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Retinal nonperfusion (RNP) is an important biomarker for diabetic retinopathy (DR). Data suggest that consistent anti-VEGF pharmacotherapy can slow RNP development. The RECOVERY trial evaluated the impact of aflibercept (Eylea, Regeneron) on RNP among eyes with proliferative DR (PDR).Prospective, randomized clinical trial with treatment crossover in the second year.Eyes with PDR and RNP.At baseline, the subjects were randomized 1:1 to monthly (arm 1) or quarterly (arm 2) intravitreal 2 mg aflibercept. At the beginning of year 2, the treatment arms were crossed over so that the monthly-dosed subjects subsequently received quarterly dosing and the quarterly-dosed subjects subsequently received monthly dosing.Change in total RNP area (mmAmong all subjects, from baseline to year 2, the mean RNP increased from 235 mmThrough year 2 of the RECOVERY trial, both treatment arms experienced significant increases in RNP. Despite the expansion of the RNP area in nearly all subjects, 82% of subjects demonstrated an improvement in DRSS levels from baseline, with no subjects experiencing worsening in DRSS scores.

Purpose The intravitreal injection (IVI) of pharmacologic agents is the most commonly performed ocular procedure and is associated with a host of complications. Most IVI-related complications data are derived from randomized controlled clinical trials, which report a high adverse event rate. The nature of these protocol-driven trials limit their applicability to the diverse circumstances seen in routine clinical practice. The goal of this study was to determine the prevalence of patient-reported IVI-related complications, their risk factors, and the manner in which patients sought treatment at a tertiary eye care center. Design Retrospective, institutional review board–approved study. Participants Forty-four thousand seven hundred thirty-four injections in 5318 unique patients at the Cleveland Clinic Cole Eye Institute from 2012 through 2016. Methods Intravitreal injection. Main Outcome Measures Complication occurrence within 15 days of injection. Results From 2012 through 2016, a total of 44734 injections were performed in 5318 unique patients. Overall, complication rates were low, representing 1.9% of all injections, with 1031 unique complications in 685 patients (12.9%). The most common minor complications, or those not requiring intervention, were irritation (n = 312) and subconjunctival hemorrhage (n = 284). The most common serious complications, or those requiring intervention, were corneal abrasion (n = 46) and iritis (n = 31). Most complications (66%) were managed adequately by a telephone or Epic (Epic Systems Corp., Verona, WI) electronic message encounter only. Importantly, no injection protocol parameter, such as type of anesthesia, preparation, or post-injection medication, increased the risk of a complication. However, a patient’s gender, age, number of previous injections, and provider strongly influenced the risk of patient-reported complications. Conclusions Overall, complication rates seen in routine clinical practice were low compared with clinical trial reporting. Providers should feel confident in the safety and administration of IVI during times when follow-up office visits and resources may be limited. When performing an IVI, factors such as a patient’s gender, age, number of previous injections, and provider must be taken into account to ensure the best possible outcomes.

Purpose To characterize the longitudinal panretinal retinal vascular dynamics in diabetic macular edema (DME) and retinal vein occlusion (RVO) over a 12-month period while being treated with intravitreal aflibercept injections (IAIs). Design Prospective open-label study ( clinicaltrials.gov identifier, NCT02503540 ). Participants Thirty-one treatment-naive eyes with foveal-involving retinal edema secondary to DME and RVO. Methods Participants received 2 mg IAI every 4 weeks for the first 6 months, followed by 2 mg every 8 weeks. Ultra-widefield fluorescein angiography (UWFA; California Optos [Optos, Dunfermline, United Kingdom]) and spectral-domain OCT (Cirrus; Zeiss, Oberkochen, Germany) scans were obtained and analyzed using a novel quantitative assessment platform. Visual acuity, central subfield thickness, and adverse events also were collected. Main Outcome Measures The primary end point was the mean change in panretinal leakage index at month 12 from baseline as measured by UWFA. Results Mean age was 67.1 years. At month 12, visual acuity significantly improved by a mean of 18.4±21.4 letters (P Conclusions Intravitreal aflibercept injections resulted in a dramatic reduction in panretinal leakage index. Panretinal ischemic index did not improve and trended toward worsening.

