LONG-TERM USE OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: Although pivotal trials have demonstrated efficacy of anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration, there is a paucity of clinical data about the long-term (>5 years) treatment. METHODS: Retrospective analysis of all patients with neovascular age-related macular degeneration who were actively treated, had received >40 anti-vascular endothelial growth factor injections, and were followed for ≥5 years. Snellen-corrected visual acuity, initial drug choice, and times elapsed between treatments were collected. Rates of endophthalmitis and outcomes of submacular hemorrhage were also evaluated. RESULTS: A total of 88 patients (162 eyes) met the inclusion criteria: the average patient age was 86.3 years with an average follow-up period of 7.6 years. The average total number of injections per eye was 69 (18.0 SD); a total of 11,208 injections were given throughout the study period, and 6 cases (0.05%) of endophthalmitis were observed. Overall, there was a clinical and statistical difference in average Snellen-corrected visual acuity at Injections #2,#3, #4, #5, #6, #10, and #20, as compared with baseline ( P = 0.03, P < 0.01, P = 0.02, P < 0.01, P = 0.01, P = 0.01, P < 0.01, respectively). Patients in the Snellen-corrected visual acuity subgroup 20/20 to 20/40 maintained vision until injection #30. Seven eyes experienced a visually significant submacular hemorrhage. CONCLUSION: This neovascular age-related macular degeneration cohort received on average eight anti-vascular endothelial growth factor injections per year for approximately 8 years; eyes with good (≥20/40) initial baseline vision maintained their visual acuity, whereas those with worse Snellen-corrected visual acuity (≤20/50) had a robust initial improvement that diminished with time. Most patients were maintained on the same initial drug of choice and the rate of endophthalmitis was low.

LONG-TERM VISUAL OUTCOMES AND THE TIMING OF SURGICAL REPAIR OF FOVEA-SPLITTING RHEGMATOGENOUS RETINAL DETACHMENTS.

PURPOSE: To evaluate the visual outcomes and the affect of timing of surgical repair of fovea-splitting rhegmatogenous retinal detachments. METHOD: A retrospective, consecutive cohort from multiple surgeons at a single center. Fovea status (fovea-on, fovea-splitting, or fovea-off) was classified by preoperative optical coherence tomography. The primary outcome measure was the visual acuity at the last follow-up that was further correlated with the timing of surgical repair. RESULTS: One hundred and ninety-five eyes were included with 62 fovea-on, 65 fovea-splitting, and 68 fovea-off detachments. The mean preoperative logarithm of the minimum angle of resolution visual acuity for fovea-on, fovea-splitting, and fovea-off groups was 0.16 ± 0.21, 0.70 ± 0.56, and 1.67 ± 0.87, respectively (P = <0.001). Mean postoperative logarithm of the minimum angle of resolution visual acuity for fovea-on, fovea-splitting, and fovea-off groups were 0.07 ± 0.13, 0.10 ± 0.15, and 0.20 ± 0.22, respectively (P = <0.001). A statistically significant difference in mean postoperative logMAR visual acuity was found between fovea-off and fovea-on groups (P = 0.003) and between fovea-off and fovea-splitting groups (P = 0.013), however not between fovea-on and fovea-splitting groups (P = 0.827). Visual acuity improved when repair was performed earlier after presentation for fovea-on (R = 0.378, P = 0.002) and fovea-off groups (R = 0.277, P = 0.022), but not for the fovea-splitting group (R = 0.089, P = 0.481). CONCLUSION: We described the favorable visual outcomes of surgery for fovea-splitting rhegmatogenous retinal detachment and correlated these with the timing of surgical repair, which may help guide the management of this urgent, vision-threatening condition.

PERIPHERAL RETINAL ANGIOGRAPHIC FINDINGS IN MACULAR TELANGIECTASIS TYPE 2.

