Extramacular Drusen and Progression of Age-Related Macular Degeneration: Age Related Eye Disease Study 2 Report 30.

PURPOSE: To identify the prevalence of extramacular drusen and their role in the progression of age-related macular degeneration (AMD). DESIGN: Retrospective analysis of a prospective cohort study. PARTICIPANTS: The study was conducted in 4168 eyes (2998 participants) with intermediate AMD in one or both eyes enrolled in the Age-Related Eye Disease Study 2 (AREDS2), a 5-year multicenter study of nutritional supplements. METHODS: Baseline 3-field 30-degree color photographs were evaluated for drusen characteristics outside the macular grid, including size, area, and location. The characteristics of extramacular drusen were compared with those of drusen within the macula. MAIN OUTCOME MEASURES: Progression rates to late AMD. RESULTS: Although extramacular drusen were observed in 3624 (86.9%) eyes, they represented a small area (< 0.5 mm2) in 50.3% of eyes, with only 17.5% exhibiting an area of > 1 disc area. Eyes with extramacular drusen exhibited larger macular drusen size and area than eyes without extramacular drusen (P < 0.001). Extramacular drusen were not associated with progression to late AMD. The hazard ratio adjusted for baseline age, sex, smoking, AMD severity level, and reticular pseudodrusen for 4043 eyes at risk of developing late AMD over 5 years was 1.17 (95% confidence interval [CI], 0.88-1.54; P = 0.27) for geographic atrophy and 0.96 (95% CI, 0.76-1.2; P = 0.7) for neovascular AMD. CONCLUSIONS: Extramacular drusen are commonly observed in eyes with AMD and are more frequent with an increasing drusen burden within the macula. In eyes with intermediate AMD, extramacular drusen do not confer additional risk to previously identified risk factors in progression to late AMD.

Prevalence, Risk, and Genetic Association of Reticular Pseudodrusen in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 Report 21.

PURPOSE: To determine the prevalence of reticular pseudodrusen (RPD) in eyes with age-related macular degeneration (AMD), assess the role of RPD as an independent risk factor for late AMD development, and evaluate genetic association with RPD. DESIGN: Prospective cohort study. PARTICIPANTS: Participants with intermediate AMD in 1 or both eyes enrolled in the Age-Related Eye Disease Study 2 (AREDS2), a 5-year multicenter study of nutritional supplement. METHODS: Fundus autofluorescence (FAF) images from a subset of AREDS2 participants were evaluated at annual visits for presence of RPD. Six single nucleotide polymorphisms-rs10490924 (ARMS2), rs1061170 (CFH), rs2230199 (C3), rs116503776 and rs114254831 (C2/CFB), and rs943080 (VEGF-A)-and the genetic risk score (GRS) were assessed for association with RPD. Development of late AMD, defined as geographic atrophy (GA) or neovascular AMD (NVAMD), was identified. MAIN OUTCOME MEASURES: Prevalence of RPD, odds ratio (OR) of late AMD development, and genetic associations of RPD. RESULTS: The FAF images were evaluated for 5021 eyes (2516 participants). Reticular pseudodrusen were seen in 1186 eyes (24% of eyes, 29% of participants). Prevalence of RPD varied with baseline AREDS AMD severity level: 6% in early AMD (n = 458), 26% in intermediate AMD (n = 2606), 36% in GA (n = 682), and 19% in NVAMD (n = 1246). Mean age of participants with RPD was 79 years (standard deviation [SD], 7) and 75 years (SD, 8) in those without RPD (P < 0.0001). Reticular pseudodrusen were more frequent in female participants (65% RPD vs. 53% no RPD). Odds ratio adjusted for baseline age, gender, race, educational status, smoking, and AMD severity level for 1710 eyes at risk of developing late AMD at the next annual visit was 2.42 (95% confidence interval [CI], 1.80-3.24; P < 0.001) for GA and 1.21 (95% CI, 0.87-1.7; P = 0.26) for NVAMD. Presence of RPD was significantly associated with higher GRS (P < 0.0001) and ARMS2 risk alleles (P < 0.0001) and, at a nominal level, with C3 risk alleles (P = 0.04) and CFH risk alleles (P = 0.048 for homozygotes). CONCLUSIONS: Participants with RPD have an increased risk of progression to GA but not NVAMD. ARMS2 risk alleles and higher GRS were associated with the presence of RPD. This study suggests that RPD are an important risk marker and should be included in classification systems used for patient prognosis.

Optical Coherence Tomography Minimum Intensity as an Objective Measure for the Detection of Hydroxychloroquine Toxicity.