Purpose Evaluate the impact of intravitreal aflibercept (Eylea, Regeneron, Tarrytown, NY) on retinal non-perfusion (RNP) in eyes with proliferative diabetic retinopathy (PDR). Design Prospective, randomized clinical trial. Subjects Eyes with treatment-naive PDR and extensive RNP without diabetic macular edema. Methods Patients were randomized 1:1 to intravitreal 2-mg aflibercept every-4-weeks (Monthly) or every-12-weeks (Quarterly). Main Outcome Measures The primary outcome measure was change in total RNP area (mm2) from baseline to year 1. Secondary outcomes included ischemic index (ISI), neovascularization area, diabetic retinopathy severity scale (DRSS) scores, visual acuity, central retinal thickness, visual function questionnaire score, and adverse events. Mean and 95% confidence interval (CI) were calculated for each outcome. Results Through 1-year, the Monthly (n=20) & Quarterly (n=20) cohorts received 11.0 & 3.95 mean aflibercept injections, & DRSS scores improved ≥2 steps in 74% & 67% of patients, respectively. Among all patients through 1-year, mean total area of RNP increased from 235 mm2 (CI, 183-288) to 266 mm2 (CI, 299-303; P=0.18) and ISI increased from 25.8% (CI, 20.9-30.7) to 31.9% (CI, 27.6-36.3; P=0.004). RNP outcomes favored monthly-dosing. Mean total RNP increased from 207 mm2 (CI, 143-270) at baseline to 268 mm2 (CI, 212-324; P=0.01) at 1-year in the Quarterly cohort, and remained stable at 264 mm2 at baseline (CI, 176-351) and 1-year (CI, 209-318; P=0.70) in the Monthly cohort (P=0.05, Monthly vs. Quarterly cohorts), with a difference of 56.8 mm2 in total RNP (CI: -47.8-161; P=0.28) at baseline and -4.19 mm2 (CI: -79.4-71.0; P=0.91) at 1-year between the Monthly and Quarterly cohorts. While many eyes demonstrated increased areas of RNP longitudinally (24, 66.7%), this was more common with Quarterly dosing (14, 77.8%), and a proportion of eyes (12, 33.3%) demonstrated localized areas of apparent reperfusion of non-perfused retina, more commonly in the Monthly cohort (8, 44.4%). Conclusions Widespread evidence of retinal reperfusion with aflibercept-dosing of PDR eyes with extensive RNP was not identified, and therefore the primary outcome of RECOVERY was not met; nevertheless, zones of apparent reperfusion were detected in some patients and a dose-response was identified with a reduction of RNP progression with monthly compared to quarterly dosing.

Purpose To evaluate the use of OCT angiography (OCTA) to detect choroidal neovascularization (CNV) in eyes with indeterminate CNV features on conventional imaging. Design Prospective observational study of OCTA in patients undergoing routine spectral-domain optical coherence tomography (SD-OCT) for macular disease. Participants Participants enrolled in the Observational Assessment of Visualizing and Analyzing Vessels with Optical Coherence Tomography Angiography in Retinal Diseases for which CNV was considered as part of a differential diagnosis based on clinical examination, prior imaging, or both, but in whom the presence of CNV was not definitive on SD-OCT and fluorescein angiography (FA) imaging. Methods All patients underwent imaging with the Avanti RTVue XR HD (Optovue, Fremont, CA) and the Cirrus HD-OCT (Zeiss, Oberkochen, Germany) systems. Main Outcome Measures OCT angiography scans were assessed for the presence or absence of CNV. Spectral-domain OCT scans were assessed for the presence of fluid, hyperreflective material, serous pigment epithelial detachment (PED), shallow irregular PED, vitreomacular adhesion, epiretinal membrane, retinal pigment epithelium (RPE) atrophy, and central subfield retinal thickness. Univariate and multivariate logistic regression analyses were performed to identify features on SD-OCT associated with the presence of CNV on OCTA. Results Twenty-nine eyes of 29 patients met the criteria for inclusion. A CNV lesion was detected on OCTA in 8 eyes (28%); 21 eyes (72%) showed negative results for CNV. After adjusting for age, gender, and central subfield retinal thickness, the presence of shallow irregular PED (odds ratio [OR], 148; 95% confidence interval [CI], 3.22–6830; P = 0.011), as well as the combinations of intraretinal fluid and sub-RPE material (OR, 16.8; 95% CI, 1.43–198; P = 0.025) on SD-OCT were associated significantly with the presence of CNV on OCTA. Conclusions OCT angiography enabled the identification of CNV that was otherwise indeterminate with prior imaging in select eyes. The presence of a shallow irregular PED as well as intraretinal fluid combined with sub-RPE material both were associated with the presence of CNV. OCT angiography may be a valuable adjunct to conventional SD-OCT and FA imaging in the detection and surveillance of CNV, particularly in diagnostic dilemmas.

