Characteristics of incident geographic atrophy in the complications of age-related macular degeneration prevention trial.
ABSTRACT: To characterize the size, location, conformation, and features of incident geographic atrophy (GA) as detected by annual stereoscopic color photographs and fluorescein angiograms (FAs).Retrospective cohort study within a larger clinical trial.Patients with bilateral large drusen in whom GA developed during the course of the Complications of Age-related Macular Degeneration Prevention Trial (CAPT).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.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.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 ?m. Twenty percent of incident GA lesions were subfoveal and an additional 18% were within 250 ?m 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 ?m 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.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.The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Project description:To evaluate the growth of geographic atrophy (GA) during anti-vascular endothelial growth factor (VEGF) therapy.Cohort within a clinical trial.Patients included in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).Participants were randomly assigned to injections of ranibizumab or bevacizumab and to a 2-year dosing regimen of monthly or pro re nata (PRN) or to monthly for 1 year and PRN the following year. Digital color photographs and fluorescein angiograms at baseline and 1 and 2 years were evaluated for GA, and the total area of GA was measured by 2 graders masked to treatment; differences were adjudicated. Multivariate linear mixed models of the annual change in the square root of the area included baseline demographic, treatment, and ocular characteristics on imaging as candidate risk factors.Geographic atrophy growth rate.Among 1185 participants, 86 (7.3%) had GA at baseline, 120 (10.1%) developed GA during year 1, and 36 (3.0%) developed GA during year 2. Among 194 eyes evaluable for growth, the rate was 0.43 mm/yr (standard error [SE], ±0.03 mm/year). In multivariate analysis, the growth rate was 0.37 mm/year in eyes receiving bevacizumab and 0.49 mm/year in eyes receiving ranibizumab (difference, 0.11 mm/yr; 95% confidence interval [CI], 0.01-0.22; P = 0.03). Growth rate did not differ between eyes treated monthly and PRN (P = 0.85). Eyes with subfoveal choroidal neovascularization (CNV) lesions had a lower growth rate than eyes with nonsubfoveal CNV lesions (difference, 0.12; 95% CI, 0.01-0.22; P = 0.03). Eyes with GA farther from the fovea had higher growth rates by 0.14 (95% CI, 0.01-27) mm/year for every millimeter farther from the fovea. The growth rate was 0.58 mm/year for eyes with predominantly classic lesions, 0.41 mm/year for eyes with minimally classic lesions, and 0.30 mm/year for eyes with occult only lesions (P < 0.01). The growth rate in eyes having a fellow eye with GA was higher by 0.13 mm/year (95% CI, 0.01-0.24; P = 0.03) than in eyes without GA in the fellow eye. Eyes with epiretinal membrane had a higher growth rate than eyes without epiretinal membrane (difference, 0.16; 95% CI, 0.03-0.30; P = 0.02).Geographic atrophy growth depends on several ocular factors. Ranibizumab may accelerate GA growth.
Project description: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.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.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).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).
Project description:PURPOSE:In an eye with geographic atrophy (GA) secondary to age-related macular degeneration, we correlated ex vivo histologic features with findings recorded in vivo using optical coherence tomography (OCT), near-infrared reflectance imaging, and fundus autofluorescence. METHODS:In the left eye of an 86-year-old white woman, in vivo near-infrared reflectance and eye-tracked OCT B-scans at each of 6 clinic visits and a baseline fundus autofluorescence image were correlated with high-resolution histologic images of the preserved donor eye. RESULTS:Clinical imaging showed a small parafoveal multilobular area of GA, subfoveal soft drusen, refractile drusen, hyperreflective lines near the Bruch membrane, subretinal drusenoid deposit (reticular pseudodrusen), and absence of hyperautofluorescent foci at the GA margin. By histology, soft drusen end-stages included avascular fibrosis with highly reflective cholesterol crystals. These accounted for hyperreflective lines near the Bruch membrane in OCT and plaques in near-infrared reflectance imaging. Subretinal drusenoid deposit was thick, continuous, extracellular, extensive outside the fovea, and associated with distinctive retinal pigment epithelium dysmorphia and photoreceptor degeneration. A hyporeflective wedge corresponded to ordered Henle fibers without cellular infiltration. The external limiting membrane descent, which delimits GA, was best visualized in high-quality OCT B-scans. Retinal pigment epithelium and photoreceptor changes at the external limiting membrane descent were consistent with our recent histologic survey of donor eyes. CONCLUSION:This case informs on the extent, topography, and lifecycle of extracellular deposits. High-quality OCT scans are required to reveal all tissue features relevant to age-related macular degeneration progression to GA, especially the external limiting membrane descent. Histologically validated signatures of structural OCT B-scans can serve as references for other imaging modalities.