PURPOSE: To evaluate the retinal periphery in patients with idiopathic juxtafoveal telangiectasis or macular telangiectasis Type 2 (MacTel2), using widefield fluorescein angiography. METHODS: Single-center, retrospective, observational case series of 50 eyes of 50 patients with MacTel2 and 50 eyes of 50 age-matched controls. RESULTS: Thirty-seven eyes in the MacTel2 group (74%) showed peripheral capillary nonperfusion or dropout, compared with 37 eyes in the control group (74%, P = 1.0). Morphologically, the MacTel2 group trended toward having a higher proportion of pruning-type capillary dropout (44%) compared with controls (28%), but this was not statistically significant (P = 0.12). Patients with MacTel2 had a higher incidence of microaneurysms compared with controls (MacTel2 56%; controls 42%; P = 0.048), independent of age or systemic risk factors. There was no difference in the incidence of venous-venous shunts (MacTel2 10%; controls 10%; P = 1.0), arteriovenous shunts (MacTel2 14%; controls 18%; P = 0.60), venous tortuosity (MacTel2 60%; controls 66%; P = 0.58), or arterial tortuosity (MacTel2 54%; controls 68%; P = 0.20), which was mild in most cases. CONCLUSION: We note a high incidence of peripheral vascular and retinal findings in both patients with MacTel2 and age-matched controls, using widefield fluorescein angiography. Patients with MacTel2 had significantly more microaneurysms, independent of age or other systemic risk factors.

CLINICAL OUTCOMES AND TREATMENT COURSE OF EYES WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION FOLLOWING THE DEVELOPMENT OF ENDOPHTHALMITIS.

PURPOSE: To evaluate the clinical course of patients with neovascular age-related macular degeneration (nAMD) after developing endophthalmitis during their treatment with intravitreal injections. METHODS: Multicenter, retrospective series. RESULTS: From April 2013 to October 2018, 196,598 intravitreal anti-vascular endothelial growth factor (VEGF) injections were performed, with 75 cases of endophthalmitis (incidence 0.0381%). There was no association between intravitreal anti-VEGF drug (P = 0.29), anesthetic method (P = 0.26), povidone concentration (P = 0.22), or any intraprocedure variable and endophthalmitis incidence. Seventy-two patients (96%) were treated with intravitreal tap and inject , while 3 underwent immediate pars plana vitrectomy. After endophthalmitis resolution, 17 patients (22.7%) were not re-treated for nAMD (in 10 cases due to inactive disease; follow-up, 115 ± 8.4 weeks). Patients required less frequent anti-VEGF injections after infection (7.4 ± 0.61 weeks vs. 11.5 ± 1.8 weeks; P = 0.004). Preinfection logarithm of the minimum angle of resolution visual acuity was 0.585 ± 0.053 (∼20/77). It worsened with endophthalmitis (1.67 ± 0.08, ∼20/935; P < 0.001) and again on postendophthalmitis treatment day 1 (1.94 ± 0.064; count fingers; P < 0.001), but improved after reinitiating nAMD therapy (1.02 ± 0.11; ∼20/209; P < 0.001). Better visual acuity on postendophthalmitis week 1 (P = 0.002) and reinitiation of nAMD treatment (P = 0.008) were associated with better final visual acuity, and streptococcal culture with worse visual acuity (P = 0.028). The postendophthalmitis treatment interval was associated with the anti-VEGF drug used (aflibercept = ranibizumab > bevacizumab; P < 0.001). CONCLUSION: Patients with nAMD required fewer injections after endophthalmitis, suggesting a biological change in disease activity. Neovascular age-related macular degeneration became quiescent in 13.3% of eyes. Most achieved better outcomes with anti-VEGF reinitiation.

The retina revolution: signaling pathway therapies, genetic therapies, mitochondrial therapies, artificial intelligence.

PURPOSE OF REVIEW: The aim of this article is to review and discuss the history, current state, and future implications of promising biomedical offerings in the field of retina. RECENT FINDINGS: The technologies discussed are some of the more recent promising biomedical developments within the field of retina. There is a US Food and Drug Administration-approved gene therapy product and artificial intelligence device for retina, with many other offerings in the pipeline. SUMMARY: Signaling pathway therapies, genetic therapies, mitochondrial therapies, and artificial intelligence have shaped retina care as we know it and are poised to further impact the future of retina care. Retina specialists have the privilege and responsibility of shaping this future for the visual health of current and future generations.

ETIOLOGY AND CLINICAL CHARACTERISTICS OF MACULAR EDEMA IN PATIENTS WITH FAMILIAL EXUDATIVE VITREORETINOPATHY.