PURPOSE: To evaluate the association of baseline ellipsoid zone (EZ) parameters on optical coherence tomography (OCT) as calculated by a semi-automated computer algorithm with baseline visual acuity in eyes with retinal vein occlusion (RVO). DESIGN: Retrospective consecutive case series. SUBJECTS: Patients affected by RVO presenting from January 2011 to December 2014 METHODS: Baseline demographics, clinical characteristics, and SD-OCT data at presentation were collected. Macular cube scans were exported into a retinal layer analysis software platform and outer retinal parameters were evaluated. Outer retinal/EZ parameters included EZ-retinal pigment epithelium (RPE) volume, central foveal EZ-RPE area, EZ-RPE central subfield thickness (CST), and EZ-RPE central foveal thickness (CFT). In addition, en face EZ mapping features were extracted including percent area with EZ attenuation (i.e., EZ-RPE thickness < 20 μm) and percent area with total EZ loss (i.e., EZ-RPE thickness = 0 μm). MAIN OUTCOME MEASURE: Correlation of EZ parameters and baseline visual acuity (VA). Secondary outcome measures: Correlation of EZ parameters with other clinical characteristics and OCT measures of cube volume, cube average thickness, central subfield thickness. RESULTS: One hundred and twelve eyes were included in this analysis. Mean baseline VA was 56.53 ±17.68 ETDRS letters and was inversely associated with total EZ loss and EZ-RPE attenuation (r= − 0.33 and −0.38 respectively, p0.05). CONCLUSION: Baseline EZ integrity is closely linked to presenting visual acuity in eyes with RVO and macular edema. EZ mapping provides an additional metric for evaluating RVO impact on retinal anatomy and potential function.

Purpose Although intravitreal anti-vascular endothelial growth factor (VEGF) injection has become the mainstay treatment for neovascular age-related macular degeneration (nAMD), emerging studies suggest that anti-VEGF may be correlated with the development of macular atrophy (MA) in chronic therapy. The purpose of the current study is to determine the prevalence and progression of MA in nAMD treated with chronic anti-VEGF in a routine clinical practice. Design Retrospective cohort. Participants Patients with nAMD who were previously treatment-naive and treated with anti-VEGF at the Cole Eye Institute for at least 4 years. Methods This is chart review on anti-VEGF treated patients with nAMD with baseline and yearly follow-up spectral domain-OCT for at least 4 years. Retinal pigment epithelium subillumination analysis was used to automate identification of atrophy. Segmentation errors were manually corrected by 4 expert raters using a standardized grading protocol to quantify MA size. Patient baseline characteristics and treatment course were analyzed to identify predictive factors for the development of MA. Main Outcome Measures MA growth rate and prevalence in cohorts with and without baseline atrophy. Results A total of 79 eyes from 66 patients (79.8±7.4 years, 63% were female) with nAMD and 4 years of follow-up with anti-VEGF injections were identified. The mean baseline visual acuity was 0.48±0.25 logarithm of the minimum angle of resolution (20/60 Snellen equivalent), and the mean final visual acuity was 0.48±0.49 logarithm of the minimum angle of resolution (20/44 Snellen equivalent, P = 0.23). The average number of injections was 19.8±9.8. MA was observed in 12.7% of eyes at baseline with an average annual growth rate of 0.7±0.5 mm2. In eyes without baseline MA, atrophy developed in 53.6% eyes by year 4 with a growth rate of 0.2±0.4 mm2 per year. Multiple linear regression analysis revealed that the progression of MA was positively correlated with age (R = 0.02, P = 0.009). Conclusions More than half of patients with nAMD treated with anti-VEGF injections for 4 years developed new MA. Atrophy progression was most strongly correlated with age, which suggests that baseline disease characteristics may be more predictive of MA progression than cumulative anti-VEGF treatment.