Project description:To evaluate cone spacing using adaptive optics scanning laser ophthalmoscopy (AOSLO) in eyes with nonneovascular AMD, and to correlate progression of AOSLO-derived cone measures with standard measures of macular structure.Adaptive optics scanning laser ophthalmoscopy images were obtained over 12 to 21 months from seven patients with AMD including four eyes with geographic atrophy (GA) and four eyes with drusen. Adaptive optics scanning laser ophthalmoscopy images were overlaid with color, infrared, and autofluorescence fundus photographs and spectral domain optical coherence tomography (SD-OCT) images to allow direct correlation of cone parameters with macular structure. Cone spacing was measured for each visit in selected regions including areas over drusen (n = 29), at GA margins (n = 14), and regions without drusen or GA (n = 13) and compared with normal, age-similar values.Adaptive optics scanning laser ophthalmoscopy imaging revealed continuous cone mosaics up to the GA edge and overlying drusen, although reduced cone reflectivity often resulted in hyporeflective AOSLO signals at these locations. Baseline cone spacing measures were normal in 13/13 unaffected regions, 26/28 drusen regions, and 12/14 GA margin regions. Although standard clinical measures showed progression of GA in all study eyes, cone spacing remained within normal ranges in most drusen regions and all GA margin regions.Adaptive optics scanning laser ophthalmoscopy provides adequate resolution for quantitative measurement of cone spacing at the margin of GA and over drusen in eyes with AMD. Although cone spacing was often normal at baseline and remained normal over time, these regions showed focal areas of decreased cone reflectivity. These findings may provide insight into the pathophysiology of AMD progression. (ClinicalTrials.gov number, NCT00254605).
Project description:Structural and compositional heterogeneity within drusen comprising lipids, carbohydrates, and proteins have been previously described. We sought to detect and define phenotypic patterns of drusen heterogeneity in the form of optical coherence tomography-reflective drusen substructures (ODS) and examine their associations with age-related macular degeneration (AMD)-related features and AMD progression.Retrospective analysis in a prospective study.Patients with intermediate AMD (n = 349) enrolled in the multicenter Age-Related Eye Disease Study 2 (AREDS2) ancillary spectral-domain optical coherence tomography (SD OCT) study.Baseline SD OCT scans of 1 eye per patient were analyzed for the presence of ODS. Cross-sectional and longitudinal associations of ODS presence with AMD-related features visible on SD OCT and color photographs, including drusen volume, geographic atrophy (GA), and preatrophic features, were evaluated for the entire macular region. Similar associations were also made locally within a 0.5-mm-diameter region around individual ODS and corresponding control region without ODS in the same eye.Preatrophy SD OCT changes and GA, central GA, and choroidal neovascularization (CNV) from color photographs.Four phenotypic subtypes of ODS were defined: low reflective cores, high reflective cores, conical debris, and split drusen. Among the 349 participants, there were 307 eligible eyes and 74 (24%) had at least 1 ODS. The ODS at baseline were associated with (1) greater macular drusen volume at baseline (P < 0.001), (2) development of preatrophic changes at year 2 (P = 0.001-0.01), and (3) development of macular GA (P = 0.005) and preatrophic changes at year 3 (P = 0.002-0.008), but not development of CNV. The ODS at baseline in a local region were associated with (1) presence of preatrophy changes at baseline (P = 0.02-0.03) and (2) development of preatrophy changes at years 2 and 3 within the region (P = 0.008-0.05).Optical coherence tomography-reflective drusen substructures are optical coherence tomography-based biomarkers of progression to GA, but not to CNV, in eyes with intermediate AMD. Optical coherence tomography-reflective drusen substructures may be a clinical entity helpful in monitoring AMD progression and informing mechanisms in GA pathogenesis.