PURPOSE: To describe the etiology and clinical characteristics of macular edema (ME) in patients with familial exudative vitreoretinopathy. METHODS: Observational, retrospective case series of 30 patients (34 eyes) with ME and familial exudative vitreoretinopathy who underwent spectral-domain optical coherence tomography imaging between 2009 and 2016. Baseline and follow-up optical coherence tomographies were correlated with color fundus photography and fluorescein angiography. RESULTS: The average age was 20.6 years (6.6-68.7). Eighteen eyes exhibited cystoid ME (52.9%), 14 noncystoid ME (41.2%), and 2 eyes (5.9%) with both. Macular edema was foveal in 52.9% (n = 18). Eighteen of 24 eyes (64.3%) with an available fluorescein angiography showed leakage from ME. The most common structural feature was posterior hyaloidal organization/contraction (n = 15). Sixteen eyes were treated with topical or intravitreal steroids (n = 6), intravitreal anti-vascular endothelial growth factor (n = 3), or pars plana vitrectomy with membrane stripping (n = 7). There was no difference between mean preoperative and postoperative LogMAR visual acuity (0.63 [20/85] vs. 0.87 [20/148], P = 0.35) after vitrectomy despite a statistical improvement in the mean central foveal thickness (596 mm vs. 303 mm, P = 0.04). CONCLUSION: Macular edema in familial exudative vitreoretinopathy occurs most commonly because of traction. Vitrectomy is effective for relieving tractional forces with anatomical improvement.

SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING OF THE MACULA AND VITREOMACULAR INTERFACE IN PERSISTENT FETAL VASCULATURE SYNDROME WITH POSTERIOR INVOLVEMENT.

PURPOSE: To describe the microstructural features of the macula and vitreomacular interface in persistent fetal vasculature syndrome (PFVS) with posterior involvement managed with early vitrectomy or with observation, with functional correlation. METHODS: We retrospectively identified 45 consecutive pediatric patients with PFVS with posterior involvement treated from 2005 to 2016. The eyes that could be imaged with spectral domain optical coherence tomography were included, and images were correlated with best-corrected visual acuity. RESULTS: Thirty-eight imaging sessions were performed on 10 eyes from 9 patients, including 7 that had been managed with vitrectomy for PFVS-related tractional retinal detachment, and 3 that had been observed. Mean age of the patients who were imaged was 9.1 years and their average length of follow-up was 5.9 years. Best-corrected visual acuities of the eyes imaged ranged from 20/30 to count fingers, with mean best-corrected visual acuity 20/163. All eyes imaged had microstructural anomalies identified. The main anomalous features included posterior hyaloidal organization, vitreoretinal traction, vitreopapillary traction, diminished foveal contour, foveal displacement, and disruption of the ellipsoid zone. Posterior hyaloidal organization (P = 0.043), diminished foveal contour (P = 0.019), and disruption of the ellipsoid zone (P = 0.014) were associated with worse best-corrected visual acuity. CONCLUSION: Macular and vitreomacular interface anomalies were identified in all pediatric patients with posterior PFVS imaged with spectral domain optical coherence tomography. These microstructural findings, together with functional measures, may inform the diagnosis and management of PFVS with posterior involvement.

Glaucoma after Lens-Sparing Vitrectomy for Advanced Retinopathy of Prematurity.