Purpose To assess the efficacy of ranibizumab for persistent diabetic macular edema (DME) previously treated with bevacizumab and compare monthly versus treat-and-extend (TREX) dosing. Design Twelve-month open-label prospective, randomized, comparative dosing study. Participants Twenty-seven participants with persistent foveal-involving DME recently treated with bevacizumab. Methods All participants were to receive 3 initial monthly 0.3-mg ranibizumab injections before randomization to monthly (n = 15) or TREX (n = 12) injection protocols over 12 months. The treatment interval was extended by 2 weeks up to a maximum interval of 12 weeks in the TREX group if central subfield thickness (CST) was 300 μm or less or complete absence of intraretinal or subretinal fluid on the macular cube was observed. The follow-up interval was decreased by 2 weeks if CST increased to 300 μm or more with associated intraretinal or subretinal fluid, or both. Main Outcome Measures Change in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), CST, and adverse events. Results Before study enrollment, participants received an average of 8.6 bevacizumab injections. At month 12, mean ETDRS BCVA improved by +5.3 letters (P Conclusions After conversion to ranibizumab in eyes with persistent DME refractory to bevacizumab, significant functional and anatomic improvements were noted. Visual and anatomic outcomes were similar in TREX and monthly treatment protocols.

Purpose To compare ultra-widefield fluorescein angiography (UWFFA) with simulated conventional fluorescein angiography (FA) to evaluate peripheral pathology and leakage and correlate with clinical activity in patients with uveitis. Design Retrospective chart review. Participants All uveitis patients initially evaluated with UWFFA (Optos 200Tx) between May 2012 and December 2013 were included in this study, including follow-up visits through August 2014. Methods Uveitis status was deemed as having active or inactive inflammation based on clinical examination. Changes to therapy, influence on management, and clinical diagnosis were also noted. UWFFA images were compared with simulated 50-degree FA images to evaluate for peripheral lesions, and leakage location was also graded. Imaging characteristics were then correlated with clinical information. Main Outcome Measures Correlation of leakage on UWFFA with clinical inflammation. Results An initial set of 243 uveitis patients and a total of 1008 eye images were reviewed. When UWFFA was compared with a simulated 50-degree FA image, UWFFA added additional information regarding the presence of peripheral vascular leakage in 25%, peripheral nonperfusion in 14%, peripheral lesions in 6.6%, and peripheral neovascularization in 3.9% of patients. A total of 600 eye images exhibited fluorescein leakage, of which 21% displayed central leakage only, 11% had central and peripheral leakage, 31% had peripheral leakage only, and 37% had diffuse vascular leakage. Based on peripheral findings on widefield angiography, the treatment was changed in 69 patients (28%). Corresponding eye examinations were reviewed for each imaging session, and of 600 eye images with vascular leakage, 567 eye images were also clinically active, which was 95% sensitive as a surrogate indicator of clinical inflammation. Anterior chamber cell and vitreous haze also significantly correlated with leakage on widefield angiography. Conclusions Retinal vascular leakage on UWFFA reveals increased pathology and leakage compared with conventional angiography, which can influence management, and accurately identifies and correlates with active inflammation in patients with uveitis. A more objective measure of inflammation in the form of leakage exhibited on UWFFA may help standardize treatment and care of patients with uveitis.