Project description:PURPOSE:To compare measurements of area of geographic atrophy (GA) and change in GA area from color photographs and fundus autofluorescence (FAF) images. DESIGN:The Age-Related Eye Disease Study 2 (AREDS2) was a prospective multicenter randomized clinical trial evaluating progression of dry age-related macular degeneration (AMD) using color photographs at annual visits over a 5-year study period. The FAF images were acquired in a subset of participants who joined the FAF ancillary study at any of the annual visits over the study period. PARTICIPANTS:The AREDS2 FAF ancillary study included 8070 corresponding color and FAF visits of 2202 participants with variable follow-up. METHODS:Corresponding color and FAF images were independently evaluated at a central reading center for GA area measurement, lesion growth, and involvement of the macula center. MAIN OUTCOME MEASURES:Presence, area, growth rate of GA, and involvement of center of macula from color and FAF images. RESULTS:Hypoautofluorescence was visible in 2048 visits (25.4%). Agreement for the presence of GA between the 2 modalities had a kappa of 0.79, with 23% of visits with hypoautofluorescence not presenting with GA on color photographs. Percentage agreement for GA presence ranged from 43% at baseline to 81% at year 5 with improving agreement over time. The mean difference in GA area between the 2 modalities was 0.5 mm2, with larger areas on FAF. Growth rate of GA was 1.45 mm2 from color photographs and 1.43 mm2 from FAF images. The center of the macula was involved in 51% of color photographs and 56% with FAF images. CONCLUSIONS:Geographic atrophy may be detected earlier by the use of FAF images, but over the course of the study, the 2 modalities become comparable. Progression of GA area is comparable between color photographs and FAF images, but evaluating involvement of the center of the macula may differ, probably because of macular pigmentation blocking autofluorescence.
Project description:Appearance of geographic atrophy (GA) on color photography (CP) is preceded by specific features on spectral-domain optical coherence tomography (SD OCT). We aimed to build SD OCT-based risk assessment models for 5-year new onset of GA and central GA on CP.Prospective, longitudinal study.Age-Related Eye Disease Study 2 Ancillary SD OCT study participants with age-related macular degeneration (AMD) with bilateral large drusen or noncentral GA and at least 1 eye without advanced disease (n = 317).For 1 eye per participant, qualitative and quantitative SD OCT variables were derived from standardized grading and semiautomated segmentation, respectively, at baseline. Up to 7 years later, annual outcomes were extracted and analyzed to fit multivariate logistic regression models and build a risk calculator.New onset of CP-visible GA and central GA.Over a follow-up median of 4.0 years and among 292 AMD eyes (without advanced disease at baseline) with complete outcome data, 46 (15.8%) developed central GA. Among 265 eyes without any GA on baseline CP, 70 (26.4%) developed CP-visible GA. Final multivariate models were adjusted for age. In the model for GA, the independent predicting SD OCT factors (P < 0.001-0.03) were: hyperreflective foci and retinal pigment epithelium (RPE) layer atrophy or absence, followed by choroid thickness in absence of subretinal drusenoid deposits, photoreceptor outer segment loss, RPE drusen complex volume, and RPE drusen complex abnormal thinning volume. For central GA, the factors (P < 0.001) were RPE drusen complex abnormal thinning volume, intraretinal fluid or cystoid spaces, hyperreflective foci, and RPE layer atrophy or absence. The models yielded a calculator that computes the probabilities of CP-visible, new-onset GA and central GA after 1 to 5 years.For AMD eyes with large drusen and no advanced disease, we built a novel risk assessment model-based on age and SD OCT segmentation, drusen characteristics, and retinal pathology-for progression to CP-visible GA over up to 5 years. This calculator may simplify SD OCT grading and with future validation has a promising role as a clinical prognostic tool.
