Pseudodrusen and Incidence of Late Age-Related Macular Degeneration in Fellow Eyes in the Comparison of Age-Related Macular Degeneration Treatments Trials.

PURPOSE: To evaluate the association between pseudodrusen and incidence of late age-related macular degeneration (AMD) in fellow eyes of patients with unilateral neovascular AMD (nAMD). DESIGN: Cohort study within the Comparison of AMD Treatments Trials (CATT). PARTICIPANTS: Patients with neither nAMD nor geographic atrophy (GA) in the fellow eye at baseline. METHODS: Presence and type (dot, reticular, or confluent) of baseline pseudodrusen were assessed using digital color fundus photography (CFP) viewed under full color, green channel, and blue channel; red-free images; and fluorescein angiography (FA). Incidence of nAMD was based on monthly clinical examination and reading center evaluation of images at years 1 and 2. Incidence of GA was based on reading center evaluation of CFP and FA images at years 1 and 2. Associations of baseline pseudodrusen with incident nAMD and GA were summarized with adjusted risk ratios (aRRs) and their 95% confidence intervals (CIs) from multivariate Cox models, with adjustment of covariates identified through backward stepwise selection. MAIN OUTCOME MEASURES: Incident nAMD and GA. RESULTS: Among 620 fellow eyes, 176 (28.4%) had baseline pseudodrusen (55% dot, 82% reticular, 35% confluent). Within 2 years, nAMD occurred in 54 eyes (30.7%) with pseudodrusen and in 72 eyes (16.2%) without pseudodrusen (aRR, 2.05; 95% CI, 1.43-2.93); GA occurred in 27 eyes (15.3%) with pseudodrusen and in 37 eyes (8.3%) without pseudodrusen (aRR, 1.89; 95% CI, 1.13-3.17); late AMD occurred in 73 eyes (41.5%) with pseudodrusen and in 101 eyes (22.8%) without pseudodrusen (aRR, 2.07; 95% CI, 1.51-2.83). Dot pseudodrusen were associated independently with nAMD (aRR, 2.53; 95% CI, 1.60-4.00), whereas confluent pseudodrusen were associated independently with GA (aRR, 4.35; 95% CI, 1.69-11.2). Eyes with pseudodrusen had increased incidence of late AMD regardless of whether the Age-Related Eye Diseases Study (AREDS) severity score was 2 (28.7% vs. 10.3%), 3 (34.9% vs. 13.7%), or 4 (50.5% vs. 32.0%). CONCLUSIONS: In fellow eyes of CATT participants, pseudodrusen were associated independently with a higher incidence of both nAMD and GA. Dot pseudodrusen were associated with nAMD, whereas confluent pseudodrusen were associated with GA. Pseudodrusen should be considered along with the AREDS severity score for predicting late AMD.

Validated System for Centralized Grading of Retinopathy of Prematurity: Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study.

IMPORTANCE: Measurable competence derived from comprehensive and advanced training in grading digital images is critical in studies using a reading center to evaluate retinal fundus images from infants at risk for retinopathy of prematurity (ROP). Details of certification for nonphysician trained readers (TRs) have not yet been described. OBJECTIVE: To describe a centralized system for grading ROP digital images by TRs in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study. DESIGN, SETTING, AND PARTICIPANTS: Multicenter observational cohort study conducted from July 1, 2010, to June 30, 2014. The TRs were trained by experienced ROP specialists and certified to detect ROP morphology in digital retinal images under supervision of an ophthalmologist reading center director. An ROP reading center was developed with standard hardware, secure Internet access, and customized image viewing software with an electronic grading form. A detailed protocol for grading was developed. Based on results of TR gradings, a computerized algorithm determined whether referral-warranted ROP (RW-ROP; defined as presence of plus disease, zone I ROP, and stage 3 or worse ROP) was present in digital images from infants with birth weight less than 1251 g enrolled from May 25, 2011, through October 31, 2013. Independent double grading was done by the TRs with adjudication of discrepant fields performed by the reading center director. EXPOSURE: Digital retinal images. MAIN OUTCOMES AND MEASURES: Intragrader and intergrader variability and monitoring for temporal drift. RESULTS: Four TRs underwent rigorous training and certification. A total of 5520 image sets were double graded, with 24.5% requiring adjudication for at least 1 component of RW-ROP. For individual RW-ROP components, the adjudication rate was 3.9% for plus disease, 12.4% for zone I ROP, and 16.9% for stage 3 or worse ROP. The weighted κ for intergrader agreement (n = 80 image sets) was 0.72 (95% CI, 0.52-0.93) for RW-ROP, 0.57 (95% CI, 0.37-0.77) for plus disease, 0.43 (95% CI, 0.24-0.63) for zone I ROP, and 0.67 (95% CI, 0.47-0.88) for stage 3 or worse ROP. The weighted κ for grade-regrade agreement was 0.77 (95% CI, 0.57-0.97) for RW-ROP, 0.87 (95% CI, 0.67-1.00) for plus disease, 0.70 (95% CI, 0.51-0.90) for zone I ROP, and 0.77 (95% CI, 0.57-0.97) for stage 3 or worse ROP. CONCLUSIONS AND RELEVANCE: These data suggest that the e-ROP system for training and certifying nonphysicians to grade ROP images under the supervision of a reading center director reliably detects potentially serious ROP with good intragrader and intergrader consistency and minimal temporal drift.