Purpose: As optical coherence tomography (OCT) minimum intensity (MI) analysis provides a quantitative assessment of changes in the outer nuclear layer (ONL), we evaluated the ability of OCT-MI analysis to detect hydroxychloroquine toxicity. Methods: Fifty-seven predominantly female participants (91.2% female; mean age, 55.7 ± 10.4 years; mean time on hydroxychloroquine, 15.0 ± 7.5 years) were enrolled in a case-control study and categorized into affected (i.e., with toxicity, n = 19) and unaffected (n = 38) groups using objective multifocal electroretinographic (mfERG) criteria. Spectral-domain OCT scans of the macula were analyzed and OCT-MI values quantitated for each subfield of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. A two-sample U-test and a cross-validation approach were used to assess the sensitivity and specificity of toxicity detection according to OCT-MI criteria. Results: The medians of the OCT-MI values in all nine of the ETDRS subfields were significantly elevated in the affected group relative to the unaffected group (P < 0.005 for all comparisons), with the largest difference found for the inner inferior subfield (P < 0.0001). The receiver operating characteristic analysis of median MI values of the inner inferior subfields showed high sensitivity and high specificity in the detection of toxicity with area under the curve = 0.99. Conclusions: Retinal changes secondary to hydroxychloroquine toxicity result in increased OCT reflectivity in the ONL that can be detected and quantitated using OCT-MI analysis. Analysis of OCT-MI values demonstrates high sensitivity and specificity for detecting the presence of hydroxychloroquine toxicity in this cohort and may contribute additionally to current screening practices.

Subjective and objective screening tests for hydroxychloroquine toxicity.

OBJECTIVE: To compare subjective and objective clinical tests used in the screening for hydroxychloroquine retinal toxicity to multifocal electroretinography (mfERG) reference testing. DESIGN: Prospective, single-center, case control study. PARTICIPANTS: Fifty-seven patients with a previous or current history of hydroxychloroquine treatment of more than 5 years' duration. METHODS: Participants were evaluated with a detailed medical history, dilated ophthalmologic examination, color fundus photography, fundus autofluorescence (FAF) imaging, spectral-domain (SD) optical coherence tomography (OCT), automated visual field testing (10-2 visual field mean deviation [VFMD]), and mfERG testing. We used mfERG test parameters as a gold standard to divide participants into 2 groups: those affected by hydroxychloroquine-induced retinal toxicity and those unaffected. MAIN OUTCOME MEASURES: We assessed the association of various imaging and psychophysical variables in the affected versus the unaffected group. RESULTS: Fifty-seven study participants (91.2% female; mean age, 55.7±10.4 years; mean duration of hydroxychloroquine treatment, 15.0±7.5 years) were divided into affected (n = 19) and unaffected (n = 38) groups based on mfERG criteria. Mean age and duration of hydroxychloroquine treatment did not differ statistically between groups. Mean OCT retinal thickness measurements in all 9 macular subfields were significantly lower (<40 µm) in the affected group (P < 0.01 for all comparisons) compared with those in the unaffected group. Mean VFMD was 11 dB lower in the affected group (P < 0.0001). Clinical features indicative of retinal toxicity were scored for the 2 groups and were detected in 68.4% versus 0.0% using color fundus photographs, 73.3% versus 9.1% using FAF images, and 84.2% versus 0.0% on the scoring for the perifoveal loss of the photoreceptor ellipsoid zone on SD-OCT for affected and unaffected participants, respectively. Using a polynomial modeling approach, OCT inner ring retinal thickness measurements and Humphrey 10-2 VFMD were identified as the variables associated most strongly with the presence of hydroxychloroquine as defined by mfERG testing. CONCLUSIONS: Optical coherence tomography retinal thickness and 10-2 VFMD are objective measures demonstrating clinically useful sensitivity and specificity for the detection of hydroxychloroquine toxicity as identified by mfERG, and thus may be suitable surrogate tests.

Ocular side effects associated with peribulbar injections of triamcinolone acetonide for diabetic macular edema.

PURPOSE: To evaluate long-term effects of anterior and posterior peribulbar injections of triamcinolone acetonide on intraocular pressure (IOP) elevation and cataract development. METHODS: This study reports on IOP and cataract progression through 2 years in 96 eyes with diabetic macular edema randomized to focal/grid photocoagulation, 20 mg triamcinolone acetonide anterior injection, anterior injection followed by laser, 40 mg triamcinolone acetonide posterior injection, or posterior injection followed by laser. RESULTS: Intraocular pressure increased from baseline by ≥ 10 mmHg at ≥ 1 visit through 2 years in 2 eyes (8%) in the laser group, 11 eyes (31%) in the anterior groups, and 6 eyes (17%) in the posterior groups. Among phakic eyes at baseline, 0, 5 (17%), and 1 (3%) in the 3 groups, respectively, underwent cataract surgery before the 2-year visit. CONCLUSION: Based on this small randomized trial, it appears that over 2 years, anterior peribulbar triamcinolone acetonide injections are associated with an increased incidence of IOP elevation and an increased risk of cataract development compared with laser or posterior peribulbar injections. The association of posterior injections with IOP elevation is less certain. Although the study involved eyes with diabetic macular edema, the results should be relevant to other conditions treated with peribulbar corticosteroids.