Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3.

PURPOSE: To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD). DESIGN: Consensus meeting. PARTICIPANTS: Panel of retina specialists, image reading center experts, retinal histologists, and optics engineers. METHODS: As part of the Classification of Atrophy Meetings (CAM) program, an international group of experts surveyed the existing literature, performed a masked analysis of longitudinal multimodal imaging for a series of eyes with AMD, and reviewed the results of this analysis to define areas of agreement and disagreement. Through consensus discussions at 3 meetings over 12 months, a classification system based on OCT was proposed for atrophy secondary to AMD. Specific criteria were defined to establish the presence of atrophy. MAIN OUTCOME MEASURES: A consensus classification system for atrophy and OCT-based criteria to identify atrophy. RESULTS: OCT was proposed as the reference standard or base imaging method to diagnose and stage atrophy. Other methods, including fundus autofluorescence, near-infrared reflectance, and color imaging, provided complementary and confirmatory information. Recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages, 4 terms and histologic candidates were proposed: complete RPE and outer retinal atrophy (cRORA), incomplete RPE and outer retinal atrophy, complete outer retinal atrophy, and incomplete outer retinal atrophy. Specific OCT criteria to diagnose cRORA were proposed: (1) a region of hypertransmission of at least 250 µm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 µm in diameter, (3) evidence of overlying photoreceptor degeneration, and (4) absence of scrolled RPE or other signs of an RPE tear. CONCLUSIONS: A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete representation of changes that occur in AMD than can be detected using color fundus photography alone. Longitudinal information is required to validate the implied risk of vision loss associated with these terms. This system will enable such future studies to be undertaken using consistent definitions.

CHANGES IN DIABETIC RETINOPATHY SEVERITY WHEN TREATING DIABETIC MACULAR EDEMA WITH RANIBIZUMAB: DRCR.net Protocol I 5-Year Report.

PURPOSE: To explore 5-year changes from baseline in diabetic retinopathy severity among eyes treated with ranibizumab for diabetic macular edema. METHODS: Diabetic retinopathy severity was assessed from study visits and annual fundus photographs among participants in Protocol I (DRCR.net). The proportion of eyes that improved at annual examinations and the cumulative probability of worsening through 5 years were estimated. RESULTS: Among 235 participants with nonproliferative diabetic retinopathy at baseline, there were 29%, 28%, and 32% of eyes with retinopathy improvement at 1, 3, and 5 years, respectively. Among 111 participants with proliferative diabetic retinopathy, corresponding improvement percentages were 38%, 35%, and 23%. The 5-year cumulative probability of worsening was 18% (95% CI: 14%-25%) among nonproliferative diabetic retinopathy eyes and 31% (95% CI: 23%-42%) among proliferative diabetic retinopathy eyes (P = 0.01). In Years 1, 3, and 5, the mean (SD) number of ranibizumab injections was 8.1 (2.5), 2.2 (2.6), and 1.8 (2.6) for nonproliferative diabetic retinopathy eyes, and 9.0 (2.8), 2.3 (2.9), and 1.7 (2.6) for proliferative diabetic retinopathy eyes, respectively. Proportions with improvement or rates of worsening did not change with time. CONCLUSION: Individuals receiving ranibizumab therapy for diabetic macular edema may have favorable changes in DR severity throughout a 5-year period concomitant with sequential reduction in anti-vascular endothelial growth factor therapy.

Peripheral Retinal Changes Associated with Age-Related Macular Degeneration in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 12 by the Age-Related Eye Disease Study 2 Optos PEripheral RetinA (OPERA) Study Research Group.