Characteristics of incident geographic atrophy in the complications of age-related macular degeneration prevention trial.

OBJECTIVE: To characterize the size, location, conformation, and features of incident geographic atrophy (GA) as detected by annual stereoscopic color photographs and fluorescein angiograms (FAs). DESIGN: Retrospective cohort study within a larger clinical trial. PARTICIPANTS: Patients with bilateral large drusen in whom GA developed during the course of the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). METHODS: Annual stereoscopic color photographs and FAs were reviewed from 114 CAPT patients in whom GA developed in the untreated eye during 5 to 6 years of follow-up. Geographic atrophy was defined according to the Revised GA Criteria for identifying early GA.(23) Color-optimized fundus photographs were viewed concurrently with the FAs during grading. MAIN OUTCOME MEASURES: Size and distance from the fovea of individual GA lesions, number of areas of atrophy, and change in visual acuity (VA) when GA first developed in an eye. RESULTS: At presentation, the median total GA area was 0.26 mm(2) (0.1 disc area). Geographic atrophy presented as a single lesion in 89 (78%) eyes. The median distance from the fovea was 395 µm. Twenty percent of incident GA lesions were subfoveal and an additional 18% were within 250 µm of the foveal center. Development of GA was associated with a mean decrease of 7 letters from the baseline VA level compared with 1 letter among matched early age-related macular degeneration eyes without GA. Geographic atrophy that formed in areas previously occupied by drusenoid pigment epithelial detachments on average were larger (0.53 vs. 0.20 mm(2); P = 0.0001), were more central (50 vs. 500 µm from the center of the fovea; P<0.0001), and were associated with significantly worse visual outcome (20/50 vs. 20/25; P = 0.0003) than GA with other drusen types as precursors. CONCLUSIONS: Incident GA most often appears on color fundus photographs and FAs as a small, singular, parafoveal lesion, although a large minority of lesions are subfoveal or multifocal at initial detection. The characteristics of incident GA vary with precursor drusen types. These data can facilitate design of future clinical trials of therapies for GA. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

New grading criteria allow for earlier detection of geographic atrophy in clinical trials.

PURPOSE: To evaluate new grading criteria for geographic atrophy (GA), as detected by annual stereoscopic color fundus photographs and fluorescein angiograms, and to assess whether application of the revised criteria provides earlier identification of GA than previous criteria involving only color fundus photography. METHODS: Annual fundus image sets from 114 CAPT patients who developed GA in the untreated eye during 5 to 6 years of follow-up were reassessed for the presence of GA, using revised grading criteria, in which GA was defined by (1) the presence of hyperfluorescence on fluorescein angiography; and (2) at least one other characteristic indicative of involution of the retinal pigment epithelium (i.e., sharp edges, excavation of the retina, or visible choroidal vessels on either color images or fluorescein angiograms). Reliability and time of initial detection of GA using the revised criteria were assessed. RESULTS: The revised criteria are reliable (97.8% intragrader, 93.3% intergrader agreement) and accurate (false-positive rate, 0.8%) for detecting individual early GA lesions. Using this revised method, individual GA lesions were identified 1-year earlier on average than was possible with criteria used in previous CFP studies. The use of two imaging modalities was more sensitive in detecting GA and its features than either imaging modality alone (P ≤ 0.0001). CONCLUSIONS: Early GA areas can be reliably identified when defining criteria are based on both color photographs and fluorescein angiograms. These methods can be used to investigate the natural history of GA earlier in the course of disease than previously possible and to facilitate the design of future clinical trials of treatments for GA. (ClinicalTrials.gov number, NCT00000167).

Association of risk factors for choroidal neovascularization in age-related macular degeneration with decreased foveolar choroidal circulation.

PURPOSE: To investigate the relationship between known risk factors for age-related macular degeneration (AMD) progression and foveolar choroidal circulation in eyes with nonexudative AMD. DESIGN: Cross-sectional study of nonexudative AMD. METHODS: Laser Doppler flowmetry measurements of relative choroidal blood velocity, choroidal blood volume (ChBVol), and choroidal blood flow (ChBFlow) were obtained in the center of the fovea of 273 study eyes of 204 AMD patients investigated at the Scheie Eye Institute, University of Pennsylvania Medical School. All study eyes had visual acuity of 20/40 or better, good fixation, no other intraocular pathologic features, and no evidence of choroidal neovascularization. RPE hypertrophy was determined from color fundus photographs by trained masked graders at the Scheie Image Reading Center. Correlation analysis and multivariate linear regression analysis with adjustments for significant covariates were carried out. RESULTS: A significant inverse correlation was observed between age and ChBFlow (r = -0.36; P < .0001), and ChBVol (r = -0.28; P < .0001), but not for choroidal blood velocity. A significant inverse correlation was observed between spherical equivalent and ChBFlow (r = -0.21; P = .006) and ChBVol (r = -0.14; P = .04), but not for choroidal blood velocity. ChBFlow and ChBVol were significantly lower in patients with a history of hypertension (P < or = .003) and in eyes with retinal pigment epithelium hypertrophy (P < or = .04), respectively. CONCLUSIONS: All the above-described risk factors for AMD development and progression are associated with decreased choroidal circulatory parameters, suggesting that decreases in choroidal circulatory parameters may be involved in the development of AMD.