PURPOSE: To report the incidence of, and factors related to, glaucoma after lens-sparing vitrectomy (LSV) surgery in advanced retinopathy of prematurity (ROP). DESIGN: Retrospective case series at a single tertiary referral pediatric vitreoretinal practice. PARTICIPANTS: Four hundred and one eyes from 270 patients were included. METHODS: The medical records of patients who underwent LSV for stage 4A, 4B, and 5 ROP were retrospectively reviewed. Data were collected from patient charts including gender, gestational age at birth, birthweight, stage of ROP at presentation, prior treatment (laser or cryotherapy), subsequent retinal surgeries, presence of glaucoma, time to glaucoma (interval between LSV and the onset of glaucoma), date of lensectomy (if performed), and retinal attachment status at last visit. Lensectomy was considered as a time-dependent covariate in the analysis. MAIN OUTCOME MEASURES: Incidence of glaucoma and potential risk factors for time to glaucoma. RESULTS: Among 401 eyes with advanced ROP, 40 eyes (10.0%) had glaucoma during a mean of 3.06±4.11 years of follow-up. The incidence of glaucoma was 6.9% (17/247) in stage 4A, 12.0% (16/133) in stage 4B, and 33.3% (7/21) in stage 5 ROP. Twenty-one percent of eyes (87/401) required lensectomy at a mean of 1.23±2.19 years after LSV. In univariate analysis, having stage 5 ROP (vs. stage 4 ROP) and presence of lensectomy were found to be significantly associated with time to glaucoma (hazard ratio = 6.76, 95% confidence interval = 2.19-20.88, P = 0.001; hazard ratio = 3.06, 95% confidence interval = 1.56-6.0, P = 0.001, respectively). In multivariate analysis, lensectomy was the only significant independent factor associated with time to glaucoma (hazard ratio = 2.76, 95% confidence interval = 1.371-5.581, P = 0.004). CONCLUSIONS: Patients with more severe ROP had a higher incidence of glaucoma after lens-sparing vitrectomy. If a patient required lensectomy owing to progression of ROP and/or presence of lens opacity, then the hazard of having glaucoma significantly increased compared with those without lensectomy.

PROGRESSIVE RETINAL DETACHMENT IN INFANTS WITH RETINOPATHY OF PREMATURITY TREATED WITH INTRAVITREAL BEVACIZUMAB OR RANIBIZUMAB.

PURPOSE: Fibrovascular contraction and tractional retinal detachment (TRD) are recognized complications associated with the use of anti-vascular endothelial growth factor agents in vasoproliferative vitreoretinopathies. The authors characterize TRDs that developed after intravitreal bevacizumab or ranibizumab therapy for vascularly active retinopathy of prematurity. METHODS: This is an international, multicenter, interventional, retrospective, case series. Thirty-five eyes from 23 infants were included. Inclusion required anti-vascular endothelial growth factor treatment of Type 1 retinopathy of prematurity with progression to TRD. RESULTS: Mean gestational age was 26 ± 2 weeks, and mean birth weight was 873 ± 341 g. Mean postmenstrual age on the day of injection was 35 ± 2 weeks. Retinal detachment was noted a mean of 70 days (median, 34; range, 4-335) after injection. Eleven percent detached within 1 week, 23% within 2 weeks, and 49% within 4 weeks. The highest stage of retinopathy of prematurity noted was 4A in 29%, 4B in 37%, and 5 in 34% of eyes. Time to RD negatively correlated with postmenstrual age at the time of injection (Rho = -0.54; P < 0.01). Three TRD configurations were observed: 1) conventional peripheral elevated ridge or volcano-shaped Stage 5 detachment, 2) midperipheral detachment with tight circumferential vectors, and 3) very posterior detachment with prepapillary contraction. Full or partial reattachment was achieved with surgical intervention in 86% of eyes. CONCLUSION: Progressive atypical TRD may occur after anti-vascular endothelial growth factor injections for retinopathy of prematurity. The configuration of the detachment varies with the extent of primary retinal vascularization present at the time of treatment.

Norrin treatment improves ganglion cell survival in an oxygen-induced retinopathy model of retinal ischemia.

Treatment of a mouse model of oxygen-induced retinopathy (OIR) with recombinant human Norrin (Norrie Disease Protein, gene: NDP) accelerates regrowth of the microvasculature into central ischemic regions of the neural retina, which are generated after treatment with 75% oxygen. While this reduces the average duration and severity of ischemia overall, we do not know if this accelerated recovery of the microvasculature results in any significant survival of retinal ganglion cells (RGCs). The purpose of this study was to investigate ganglion cell survival with and without the intravitreal injection of Norrin in the murine model of oxygen induced retinopathy (OIR), using two strains of mice: C57BL/6J and Thy1-YFP mice. Intravitreal injections of Norrin or vehicle were done after five days of exposure to 75% oxygen from ages P7 to P12. The C57BL/J mice were followed by Spectral-Domain Optical Coherence Tomography (SD-OCT), and the average nerve fiber layer (NFL) and inner-plexiform layer (IPL) thicknesses were measured at twenty-four locations per retina at P42. Additionally, some C57BL/J retinas were flat mounted and immunostained for the RGC marker, Brn3a, to compare the population density of surviving retinal ganglion cells. Using homozygous Thy1-YFP mice, single intrinsically fluorescent RGCs were imaged in live animals with a Micron-III imaging system at ages P21, 28 and P42. The relative percentage of YFP-fluorescent RGCs with dendritic arbors were compared. At age P42, the NFL was thicker in Norrin-injected OIR eyes, 14.4 µm, compared to Vehicle-injected OIR eyes, 13.3 µm (p = 0.01). In the superior retina, the average thickness of the IPL was greater in Norrin-injected OIR eyes, 37.7 µm, compared to Vehicle-injected OIR eyes, 34.6 µm (p = 0.04). Retinas from Norrin injected OIR mice had significantly more surviving RGCs (p = 0.03) than vehicle-injected mice. Based upon NFL thickness and counts of RGCs, we conclude that Norrin treatment, early in the ischemic phase, increased the relative population density of surviving RGCs in the central retinas of OIR mice.