PURPOSE: To compare rates of peripheral retinal changes in Age-Related Eye Disease Study 2 (AREDS2) participants with at least intermediate age-related macular degeneration (AMD) with control subjects without intermediate age-related changes (large drusen). DESIGN: Cross-sectional evaluation of clinic-based patients enrolled in AREDS2 and a prospective study. PARTICIPANTS: Participants from prospective studies. METHODS: The 200° pseudocolor and fundus autofluorescence (FAF) images were captured on the Optos 200 Tx Ultrawide-field device (Optos, Dunfermline, Scotland) by centering on the fovea and then steering superiorly and inferiorly. The montaged images were graded at a reading center with the images divided into 3 zones (zone 1 [posterior pole], zone 2 [midperiphery], and zone 3 [far periphery]) to document the presence of peripheral lesions. MAIN OUTCOME MEASURES: Peripheral retinal lesions: drusen, hypopigmentary/hyperpigmentary changes, reticular pseudodrusen, senile reticular pigmentary changes, cobblestone degeneration, and FAF abnormalities. RESULTS: A total of 484 (951 eyes) AREDS2 participants with AMD (cases) and 89 (163 eyes) controls without AMD had gradable color and FAF images. In zones 2 and 3, neovascularization and geographic atrophy (GA) were present, ranging from 0.4% to 6% in eyes of cases, respectively, and GA was present in 1% of eyes of controls. Drusen were detected in 97%, 78%, and 64% of eyes of cases and 48%, 21%, and 9% of eyes of controls in zones 2 and 3 superior and 3 inferior, respectively (P < 0.001 for all). Peripheral reticular pseudodrusen were seen in 15%. Senile reticular pigmentary change was the predominant peripheral change seen in 48% of cases and 16% of controls in zone 2 (P < 0.001). Nonreticular pigment changes were less frequent in the periphery than in the posterior pole (46% vs. 76%) and negligible in controls. CONCLUSIONS: Peripheral retinal changes are more prevalent in eyes with AMD than in control eyes. Drusen are seen in a majority of eyes with AMD in both the mid and far periphery, whereas pigment changes and features of advanced AMD are less frequent. Age-related macular degeneration may be more than a "macular" condition but one that involves the entire retina. Future longitudinal studies of peripheral changes in AMD and their impact on visual function may contribute to understanding AMD pathogenesis.

RELATIONSHIP BETWEEN RETINAL THICKNESS AND VISUAL ACUITY IN EYES WITH RETINAL VEIN OCCLUSION TREATED WITH DEXAMETHASONE IMPLANT.

PURPOSE: To evaluate the relationship between changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) in eyes from two clinical trials of dexamethasone intravitreal implant 0.7 mg for macular edema after branch or central retinal vein occlusion. METHODS: Patients with vision loss as a result of macular edema (≥6-week duration) after branch retinal vein occlusion or central retinal vein occlusion were treated with a single dexamethasone intravitreal implant or sham. Prospectively defined outcomes included BCVA and CRT (as assessed by optical coherence tomography). RESULTS: There was a modest but statistically significant negative linear correlation between changes in CRT and changes in BCVA in both treatment groups at Days 90 and 180 (correlation coefficient: -0.23 to -0.34; P < 0.001). Improvements in BCVA at Day 180 were significantly greater (P < 0.001) in eyes that achieved and maintained CRT ≤250 µm from Day 90 to 180 (mean BCVA improvement: 14 letters; 49% of eyes with ≥15-letter gain) than in eyes that never achieved CRT ≤250 µm (mean BCVA improvement: 2 letters; 13% of eyes with ≥15-letter gain). CONCLUSION: The greatest improvements in BCVA were seen in eyes that achieved and maintained the greatest improvements in CRT.

Darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in diabetic macular edema: a 3-month placebo-controlled study.

PURPOSE: To investigate the potential of lipoprotein-associated phospholipase A2 inhibition as a novel mechanism to reduce edema and improve vision in center-involved diabetic macular edema (DME). DESIGN: Prospective, multicenter, randomized, double-masked, placebo-controlled phase IIa study. PARTICIPANTS: Fifty-four center-involved DME patients randomized 2:1 to receive darapladib (n = 36) or placebo (n = 18). METHODS: Darapladib 160 mg or placebo monotherapy was administered orally once daily for 3 months, and patients were followed up monthly for 4 months. MAIN OUTCOME MEASURES: Mean change from baseline in best-corrected visual acuity (BCVA) and the center subfield and center point of the study eye at month 3 as determined by spectral-domain optical coherence tomography. RESULTS: Five patients in the study received intravitreal anti-vascular endothelial growth factor rescue therapy before the day 90 assessment, 2 of 36 (6%) in the darapladib arm and 3 of 18 (17%) in the placebo arm. Administration of 160 mg darapladib for 3 months resulted in statistically significant mean improvements, from baseline to month 3, in BCVA of 4.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% confidence interval [CI], 2.3-5.8) and of 57 µm in central subfield thickness (95% CI, -84 to -30) in the study eyes. An increase in BCVA of 1.7 ETDRS letters (95% CI, -1.0 to 4.4) and a decrease in center subfield thickness of 34 µm (95% CI, -75 to 6.8) for the placebo group were not significant. No ocular severe adverse events (SAEs) or SAEs considered related to darapladib were reported. One SAE of myocardial infarction, not considered related to darapladib, was reported, and 1 SAE of severe diarrhea was reported in a placebo patient, subsequently withdrawn from the study. Study eye ocular adverse events (AEs) and nonocular AEs were similar between treatment groups. CONCLUSIONS: Once-daily oral darapladib administered for 3 months demonstrated modest improvements in vision and macular edema that warrant additional investigation of this novel lipoprotein-associated phospholipase A2 inhibitory mechanism for the treatment of DME.

