vitreous-induced expression of MDM2 and survival of primary human retinal pigment epithelial (hRPE) cells in vitro. The goal of this study was to determine whether this MDM2 T309G contributes to the development of experimental PVR. Methods: hRPE cells expressing MDM2 T309G or T309T only were treated with vitreous from human PVR donors (HV). The expression of MDM2 and p53 in the treated cells was examined by Western blot. The in vitro vitreous-induced cellular responses, such as contraction were assessed, and PVR was induced by intravitreal injection of the hRPE cells with MDM2 T309G or T309T only into rabbit eyes. Results: Western blot analyses indicated that treatment of hRPE cells with HV led to a significant increase (1.7 ± 0.2-fold) in the expression of MDM2 and a significant decrease in p53 in the cells expressing MDM2 T309G compared with those with MDM2 T309T. In addition, HV promoted contraction of the hRPE cells expressing MDM2 T309G significantly more than those with MDM2 T309T only. Furthermore, MDM2 T309G in the hRPE cells enhanced the development of PVR in a rabbit model. Conclusions: The MDM2 SNP309 in RPE cells enhances their potential of PVR pathogenesis.

Analysis of patient outcomes following proton radiation therapy for retinoblastoma.

PURPOSE: Proton radiotherapy (PRT) is used in the treatment of retinoblastoma (RB) and has the potential to minimize exposure of normal tissue to radiation and thus decrease risk of toxicity and second malignancies. However, comprehensive analyses of long-term patient outcomes are not available. METHODS: RB patients treated with PRT at our institution between 1986 and 2012 were invited to return for participation in a study designed to assess long-term outcomes. Enrolled patients underwent comprehensive analysis including oncologic, ophthalmic, endocrine, cephalometric, and quality of life (QOL) assessments. RESULTS: A total of 12 patients were enrolled in this study, and the average length of follow-up among enrolled patients was 12.9 years (range 4.8-22.2 years). All enrolled patients had bilateral disease, and the disease and visual outcomes for enrolled patients were similar to outcomes for all RB patients treated with PRT over the same time period at our institution. Endocrine evaluation revealed no growth abnormalities or hormonal deficiencies across the cohort. Based on MRI and external cephalometry, PRT was associated with less facial hypoplasia than enucleation. Patient and parent-proxy QOL assessments revealed that RB treatment did not appear to severely impact long-term QOL. CONCLUSIONS: In addition to providing an opportunity for long-term disease control and functional eye preservation, PRT does not appear to be associated with unexpected late visual, endocrine, or QOL effects in this cohort.

Editing VEGFR2 Blocks VEGF-Induced Activation of Akt and Tube Formation.

Purpose: Vascular endothelial growth factor receptor 2 (VEGFR2) plays a key role in VEGF-induced angiogenesis. The goal of this project was to test the hypothesis that editing genomic VEGFR2 loci using the technology of clustered regularly interspaced palindromic repeats (CRISPR)-associated DNA endonuclease (Cas)9 in Streptococcus pyogenes (SpCas9) was able to block VEGF-induced activation of Akt and tube formation. Methods: Four 20 nucleotides for synthesizing single-guide RNAs based on human genomic VEGFR2 exon 3 loci were selected and cloned into a lentiCRISPR v2 vector, respectively. The DNA fragments from the genomic VEGFR2 exon 3 of transduced primary human retinal microvascular endothelial cells (HRECs) were analyzed by Sanger DNA sequencing, surveyor nuclease assay, and next-generation sequencing (NGS). In the transduced cells, expression of VEGFR2 and VEGF-stimulated signaling events (e.g., Akt phosphorylation) were determined by Western blot analyses; VEGF-induced cellular responses (proliferation, migration, and tube formation) were examined. Results: In the VEGFR2-sgRNA/SpCas9-transduced HRECs, Sanger DNA sequencing indicated that there were mutations, and NGS demonstrated that there were 83.57% insertion and deletions in the genomic VEGFR2 locus; expression of VEGFR2 was depleted in the VEGFR2-sgRNA/SpCas9-transduced HRECs. In addition, there were lower levels of Akt phosphorylation in HRECs with VEGFR2-sgRNA/SpCas9 than those with LacZ-sgRNA/SpCas9, and there was less VEGF-stimulated Akt activation, proliferation, migration, or tube formation in the VEGFR2-depleted HRECs than those treated with aflibercept or ranibizumab. Conclusions: The CRISPR-SpCas9 technology is a potential novel approach to prevention of pathologic angiogenesis.