THE CUTTING EDGE OF RETINOPATHY OF PREMATURITY CARE: Expanding the Boundaries of Diagnosis and Treatment.

PURPOSE: To discuss the latest advances and controversies in the diagnosis and care of infants with retinopathy of prematurity (ROP). METHODS: Literature review. RESULTS: Retinopathy of prematurity remains a major global issue. Industrialized nations now treat profoundly premature infants with posterior and aggressive disease, and middle-income nations are experiencing ROP epidemics. Remote digital imaging may address the decreasing ratio of ROP providers to premature infants, in addition to improving patient care. Widefield angiography, optical coherence tomography, and the Wnt signaling pathway have provided new insights into ROP pathogenesis. Anti-vascular endothelial growth factor treatment is increasing in popularity, but the dearth of information to guide dosing, unpredictable reactivation, persistent vascular abnormalities, the "crunch" phenomenon, and the presently unknown effects of systemic vascular endothelial growth factor suppression remain issues to continue investigating. Neurodevelopmental delay has been raised as a potential consequence, but the evidence currently is weak. Vitrectomy is the treatment of choice for Stages 4 and 5. Illumination techniques, ab interno incisions, plasmin-assisted vitrectomy, staged surgery in the interest of corneal clearing for advanced Stage 5, and immediate sequential bilateral vitreoretinal surgery, are useful techniques. CONCLUSION: We are making progress in ROP management. Our goal as clinicians is to continue expanding the boundaries of our abilities to keep this blinding disease in check globally.

Evaluation of Screening for Retinopathy of Prematurity by ROPtool or a Lay Reader.

PURPOSE: To determine if (1) tortuosity assessment by a computer program (ROPtool, developed at the University of North Carolina, Chapel Hill, and Duke University, and licensed by FocusROP) that traces retinal blood vessels and (2) assessment by a lay reader are comparable with assessment by a panel of 3 retinopathy of prematurity (ROP) experts for remote clinical grading of vascular abnormalities such as plus disease. DESIGN: Validity and reliability analysis of diagnostic tools. PARTICIPANTS: Three hundred thirty-five fundus images of prematurely born infants. METHODS: Three hundred thirty-five fundus images of prematurely born infants were obtained by neonatal intensive care unit nurses. A panel of 3 ROP experts graded 84 images showing vascular dilatation, tortuosity, or both and 251 images showing no evidence of vascular abnormalities. These images were sent electronically to an experienced lay reader who independently graded them for vascular abnormalities. The images also were analyzed using the ROPtool, which assigns a numerical value to the level of vascular abnormality and tortuosity present in each of 4 quadrants or sectors. The ROPtool measurements of vascular abnormalities were graded and compared with expert panel grades with a receiver operating characteristic (ROC) curve. Grades between human readers were cross-tabulated. The area under the ROC curve was calculated for the ROPtool, and sensitivity and specificity were computed for the lay reader. MAIN OUTCOME MEASURES: Measurements of vascular abnormalities by ROPtool and grading of vascular abnormalities by 3 ROP experts and 1 experienced lay reader. RESULTS: The ROC curve for ROPtool's tortuosity assessment had an area under the ROC curve of 0.917. Using a threshold value of 4.97 for the second most tortuous quadrant, ROPtool's sensitivity was 91% and its specificity was 82%. Lay reader sensitivity and specificity were 99% and 73%, respectively, and had high reliability (κ, 0.87) in repeated measurements. CONCLUSIONS: ROPtool had very good accuracy for detection of vascular abnormalities suggestive of plus disease when compared with expert physician graders. The lay reader's results showed excellent sensitivity and good specificity when compared with those of the expert graders. These options for remote reading of images to detect vascular abnormalities deserve consideration in the quest to use telemedicine with remote reading for efficient delivery of high-quality care and to detect infants requiring bedside examination.