The epidemiology of vitreoretinal interface abnormalities as detected by spectral-domain optical coherence tomography: the beaver dam eye study.

PURPOSE: To describe the prevalence and interrelationships of epiretinal membranes (ERMs), vitreomacular traction (VMT), macular cysts, paravascular cysts (PVCs), lamellar macular holes (LMHs), full-thickness macular holes (FTMHs), and visual impairment in a population-based study of older adults. DESIGN: Cross-sectional study. PARTICIPANTS: There were 1913 participants aged 63 to 102 years at the 20-year Beaver Dam Eye Study follow-up examination in 2008-2010, of whom 1540 (2980 eyes) had gradable spectral-domain optical coherence tomography (SD OCT) scans of the macula in at least 1 eye. METHODS: The presence of ERMs and other retinal lesions was determined by standardized grading of macular SD OCT scans and photographs of 3 standard fields. MAIN OUTCOME MEASURES: Epiretinal membranes, VMT, macular cysts, PVCs, LMHs, FTMHs, and visual impairment. RESULTS: By using SD OCT, the prevalence of ERMs (34.1%), VMT (1.6%), macular cysts (5.6%), PVCs (20.0%), LMHs (3.6%), and FTMHs (0.4%) was estimated. The prevalence of macular cysts (P < 0.001), ERMs (P < 0.001), and VMT (P = 0.005) increased with age; the prevalence of PVCs (P = 0.05) decreased with age; and the prevalence of LMHs was not associated with age (P = 0.70). The prevalence of macular cysts, LMHs, and ERMs was higher in eyes with a history of cataract surgery. Macular cysts and ERMs were more common in eyes with retinal diseases, such as proliferative diabetic retinopathy, retinal vein occlusion, and retinal detachment, than in eyes without these conditions. Macular cysts, ERMs, and FTMHs were associated with visual impairment. While adjusting for age and sex, macular cysts (odds ratio [OR], 3.96; P < 0.0001), PVCs (OR, 1.45, P = 0.007), LMHs (OR, 10.62; P < 0.001), VMT (OR, 2.72, P = 0.01), and visual impairment (OR, 3.23; P < 0.001) were more frequent in eyes with ERMs compared with eyes without ERMs. CONCLUSIONS: Epiretinal membranes are associated with macular cysts, PVCs, LMHs, VMT, and visual impairment. Further follow-up will allow better understanding of the natural history of ERMs and VMT and their relationships to the development of macular cysts and LMHs in the aging population.

Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration.

PURPOSE: To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops. PARTICIPANTS: A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections. METHODS: Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed. MAIN OUTCOME MEASURES: The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24. RESULTS: At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported. CONCLUSIONS: Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.

Randomized trial of a home monitoring system for early detection of choroidal neovascularization home monitoring of the Eye (HOME) study.