Project description:Describe qualitative spectral-domain optical coherence tomography (SD-OCT) characteristics of eyes classified as intermediate age-related macular degeneration (nonadvanced AMD) from Age-Related Eye Disease Study 2 (AREDS2) color fundus photography (CFP) grading.Prospective cross-sectional study.We included 345 AREDS2 participants from 4 study centers and 122 control participants who lack CFP features of intermediate AMD.Both eyes were imaged with SD-OCT and CFP. The SD-OCT macular volume scans were graded for the presence of 5 retinal, 5 subretinal, and 4 drusen characteristics. In all, 314 AREDS2 participants with ?1 category-3 AMD eye and all controls each had 1 eye entered into SD-OCT analysis, with 63 eyes regraded to test reproducibility.We assessed SD-OCT characteristics at baseline.In 98% of AMD eyes, SD-OCT grading of all characteristics was successful, detecting drusen in 99.7%, retinal pigment epithelium (RPE) atrophy/absence in 22.9%, subfoveal geographic atrophy in 2.5%, and fluid in or under the retina in 25.5%. Twenty-eight percent of AMD eyes had characteristics of possible advanced AMD on SD-OCT. Two percent of control eyes had drusen on SD-OCT. Vision loss was not correlated with foveal drusen alone, but with foveal drusen that were associated with other foveal pathology and with overlying focal hyperreflectivity. Focal hyperreflectivity over drusen, drusen cores, and hyper- or hyporeflectivity of drusen were also associated with RPE atrophy.Macular pathologies in AMD can be qualitatively and reproducibly evaluated with SD-OCT, identifying pathologic features that are associated with vision loss, RPE atrophy, and even possibly the presence of advanced AMD not apparent on CFP. Qualitative and detailed SD-OCT analysis can contribute to the anatomic characterization of AMD in clinical studies of vision loss and disease progression.Proprietary or commercial disclosure may be found after the references.
Project description:To estimate the incidence, size, and growth rate of geographic atrophy (GA) during 5 years of follow-up among participants in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Cohort within a clinical trial.Participants included in CATT.A total of 1185 CATT participants were randomly assigned to ranibizumab or bevacizumab treatment and to 3 treatment regimens. Participants were released from protocol treatment at 2 years and examined at approximately 5 years (N = 647). Two masked graders assessed the presence and size of GA in digital color photographs (CPs) and fluorescein angiograms (FAs) taken at baseline and years 1, 2, and 5. Cox proportional hazard models were used to identify risk factors for incidence of GA. Annual change in the square root of the total area of GA was the measure of growth. Multivariate linear mixed models including baseline demographic, treatment, and ocular characteristics on CP/FA and optical coherence tomography (OCT) as candidate risk factors were used to estimate adjusted growth rates, standard errors (SEs), and 95% confidence intervals (CIs).Geographic atrophy incidence and growth rate.Among the 1011 participants who did not have GA at baseline and had follow-up images gradable for GA, the cumulative incidence was 12% at 1 year, 17% at 2 years, and 38% at 5 years. At baseline, older age, hypercholesterolemia, worse visual acuity, larger choroidal neovascularization (CNV) area, retinal angiomatous proliferation (RAP) lesion, GA in the fellow eye, and intraretinal fluid were associated with a higher risk of incident GA. Thicker subretinal tissue complex and presence of subretinal fluid were associated with less GA development. The overall GA growth rate was 0.33 mm/year (SE, 0.02 mm/year). Eyes treated with ranibizumab in the first 2 years of the clinical trial had a higher growth rate than eyes treated with bevacizumab (adjusted growth rate, 0.38 vs. 0.28 mm/year; P = 0.009). Geographic atrophy in the fellow eye, hemorrhage, and absence of sub-retinal pigment epithelium fluid at baseline were associated with a higher growth rate.Development of GA is common 5 years after initiating therapy. Several risk factors identified at 2 years of follow-up persist at 5 years of follow-up.
Project description:BACKGROUND:To evaluate the difference in the long-term treatment outcomes of type 3 neovascularization between eyes with geographic atrophy and those with fibrotic scars. METHODS:This retrospective study included 195 eyes diagnosed with type 3 neovascularization and treated with anti-vascular endothelial growth factor (VEGF) agents. The included eyes were divided into three groups according to the fundus findings at the final visit: patients with fovea-involving geographic atrophy (GA group), patients with fovea-involving fibrotic scars (scar group), and patients with no fovea-involving geographic atrophy or fibrotic scars (non-GA/scar group). The best-corrected visual acuities (BCVA) of the three groups at the final visits were compared. RESULTS:The mean follow-up period was 47.5 ± 20.7 months. The mean logMAR BCVA at the final visit was 1.18 ± 0.58 in the GA group (n = 58), 1.67 ± 0.58 in the scar group (n = 62), and 0.69 ± 0.64 in the non-GA/scar group (n = 75). The BCVA was significantly worse in the scar group than in the GA (p < 0.001) and the non-GA/scar groups (p < 0.001). CONCLUSION:Eyes with fibrotic scars showed the poorest visual outcomes in type 3 neovascularization among the studied groups. Preventing the development of fibrotic scars should be considered an important treatment goal.