Plus Disease in Retinopathy of Prematurity: A Continuous Spectrum of Vascular Abnormality as a Basis of Diagnostic Variability.

PURPOSE: To identify patterns of interexpert discrepancy in plus disease diagnosis in retinopathy of prematurity (ROP). DESIGN: We developed 2 datasets of clinical images as part of the Imaging and Informatics in ROP study and determined a consensus reference standard diagnosis (RSD) for each image based on 3 independent image graders and the clinical examination results. We recruited 8 expert ROP clinicians to classify these images and compared the distribution of classifications between experts and the RSD. PARTICIPANTS: Eight participating experts with more than 10 years of clinical ROP experience and more than 5 peer-reviewed ROP publications who analyzed images obtained during routine ROP screening in neonatal intensive care units. METHODS: Expert classification of images of plus disease in ROP. MAIN OUTCOME MEASURES: Interexpert agreement (weighted κ statistic) and agreement and bias on ordinal classification between experts (analysis of variance [ANOVA]) and the RSD (percent agreement). RESULTS: There was variable interexpert agreement on diagnostic classifications between the 8 experts and the RSD (weighted κ, 0-0.75; mean, 0.30). The RSD agreement ranged from 80% to 94% for the dataset of 100 images and from 29% to 79% for the dataset of 34 images. However, when images were ranked in order of disease severity (by average expert classification), the pattern of expert classification revealed a consistent systematic bias for each expert consistent with unique cut points for the diagnosis of plus disease and preplus disease. The 2-way ANOVA model suggested a highly significant effect of both image and user on the average score (dataset A: P < 0.05 and adjusted R2 = 0.82; and dataset B: P < 0.05 and adjusted R2 = 0.6615). CONCLUSIONS: There is wide variability in the classification of plus disease by ROP experts, which occurs because experts have different cut points for the amounts of vascular abnormality required for presence of plus and preplus disease. This has important implications for research, teaching, and patient care for ROP and suggests that a continuous ROP plus disease severity score may reflect more accurately the behavior of expert ROP clinicians and may better standardize classification in the future.

Plus Disease in Retinopathy of Prematurity: Improving Diagnosis by Ranking Disease Severity and Using Quantitative Image Analysis.

PURPOSE: To determine expert agreement on relative retinopathy of prematurity (ROP) disease severity and whether computer-based image analysis can model relative disease severity, and to propose consideration of a more continuous severity score for ROP. DESIGN: We developed 2 databases of clinical images of varying disease severity (100 images and 34 images) as part of the Imaging and Informatics in ROP (i-ROP) cohort study and recruited expert physician, nonexpert physician, and nonphysician graders to classify and perform pairwise comparisons on both databases. PARTICIPANTS: Six participating expert ROP clinician-scientists, each with a minimum of 10 years of clinical ROP experience and 5 ROP publications, and 5 image graders (3 physicians and 2 nonphysician graders) who analyzed images that were obtained during routine ROP screening in neonatal intensive care units. METHODS: Images in both databases were ranked by average disease classification (classification ranking), by pairwise comparison using the Elo rating method (comparison ranking), and by correlation with the i-ROP computer-based image analysis system. MAIN OUTCOME MEASURES: Interexpert agreement (weighted κ statistic) compared with the correlation coefficient (CC) between experts on pairwise comparisons and correlation between expert rankings and computer-based image analysis modeling. RESULTS: There was variable interexpert agreement on diagnostic classification of disease (plus, preplus, or normal) among the 6 experts (mean weighted κ, 0.27; range, 0.06-0.63), but good correlation between experts on comparison ranking of disease severity (mean CC, 0.84; range, 0.74-0.93) on the set of 34 images. Comparison ranking provided a severity ranking that was in good agreement with ranking obtained by classification ranking (CC, 0.92). Comparison ranking on the larger dataset by both expert and nonexpert graders demonstrated good correlation (mean CC, 0.97; range, 0.95-0.98). The i-ROP system was able to model this continuous severity with good correlation (CC, 0.86). CONCLUSIONS: Experts diagnose plus disease on a continuum, with poor absolute agreement on classification but good relative agreement on disease severity. These results suggest that the use of pairwise rankings and a continuous severity score, such as that provided by the i-ROP system, may improve agreement on disease severity in the future.