OBJECTIVE: To determine whether home monitoring with the ForeseeHome device (Notal Vision Ltd, Tel Aviv, Israel), using macular visual field testing with hyperacuity techniques and telemonitoring, results in earlier detection of age-related macular degeneration-associated choroidal neovascularization (CNV), reflected in better visual acuity, when compared with standard care. The main predictor of treatment outcome from anti-vascular endothelial growth factor (VEGF) agents is the visual acuity at the time of CNV treatment. DESIGN: Unmasked, controlled, randomized clinical trial. PARTICIPANTS: One thousand nine hundred and seventy participants 53 to 90 years of age at high risk of CNV developing were screened. Of these, 1520 participants with a mean age of 72.5 years were enrolled in the Home Monitoring of the Eye study at 44 Age-Related Eye Disease Study 2 clinical centers. INTERVENTIONS: In the standard care and device arms arm, investigator-specific instructions were provided for self-monitoring vision at home followed by report of new symptoms to the clinic. In the device arm, the device was provided with recommendations for daily testing. The device monitoring center received test results and reported changes to the clinical centers, which contacted participants for examination. MAIN OUTCOME MEASURES: The main outcome measure was the difference in best-corrected visual acuity scores between baseline and detection of CNV. The event was determined by investigators based on clinical examination, color fundus photography, fluorescein angiography, and optical coherence tomography findings. Masked graders at a central reading center evaluated the images using standardized protocols. RESULTS: Seven hundred sixty-three participants were randomized to device monitoring and 757 participants were randomized to standard care and were followed up for a mean of 1.4 years between July 2010 and April 2013. At the prespecified interim analysis, 82 participants progressed to CNV, 51 in the device arm and 31 in the standard care arm. The primary analysis achieved statistical significance, with the participants in the device arm demonstrating a smaller decline in visual acuity with fewer letters lost from baseline to CNV detection (median, -4 letters; interquartile range [IQR], -11.0 to -1.0 letters) compared with standard care (median, -9 letters; IQR, -14.0 to -4.0 letters; P = 0.021), resulting in better visual acuity at CNV detection in the device arm. The Data and Safety Monitoring Committee recommended early study termination for efficacy. CONCLUSIONS: Persons at high risk for CNV developing benefit from the home monitoring strategy for earlier detection of CNV development, which increases the likelihood of better visual acuity results after intravitreal anti-VEGF therapy.

The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study.

PURPOSE: To report additional ocular outcomes of intensive treatment of hyperglycemia, blood pressure, and dyslipidemia in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. DESIGN: Double 2×2 factorial, multicenter, randomized clinical trials in people with type 2 diabetes who had cardiovascular disease or cardiovascular risk factors. In the glycemia trial, targets of intensive and standard treatment were: hemoglobin A1c <6.0% and 7.0% to 7.9%, respectively, and in the blood pressure trial: systolic blood pressures of <120 and <140 mmHg, respectively. The dyslipidemia trial compared fenofibrate plus simvastatin with placebo plus simvastatin. PARTICIPANTS: Of the 3472 ACCORD Eye Study participants enrolled, 2856 had 4-year data (85% of survivors). METHODS: Eye examinations and fundus photographs were taken at baseline and year 4. Photographs were graded centrally for retinopathy severity and macular edema using the Early Treatment Diabetic Retinopathy Study (ETDRS) methods. MAIN OUTCOME MEASURES: Three or more steps of progression on the ETDRS person scale or treatment of retinopathy with photocoagulation or vitrectomy. RESULTS: As previously reported, there were significant reductions in the primary outcome in the glycemia and dyslipidemia trials, but no significant effect in the blood pressure trial. Results were similar for retinopathy progression by 1, 2, and 4 or more steps on the person scale and for ≥ 2 steps on the eye scale. In the subgroup of patients with mild retinopathy at baseline, effect estimates were large (odds ratios, ∼0.30; P < 0.001), but did not reach nominal significance for participants with no retinopathy or for those with moderate to severe retinopathy at baseline. CONCLUSIONS: Slowing of progression of retinopathy by intensive treatment of glycemia was observed in ACCORD participants, whose average age and diabetes duration were 62 and 10 years, respectively, and who had cardiovascular disease or cardiovascular risk factors. The effect seemed stronger in patients with mild retinopathy. Similar slowing of progression was observed in patients treated with fenofibrate, with no effect observed with intensive blood pressure treatment. This is the second study to confirm the benefits of fenofibrate in reducing diabetic retinopathy progression, and fenofibrate should be considered for treatment of diabetic retinopathy.

Sustained delivery fluocinolone acetonide vitreous implants: long-term benefit in patients with chronic diabetic macular edema.

