Association of Predominantly Peripheral Lesions on Ultra-Widefield Imaging and the Risk of Diabetic Retinopathy Worsening Over Time.

Importance: Ultra-widefield (UWF) imaging improves the ability to identify peripheral diabetic retinopathy (DR) lesions compared with standard imaging. Whether detection of predominantly peripheral lesions (PPLs) better predicts rates of disease worsening over time is unknown. Objective: To determine whether PPLs identified on UWF imaging are associated with increased disease worsening beyond the risk associated with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) score. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study conducted at 37 US and Canadian sites with 388 participants enrolled between February and December 2015. At baseline and annually through 4 years, 200° UWF-color images were obtained and graded for DRSS at a reading center. Baseline UWF-color and UWF-fluorescein angiography (FA) images were evaluated for the presence of PPL. Data were analyzed from May 2020 to June 2022. Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Predominantly peripheral lesions were defined as DR lesions with a greater extent outside vs inside the 7 standard ETDRS fields. Primary outcome was disease worsening defined as worsening 2 steps or more on the DRSS or receipt of DR treatment. Analyses were adjusted for baseline DRSS score and correlation between 2 study eyes of the same participant. Results: Data for 544 study eyes with nonproliferative DR (NPDR) were analyzed (182 [50%] female participants; median age, 62 years; 68% White). The 4-year disease worsening rates were 45% for eyes with baseline mild NPDR, 40% for moderate NPDR, 26% for moderately severe NPDR, and 43% for severe NPDR. Disease worsening was not associated with color PPL at baseline (present vs absent: 38% vs 43%; HR, 0.78; 95% CI, 0.57-1.08; P = .13) but was associated with FA PPL at baseline (present vs absent: 50% vs 31%; HR, 1.72; 95% CI, 1.25-2.36; P < .001). Conclusions and Relevance: Although no association was identified with color PPL, presence of FA PPL was associated with greater risk of disease worsening over 4 years, independent of baseline DRSS score. These results suggest that use of UWF-FA to evaluate retinas peripheral to standard ETDRS fields may improve the ability to predict disease worsening in NPDR eyes. These findings support use of UWF-FA for future DR staging systems and clinical care to more accurately determine prognosis in NPDR eyes.

Association of Ultra-Widefield Fluorescein Angiography-Identified Retinal Nonperfusion and the Risk of Diabetic Retinopathy Worsening Over Time.

Importance: Presence of predominantly peripheral diabetic retinopathy (DR) lesions on ultra-widefield fluorescein angiography (UWF-FA) was associated with greater risk of DR worsening or treatment over 4 years. Whether baseline retinal nonperfusion assessment is additionally predictive of DR disease worsening is unclear. Objective: To assess whether the extent and location of retinal nonperfusion identified on UWF-FA are associated with worsening in Diabetic Retinopathy Severity Scale (DRSS) score or DR treatment over time. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study with data for 508 eyes with nonproliferative DR and gradable nonperfusion on UWF-FA at baseline. All images were graded at a centralized reading center; 200° ultra-widefield (UWF) color images were graded for DR at baseline and annually for 4 years. Baseline 200° UWF-FA images were graded for nonperfused area, nonperfusion index (NPI), and presence of predominantly peripheral lesions on UWF-FA (FA PPL). Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Association of baseline UWF-FA nonperfusion extent with disease worsening, defined as either 2 or more steps of DRSS worsening within Early Treatment Diabetic Retinopathy Study fields on UWF-color images or receipt of DR treatment. Results: After adjusting for baseline DRSS, the risk of disease worsening over 4 years was higher in eyes with greater overall NPI (hazard ratio [HR] for 0.1-unit increase, 1.11; 95% CI, 1.02-1.21; P = .02) and NPI within the posterior pole (HR for 0.1-unit increase, 1.35; 95% CI, 1.17-1.56; P < .001) and midperiphery (HR for 0.1-unit increase, 1.08; 95% CI, 1.00-1.16; P = .04). In a multivariable analysis adjusting for baseline DRSS score and baseline systemic risk factors, greater NPI (HR, 1.11; 95% CI, 1.02-1.22; P = .02) and presence of FA PPL (HR, 1.89; 95% CI, 1.35-2.65; P < .001) remained associated with disease worsening. Conclusions and Relevance: This 4-year longitudinal study has demonstrated that both greater baseline retinal nonperfusion and FA PPL on UWF-FA are associated with higher risk of disease worsening, even after adjusting for baseline DRSS score and known systemic risk. These associations between disease worsening and retinal nonperfusion and FA PPL support the increased use of UWF-FA to complement color fundus photography in future efforts for DR prognosis, clinical care, and research.