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.

A RANDOMIZED, PLACEBO-CONTROLLED STUDY OF INTRAVITREAL OCRIPLASMIN IN PEDIATRIC PATIENTS SCHEDULED FOR VITRECTOMY.

PURPOSE: To evaluate safety and preliminary efficacy of 175 µg of intravitreal ocriplasmin in pediatric patients scheduled for vitrectomy. METHODS: Based on a single-center, prospective, randomized, placebo-controlled, and double-masked Phase 2 study, 22 pediatric patients scheduled for vitrectomy were randomized 2:1 to 175-µg ocriplasmin injection or placebo. Treatment was administered midvitreous 30 minutes to 60 minutes before vitrectomy. Safety was assessed by reported adverse events (AEs), ophthalmologic examinations, fundus photography, and fluorescein angiography. The primary efficacy endpoint was the proportion of eyes with total macular posterior vitreous detachment before vitrectomy or after application of suction. Secondary endpoints included vitreous liquefaction assessment before vitrectomy and immediate postoperative retinal reattachment. RESULTS: All patients experienced at least 1 AE. Most AEs were ocular and occurred in the study eye. Serious AEs were reported for 2 of 16 eyes (3.4%) in the ocriplasmin group and 2 of 8 eyes (11.1%) in the placebo group. One case of lens subluxation due to zonular disruption was observed in the ocriplasmin group. A clear efficacy signal was not observed. CONCLUSION: Intravitreal injection of 175 µg of ocriplasmin was tolerated in pediatric patients before vitrectomy; however, the small sample size in this study precluded adequate efficacy comparisons. AEs reported were consistent with those anticipated in pediatric patients.

WIDE-FIELD IMAGING OF NONEXUDATIVE AND EXUDATIVE CONGENITAL X-LINKED RETINOSCHISIS.

PURPOSE: To describe wide-field imaging features of patients with congenital X-linked retinoschisis. METHODS: This is a retrospective nonconsecutive series of 36 eyes from 18 patients with congenital X-linked retinoschisis from 2008 to 2014. Wide-field color fundus photographs, optical coherence tomography images, and wide-field fluorescein angiography images were reviewed. Patients were classified to have either exudative or nonexudative retinoschisis based on the presence or absence of lipid exudates. RESULTS: Eleven eyes exhibited exudative retinoschisis (30%), whereas the remaining were nonexudative. Exudative disease occurred more commonly in older patients (14.4 vs. 4.0 years; P < 0.001). The most frequent location of exudation was the macula. Subretinal hemorrhage was present in 4 eyes (11%). Macular findings included an atypical foveal avascular zone in 7 eyes (19%) and submacular fibrosis or retinal folds in 6 eyes (17%). Peripheral characteristics included fibrosis or folds (11%), bridging vessels (8%), and vascular sheathing (8%). Thirteen of the 22 eyes (59%) demonstrated leakage on fluorescein angiography. CONCLUSION: Exudation may be more common in congenital X-linked retinoschisis than previously recognized. The presence of exudates with concurrent angiographic leakage suggests that exudation may be due to chronic vascular permeability and not solely caused by intraschisis hemorrhage, which has been classically described.

Familial Exudative Vitreoretinopathy: Spectral-Domain Optical Coherence Tomography of the Vitreoretinal Interface, Retina, and Choroid.