PURPOSE: To present the safety and efficacy of intravitreal implants releasing 0.2 µg/day fluocinolone acetonide (FAc) in patients with chronic versus nonchronic diabetic macular edema (DME). To assess ocular characteristics, anatomic changes, and re-treatment and ancillary therapies that may explain the differential treatment effect seen with intravitreal implants releasing FAc 0.2 µg/day in patients with chronic and nonchronic DME. An overall benefit-to-risk assessment for the FAc 0.2-µg/day and FAc 0.5-µg/day doses has been reported previously. DESIGN: Preplanned subgroup analysis of chronic (duration of diagnosis, ≥3 years) and nonchronic (duration of diagnosis, <3 years) DME in patients from 2 randomized, sham injection-controlled, double-masked, multicenter clinical trials. PARTICIPANTS: Patients with persistent DME despite 1 or more macular laser treatment were randomized 1:2:2 to sham injection (n = 185), FAc 0.2 µg/day (n = 375), or FAc 0.5 µg/day (n = 393). METHODS: Patients received study drug or sham injection and after 6 weeks were eligible for rescue laser. Based on re-treatment criteria, additional masked study drug could be given after 1 year. MAIN OUTCOME MEASURES: Percentage of patients with improvement of 15 letters or more from baseline. Secondary outcomes included other parameters of visual function and foveal thickness. RESULTS: At month 36, the difference between FAc 0.2 µg/day and sham control in the percentage of patients who gained 15 letters or more was significantly greater in chronic DME patients (FAc 0.2 µg/day, 34.0% vs. sham, 13.4%; P<0.001), compared with patients with nonchronic DME (FAc 0.2 µg/day, 22.3% vs. sham, 27.8%; P = 0.275). The greater response in patients with chronic DME was not associated with baseline ocular characteristics, changes in anatomic features, or differences in re-treatment or ancillary therapies. The ocular adverse event profile for FAc 0.2 µg/day was similar regardless of DME duration. CONCLUSIONS: This is the first published analysis correlating duration of diagnosis of DME with treatment effect. In patients with chronic DME, FAc 0.2 µg/day provides substantial visual benefit for up to 3 years and would provide an option for patients who do not respond to other therapy.

Retinal vascular abnormalities in neovascular age-related macular degeneration.

PURPOSE: To determine the prevalence of retinal vascular abnormalities (RVA) in neovascular age-related macular degeneration (AMD). METHODS: A post hoc subanalysis of images acquired during a Phase III randomized controlled trial was undertaken, selecting images from participants with untreated, neovascular AMD in at least one eye. Protocol mandated fundus photographs and fluorescein angiograms were acquired at baseline and Year 2, from 107 sham-treated study eyes with neovascular AMD and 107 untreated fellow eyes. Images were reanalyzed by an independent reading center for the presence of RVA, defined as at least one of the following: microaneurysms, vessel staining or leakage, dilated or tortuous vessels, intraretinal hemorrhage, vessel sheathing or narrowing, capillary nonperfusion, or capillary infarcts. RESULTS: The baseline prevalence of RVA in the sham-treated study eyes was 14.4% (15 of 104 gradable images) versus 8.3% (5 of 60) in the fellow eyes with dry AMD. The baseline prevalence of individual RVAs in study eyes was: microaneurysms (6.7%), vessel staining or leakage (6.7%), dilated or tortuous vessels (4.8%), intraretinal hemorrhage (4.8%), vessel sheathing or narrowing (2.9%), capillary nonperfusion (0%), and capillary infarcts (0%). Results were similar at 24 months. CONCLUSION: Compared with several studies that relied solely on fundus photographs, this study included fluorescein angiography and found a higher prevalence of RVAs occurring in eyes with neovascular AMD.

Effects of medical therapies on retinopathy progression in type 2 diabetes.

BACKGROUND: We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy. METHODS: In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. RESULTS: At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29). CONCLUSIONS: Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)

Circularity index as a risk factor for progression of geographic atrophy.