Retinal findings and a novel TINF2 mutation in Revesz syndrome: Clinical and molecular correlations with pediatric retinal vasculopathies.

BACKGROUND: Revesz syndrome is a telomere disorder in the dyskeratosis congenita (DKC) spectrum characterized by exudative retinopathy, bone marrow failure, neuroradiographic abnormalities, and integumentary findings. MATERIALS/METHODS: We report the ophthalmologic findings, documented by examinations under anesthesia with clinical photography and fluorescein angiography, as well as the systemic manifestations and genetic and molecular testing, in identical twins with Revesz syndrome, and compare and contrast these features to those of other pediatric retinal vasculopathies. RESULTS: Both twins exhibited widespread avascularity and anomalous vasculature of the retinal periphery, retinal telangiectasias, and exudation. One twin developed a combination exudative/tractional/rhegmatogenous retinal detachment, while the other exhibited a focal collection of buds of retinal neovascularization. Both twins developed bone marrow failure and were found to have cerebellar hypoplasia and widespread cerebral calcifications. Telomere testing in lymphocytes and granulocytes revealed telomere length less than the 1st percentile for age, and gene sequencing revealed a novel mutation in the TINF2 gene, resulting in the T284P TIN2 protein variant. CONCLUSIONS: We report ophthalmic findings in twins with Revesz syndrome due to a previously unreported mutation in TINF2 and propose that phenotypic and molecular overlaps between DKC spectrum disorders and pediatric retinal vasculopathies may reflect a shared pathophysiologic basis.

Prevention of Proliferative Vitreoretinopathy by Suppression of Phosphatidylinositol 5-Phosphate 4-Kinases.

PURPOSE: Previous studies have shown that vitreous stimulates degradation of the tumor suppressor protein p53 and that knockdown of phosphatidylinositol 5-phosphate 4-kinases (PI5P4Kα and -ß) abrogates proliferation of p53-deficient cells. The purpose of this study was to determine whether vitreous stimulated expression of PI5P4Kα and -ß and whether suppression of PI5P4Kα and -ß would inhibit vitreous-induced cellular responses and experimental proliferative vitreoretinopathy (PVR). METHODS: PI5P4Kα and -ß encoded by PIP4K2A and 2B, respectively, in human ARPE-19 cells were knocked down by stably expressing short hairpin (sh)RNA directed at human PIP4K2A and -2B. In addition, we rescued expression of PI5P4Kα and -ß by re-expressing mouse PIP4K2A and -2B in the PI5P4Kα and -ß knocked-down ARPE-19 cells. Expression of PI5P4Kα and -ß was determined by Western blot and immunofluorescence. The following cellular responses were monitored: cell proliferation, survival, migration, and contraction. Moreover, the cell potential of inducing PVR was examined in a rabbit model of PVR effected by intravitreal cell injection. RESULTS: We found that vitreous enhanced expression of PI5P4Kα and -ß in RPE cells and that knocking down PI5P4Kα and -ß abrogated vitreous-stimulated cell proliferation, survival, migration, and contraction. Re-expression of mouse PIP4Kα and -ß in the human PI5P4Kα and -ß knocked-down cells recovered the loss of vitreous-induced cell contraction. Importantly, suppression of PI5P4Kα and -ß abrogated the pathogenesis of PVR induced by intravitreal cell injection in rabbits. Moreover, we revealed that expression of PI5P4Kα and -ß was abundant in epiretinal membranes from PVR grade C patients. CONCLUSIONS: The findings from this study indicate that PI5P4Kα and -ß could be novel therapeutic targets for the treatment of PVR.

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.