PURPOSE: The in vivo microstructural features of familial exudative vitreoretinopathy (FEVR) have not been well described. We present new anatomic features of FEVR with functional and genetic correlations. DESIGN: Consecutive, retrospective, observational case series. PARTICIPANTS: Patients with FEVR treated from 2009 to 2014. METHODS: We identified 346 patients with FEVR. Those imaged with spectral-domain optical coherence tomography (SD OCT) with or without enhanced depth imaging (EDI) were included, and images were correlated with best-corrected visual acuity (BCVA), widefield angiography, fundus autofluorescence (AF), and wnt signaling pathway mutations. MAIN OUTCOME MEASURES: Exploratory SD OCT findings and BCVA. RESULTS: A total of 225 imaging sessions were acquired in 74 eyes from 41 patients. Mean age was 19.0 years. Sixty-seven eyes (91%) had interpretable images, of which 50 (75%) had anomalous microstructural findings; all eyes with FEVR severity of stage 2 or greater had abnormalities. A broad spectrum of features were identified: various forms of posterior hyaloidal organization, vitreomacular traction (VMT), vitreopapillary traction, vitreo-fold traction, vitreo-laser scar adhesion, diminished foveal contour, persistent fetal foveal architecture, cystoid macular edema (CME), intraretinal exudates and subretinal lipid aggregation, dry or edematous radial folds, and disruption of the ellipsoid zone. Mean foveal, central macular, and choroidal thicknesses were 305±145 µm, 337±160 µm, and 216±64 µm, respectively. In stages 1 to 2, greater foveal and central macular thicknesses (Rho=0.493, 0.544, respectively; both P<0.001) correlated with poorer BCVA, but not choroidal thickness (Rho=0.032; P=0.868). Posterior hyaloidal organization (P<0.001), VMT (P<0.001), CME (P<0.001), exudation (P<0.001), and disruption of the ellipsoid zone (P<0.001) were associated with poorer BCVA. Disruption of the ellipsoid zone (ß=0.699; P<0.001) and posterior hyaloidal organization (ß=0.289; P=0.011) retained significance in multivariate modeling (R2=0.627; P<0.001). Spectral-domain OCT detected all cases of angiographic edema and areas of outer retinal dysfunction that were hypoautofluorescent on AF. Microstructural-genetic associations were not identified. CONCLUSIONS: Spectral-domain OCT imaging identified microstructural anomalies in the majority of patients with FEVR.

Frizzled-4 Variations Associated with Retinopathy and Intrauterine Growth Retardation: A Potential Marker for Prematurity and Retinopathy.

PURPOSE: To present the association between mutations affecting the Wnt-signaling receptor protein (FZD4), inherited vitreoretinopathies, and retinopathy of prematurity (ROP). DESIGN: Retrospective analysis of prospective samples at a tertiary referral center. PARTICIPANTS: Patients referred to our practice for management of a variety of pediatric vitreoretinopathies were offered participation in an ophthalmic biobank (421 participants with vitreoretinopathies were included in this study). Full-term healthy infants (n = 98) were recruited to the study as controls. METHODS: Patients with various vitreoretinopathies were prospectively enrolled in an ophthalmic biobank, approved by the Human Investigation Committee at William Beaumont Hospital. Retrospective genetic analysis of the FZD4 gene was performed (Sanger sequencing). Participants with a diagnosis of familial exudative vitreoretinopathy (FEVR), Norrie disease, Coats' disease, bilateral persistent fetal vasculature, and ROP were reviewed for the presence of a FZD4 variant. Data retrieval included status of retinopathy (including staging when possible), gestational age (GA), birth weight (BW) (when available), and family and birth histories. MAIN OUTCOME MEASURES: The association of FZD4 variants with the presence of vitreoretinopathy. RESULTS: The sequence variation p.[P33S(;)P168S] is the most prevalent FZD4 variant and is statistically significant for ROP and FEVR (P = 4.6E-04 and P = 2.4E-03, respectively) compared with full-term newborns (P = 1.7E-01). In addition, infants expressing the sequence variation tended to have significantly lower BWs for respective GA (P = 0.04). This suggests that the FZD4 p.[P33S(;)P168S] variant may be a risk factor for retinopathy and restricted intrauterine growth. CONCLUSIONS: Testing for FZD4 gene mutations is useful in patients with suspected FEVR and ROP. The relatively high prevalence of the p.[P33S(;)P168S] variant in ROP and intrauterine growth restriction suggests that it also may be a marker for increased risk of developing ROP and preterm birth.