OBJECTIVE: To develop a parameter that can assess the relative rate of progression of geographic atrophy (GA) based on the hypothesis that noncircular configuration of the atrophic lesion may be a risk factor for enlargement. DESIGN: Cohort study. PARTICIPANTS: Digitized color photographs of 593 eyes with GA from the Age-Related Eye Disease Study (AREDS). METHODS: A novel parameter called the "Geographic Atrophy Circularity Index" (GACI) was developed on the basis of area and perimeter measurements to categorize the irregularity of the shape of GA. The GACI ranges from 0.0 to 1.0 and is categorized into 3 groups: 0.25 (very irregular), 0.25 to <0.75 (partly irregular), and ≥ 0.75 (circular). MAIN OUTCOME MEASURES: Growth rate of GA. RESULTS: The mean growth rate in the 3 categories was 0.40 (± 0.18), 0.36 (± 0.30), and 0.21 (± 0.22) mm/year, respectively (P < 0.001). By adjusting for known confounders, baseline area, duration of GA, and configuration, GACI categories were significantly associated with increased growth rate of GA (P < 0.001). CONCLUSIONS: The GACI was associated with the progression rate of GA and may be a useful measure for clinical trial eligibility. The association also suggests that enlargement of GA may be related to the extent of the junctional zone of damaged retinal pigment epithelium, which increases with noncircularity for a given GA area.

Vascular changes in eyes treated with dexamethasone intravitreal implant for macular edema after retinal vein occlusion.

OBJECTIVE: To evaluate the angiographic findings in eyes from 2 clinical trials of the dexamethasone intravitreal implant (DEX implant) 0.7 mg in the treatment of macular edema (ME) after branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). DESIGN: Post hoc analysis of pooled data from 2 identical phase 3 clinical trials. PARTICIPANTS: Patients with vision loss as a result of ME (≥ 6 weeks' duration) after BRVO or CRVO for whom angiographic data were available (n = 329 eyes). METHODS: Fluorescein angiography (FA) results assessed by masked, certified graders using standardized grading protocols. MAIN OUTCOME MEASURES: The primary outcome measure in the parent studies was change from baseline in best-corrected visual acuity. Prospectively defined secondary outcomes included FA measurements (to assess macular capillary leakage, neovascularization, and nonperfusion) and optical coherence tomography results (to assess central retinal thickness [CRT]). RESULTS: At baseline, 42% of eyes in the DEX implant group and 38% of eyes in the sham group had unreadable assessments because of hemorrhage. At day 180, significantly fewer DEX implant-treated eyes (2%) than sham-treated eyes (9%) had unreadable assessments because of hemorrhage (P = 0.029). Among eyes with gradable assessments, the incidence of nonperfusion remained fairly steady from baseline to day 180. The proportion of eyes with active neovascularization increased from baseline to day 180 in the sham group, but stayed relatively constant in the DEX implant group (P = 0.026 for DEX vs. sham). The mean area of overall nonperfusion and the mean area of macular capillary nonperfusion increased from baseline to day 180 in both treatment groups (no statistically significant between-group difference). There was a statistically significant positive correlation between changes in macular leakage and changes in CRT in both the DEX implant group (r = 0.22; 95% confidence interval, 0.03-0.40; P = 0.023) and the sham group (r = 0.29; 95% confidence interval, 0.10-0.46; P = 0.003). CONCLUSIONS: This study demonstrated that the clinical improvements observed with the DEX implant were accompanied by significant improvements in vascular parameters and suggests that treatment with the DEX implant may be associated with some clinically significant improvements in angiographic findings, specifically active neovascularization.

Validity of self-report in type 1 diabetic subjects for laser treatment of retinopathy.