Optical Coherence Tomography Angiography Quality Across Three Multicenter Clinical Studies of Diabetic Retinopathy.

Purpose: To explore optical coherence tomography angiography (OCTA) quality and associated factors in multicenter clinical studies. Methods: OCTA scans were obtained from participants with diabetic retinopathy from three DRCR Retina Network clinical studies using the Optovue AngioVue and ZEISS AngioPlex. Macular (3 × 3 mm and 6 × 6 mm) and optic nerve scans were captured. Quality was assessed by the Casey Reading Center. Scans were considered "poor" if the signal strength index (SSI) was less than 55 (AngioVue) or 7 (AngioPlex) or if excess motion, media opacities, beam defocus, incorrect axial position, or other artifacts were present. Results: Included were 7539 scans from 787 eyes (461 participants). Sixty-one percent of scans were considered "good" (n = 4630). Of the 3 × 3-mm (n = 2294), 6 × 6-mm (n = 2705), and optic nerve scans (n = 2540), 62%, 63%, and 59%, respectively, were good. Differences in percentage of good scans by machine were not identified (61% of 6216 for the AngioVue and 63% of 1323 for the AngioPlex). The primary reason for poor scans was low SSI for the AngioVue (67%) and excess motion for the AngioPlex (47%). Good scans were associated with younger age (60 ± 12 years vs. 65 ± 11 years; P < 0.001), male gender (64% of males had good scans vs. 57% female; P = 0.007), and better visual acuity (ETDRS letter score 86.5 ± 6.4 [approximate Snellen equivalent 20/20] vs. 81.6 ± 9.7 [approximate Snellen equivalent 20/25]; P < 0.001). Conclusions: Scan quality or analysis must be improved for OCTA metrics to be used as outcomes in future research. Translational Relevance: Clinicians and researchers should be aware that poor SSI and artifacts are common issues for OCTA images.

Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema.

PURPOSE: To compare long-term vision and anatomic effects of ranibizumab with prompt or deferred laser vs laser or triamcinolone + laser with very deferred ranibizumab in diabetic macular edema (DME). DESIGN: Randomized clinical trial. METHODS: Eight hundred and twenty-eight study eyes (558 [67%] completed the 5-year visit), at 52 sites, with visual acuity 20/32 to 20/320 and DME involving the central macula were randomly assigned to intravitreous ranibizumab (0.5 mg) with either (1) prompt or (2) deferred laser; (3) sham injection + prompt laser; or (4) intravitreous triamcinolone (4 mg) + prompt laser. The latter 2 groups could initiate ranibizumab as early as 74 weeks from baseline, for persistent DME with vision impairment. The main outcome measures were visual acuity, optical coherence central subfield thickness, and number of injections through 5 years. RESULTS: At 5 years mean (± standard deviation) change in Early Treatment Diabetic Retinopathy Study visual acuity letter scores from baseline in the ranibizumab + deferred laser (N = 111), ranibizumab + prompt laser (N = 124), laser/very deferred ranibizumab (N = 198), and triamcinolone + laser/very deferred ranibizumab (N = 125) groups were 10 ± 13, 8 ± 13, 5 ± 14, and 7 ± 14, respectively. The difference (95% confidence interval) in mean change between ranibizumab + deferred laser and laser/very deferred ranibizumab and triamcinolone + laser/very deferred ranibizumab was 4.4 (1.2-7.6, P = .001) and 2.8 (-0.9 to 6.5, P = .067), respectively, at 5 years. CONCLUSIONS: Recognizing limitations of follow-up available at 5 years, eyes receiving initial ranibizumab therapy for center-involving DME likely have better long-term vision improvements than eyes managed with laser or triamcinolone + laser followed by very deferred ranibizumab for persistent thickening and vision impairment.

Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction.

PURPOSE: To evaluate vitrectomy for diabetic macular edema (DME) in eyes with at least moderate vision loss and vitreomacular traction. DESIGN: Prospective cohort study. PARTICIPANTS: The primary cohort included 87 eyes with DME and vitreomacular traction based on investigator's evaluation, visual acuity 20/63-20/400, optical coherence tomography (OCT) central subfield >300 microns and no concomitant cataract extraction at the time of vitrectomy. METHODS: Surgery was performed according to the investigator's usual routine. Follow-up visits were performed after 3 months, 6 months (primary end point), and 1 year. MAIN OUTCOME MEASURES: Visual acuity, OCT retinal thickening, and operative complications. RESULTS: At baseline, median visual acuity in the 87 eyes was 20/100 and median OCT thickness was 491 microns. During vitrectomy, additional procedures included epiretinal membrane peeling in 61%, internal limiting membrane peeling in 54%, panretinal photocoagulation in 40%, and injection of corticosteroids at the close of the procedure in 64%. At 6 months, median OCT central subfield thickness decreased by 160 microns, with 43% having central subfield thickness <250 microns and 68% having at least a 50% reduction in thickening. Visual acuity improved by > or =10 letters in 38% (95% confidence interval, 28%-49%) and deteriorated by > or =10 letters in 22% (95% confidence interval, 13%-31%). Postoperative complications through 6 months included vitreous hemorrhage (5 eyes), elevated intraocular pressure requiring treatment (7 eyes), retinal detachment (3 eyes), and endophthalmitis (1 eye). Few changes in results were noted between 6 months and 1 year. CONCLUSIONS: After vitrectomy performed for DME and vitreomacular traction, retinal thickening was reduced in most eyes. Between 28% and 49% of eyes with characteristics similar to those included in this study are likely to have improvement of visual acuity, whereas between 13% and 31% are likely to have worsening. The operative complication rate is low and similar to what has been reported for this procedure. These data provide estimates of surgical outcomes and serve as a reference for future studies that might consider vitrectomy for DME in eyes with at least moderate vision loss and vitreomacular traction.

Risk of endophthalmitis after intravitreal drug injection when topical antibiotics are not required: the diabetic retinopathy clinical research network laser-ranibizumab-triamcinolone clinical trials.

OBJECTIVE: To report the incidence of endophthalmitis after intravitreal drug injection by means of a standardized procedure that does not require topical antibiotics, sterile gloves, or a sterile drape. METHODS: Intravitreal injections of preservative-free triamcinolone acetonide or ranibizumab were administered in 2 prospective randomized clinical trials performed by the Diabetic Retinopathy Clinical Research Network. The standardized procedure for these trials requires the use of a topical combination product of povidone-iodine, a sterile lid speculum, and topical anesthetic, but does not require the use of topical antibiotics before, on the day of, or after injection. RESULTS: As of February 23, 2009, a total of 3226 intravitreal injections of ranibizumab and 612 injections of preservative-free triamcinolone had been administered. Topical antibiotics were given on the day of injection in 361 (9.4%) of the 3838 cases, for several days after injection in 813 cases (21.2%), on the day of injection and after injection in 1388 cases (36.2%), and neither on the day of injection nor after injection in 1276 cases (33.3%). Three cases of culture-positive endophthalmitis occurred after ranibizumab injections (0.09%), and no cases occurred after triamcinolone injections. In all 3 cases of endophthalmitis, topical antibiotics were given for several days after the injection but not before injection. CONCLUSIONS: The results suggest that a low rate of endophthalmitis can be achieved by means of a protocol that includes use of topical povidone-iodine, a sterile lid speculum, and topical anesthetic, but does not require topical antibiotics, sterile gloves, or a sterile drape. Trial Registration clinicaltrials.gov Identifiers: NCT00444600 and NCT00445003.