PURPOSE: This study sought to determine the validity of self-report of prior panretinal photocoagulation (PRP) and focal photocoagulation (FP) compared with fundus photography. DESIGN: Prospective cohort study. PARTICIPANTS: One thousand three hundred sixty-three type 1 diabetic subjects from the Epidemiology of Diabetes Interventions and Complications (EDIC) study, a subset of the 1441 subjects originally enrolled in the multicenter Diabetes Control and Complications Trial. METHODS: At each annual visit, subjects were asked by EDIC staff whether they had undergone PRP, FP, or both since the last completed annual clinic visit. Fundus photographs were collected from one quarter of the cohort each year and from the entire cohort at EDIC years 4 and 10. Photographs were graded for the presence and extent of PRP and FP. Seventeen years of subject reporting and photograph grading of PRP and FP were compared in EDIC subjects. MAIN OUTCOME MEASURES: The κ, sensitivity, specificity, and positive and negative predictive values were calculated for subject-reported PRP and FP. Factors influencing subject misreporting were investigated. RESULTS: For subject reporting, 1244 (96%) of 1296 subjects with gradable photographs accurately reported whether they had a history of PRP in one or both eyes, and 1259 (97.5%) of 1291 with valid photographs correctly reported their history of FP. For PRP and FP, sensitivities were 90.4% and 74.0%, respectively; specificities were 96.0% and 98.8%, respectively; positive predictive values were 75.9% and 80.3%, respectively; negative predictive values were 98.9% and 98.4%, respectively; and κ values were 0.80 and 0.76, respectively. Risk factors associated with misreporting included prior laser for diabetic retinopathy and prior ocular surgery (each P<0.04). CONCLUSIONS: For subjects with type 1 diabetes, in the absence of a clinical examination or fundus photographs, subject self-report could be a reliable tool in a well-monitored study for assessing laser treatment type in diabetic retinopathy.

Comparison of standardized clinical classification with fundus photograph grading for the assessment of diabetic retinopathy and diabetic macular edema severity.

PURPOSE: To compare evaluation by clinical examination with image grading at a reading center for the classification of diabetic retinopathy and diabetic macular edema. METHODS: Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Family Investigations of Nephropathy in Diabetes (FIND) had similar methods of clinical and fundus photograph evaluation. For analysis purposes, the photographic grading scales were condensed to correspond to the clinical scales, and agreement between clinicians and reading center classification were compared. RESULTS: Six thousand nine hundred and two eyes of ACCORD participants and 3,638 eyes of FIND participants were analyzed for agreement (percent, kappa) on diabetic retinopathy on a 5-level scale. Exact agreement between clinicians and reading center on diabetic retinopathy severity category was 69% in ACCORD and 74% in FIND (kappa 0.42 and 0.65). Sensitivities of the clinical grading to identify the presence of mild nonproliferative retinopathy or worse were 0.53 in ACCORD and 0.84 in FIND. Specificities were 0.97 and 0.96, respectively. Diabetic macular edema agreement in 6,649 eyes of ACCORD participants and 3,366 eyes of FIND participants was similar (kappa 0.35 and 0.41). Sensitivities of the clinical grading to identify diabetic macular edema were 0.44 and 0.53 and specificities were 0.99 and 0.94, respectively. CONCLUSION: The results support the use of clinical information for defining broad severity categories but not for documenting small-to-moderate changes in diabetic retinopathy over time.

Transition from film to digital fundus photography in the Longitudinal Studies of the Ocular Complications of AIDS.

PURPOSE: To describe the transition to digital imaging and assess any impact on ocular disease classification. METHODS: Film and digital images, acquired by certified photographers, were evaluated independently according to standard procedures for the following: image quality, presence of cytomegalovirus retinitis lesions, and their extent and proximity from disk and macula. Intergrader agreement within the digital medium was also assessed. RESULTS: Among the 15 eyes with cytomegalovirus retinitis, the mean difference between film and digital images for linear distance of lesion edge to disk was 0.02 disk diameters, for distance to center of macula was -0.04 disk diameters, and area covered by cytomegalovirus retinitis was 0.95 disk area. There was no statistically significant difference in distance and area measurements between media. Intergrader agreement in measurements of digital images was excellent for distance and area estimated. CONCLUSION: Our results suggest that digital grading of cytomegalovirus retinitis in Longitudinal Studies of the Ocular Complications of AIDS is comparable with that from film regarding disease classification, measurements, and reproducibility. These findings provide support for continuity of grading data, despite the necessary transition in imaging media.

Imaging of diabetic retinopathy and diabetic macular edema.

Imaging of the retinal complications of diabetes mellitus is rapidly changing from the emergence of new technology such as optical coherence tomography. In particular, the characterization of diabetic macular edema is much easier for the clinician and there are new, more sensitive clinical research end points. However, our understanding of structure-functional relationships remains suboptimal and the classification of macular edema by optical coherence tomography continues to evolve. The classification of diabetic retinopathy severity continues to rely upon fundus photography, although the transition from film to digital photography presents both challenges and advantages.

Effect of ruboxistaurin (RBX) On visual acuity decline over a 6-year period with cessation and reinstitution of therapy: results of an open-label extension of the Protein Kinase C Diabetic Retinopathy Study 2 (PKC-DRS2).

PURPOSE: The PKC-DRS2 was a Phase 3, randomized, double-masked, placebo (PBO)-controlled, 3-year study of the effect of 32 mg/day of ruboxistaurin (RBX), an orally administered protein kinase C inhibitor, on vision loss in patients with moderate to severe nonproliferative diabetic retinopathy. Ruboxistaurin reduced the occurrence of sustained moderate visual loss (SMVL; ≥15-letter decline in visual acuity sustained for the last 6 months of study participation) from 9.1% in the PBO group (N = 340) to 5.5% in the RBX group (N = 345, P = 0.034). This study evaluates the primary end point of SMVL in a 2-year open-label extension (OLE) of the PKC-DRS2, which began a median of 466 days (range, 263-1,296 days) after the conclusion of PKC-DRS2. METHODS: Visual acuity was measured by certified examiners using the Early Treatment Diabetic Retinopathy Study chart. RESULTS: Of the 514 patients who completed PKC-DRS2, 366 did so in the 32 study centers participating in the OLE, and of these, 203 (55%) enrolled in the OLE for treatment with 32 mg/day of RBX for 2 years. Of the 203 enrolled in the OLE, 100 had previously been treated with PBO (prior PBO subgroup) and 103 had been treated with RBX (prior RBX subgroup). PKC-DRS2 baseline patient and ocular characteristics were well matched between these two subgroups and were similar to the PKC-DRS2 patient population as a whole. Using the PKC-DRS2 baseline as the starting point, SMVL occurred in 6% of the prior PBO subgroup during the PKC-DRS2, increasing to 26% by the end of the OLE. However, in the prior RBX subgroup, SMVL occurred in only 4% and 8% during the PKC-DRS2 and by the end of the OLE, respectively (P < 0.001 for difference at the end of the OLE). In the prior PBO subgroup, mean visual acuity declined from 79.6 letters at PKC-DRS2 baseline to 73.1 letters at OLE end point (-6.5 letters). In the prior RBX subgroup, this loss was 2.7 letters (79.8 to 77.1) over the same period (P = 0.02). CONCLUSION: Over a 6-year study period incorporating 3 years of a rigorously placebo-controlled trial, approximately 1 year off treatment and 2-year OLE where all groups received therapy, those patients with greatest RBX exposure (∼5 years) experienced less SMVL compared with those in the original PBO group (∼2-year RBX exposure).

Mosaics versus Early Treatment Diabetic Retinopathy seven standard fields for evaluation of diabetic retinopathy severity.

PURPOSE: To compare agreement between mosaicked and seven field photographs for classification of the diabetic retinopathy (DR) severity. METHODS: Mosaic digital (MosD) images were compared with seven field stereo film (7FF) and stereo digital (7FD) photographs from a 152-eye cohort with full-spectrum Early Treatment of Diabetic Retinopathy severity levels for agreement on severity level, DR presence with ascending severity thresholds, DR index lesion presence, and classification repeatability. RESULTS: There was a substantial agreement classifying the Early Treatment Diabetic Retinopathy Study DR severity level between MosD and 7FF (kunweighted = 0.59, klinear weighted = 0.83), MosD and 7FD (κ = 0.62, κ weighted = 0.86), and 7FD and 7FF (κ = 0.62, κ weighted = 0.86) images. Marginal homogeneity analyses found no significant difference between MosD and 7FF (P = 0.44, Bhapkar's test). Kappa between MosD and 7FF ranged from 0.75 to 0.91 for the presence or absence of DR at 8 ascending severity thresholds. Repeatability among readers using MosD images was similar to repeatability among those using 7FF or 7FD. Repeatability among readers using MosD and 7FF images at various severity thresholds was similar. Kappa between MosD and 7FF grading for identifying DR lesions ranged from 0.61 to 1.00. CONCLUSION: Mosaic images are generally comparable with standard seven-field photographs for classifying DR severity.